MedGen

Hypophosphatasia is characterized by defective mineralization of growing or remodeling bone, with or without root-intact tooth loss, in the presence of low activity of serum and bone alkaline phosphatase. Clinical features range from stillbirth without mineralized bone at the severe end to pathologic fractures of the lower extremities in later adulthood at the mild end. While the disease spectrum is a continuum, seven clinical forms of hypophosphatasia are usually recognized based on age at diagnosis and severity of features: Perinatal (severe): characterized by pulmonary insufficiency and hypercalcemia. Perinatal (benign): prenatal skeletal manifestations that slowly resolve into one of the milder forms. Infantile: onset between birth and age six months of clinical features of rickets without elevated serum alkaline phosphatase activity. Severe childhood (juvenile): variable presenting features progressing to rickets. Mild childhood: low bone mineral density for age, increased risk of fracture, and premature loss of primary teeth with intact roots. Adult: characterized by stress fractures and pseudofractures of the lower extremities in middle age, sometimes associated with early loss of adult dentition. Odontohypophosphatasia: characterized by premature exfoliation of primary teeth and/or severe dental caries without skeletal manifestations. [from GeneReviews]

Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. [from GeneReviews]

Spondylocostal dysostosis (SCDO), defined radiographically as multiple segmentation defects of the vertebrae (M-SDV) in combination with abnormalities of the ribs, is characterized clinically by: a short trunk in proportion to height; short neck; non-progressive mild scoliosis in most affected individuals, and occasionally, more significant scoliosis. Respiratory function in neonates may be compromised by reduced size of the thorax. By age two years lung growth may improve sufficiently to support relatively normal growth and development; however, even then life-threatening complications can occur, especially pulmonary hypertension in children with severely restricted lung capacity from birth. Males with SCDO appear to be at increased risk for inguinal hernia. [from GeneReviews]

Lamb-Shaffer syndrome is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, poor expressive speech, and mild dysmorphic facial features. Additional variable skeletal abnormalities may also be present (summary by Nesbitt et al., 2015). [from OMIM]

X-linked holoprosencephaly-13 (HPE13) is a neurologic disorder characterized by midline developmental defects that mainly affect the brain and craniofacial structure. The severity and manifestations are variable: some patients may have full alobar HPE with cyclopia, whereas others have semilobar HPE or septooptic dysplasia. Dysmorphic features include microcephaly, hypotelorism, low-set ears, micrognathia, and cleft lip/palate. Patients with a more severe phenotype may die in the newborn period, whereas those with a less severe phenotype show global developmental delay. Additional variable features include congenital heart defects and vertebral anomalies. Phenotypic variability may be related to the type of mutation, X-inactivation status, and possible incomplete penetrance. The STAG2 protein is part of the multiprotein cohesin complex involved in chromatid cohesion during DNA replication and transcriptional regulation; HPE13 can thus be classified as a 'cohesinopathy' (summary by Kruszka et al., 2019). For a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100). [from OMIM]

A rare developmental anomaly, affecting primarily the anterior part of the maxilla and nasal complex. Affected individuals typically have an unusually flat, underdeveloped midface, with an abnormally short nose and flat nasal bridge, underdeveloped upper jaw, relatively protruding lower jaw and/or a ''reverse overbite'' (or class III malocclusion). Hypoplasia of distal phalanges of fingers was reported in some cases. The pathogenesis remains uncertain, most reported cases were sporadic. [from SNOMEDCT_US]

EVEN-plus syndrome (EVPLS) is characterized by prenatal-onset short stature, vertebral and epiphyseal changes, microtia, midface hypoplasia with flat nose and triangular nares, cardiac malformations, and other findings including anal atresia, hypodontia, and aplasia cutis. The features overlap those reported in patients with CODAS syndrome (600373; Royer-Bertrand et al., 2015). [from OMIM]

Sacral agenesis with vertebral anomalies (SAVA) is an autosomal recessive syndrome comprising sacral agenesis, abnormal ossification of the vertebral bodies, and a persistent notochordal canal spanning the complete vertebral column (Postma et al., 2014). [from OMIM]

Schisis (cleft or cleavage) of vertebral bodies. [from HPO]