Clinical, Histochemical, and Molecular Study of Three Turkish Siblings Diagnosed with H Syndrome, and Literature Review

Abstract

Background: The term “H syndrome” was coined to denote the major clinical findings, which include hyperpigmentation, hypertrichosis, hearing loss, hepatosplenomegaly, hyperglycaemia, hypogonadism, hallux flexion contractures, and short height. Objective: To report the clinical, endocrinological, histochemical, and genetic findings of three siblings. Methods: Skin and liver biopsies were taken to investigate the histochemical characteristics of hyperpigmented hypertrichotic skin lesions and massive hepatomegaly. The levels of basal serum thyroid hormones, oestradiol, total testosterone, follicle-stimulating hormone, luteinising hormone, and stimulated growth hormone (GH) were measured to investigate the endocrine aspects of the syndrome. Mutation analysis was carried out in all six exons and exon-intron boundaries of SLC29A3 by direct sequencing. Results: Physical examination of the patients revealed common charac­teristic findings of H syndrome. Additional clinical findings were sectorial iris atrophy in the younger sister. Laboratory evaluation revealed microcytic anaemia, markedly increased erythrocyte sedimentation rate and C-reactive protein levels, and humoral immune deficiency in the younger siblings, who presented with recurrent fever and sinopulmonary infection. Two different GH stimulation tests revealed GH deficiency in the younger sister with short stature. Liver and skin biopsies revealed polyclonal lymphohistiocytic and plasma cell infiltration. Sequencing of SLC29A3 in the three siblings revealed a novel homozygous mutation in exon 6, which caused the transition of arginine to tryptophan. Conclusion: This study not only extended the clinical and mutation spectrum of SLC29A3 in H syndrome, but also showed that short children should be assessed according to the guidelines for short stature in children.

Case report of H-syndrome with a review from a rheumatological perspective

“…Similar to what Enver Simsek8 found in three Turkish siblings with H-syndrome, our patient had early-onset sensorineural hearing loss, hallux valgus (figure 2B), bilateral medial thigh hyperpigmentation/induration, hypertrichosis, dilated scleral vessels, short stature, microcytic hypochromic anaemia, raised inflammatory markers and SLC29A3 mutation. Our patient exhibited pericardial thickness instead of mitral valve/ Atrial Septal defect cardiac problems, did not have type I diabetes but did have a pancreatic exocrine deficiency and had normal secondary sexual characteristics, in contrast to theirs.…”

Identification of the Novel Methylated Genes’ Signature to Predict Prognosis in INRG High-Risk Neuroblastomas

“…SLC29A3 encodes a nucleoside transporter which plays a significant role in the cellular uptake of nucleosides and nucleobases. It was previously reported that many diseases were related to RAD51AP1 expression, including autoinflammatory diseases [ 46 ], H syndrome [ 47 ], insulin-dependent diabetes [ 48 ], pigmentary hypertrichosis, autoimmune insulin-dependent diabetes mellitus [ 49 ], and sclerosing bone dysplasias [ 50 ]. Meanwhile, MIMT1 is an MER1 repeat-containing imprinted transcript, which can undergo hypermethylation in the placenta of intrauterine growth-restricted fetuses in cattle [ 51 ], and truncation of exons 3 and 4 of the MIMT1 gene caused intrauterine growth restriction [ 52 ].…”

Atypical comorbidities in a child considered to have type 1 diabetes led to the diagnosis of SLC29A3 spectrum disorder

“…Among several features defining SLC29A3 spectrum disorder, cutaneous findings are considered to comprise the hallmark clinical presentation ( 1 , 2 ). Almost all patients reported in the literature presented with different musculoskeletal and/or dermatological phenotypical characteristics, including hyperpigmentation, hypertrichosis, facial telangiectasias, flexion contractions, or foot deformities ( 2 , 4 , 6 , 9 , 15 , 16 ). Diabetes was the first and only presenting feature in our patient.…”

“…Based on the results of empirical treatment trials for SLC29A3 spectrum disorders in the literature, tocilizumab (8 mg/kg/d), a human monoclonal interleukin-6 receptor antibody, was administered ( 6 , 15 , 16 ). However, the anemia did not improve, and transaminase levels increased 2-3-fold after two doses of this hepatotoxic agent.…”