Fucosidosis is an autosomal recessive lysosomal storage disease caused by defective alpha-L-fucosidase with accumulation of fucose in the tissues. Clinical features include angiokeratoma, progressive psychomotor retardation, neurologic signs, coarse facial features, and dysostosis multiplex. Fucosidosis has been classified into 2 major types. Type 1 is characterized by rapid psychomotor regression and severe neurologic deterioration beginning at about 6 months of age, elevated sweat sodium chloride, and death within the first decade of life. Type 2 is characterized by milder psychomotor retardation and neurologic signs, the development of angiokeratoma corporis diffusum, normal sweat salinity, and longer survival (Kousseff et al., 1976).

Achondrogenesis type II (ACG2) is characterized by severe micromelic dwarfism with small chest and prominent abdomen, incomplete ossification of the vertebral bodies, and disorganization of the costochondral junction. ACG2 is an autosomal dominant trait occurring mostly as new mutations. However, somatic and germline mosaicism have been reported (summary by Comstock et al., 2010).

The term achondrogenesis has been used to characterize the most severe forms of chondrodysplasia in humans, invariably lethal before or shortly after birth. Achondrogenesis type I is a severe chondrodystrophy characterized radiographically by deficient ossification in the lumbar vertebrae and absent ossification in the sacral, pubic and ischial bones and clinically by stillbirth or early death (Maroteaux and Lamy, 1968; Langer et al., 1969). In addition to severe micromelia, there is a disproportionately large cranium due to marked edema of soft tissues. Classification of Achondrogenesis Achondrogenesis was traditionally divided into 2 types: type I (Parenti-Fraccaro) and type II (Langer-Saldino). Borochowitz et al. (1988) suggested that achondrogenesis type I of Parenti-Fraccaro should be classified into 2 distinct disorders: type IA, corresponding to the cases originally published by Houston et al. (1972) and Harris et al. (1972), and type IB (600972), corresponding to the case originally published by Fraccaro (1952). Analysis of the case reported by Parenti (1936) by Borochowitz et al. (1988) suggested the diagnosis of achondrogenesis type II, i.e., the Langer-Saldino type (200610). Type IA would be classified as lethal achondrogenesis, Houston-Harris type; type IB, lethal achondrogenesis, Fraccaro type; and type II, lethal achondrogenesis-hypochondrogenesis, Langer-Saldino type. Superti-Furga (1996) suggested that hypochondrogenesis should be considered separately from achondrogenesis type II because the phenotype can be much milder. Genetic Heterogeneity of Achondrogenesis Achondrogenesis type IB (ACG1B; 600972) is caused by mutation in the DTDST gene (606718), and achondrogenesis type II (ACG2; 200610) is caused by mutation in the COL2A1 gene (120140).

Dyggve-Melchior-Clausen disease (DMC) is an autosomal recessive disorder characterized by progressive spondyloepimetaphyseal dysplasia and impaired intellectual development. Short-trunk dwarfism and microcephaly are present, and specific radiologic appearances most likely reflect abnormalities of the growth plates, including platyspondyly with notched end plates, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small iliac wings with lacy iliac crests (summary by El Ghouzzi et al., 2003).

Paget disease of bone-5 is an autosomal recessive, juvenile-onset form of Paget disease, a disorder of the skeleton resulting from abnormal bone resorption and formation. Clinical manifestations include short stature, progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and hyperostosis with progressive deafness. There is phenotypic variability, with some patients presenting in infancy, while others present later in childhood (summary by Naot et al., 2014). For discussion of genetic heterogeneity of Paget disease of bone, see 167250.

Wolcott-Rallison syndrome is a rare autosomal recessive disorder characterized by permanent neonatal or early infancy insulin-dependent diabetes. Epiphyseal dysplasia, osteoporosis, and growth retardation develop at a later age. Other frequent multisystem manifestations include hepatic and renal dysfunction, mental retardation, and cardiovascular abnormalities (summary by Delepine et al., 2000).

The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.

Osteoporosis-pseudoglioma syndrome is a rare condition characterized by severe thinning of the bones (osteoporosis) and eye abnormalities that lead to vision loss. In people with this condition, osteoporosis is usually recognized in early childhood. It is caused by a shortage of minerals, such as calcium, in bones (decreased bone mineral density), which makes the bones brittle and prone to fracture. Affected individuals often have multiple bone fractures, including in the bones that form the spine (vertebrae). Multiple fractures can cause collapse of the affected vertebrae (compressed vertebrae), abnormal side-to-side curvature of the spine (scoliosis), short stature, and limb deformities. Decreased bone mineral density can also cause softening or thinning of the skull (craniotabes).\n\nMost affected individuals have impaired vision at birth or by early infancy and are blind by young adulthood. Vision problems are usually caused by one of several eye conditions, grouped together as pseudoglioma, that affect the light-sensitive tissue at the back of the eye (the retina), although other eye conditions have been identified in affected individuals. Pseudogliomas are so named because, on examination, the conditions resemble an eye tumor known as a retinal glioma.\n\nRarely, people with osteoporosis-pseudoglioma syndrome have additional signs or symptoms such as mild intellectual disability, weak muscle tone (hypotonia), abnormally flexible joints, or seizures.

The main clinical manifestations of chromosome 18p deletion syndrome are mental retardation, growth retardation, craniofacial dysmorphism including round face, dysplastic ears, wide mouth and dental anomalies, and abnormalities of the limbs, genitalia, brain, eyes, and heart. The round face characteristic in the neonatal period and childhood may change to a long face with linear growth of the height of the face (summary by Tsukahara et al., 2001).

While the majority of individuals with Costello syndrome share characteristic findings affecting multiple organ systems, the phenotypic spectrum is wide, ranging from a milder or attenuated phenotype to a severe phenotype with early lethal complications. Costello syndrome is typically characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; developmental delay or intellectual disability; coarse facial features (full lips, large mouth, full nasal tip); curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement including: cardiac hypertrophy (usually typical hypertrophic cardiomyopathy), congenital heart defect (usually valvar pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially chaotic atrial rhythm/multifocal atrial tachycardia or ectopic atrial tachycardia). Relative or absolute macrocephaly is typical, and postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia. Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults.

Spondyloperipheral dysplasia is a disorder that impairs bone growth. This condition is characterized by flattened bones of the spine (platyspondyly) and unusually short fingers and toes (brachydactyly), with the exception of the first (big) toes. Other skeletal abnormalities associated with spondyloperipheral dysplasia include short stature, shortened long bones of the arms and legs, exaggerated curvature of the lower back (lordosis), and an inward- and upward-turning foot (clubfoot). Additionally, some affected individuals have nearsightedness (myopia), hearing loss, and intellectual disability.

CHST3-related skeletal dysplasia is characterized by short stature of prenatal onset, joint dislocations (knees, hips, radial heads), clubfeet, and limitation of range of motion that can involve all large joints. Kyphosis and occasionally scoliosis with slight shortening of the trunk develop in childhood. Minor heart valve dysplasia has been described in several persons. Intellect and vision are normal.

Syndrome with the association of skeletal abnormalities, cutis laxa, craniostenosis, ambiguous genitalia, psychomotor retardation and facial abnormalities. So far, it has been described in two males (maternal first cousins). The mode of inheritance was suggested to be X-linked recessive.

Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is an immunoosseous dysplasia combining the typical metaphyseal and vertebral bone lesions of spondyloenchondrodysplasia (SPENCD) with immune dysfunction and neurologic involvement. The skeletal dysplasia is characterized by radiolucent and irregular spondylar and metaphyseal lesions that represent islands of chondroid tissue within bone. The vertebral bodies show dorsally accentuated platyspondyly with disturbance of ossification. Clinical abnormalities such as short stature, rhizomelic micromelia, increased lumbar lordosis, barrel chest, facial anomalies, and clumsy movements may be present (Menger et al., 1989). Central nervous system involvement includes spasticity, mental retardation, and cerebral calcifications, and immune dysregulation ranges from autoimmunity to immunodeficiency. Neurologic and autoimmune manifestations have been observed in different combinations within a single family, suggesting that this disorder may be defined by specific radiographic features but has remarkably pleiotropic manifestations (Renella et al., 2006). Briggs et al. (2016) also noted variability in skeletal, neurologic, and immune phenotypes, which was sometimes marked between members of the same family. Classification of the Enchondromatoses In their classification of the enchondromatoses, Spranger et al. (1978) called Ollier disease and Maffucci syndrome types I and II enchondromatosis, respectively; metachondromatosis (156250), type III; and spondyloenchondrodysplasia (SPENCD), also called spondyloenchondromatosis, type IV; enchondromatosis with irregular vertebral lesions, type V; and generalized enchondromatosis, type VI. Halal and Azouz (1991) added 3 tentative categories to the 6 in the classification of Spranger et al. (1978). Pansuriya et al. (2010) suggested a new classification of enchondromatosis (multiple enchondromas).

The Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome (AARRS) is a rare autosomal recessive disorder characterized by severe malformations of upper and lower limbs with severely hypoplastic pelvis and abnormal genitalia. The disorder is believed to represent a defect of dorsoventral patterning and outgrowth of limbs (summary by Kantaputra et al., 2010).

Autosomal domiant spondyloepiphyseal dysplasia tarda (autosomal dominant SEDT) is an inherited condition that affects bone growth. Signs and symptoms are generally physically apparent by puberty; however, abnormalities may be seen on X-ray at an earlier age. Affected people may have skeletal abnormalities, short stature (with a short neck and trunk, specifically), scoliosis, kyphosis, lumbar hyperlordosis (exaggerated curvature of the lower back), and early-onset progressive osteoarthritis of the hips and knees. Some cases of autosomal dominant SEDT may be caused by changes (mutations) in the COL2A1 gene. As the name suggests, the condition is inherited in an autosomal dominant manner. Treatment is based on the signs and symptoms present in each person and may include surgery and pain management strategies.

Contractures, pterygia, and spondylocarpotarsal fusion syndrome-1A (CPSFS1) is characterized by contractures of proximal and distal joints, pterygia involving the neck, axillae, elbows, and/or knees, as well as variable vertebral, carpal, and tarsal fusions and short stature. Progression of vertebral fusions has been observed, and inter- and intrafamilial variability has been reported (Carapito et al., 2016; Zieba et al., 2017; Cameron-Christie et al., 2018). An autosomal recessive form of CPSFS (CPSFS1B; 618469) is caused by compound heterozygous mutation in the MYH3 gene.

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity: OI type I, with blue sclerae (166200); perinatal lethal OI type II, also known as congenital OI (166210); OI type III, a progressively deforming form with normal sclerae (259420); and OI type IV, with normal sclerae (166220). Most forms of OI are autosomal dominant with mutations in one of the 2 genes that code for type I collagen alpha chains, COL1A1 (120150) and COL1A2 (120160). Cabral et al. (2007) described a form of autosomal recessive OI, which they designated OI type VIII, characterized by white sclerae, severe growth deficiency, extreme skeletal undermineralization, and bulbous metaphyses.

Endocrine-cerebro-osteodysplasia (ECO) syndrome is characterized by various anomalies of the endocrine, cerebral, and skeletal systems resulting in neonatal mortality.

X-linked intellectual disability-craniofacioskeletal syndrome is a rare, hereditary, syndromic intellectual disability characterized by craniofacial and skeletal abnormalities in association with mild intellectual disability in females and early postnatal lethality in males. In addition to mild cognitive impairment, females present with microcephaly, short stature, skeletal features and extra temporal lobe gyrus. In males, intrauterine growth impairment, cardiac and urogenital anomalies have been reported.

Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant chondrodysplasia characterized by disproportionate short stature (short trunk), abnormal epiphyses, and flattened vertebral bodies. Skeletal features are manifested at birth and evolve with time. Other features include myopia and/or retinal degeneration with retinal detachment and cleft palate (summary by Anderson et al., 1990).

A new form of skeletal dysplasia with manifestations of severe short stature, facial dysmorphism and characteristic radiographic findings. To date, three cases have been described, all originating from the same family. The disease results from a missense mutation affecting the C-type lectin domain of aggrecan (AGC1 gene; chromosome 15) which regulates endochondral ossification. Transmission is autosomal recessive.

Greenberg dysplasia (GRBGD), also known as hydrops-ectopic calcification-moth-eaten (HEM) skeletal dysplasia, is a rare autosomal recessive osteochondrodysplasia characterized by gross fetal hydrops, severe shortening of all long bones with a moth-eaten radiographic appearance, platyspondyly, disorganization of chondroosseous calcification, and ectopic ossification centers. It is lethal in utero. Patient fibroblasts show increased levels of cholesta-8,14-dien-3-beta-ol, suggesting a defect of sterol metabolism (summary by Konstantinidou et al., 2008). Herman (2003) reviewed the cholesterol biosynthetic pathway and 6 disorders involving enzyme defects in postsqualene cholesterol biosynthesis: Smith-Lemli-Opitz syndrome (SLOS; 270400), desmosterolosis (602398), X-linked dominant chondrodysplasia punctata (CDPX2; 302960), CHILD syndrome (308050), lathosterolosis (607330), and HEM skeletal dysplasia.

X-linked spondyloepiphyseal dysplasia tarda is a condition that impairs bone growth and occurs almost exclusively in males. The name of the condition indicates that it affects the bones of the spine (spondylo-) and the ends of long bones (epiphyses) in the arms and legs. "Tarda" indicates that signs and symptoms of this condition are not present at birth, but appear later in childhood, typically between ages 6 and 10.\n\nMales with X-linked spondyloepiphyseal dysplasia tarda have skeletal abnormalities and short stature. Affected boys grow steadily until late childhood, when their growth slows. Their adult height ranges from 4 feet 6 inches (137 cm) to 5 feet 4 inches (163 cm). Impaired growth of the spinal bones (vertebrae) primarily causes the short stature. Spinal abnormalities include flattened vertebrae (platyspondyly) with hump-shaped bulges, progressive thinning of the discs between vertebrae, and an abnormal curvature of the spine (scoliosis or kyphosis). These spinal problems also cause back pain in people with this condition. Individuals with X-linked spondyloepiphyseal dysplasia tarda have a short torso and neck, and their arms are disproportionately long compared to their height.\n\nOther skeletal features of X-linked spondyloepiphyseal dysplasia tarda include an abnormality of the hip joint that causes the upper leg bones to turn inward (coxa vara); multiple abnormalities of the epiphyses, including a short upper end of the thigh bone (femoral neck); and a broad, barrel-shaped chest. A painful joint condition called osteoarthritis that typically occurs in older adults often develops in early adulthood in people with X-linked spondyloepiphyseal dysplasia tarda and worsens over time, most often affecting the hips, knees, and shoulders.

Smith-McCort dysplasia is a rare autosomal recessive osteochondrodysplasia characterized by short trunk dwarfism with a barrel-shaped chest, rhizomelic limb shortening, and specific radiologic features including marked platyspondyly with double-humped end-plates, kyphoscoliosis, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small pelvis with a lace-like appearance of iliac crests. These clinical and radiologic features are also common to Dyggve-Melchior-Clausen syndrome (DMC; 223800), which is distinguished from SMC by the additional feature of mental retardation (summary by Dupuis et al., 2013). For a discussion of genetic heterogeneity of Smith-McCort dysplasia, see SMC1 (607326).

Any Smith-McCort dysplasia in which the cause of the disease is a mutation in the DYM gene.

Congenital myasthenic syndrome-19 (CMS19) is an autosomal recessive disorder resulting from a defect in the neuromuscular junction, causing generalized muscle weakness, exercise intolerance, and respiratory insufficiency. Patients present with hypotonia, feeding difficulties, and respiratory problems soon after birth, but the severity of the weakness and disease course is variable (summary by Logan et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).

The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes the following phenotypes: Metaphyseal dysplasia without hypotrichosis (MDWH). Cartilage-hair hypoplasia (CHH). Anauxetic dysplasia (AD). CHH-AD spectrum disorders are characterized by severe disproportionate (short-limb) short stature that is usually recognized in the newborn, and occasionally prenatally because of the short extremities. Other findings include joint hypermobility, fine silky hair, immunodeficiency, anemia, increased risk for malignancy, gastrointestinal dysfunction, and impaired spermatogenesis. The most severe phenotype, AD, has the most pronounced skeletal phenotype, may be associated with atlantoaxial subluxation in the newborn, and may include cognitive deficiency. The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family.

Osteogenesis imperfecta type XXI (OI21) is a progressively deforming disorder, characterized by multiple fractures that often occur after minor trauma. Fractures may be present at birth in some affected individuals. Patients exhibit disproportionate short stature and scoliosis, and are often wheelchair-bound by adulthood (van Dijk et al., 2020).