SLC39A13-related spondylodysplastic Ehlers-Danlos syndrome (ORPHA:157965)
A form of spondylodysplastic Ehlers-Danlos syndrome (EDS) due to variants in the SLC39A13 gene and characterized by the presence of thin and finely wrinkled skin of the hands and feet, hypermobile distal joints, characteristic facial features (downslanting palpebral fissures, mild hypertelorism, prominent eyes with a paucity of periorbital fat, blueish sclerae, microdontia or oligodontia), muscular hypotonia, associated with significant short stature of childhood-onset, ocular findings (myopia and keratoconus) and, more rarely, vascular complications. Mild radiographic changes were observed, among which platyspondyly is a useful diagnostic feature.
Epidemiology
To date, 13 individuals with molecularly diagnosed SLC39A13-related spondylodysplastic Ehlers-Danlos syndrome, have been reported.
Clinical description
The main features in affected individuals are significant short stature of childhood-onset, characteristic facial features which may be sufficient to suggest the diagnosis (downslanting palpebral fissures, mild hypertelorism, prominent eyes with a paucity of periorbital fat, blueish/greyish sclerae, small mouth, and microdontia or oligodontia), connective tissue weakness affecting mainly the skin and peripheral joints, muscular hypotonia and a moderate skeletal dysplasia. The skin is soft, thin and finely wrinkled, especially on the hands and feet, moderately hyperelastic with bruisability and atrophic scars. Affected patients present moderate hypermobility (especially of the small joints) hands with finely wrinkled palms, thenar and hypothenar atrophy, and tapering fingers. Due to muscular hypotonia, motor development may be slightly delayed, but intelligence in reported cases is normal. Body proportions are normal and post-natal short stature seems to be more intrinsic and represents a true growth failure and not a consequence of bone dysplasia. Skeletal radiographs show mild changes, among which platyspondyly of the thoracic and lumbar spine is a useful diagnostic pointer. Other signs are the following: irregular vertebral end plates, with concave conformation, minor epimetaphyseal alterations in appendicular bones, especially of the distal ulna, diaphyseal overconstriction of radius and ulna. Bowing of limbs, pes planus and osteopenia have been described. Hypodontia and oligodontia are particular features of the disorder. Among the eye findings, myopia has been described in various patients, in addition to keratoconus, particularly dangerous due to the possibility of perforation or rupture. Vascular complications, such as varicose veins of the lower legs and cerebral hemorrhage have been described in the 2 elderly patients.
Etiology
The disorder is due to variants of the SLC39A13 gene (11p11.2), encoding for the zinc transporter protein Zrt- and Irt-like protein 13 (ZIP13) which forms a homo-dimer consisting of 8 transmembrane domains and 4 intracellular loops.
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 significant short stature of childhood-onset, joint hypermobility, and thin and finely wrinkled skin.
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. Ophthalmologic investigation should be required in all confirmed cases.
Prognosis
Whilst only 3 adult patients have been reported in the literature, data is currently limited with respect to life expectancy. Cerebral hemorrhage has been described in 2 elderly patients; however, it unclear whether this complication is related to the disease and, to date, there are no known reasons to suspect a reduced life expectancy. The functional consequences and quality of life depend on disease severity. The pathology is not progressive.

                            Last update: 
                            December 2020


                            - Expert reviewer(s): 
                            Dr Livia GARAVELLI | ITHACA* - Dr Gabriele TRIMARCHI | ITHACA*


                                * European Reference Network