The prevalence of non-syndromic agenesis in permanent teeth (third molars excluded) in European population (summarized data).
\r\n\tThis book will intend to look at different migrant patterns, voluntary and involuntary migration, over the last three centuries. What influenced people to leave their home countries, family, and friends and settle somewhere else? The book may include histories of the 19th century, consider tragedies and movements activated by political events in the 20th century, and/or look at recent events of the 21st century. Push and pull factors are important points. While most of us may be influenced in a negative way by the current happenings in Eastern Europe, the Russian invasion and resulting tragedies also demonstrate some very positive human traits – the preparedness of Ukraine’s surrounding countries to help those in need and to provide a safe place for the present.
\r\n\tWhether one looks at voluntary or involuntary migration into any country, after a period of adjustment, migrants do play a positive role. The research found that migrants contribute to the economy (food, shelter, employment, tax) and enrich a country’s cultural norms. Prerequisites for successful settlements are that the host society adopts a tolerant approach and that the migrants recognize the law and the language of the host country. Nothing is ever easy or without controversy, but I am a migrant (German Australian), and life in Australia has been relatively harmonious. Issues that could be considered in the book are multicultural societies (do monocultural societies still exist?) and theories of acculturation versus integration (settlement processes).
\r\n\tTwo further issues are very important in relation to human migration. There is climate change, global warming, and the environment, which clearly affect people’s movement. Small island populations are very concerned about rising sea levels. 2021 has also seen floods costing human lives: Turkey (August 2021), Brazil (December 2021), Chile (January 2021), and South India (November 2021), to name but a few. In Australia (March 2022), farms and whole townships in New South Wales and Queensland have been flooded for the second time in five years, and plans to resettle these towns are considered. Official and social media provide ample coverage of the events, which leads me to the next issue. There is today’s very important role of the media, of the official and social media. We are constantly bombarded with images of human war tragedies and flood victims. People in industrialized, western countries must be the best-informed populace. How far do the images and up-to-date TV news influence us, make us change our behavior, and perhaps even consider us more generous than we have been?
\r\n\tClimate change and the media are relatively new to the human migration debate, but both issues play important parts, and some interesting discussions are appreciated.
\r\n\t
Chemoprevention is a promising and relatively new approach to cancer prevention that has precedence in cardiology, in which cholesterol lowering antihypertensive, and antiplatelet agents are administered to prevent coronary heart disease in high-risk individuals [1]. Chemoprevention can be defined as “the use of natural or synthetic chemical compounds to reverse, suppress or to prevent one or more of the biological events leading to the development of invasive cancer”
A chemopreventive strategy could potentially either prevent further DNA damage that might enhance carcinogenesis or suppress the appearance of the cancer phenotype [2]. Chemopreventive agents inhibit or reverse cellular events associated with tumor initiation, promotion, and/or progression. The mechanism of chemoprotective activities might correlate and balance between phase I + phase II enzymes levels, and influence cellular macromolecules, transporters, release of carcinogens, or DNA adducts and DNA repair [3].
More than 1000 potential chemopreventive agents have been identified in dietary sources, and many are being tested
Broadly defined on the basis of their mechanisms of action, chemopreventive agents can be grouped into two general classes: blocking agents and suppressing agents. Blocking agents (e.g., flavonoids, oltipraz, indoles, and isothiocyanates) prevent carcinogenic compounds from reaching or reacting with critical target sites by preventing the metabolic activation of carcinogens or tumor promoters via enhancing detoxification systems and by trapping reactive carcinogens [5]. Suppressing agents (e.g., vitamin D and related compounds, nonsteroidal anti-inflammatory drugs [NSAIDS], vitamin A and retinoids, DFMO (2-difluoromethylornithine), monoterpenes and calcium) prevent the evolution of the neoplastic process in cells that would otherwise become malignant. Mechanisms of action for suppressing agents are not well understood. Some produce differentiation, some counteract the consequences of genotoxic events such as oncogene activation, some inhibit cell proliferation, and some have undefined mechanisms [5].
An ideal chemopreventive agent should have 1. Little or no toxic effects 2. High efficacy against multiple sites 3. Capability of oral administration 4. a known mechanism of action 5. Human acceptance [6]. A chemopreventive program identifies and accesses specific chemical substances, many naturally occurring in foods, with the potential to prevent cancer initiation and to either slow or reverse the progression of premalignant lesions to invasive cancer.
Promising chemopreventive agents being investigated include micronutrients (e.g. vitamin A, C and E, β-carotene, molybdenum, and calcium), phytochemicals (e.g. indoles, polyphenols, isothiocyanates, flavonoids, monoterpenes, and organosulfides), and synthetics (e.g. vitamin A derivatives, piroxicam, tamoxifen, 2-difluoromethylornithine [DFMO] and oltipraz). More than 40 promising agents and agent combinations are being evaluated clinically as chemopreventive drugs for major cancer targets [7].
Several studies have reported a 40-50% decrease in the relative risk of colorectal cancer in persons who are continuous users of aspirin or other non steroidal anti-inflammatory drugs (NSAIDS) [8], suggesting that these drugs can serve as effective cancer chemopreventive agents. Hixson
Other mechanisms that can explain the antiproliferative antitumor effects of NSAIDS include: interference with membrane-associated processes, such as G-protein signal transduction and transmembrane calcium influx, and inhibition of other enzymes, such as phospho-diesterase, folate-dependant enzymes, and cyclic adenosine-5`-monophosphatase-dependent protein kinase, as well as enhancement of immunologic responses and cellular apoptosis [10].
At a macroscopic level, NSAIDS prevent incident neoplasia (adenomas and carcinomas), and suppress the growth of carcinomas. Therefore, NSAIDS are effective when given “early” (proceeding adenoma-formation), as well as “late” (following the emergence of adenomas) [11]. An alternative explanation for the efficacy of NSAIDS in the prevention of colorectal cancer is their ability to scavenge reactive oxygen species [12].
Frequent consumption of fruits and vegetables has been associated with lower incidence of cancers at different organ sites. Several factors can contribute to this association, first, the nutrients in fruits and vegetables, notably vitamin C, vitamin E, folic acid, provitamin A, selenium and zinc, are essential for normal cellular functions, a deficiency in these nutrients can enhance the susceptibility of an individual to cancer, second, some nutrients, such as vitamin C, vitamin E, selenium and β-carotene, at levels above nutritional needs, can display inhibitory activities against carcinogenesis. A third factor is that non-nutritive constituents, such as polyphenols, organosulfur compounds, and indoles have anticarcinogen activities. Finally, fruits and vegetables contribute fibers and bulkiness to the diet. Persons who consume large amounts of fruits and vegetables can eat smaller amounts of meat and other animal products that can contribute to higher cancer incidence in the western countries. Supplementation with these antioxidant nutrients apparently produces a protective effect against cancer.
Comprehensive reviews of case-control and prospective cohort studies found that the relationship between high vegetable and fruit intake and reduced cancer risk appears to be strongest for cancers of the alimentary and respiratory tracts (cancers of the colon, esophagus, oral cavity and lung) and weakest for hormone related cancers (cancers of the breast, ovary, cervix, endometrium and prostate) [13-15]. Reduced cancer risk has been linked primarily to consumption of raw vegetables and fresh fruits (citrus, carrots, green leaf vegetables, cruciferous vegetables, soy products, and whole grain wheat products) [13-15]. The beneficial effect of vegetables, fruits and whole grains can be due to either individual or combined effects of their constituents, including, fiber, micronutrients and phytochemicals.
Polyphenols constitute one of the largest and ubiquitous groups of phytochemicals. One of the primary functions of these plant-derived polyphenols is to protect plants from photosynthetic stress, reactive oxygen species, and consumption by herbivores. Polyphenols are also an essential part of the human diet, with flavonoids and phenolic acids being the most common ones in food. Not surprisingly, there is a growing realization that lower incidence of cancer in certain populations can probably be due to consumption of certain nutrients, and especially polyphenol rich diets. Consequently, a systematic dissection of the chemopreventive potential of polyphenolic compounds in the recent years has clearly supported their health benefits, including anti-cancer properties. Given the challenges of cancer therapy, ‘chemoprevention’-which uses pharmacological or natural agents to impede, arrest or reverse carcinogenesis at its earliest stages’ remains the most practical and promising approach for the management of cancer patients [16].
Till date, A substantial number of studies in cultured cells, animal models and human clinical trials have illustrated a protective role of dietary polyphenols against different types of cancers [17–20]. Polyphenols are present in fruits, vegetables, and other dietary botanicals. Some estimates suggest that more than 8000 different dietary polyphenols exist, and these can be divided into ten different general classes based on their chemical structure [21]. Phenolic acids, flavonoids, stilbenes and lignans are the most abundantly occurring polyphenols that are also an integral part of everyday nutrition in populations worldwide. Some of the common examples of the most studied and promising cancer chemopreventive polyphenols include EGCG (from green tea), curcumin (from curry) and resveratrol (from grapes and berries). Significant gains have been made in understanding the molecular mechanisms underpinning the chemopreventive effects of polyphenols, and consequently, a wide range of mechanisms and gene targets have been identified for individual compounds. Various mechanistic explanations for their chemopreventive efficacy include their ability to interrupt or reverse the carcinogenesis process by acting on intracellular signaling network molecules involved in the initiation and/or promotion of cancer, or their potential to arrest or reverse the promotion stage of cancer [22; 23]. Polyphenolic compounds can also trigger apoptosis in cancer cells through the modulation of a number of key elements in cellular signal transduction pathways linked to apoptosis (caspases,
Tea (
An estimated 2.5 million metric tons of dried tea are manufactured annually. Of this amount about 20% is green tea, mainly consumed in Asian countries where tea is a major beverage. About 78% is black tea mainly consumed in the western nations and some Asian countries and about 2% is oolong tea mainly produced and consumed in South Eastern China.
Manufacture of black tea takes place by crushing the leaves causing polyphenol oxidase-dependent oxidative polymerization that leads to the formation of theaflavins, thearubigins and other oligomers in a process known as fermentation. Theaflavins (about 1% - 2% of the total dry matter of black tea) including theaflavin, theaflavin-3-O-gallate, theaflavin-3/-O-gallate and theaflavin-3-3/-O-digallate, possess benzotropolone rings with dihydroxy or trihydroxy substitution systems which give the characteristic color and taste of black tea. About 10 - 20% of the dry weight of black tea is due to thearubigens, which are even more extensively oxidized and polymerized, have a wide range of molecular weights and are less well characterized.
Oolong tea, a partially fermented tea, contains monomeric catechins, theaflavins and thearubigins. Some characteristic components, such as epigallocatechin esters, theasinensins, dimeric catechins and dimeric proanthocyanidins are also found in oolong tea.
Commercial green tea is made by steaming or drying fresh tea leaves at elevated temperature. Its chemical composition is similar to that of fresh tea leaves. Green tea contains polyphenols that include flavanols, flavandiols, flavonoids and phenolic acids. These compounds can account for up to 30% of the dry weight. Most of the green tea polyphenols are flavonols commonly known as catechin. Some major green tea catechins are epigallocatechin-3-gallate (EGCG), (-) - epigallocatechin (EGC), epicatechin-3-gallate (ECG), - (-) -epicatechin (EC), (+) -gallocatechin and (+)-catechin (Figure 1). Caffeine, theobromine and theophylline the principal alkaloids account for about 4% of the dry weight.
Components of green tea
It has been stated that a cup (200 ml) of green tea contains about 142 mg EGCG, 65 mg EGC, 17 mg EcC and 76 mg caffeine. The most important chemicals present in tea, which are of considerable pharmacological significance, are the polyphenols and caffeine [28]. Polyphenols are present to the extent of 30-35% in the dry tea leaf and determine the quality of the beverage. The amount of polyphenols depends on the genetic make up of tea and environmental factors such as climate, light, rainfall, temperature, nutrient availability and leaf age [27].
Because the mechanisms of antimutagenesis and anticarcinogenesis by tea polyphenols vary for different cancers and for the same cancer in different population, tea consumption can affect carcinogenesis only in selected situations. Many laboratory studies have demonstrated inhibitory effects of tea preparation and tea polyphenols against tumor formation and growth. This inhibitory effect is believed to be mainly due to the antioxidative and possible antiproliferative effects of polyphenolic compounds in green and black tea. These polyphenolics can also inhibit carcinogenesis by blocking the endogenous formation of N-nitroso compounds, suppressing the activation of carcinogen and trapping of genotoxic agents. Yang and Wang [28] showed that tea polyphenols also have high complexation affinity to metals, alkaloids and biologic macromolecules such as lipids, carbohydrates, proteins and nucleic acids.
Work of Kuroda and Hara [27] illustrates that the polyphenols in tea have a strong radical scavenging and reducing activity. They capture and detoxify radicals of various promoters of carcinogenesis and radicals produced in the process of exposure to radiation and light. Since tea polyphenols inactivate enzyme and virus activity, they could be effective against carcinogenesis caused by some viruses. Tea polyphenols exert their inhibitory actions via various mechanisms at different stages of mutagenesis, carcinogenesis, invasion and metastasis of tumor cells; they act extracellularly as desmutagens and intracellularly as bio-antimutagens. Tea polyphenols modulate metabolism, block, suppress, or affect DNA replication and repair effects.
Green tea has been extensively studied in people, animals, and laboratory experiments. Results from these studies suggest that green tea can be useful for the several health conditions.
It has been found that green tea consumption is significantly associated with a lower risk of mortality due to stroke [29] and pneumonia [30] and imparts a lower risk of cognitive impairment [31], depression [32], and psychological distress [33]. These results have been confirmed by other researchers [34–37]. In addition, other epidemiologic studies have indicated that green tea consumption is associated with a lower risk of osteoporosis [38, 39], and randomized placebo-controlled trials have indicated that green tea is effective in lowering cardiovascular risk factors [40, 41]. Because all of the above conditions are major causes of functional disability [42–44], it is expected that green tea consumption would contribute to disability prevention. Green tea consumption is associated with a lower risk of developing functional disability.
Population-based clinical studies indicate that the antioxidant properties of green tea can help prevent atherosclerosis, particularly coronary artery disease. (Population-based studies mean studies that follow large groups of people over time or studies that are comparing groups of people living in different cultures or with different dietary habits.) Researchers are not sure why green tea reduces the risk of heart disease by lowering cholesterol and triglyceride levels. Studies show that black tea has similar beneficial effects. In fact, researchers estimate that the rate of heart attack decreases by 11% with consumption of 3 cups of tea per day [45].
Research shows that green tea lowers total cholesterol and raises HDL ("good") cholesterol in both animals and people. One population-based clinical study found that men who drink green tea are more likely to have lower total cholesterol than those who do not drink green tea. Results from one animal study suggest that polyphenols in green tea can block the intestinal absorption of cholesterol and promote its excretion from the body. In another small study of male smokers, researchers found that green tea significantly reduced blood levels of harmful LDL cholesterol.
Substantial evidence from
Obesity and its related metabolic abnormalities, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) axis, and the state of chronic inflammation, increase the risk of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). However, these findings also indicate that the metabolic disorders caused by obesity might be effective targets to prevent the development of CRC and HCC in obese individuals. Green tea catechins (GTCs) possess anticancer and chemopreventive properties against cancer in various organs, including the colorectal and liver. GTCs have also been known to exert anti-obesity, antidiabetic, and anti-inflammatory effects, indicating that GTCs might be useful for the prevention of obesity-associated colorectal and liver carcinogenesis. Further, branched-chain amino acids (BCAA), which improve protein malnutrition and prevent progressive hepatic failure in patients with chronic liver diseases, might be also effective for the suppression of obesity-related carcinogenesis because oral supplementation with BCAA reduces the risk of HCC in obese cirrhotic patients. BCAA shows these beneficial effects because they can improve insulin resistance. Here, we review the detailed relationship between metabolic abnormalities and the development of CRC and HCC. We also review evidence, especially that based on our basic and clinical research using GTCs and BCAA, which indicates that targeting metabolic abnormalities by either pharmaceutical or nutritional intervention can be an effective strategy to prevent the development of CRC and HCC in obese individuals [52].
Several studies have reported a protective effect for tea consumption on incident diabetes, and the results of a recent meta-analysis indicated that drinking more than 3–4 cups of tea (black, green or oolong) per day decreases the risk of Diabetes Mellitus by 20% [53]. Despite very high intake of black tea, no significant association for black tea consumption was observed, but an inverse correlation was found between green tea drinking and diabetes prevalence. Several animal and human studies have shown an antidiabetic effect for green tea polyphenols, specifically epigallocatechin gallate (EGCG) [54-57]. EGCG induces its antidiabetic effects mostly through reduced hepatic glucose production and enhanced pancreatic function [56]. Green tea has been shown to improve glucose tolerance and has been suggested as a prophylactic agent against diabetes [55].
Clinical studies suggest that green tea extract can boost metabolism and help burn fat. One study confirmed that the combination of green tea and caffeine improved weight loss and maintenance in overweight and moderately obese individuals. Some researchers speculate that substances in green tea known as polyphenols, specifically the catechins, are responsible for the herb\'s fat-burning effect.
Many studies suggest an inverse relationship between green tea intake and the risk of a variety of cancers, although other studies have found no association. Clinical trials have been small and heterogenous with contradictory results. Dietary, environmental, and population differences can account for these inconsistencies [58].
Several population-based clinical studies have shown that both green and black teas help protect against cancer. For example, cancer rates tend to be low in countries such as Japan where people regularly consume green tea. However, it is not possible to determine from these population-based studies whether green tea actually prevents cancer in people. Emerging clinical studies suggest that the polyphenols in tea, especially green tea, can play an important role in the prevention of cancer [59].
The most recent meta-analysis included 7 (2 cohort, 1 nested case–control and 4 case–control) epidemiological studies of green tea and breast cancer that were published as of December 2008 [64]. An inverse association between green tea and breast cancer risk was reported from case–control data, while no association was observed from cohort data [64]. The nested case–control study reported no association [65], so even if it had been included as a cohort study in the pooled analyses, the overall finding would have remained the same.
In summary, green tea could exert beneficial effects on breast carcinogenesis through inhibition of estrogen’s pro-carcinogenic activity either alone by itself or in combination with other estrogen-inhibiting factors. Black tea does not appear to have protective effects on breast cancer incidence, and can increase risk of hormone-dependent tumors. Future research is needed to elucidate the interactive role of tea catechins and other dietary cancer-inhibitory compounds in mammary carcinogenesis in humans.
The higher content of tea catechins present in green tea than in black tea can explain the more consistent inverse association between tea and esophageal cancer risk in studies conducted in China and Japan than in European and American countries. The putative protective effect of tea consumption, if any, on esophageal cancer development could be confounded and/or overshadowed by the thermal effect of tea beverages, if consumed at high temperature, as well as cigarette smoking or alcohol intake. Future prospective cohort studies are required to collect detailed information on tea temperature and histories of tobacco and alcohol use that can then be adjusted for when evaluating the protective effect of tea on esophageal cancer.
In summary, observational studies do not provide strong evidence for a protective effect of green tea or black tea intake against the development of prostate cancer. There is some suggestive evidence that green tea intake can reduce the risk of advanced prostate cancer. The phase II clinical trials have provided encouraging evidence in the development of green tea catechins as a chemopreventive agent against prostate carcinogenesis.
In the study by Kinlen et al., the positive association between black tea consumption and stomach cancer death could be, at least partly, due to the effects of smoking and social class [86]. Whereas in the cohort analysis by Khan et al. that included approximately 3100 Japanese men and women, black tea consumption was associated with a statistically significantly increased risk of stomach cancer for women [87]. Given the small sample size and low intake of black tea in a population that usually consumed green tea, this positive association could be a chance finding.
Both case–control and cohort studies demonstrated an inverse association between green tea consumption and risk of stomach cancer. The protection can be stronger for women than men since the former are less likely to smoke cigarettes or drink alcoholic beverages. There is lack of evidence in support of a protective role of black tea consumption against the development of stomach cancer.
In the same review by Arts [93], 11 of the 19 studies included examined the association between black tea consumption and lung cancer risk. Among them, two reported a statistically significantly reduced risk while one reported an increased risk for lung cancer associated with black tea intake. The remaining 8 studies reported a null association [93]. In a more recent meta-analysis by Tang et al., no statistically significant association was observed between black tea consumption and lung cancer risk based on 14 studies included [94]. Not included in the meta-analyses was a case–control study in Los Angeles, CA with 558 cases and 837 controls. The results showed that high consumption of dietary epicatechin, mainly from black tea, was associated with significantly reduced risk of lung cancer, especially among smokers [95].
One potential mechanism for the chemopreventive effect of tea on carcinogenesis is the strong antioxidant effect of tea polyphenols. Hakim et al. conducted a phase II randomized controlled tea intervention trial to evaluate the efficacy of regular green tea drinking in reducing DNA damage as measured by urinary 8-hydroxydeoxyguanosine among heavy smokers [96]. After consuming 4 cups/day of decaffeinated green tea for 4 months, smokers showed a statistically significant 31% decrease in urinary 8-hydroxydeoxyguanosine compared with the baseline value. In the same study, no change in urinary 8-hydroxydeoxyguanosine was seen among smokers assigned to the black tea group [96]. These findings support that tea catechins, with highest levels in green tea, exert their antioxidative role in reducing the formation of 8-hydroxydeoxyguanosine. However, a lack of inverse association between green tea consumption and lung cancer risk in smokers suggest that the antioxidation mechanism plays a limited role in reducing the risk of lung cancer development. Furthermore, the protective effect of tea consumption on lung cancer development for nonsmokers, especially among women, indicates an alternative cancer-preventive mechanism of tea that is not driven by antioxidation. Additional experimental studies that utilize animal models to elucidate the cancer-preventive mechanisms of tea catechins on lung carcinogenesis are needed.
Available epidemiological data are insufficient to conclude that either green tea or black tea can protect against the development of pancreatic cancer. Given the short survival and rapid progression of pancreatic cancer, the low participation rates of pancreatic cancer patients in retrospective case–control studies or the use of proxy respondents in interview for collection of information on tea consumption and other risk factors could bias the results of case–control studies. Prospective cohort studies offer methodological advantages over case–control studies. Additional data from well-designed and well-executed prospective cohort studies are required before any conclusion on the protective effect of green tea and/or black tea against the development of pancreatic cancer can be reached.
The NIH-AARP cohort study enrolled 481,563 AARP members aged 51–71 years who resided in eight states of the United States in 1995–1996. After up to 8 years of follow-up, 392 study participants developed oral cancer and 178 developed pharyngeal cancer. The study demonstrated a statistically significant positive relationship between consumption of hot tea and risk of pharyngeal cancer. There was a suggestive positive relationship between hot tea intake and risk of oral cancer [104]. Consumption of iced tea was not associated with risk of oral or pharyngeal cancer.
There was one prospective cohort study that examined the association between green tea consumption and risk of oral cancer in the Japan Collaborative Cohort Study. The cohort consisted of 50,221 Japanese men and women aged 40–79 years at baseline and identified 37 incident oral cancer cases after 10.3 years of follow-up. The inverse association was slightly stronger for women than for men [105]. The inverse relation did not reach statistical significance due to the relatively small number of cancer cases included in the analysis.
A randomized, placebo-controlled, phase II clinical trial was conducted to examine the effect of green tea extract on the oral mucosa leukoplakia, a well established precancerous lesion of oral cancer [106]. Fifty-nine patients were randomly assigned to either the treatment group, who were given 3 g/day of a mixed green tea product composed of dried water extract, polyphenols and pigments, or the placebo group. After 6 months, 37.9% patients in the green tea treatment arm showed reduced size of oral lesions whereas 3.4% patients had increased lesion size. In contrast, 6.7% patients in the placebo group had decreased and 10% patients had increased size of oral mucosa leukoplakia. The differences in the changes of lesion sizes between the treatment and placebo arms are statistically significant [106]. Recently, Tsao et al. completed another randomized, placebo-controlled phase II trial to evaluate the oral cancer prevention potential of green tea extract [107]. Forty-two patients with one or more histologically confirmed, bidimentionally measurable oral premalignant lesions with high-risk features of malignant transformation that could be sampled by biopsy were randomly assigned to receive 500, 750, or 1000 mg/m2 of green tea extract per day or placebo orally. The efficacy was determined by the disappearance of all lesions (a complete response) or 50% or greater decrease in the sum of products of diameters of all measured lesions (a partial response). At 12 weeks after the initiation of the treatment, 39 patients who completed the trial were evaluated; 14 (50%) of the 28 patients in the three combined green tea extract groups had a favorable response whereas only 2 (18.2%) of the 11 patients in the placebo group showed the similar response. A dose-dependent effect was observed; the favorable response rates were 58% in patients given 750 or 1000 mg/m2 green tea extract and 36.4% in those given 500 mg/m2, but only 18.2% in those assigned to the placebo arm [107].
Although limited, data from the prospective cohort study suggest a moderate protective effect of green tea consumption against the development of oral cancer. Both phase II clinical trials further support a protective role of green tea extract against the progression of precancerous lesions in the oral cavity towards malignant transformation. Phase III clinical trials with large number of patients are required to confirm the efficacy of green tea extract against the formation of oral cancer in humans. Data on the effect of black tea consumption against the development of oral cancer are too limited to draw any conclusion. One prospective study showed a statistically significant inverse association between black tea consumption and risk of pharyngeal cancer, more epidemiological studies are warranted to evaluate the potential protective effect of either green tea or black tea on the development of pharyngeal cancer in humans.
Following the meta-analysis, several studies examined and published the results on the green tea consumption and colorectal cancer risk. After analyzing the database of the Singapore Chinese Health Study, a prospective cohort study of diet and cancer involved over 60,000 Chinese men and women aged 45–74 years, Sun et al. found that subjects who drank green tea daily had a statistically non-significant increased risk for colorectal cancer relative to nondrinkers of green tea. This association was confined to men and was stronger for colon cancer than rectal cancer, especially for the advanced stage of colon cancer [109]. These data suggest that substances in green tea can exert an adverse, late-stage effect on the development of colorectal cancer.
Yang et al. prospectively evaluated the association between green tea consumption and colorectal cancer risk in a cohort of 69,710 Chinese women aged 40–70 years, most of which were Lifelong nonsmokers (97.3%) or nondrinkers of alcoholic beverages (97.7%). Information on tea consumption was assessed through inperson interviews at baseline and reassessed 2–3 years later in a follow-up survey. During the first 6 years of follow-up, 256 incident cases of colorectal cancer were identified. Regular tea drinkers had significantly reduced risk of colorectal cancer compared with nondrinkers. The reduction in risk was most evident among those who consistently reported to drink tea regularly at both the baseline and follow-up surveys [110].
There were two recent prospective studies on green tea consumption and colorectal cancer incidence and mortality in Japan [111, 112]. The first consisted of 96,162 Japanese men and women, and 1163 incident cases of colorectal cancer [111]. There was no statistically significant association between green tea consumption and incidence of colon and rectal cancers combined or separately in either men or women or both. The second cohort consisted of 14,001 Japanese men and women. After up to 6 years of follow-up, 43 subjects died from colorectal cancer. Given the small number of cases, the results should be interpreted with caution. Using validated biomarkers of specific tea polyphenols, Yuan et al. prospectively examined the urinary levels of specific tea catechins and their metabolites and the risk of developing colorectal cancer in the Shanghai Cohort Study as described above [113]. EGC, 4_-O-methyl-epigallocatechin (4_-MeEGC) and EC, and their metabolites in baseline urine samples were measured in 162 incident colorectal cancer cases (83 colon and 79 rectal cancer cases) and 806 matched controls. Individuals with high prediagnostic urinary catechin levels had a lower risk of colon cancer. There was no association between urinary green tea catechins or their metabolites and risk of rectal cancer. This study provided a direct evidence for the chemopreventive effect of tea catechins against the development of colon cancer in humans [113].
In terms of black tea, the meta-analysis by Sun et al. [108] included 20 studies that examined black tea consumption and colorectal cancer risk and found no association. No association was found separately in case–control studies or prospective cohort studies. In our analysis of the Singapore Chinese Health Study, we did not find any association between black tea consumption and risk of colon cancer and rectal cancer combined or separately [109]. More recently, Zhang et al. conducted a pooled analysis for black tea intake and colon cancer risk on the combined dataset of 13 cohort studies conducted in North America or Western Europe. The analysis included 731,441 subjects and 5604 incident colon cancer cases [114]. Compared with nondrinkers, consumption of 900 g/day tea (approximately four 8-oz cups/day) was associated with a modest, but statistically significantly increased risk of colon cancer. This increased risk for colon cancer was only in women, but not in men.
Epidemiological studies provided suggestive evidence to support a protective role of green tea consumption, especially in high amount and long-term duration of consumption, in reducing the risk of colon cancer. This effect of green tea on colon carcinogenesis can depend on the time of exposure, where late exposure can promote the growth of colon tumor cells. Current epidemiological data suggest that black tea consumption can increase, instead of decrease, the risk of colorectal cancer.
Similarly, a more recent case–control study of renal cell cancer in Italy including 767 cases and 1534 controls did not find any association between tea consumption and risk of renal cell cancer [117]. Lee et al. analyzed datasets of the Nurses’ Health Study and the Health Professionals Follow-up Study and found that consumption of ˃1 cup/day tea was associated with statistically non-significantly reduced risk of renal cell cancer relative to <1 cup/month [118]. In a pooled analysis, Lee et al. combined data of 13 prospective cohorts including more than 774,000 men and women and 1478 incident renal cell cancer cases. Compared with nondrinkers, individuals who consumed ≥1 cups/day of tea had a statistically borderline significant 15% risk reduction in renal cell cancer after adjustment for body mass index, cigarette smoking, hypertension and other potential confounders [119]. All these studies were conducted in North America and West Europe and examined the effect of presumably black tea on renal cell cancer risk. These findings do not support a protective role of black tea on kidney cancer. Additional prospective epidemiological studies are warranted to examine the association between green tea consumption and kidney cancer risk.
Plasma EGCG, EGC and EC exist in free and conjugated (glucuronide and sulfate) forms. The plasma tea polyphenol levels in rats and mice in some anticarcinogenesis experiments were comparable to the peak levels in humans after consuming two or three cups of tea [125]. In a preliminary experiment, after administration of regular green tea in drinking fluid to rats, the EGCG was detected in the esophagus (410 ng/g) but not in the lung, the EGCG, EGC and EC levels in the small intestine and intestinal contents were rather high (1.5 - 5.5 mg/g) due to the unabsorbed and biliary excreted glucuronides of polyphenols in the intestine. High EGC and EC levels were also observed in the colon tissues (1.8 and 0.3 mg/g respectively). Due to possible glucuronidase and esterase activities in the colon, most of the EGC and EC were found in the free form and EGCG was found at lower levels. EGCG has been usually considered the active anticarcinogenic components in tea because it is the most abundant polyphenol in tea.
Hackett
Matsumoto
Tea catechins and crude extracts, however, have some beneficial effects on human health, such as suppression of high blood pressure [128], reduction of blood glucose levels [129] suppression of cholesterol and prevention of fat increase [130]. Tea drinking can also induce higher levels of glutathione [131], so that detoxification of reactive forms of carcinogens can occur more efficiently, other biochemical mechanisms have been hypothesized for the anticancer properties of tea e.g. induction of DNA repair, binding with activated carcinogens. Moderate tea consumption (5 cups / day an extract of about 11 g of tea) can be readily curable in some types of human cancer [132]. In other studies on the inhibitory effects of tea catechins, black tea extract and oolong tea extract and EC, EGC, ECG, EGCG and other tea extracts (0.05 or 0.1%) showed a significant decrease in the number and area of preneoplastic glutathione S-transferase placental form (GSTP)-positive foci in the liver of rats [133].
The most noteworthy properties of tea polyphenols and other flavonoids are their antioxidative activities. Reactive oxygen species may play important roles in carcinogenesis through damaging DNA, altering gene expression, or affecting cell growth and differentiation. The anticarcinogenic activities of tea polyphenols are believed to be closely related to their antioxidative properties. The findings that green tea preparations inhibited 12-0-tetradecanoylphorbol- 1 3-acetate-induced hydrogen peroxide formation in mouse epidermis and NNK-induced 8-hydroxydeoxyguanosine formation in mouse lung are consistent with this concept. Inhibition of tumor promotion-related enzymes such as ornithine decarboxylase, protein kinase C, lipoxygenase, and cyclooxygenase by tea preparations has also been reported. Although inhibition of carcinogen activation by tea or green tea polyphenol fractions could be demonstrated
As to the genotoxic profile of tea catechins when tested alone, Chang
Imanishi
Hot water extracts of green tea effectively suppressed AFB1 (aflatoxin B1) induced chromosome aberrations in bone marrow cells in rats when given green tea extract 24 h before injection with AFB1 [140]. Rats administered green tea extract 2 h before or after the AFB1 injection showed no suppressive effect. The suppressive effect of green tea extracts on AFB1 induced chromosome aberration was directly related to the dose of green tea extract (in the range of 0.1 to 2 g/kg). Black tea or coffee given 24 or 2 h before the AFB1 injection produced no suppressive effect.
De boer, [141] showed that the mutagenic potency of several chemicals including the dietary heterocyclic amine 2-amino-1-methyl-6-phenyl-imidazo(4,5-b) pyridine (PhIP)(the environmentally important aromatic hydrocarbon benzo(a)pyrene) and the food contaminant aflatoxin B1 can be modulated by dietary compounds including green tea in lacI transgenic rodent.
Green tea effectively inhibited oxidative DNA damage and cell proliferation in liver of 2-nitropropane (2NP) treated rats [142]. It was suggested that pyrogallol-related compounds of green tea such as EGCG, ECG and EGC are antimutagenic factors in the
Significant inhibition activity of the tea catechins ECG and EGCG, against the mutagenicity of Trp-P-2 and N-OH-Trp-P-2 has been found by [143] using
A study performed by [148] reported that EGCG suppressed the direct-acting mutagenicity of 3-hydroxyamino-1-methyl-5H-pyrido-(4,3-b) indole (Trp-p-2(NHOH)) and 2-hydroxyamino-6-methyldipyrido(1,2-a:3,2-d) imidazole (Glu-p-1(NHOH)) in the Ames
Kada
Green tea extract reduced the levels of ischemia/reperfusion induced hydrogen peroxide, lipid peroxidation and oxidative DNA damage (formation of 8-hydroxydeoxyguanosine) by pretreatment of 0.5 or 2% green tea water extract for 3 weeks, respectively in Mongolian gerbils. Moreover, green tea also reduced the number of ischemia/reperfusion- induced apoptotic cells and locomotors activity [149].
Li
Katiyar
Binding of AFB1 to hepatic nuclear DNA was inhibited in rats given 0.5% instant green tea for 2 or 4 weeks before a single injection of AFB1 [153].
The oral administration of 0.2% green tea or 0.1% black tea for 28 days decreased the extent of chromosome damages (micronuclei) in the peripheral blood of mice subsequently treated with B[a]P [154].
The level of one of the two lung DNA adducts produced by the lung carcinogen NNK (4(methylnitrosamino)-1-(3-pyridyl)-1-butanone) during and after carcinogen treatment was reduced in mice given 2% green tea as their sole source of drinking water [155]. Green tea suppressed 8-OH-2’deoxyguanosine or 8-OH-guanosine, but not 6O-methylguanine levels, in lung DNA.
Recently, it has been demonstrated that the administration of green tea extract 24 hr before the dimethylnitrosoamine (DMN) injection significantly suppressed DMN-induced chromosomal aberrations and sister chromatid exchanges. The suppression was observed 18 hr, 24 hr and 48 hr after the DMN treatment but no suppressive effect was observed at the early period (6 hr and 12 hr) after the DMN treatment. Furthermore, the suppression was observed for all doses of DMN investigated. Mice given green tea 2 hr before the DMN injection displayed no suppressive effect. Mice that were given 2% green tea extract as the sole source of drinking water for four days before sacrifice displayed significantly suppressed DMN-induced chromosomal aberrations and sister chromatid exchanges [156]. They conclude that the suppression of DMN-induced chromosomal aberrations and sister chromatid exchanges should be considered as a green tea exerting a preventive action.
Studies with cell lines had demonstrated that tea polyphenols affect signal transduction pathways, inhibit cell proliferation and induce apoptosis, but the effective concentrations are usually much higher than those observed in blood and tissue [157].
Islami
Supplementation with green tea extract significantly decreased malondialdehyde production and DNA damage after Fe(+2) oxidative treatment in jurkat T-cell line [159]. EGCE was effective in reducing the mutagenecity of Trp-p-2(NHOH) in mouse FM3A cells in culture. EGCE was also effective in inhibiting DNA single strand breaks
Jain
In cultured mammalian cells, the frequencies of mitomycin C or ultraviolet light-induced sister-chromatid exchanges and chromosomal aberrations were suppressed by subsequent treatment with tea polyphenols in the presence of liver-metabolizing enzymes (S9 fraction). In the absence of such enzymes, however, the tea extracts suppressed sister chromatid exchanges and chromosomal aberrations at low concentrations but enhanced them at high concentration [162].
It was shown that EGCG and EGC rather than ECG and EC were found to induce apoptosis in lovo cells. Moreover, EGCG, EGC and ECG caused the arrest at the G1-phase of the cell cycle, whereas EC induced the S-phase arrest [163].
Zhao
Ahmed
Caffeic acid and chlorogenic acid are catechol-containing coffee polyphenols that, in a similar way to the tea polyphenols, have shown to be demethylating agents. Lee et al., studied the modulating effects of these two compounds on the
Caffeic acid phenethyl ester (CAPE), which also is a chatechol, kills various types of cancer cells but is innocuous to normal cells. There are several studies reporting the
Sulforaphane, a dietary phytochemical obtained from broccoli, has been implicated in several physiological processes consistent with anticarcinogenic activity, including enhanced xenobiotic metabolism, cell cycle arrest, and apoptosis. Although the effect of sulforaphane as a demethylating agent has not been specifically studied, this compound was found to down regulate DNMT1 in CaCo-2 colon cancer cells [177].
Isothiocyanates comprise another class of dietary compounds known to affect the epigenome. Isothiocyanates are metabolites of glucosinolates present in a wide variety of cruciferous vegetables and demonstrated to have anticancer properties. Treatment of prostate cancer cells with phenethyl isothiocyanate, a metabolite of gluconasturtin from watercress, was shown to lead to demethylation and re-expression of
Curcumin is a polyphenolic compound derived from the dietary spice turmeric and possesses diverse pharmacological effects including antioxidant, anti-inflammatory, anti-proliferative, and anti-angiogenic activities. Curcumin has been used for centuries in Asia, both in traditional medicine and in cooking where curcumin gives natural yellow color to the food. It has been well known that curcumin possesses potent antiinflammatory activity because of its inhibitory effects on cyclooxygenases 1, 2 (COX-1, COX-2), lipoxygenase (LOX), TNF-α, interferon γ (IFN-γ), inducible nitric oxide synthase (iNOS), and NF-κB [180, 181]. Importantly, experimental evidences suggest that curcumin could exert its inhibitory effects on cancer development and progression. The mechanisms implicated in the inhibition of tumorigenesis by curcumin are unclear but could involve a combination of anti-oxidant, anti-proliferation, pro-apoptotic, and anti-angiogenic properties through the regulation of genes and molecules that are involved in multiple signaling pathways. Moreover, preclinical animal experiments and phase I clinical trials have demonstrated minimal toxicity of curcumin even at relatively high doses (12 g/day) [182]. However, curcumin exhibits poor bioavailability because of poor absorption and rapid metabolism [182]. To improve the bioavailability of curcumin, liposomal curcumin, nanoparticle curcumin, and structural analogs of curcumin have been synthesized and investigated to determine the absorption and anti-cancer activity [183, 184]. The results are promising, which further suggest that curcumin or its novel structural analogs could serve as potent agents for the prevention and/or treatment of human malignancies, and thus requires more phase II and III clinical trials.
Rosmarinic acid is a natural polyphenol antioxidant carboxylic acid found in many
Resveratrol, a phytoalexin made naturally by several plants, has been produced by chemical synthesis because of its potential anti-cancer, anti-inflammatory, blood-sugar-lowering and other beneficial cardiovascular effects. There is limited evidence about the potential demethylating activity of this compound. Resveratrol has shown to be a weak DNMT activity inhibitor in nuclear extracts from MCF7 cells, and as rosmarinic acid, was unable to reverse the methylation of several tumor suppressor genes [185]. In MCF-7 cells, resveratrol improved the action of adenosine analogues to inhibit methylation and to increase expression of RARβ2, although without significant effect on its own [186].
There is traditional and widespread use of dietary polyphenols all around the world. While the anecdotal epidemiological evidence has historically supported the idea of different diet and good health, experimental evidence accumulated in the recent years from various preclinical and clinical studies clearly support the idea that dietary polyphenols have potentially beneficial effects on multitude of health conditions, including cancer. Although the health effects of dietary polyphenols in humans are generally considered promising, there are definite challenges and limitations of the current data in better understanding the molecular mechanisms responsible for this effect, together with the possible interactions between different polyphenols and other dietary constituents. While
Additional clinical work is required to examine the safety profile of various doses of dietary polyphenols, and more basic science studies are needed to improve our understanding of the molecular mechanisms underlying the chemopreventive effect of various dietary polyphenols. It is really exciting to witness that we have at least begun to explore the molecular mechanistic underpinnings of the “goodness” of certain diets and diet-related factors, which have been in existence for centuries.
The mere fact that currently hundreds of dietary polyphenols are being characterized from an “epigenomic” perspective clearly reflects our enthusiasm and trust we pose in the concept of safe and natural agents for cancer chemoprevention. Of course, the current evidence is thin and it is a long and treacherous road ahead of us; nonetheless, given the promise and potential of these polyphenols it is realistic to fathom that some of these compounds can become integral for the cancer chemoprevention in future.
The craniofacial growth and its harmonization with the dental apparatus take place according to a genetic program that acts in a coordinated manner, in both embryo foetal and postnatal stages. In addition to the structural pattern of development, the genetic program also ensures the control of each stage of ontogenesis, both in space and time, which eliminates the risk of developmental errors. During odontogenesis intricate genetic, molecular and cellular regulations establish accurate tooth number and precise location, size, morphology, and composition of each tooth.
However, deviations from usual structure, or function are possible. Any deviation, qualitative and/or quantitative, from usual pattern of development may be called developmental abnormality or anomaly. Developmental anomalies are also known as congenital anomalies or birth defects. Congenital anomalies are defined by the World Health Organization (WHO)“as structural or functional anomalies”. They can occur during antenatal life and can be detected”prenatally, at birth, or later in infancy” [1].
Development failure of one or more teeth is a result of specific disturbances (failure in the initiation of tooth formation, reduced odontogenic potential of the dental lamina, or premature arrest of tooth development) during the early stages (tooth initiation or morphogenesis stage) of odontogenesis affecting reciprocal interactions between the dental epithelium and mesenchyme and leading to absence of tooth germ [2]. Therefore, the usual number of deciduous and permanent dentitions, in both jaws, decrease and the condition is known as tooth agenesis. Family, twin, adoption and tooth development at molecular levels studies provide evidence-based interpretation of genetics as the predominant factors in the etiology of tooth agenesis. Frequently association of tooth agenesis with inherited monogenic syndromes supports the role of genetics in the etiology of missing teeth.
Absence of tooth developmental has direct clinical implications causing physical appearance, emotional, and functional impact on the affected individual. Most affected individuals lack only one or two permanent teeth, but patients who experience agenesis of more teeth are frequently encountered in dental practice as well. Severe forms of missing teeth lead to greater oral impairments. The lack of teeth, especially anterior teeth, malocclusion, drifting of teeth, diastemas between present teeth have negative impact on the oral health-related quality of life of the patients. Tooth agenesis poses medical problems due to ddysmorphic features that may only require cosmetic concern, or major anomalies that require clinical or cosmetic attention. Multidisciplinary teams1 will manage therapeutic options, such as retaining the primary tooth, orthodontic treatment to close the edentulous spaces, dental surgical implants, and fixed or removable dental prosthetic appliances. The proper treatment may be tailored to the individual. It not only improves speech and masticatory function but also psychosocial distress that may help to restore self-confidence.
There are several terms used to describe tooth agenesis: congenital absence of teeth, congenitally missing teeth, lack of teeth, or aplasia of teeth. Some suggest that the term” congenitally missing” teeth could be misleading because teeth are not visible at birth in the oral cavity and tooth development is completed after birth, or teeth may be lost by dental disease, or trauma, or extracted on clinical grounds. In the case of teeth, the development and differentiation continue long after birth, and instead of congenital many anomalies could rather be called developmental anomalies [3]. For the purpose of this chapter the term tooth agenesis will be used throughout. In the literature are used, most commonly, other descriptive terms mainly defined according to the number of missing teeth:
Hypodontia is the lack of one to six teeth missing (excluding the third molars) with mild to moderate levels of severity.
Oligodontia is the failure of development of more than six teeth missing (excluding the third molars) with severe level of severity.
Anodontia means the lack of all teeth without any associated abnormalities causing an extremely severe dental phenotype.
The terms hypodontia and oligodontia are sometimes used interchangeably being considered as a unique clinical entity. As stated by Nieminen [3] and Vastardis [4], this classification of tooth agenesis may not properly reflect the severity of the phenotype as the third molars are excluded. Wherefore tooth agenesis based on dental phenotype severity may be partial or selective, or hypodontia (mild forms of agenesis), severe forms of agenesis or oligodontia, and very rare cases of agenesis of whole the dentition or anodontia. According to OMIM [5], selective tooth agenesis (STHAG) with no other associated systemic features or isolated tooth agenesis has been separated into two entities. The first entity refers to oligodontia characterized by the developmental absence of six or more permanent teeth. The second one refers to hypodontia characterized by the developmental failure of fewer than six teeth. The number of missing teeth in both cases excludes agenesis of third molars, commonly called wisdom teeth.
Incisor-premolar hypodontia (IPH) is a term also used in the literature based on the high frequency of incisors and premolars missing teeth [6]. For the purpose of this chapter the term tooth agenesis will be used throughout.
Prevalence of tooth agenesis is an important information to be of use not only for the clinician and patients but also for policy makers, given the implication for treatment protocols. Many published studies reported large variation in the prevalence of tooth agenesis across the world due to differences between methods of sampling, sample size, age of subjects, orthodontic or non-orthodontic enrolled subjects, number of males and females, the third molars included or excluded, or ethnic population groups. Moreover, it has been claimed that agenesis of permanent teeth has increased over the years. Mattheeuws et al. [7] considered that the period of time was too short and the available data too limited to describe a possible trend in the human dentition. Their meta-analysis seems to confirm that tooth agenesis has been diagnosed more often in recent studies.
Both the primary and permanent dentitions may be affected by variations in the number of teeth, but the prevalence is different. A prevalence of less than 1% in the primary dentition has been reported in the European population ranging from 0.4 to 0.9%, and it has been reported to be 2.4% in Japanese population. [6, 8, 9]
Prevalence of permanent dentition has been studied extensively because it is no doubt more affected than primary dentition. Prevalence of tooth agenesis in permanent dentition also differs among studies of orthodontic/non-orthodontic subjects. Non-orthodontic population prevalence across the world varies between 1.6 and 9.6 per cent (most often-cited) [10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21] and calculated overall prevalence of tooth agenesis was estimated to be 6.53% ± 3.3% [22]. So far, some systematic reviews compare and evaluate prevalence studies on non-syndromic permanent teeth agenesis in various populations showing the prevalence varying from 0.3% in Indian population [16] to 15.7% in Hungarian population [17]. Polder et al. [11] reported the prevalence of non-syndromic agenesis in permanent teeth of European population (third molars excluded) varying between 3.4% in Switzerland to 10.1% in Norway. The wide range of prevalence values observed in population studies has suggested geographic differences. Published data reviewed by Pemberton et al. [23] reported that people of Scandinavian descent are the most susceptible to tooth agenesis in the permanent dentition whilst those of Asian or Arabic descent are the most susceptible in the primary dentition.
Gender predominance in tooth agenesis has been reported (Table 1) suggesting gender as a risk factor. Tooth agenesis show prevalence rates higher in females compared to males [11, 12, 24]. However, other studies reported no significant difference between the prevalence of tooth agenesis in males and females [19, 20].
Type of dentition | Prevalence % | Prevalence % | ||
---|---|---|---|---|
Minimum | Maximum | Male | Females | |
Primary | 0.4 | 0.9 | No significant differences | |
Permanent | 3.4 | 10.1 | 4.6 | 6.3 |
The prevalence of non-syndromic agenesis in permanent teeth (third molars excluded) in European population (summarized data).
In most patients, dental agenesis involved only one (47.8%) (Figure 1) or two teeth (35.1%) (Figure 2) [11]. Absence of one or two permanent teeth was reported in 83% - 87.9% of the subjects with tooth agenesis [11, 19, 20]. Thus, most of the affected individuals suffer only a mild form of tooth agenesis.
Female patient, 22 years old with non-syndromic tooth agenesis. (1,2,3) intraoral photos showing the missing upper right lateral incisor and the microdontia of the contralateral tooth. (4) panoramic radiograph confirming the agenesis of the maxillary right lateral incisor. * position of the missing tooth.
A 28-year-old female patient with trisomy 21 presenting lower second premolars agenesis. Several dental anomalies are observed on the intraoral photos (1,2,3): Upper diastema, maxillary lateral incisors microdontia, ectopic canines and spaced lower teeth. (4) panoramic radiograph shows the absence of the lower second premolars and an agenesis diagnosis can be confirmed. * position of the missing tooth.
Although tooth agenesis is a common development anomaly, the prevalence becomes progressively smaller as the number of missing teeth increases. For example, isolated agenesis of at least six teeth is relatively rare, affecting 0.08% of the Dutch population [25] and 0.16% of the Danish population. [26] Polder et al. [11] reported an overall prevalence of 0.14% in affected patients with six or more teeth. In addition, lack of all teeth without associated abnormalities is extremely rare, and prevalence is unknown. [19]
Apparently, any tooth in the arch can be missing, but tooth agenesis tends to affect distinct tooth classes differentially. Some tooth types were more often missing than other ones. Thus, the frequency of the individual teeth involved varies [11].
In the deciduous dentition, the upper lateral incisors account for more than 50% and together with lower incisors for 90% of all affected teeth [27]. Nieminen highlighted that there is an obvious association between the agenesis of the temporary teeth and the permanent teeth; a temporary tooth affected by agenesis is almost every time followed by missing of the corresponding permanent tooth [3, 27].
The third molars are the most prevalent missing teeth in all reports. Up to 70% of the population experience problems with their third molars, whether it is failure of proper eruption (impaction) or not erupting at all (agenesis). Up to 25% of the population may lose at least one third molar [10] and therefore, usually, third molar is excluded from the classification. The lowest prevalence of third molar agenesis reported so far was 10.1% for African American population [28] and the highest prevalence was 41% for the Korean population. [30] Excluding the third molars, in European population, the most frequently missing tooth is mandibular second premolar (2.91%–3.22%), followed by maxillary lateral incisor (1.55%–1.78%) or second premolar (1.39%–1.61%), as reviewed by Gracco et al. [19].
Other data support the conclusion that the most commonly missing tooth was the maxillary lateral incisor, followed by mandibular and maxillary second premolars [22]. Figure 3 illustrates the bilateral absence of second lower premolars. Agenesis of lower central incisors is common in Asian populations in both primary and permanent dentitions [9].
Female patient aged 7 years old with confirmed trisomy 21 presenting all four second premolars agenesis. Intraoral photos (1,2,3) emphasize a mixed dentition with lack of space for the alignment of the permanent teeth. (4) panoramic radiograph shows the congenital absence of the second premolars in both dental arches. * position of the missing tooth.
Less commonly affected teeth are, in order, lower incisors, maxillary first premolars, mandibular first premolars, maxillary canines and mandibular second molars (Figure 4). Patients who experience agenesis of these teeth (e.g., canine or maxillary central incisor) more often present with many missing teeth [11].
Tooth agenesis in a non-syndromic 21-year-old female patient. Intraoral photos (1,2,3) emphasizing a generalized microdontia and as a result, teeth are spaced with larger gaps in the lower arch. (4) Anamnesis and the examination of the panoramic x-ray reveal the congenital absence of the lower second molars, both in the right and in the left quadrant. * position of the missing teeth.
The most stable teeth are maxillary central incisors (prevalence of agenesis 0.016%) and mandibular first molars and canines (prevalence of agenesis about 0.03%) [3]. Recently, Eshgian et al. [21] concluded that hypodontia affected specific type of teeth. In their study, the most commonly missing teeth were maxillary premolars, lateral incisors and mandibular premolars. Comparing their results with other data from previous studies, they explained the differences in patterns and prevalence of tooth agenesis between different population groups by ethnic diversity in the distributions of mutant genes. The explanation was supported by the prevalence of people with missing permanent teeth which was significantly lower in blacks than in whites in U.S.A. [28], and different type of affected tooth, mandibular incisor in Hong Kong children population [29] and mandibular second premolars among Italians. [19] Polder et al. [11] considered that difference in the ethnic groups is not the explanation of differences in prevalence between populations due to the small number of reported hypodontia cases and the difficulty of detecting the anomaly without appropriate evidence.
Distinct patterns of permanent teeth agenesis have been reported but, as a general rule, if only one or a few teeth are missing, the absent tooth will be the most distal tooth of any given morphological class [3, 15, 24, 31].
It is known that upper lateral incisors, second premolars, and third molars are the last forming teeth in their tooth family, are in the embryonic fusion of the maxilla and the medial nasal processes and erupt in the critical terminal area of the dental lamina. For these reasons, the last forming teeth are more vulnerable to the critical actions of both genetic and environmental factors during odontogenesis and fail to develop. This can explain why tooth agenesis most frequently affects premolars, lateral incisors, and molars. (Figure 5) The anomaly was called ‘end-of-series. [31, 32] In 2017, it has been assumed by Juuri and Balic that tooth agenesis most frequently affects the last tooth to develop within the tooth family due to a gradual decrease of the odontogenic potential of the dental lamina. [33]
A 13-year-old male with confirmed Down syndrome presenting different dental anomalies. Intraoral photos (1–3) show mixed dentition with delayed eruption of permanent teeth, remarking the absence of the upper left lateral incisor. (4) Examination of the panoramic radiograph reveals the absence of the upper second premolars and of the maxillary left lateral incisor. * position of the missing teeth.
Tooth agenesis may be either bilateral or unilateral. Pinho et al. [32] hypothesized that if the etiology of hypodontia is primarily genetic, then bilateral missing teeth phenotype would be expected to be more commonly observed. Unilateral hypodontia might be a variation in severity of a genetic trait showing a microdont or peg-shaped contralateral tooth.
Most studies reported predominance of bilateral missing teeth, as reviewed by Rakhshan [15]. Goya et al. [34] found that symmetry of congenitally missing teeth was predominant (74.6%), Kirzioglu et al. [35] observed that bilaterally missing teeth was 73.2%, and Endo et al. [36] reported that 89% of the patients presented bilaterally missing teeth. Other researchers have found unilateral tooth agenesis more common. [37] Polder et al. [11] compared (based on nine studies) the occurrence of bilateral and unilateral agenesis for the most four affected teeth showing that only for maxillary lateral incisors prevalence of unilateral agenesis was lower than bilateral agenesis.
Bilateral agenesis of maxillary lateral incisors occurred more often.
Unilateral agenesis involving mandibular second premolars occurred more common.
Unilateral agenesis affecting maxillary second premolars was more frequently.
Unilateral agenesis of mandibular central incisors occurred more often.
Medina [38] stated that while symmetrical dental missing affects the maxilla (Figure 6), the mandible shows mostly unilateral agenesis. In the opinion of other researchers, the most common symmetric missing tooth could be the mandibular second premolar agenesis, followed by the absence of the maxillary second premolar or maxillary lateral incisor, as reviewed by Rakhshan [15].
Non-syndromic tooth agenesis in a 26-year-old female patient. Clinical intraoral appearance (1,2,3) emphasizing multiple dental problems, accentuated by the bilateral absence of the upper lateral incisors and of the second premolars. (4) panoramic radiograph confirming the agenesis of the four upper teeth. * position of the missing teeth.
No overall difference in tooth agenesis has been reported between maxilla and mandible for permanent dentition [11]. However, Gomes et al. [20] found maxillary hypodontia in 59.2% of patients and in the mandible of 40.8% with an overall ratio of 1.45:1 in orthodontic patients. Several reports mentioned a small but not always significant predominance of missing teeth in the maxilla [19, 20, 24] whilst other reported more missing teeth in the mandible than in the maxilla [36].
For the primary teeth, agenesis is more common in the maxilla [27].
No significant difference between left and right sides of the jaw has been reported. Nevertheless, predominance of tooth agenesis on the left side has been reported in some Scandinavian studies, as reviewed by Arte S. [18] and Fekonja A. [24] have found the missing teeth were more commonly absent on the right side.
No clear difference in tooth agenesis has been found between the anterior and posterior regions. Most studies showed higher prevalence in the anterior segment [15] and the few remaining analyses found no significant differences [36]. Endo et al. [36] suggested that in mild cases of tooth agenesis, the anterior segment might be more involved while the posterior segment might be predominant in severe cases.
Polder et al. considered the age of detectability as an important issue. A meta-analysis study made by Polder et al. revealed that the visibility of tooth germs by X-ray examination hangs on their degree of mineralization. Subjects at the same chronological age can show significant differences in mineralization stages and dental age. The major differences in mineralization can be found especially in mandibular second premolar buds or third molar buds which present a late onset of mineralization. Therefore, radiographic examination may show a false-positive result and a misdiagnosis of tooth agenesis. [11]
All primary teeth have erupted by the age of three and all permanent teeth except the third molars between the age of 12 and 14. Therefore, three to four years of age children are suitable for diagnosis of missing primary teeth by clinical examination, and 12 to 14-year-old children (the precise determination of teeth mineralization stages), for diagnosis of permanent teeth [22, 39]. While some studies reported age of detectability after eight years of age for the permanent dentition, and failure for the third molar to form is detectable by age 11.
Investigations so far show that several heterogenous factors may be involved in tooth agenesis. Tooth development is a complex process which involves a combination of genetic, epigenetic, and environmental factors. Thus, there is no single etiology of tooth agenesis. Family, twin, and adoption studies2 are the primary exploration by which the genetic basis of a condition may be established. In addition, observed prevalence differences between populations, and association with heritable syndromes supplied evidence for strong genetic influences on tooth agenesis [8]. These findings provided the reasoning for recent efforts to identify the relevant susceptibility genes and the molecular mechanisms by which they interact with environmental influences, and to correlate tooth agenesis phenotypes with their causative factors. Furthermore, genetic studies on mouse models with dental agenesis have identified a few transcription factors and signaling molecules, such as WNTs (wingless-related integration site), BMPs (bone morphogenetic proteins), FGFs (fibroblast growth factor), and NF–κB (nuclear factor kappa B) as candidate genes in human isolated and syndromic agenesis [40].
More than 300 genes are expressed and control odontogenesis and, apparently, any of these gene mutations may cause tooth agenesis. Among these genes, PAX9 (paired box gene 9), MSX1 (muscle segment homeobox 1), EDA (ectodysplasin A), WNT10A (wingless-type MMTV integration site family, member 10A), and AXIN2 (axis inhibitor 2) are the most frequently reported mutations associated with non-syndromic tooth agenesis (hypodontia/oligodontia), as reviewed by Al-Ani et al. [41] and Liu et al. [42]. (Table 2) These all genes have roles in both signaling pathways and in mediating the signal transduction cascades.
Normal expression of these genes is important for the tooth development. MSX1 is a transcription factors active in regions of condensing ectomesenchyme in the tooth germ. PAX9 is a transcription factor as well, it is expressed in the tooth mesenchyme, playing a significant role during odontogenesis in the progressive and reciprocal signal transduction pathways that normally occur in epithelial–mesenchymal cells. Both Msx1 and Pax9 are involved in the Bmp and Fgf pathways and interact during the tooth-bud-to-cap transition. Their expression profiles during early tooth development are largely overlapping, and Pax9 is known to activate transcription of
Studying 34 unrelated patients with isolated tooth agenesis, van den Boogaard et al. [43] reported that 19 patients, representing 56% of them, had mutations in the WNT10A gene. Of 34 patients, 3% presented mutations in the MSX1 gene, 9% and 3% had mutations in the PAX9 and AXIN2 genes, respectively. It was concluded that WNT10A is a significant gene in the etiology of isolated hypodontia.
Frameshift and nonsense mutations are highly likely all causative because they involve profound alteration of the protein primary structure, but missense mutations in these genes are found to cause tooth agenesis phenotypes characteristic in terms of severity and affected teeth as well [44].
As a rule, homozygous (identical mutation on both alleles of a specific gene) or compound heterozygous (both alleles of a gene are mutant, but the mutations are different) carriers of gene mutations exhibit more severe phenotype of tooth agenesis than heterozygous carriers (two different alleles, but only one is mutant).
Besides the single-gene mutations, Michon [45] reported the functional role of miRNAs in proliferation and differentiation of cells and tissues during odontogenesis and possible dental defects development. His results support the view of complex genetic etiology of tooth agenesis.
Attention should be turned to the expression of a mutation in a family. In families with a probable dominant or recessive Mendelian inheritance, there seems to be a variable missing teeth phenotype. In other words, tooth agenesis patterns are different in expressivity among the affected members within a family having the same molecular cause. Vastardis studied incisor agenesis in families with dominant pattern of inheritance. Autosomal dominant disorders express variability in clinical manifestation caused by reduced penetrance and variable expressivity of mutant gene. Consequently, individuals in the same family who carry an identical mutation can vary in the severity of their incisor agenesis. Variable expressivity determines developmental alteration of lateral incisor shape (peg-shaped) or rudimentary third molars and unilateral agenesis may be the result of incomplete penetrance. [46]
Mostowska et al. described a three-generation family with severe autosomal dominant oligodontia. Those affected lacked all permanent molars, second premolars, and mandibular central incisors. The authors found a novel mutation of MSX1. Mutation occurs in exon 2, at nucleotide 581 a cytosine is changed to a thymine (c.581C → T transition), and disrupts the homeobox domain, which is highly conserved. The new mutation causes non-syndromic oligodontia (absence of 14 permanent teeth) in their proband. Two healthy members from the proband’s family carry the same missense mutation. [47] To date, many studies provide evidence for great intra- and inter-familial clinical variability in families with isolated tooth agenesis. [3, 13, 41]
There are several possible genetic mechanisms to explain these major differences in expressivity of the phenotype with the same molecular cause. One of them lies in the concepts of penetrance and expressivity. Reduced (incomplete) penetrance and variable expressivity are factors that influence the effects of particular genetic changes and are commonly seen with Mendelian dominant traits. Tooth agenesis shows incomplete penetrance, since pedigree studies demonstrate individuals who must carry the mutation but who do not appear to be affected themselves. Reduced penetrance probably occurs when final effect of a gene mutation can be indirectly influenced by modifier genes, epigenetic factors, or miRNAs. Potential modifier genes may act in the same or in different development pathways altering (exacerbate or attenuate the effect of the gene mutation) the clinical phenotype.
Epigenetic factors do not change the gene sequence. Epigenetic alterations may be induced spontaneously, in response to environmental factors, or may be part of a person’s make up (allele dosage, copy number variants, allele variants). Identical twins are ideal subjects for studying the effects of epigenetic modifications. Monozygotic co-twins sharing sex, age, and identical genomes display discordant phenotypes for missing teeth which may be explained by epigenetic differences. In their twin study, Townsend et al. supported the view that, even though there is a relatively strong genetic basis to missing teeth, the number or position of affected teeth can be influenced by epigenetic factors. Epigenetic alteration activities, such as DNA methylation and histone modification, at each stage, at the local level during the odontogenesis process, may account for distinct phenotypic differences in the final appearance of teeth of the identical twins. During tooth development, odontogenetic cells reply differently to epigenetic variation in spatiotemporal expression of local signaling molecules passing between cells. [48]
miRNAs play an important role in controlling gene activity by regulating translation during tooth development. Changes in miRNAs levels have been linked to several dental defects [45]. Thus, in a population, the missing teeth phenotype might not occur so often as the abnormal genotype. On the other hand, individuals with the same genetic condition may have more missing teeth than another having only one missing tooth. Thus, expressivity describes individual variability. Variable expressivity is probably caused by a combination of genetic, environmental, and lifestyle factors, most of which have not been identified.
Dreesen et al. analyzed hypo−/oligodontia phenotype variations in nine families at individual, intrafamilial and interfamilial levels aiming to evaluate whether the different agenesis patterns in the pedigrees are predictive of mutations in specific genes based on reported genotype–phenotype associations. Familial aggregation was noted but the tooth agenesis patterns were variable between family members, in terms of number of missing teeth. Therefore, tooth agenesis is not (always) a simple monogenic disorder. The authors proposed a multifactorial aetiological model with many genes and environmental factors modulating the clinical expression. [49]
Genetic heterogeneity describes different gene mutations or genetic mechanisms that produce the same or similar clinical phenotype. Heterogeneity can be recognized by subtle differences in clinical phenotype or evidence of different patterns of inheritance. Genetic testing can confirm the gene mutation responsible for a certain clinical phenotype. Usually, genetic heterogeneity complicates the risk estimation in genetic counseling and genetic prognoses.
Two types of genetic heterogeneity are recognized: locus heterogeneity (clinical phenotype is caused by mutations at two or more different loci), and allelic heterogeneity (clinical phenotype is caused by more than one mutation within the same gene, same locus).
Locus heterogeneity is well documented in selective tooth agenesis (STHAG).
There are ten loci associated with STHAG. Nine of them are autosomal loci (STHAG1 to STHAG9) and one STHAGX1 is sex-linked locus as it follows the X-linked dominant pattern of inheritance. The corresponding gene located at
In 1998, Ahmad et al. [50] reported an autosomal recessive form of hypodontia in a large consanguineous Pakistani family. This was the first report of hypodontia associated with other dental anomalies, such as enamel hypoplasia and failure of teeth eruption, leading to the edentulous state prematurely. The locus was named
In 2000, Wang et al. [51] described a rare, heritable, form of agenesis of permanent teeth. The tooth number anomaly was named He-Zhao deficiency. The only clinical feature of affected individuals was oligodontia. It was transmitted in an autosomal dominant manner with reduced penetrance in a large six successive generation family coming from a small village in China. The number of missing teeth ranged from “a few teeth to the entire set of teeth”. Some of the patients were more likely to have first and second molars. This distinct form of permanent tooth agenesis is associated with
In 2015, Huckert et al. [52] reported mutations in LTBP3 (latent transforming growth factor-beta-binding protein 3) gene causing different dental phenotypes and brachyolmia (short trunk, mild short stature with platyspondyly and scoliosis). The association of oligodontia with hypoplastic amelogenesis imperfecta, taurodontic molars and short stature has been designed as a distinct entity named DASS (dental anomalies and short stature) (OMIM 601216). So, STHAG6 was incorporated into DASS.
Another example of locus heterogeneity is provided by mutations in EDA, EDAR and EDARADD genes which express the similar phenotype of hypohidrotic ectodermal dysplasia. (Table 3).
Gene symbol/locus | Gene name | Cytogenetic location | Gene /locus OMIM number | Description of tooth agenesis clinical features | Inheritance | Phenotype OMIM Number |
---|---|---|---|---|---|---|
AXIN2 | axis inhibitor 2 | 17q24.1 | 604025 | Oligodontia – severe permanent teeth agenesis | Autosomal DOMINANT | 608615 |
EDA | ectodysplasin A | Xq13.1 | 300451 | Tooth agenesis, selective, X-linked 1 (STHAGX1) | X-linked DOMINANT | 313500 |
GREM2 | GREMLIN-2 homolog, cystine knot superfamily gene | 1q43 | 608832 | Tooth agenesis, selective,9 (STHAG9) | Autosomal DOMINANT | 617275 |
LRP6 | low density lipoprotein receptor-related protein-6 | 12p13.2 | 603507 | Tooth agenesis, selective,7 (STHAG7) | Autosomal DOMINANT | 616724 |
MSX1 | muscle segment homeobox 1 | 4p16.2 | 142983 | Tooth agenesis, selective,1, with or without orofacial cleft (STHAG1) | Autosomal DOMINANT | 106600 |
PAX9 | paired box gene 9 | 14q13.3 | 167416 | Tooth agenesis,selective,3 (STHAG3) Hypodontia/Oligodontia 3 | Autosomal DOMINANT | 604625 |
STHAG2 | 16q12.1* (*the disorder was placed on the map by statistical methods) | 602639 | Tooth agenesis, selective, (STHAG2) | Autosomal recessive | 602639 | |
STHAG5 | 10q11.2-q21* (*the disorder was placed on the map by statistical methods) | 610926 | Tooth agenesis, selective,5 (STHAG5) Hypodontia/Oligodontia 5 (He-Zhao deficiency) | 610926 | ||
WNT10A | wingless-type MMTV integration site family, member 10A | 2q35 | 606268 | Tooth agenesis, selective,4 (STHAG4) with or without ectodermal dysplasia | Autosomal DOMINANT or recessive | 150400 |
WNT10B | wingless-type MMTV integration site family, member-10B | 12q13.12 | 601906 | Tooth agenesis, selective,8 (STHAG8) | Autosomal DOMINANT | 617073 |
Gene mutations involved in NON-SYNDROMIC tooth agenesis are passed on to the next generation following different Mendelian patterns of inheritance (according to OMIM database).
Online Mendelian Inheritance in Man (OMIM™) is a comprehensive, authoritative and timely knowledgebase of human genes and genetic phenotype compiled to support research and education in human genomics and the practice of clinical genetics. It is freely available and updated daily.
Gene symbol | Gene name | Cytogenetic location | Gene/locus OMIM number | Name of disorder associated with tooth agenesis | Inheritance | Phenotype OMIM Number |
---|---|---|---|---|---|---|
AXIN2 | axis inhibitor 2 | 17q24.1 | 604025 | Oligodontia-colorectal cancer syndrome | Autosomal DOMINANT | 608615 |
EDA | ectodysplasin A | Xq13.1 | 300451 | Hypohidrotic ectodermal dysplasia 1 (HED) | X-linked reccessive | 305100 |
EDAR | ectodysplasin A receptor | 2q13 | 604095 | Ectodermal dysplasia 10A, hypohidrotic/hair/nail type Ectodermal dysplasia 10B, hypohidrotic/hair/nail type | Autosomal DOMINANT Autosomal recessive | 129490 224900 |
EDARADD | edar-associated death domain | 1q42-q43 | 606603 | Ectodermal dysplasia 11A, hypohidrotic/hair/tooth type Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type | Autosomal DOMINANT Autosomal recessive | 614940 614941 |
LTBP3 | latent transforming growth factor-beta-binding protein 3 | 11q13.1 | 602090 | Dental anomalies and short stature | Autosomal recessive | 601216 |
MSX1 | muscle segment homeobox 1 | 4p16.2 | 142983 | Ectodermal dysplasia 3, Witkop type Orofacial cleft 5 Wolf-Hirschhorn syndrome* (*a contiguous gene deletion syndrome in which multiple genes are involved) | Autosomal DOMINANT Autosomal DOMINANT Isolated cases | 189500 608874 194190 |
NEMO (IKBKG) | inhibitor of nuclear factor kappa-b kinase, regulatory subunit gamma | xq28 | 300248 | Incontinentia pigmenti | X-linked DOMINANT | 308300 |
PITX2 | paired-like homeodomain transcription factor 2 | 4q25 | 601542 | Axenfeld-Rieger syndrome, type 1 | Autosomal DOMINANT | 180500 |
WNT10A | wingless-type MMTV integration site family, member 10A | 2q35 | 606268 | Schopf-Schulz-Passarge syndrome Odontoonychodermal dysplasia | Autosomal recessive Autosomal recessive | 224750 257980 |
Gene mutations frequently associated with SYNDROMIC tooth agenesis.
Allelic heterogeneity is illustrated by the different mutations in the MSX1 and PAX9 genes. For example, MSX1 mutations show overlapping and non-overlapping phenotypes. Almost all mutations are responsible for autosomal dominant STHAG1 involving second premolars, first molars and third molars. Few MSX1 mutations are associated with combinations of tooth agenesis with oral clefting (cleft palate only and cleft lip and cleft palate) and nail abnormalities (Witkop syndrome). [49] (Table 3)
Genotype–phenotype correlations refer to the association between specific germline mutations, meaning genotype, and the resulting spectrum of disease expression of that mutation in the affected individual, meaning phenotype. Usually, such correlations are made for monogenic disorders which follow Mendelian inheritance patterns. Moreover, the correlations can clarify which characteristics of a mutation affect the severity of dental anomaly with a genetic background. On the other hand, the pattern of tooth agenesis provides useful information about how gene mutation might affect an individual and other member of the family. Tooth agenesis runs in families and hypodontia/oligodontia patients have one or more affected family members. [48] So, the family members can be appropriately counseled by a geneticist, and predictive/pre-symptomatic genetic testing should be considered for early diagnosis and early intervention, especially for children.
Research studies have linked non-syndromic hypodontia/oligodontia phenotype with specific gene mutations. For example, among identified mutations, MSX1 and PAX9 genes can cause variation in clinical phenotype of tooth agenesis. Kim et al. [53] studied the pattern of missing teeth in families with certain MSX1 and PAX9 mutations. The missing teeth pattern associated with MSX1 mutants was different from that associated with mutations in PAX9. MSX1-associated tooth agenesis involved bilaterally symmetrical absence of maxillary and mandibular second premolars and maxillary first premolars. PAX9-associated tooth agenesis involved also bilaterally symmetrical missing teeth, usually maxillary and mandibular second molars were affected. Yu et al. [54] stated that WNTB10B-associated oligodontia affected most lateral incisors. In contrast, genotype–phenotype analysis of oligodontia pattern associated with WNT10A mutations revealed that premolars were the most frequently missing teeth.
Mutations in nine genes (MSX1, PAX9, AXIN2, WNT10A, EDA, EDAR, EDARADD, NEMO and KRT17) have been associated with non-syndromic oligodontia, as reviewed by Liu et al. [42] Oligodontia phenotype is caused by haploinsufficiency. Mutations produce a reduction in functional gene product below a threshold required for normal dental development [8].
Apparently, reduced quantities of a gene product should equally affect the formation of all teeth. Oligodontia caused by defects in MSX1 and PAX9 yields typical, although variable and overlapping patterns of tooth agenesis [8]. Mutations of MSX1 result in the absence of all permanent third molars, all second premolars, maxillary first premolars and variably other teeth, whereas defects in PAX9 cause mainly agenesis of molars, typically of all permanent maxillary and the second and third mandibular molars as well as variably of other teeth. [55] Regarding AXIN2 gene, five mutations were reported to be associated with non-syndromic tooth agenesis: four missense and one frameshift mutations. The phenotype is variable in expression and involved at least seven teeth. One study reported that a mutation in EDARADD gene led to non-syndromic oligodontia. [41]
Not all of the tooth agenesis forms can be linked to precis genetic mutations, at a single gene locus. Tooth agenesis is a common developmental anomaly and has a definite familial tendency. However, the proportion of affected near relatives is less than what expected for a monogenic trait. One way to recognize a complex trait is through unpredictable inheritance patterns in successive generations. Tooth agenesis is probably caused by several independent defective genes, acting alone or in combination with other genes, and interacting with environmental factors, leading to a specific clinical phenotypic pattern. Being produced by multiple genes, a multifactorial trait seems to be more susceptible to environmental/stochastic or nongenetic factors.
Incomplete penetrance, genetic background, and variable expression levels did not explain all major differences in the expressivity of the phenotype with the same molecular cause. For these reasons, some authors based on evidence from genetic studies, animal models, and environmental correlates suggested an oligogenic or polygenic inheritance of tooth agenesis. [42, 45, 46, 47, 48]
For instance, Vastardis [45] stated that tooth development is a very complex process and involves many” players”. Thus, third molar agenesis cannot be explained in most cases with a simple model of autosomal dominant transmission. Fekonja et al. [24] suggested that genes could be the dominant factor for the agenesis in the anterior region, while the posterior teeth could be missing sporadically. Townsend et al. [56] proposed a multifactorial aetiological model, with possibly many genes, and also environmental and epigenetic factors contributing to tooth development based on lack of complete concordance for missing teeth in monozygotic twins.
It has been documented by various statistical analyses using single locus and polygenic patterns that both approaches are possible. From genetical point of view, multifactorial inheritance of tooth agenesis is troublesome to analyze. It is difficult to state whether hypodontia is a result of a polygenic or single gene defect. It arrives at a diagnosis of multifactorial inheritance for tooth agenesis only after the monogenic forms of inheritance have been considered and found unlikely.
Molecular basis or locus of isolated anodontia (OMIM 206780) are unknown. Gorlin et al. [57] described complete absence of the permanent dentition with the entire primary dentition present and erupted at a normal time. Anodontia presented evidence of autosomal recessive inheritance, including multiple affected sibs and consanguineous parents. Based on three family studies, it was documented that anodontia of permanent teeth is a homozygous state of the gene responsible for pegged or missing maxillary lateral incisors. [5]
Pseudoanodontia should not be confused with anodontia. Pseudoanodontia or false anodontia occurs, when teeth are absent clinically because of impaction, delayed eruption, exfoliation or extraction. In GAPO syndrome (GAPO syndrome is the acronymic designation for a complex of growth retardation, alopecia, pseudoanodontia, and progressive optic atrophy - OMIM 230740) is described pseudoanodontia, failure of tooth eruption. The syndrome is caused by mutations of ANTXR1 gene (anthrax toxin receptor 1) located on 2p13.3, and the pattern of inheritance is autosomal recessive [58].
Tooth agenesis is usually isolated, but gene mutations have been identified that either cause tooth agenesis as a sole isolated agenesis, or tooth agenesis in association with a wide variety of multiorgan malformation syndromes. (Table 3
Thus, tooth agenesis is a primary feature of many single-gene Mendelian syndromes that affect not only teeth but also several other ectodermal derivatives indicating that the development of teeth and certain tissues/organs are under the control of the same gene molecular functions and common molecular mechanisms are responsible for tooth and other organ development. A pleiotropic mutation may influence several, apparently unrelated, traits simultaneously, due to the gene coding for a product used by a myriad of cells or different targets that have the same signaling function. For instance, two AXIN2 nonsense mutations caused syndromic tooth agenesis, such as oligodontia and predispose to colorectal cancer, or oligodontia and variable other findings, including colonic polyposis, gastric polyps, a mild ectodermal dysplasia phenotype with sparse hair and eyebrows, and early onset colorectal and breast cancers [42].
Adventitious chromosomal abnormalities cause tooth agenesis in association with other clinical features and recognizable patterns of malformations known as chromosomal syndromes.
Down syndrome and tooth agenesis (OMIM 190685)
Down syndrome (DS), a common and well-known syndrome, is caused by an autosomal aneuploid defect called trisomy involving the human chromosome 21 (Ts21). The extra chromosome 21 or part of its long arm (including many genes) may come in distinct genetic ways, such as full trisomy 21, mosaic trisomy 21 or unbalanced translocation trisomy 21 causing DS distinctive facial features. The difference between DS people could be made by chromosome analysis because craniofacial features are similar. So, cytogenetic analysis is not relevant for predicting the severity of oro-dental features in DS [59].
Missing teeth were reported in 23–47% of cases (Figure 7). Third molars, second premolars, and lateral incisors are most frequently absent in the permanent dentition. Peg-shaped maxillary lateral incisors have been observed in 10%. In 12–17% of cases, deciduous lateral incisors are missing. Extreme hypodontia and anodontia have been noted occasionally. [60] There is a higher incidence of dental anomalies, such as taurodontism, fusion of deciduous lower lateral incisor with a canine, morphologic crown alterations, enamel hypoplasia and hypocalcification. Irregular alignment is common as well. Tooth eruption of both deciduous and permanent teeth is delayed in 75% of cases and irregular sequence of eruption is common. [60] DS children with missing teeth have a more obvious tendency in developing a Class III relationship of the jaws than DS children without tooth agenesis. This must be taken into account when treating a DS patient [61].
Wolf-Hirschhorn syndrome and missing teeth (OMIM 194190)
The deletion of the distal short arm of human chromosome 4 causes del(4p) syndrome known as Wolf-Hirschhorn syndrome. The critical region is 4p16.3 (WHSCR) and lies approximately 2 Mb from the telomere, so that multiple genes are deleted. Most important genes, playing a major role in early development, are NDS2 (nuclear receptor binding SET domain protein 2), LETM1 (leucine zipper and EF-hand containing transmembrane protein 1), and MSX1 (muscle segment homeo box homolog 1) cause the typical signs and symptoms of this disorder, such as characteristic facial appearance (microcephaly, high forehead, prominent glabella,” Greek warrior helmet” facies, broad and/or beaked nose, hypertelorism, short philtrum, micrognathia, downturned corners of the mouth, short upper lip, dysplastic ears, preauricular tags), delayed growth and development, intellectual disability, and seizures. Agenesis of many permanent teeth has been reported. [60]
About 10% of the patients have cleft lip and palate, 25% present cleft palate, and 50% with micrognathia and high arched palate.
Although, MSX1 gene is outside the WHSCR, in people with Wolf-Hirschhorn syndrome it is frequently deleted. Previous studies reported the critical role of MSX1 in dental, lip, and palate development. [62, 63] Some people with Wolf-Hirschhorn syndrome present mutations of MSX1 gene. It is expected that deletion of MSX1 gene might disrupt the formation of oral structures in early development, causing missing teeth and other dental abnormalities associated with an opening in the roof of the mouth (cleft palate) and/or a split in the upper lip (cleft lip). Nieminen et al. considered that haploinsufficiency of MSX1 gene is a possible mechanism for selective tooth agenesis 1 but a single copy of the gene is not sufficient to produce the oral cleft phenotype. [64]
Multiple tooth agenesis in a 14-year-old female patient with trisomy 21. (1–3) intraoral photos reveal a mixed dentition. It is important to note that the prolonged retention of several primary teeth, either due to the congenital absence of the permanent successor tooth (which is the case of the missing maxillary right lateral incisor) or the deviation in the eruptive path of the permanent successor which determinate the concomitant presence of both the deciduous and the permanent teeth on the arch (in the figures, the deciduous teeth are marked with red arrows while the permanent ones are labeled by blue arrows). The degree of complexity involved in this case is increased not only by the agenesis of the upper right lateral incisor, but its association with another three missing incisors in the lower arch. (4) based on the anamnesis and the examination of the panoramic radiograph, it was confirmed the agenesis of the upper right lateral incisor, lower lateral incisors, and the lower right central incisor. Moreover, left second molars in both arches present an elongated pulp chamber and apically displaced furcations, which are specific for the diagnosis of taurodontism. * position of the missing teeth.
Tooth agenesis cases are either familial or sporadic. Sporadic cases are commonly considered to be nonhereditary, with low risk for relatives or offspring.
By definition, a sporadic disorder arises in the absence of evidence for a heritable or environmental etiology. Affected individuals occur occasionally in families with no reported medical history of tooth agenesis. Consequently, apparently sporadic tooth agenesis may be not inherited from parents but may arise from different aetiologies. Fisher et al. considered that apparently sporadic disorders imply genetic or environmental factors. Sporadic cases can arise from new mutations in germs cells or somatic cells, as well as disorders with an environmental cause. [65].
Usually, environmental factors may cause arrested tooth development. Different kinds of trauma in the dental region, such as fractures, surgical procedures on the jaw, and extraction of the preceding primary tooth are mentioned in the literature, as reviewed by Arte. [18] Furthermore, Vastardis H. [46] reported that dental agenesis in association with other developmental abnormalities may occur because of syphilis, scarlet fever, rickets or nutritional disorders during pregnancy or childhood that act in the early stages of a developmental process. Besides, the authors emphasized the effects of cranial irradiation on endocrine function and tooth development.
Tooth agenesis is diagnosed by intraoral examination (teeth did not erupt), radiographic assessment of oral cavity (no visible mineralization), and a detailed dental history to rule out extractions and trauma. Unusual spacing in a child’s dentition should lead the parent or dentist to suspect tooth agenesis. Occasionally, tooth agenesis could be a clinical sign of a possible underlying syndrome and not only an isolated disease. Referrals to genetic specialists should be considered if a dentist suspects a patient is affected with tooth agenesis.
Using genetic testing, it is possible to screen or diagnose a patient and make a precise etiological diagnosis. Tooth agenesis may occur without a family history, although it is often familial. Monogenic forms of tooth agenesis have a strong genetic component and genetic testing has usually a confirmatory role. The known mutations in some genes can be screened for early signs of developing problems and identification of the individuals at risk.
The analysis is available for genes involved in both syndromic and non-syndromic forms of tooth agenesis, but the test is expensive, and it is not always covered by health insurance.
Known genotype–phenotype correlations can be used for mutation detection. Clinical features in tooth agenesis might be predictive of underlying genotype. For example, if specific teeth are missing, such as maxillary first premolars associated with MSX1 mutations or lateral incisors associated with WNT10B mutations, tooth agenesis pattern gives clue to the most appropriate genetic tests to follow. Genetic testing panel for selective tooth agenesis analyses changes in nine genes at once. Looking for tooth agenesis-associated gene mutations, MSX1, PAX9, WNT10A, LRP6, EDA, WNT10B cause non-syndromic selective tooth agenesis, AXIN2 causes oligodontia-colorectal cancer syndrome, LTBP3 causes dental anomalies and short stature, and PTH1R causes primary failure of tooth eruption.
http://ctgt.net/panel/oligodontia-selective-tooth-agenesis-ngs-panel
Combining the clinical features with genetic data is possible to increase precision in diagnosis, assess prognosis, and prediction of treatment response, provide information for healthcare management and family planning. Genetic counseling is indicated if an individual has a positive family history. For example, Boogaard et al. [43] consider that by including WNTA10A in the DNA diagnostics of isolated tooth agenesis, the yield of molecular testing in this condition was significantly increased from 15% to 71%.
Several dental anomalies have been reported in association with congenitally missing teeth. Tooth number reduction is frequently associated with a reduction in tooth size of (microdontia), altered crown morphology (molars with fewer cusps), short-rooted teeth, and enlarged tooth body and pulp chamber (taurodontic molar). The fusion of primary teeth is often followed by hypodontia in the permanent successors.
Clefting, or an aberrant space between normally fused tissues, usually occurs as either cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO). Whether cases of clefts with dental anomalies should be considered isolated or syndromic cleft can be debated. However, the co-occurrence of cleft lip/palate and tooth agenesis is sometimes described as CL/P-hypodontia syndrome. Arte [18] described hypodontia as a very common anomaly in patients with oral and facial clefts. More studies analyzed tooth agenesis patterns in unilateral/bilateral, complete/incomplete, CL, CL/P or CPO, inside or outside the cleft region.
Published data show that tooth agenesis is more frequently observed in patients with cleft lip and palate (CLP) or their unaffected sisters and brother than in the general population because of close relationship between tooth and cleft formation with respect to the critical time of development and anatomical position. [66, 67, 68, 69] Bartzela et al. reported a higher prevalence of dental anomalies in people with cleft lip and palate than in the non-cleft population, even outside of the cleft region. They studied tooth agenesia patterns in human unilateral and bilateral cleft lip and palate and identified more than 50 different patterns of missing teeth. The most common pattern involved maxillary lateral incisors, and maxillary and mandibular second premolars. The frequency of tooth anomalies seems to be related to the severity of the cleft type. The prevalence of missing teeth reaches 100% in patients with the most severe type of isolated cleft, such as complete bilateral mixed clefting phenotype.
The prevalence of tooth agenesis in people complete unilateral cleft lip and palate has been reported within a range of 48.8% to 75.9% inside the cleft area. The prevalence outside the cleft region was found to be between 27.2% and 48.8%. [66] when compared with the prevalence of tooth agenesis in general population, which ranges between 3.2% to 7.6%, the prevalence of tooth agenesis in non-affected siblings of cleft lip and palate patients was found to be 11.1% outside the cleft area. [11, 70]
The high prevalence of missing teeth outside of cleft region suggests the common genetic background for both tooth agenesis and clefts. So, odontogenesis and palate formation are developmentally related events, and one gene or few genes, might be involved in both processes, in common genetic pathways. Other studies reported no absence of permanent teeth in the maxillary arch outside the cleft (distal to the canines) in unoperated patients with cleft, suggesting that the surgical procedure done to close palatal clefts disrupts the formation of the developing tooth buds, as reviewed by Slayton et al. [68]
Slayton et al. provided an overview of published data related to similar genetic component for non-syndromic simultaneous presence of both orofacial clefts and hypodontia. The combined phenotype of tooth agenesis with orofacial clefts outside the cleft region was described in both humans and animal models and provide evidence to support a common genetic etiology. Mouse knockout models for deficiency of MSX1 and PAX9 failed to form teeth and had cleft palate. [68]
Few monogenic disorders, such as Van der Woude syndrome (caused by mutation in the IRF6 gene - interferon regulatory factor 6), ectrodactyly-ectodermal dysplasia-clefting syndrome 3 (caused by mutation in the TP63 gene - tumor protein p63), and Kallmann’s syndrome (caused by mutation in the FGFR1 gene - fibroblast growth factor receptor 1) have both clefting and hypodontia as typical phenotypic findings. (Table A1) It should be pointed out that the same gene, IRF6 (interferon regulatory factor 6) may cause a disease as rare as Van der Woude syndrome and also to contribute to much more common defects, such as isolated cleft with or without cleft palate. [71]
Primary failure of tooth eruption (OMIM 125350) was reported in association with hypodontia. The most affected teeth are first, and second molars and involvement can be unilateral or bilateral. Based on family studies, the reported pattern of inheritance was consistent with autosomal dominant ones and molecular cause involved mutation of PTHR1 gene (parathyroid hormone 1 receptor) located on 3p21.31 [72]. Regarding permanent dentition, delayed development of posterior permanent teeth in association with the third molar agenesis was reported in the literature, as reviewed by Nieminen [3]. An average delay of two years was observed, with great variation, in a group of 85 patients with agenesis of on the average seven permanent teeth. It was also reported excessive retardation of development of teeth contralateral to missing teeth. Schalk-van der Weide [25] reported a tendency of early developing teeth of males to be retarded in association with severe agenesis, and in females with severe agenesis second mandibular molars to be significantly delayed in development (only mandibular teeth were studied). The delay correlated with the extent of agenesis was most prominent in positions next to the teeth that had failed to develop.
In population studies the relationship of tooth agenesis and microdontia has been shown to be statistically significant. Microdont teeth is small enough to be outside the usual limit of variation and along with the reduction in size, these teeth often exhibit a change in shape. Microdont teeth may be either usual form or with tapering (peg or conical) crowns (Figure 8). The most common form of microdontia is localized type, affecting maxillary incisors. Peg maxillary lateral incisors are seen in 1.2 to 3.2% of general population. This is a genetic trait which is manifest as either peg or missing maxillary lateral incisors. The microdont teeth show an autosomal dominant inheritance pattern and variable expressivity. Some studies reported families in which both genitors have pegged permanent maxillary lateral incisors. Their children had severe tooth agenesis involving primarily agenesis of succedaneous permanent teeth. It was suggested that children expressed the gene mutation in homozygous status. Some studies reported a 2:1 preference for the left side. In addition, reduced tooth sizes have also been observed within the healthy relatives of patients with severe tooth agenesis [3]. Baccetti [73] reported a significant reciprocal association between agenesis of second premolars and reduced upper lateral incisors. Third molar agenesis was associated with reduction in the cusp number of the molars, as reviewed by Arte. [18] The association of microdontia and tooth agenesis is frequently observed in Down syndrome and various types of ectodermal dysplasia. Generalized microdontia of all teeth is extremely rare in people without some sort of syndrome.
Tooth agenesis in a down syndrome male patient, aged 8 years old. (1–3) intraoral evaluation shows the absence of the right lateral incisors both in the upper and lower arches. (4) the panoramic radiograph confirms the agenesis of maxillary right lateral incisor which is associated to a peg-shaped in the contralateral quadrant. Moreover, agenesis of the lower right lateral incisor is also revealed together with a hypotaurodontism in all four first molars. * position of the missing teeth.
Abnormal positions, or ectopic placement, of teeth (OMIM 189490) are believed to result from a disturbance of the tooth developmental structure. Various forms of the position or eruption disturbance of teeth tend to be associated with tooth agenesis. Differences in frequencies of the abnormal trait between population groups have been observed, as well as differences in the pattern of associations among displaced maxillary canines (a typical type of malposition of canines) and tooth agenesis.
Pirinen et al. [74] studied the palatal displacement of the canine in regard to congenital absence of permanent teeth in 106 Finnish probands and their first- and second-degree relatives. All the probands had had surgical and orthodontic treatment for displaced maxillary canines. Incisor-premolar hypodontia and peg-shaped incisors were found to be strongly associated with palatally displaced canines. The authors concluded that palatally displaced canine belongs to a spectrum of dental anomalies related to incisor-premolar hypodontia.
Peck et al. reported a strong association of displaced maxillary canines with third molar agenesis and second premolar agenesis, whereas upper lateral incisor agenesis was not significantly interrelated [75]. Garib et al. reported an increased occurrence of displaced maxillary canines associated with second premolars agenesis [76]. Lagana et al. concluded that only the agenesis of maxillary lateral incisors should be considered directly connected with displaced maxillary canine. [77]
Taurodontism (OMIM 272700) is characterized by large pulp chambers, with changes usually most striking in the molars. The taurodont tooth lies deep in alveolar bone. Taurodont teeth are associated with missing teeth in chromosome aneuploydies, such as Down syndrome (Figure 9). It occurs also in other syndromes, especially those having an ectodermal defect, e.g., otodental dysplasia. A family having affected sibs with a combination of sparse hair, oligodontia, and taurodontism was reported in the literature. [78]
Multiple tooth agenesis in an 8-year-old male patient with down syndrome. (1,2,3) examination of the dental arches reveals a mixed dentition, with a delayed tooth eruption pattern. (4) panoramic radiograph showing the absence of both the lateral incisors in the maxillary arch and the agenesis of the lower right lateral incisor and the left central incisor. Moreover, the agenesis is associated with mesotaurodont first molars in both upper and lower arches * position of the missing teeth.
It has been documented by Baccetti T. [73] that rotation of premolars is significantly associated with missing upper lateral incisors. The author found a significant association between unilateral agenesis of upper lateral incisors and rotation of the lateral incisor on the other side of the dental arch, and between unilateral agenesia of premolars and rotation of premolars on the other side of the arch.
The finding that there is a significant association between enamel hypoplasia and hypodontia not involving systemic syndromes has been reported by Baccetti T. [73] and Lai et al. [79] It may indicate a common genetic origin for both dental anomalies. However, it also is possible that a single or concurrent environmental factor may have been responsible for the etiology of both defects. Some authors have noted that local infection, as well as radiation, may cause both hypodontia and enamel hypoplasia, as review by Lai et al. [79]
Concomitant hypo-hyperdontia (CHH) is a rare mixed numeric dental anomaly characterized by congenitally missing teeth and supernumerary teeth occurring in the same individual. These two conditions are considered as the opposite extremes in the development of the dentition. [80] The prevalence of CHH was found to range from 0.002 to 0.7%. Due to its rarity and sporadicity, the causes of CHH have been completely unknown. So far, only 80 cases have been reported in the literature. Wang et al. summarized prior research and concluded that more than two-thirds of cases had one supernumerary tooth, and the remaining, two or more teeth. The most commonly supernumerary tooth was mesiodens. Most frequently missing teeth were upper lateral incisors, lower incisors, and premolars. Only a few cases had canines and molars agenesis. Both jaws were affected, bimaxillary hypo-hyperdontia, in about three fourth of the cases. The remaining one-fourth presented maxillary hypo-hyperdontia, the only maxilla being involved. [81]. In most cases, CHH was diagnosed during a regular dental examination. Recently, Wang et al. [81] presented 21 cases of CHH, including 4 familial cases and a syndromic case, and scrutinized their dental phenotypes. Their study results indicated molar taurodontism as the most frequently (29%) observed concurrent dental anomaly of CHH. They also described the fusion of primary lower lateral incisors and canines followed by missing permanent lower laterals. More results described the central cusps of premolars identifiable from the panoramic radiograph of 3 cases. Only one case presented macrodontia of tooth number 9 (upper left central incisor), a premaxillary supernumerary toothand missing tooth number 10 (upper left lateral incisor). The authors concluded,” these concurrent dental aberrations suggested that molecular and cellular mechanisms regulating tooth number also play significant roles in tooth morphogenesis”.
Tooth agenesis has a high prevalence in human population. It was documented that missing tooth has a negative impact on daily quality of life causing significant complications, such as physical appearance problems, oral functional limitations, or psychosocial distress, and cost not only for the affected individual but also for the public health care system worldwide. Early diagnosis is still the best way to prevent complications of missing teeth but understanding the genetic make-up of affected individuals, the dentist must integrate the tools of genetics in the dental practice for prediction, prevention, and personalized dental therapy.
The authors declare no conflict of interest.
Syndrome name and prevalence | Tooth agenesis - levels of severity | Associated phenotypic features by region | Genetic cause | Inheritance | OMIM Orpha-code |
---|---|---|---|---|---|
ADULT syndrome <1/1,000,000 | associated dental anomalies: small teeth, dysplastic teeth, premature loss of secondary teeth (<25 years) | • Lacrimal duct obstruction • Conjunctivitis • Breast hypoplasia • Mammary gland hypoplasia • Widely spaced nipples • Absent nipples • Hypoplastic nipples • Ectrodactyly • Syndactyly • Ectodermal dysplasia • Atrophic skin • Thin skin • Dry skin • Freckling • Photosensitive skin • Dermatitis • Adermatoglyphia • Dysplastic nails • Nail pits • Blond hair • Thin scalp hair • Sparse axillary hair • Premature scalp hair loss (>30 years) | mutations of TP63 gene (tumor protein p63) 3q28 | AD | 103285 978 |
Axenfeld-Rieger syndrome, type 1 1/200,000 | • Maxillary hypoplasia • Short philtrum • Prominent supraorbital ridges • Iris dysplasia (goniodysgenesis) • Iris hypoplasia • Prominent Schwalbe line (posterior embryotoxon) • Glaucoma • Displaced pupils • Dyscoria • Polycoria • Aniridia • Microcornea • Megalocornea • Strabismus • Broad nasal bridge • Thin upper lip • Umbilical defect (redundant periumbilical skin) • Imperforate anus • Anal stenosis • Hypospadias • Growth hormone deficiency | mutations of PITX2 (paired-like homeodomain transcription factor 2) 4q25 | AD Genetic heterogeneity Variable expressivity | 180500 782 | |
Ectodermal dysplasia 3, Witkop type 1–2/10,000 | Normal to small primary teeth Partial to total absence of permanent teeth ( | • Normal facies • Lip eversion • Normal sweat glands • Thin, small friable nails • Koilonychia • Longitudinal ridging • Nail pits • Toenails often more affected than fingernails • Nail changes improve with age • Normal hair | mutations of MSX1 (muscle segment homeobox 1) 4p16.1 | AD | 189500 2228 |
Ectrodactyly, Ectodermal Dysplasia, and cleft lip/palate syndrome 3; EEC type 3 1–9/100.000 | Microdontia Caries | • Maxillary hypoplasia • Malar hypoplasia • Hearing loss • Small ears • Malformed auricles • Blue irides • Photophobia • Blepharophimosis • Blepharitis • Dacryocystitis • Lacrimal duct abnormalities • Flat nasal tip • Cleft lip • Cleft palate • Xerostomia • Absence of Stensen duct • Growth hormone deficiency • Hypogonadotropic hypogonadism • Central diabetes insipidus | mutations of TP63 3q28 | AD | 604292 1896 |
Hypohidrotic ectodermal dysplasia 1 (XHED) or Christ-Siemens-Touraine syndrome 1/15,000 (1/50,000 to 1/100,000 male births) | Microdontia Conical teeth Taurodontism | • Small cranial length • Frontal bossing • Hypoplastic maxilla • Small chin • Small facial height • Prominent supraorbital ridges • Periorbital wrinkles • Periorbital hyperpigmentation • Absent tears • Absent miebomian glands • Scant-absent eyebrows • Scant-absent eyelashes • Small nose • Hypoplastic alae nasi • Nasal mucosa atrophy • Ozena • Depressed nasal root and bridge (‘saddle nose’) • Decreased palatal depth • Prominent lips • Respiratory difficulties • Atrophic rhinitis • Atrophic pharyngeal mucosa • Hypoplastic or absent mucous glands which may lead to dried secretions and obstruction • Atrophic mucosa causing dysphonia • Hypoplastic-absent mammary glands • Hypoplastic-absent nipples • Hypohidrosis • Anhidrosis • Sweat pore aplasia • Soft, thin skin • Dry skin • Mild localized pigmentation abnormalities • Skin peeling/scaling (newborn) • Eczema • Periorbital wrinkling • Periorbital hyperpigmentation • Hypoplastic-absent sebaceous glands • Hypoplastic-absent eccrine sweat glands • Spoon-shaped nails • Hypotrichosis • Fine, brittle hair • Scanty hair • Absent or scanty eyelashes • Absent or scanty eyebrows • Blonde, fine scalp hair • Hoarse voice due to dry laryngeal mucosa • Intolerance to heat and fevers • Susceptible to hyperthermia | mutations of EDA (ectrodysplasin A) Xq13.1 | X-linked recessive Xq13.1 Heterozygous females show variable expressivity (mild to severe manifestations) including hypodontia, conical teeth, reduction in scalp/body hair, and difficulty nursing | 305100 238468 |
Kallmann syndrome 2 hypogonado-tropic hypogonadism 2 with or without anosmia; HH2 1/8,000 males and 1/40,000 females, but is probably underestimated. | (in some patients) | • Hearing loss, unilateral (rare) • Iris coloboma (rare) • Hyposmia/anosmia (in some patients) • Absence of nasal cartilage, unilateral (rare) • Cleft lip • Cleft palate • Osteopenia (in some patients) • Clinodactyly (rare) • Fusion of fourth and fifth metacarpal bones (rare) • Ectrodactyly (rare) • Ectrodactyly (rare) • Hypogonadotropic hypogonadism • Delayed or absent puberty • Low to undetectable gonadotropin levels • Low testosterone level • Low estradiol level • Micropenis • Cryptorchidism • Primary amenorrhea | mutation of FGFR1 (fibroblast growth factor receptor 1) 8p11.23 | AD | 147950 478 |
KBG syndrome unkown prevalence | Associated dental anomalies: macrodontia of the upper central incisors, wide upper central incisors, ridged teeth, fused incisors | • microcephaly • round face early in life • triangular face later in life • long philtrum • large prominent ears • hypertelorism • telecanthus • long palpebral fissures • broad bushy eyebrows • anteverted nares • hypoplastic alae nasi • cervical rib fusion • accessory cervical ribs • cryptorchidism • delayed bone maturation • vertebral body fusion • vertebral arch abnormalities • thoracic kyphosis • clinodactyly • decreased hand length • syndactyly • simian crease • broad bushy eyebrows • low anterior hairline • low posterior hairline • developmental delay • mental retardation • eeg anomalies (in some patients) • seizures (in some patients) | ankrd11 (ankyrin repeat-containing cofactor 1) 16q24.3 | AD | 148050 2332 |
1/50,000 – 1/250,000 | Dental caries Anomalous anterior teeth Enamel hypoplasia Supernumerary teeth | • Microcephaly • Frontal bossing • Facial asymmetry • Microretrognathia • Hypoplasia of the malar bones • Low-set ears • Hearing loss • Epicanthus • Hypertelorism • Telecanthus • Downslanting palpebral fissures • Broad nasal bridge • Hypoplastic alar cartilage • Hyperplastic oral frenuli • Buccal frenuli • Median cleft lip (in 45% of patients) • Pseudocleft of the upper lip • Lobulated tongue (30–45%) • Bifid tongue (30–45%) • Tongue nodule • Cleft palate • Tongue hamartoma (70%) • High-arched palate • Thickened alveolar ridges • Irregular margin of the lips • Cardiac anomalies • Fibrocystic liver (45%) • Dilatation and beading of the intrahepatic bile ducts • Hepatic fibrosis • Pancreatic cysts (29%) • Ovarian cysts • Adult onset polycystic kidney (50%) • Abnormalities of the fingers (45%) • Clinodactyly • Syndactyly • Brachydactyly • Polydactyly, preaxial or postaxial (rare) • X-ray shows irregular pattern of radiolucency and/or spicule-like formation in metacarpals and phalanges • Abnormalities of the toes (25%) • Duplication of the hallux • Polydactyly, preaxial or postaxial (rare) • Milia of upper face and ears (infancy) • Dry scalp • Dry, rough, sparse hair • Alopecia • Variable mental retardation (40%) • Central nervous system malformations (40%) • Abnormal gyrations • Absence of corpus callosum • Gray matter heterotopias • Myelomeningocele (rare) • Stenosis of the aqueduct of Sylvius (rare) • Hydrocephalus • Arachnoid cysts • Cerebellar abnormalities • Seizures • Hypothalamic hamartoma • Porencephaly • Major depression (rare) • Abnormal liver enzymes in those with hepatic cysts or fibrosis • Proteinuria in those with cystic kidneys | mutations of OFD1 gene Xp22.2 | X-linked DOMINANT Xp22.2 (usually lethal in males) | 311200 2750 |
Van der Woude syndrome 1 (VWS1) 1/35,000 – 1/100,000 | • Lower lip pits • Cleft lip • Cleft palate • Cleft uvula | mutations of IRF6 gene (interferon regulatory factor 6) 1q32.2 | AD | 119300 888 |
Tooth agenesis associated frequent in genetic syndromes based on OMIM database.
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