Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome

Abstract

BackgroundSpondylodysplastic EDS (spEDS) is a rare connective tissue disorder that groups the phenotypes caused by biallelic B4GALT7, B3GALT6, and SLC39A13 mutations. In the 2017 EDS nosology, minimal criteria (general and gene-specific) for a clinical suspicion of spEDS have been proposed, but molecular analysis is required to reach a definite diagnosis. The majority of spEDS patients presented with short stature, skin hyperextensibility, facial dysmorphisms, peculiar radiological findings, muscle hypotonia and joint laxity and/or its complications. To date only 7 patients with β4GALT7-deficiency (spEDS-B4GALT7) have been described and their clinical data suggested that, in addition to short stature and muscle hypotonia, radioulnar synostosis, hypermetropia, and delayed cognitive development might be a hallmark of this specific type of spEDS. Additional 22 patients affected with an overlapping phenotype, i.e., Larsen of Reunion Island syndrome, all carrying a homozygous B4GALT7 mutation, are also recognized.ResultsHerein, we report on a 30-year-old Moroccan woman who fitted the minimal criteria to suspect spEDS, but lacked radioulnar synostosis and intellectual disability and presented with neurosensorial hearing loss and limb edema of lymphatic origin. Sanger sequencing of B4GALT7 was performed since the evaluation of the spEDS gene-specific minor criteria suggested this specific subtype. Mutational screening revealed the homozygous c.829G>T, p.Glu277* pathogenetic variant leading to aberrant splicing.ConclusionsOur findings expand both the clinical and mutational spectrum of this ultrarare connective tissue disorder. The comparison of the patient’s features with those of the other spEDS and Larsen of Reunion Island syndrome patients reported up to now offers future perspectives for spEDS nosology and clinical research in this field.

Genetic Burden Contributing to Extremely Low or High Bone Mineral Density in a Senior Male Population From the Osteoporotic Fractures in Men Study (MrOS)

“…Also of note, the EDS gene set showed significant associations with low BMD, which is compatible with the clinical observation that cohorts of EDS patients displayed significantly increased prevalence of vertebral fractures . Of the EDS genes we examined, SLC39A13 and B4GALT7 are known to cause spondylodysplastic EDS, where short stature and pathognomonic radiological findings were included as the diagnostic criteria . The inclusion of skeletal findings for the EDS diagnosis suggests convergence of the biological pathways regulating skeletal, tendon, ligament, and skin development.…”

“…(36)(37)(38) Of the EDS genes we examined, SLC39A13 and B4GALT7 are known to cause spondylodysplastic EDS, where short stature and pathognomonic radiological findings were included as the diagnostic criteria. (39) The inclusion of skeletal findings for the EDS diagnosis suggests convergence of the biological pathways regulating skeletal, tendon, ligament, and skin development. Interestingly, several groups have reported EDS-like phenotypes caused by classical OI genes such as COL1A1.…”

A B3GALT6 variant in patient originally described as Al‐Gazali syndrome and implicating the endoplasmic reticulum quality control in the mechanism of some β3GalT6‐pathy mutations

“…The main clinical features of this type of EDS include: characteristic craniofacial dysmorphic features, kyphoscoliosis, joint hypermobility, joint contractures, short stature, hypotonia, osteoporosis with multiple fractures, radiographic skeletal abnormalities of SMED, and intellectual disability. Furthermore, in view of the significant clinical overlap between EDS caused by B3GALT6 variants and the phenotypes caused by B4GALT7 and by SLC39A13 variants, these 3 conditions are grouped under the same clinical entity spondylodysplastic EDS in the new EDS classification . There are only 8 molecularly confirmed patients from 7 families with spEDS‐B4GALT7 reported.…”

“…The hallmark of this type of EDS is short stature, hypotonia, radio‐ulnar synostosis and intellectual disability . However, recently a patient with B4GALT7 mutation who had no radio‐ulnar synostosis or intellectual disability was reported . The third type of EDS under spEDS group is the 1 caused by variants in SLC39A13 .…”

“…5 22 However, recently a patient with B4GALT7 mutation who had no radio-ulnar synostosis or intellectual disability was reported. 23 The third type of EDS under spEDS group the other hand, the new classification of EDS is still debatable and perhaps a more "genetic" term for the classification of these phenotypes, such as B3GALT6-pathies would be more appropriate.…”