B3GALT6-related spondylodysplastic Ehlers-Danlos syndrome (ORPHA:536467)
A form of spondylodysplastic Ehlers-Danlos syndrome due to variants in B3GALT6 and characterized by short stature, variable degrees of muscle hypotonia, joint hypermobility, especially of the hands, bowing of limbs and congenital or early onset, progressive kyphoscoliosis. Additional features include the typical craniofacial gestalt (prominent forehead, sparse hair, mid-face hypoplasia, blue sclerae, proptosis and abnormal dentition), hyperextensible, soft, thin, translucent and doughy skin, delayed motor and/or cognitive development, characteristic radiographic findings (spondyloepimetaphyseal dysplasia, platyspondyly, anterior beak of vertebral body, short ilia, elbow malalignment and generalized osteoporosis), joint contractures and ascending aortic aneurysm.
Epidemiology
To date, 41 individuals with molecularly diagnosed B3GALT6-related spondylodysplastic EDS, have been reported.
Clinical description
The main features are short stature, variable degrees of muscle hypotonia, joint hypermobility, bowing of limbs and congenital or early onset, progressive kyphoscoliosis. Joint hypermobility, especially of the hands and feet, and soft, doughy and hyperextensible skin are some of the most striking characteristics. Facial dysmorphism includes prominent forehead, sparse hair, mid-face hypoplasia, blue sclerae, proptosis and abnormal dentition with discoloration of teeth. Most affected children present from infancy with delayed motor development and hypotonia; half of patients have delayed cognitive development. The majority of patients display severe kyphoscoliosis, which is usually congenital or early onset and progressive. Skeletal anomalies include platyspondyly, short iliac bones and elbow dislocation. Osteopenia has been frequently reported, usually in conjunction with fractures and luxations. Less frequent skeletal anomalies include cervical spine instability, pectus carinatum/excavatum, joint contractures, radioulnar synostosis, limited elbow extension, carpal synostosis, short metacarpals, ulnar deviation of fingers, oligodactyly, hip dysplasia, epiphyseal dysplasia of femoral heads, genu valgus, pes planus, talipes equinovarus, recurrent luxation of the toes and hallux valgus. Approximately one third of the patients have ophthalmological abnormalities, such as myopia, corneal opacity, sclerocornea, blue sclerae, microcornea, glaucoma, optic nerve atrophy and retinal detachment. Cardiovascular anomalies infrequently reported include mitral valve prolapse, aortic valve stenosis and aortic root aneurysm. Other less common features include urinary defects with nephroptosis, bilateral caliceal and ureteral dilatation, laryngeal cleft, tracheomalacia, spontaneous repeated pneumothoraces, chronic respiratory insufficiency, Wilms tumor, cryptorchidism, prominent superficial veins, hypoplastic nails. There are rare reports of sensorineural and conductive hearing loss and cleft palate.
Etiology
The disorder is due to variants of the B3GALT6 gene (1p36.33), encoding for galactosyltransferase II. This gene is responsible for the synthesis of the linker region of proteoglycans, which are essential components of the extracellular matrix of connective tissues.
Diagnostic methods
Diagnosis is based on clinical examination, radiological studies and molecular findings.
Differential diagnosis
Differential diagnosis includes spondyloepimetaphyseal dysplasias (e.g due to KIF22 or EXOC6B), the other forms of spondylodysplastyic EDSs, as well as other genetic syndromes characterized by kyphoscoliosis, joint hypermobility, skin hyperextensibility and short stature.
Antenatal diagnosis
Prenatal diagnosis is possible where a known pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management requires a multidisciplinary approach. Musculoskeletal anomalies, in particular kyphoscoliosis, may require a precocious orthopedic intervention. Specific regular follow-up is recommended based on the patient's clinical manifestation. Rehabilitation therapies must be tailored to the patient's characteristics.
Prognosis
Currently, data is limited with regard to life expectancy. Whilst four cases of death in infancy have been described, there are no known reasons to suspect reduced life expectancy. Functional consequences and quality of life depend on disease severity.

                            Last update: 
                            December 2020


                            - Expert reviewer(s): 
                            Dr Stefano Giuseppe CARAFFI  - Dr Livia GARAVELLI | ITHACA*


                                * European Reference Network