Skeletal dysplasia, global developmental delay, and multiple congenital anomalies in a 5‐year‐old boy—Report of the second family with B3GAT3 mutation and expansion of the phenotype

Abstract

As a major component of the extracellular matrix, proteoglycans influence the mechanical properties of connective tissue and play an important role in cell-cell and cell-matrix interactions. Genetic defects of proteoglycan biosynthesis lead to multi-system disorders, often most prominently affecting the skeletal system and skin. Specific deficiencies in the enzymes involved in the biosynthesis of the linkage region between the core of the proteoglycan protein and its glycosaminoglycan side chains are known as linkeropathies. We report on a patient from a second family with a homozygous c.830 G>A (p.Arg277Gln) mutation in the B3GAT3 gene. The clinical features expand the previously reported phenotype of B3GAT3 mutations and of linkeropathies in general. This patient has short stature, facial dysmorphisms, skeletal findings, joint laxity, and cardiac manifestations similar to those previously associated with B3GAT3 mutations. However, he also has developmental delay, a visual refractory defect, dental defects, pectus carinatum, and skin abnormalities that have only been associated with linkeropathies caused by mutations in B4GALT6 and B4GALT7. He has bilateral inguinal hernias and atlanto-axial as well as atlanto-occipital instability that have not been previously associated with B3GAT3 mutations. We provide a detailed clinical report and a comparative overview of the phenotypic features of the linkeropathies caused by mutations in B3GAT3, B4GALT6 and B4GALT7.

Functional validation of novel compound heterozygous variants in B3GAT3 resulting in severe osteopenia and fractures: expanding the disease phenotype

“…Consistent with all patients reported to have B3GAT3-related disease, cmh000720 has a cardiac defects, joint laxity, dislocations, contractures, broad tips of fingers and a short neck [11, 15–17]. Our patient’s features overlap with those of a patient with severe disease associated with a homozygous G223S variant; including multiple fractures, arachnodactyly, and blue sclerae.…”

“…variant is functionally null and the p.L224Q variant has glucuronosyltransferase activity ~3% of wild-type. Both of cmh000720’s parents are healthy and no disease phenotype has been reported to date [11, 16, 17]. Consistent with the reported human phenotypes; null mice were embryonic lethal while heterozygous mice did not have a phenotype and were born at Mendelian frequencies [24].…”

“…However, these are a relatively new class of disorders, therefore it is unlikely the phenotypic spectrum has been fully recognized. Specifically, for B3GAT3 , only 7 individuals, all with homozygous missense variants have been described ranging in phenotypic severity from mild to severe, with all patients having congenital heart defects, joint hypermobility, and fractures [11, 15–17]. …”

Chondrodysplasia with multiple dislocations: comprehensive study of a series of 30 cases

“…Moreover, hand signs are insufficient to orient the diagnosis: B4GALT7 cases can have brachymesophalangy of 2-4 fingers, and show frequent phalangeal dislocations or bifid thumb, but some have no specific hand features (10,37). Cardiovascular defects are very frequent within B3GAT3 cases, but are not highly specific, as 25% of non-B3GAT3 cases of our series are showing cardiac malformations, mainly atrial or ventricular septal defects (9,34,36) (this publication). Other clinical features are more useful to the clinician: radiocubital synostosis is suggestive of B4GALT7 (10) or B3GAT3 (34) (this publication).…”

Physiology of Bone

“…These disorders include Desbuquois dysplasia 2 (#615777), progeroid EDS types 1 and 2 (#130070; #615349) (see Case 19-84) and multiple joint dislocations, short stature, craniofacial dysmorphism and congenital heart defects (previously known as AR Larsen syndrome) (#245600) ( table 1 ). Mutations in EXT1 ( * 608177) and EXT2 ( * 608210), which encode enzymes that catalyse the formation of heparan sulphate, are associated with chondrosarcoma (#215300) and hereditary multiple exostoses type 2 (#133701), while mutations in CHSY1 ( * 608183), CHST3 ( * 603799) and CHST14 ( * 608429), which encode enzymes that catalyse the formation of chondroitin and dermatan sulphates, are associated with Temtamy preaxial brachydactyly syndrome (#605282), spondyloepiphyseal dysplasia with congenital joint dislocations (#143095) and EDS musculocontractural type 1 (#601776) ( table 1 and see [22,23] ).…”