MedGen

Holt-Oram syndrome (HOS) is characterized by upper-limb defects, congenital heart malformation, and cardiac conduction disease. Upper-limb malformations may be unilateral, bilateral/symmetric, or bilateral/asymmetric and can range from triphalangeal or absent thumb(s) to phocomelia. Other upper-limb malformations can include unequal arm length caused by aplasia or hypoplasia of the radius, fusion or anomalous development of the carpal and thenar bones, abnormal forearm pronation and supination, abnormal opposition of the thumb, sloping shoulders, and restriction of shoulder joint movement. An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. A congenital heart malformation is present in 75% of individuals with HOS and most commonly involves the septum. Atrial septal defect and ventricular septal defect can vary in number, size, and location. Complex congenital heart malformations can also occur in individuals with HOS. Individuals with HOS with or without a congenital heart malformation are at risk for cardiac conduction disease. While individuals may present at birth with sinus bradycardia and first-degree atrioventricular (AV) block, AV block can progress unpredictably to a higher grade including complete heart block with and without atrial fibrillation. [from GeneReviews]

Campomelic dysplasia (CD) is a skeletal dysplasia characterized by distinctive facies, Pierre Robin sequence with cleft palate, shortening and bowing of long bones, and clubfeet. Other findings include laryngotracheomalacia with respiratory compromise and ambiguous genitalia or normal female external genitalia in most individuals with a 46,XY karyotype. Many affected infants die in the neonatal period; additional findings identified in long-term survivors include short stature, cervical spine instability with cord compression, progressive scoliosis, and hearing impairment. [from GeneReviews]

GNPTAB-related disorders comprise the phenotypes mucolipidosis II (ML II) and mucolipidosis IIIa/ß (ML IIIa/ß), and phenotypes intermediate between ML II and ML IIIa/ß. ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. ML IIIa/ß becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. Phenotypes intermediate between ML II and ML IIIa/ß are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML IIIa/ß. [from GeneReviews]

Cleidocranial dysplasia (CCD) spectrum disorder is a skeletal dysplasia that represents a clinical continuum ranging from classic CCD (triad of delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and dental abnormalities) to mild CCD to isolated dental anomalies without the skeletal features. Most individuals come to diagnosis because they have classic features. At birth, affected individuals typically have abnormally large, wide-open fontanelles that may remain open throughout life. Clavicular hypoplasia can result in narrow, sloping shoulders that can be opposed at the midline. Moderate short stature may be observed, with most affected individuals being shorter than their unaffected sibs. Dental anomalies may include supernumerary teeth, eruption failure of the permanent teeth, and presence of the second permanent molar with the primary dentition. Individuals with CCD spectrum disorder are at increased risk of developing recurrent sinus infections, recurrent ear infections leading to conductive hearing loss, and upper-airway obstruction. Intelligence is typically normal. [from GeneReviews]

The X-linked otopalatodigital (X-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following: Otopalatodigital syndrome type 1 (OPD1). Otopalatodigital syndrome type 2 (OPD2). Frontometaphyseal dysplasia type 1 (FMD1). Melnick-Needles syndrome (MNS). Terminal osseous dysplasia with pigmentary skin defects (TODPD). In OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In OPD2, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FMD1, females are less severely affected than related affected males. Males do not experience a progressive skeletal dysplasia but may have joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. MNS in males results in perinatal lethality in all recorded cases. TODPD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the digits, pigmentary defects of the skin, and recurrent digital fibromata. [from GeneReviews]

Microcephalic osteodysplastic primordial dwarfism type II (MOPDII), the most common form of microcephalic primordial dwarfism, is characterized by extreme short stature and microcephaly along with distinctive facial features. Associated features that differentiate it from other forms of primordial dwarfism and that may necessitate treatment include: abnormal dentition, a slender bone skeletal dysplasia with hip deformity and/or scoliosis, insulin resistance / diabetes mellitus, chronic kidney disease, cardiac malformations, and global vascular disease. The latter includes neurovascular disease such as moyamoya vasculopathy and intracranial aneurysms (which can lead to strokes), coronary artery disease (which can lead to premature myocardial infarctions), and renal vascular disease. Hypertension, which is also common, can have multiple underlying causes given the complex comorbidities. [from GeneReviews]

The NSDHL-related disorders include: CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, an X-linked condition that is usually male lethal during gestation and thus predominantly affects females; and CK syndrome, an X-linked disorder that affects males. CHILD syndrome is characterized by unilateral distribution of ichthyosiform (yellow scaly) skin lesions and ipsilateral limb defects that range from shortening of the metacarpals and phalanges to absence of the entire limb. Intellect is usually normal. The ichthyosiform skin lesions are usually present at birth or in the first weeks of life; new lesions can develop in later life. Nail changes are also common. The heart, lung, and kidneys can also be involved. CK syndrome (named for the initials of the original proband) is characterized by mild to severe cognitive impairment and behavior problems (aggression, attention deficit hyperactivity disorder, and irritability). All affected males reported have developed seizures in infancy and have cerebral cortical malformations and microcephaly. All have distinctive facial features, a thin habitus, and relatively long, thin fingers and toes. Some have scoliosis and kyphosis. Strabismus is common. Optic atrophy is also reported. [from GeneReviews]

Osteoglophonic dysplasia (OGD) is characterized by rhizomelic dwarfism, nonossifying bone lesions, craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge (summary by White et al., 2005). [from OMIM]

Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is a multiple congenital anomaly syndrome characterized by typical craniofacial features and intellectual disability. Many (but not all) affected individuals have pachygyria that is predominantly frontal, wasting of the shoulder girdle muscles, and sensory impairment due to iris or retinal coloboma and/or sensorineural deafness. Intellectual disability, which is common but variable, is related to the severity of the brain malformations. Seizures, congenital heart defects, renal malformations, and gastrointestinal dysfunction are also common. [from GeneReviews]

Ulnar-mammary syndrome (UMS) is an autosomal dominant disorder characterized by posterior limb deficiencies or duplications, apocrine/mammary gland hypoplasia and/or dysfunction, abnormal dentition, delayed puberty in males, and genital anomalies (Bamshad et al., 1996). [from OMIM]

Fibrochondrogenesis is a severe, autosomal recessive, short-limbed skeletal dysplasia clinically characterized by a flat midface with a small nose and anteverted nares, significant shortening of all limb segments but relatively normal hands and feet, and a small bell-shaped thorax with a protuberant abdomen. Radiographically, the long bones are short and have broad metaphyseal ends, giving them a dumb-bell shape. The vertebral bodies are flat and, on lateral view, have a distinctive pinched appearance, with a hypoplastic posterior end and a rounded anterior end. The ribs are typically short and wide and have metaphyseal cupping at both ends (summary by Tompson et al., 2010). Genetic Heterogeneity of Fibrochondrogenesis Fibrochondrogenesis-2 (FBCG2; 614524) is caused by mutation in the COL11A2 gene (120290) on chromosome 6p21.3. [from OMIM]

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). [from OMIM]

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). [from OMIM]

Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500). [from OMIM]

Yunis-Varon syndrome (YVS) is a severe autosomal recessive disorder characterized by skeletal defects, including cleidocranial dysplasia and digital anomalies, and severe neurologic involvement with neuronal loss. Enlarged cytoplasmic vacuoles are found in neurons, muscle, and cartilage. The disorder is usually lethal in infancy (summary by Campeau et al., 2013). [from OMIM]

Bartsocas-Papas syndrome-1 (BPS1) is an autosomal recessive disorder characterized by multiple popliteal pterygia, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and syndactyly. Early lethality is common, although survival into childhood and beyond has been reported (summary by Mitchell et al., 2012). Genetic Heterogeneity of Bartsocas-Papas Syndrome Bartsocas-Papas syndrome-2 (BPS2) is caused by mutation in the CHUK gene (600664). A less severe form of popliteal pterygium syndrome (PPS; 119500) is caused by mutation in the IRF6 gene (607199). [from OMIM]

Proteasome-associated autoinflammatory syndrome-1 (PRAAS1) is an autosomal recessive disorder characterized by early childhood onset of annular erythematous plaques on the face and extremities with subsequent development of partial lipodystrophy and laboratory evidence of immune dysregulation. More variable features include recurrent fever, severe joint contractures, muscle weakness and atrophy, hepatosplenomegaly, basal ganglia calcifications, and microcytic anemia (summary by Agarwal et al., 2010; Kitamura et al., 2011; Arima et al., 2011). This disorder encompasses Nakajo-Nishimura syndrome (NKJO); joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome); and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE). Among Japanese patients, this disorder is best described as Nakajo-Nishimura syndrome, since both Nakajo (1939) and Nishimura et al. (1950) contributed to the original phenotypic descriptions. Genetic Heterogeneity of Proteasome-Associated Autoinflammatory Syndrome See also PRAAS2 (618048), caused by mutation in the POMP gene (613386) on chromosome 13q12; PRAAS3 (617591), caused by mutation in the PSMB4 gene (602177) on chromosome 1q21; PRAAS4 (619183), caused by mutation in the PSMG2 gene (609702) on chromosome 18p11; PRAAS5 (619175), caused by mutation in the PSMB10 gene (176847) on chromosome 16q22; and PRAAS6 (620796), caused by mutation in the PSMB9 gene (177045) on chromosome 6p21. [from OMIM]

Schneckenbecken dysplasia (SHNKND) is a perinatally lethal skeletal dysplasia. The German term 'Schneckenbecken' refers to the distinctive, snail-like appearance of the ilia that results from a medial bone projection from the inner iliac margin. Other hallmarks of the disorder include thoracic hypoplasia, severe flattening of the vertebral bodies, and short, thick long bones (summary by Hiraoka et al., 2007). [from OMIM]

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

Van den Ende-Gupta syndrome (VDEGS) is an autosomal recessive disorder characterized by severe contractual arachnodactyly from birth and distinctive facial dysmorphism, including triangular face, malar hypoplasia, narrow nose, everted lips, and blepharophimosis. Skeletal anomalies include slender ribs, hooked clavicles, and dislocated radial head. There is no neurologic involvement (summary by Patel et al., 2014). [from OMIM]