Ehlers-Danlos Syndrome, Spondylodysplastic Type, 1

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2019-09-22
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A number sign (#) is used with this entry because Ehlers-Danlos syndrome spondylodysplastic type 1 (EDSSPD1) is caused by homozygous or compound heterozygous mutation in the B4GALT7 gene (604327) on chromosome 5q35.

Description

Ehlers-Danlos syndrome spondylodysplastic type 1 is characterized by short stature, developmental anomalies of the forearm bones and elbow, and bowing of extremities, in addition to the classic stigmata of Ehlers-Danlos syndrome, including joint laxity, skin hyperextensibility, and poor wound healing. Significant developmental delay is not a consistent feature (Guo et al., 2013).

Genetic Heterogeneity of Ehlers-Danlos Syndrome, Spondylodysplastic Type

See EDSSPD2 (615349), caused by mutation in the B3GALT6 gene (615291), and EDSSPD3 (612350), caused by mutation in the SLC39A13 gene (608735).

Nomenclature

The former preferred title/symbol of this syndrome was 'Ehlers-Danlos Syndrome, Progeroid Type, 1; EDSP1.' Guo et al. (2013) tabulated the clinical features of the 4 patients with confirmed B4GALT7 deficiency and noted that a progeroid facial appearance was not strongly associated with the deficiency; they suggested that the term 'progeroid' be removed from the designation of the syndrome.

Clinical Features

Payet (1975) reported 5 unrelated children from Reunion Island who had severe short stature, with height and weight at least 4 standard deviations below the mean, as well as generalized muscular hypotonia and ligamentous laxity, with dislocations of the elbows, hips, and knees. Skin was soft, hyperextensible, and prone to infection. Dysmorphic features included a relatively small face with prominent forehead, flattened nasal bridge, large and protuberant eyes, small ears, deep nasolabial folds, small mouth, and short neck. There was also an aged appearance to the face. Teeth were poorly implanted and cavity-ridden, and 1 patient had cleft palate. Other malformations included pectus carinatum, relatively short forearms and long hands, clubfeet, and flat feet; 1 patient had cardiovascular malformations consisting of patent ductus with anomalous venous return. X-rays revealed generalized osteoporosis, early bone maturation with multiple ossification centers, and metaphyseal enlargement with diaphyseal bowing; 1 patient had C2-C3 synostosis. Payet (1975) observed that these children were outgoing and cheerful but easily irritated, with significant verbal delay. The author stated that the phenotype was most similar to that of Larsen syndrome (see 150250), but that the facial dysmorphism differed in that flattening was not the most striking characteristic, and there was no epiphyseal involvement in these patients.

Bonaventure et al. (1992) stated that the autosomal recessive disorder resembling Larsen syndrome was unusually frequent on the island of La Reunion. Among the island's 600,000 inhabitants, more than 40 affected children had been identified during the previous 20 years, giving an approximate incidence of 1 per 1,500 births, compared with the approximate frequency in France of 1 per 100,000 births. Distinguishing the patients from those originally described by Larsen et al. (1950), however, was short stature in all affected persons and an unusually severe form of the disorder. Bonaventure et al. (1992) examined 7 affected children from 3 large consanguineous pedigrees from La Reunion with multiple affected children, 2 of whom were originally described by Payet (1975) and several of whom died in early childhood. The children exhibited severe short stature, hyperextensible skin, joint laxity with multiple dislocations involving the elbows, hips, and knees, equinovarus or valgus deformity, and a characteristic facial appearance.

Hernandez et al. (1979) reported 2 unrelated male patients with what appeared to be a new variety of EDS. Mental retardation, short stature, wrinkled facies, curly and fine hair, scanty eyebrows and eyelashes, telecanthus, periodontitis, multiple nevi, pectus excavatum, and bilateral cryptorchidism were present in addition to joint hypermobility, hyperextensibility and fragility of skin, papyraceous scars, bruisability, varicose veins, and pes planus--features suggesting a form of EDS. One of the patients had mild aortic and pulmonary stenosis; this and some of the other features are reminiscent of the Noonan syndrome (163950). In both patients, paternal age was increased, suggesting de novo dominant mutation. Hernandez et al. (1986) reported clinical and histopathologic studies of 2 new cases. They emphasized the presence of progeroid facies and mild mental retardation.

Kresse et al. (1987) described a boy, aged 4 years 9 months, with what appeared to be a new variety of Ehlers-Danlos syndrome. In addition to delayed mental development, there were multiple abnormalities of connective tissue, including short stature, osteopenia of all bones and dysplasia of some, defective deciduous teeth, loose but elastic skin, delayed wound healing with the formation of thin, atrophic scars, scanty scalp hair, hypotonic muscles, and hypermobile joints. The patient lacked several characteristic features of progeria (176670) such as diminished subcutaneous fat, prominent scalp veins, generalized alopecia, and joint contractures. He also did not conform with well-defined progeroid syndromes since he lacked the severe mental deficiency and neurologic abnormalities of de Barsy syndrome (219150), the deafness and photosensitivity of Cockayne syndrome (216400), and the ocular abnormalities of Hallermann-Streiff syndrome (234100).

Topley et al. (1994) described an Emirati brother and sister with marked short stature who resembled the patients reported from La Reunion. Their first-cousin parents were unaffected. One of the sibs had diaphragmatic hernia.

Faiyaz-Ul-Haque et al. (2004) described a 2-year-old girl and her 33-year-old uncle from a large consanguineous Arab family who had features consistent with the progeroid form of Ehlers-Danlos syndrome. The affected individuals exhibited somewhat milder skin changes than those previously described: they had only slight facial wrinkling and their skin was not remarkably loose. Guo et al. (2013) reexamined these 2 patients from Qatar, who were then 15 and 43 years of age, and stated that neither patient had developed progeroid features.

Guo et al. (2013) reported a 10-year-old boy who presented at 4 months of age with bowing of forearms and marked joint flexibility. He exhibited slow growth in height and weight, remaining below the 5th centile in both, and did not respond to a trial of growth hormone therapy. Other features included skin hyperextensibility and poor wound healing. Examination at age 10 years showed proportionate short stature and soft, velvety, hyperextensible skin, without wrinkles. He had a prominent venous pattern on his chest. Skeletal features included mild pectus carinatum, bilateral elbow contractures with decreased supination, hyperextension of the shoulders, wrists, fingers, and knees, varus bowing of the lower legs, marked pes planus, and long toes. Neurologic examination showed mild hypotonia, and he had mild learning disability. Radiography showed bilateral radioulnar synostoses, with posterior subluxation of the proximal radial head, shortening of the ulna, and ulnar bowing of the radial shaft. His lower legs showed mild shortening with flaring of the tibial metaphyses as well as less prominent bowing of the lower leg. In addition, there was a bulbous appearance to the distal phalangeal tufts of the hands, and his head appeared dolichocephalic.

Salter et al. (2016) studied 2 unrelated patients, a 3.5-year-old boy and 13-year-old girl with mutations in B4GALT7 (see MOLECULAR GENETICS), and compared their features to those of the 4 patients with B4GALT7 mutations reported by Kresse et al. (1987), Faiyaz-Ul-Haque et al. (2004), and Guo et al. (2013). Salter et al. (2016) stated that the 6 patients shared a clinically recognizable phenotype comprising short stature, joint hypermobility, radioulnar synostosis, osteopenia, and severe hypermetropia, as well as a common facial appearance involving a triangular face with wide forehead, narrow mouth, and proptosis. Notably, although their phenotype overlapped with that of the patients described by Hernandez et al. (1979) and Hernandez et al. (1986), the mutation-positive patients did not display the classic progressive premature aging features associated with progeria seen in the latter patients, and Salter et al. (2016) suggested that the 2 groups of patients might represent 2 separate conditions. In addition, the authors noted that the Reunion Island patients described by Payet (1975) and Bonaventure et al. (1992) exhibited large joint dislocations and other skeletal features not seen in these 6 patients, including delta phalanx, phalangeal dislocations, and advanced carpal ossification, and were not reported to have hypermetropia; Salter et al. (2016) suggested that the differences seen in the patients from the isolated white creole population of Reunion Island might be influenced by other modifier genes in that population.

Biochemical Features

Kresse et al. (1987) concluded that the abnormalities in the patient they described with Ehlers-Danlos syndrome were the result of a mutation that led to defective biosynthesis of a small proteodermatan sulfate (PDS) described by Krusius and Ruoslahti (1986). Whereas fibroblasts from the patient produced at most only traces of the PDS or PDS-like material, fibroblasts from the mother showed no abnormality in the biosynthesis and secretion of PDS. The patient's fibroblasts secreted only chain-free core protein. Skin fibroblasts of the patient converted only about half of the core protein of the small PDS to a mature glycosaminoglycan chain-bearing proteoglycan. Several possible explanations for the abnormality were proposed, including the possibility that the product of a mutant allele for the small PDS core protein has either an absent or buried recognition site for glycosaminoglycan-chain synthesis.

Quentin et al. (1990) demonstrated that fibroblasts from the patient reported by Kresse et al. (1987) had a deficiency of galactosyltransferase I (xylosylprotein 4-beta-galactosyltransferase; B4GALT7), which catalyzes the second glycosyl transfer reaction in the assembly of the dermatan sulfate chain. The glycosaminoglycan-free core protein secreted by the patient's fibroblasts had an unsubstituted xylose residue. The mutant enzyme was abnormally thermolabile. Preincubation of fibroblasts at 41 degrees C led to a further reduction in the production of mature proteoglycan and affected the capacity for glycosaminoglycan synthesis more strongly in the mutant than in control cells.

Okajima et al. (1999) demonstrated that galactosyltransferase I activity in the fibroblasts of the patient reported by Kresse et al. (1987) were reduced to a level less than one-twentieth of normal, and a moderate decrease (approximately one-half normal) was found in the parents.

Molecular Genetics

Okajima et al. (1999) and Almeida et al. (1999) independently performed mutation analysis of the B4GALT7 gene in fibroblasts from the patient reported by Kresse et al. (1987). They found that the patient was compound heterozygous for 2 mutations in the B4GALT7 gene (604327.0001-604327.0002), which were present in the mother and the father, respectively.

In 2 individuals in 2 sibships of a large consanguineous Arab family who had features consistent with a form of Ehlers-Danlos syndrome, Faiyaz-Ul-Haque et al. (2004) identified a homozygous arg270-to-cys mutation in the B4GALT7 gene (R270C; 604327.0003) that cosegregated with the disease.

In a 10-year-old boy with skin hyperextensibility, joint laxity, short stature, radioulnar synostosis, and bowing of the long bones, who had normal collagen levels and was negative for mutation in the SHOX (312865) and RMRP (157660) genes, Guo et al. (2013) performed exome sequencing and identified compound heterozygosity for missense mutations in the B4GALT7 gene: R270C and L41P (604327.0004). His unaffected parents were each heterozygous for 1 of the mutations, and an unaffected sib carried neither mutation.

In 22 patients from the 'white creole' population of Reunion Island who had short stature, hyperextensible skin, joint laxity, multiple dislocations, and distinctive but not progeroid facial features, originating from the related families previously studied by Payet (1975) and Bonaventure et al. (1992), Cartault et al. (2015) excluded mutation in the FLNB (603381), CHST3 (603799), and CANT1 (613165) genes. By exome sequencing, they identified homozygosity for the R270C mutation in the B4GALT7 gene in all 22 affected individuals; unaffected family members were heterozygous for R270C or did not carry the mutation. Analysis of 500 ethnically matched control individuals revealed no homozygotes, but the allelic frequency for the R270C variant was 2%, corresponding to a prevalence of 1 in 2,500 births. Cartault et al. (2015) suggested that phenotypic differences between these patients and those reported by Faiyaz-Ul-Haque et al. (2004), who were also homozygous for R270C, might be explained by other variants in linkage disequilibrium with B4GALT7 or by modifier genes, given the insular peopling pattern and the high level of homozygosity in the white creole population of Reunion Island.

In an unrelated boy and girl with short stature, joint hypermobility, radioulnar synostosis, and severe hypermetropia, Salter et al. (2016) performed exome sequencing of the parent-child trios and identified compound heterozygosity for mutations in the B4GALT7 gene, including R270C and another missense mutation (R141W; 604327.0005) in the girl, and a 1-bp duplication (604327.0006) and a missense mutation (C214Y; 604327.0007) in the boy. The boy had severe generalized osteopenia with low-trauma rib fractures and multiple vertebral compression fractures, and family history revealed that his mother, who was heterozygous for the C214Y mutation, also experienced multiple fractures and vertebral collapse in her thirties. However, she was of normal height and did not exhibit any other signs of galactosyltransferase-I deficiency. Salter et al. (2016) suggested that the family might have an additional factor contributing to the osteopenia and explaining the severity of that feature in the proband.

Exclusion Studies

Bonaventure et al. (1992) studied 56 unaffected members and 7 affected children from 3 families originating from the island of La Reunion with severe short stature, hyperextensible skin, joint laxity with multiple dislocations, and a characteristic facial appearance. The lod scores obtained in a pairwise study with 4 different fibrillar collagen genes, COL1A1 (120150), COL1A2 (120160), COL3A1 (120180), and COL5A2 (120190), excluded these genes as the site of the mutation. Furthermore, electrophoretic analysis of collagens derived from fibroblast cultures failed to show defective molecules.