A number sign (#) is used with this entry because of evidence that multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects (JDSCD) is caused by homozygous or compound heterozygous mutation in the B3GAT3 gene (606374) on chromosome 11q12.

Steel and Kohl (1972) described 3 sibs with shoulder, elbow, hip, and knee dislocations and clubfeet. The hands of all 3 sibs displayed shortened metacarpals and spatulate deformity of the tuft of the thumb, the so-called 'delta phalanx;' 2 of the sibs also had multiple ossification centers in the carpal bones, resulting in subluxation of the wrist in 1 of them. These patients also demonstrated abnormal segmentation of the cervical and thoracic spine, with decreased interpedicular distance in the thoracic vertebrae. Steel and Kohl (1972) noted a 'striking resemblance' between the facies of the 3 affected sibs and the typical facial characteristics seen in Larsen syndrome (150250), despite the presence of arrested hydrocephalus in 2 of the 3 sibs. There was no mental retardation, and chromosome studies were normal.

Strisciuglio et al. (1983) reported a brother and sister, born to unaffected consanguineous parents, who had the typical features of Larsen syndrome, including facial dysmorphism, but who also had severe cardiac manifestations. Facial features included prominent forehead, depressed nasal bridge, wide-set eyes, proptosis, and blue sclerae. The sister had dislocation of the elbows, hips, and knees, supernumerary carpal bones, broad spatulate thumbs, and right clubfoot. On chest x-ray at 19 months of age, she was noted to have a globular cardiac silhouette, and a clinical diagnosis of pulmonary stenosis was made. Invasive cardiac studies were refused, and the patient died 4 months later of heart failure. Her deceased older brother had supernumerary carpal bones, bilateral knee dislocations, and right clubfoot. He was diagnosed with cyanotic congenital heart disease at 2 years of age. Three months later he was admitted to the hospital in critical condition and received a diagnosis of mitral insufficiency secondary to endocardial fibroelastosis; further studies were not performed and he died of heart failure at 2.5 years of age. Additional features in both sibs included pectus carinatum, lumbar scoliosis, and left inguinal hernia. Strisciuglio et al. (1983) suggested that the phenotype in these sibs represented a recessive form of Larsen syndrome that was more severe than the dominant form due to the frequent presence of concomitant cardiac anomalies.

Knoblauch et al. (1999) reported 2 sisters, born of unaffected first-cousin Egyptian parents, who had dysmorphic facies, bilateral hip dislocation, and clubfeet. Their facial features included prominent forehead, depressed nasal bridge, and widely spaced and protuberant eyes, and both sibs showed pseudoclubbing of fingers and deep palmar creases. The older sister had severe kyphoscoliosis and severe hyperextensibility of all joints except for the elbows, where she had impaired pronation/supination due to radioulnar synostosis. Her younger sister had mild scoliosis and milder hyperextensibility, without impaired pronation/supination of the elbow. Unlike previously described patients with presumed recessive inheritance, the sisters did not have short stature.

In the newborn offspring of consanguineous Turkish parents, Caksen and Kurtoglu (2001) found severe congenital hydrocephalus in association with multiple dislocations involving the elbows, hips, and knees, and flattened facies with depressed nasal bridge. The female infant, who also had respiratory distress at birth and developed fever and seizures in the neonatal period, died at 4 months of age from meningitis and septicemia.

Baasanjav et al. (2011) studied a consanguineous family in the United Arab Emirates in which 5 of 7 sibs had multiple joint dislocations and congenital heart defects in various combinations, including bicuspid aortic valve with dilation of the aortic root, mitral valve prolapse, patent foramen ovale, and ventricular septal defect. All affected children had short stature and presented variable craniofacial dysmorphic features: brachycephaly, thick eyebrows, large eyes with downslanting palpebral fissures, depressed nasal bridge, narrow mouth, and micrognathia or microretrognathia. The ears in some patients were small and low set, with prominent antitragus and slight uplift of the lobe. The neck was short with low posterior hairline; webbing was present in 1 sib. There was mild chest asymmetry. All affected individuals had congenital dislocations and contractures of the elbow joints as well as talipes equinovarus and/or metatarsus varus, and 1 sib also had dislocation of the shoulder and proximal radioulnar joints. Joint laxity was present in the wrists and interphalangeal joints, and the fingertips and the halluces bilaterally appeared wide. Radiographs showed dislocations of the shoulder, elbow, and proximal radioulnar joints, mild shortening of the first metacarpal bone, delayed and dissociated bone age, mild dysplasia of the hip joints, and foot deformities. The vertebral column showed signs of osteopenia; several vertebrae were already flattened. The children all had normal mental and motor development. Baasanjav et al. (2011) noted similarities between this phenotype and spondyloepiphyseal dysplasia with multiple joint dislocations (143095). However, the sibs studied by Baasanjav et al. (2011) did not show vertebral notching on radiography, and the 3 oldest affected sibs had no kyphoscoliosis or trunk shortening at ages 17, 14, and 13 years.

Von Oettingen et al. (2014) reported a 5-year-old Emirati boy, born of consanguineous parents related as first cousins through their mothers and second cousins through their fathers, who had features similar to those in the Emirati family reported by Baasanjav et al. (2011), including joint laxity and multiple dislocations, short stature, facial dysmorphism, and cardiac manifestations. Other features present in this patient included mild developmental delay; generalized cortical atrophy on brain MRI; hypertropia, esotropia, and right-sided amblyopia; small-appearing teeth with multiple cavities; asymmetric pectus carinatum with protrusion of the sternum to the right; excessive skin wrinkling of the palms and soles; bilateral inguinal hernias; and atlantoaxial and -occipital instability.

Budde et al. (2015) studied 8 affected children from 2 sibships of a large consanguineous Indonesian kindred from the island of Nias. Features in common included short stature, midface hypoplasia, rhizomelic shortening of the arms, dislocated joints, and broad ends of fingers and toes. Most patients exhibited foot deformity, with brachymetatarsia and brachymetapody, and less frequent features included depressed nasal bridge, small mouth, short webbed neck, and elbow contractures. All 4 affected children from the first sibship had some degree of kyphoscoliosis, which manifested before the age of 4 years. The 4 patients from the second sibship were more mildly affected, with less growth retardation, less pronounced involvement of hands and feet, and no kyphoscoliosis. Budde et al. (2015) noted that in contrast to the Emirati patients reported by Baasanjav et al. (2011), their patients did not have large prominent eyes, low-set or dysmorphic ears, or joint laxity, and there was no evidence of structural heart defects or conduction disturbances in the 3 patients from the first sibship who underwent cardiac evaluation.

Jones et al. (2015) reported a 1-year-old Mexican boy, born to consanguineous parents, who had femur fractures at birth and sustained approximately 25 fractures in the first year of life, in all 4 extremities and in vertebrae, some of which were incurred during routine blood pressure monitoring. He also had 11 ribs and a small thorax, which resulted in restrictive lung disease that required significant respiratory support, including periods of intubation. Features in common with previously reported patients included facial dysmorphism, with prominent forehead and eyes, hypertelorism, blue sclerae, flat nasal bridge, and small mouth, as well as short neck, bilateral radioulnar synostosis, severe osteopenia, atrial and ventricular septal defects, diaphragmatic hernia, sandal gap, and bilateral clubfeet. Additional features in the Mexican boy included bilateral glaucoma, hypertelorism, upturned nose with anteverted nares, small chest, arachnodactyly, overlapping fingers with ulnar deviation, lymphedema, hypotonia, and hearing loss. No joint dislocations were present in this patient.

Yap et al. (2016) reported 2 sibs, clinically diagnosed with pseudodiastrophic dysplasia (PDD; see 264180), whose healthy, unrelated Caucasian parents also had 2 healthy sons. The first sib was a male fetus (patient 1A) that died in utero at 16 weeks' gestation. Postmortem examination showed marked nuchal edema, cleft hard palate, and hypoplastic nares, as well as significant shortening and bowing of all long bones, more marked in the radii, ulnae, and femora. The sacrum was small with absent ossification of the pubic bones. There was platyspondyly and reduced ossification of the cervical vertebral segments. The ribs were short, but of normal morphology. The abdomen was distended and significant intestinal and genitourinary anomalies were present, including anorectal agenesis, absence of external genitalia, small and large intestinal malrotation, blind-ending large bowel attached to the dome of an enlarged bladder with no outlet, absent left kidney, and right kidney with marked reduction of nephrons and tortuous ureter. The second sib was a female (patient 1B), born at 37 weeks' gestation due to polyhydramnios. She had generalized micromelia and craniofacial dysmorphisms including midface hypoplasia, protuberant eyes with blue sclera, small anteverted nose, large fleshy earlobes, small mouth with restricted opening, cleft palate, and micrognathia. Subcutaneous edema of head, neck, and thoracic wall was evident, with short neck. The wrists were held in fixed flexion and ulnar deviation, and contractures were present at the elbows, shoulders, knees, and hips. There was severe talipes equinovarus and camptodactyly in association with hyperextensible and subluxable fingers. Ophthalmologic examination revealed bilateral anterior polar cataracts. Skeletal survey showed mild platyspondyly and thoracolumbar kyphosis, broad and flared ilia, short long bones with broadened distal metaphyses, proximal radial head dislocation, bilateral hip dislocation, and bilateral talipes equinovarus. There was marked ulnar deviation at the radiocarpal joint, and phalanges appeared broad and short, with subluxation of proximal interphalangeal (PIP) joints. No cardiac or genitourinary anomalies were present. The authors noted that the significant bowing of long bones seen on prenatal ultrasound had resolved almost completely by term. The patient developed respiratory distress and severe pulmonary hypertension, requiring intensive care and mechanical ventilation; care was withdrawn at 6 months of age.

Consanguinity and multiple affected sibs with a Larsen syndrome-like phenotype suggested autosomal recessive inheritance (Steel and Kohl, 1972; Strisciuglio et al., 1983).

Knoblauch et al. (1999) presented a presumed incidence of autosomal recessive Larsen syndrome in 2 sisters whose parents were first cousins.

In a consanguineous family segregating autosomal recessive multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defects, Baasanjav et al. (2011) performed genomewide linkage analysis and obtained a multipoint lod score of 3.76 at chromosome 11q12. Fine mapping narrowed the region to an 8-cM interval, with a final multipoint lod of 3.89.

In a large consanguineous Indonesian kindred with bone dysplasia, dislocated joints, and disproportionate short stature, Budde et al. (2015) performed a genomewide linkage scan and obtained a maximum lod score of 3.9 on chromosome 11q. Fine mapping narrowed the candidate interval to a 4.7-cM region between markers D11S4076 and D11S4178.

In a consanguineous Emirati family with multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defects mapping to chromosome 11q12, Baasanjav et al. (2011) sequenced 30 functional candidate genes and identified homozygosity for a missense mutation in the B3GAT3 gene (R277Q; 606374.0001) that segregated with disease in the family.

In a 5-year-old Emirati boy born of multiply consanguineous parents, who had joint laxity and multiple dislocations, short stature, facial dysmorphism, and cardiac anomalies, von Oettingen et al. (2014) identified homozygosity for the same R277Q mutation in the B3GAT3 gene that had been identified in an Emirati family with a similar phenotype (Baasanjav et al., 2011). Von Oettingen et al. (2014) noted that their patient exhibited additional features that expand the phenotype associated with B3GAT3 mutations, including developmental delay, refractive errors, dental defects, atlantoaxial and -occipital instability, pectus carinatum, and skin abnormalities. Because a high degree of parental consanguinity increases the risk of a comorbid autosomal recessive condition, the authors performed whole-exome sequencing, but did not detect any other pathogenic variants.

In a large consanguineous Indonesian kindred in which 8 affected individuals from 2 sibships had bone dysplasia, dislocated joints, and disproportionate short stature mapping to 11q, Budde et al. (2015) analyzed the candidate gene TBX10 (604648) but did not find any mutations. Whole-exome sequencing in an affected individual revealed homozygosity for a missense mutation in the B3GAT3 gene (P140L; 606374.0002) that segregated fully with disease in the family and was not found in 350 ethnically matched control chromosomes. Functional analysis demonstrated markedly reduced glucuronyl transferase activity and a reduction in glycosaminoglycan side chains in patient lymphoblastoid cells compared to controls. Noting that the patients from 1 sibship were more severely affected than the patients from the other sibship, Budde et al. (2015) suggested that inter-sibship differences might be due to a modifier gene influencing phenotypic expression.

In a 1-year-old Mexican boy with a severe phenotype involving multiple fractures, severe osteopenia, joint contractures, and cardiovascular anomalies, who was negative for mutation in the WNT1 (164820), B4GALT7 (604327), B3GALT6 (615291), and IFITM5 (614757) genes, Jones et al. (2015) sequenced the candidate gene B3GAT3 and identified homozygosity for a missense mutation (G223S; 606374.0003). Because this patient's phenotype was more severe than that reported for other patients with mutations in B3GAT3, the authors performed exome sequencing but did not find any additional causative mutations.

In an Australian family (family 1) originally reported by Yap et al. (2016), in which 2 sibs had shortening of all long bones, multiple joint dislocations and contractures, and dysmorphic craniofacial features, Byrne et al. (2020) performed whole-exome sequencing and identified compound heterozygosity for mutations in the B3GAT3 gene (R169W, 606374.0004 and R225X, 606374.0005) that segregated fully with disease. The sibs had been clinically diagnosed as having pseudodiastrophic dysplasia (PDD); Byrne et al. (2020) noted the extensive phenotypic similarities between PDD and JDSCD, and suggested that PDD is likely not a separate genetic disorder but rather the most severe phenotypic manifestation of skeletal dysplasias arising from defects in proteoglycan biosynthesis.

Bloch and Peck (1965) reported a family that had been cited as a possible example of a recessive form of Larsen syndrome; however, follow-up on this family by Petrella et al. (1993) demonstrated autosomal dominant inheritance.