2.1. Skeletal dysplasia
The specific clinical trait of the skeletal dysplasia is a disproportionate short stature, with associated signs such as shorter and bowed long bones, shorter ribs, polydactyly, impaired bone density and bone modelling, disorganized development of growth cartilage and ossification defects. Growth retardation is seen in some skeletal dysplasia beginning with intrauterine life or, for others, has a post‐natal onset in the first year of life or even later in some cases. The diagnosis is usually established by clinical and radiological signs. Molecular analysis for confirmation is required particularly in the situation of genetic counselling in order to evaluate a future pregnancy by pre‐natal diagnosis. Otherwise, sometimes a skeletal dysplasia can be diagnosed even for a patient with isolated short stature, apparently proportionate, whom only a radiological assessment may show the signs of dysplasia .
Skeletal dysplasia is a group of disorders, and is very heterogeneous; clinically and molecularly, more than 400 syndromes have been described, the more recent classification dividing them into 40 principal groups . Skeletal dysplasia without identified molecular bases is also identified. In the following section, the most common and molecularly well‐characterized skeletal dysplasia are presented.
2.1.1. The FGFR3‐related chondrodysplasias
The FGFR gene (4p16.3) encodes for fibroblast growth factor receptor 3 that has a main effect in the regulation of chondrocyte proliferation, differentiation and apoptosis [12, 13]. FGFR3 regulates osteogenesis and post‐natal bone mineralization by osteoblasts, the main role being in endochondral ossification [12, 13]. It has an extracellular region with three immunoglobulin‐like domains, a transmembrane domain and an intracellular region with tyrosine kinase domains. Mutations in FGFR3 gene lead to several syndromes with a phenotype more or less severe according to the affected region of the receptor, such as achondroplasia, hypochondroplasia, SADDAN syndrome (Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans) and thanatophoric dysplasia. The FGFR3 mutations responsible for these syndromes are mutations with gain of function, inducing an activation of the receptor.
It is the most known form of disproportionate short stature and has a frequency of 1:25,000 births. In achondroplasia, FGFR3 gene mutations affect the transmembrane region of the receptor . Note that 98% of cases show G1138A mutation, an additional 1% of cases presenting the G1138C mutation [15, 16]. Achondroplasia is an autosomal dominant disorder with complete penetrance. About 80% of cases occur as a result of de novo mutations, often produced in paternal gametes, usually in case of an advanced paternal age at procreation . These mutations are activating ones and affect mainly the endochondral ossification, with impact on hypertrophic cellular compartment, chondrocyte proliferation in growth cartilages and cartilage formation [12, 13].
Disproportionate short stature is a characteristic of the disease, adult height usually not exceeding 125–130 cm. The clinical picture is represented by the specific skeletal features: short rhizomelic limbs, relative macrocephaly, frontal bossing with mid‐face hypoplasia, trident hands and hyperlordosis. The patients had associated with hypotonia (at young age) and obesity (often in adults).
Hypochondroplasia is a pathology often produced by FGFR3 mutations in the extracellular or intracellular region in the proximal tyrosine kinase domain . In 70% of cases, FGFR3 mutations are described . Some authors have noticed, in some cases, the association of hypochondroplasia with IGF1 mutations . There are some cases for which genetic determinant is not yet identified. Thus, unlike the achondroplasia, the hypochondroplasia is characterised by genetic heterogeneity.
The clinical picture is that of a mild achondroplasia and is represented by disproportionate short stature with short limbs but without an obvious rhizomelia, brachydactyly affected spine by narrowing the interpediculate distance at the lumbar level . Final height is not as severely affected as in achondroplasia and is usually in the range 130–165 cm.
22.214.171.124. SADDAN syndrome
SADDAN syndrome is a severe form of achondroplasia associated with developmental delay and acanthosis nigricans, the name of syndrome being an acronym of the main clinical signs. In these disorders, a FGFR3 missense mutation Lys650Met was described, located at the distal tyrosine kinase domain . This mutation is located in the same codon as the specific mutations that produce thanatophoric dysplasia.
Patients have bone dysplasia as described in achondroplasia, but more severe are important short stature, micromelia, macrocephaly, frontal bossing, wide anterior fontanelle, mid‐face hypoplasia, bowed tibia and narrow thorax . In addition, they also have progressive acanthosis nigricans, CNS abnormalities, epilepsy and severe developmental delay . SADDAN syndrome clinically overlaps with thanatophoric dysplasia, but survival in the first one is beyond the neo‐natal period, cases with this pathology are even reported in young adulthood.
126.96.36.199. Thanatophoric dysplasia
It is the most common lethal skeletal dysplasia in the neo‐natal period. Two subtypes have been described: thanatophoric dysplasia type I, caused by mutations in the extracellular or intracellular region of FGFR3 gene, and thanatophoric dysplasia type II, which is produced by mutations at the distal tyrosine kinase domain [23, 24]. The most common mutation in type I is R248C, confirmed in about 50% of the patients . In type II, the K650E mutation is the only one reported, which is present in more than 99% of the patients [23, 24].
The two forms of thanatophoric dysplasia were divided according to the clinical picture. In type I, the clinical characteristics are the short and bowed long bones with skull normal appearance [25, 26]. In type II, the traits are represented by the cloverleaf skull with short and straight long bones . Other associated signs, common to the two types are: platyspondyly, narrow and short thorax, ventriculomegaly and polyhydramnios .
2.1.2. Disorders produced by abnormalities of collagen and other extracellular structural protein
188.8.131.52. Osteogenesis imperfecta
It occurs in 95% of cases due to COL1A1 (17q21.33) and COL1A2 (7q21.3) mutations, genes encoding α1 and α2 polypeptide chains of type I collagen . Type I collagen is the most abundant collagen found in extracellular matrix protein and it is mainly present in cartilage, bone, ligaments, tegument, dentin and sclera [28, 29]. Its role is structural, which interacts with other matrix proteins (proteoglycans or fibronectins) and with the cells by anchoring them into the matrix. A functional role was also described in signalling receptors on surface cells to regulate cell growth, motility and differentiation [28–30].
The mutations of the chains of type I collagen lead to quantitative or qualitative impairment and the clinical picture will be represented by the signs of the organs more abundant in type I collagen: bones, articulations, dentin and sclera. These signs are multiple fractures arisen usually after minor traumatisms, bone deformities, short stature, osteoporosis, joint hyperlaxity, dentinogenesis imperfecta, blues sclera, deafness and wormian bones. The skeletal impairment is secondary to osseous fragility and osteopenia. Short stature is observed usually secondary to the pathologic bone and its deformities. There are several clinical forms of osteogenesis imperfecta, with different degree of severity. In 1979, Sillence and colleagues described the four classical types of osteogenesis . The actual classification includes fifteen types, the first four being the known ones, produced by type I collagen mutations, the others being the result of different gene mutations. Type I is a mild non‐deforming form of osteogenesis imperfecta, with a blue sclera and a little or absent effect on growth. Type II is the most severe form, lethal in the peri‐natal period. The clinical picture is represented by an important osteopenia that leads to multiple fractures, secondary deformities and very short length from the intrauterine period. Type III has also a severe phenotype, but less than the type II, represented by very short stature, deformities, dentinogenesis imperfecta and blue sclera. Type IV has an intermediate severity with a mild short stature, moderate deformities after recurrent fractures, dentinogenesis imperfecta and normal sclera. If the chains of type I collagen are affected, the transmission is autosomal dominant. In 5% of cases, osteogenesis imperfecta is secondary to mutations of different genes, such as SERPINF1 (17p13.3), LEPRE1 (1p34.1), CRTAP (3p22), PPIB (15q21‐q22), SERPINH1 (11q13.5), FKBP10 (17q21.2), SP7 (12q13.13), BMP1 (8p21.3), TMEM38B (9q31.2) and WNT1 (12q13.12); these disorders having an autosomal recessive transmission, usually with a severe clinical phenotype .
184.108.40.206. Skeletal dysplasia in type II collagen abnormalities
Type II collagen is mostly found in cartilage, intervertebral disc and eye, and various mutations lead to a group of diseases that have in common the abnormalities of epiphysis, spine and eyes, which can easily be recognized by the signs in these structures . The disorders of this group of pathologies are specifically produced by different mutations of the same gene COL2A1 (12q13.11) that encodes for α1 chain of type II collagen . The majority of COL2A1 mutations were observed in the triple‐helical region of alpha 1 chain . These disorders have an autosomal dominant transmission. However, they are often produced by de novo mutations and show a great variability of clinical expression.
Achondrogenesis is one of the most severe skeletal dysplasia, with an important lethality, in foetal life or in the neo‐natal period. There are two forms that differ by the type of transmission (type I, recessive, and type II, dominant) and by the length and structure of long bones. The clinical picture is characterized by very small length, extreme micromelia, very short trunk, vertebral, skull and pelvis ossification defects, cupping metaphysis, cystic hygroma and polyhydramnios . Type II is secondary to neo‐mutations in type II collagen and is less severe than achondrogenesis type I that is produced by TRIP11 or DTDST mutations. Achondrogenesis type II is the most severe pathology of type II collagen group of disorders. Hypochondrogenesis represents a mild form of achondrogenesis type II and is also produced by mutations in type II collagen .
220.127.116.11.2. Spondyloepiphyseal dysplasia congenita
It is characterized by poor somatic growth since intrauterine life. An important associated sign is vertebral dysplasia, usually seen as platyspondyly. Other abnormalities often seen in this disorder are cleft palate, ophthalmologic abnormalities (myopia, nystagmus, cataracts and retinal detachment) and deafness. Short stature is also an important sign in the post‐natal period, the height not exceeding 130 cm, other signs of skeletal dysplasia being deformation of femoral head with a secondary coxa vara, scoliosis and impaired cervical spine . There is a significant clinical variability, the clinical spectrum including various forms of severity. The responsible mutations that occur are missense mutations that substitute bulky amino acids for glycine residues in the triple‐helical region of α1 chain of type II collagen .
18.104.22.168.3. Kniest dysplasia
Kniest dysplasia is characterized by extreme short stature, prominent joints, especially in knee, and mid‐face hypoplasia. It is also associated with myopia, deafness or cleft palate. At vertebral region, platyspondyly can be seen with vertical clefts, kyphoscoliosis or hyperlordosis . Epiphysis is generally large, especially in the knee. The femoral head is often absent due to a developmental defect of the femoral epiphysis and the iliac bones are characteristically shaped . In Kniest dysplasia, the α1 chain of type II collagen is modified by exon skipping due to splice‐site mutations in the region encoding the triple‐helical region .
22.214.171.124.4. Stickler dysplasia type I
Stickler dysplasia is characterized by genetic heterogeneity, the mutations in type II collagen or type XI collagen being responsible for this pathology. The abnormalities of type II collagen lead to Stickler dysplasia type I. The haploinsufficiency of truncation mutations that occur in the triple‐helical region of α1 chain of type II collagen is responsible for the phenotype . This syndrome also presents a clinical variability. The main clinical signs are represented by skeletal and ophthalmologic disorders (high myopia and retinal detachment), auditory abnormalities (deafness) and craniofacial dysmorphia (mid‐face hypoplasia, micrognathia, midline cleft of the face and Pierre Robin sequence) [38, 39]. The patients usually present a short stature associated with a moderate spondyloepiphyseal dysplasia . Radiologic signs are often minor, such as discreet flattening and irregularities at the epiphyseal region or a minimum platyspondyly, especially in the dorsal region. Patients associate widening joints, especially in the knee, and osteoarthritis with early onset .
126.96.36.199. Skeletal dysplasia in type IX collagen, cartilage oligomeric matrix protein (COMP) and matrilin 3 (MATN3) abnormalities
Type IX collagen, cartilage oligomeric matrix protein and matrilin 3 are components of the cartilage extracellular matrix that strongly interacts to maintain cartilage assembly and integrity [40, 41]. A mutation of one of these components modifies the secretion of the others and the common pathology produced for each gene mutation is multiple epiphyseal dysplasia (MED) . The pathogenesis is represented by the impairment of endochondral ossification due to cartilage abnormalities.
There are six types of MED produced by mutations of COMP (19p13.1) (MED type I), COL9A2 (1p32.2–33) (MED type II), COL9A3 (20q13.3) (MED type III), DTDST (5q32–33) (MED type IV), MATN3 (2p23–24) (MED type V) and COL9A1 (6q13) (MED type VI) . With the exception of MED type IV, all these disorders are transmitted in autosomal dominant manner. All these types share a common clinical picture; some particularities being observed in each type. The most specific signs of these disorders are short stature and precocious osteoarthritis. Characteristically, the patients present pain and precocious fatigability when a physical activity is initiated. The phenotypic signs are observed only post‐natally, after an apparently normal initial development. Even if the skeletal impairment is generalized, the bones of inferior limbs are more frequently involved, being often observed an angular deformation at this level, such as coxa vara, genu varum, genu valgum and valgum deformities at the distal tibia.
The mutations of α1, α2 or α3 chain of type IX collagen (COL9A1, COL9A2, COL9A3) are associated with a preponderant impairment of the knee .
In COMP mutations, the impairment of proximal femur and acetabulum is particularly observed .
In MATN3 mutations, the clinical picture is similar with that observed in COMP mutations, but less severe .
188.8.131.52. Skeletal dysplasia in type X collagen abnormalities
Type X collagen also has an important role in endochondral ossification, influencing the compartmentations of different matrix components and also the regulation of the mineralization .
184.108.40.206.1. Metaphyseal chondrodysplasia, Schmid type
It is produced by mutations of α1 chain of type X of collagen gene (COL1A10) (6q21–22.3), and the transmission of the disorder is autosomal dominant. It is characterized by moderately short stature with post‐natal onset, the size at birth being within normal limits. Radiography showed irregularities in the metaphysis of long bones. The consequence of COL10A1 mutations is the bowing and the shortening of the long bones, coxa vara being usually observed. Often, the patients may develop the spine impairment, such as mild platyspondyly or other abnormalities of the vertebral body.
220.127.116.11. Skeletal dysplasia in type XI collagen abnormalities
Type XI collagen has an important interaction with type II collagen, helping in maintaining the spacing and the architecture of the type II collagen. Two polypeptide chains, α1 and α2, contribute to the formation of type XI collagen; the genes that encode these chains being COL11A1 (1p21) and COL11A2 (6p21.3). The mutations in these genes lead to a clinical phenotype of skeletal dysplasia overlapping with that produced by type II collagen abnormalities.
18.104.22.168.1. Stickler dysplasia type II
It is the consequence of COL11A1 mutations. These mutations lead to a clinical picture similar to that described in Stickler syndrome type I (see Section 22.214.171.124.4), the main clinical signs being the consequence of skeletal, ophthalmologic and auditory impairments. However, the clinical severity is higher in terms of ophthalmologic (severe myopia, bilateral retinal detachment) and auditory (deafness) phenotypes . The craniofacial dysmorphic features that are specific for Stickler syndrome type I or II are as follows: mid‐facial hypoplasia, midline clefting and retromicrognatia (Pierre Robin syndrome). The short stature is also seen associated with hip abnormalities, such as slipped capital femoral epiphysis and mild thoracolumbar spinal abnormalities that often lead to scoliosis [47, 48]. The disease has an autosomal dominant transmission.
126.96.36.199.2. Otospondylomegaepiphyseal dysplasia (OSMED syndrome)
This dysplasia is the consequence of COL11A2 mutations and is also called non‐ocular Stickler dysplasia. The disease has an autosomal recessive transmission. Skeletal similarities with Kniest dysplasia is noticed, but without ophthalmologic involvement. However, the hearing impairment is much more important. Thus, the clinical picture is represented by sensorineural hearing loss, disproportionate short stature with micromelia, enlarged epiphyses and spine abnormalities, and dysmorphic facial features .
188.8.131.52. Sulfation disorders group
In this group of disorders, the main gene mutated is DTDST (5q32–33) that encodes for sulphate transporter SLC26A2 that influences the sulfation of proteoglycans in cartilage matrix . The pathologies of this group are autosomal recessives, in contrast to the previously presented anomalies that are characterized by autosomal dominant inheritance. The disorders produced by DTDST mutations are diastrophic dysplasia, achondrogenesis type IB, atelosteogenesis type II and MED type IV .
184.108.40.206.1. Diastrophic dysplasia
It is characterized by disproportionate growth retardation with micromelia, debuted in pre‐natal period . Progressively, after birth, multiple joint contractures occur, especially in the shoulders, elbows, hip and interphalangeal joints . At birth, the congenital club foot, the hypoplasia of the first metacarpal, thumb subluxation or cervical subluxation is also noted. Long bones are short and large . There is a progressive scoliosis. Other specific features are the cysts observed at the ear pavilion . Radiographic findings are metaphyseal widening and epiphyseal dysplasia.
220.127.116.11. Skeletal dysplasia in perlecan disorders
The perlecan is a heparan sulphate proteoglycan that acts as a co‐receptor for FGF2, thus having a role in intercellular adhesion and in promoting cells proliferation and angiogenesis. The mutations of gene encoding perlecan (PLC, 1q36–34) induce different skeletal disorders transmitted by autosomal recessive mode: dyssegmental dysplasia, Silverman‐Handmaker type; dyssegmental dysplasia, Rolland‐Desbuquois type; and Schwartz‐Jampel syndrome .
18.104.22.168.1. Dyssegmental dysplasias
They are represented by two disorders, Silverman‐Handmaker and Rolland‐Desbuquois, which are the forms of neo‐natal short‐limbed dwarfism. Both are produced by different mutations of the same gene, PLC. The Silverman‐Handmaker type is the most severe, being lethal in peri‐natal period, compared to Rolland‐Desbuquois, which is less severe . The skeletal abnormalities are represented by vertebral segmentation associated with long bones impairments that are shorter, larger and bowed . The vertebral segmentation is observed as marked differences in size and shape of vertebral bodies. A reduced joint mobility is often associated. A cleft palate as well as the encephalocele was described.
22.214.171.124.2. Schwartz‐Jampel syndrome
It is characterized by short stature, myotonic myopathy, joint contractures, pectus carinatum, kyphosis, coxa valga, myopia and blepharophimosis [55, 56]. Radiological abnormalities include platyspondyly, short long bones with metaphyseal widening, wide epiphysis of the distal femur and tibia, and fragmented capital femoral epiphysis.
126.96.36.199. Skeletal dysplasia in aggrecan disorders
The aggrecan, also known as cartilage‐specific proteoglycan core protein (CSPCP), is a chondroitin sulphate proteoglycan, the most abundant structural component in the cartilage. It leads to a normal chondroskeletal morphogenesis and it also provides a hydrated gel structure in articular cartilage that is important for its resistance . Different mutations of the gene that encodes for aggrecan, AGC1 (15q26), are responsible for different diseases: spondyloepiphyseal dysplasia, Kimberley type; spondyloepimetaphyseal and metaphyseal dysplasia, aggrecan type; and familial osteochondritis dissecans .
188.8.131.52.1. Spondyloepiphyseal dysplasia, Kimberley type
It leads to a proportionate short stature, osteoarthritis with early onset and sometimes to a craniofacial dysmorphia . It is also defined by platyspondyly, vertebral cleft, metaphyseal widening, epiphyseal irregularities and flattening of femoral epiphysis. It is an autosomal dominant pathology.
184.108.40.206. Skeletal disorders in transient receptor potential vanilloid 4 (TRPV4) abnormalities
Transient receptor potential vanilloid 4 (12q24.1) mediates calcium influx, late in osteoclast differentiation, thus influencing bone resorption . TRPV4 mutations produce not only skeletal pathologies but also non‐skeletal (such as spinal muscular atrophy, Charcot‐Marie‐Tooth disease). The skeletal disorders are transmitted in autosomal dominant mode and include metatropic dysplasia; spondyloepimetaphyseal dysplasia, Maroteaux type; spondylometaphyseal dysplasia, Kozlowski type; brachyolmia; and familial digital arthropathy with brachydactyly .
220.127.116.11.1. Metatropic dysplasia
It is a severe form of skeletal dysplasia, often lethal in the neo‐natal period, and is characterized by important disproportionate short length in newborn with micromelia, wide metaphyses, platyspondyly, severe kyphoscoliosis, iliac areas in halberd, and limitations and enlargements of the joints .
2.1.3. Defects in intracellular structural proteins
18.104.22.168. Filamin group
Although these intracellular structural proteins are expressed in all cells, it has been observed that their mutations often induce a very severe skeletal pathologic phenotype. The filamin A and B are cytoskeleton proteins, their role being structural, in signal transduction, in transport or in intracellular and extracellular communication. Their mutations lead to the absence of some bones or to joint dislocations.
22.214.171.124.1. Filamin A disorders
Mutations of filamin A gene (FLNA, Xq28) lead to dominant X‐linked disorders. These are: frontometaphyseal dysplasia, otopalatodigital syndromes type I and type II, Melnick‐Needles syndrome and terminal osseous dysplasia with pigmentary defects .
Frontometaphyseal dysplasia is characterized by skeletal dysplasia, urogenital abnormalities and deafness. Otopalatodigital syndrome type I is characterized by auricular impairment, cleft palate and mild skeletal damage. Type II shows a more pronounced skeletal clinical picture associated with multiple internal malformations (brain, heart and digestive). The Melnick‐Needles syndrome is the most severe disorder of filamin A group, being lethal, most often for intrauterine life.
126.96.36.199.2. Filamin B disorders
Mutations of filamin B gene (FLNB, 3p14.3) lead to different disorders transmitted in autosomal dominant (the majority) and recessive mode (spondylo‐carpal‐tarsal dysplasia). These disorders are atelosteogenesis type I, atelosteogenesis type III, Larsen syndrome and spondylocarpotarsal syndrome .
Many of these diseases are lethal in the early neo‐natal period. In spondylocarpotarsal syndrome, spine fusions were observed. The fusions also implied the carpal and tarsal bones. On the other hand, a hyperlaxity was observed in some joints.
2.1.4. Disorders associated with SHOX gene mutations
Short stature homeobox gene belongs to the paired homeobox family and is localized in the pseudoautosomal region 1 (PAR1) of X (Xp22) and Y (Yp11.3) chromosomes. SHOX gene is expressed in hypertrophic chondrocytes of the growth plate, having a role in regulating chondrocyte differentiation [61, 62]. The diseases associated with SHOX gene abnormalities are Leri‐Weill dyschondrosteosis (heterozygous mutations and deletions) and Langer mesomelic dysplasia (homozygous mutations). The skeletal features of Turner syndrome are also a consequence of SHOX gene haploinsufficiency. Otherwise, SHOX gene mutations were observed at 2–5% of patients with idiopathic isolated short stature [63–65].
SHOX gene is an important determinant of growth, SHOX deletions being associated with short stature and SHOX duplications with tall stature. SHOX gene is expressed in the first and second pharyngeal arches and also in elbow, radius, ulna, and wrist and in the equivalent bones of inferior limbs . Thus, the clinical picture in SHOX deficiency is represented by short stature, mesomelia with shortening and bowing of the forearms and tibia, cubitus valgus, Madelung deformity of the wrist, brachymetacarpia, brachymetatarsia, high‐arched palate, micrognathia and short neck . SHOX gene deficiency leads to a marked phenotypic variability, even for the same mutation or in the same family. The clinical picture is more expressed in females and is usually more evident in the beginning of the puberty .
188.8.131.52. Leri‐Weill dyschondrosteosis
It is the most common form of mesomelic dysplasia and is characterized by disproportionate short stature (145–155 cm) with mesomelia and Madelung deformity . There is an important clinical variability, even in the same family, the females often being more affected. Short stature is observed from the childhood, even from the first year and usually the amplitude of the growth deficiency is correlated with the degree of wrist deformity . The causes of Leri‐Weill dyschondrosteosis are heterozygous mutations or deletions of SHOX gene.
184.108.40.206. Langer mesomelic dysplasia
It is secondary to homozygous mutations of SHOX gene and the clinical picture is represented by severe short stature (‐6DS and ‐7DS) with severe abnormalities of the limbs: hypoplasia and aplasia of the ulna and fibula .
2.2. Genetic syndromes with primary effect on growth
2.2.1. Turner syndrome
The Turner syndrome is due to complete or partial loss of one of the two sex chromosomes, homogeneous or in mosaic, in a female patient. Only 50% of the cases present the classical homogeneous monosomy 45,X, the other half having X chromosome mosaicism, X chromosome structural abnormalities (deletions, ring chromosome and isochromosome) or Y chromosome abnormalities (2–5%). The phenotypic features are represented by short stature, dysmorphic syndrome, gonadal dysgenesis and internal malformations. There is a great variability of phenotypic traits, clinical spectrum including complete forms and more often partial forms, represented sometimes only by short stature.
Short stature is the most constant clinical sign, observed in up to 98% of patients [69, 70]. It is secondary to SHOX gene haploinsufficiency. The growth retardation might be seen in about half of patients beginning with pre‐natal life . In the others, the short stature will be developed usually after the age of 3–4 years, due to a diminished velocity of growth. The growth worsens progressively until 10 years and the lack of puberty growth spurt will accentuate the deficit. Finally, height will be usually between the interval 122–147 cm .
The dysmorphias include triangular face, epicanthus, down‐slanted palpebral fissure, macrostomy, high‐arched palate, dental abnormalities, micrognathia, low posterior hair insertion line ‘in trident’, pterygium colli, large thorax, cubitus valgus, short IV and/or V metacarpals, genu valgum, extremities lymphedema at birth, multiple pigmented nevi and dysplastic nails .
The puberty delay is one of the most common signs being observed in up to 95% of cases .
Most patients with Turner syndrome show a normal intellectual development, excepting those presenting ring X chromosome, who often present intellectual disability .
Cardiovascular malformations are particularly important in terms of evolution and prognosis, being found in 25–40% of cases [69, 70]. The most specific cardiac abnormalities are bicuspid aortic valve and aortic coarctation. Reno‐urinary malformations are observed in 40–60% of the cases, the most representative being horseshoe kidney, polycystic kidney, renal agenesis and duplicated collecting system .
Bone abnormalities, affecting more than 60% of patients, have a significant contribution to the external phenotype of the Turner syndrome. Typically, these patients present a lower value for upper segment/lower segment ratio, short neck, large thorax, scoliosis, kyphosis, cubitus valgus, Madelung deformity, congenital hip dislocation, genu valgum, and short IV and/or V metacarpal and metatarsal [63, 70].
2.2.2. Russell‐Silver syndrome
It represents a genetic pathology in which the short stature is the most specific sign. It is very heterogeneous in terms of genetic aetiology and in many cases (about 50%) with typical clinical picture, the aetiology is unknown. Note that 40% of patients present hypomethylation of imprinting centre 1 (IC1) (H19, 11p15) [73, 74]. This hypomethylation could occur by epigenetic mechanisms or by duplications of maternal chromosome in 11p15 region. About 10% of patients present maternal uniparental disomy of chromosome 7 . There were reported cases with 17q25 translocations, ring chromosome 2 or other structural abnormalities of 1, 15 or X chromosomes that also had a clinical phenotype of Russell‐Silver syndrome [75–77].
The clinical picture is specifically represented by intrauterine growth retardation without catch‐up growth in the first year of life . This deficit is maintained or it gets even worse over time, the adult height being lower than ‐3DS for average height. At birth, the weight is more impaired than height. The head circumference is normal for age, being in contrast with a lower height, thus the patient has an appearance of macrocephaly. The craniofacial dysmorphias include triangular face, high forehead, micrognathia and down‐slanted oral commissures. The limbs are often asymmetrical and a clinodactyly or a camptodactyly of one (fifth finger) or more fingers can be frequently observed. Eating difficulties in infancy, fasting hypoglycemia in infancy and childhood, global developmental delay and cognitive impairments (at about 50% of patients) were also observed. Bone age is retarded, and the radiography also shows a hypoplasia of middle phalanx of fifth finger, which give the appearance of clinodactyly (observed in up to 80% of patients). Sometimes, the patients associate urogenital (hypospadias) or cardiovascular malformations.
2.2.3. Noonan syndrome
This syndrome is very heterogeneous as aetiology, and usually, all the gene mutations described are acting on the signal transduction pathway RAS/RAF/MEK/ERK that has a role in regulating cell growth. About 50% of patients have mutations in PTPN11 gene . An additional percentage of 30% shows mutations in SOS1 gene and RAF1 gene. Other gene mutations that lead to Noonan syndrome phenotype are KRAS, NRAS, BRAF and MAP2K1 .
The characteristic features of Noonan syndrome are short stature, craniofacial dysmorphic features, cardiac malformation and thoracic deformity. Short stature has a post‐natal onset. The dysmorphias are represented by triangular face, down‐slanted palpebral fissure, hypertelorism, low‐set ears and pterygium colli. Note that 80% of patients have cardiovascular malformations. The most frequent is pulmonary artery stenosis. About 30% of patients may present hypertrophic cardiomyopathy. Thorax deformation can be pectus excavatum or pectus carinatum. The patients can associate cryptorchidism (50% of male patients), kidney abnormalities, bleeding disorders, articular hyperlaxity, lymphedema, multiple nevi, hypotonia and epilepsy. The intellectual disability is observed in about 25% of cases.
2.2.4. Cornelia de Lange syndrome
About 50% of patients with Cornelia de Lange syndrome show mutations in NIPBL gene . Rarer mutations have been described for SMC1L1, SMC3 and RAD21 genes .
It is characterized by pre‐ and post‐natal growth retardation, characteristic craniofacial dysmorphic features (narrow forehead with low hair insertion line, synophrys, nostrils anteversion, prognathism, long philtrum, thin lips and down‐slanted oral commissures) intellectual disability, upper limbs abnormalities and hypertrichosis. Male patients often present hypospadias and cryptorchidism. Cardiovascular malformations, ophthalmologic abnormalities, deafness, behaviour disorders, global developmental delay, epilepsy and ophthalmologic abnormalities were described. There is a wide phenotypic variability of the syndrome, even some cases with normal IQ have been described.
2.2.5. Rubinstein‐Taybi syndrome
This syndrome is also characterized by genetic heterogeneity: CREBBP mutation (30–50% of cases), CREBBP deletion/ duplication (10–20%), 16p13.3 deletions (including CREBBP) (below 10%) and EP300 mutation (5%) .
Clinically, it is characterized by short stature with post‐natal onset, intellectual deficiency, characteristic craniofacial dysmorphia (prominent beaked nose, downslanted palpebral fissures, upper jaw hypoplasia, high arched palate, low‐set ears, thin superior lip, microcephaly), and broad thumb with radial angulation, broad hallux, syndactyly, eating difficulties and respiratory disorders in infancy. These patients associate language retardation, hypotonia, cardiac malformations or cryptorchidism.
2.2.6. Prader‐Willi syndrome
The Prader‐Willi syndrome is the result of paternal loss of imprinted 15q11.2‐13 region. This is produced through deletions (70% of cases), uniparental maternal disomy (28%), unbalanced translocations (1%) or mutations in imprinting centre (1%) . Several genes are located in this region, whose function has been already associated with various phenotypic traits of Prader‐Willi syndrome (SNRPN gene with brain expression, P gene with oculocutaneous albinism and NDN gene with brain expression) .
Most of the clinical specific signs are due to hypothalamic impairment. The clinical presentation is variable, depending on age. Infants with Prader‐Willi syndrome show generalized hypotonia, eating difficulties, males with genital abnormalities (cryptorchidism and scrotal hypoplasia) and motor acquisition delays. After the age of 2, children progressively develop obesity due to hyperphagia. A gradually slowdown in growth, the short stature being often installed before pubertal age and accentuated thereafter by the lack of pubertal growth spurt were also noticed. Most patients also have a deficiency of GH, for which a hormonal treatment is proposed, which also ameliorate the associated metabolic abnormalities. The hypothalamic involvement also induces a hypogonadotropic hypogonadism manifested by cryptorchidism and hypospadias in males or delayed puberty in both sexes, which requires hormonal substitution therapy. Often, the intellectual deficiency is mild. Lifespan is usually influenced by the complications of morbid obesity, often seen in the patients with sleep apnoea, diabetes, atherosclerosis and cardiovascular complications.
2.2.7. Kabuki syndrome
The genes involved in Kabuki syndrome are KDM6A (Xp11.3) and KMT2D (12q13.12) .
Clinically, it is characterized by short stature with post‐natal onset, global developmental delay/intellectual disability, specific craniofacial dysmorphia (long palpebral fissures, ectropion in the third external region of the upper eyelid, sparse eyebrow in third external region, flattening of the nasal pyramid, large and prominent ears, high arched palate and cleft palate), scoliosis, fifth finger brachydactyly and persistence of finger pads. The associated skeletal abnormalities are spine anomalies, often with vertebral cleft, hip joint abnormalities and fifth finger brachydactyly. Cardiovascular malformations are associated in 50% of cases (Tetralogy of Fallot, atrial septum defects or ventricular septum defects). The characteristic craniofacial dysmorphias, post‐natal growth retardation and intellectual disability are among the cardinal manifestations of the disease.
2.2.8. Williams syndrome
Williams syndrome is secondary to recurrent deletion in 7q11.23 region comprising elastin gene (ELN).
The specific features are craniofacial dysmorphias, cardiovascular malformation, short stature, neuropsychiatric and behavioural disorders, and idiopathic hypercalcemia . Growth retardation is observed in both pre‐natal and post‐natal periods. The patients often present a delayed bone age and low levels of IGF1. Craniofacial phenotype is represented by stellate iris, periorbital oedema, flattening of nasal pyramid, short nose with anteverted nostrils, long philtrum, macrostomy, thick lips, microdontia, multiple diastema, dental malocclusion and micrognathia. The specific cardiovascular malformation is represented by supravalvular aortic stenosis, seen in more than 80% of patients. Other major arteries stenosis could also be seen. Other frequent signs are hyperacusis, thick voice, articular hyperlaxity, kyphoscoliosis and lordosis. Usually the intellectual disability is moderate, although sometimes, it can be very severe and there are also cases described with IQ in the normal range. These children are hypersociable and hyperactive with attention deficit, often characterized as having a ‘cocktail party’ personality.