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

Abstract

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.

Animal Models of Ehlers–Danlos Syndromes: Phenotype, Pathogenesis, and Translational Potential

“…Biallelic mutations in the SLC39A13 gene, encoding the metal transporter Zrt/irt-like protein 13 (ZIP13), result in a phenotype which clinically overlaps with spEDS due to B4GALT7 and B3GALT6 mutations and is therefore grouped within the same clinical entity ( Malfait et al, 2017 ). spEDS- SLC39A13 patients present with moderate short stature, combined with specific facial characteristics, hypo- or oligodontia, distal joint hypermobility, thin and fragile skin, wrinkled palms, and characteristic radiographic abnormalities ( Brady et al, 2017 ; Malfait et al, 2017 ; Kumps et al, 2020 ). spEDS- SLC39A13 patients display collagen underhydroxylation, despite normal activity of lysyl and prolyl hydroxylases ( Fukada et al, 2008 ; Giunta et al, 2008 ).…”

Systemic Associations with Keratoconus

“…Data regarding the findings of keratoconus in patients with EDS is mixed. Small-scale studies have noted keratoconus diagnoses in patients with EDS spondylodysplastic form Type III [ 67 ] and in patients with EDS Type VI [ 68 ]. However, an examination of 36 EDS patients found no keratoconus via slit lamp biomicroscopy, retinoscopy, and videokeratography methods [ 69 ].…”

Coexistence of spinocerebellar ataxia autosomal recessive type 21 and Ehlers-Danlos syndrome spondylodysplastic type 3 in a patient

“…EDSSPD3 is characterized by joint hypermobility, hyperelasticity of skin with atrophic scars, bluish sclerae, osteopenia, short stature, platyspondyly, widened metaphyses, finger contractures, tapered fingers with wrinkled palms and thenar/hypothenar muscle atrophy (Giunta et al , 2008). The facial dysmorphism is characterized by a flat face, downslanting palpebral fissures, protuberant eyes, and a small mouth (Kumps et al , 2020). Myopia, keratoconus, bifid uvula, delayed tooth eruption, and hypodontia may be accompanying features of the disorder (Kumps et al , 2020).…”

“…The facial dysmorphism is characterized by a flat face, downslanting palpebral fissures, protuberant eyes, and a small mouth (Kumps et al , 2020). Myopia, keratoconus, bifid uvula, delayed tooth eruption, and hypodontia may be accompanying features of the disorder (Kumps et al , 2020). Affected individuals were reported to have increased urinary lysyl pyridinoline/hydroxylysyl pyridinoline ratio of approximately 1, whereas both lysyl hydroxylase and prolyl 4-hydroxylase activities were normal (Giunta et al , 2008).…”