B4GALT7-related spondylodysplastic Ehlers-Danlos syndrome (ORPHA:75496)
A form of spondylodysplastic Ehlers-Danlos syndrome due to variants in B4GALT7 and characterized by short stature, variable degrees of muscle hypotonia, joint hypermobility, especially of the hands, and bowing of limbs. Additional features include the typical craniofacial gestalt (mid-face hypoplasia, round, flat face, proptosis and narrow mouth), hyperextensible skin that is soft, thin, translucent and doughy, delayed motor and/or cognitive development, characteristic radiographic findings (such as radio-ulnar synostosis, radial head subluxation or dislocation, metaphyseal flaring and osteopenia) and ocular abnormalities.
Epidemiology
To date, 34 individuals with molecularly diagnosed B4GALT7-related spondylodysplastic Ehlers-Danlos syndrome have been reported.
Clinical description
The main features in affected individuals are short stature, bowing of limbs, small joint hypermobility, hyperextensible, soft, doughy skin with delayed wound healing, and radioulnar synostosis. Facial dysmorphism includes short face with midface hypoplasia, proptosis, narrow mouth and loose skin also evident in the face. Most affected children present from infancy with delayed motor development and hypotonia; half of patients have delayed cognitive development. The most frequent skeletal anomalies are contractures or limited elbow movements, radioulnar synostosis, bowing of the ulna and radius, pes planus and osteopenia. Less frequently observed skeletal features include sagittal craniosynostosis, temporomandibular joint dislocation, scoliosis/kyphosis, vertebral coronal cleft, pectus carinatum, clavicular exostoses, patellar dislocation, hip dysplasia, bifid thumb, broad fingertips, ulnar deviation of fingers, equinovarus deformity and hallux valgus. Approximately half of the patients have ophthalmological abnormalities, such as hypermetropia, myopia, strabismus, blue sclerae, ptosis, nystagmus, glaucoma, megalocornea, iris and optic nerve coloboma, small optic nerves and cataracts. Dental anomalies include defective and discoloration of teeth. Less frequently reported features include cardiovascular anomalies (such as aortic/pulmonary stenosis and atrial septal defects) and urinogenetial defects (vesicoureteral reflux, cryptorchidism, hypogonadism, inguinal hernia) as well as hemidiaphragmatic eventration, varicose veins, lymphedema and multiple nevi. Sensorineural/conductive hearing loss and cleft palate are rarely reported.
Etiology
The disorder is due to variants of the B4GALT7 gene (5q35.3), encoding for galactosyltransferase I. This gene is responsible for the synthesis of the linker region of proteoglycans, essential components of the extracellular matrix in connective tissues.
Diagnostic methods
Diagnosis is based on clinical examination, radiological studies and molecular findings.
Differential diagnosis
Differential diagnosis includes other spondylodysplastic Ehlers-Danlos syndromes and genetic conditions with 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 multi-disciplinary approach. Specific regular follow-up is recommended based on the patient's clinical manifestations. Rehabilitation therapy must be tailored to the patient's characteristics. Musculoskeletal anomalies may require a precocious orthopedic intervention.
Prognosis
Data is limited with respect to life expectancy; whilst there is only one adult patient reported in the literature, there are currently no known reasons suspect a reduced life expectancy. Functional consequences and quality of life depend on disease severity. The pathology is not progressive.

                            Last update: 
                            December 2020


                            - Expert reviewer(s): 
                            Dr Gianluca CONTRO  - Dr Livia GARAVELLI | ITHACA*


                                * European Reference Network