Skin-Dominant Phenotype in a Patient with H Syndrome: Identification of a Novel Mutation in the <b><i>SLC29A3</i></b> Gene

Abstract

H syndrome (OMIM 602782) is a very rare autosomal recessive genodermatosis with multisystem involvement. Hallmarks of this disorder are juvenile onset and progressive, hyperpigmented, hypertrichotic lesions with histiocytic infiltration. Associated systemic manifestations form a long list, and there is high variability between patients. In some patients, dysmorphic and other systemic features may be so subtle that the disorder may readily be mistaken as an acquired skin disease and treated as such. Herein, we report a novel homozygous c.1339G>A (p.Glu447Lys) mutation in the SLC29A3 gene in a patient with skin-dominant presentation of H syndrome. Additionally, due to the present case, double superior vena cava can be added to the list of possible cardiovascular manifestations of H syndrome.

H syndrome: Clinical, histological and genetic investigation in Tunisian patients

“…Previous studies have shown that the spectrum of cardiac involvement in H syndrome is widely diversified, including atrial septal defect, ventricular septal defect, mitral valve prolapse, cardiomegaly, left ventricular dilation, pulmonary hypertension, pulmonic stenosis, pericardial effusion, cardiac septal thickening, left superior vena cava, pericarditis, thickening of the posterior pericardium and right atrial wall, bicommissural aortic valve with mild aortic incompetence and acute coronary syndrome . These cardiovascular abnormalities seen in H syndrome patients raise a possible role of hENT3 in normal cardiac activity and morphogenesis …”

“…19 These cardiovascular abnormalities seen in H syndrome patients raise a possible role of hENT3 in normal cardiac activity and morphogenesis. 19,20 We hypothesize that the expression of mutant hENT3 in the heart could be altered, which probably affects the nucleoside transport activity.…”

“…Since 2014, 17 patients have been reported. 11,20,[23][24][25][26][27][28][29][30] Molho-Pessach et al 5 emphasized that the finding of several different mutations in a small geographic region implies that H syndrome may be rather common and underdiagnosed owing to the fact that many patients have a very mild clinical presentation. In our context, geographic endogamy is frequent in Tunisia, especially in rural areas where it could reach 90% and familial endogamy or interrelated marriages are profoundly rooted with an estimated rate of 30% of all kind of unions.…”

Hyperpigmented and hypertrichotic sclerotic plaques in a child

“…H syndrome (OMIM 602782), first described in 2008 by Molho‐Pessach et al, is a rare, autosomal recessive, multisystem fibrosing histiocytic disorder characterized by hyperpigmentation, hypertrichosis, hepatosplenomegaly, hearing loss, heart abnormalities, hypogonadism, low height (short stature), hyperglycemia, hallux valgus/flexion contractures (camptodactyly), and heritable histiocytosis 4 . Also known as histiocytosis‐lymphadenopathy plus syndrome, it shares features of 3 other histiocytic disorders once thought to be distinct entities: Faisalabad histiocytosis, familial sinus histiocytosis with massive lymphadenopathy (familial Rosai‐Dorfman disease), and pigmented hypertrichosis with insulin‐dependent diabetes mellitus syndrome.…”

ENT3 utilizes a pH Sensing Mechanism for Transport

“…Coincidentally, around the time our work was published, another group investigated a case of H Syndrome that arose from a novel mutation (Glu447Lys) in the SLC29A3 gene. 7 They hypothesized a link between the mutation and the symptoms experienced, ranging from various cardiovascular anomalies to skin-dominant features including hyperpigmentation and hypertrichosis. Our lab's research may hold an explanation for this molecular pathogenesis.…”