The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers–Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases
Division of Genetic Medicine, Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland
Department of Clinical Genetics, Leiden University Medical Centre, 2333 ZA Leiden, The Netherlands
Department of Human Genetics, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The Netherlands
Clinic for Endocrinology, Diabetes & Metabolism, University Hospital Basel, 4031 Basel, Switzerland
FDNA Inc., Boston, MA 02111, USA
Author to whom correspondence should be addressed.
Genes 2020, 11(4), 420; https://doi.org/10.3390/genes11040420
Received: 2 April 2020 / Revised: 9 April 2020 / Accepted: 10 April 2020 / Published: 14 April 2020
(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Ehlers–Danlos Syndrome and Related Connective Tissue Disorders)
Recessive loss-of-function variants in SLC39A13, a putative zinc transporter gene, were first associated with a connective tissue disorder that is now called “Ehlers–Danlos syndrome, spondylodysplastic form type 3” (SCD-EDS, OMIM 612350) in 2008. Nine individuals have been described. We describe here four additional affected individuals from three consanguineous families and the follow up of two of the original cases. In our series, cardinal findings included thin and finely wrinkled skin of the hands and feet, characteristic facial features with downslanting palpebral fissures, mild hypertelorism, prominent eyes with a paucity of periorbital fat, blueish sclerae, microdontia, or oligodontia, and—in contrast to most types of Ehlers–Danlos syndrome—significant short stature of childhood onset. Mild radiographic changes were observed, among which platyspondyly is a useful diagnostic feature. Two of our patients developed severe keratoconus, and two suffered from cerebrovascular accidents in their twenties, suggesting that there may be a vascular component to this condition. All patients tested had a significantly reduced ratio of the two collagen-derived crosslink derivates, pyridinoline-to-deoxypyridinoline, in urine, suggesting that this simple test is diagnostically useful. Additionally, analysis of the facial features of affected individuals by DeepGestalt technology confirmed their specificity and may be sufficient to suggest the diagnosis directly. Given that the clinical presentation in childhood consists mainly of short stature and characteristic facial features, the differential diagnosis is not necessarily that of a connective tissue disorder and therefore, we propose that SLC39A13 is included in gene panels designed to address dysmorphism and short stature. This approach may result in more efficient diagnosis.