Mutation in the SLC29A3 Gene in an Egyptian Patient with H Syndrome: A Case Report and Review of Literature

Abstract

Histiocytosis-lymphadenopathy plus syndrome (H syndrome) is caused by mutations in the SLC29A3 gene that result in histiocytic infiltration of numerous organs. Patients suffering from this disorder can be easily mistaken for similar conditions such as Muckle–Wells syndrome. We present a 9.5-year-old boy, who is the offspring of a consanguineous marriage. He suffered from sensorineural hearing loss, dark hyperpigmented indurated dry areas on the medial thighs sparing the knees with hypertrichosis on the affected areas, and areas of hypopigmentation on the abdomen. The patient displayed mild dysmorphism including frontal bossing, synophrys, bilateral proptosis (with normal thyroid function), thick eyebrows, flat nose, long philtrum, and pectus excavatum. Formal intelligence testing showed that he was a slow learner. Laboratory findings included elevated serum amyloid-A, erythrocyte sedimentation rate, and total proteins in urine tests. Complete blood count showed mild microcytic hypochromic anemia. The molecular analysis was crucial to confirm the provisional clinical diagnosis. H syndrome is a rare autoinflammatory syndrome with pleiotropic manifestations that affect many organs and can be mistaken for other conditions. Our patient's description may expand the phenotype of H syndrome, as areas of hypopigmentation were observed on the abdomen. Molecular analysis of SLC29A3-related diseases is essential to highlight the variability and increase the awareness of H syndrome aiming for early diagnosis and proper treatment.

Keywords

H syndrome - SLC29A3 gene - hyperpigmentation - autoinflammatory syndrome

• References

• 1 Awake PP, Penmetcha LC, Fonseca A, Jawalkar PP. A tale of H Syndrome with typical radiographic findings. Indian J Dermatol 2018; 63 (02) 172-175
• 2 Molho-Pessach V, Agha Z, Aamar S. , et al. The H syndrome: a genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin with systemic manifestations. J Am Acad Dermatol 2008; 59 (01) 79-85
• 3 Molho-Pessach V, Lerer I, Abeliovich D. , et al. The H syndrome is caused by mutations in the nucleoside transporter hENT3. Am J Hum Genet 2008; 83 (04) 529-534
• 4 Molho-Pessach V, Ramot Y, Camille F. , et al. H syndrome: the first 79 patients. J Am Acad Dermatol 2014; 70 (01) 80-88
• 5 Bloom JL, Lin C, Imundo L. , et al. H syndrome: 5 new cases from the United States with novel features and responses to therapy. Pediatr Rheumatol Online J 2017; 15 (01) 76
• 6 Kang N, Jun AH, Bhutia YD, Kannan N, Unadkat JD, Govindarajan R. Human equilibrative nucleoside transporter-3 (hENT3) spectrum disorder mutations impair nucleoside transport, protein localization, and stability. J Biol Chem 2010; 285 (36) 28343-28352
• 7 Al-Haggar M, Salem N, Wahba Y. , et al. Novel homozygous SLC29A3 mutations among two unrelated Egyptian families with spectral features of H-syndrome. Pediatr Diabetes 2015; 16 (04) 305-316
• 8 Molho-Pessach V, Varma M, Godbole K, Kamath N, Zlotogorski A. H syndrome--four new patients from India. Indian J Dermatol Venereol Leprol 2014; 80 (06) 579
• 9 Kuemmerle-Deschner JB, Koitschev A, Tyrrell PN. , et al. Early detection of sensorineural hearing loss in Muckle-Wells-syndrome. Pediatr Rheumatol Online J 2015; 13 (01) 43
• 10 Bolze A, Abhyankar A, Grant AV. , et al. A mild form of SLC29A3 disorder: a frameshift deletion leads to the paradoxical translation of an otherwise noncoding mRNA splice variant. PLoS One 2012; 7 (01) e29708
• 11 El-Darouti MA, Marzouk SA, Abdel-Halim MR. Muckle-Wells syndrome: report of six cases with hyperpigmented sclerodermoid skin lesions. Int J Dermatol 2006; 45 (03) 239-244
• 12 Molho-Pessach V, Zlotogorski A. H syndrome and Muckle-Wells syndrome. J Am Acad Dermatol 2009; 61 (02) 365
• 13 Doviner V, Maly A, Ne'eman Z. , et al. H syndrome: recently defined genodermatosis with distinct histologic features. A morphological, histochemical, immunohistochemical, and ultrastructural study of 10 cases. Am J Dermatopathol 2010; 32 (02) 118-128
• 14 Kismet E, Köseoglu V, Atay AA, Deveci S, Demirkaya E, Tuncer K. Sinus histiocytosis with massive lymphadenopathy in three brothers. Pediatr Int 2005; 47 (04) 473-476
• 15 Melki I, Lambot K, Jonard L. , et al. Mutation in the SLC29A3 gene: a new cause of a monogenic, autoinflammatory condition. Pediatrics 2013; 131 (04) e1308-e1313
• 16 Senniappan S, Hughes M, Shah P. , et al. Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome is associated with severe chronic inflammation and cardiomyopathy, and represents a new monogenic autoinflammatory syndrome. J Pediatr Endocrinol Metab 2013; 26 (9,10): 877-882
• 17 Lane T, Gillmore JD, Wechalekar AD, Hawkins PN, Lachmann HJ. Therapeutic blockade of interleukin-6 by tocilizumab in the management of AA amyloidosis and chronic inflammatory disorders: a case series and review of the literature. Clin Exp Rheumatol 2015; 33 (06) (Suppl. 94) S46-S53
• 18 Elbarbary NS, Tjora E, Molnes J. , et al. An Egyptian family with H syndrome due to a novel mutation in SLC29A3 illustrating overlapping features with pigmented hypertrichotic dermatosis with insulin-dependent diabetes and Faisalabad histiocytosis. Pediatr Diabetes 2013; 14 (06) 466-472
• 19 Morgan NV, Morris MR, Cangul H. , et al. Mutations in SLC29A3, encoding an equilibrative nucleoside transporter ENT3, cause a familial histiocytosis syndrome (Faisalabad histiocytosis) and familial Rosai-Dorfman disease. PLoS Genet 2010; 6 (02) e1000833