Phenotypic intrafamilial variability including H syndrome and Rosai–Dorfman disease associated with the same c.1088G > A mutation in the SLC29A3 gene

Background Mutations in the SLC29A3 gene, which encodes the nucleoside transporter hENT3, have been implicated in syndromic forms of histiocytosis including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, Faisalabad histiocytosis and Familial Rosai–Dorfman disease (RDD). Herein, we report five new patients from a single family who present with phenotypes that associate features of H syndrome and Familial Rosai–Dorfman disease. Methods We investigated the clinical, biochemical, histopathological and molecular findings in five Tunisian family members' diagnosed with Familial RDD and/or H syndrome. The solute carrier family 29 (nucleoside transporters), member 3 (SLC29A3) gene was screened for molecular diagnosis using direct Sanger sequencing. Results Genetic analysis of all affected individuals revealed a previously reported missense mutation c.1088 G > A [p.Arg363Gln] in exon 6 of the SLC29A3 gene. Four affected members presented with clinical features consistent with the classical H syndrome phenotype. While their cousin’s features were in keeping with Familial Rosai–Dorfman disease diagnosis with a previously undescribed cutaneous RDD presenting as erythematous nodular plaques on the face. This report underlines the clinical variability of SLC29A3 disorders even with an identical mutation in the same family. Conclusion We report a rare event of 5 Tunisian family members' found to be homozygous for SLC29A3 gene mutations but showing a different phenotype severity. Our study reveals that despite a single mutation, the clinical expression of the SLC29A3 disorders may be significantly heterogeneous suggesting a poor genotype–phenotype correlation for the disease.

Phenotypic intrafamilial variability including H syndrome and Rosai Dorfman Disease associated with the same c.1088G>A mutation in the SLC29A3 gene.

Background: Mutations in the SLC29A3 gene, which encodes the nucleoside transporter hENT3, has been implicated in syndromic forms of Histiocytosis including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, Faisalabad histiocytosis and Familial Rosai Dorfman disease (RDD). Herein, we report five new patients from a single family who present with phenotypes that associate features of H syndrome and Familial Rosai Dorfman Disease.Methods: We investigated the clinical, biochemical, histopathological and molecular findings in five Tunisian family Members' diagnosed as Familial RDD and/or H syndrome. The solute carrier family 29 (nucleoside transporters), member 3 ( SLC29A3 ) gene was screened for molecular diagnosis using direct Sanger sequencing.Results: Genetic analysis of all affected individuals revealed a previously reported missense mutation c.1088 G>A [p.Arg363Gln] in exon 6 of the SLC29A3 gene. Four affected members presented with clinical features consistent with classical H syndrome phenotype. While their cousin’s features were in keeping with the diagnosis of Familial Rosai Dorfman disease with a previously undescribed cutaneous RDD presenting as erythematous nodular plaques on the face. This report underlines the clinical variability of SLC29A3 disorders even with an identical mutation in the same family.Conclusion: We report a rare event of 5 Tunisian family Members' found to be homozygous for SLC29A3 gene mutations but showing a different phenotype severity. Our study reveals that despite a single mutation, the clinical expression of the SLC29A3 disorders may be significantly heterogeneous suggesting a poor genotype-phenotype correlation for the disease.

Phenotypic Intrafamilial Variability Including H Syndrome and Rosai Dorfman Disease Associated With the Same c.1088G>A mutation in the SLC29A3 gene.

BackgroundMutations in the SLC29A3 gene, which encodes the nucleoside transporter hENT3, has been implicated in syndromic forms of Histiocytosis including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, Faisalabad histiocytosis and Familial Rosai Dorfman disease (RDD). Herein, we report five new patients from a single family who present with phenotypes that associate features of H syndrome and Familial Rosai Dorfman Disease.MethodsWe investigated the clinical, biochemical, histopathological and molecular findings in five Tunisian family Members' diagnosed with Familial RDD and/or H syndrome. The solute carrier family 29 (nucleoside transporters), member 3 (SLC29A3) gene was screened for molecular diagnosis using direct Sanger sequencing.ResultsGenetic analysis of all affected individuals revealed a previously reported missense mutation c.1088 G>A [p.Arg363Gln] in exon 6 of the SLC29A3 gene. Four affected members presented with clinical features consistent with the classical H syndrome phenotype. While their cousin’s features were in keeping with the diagnosis of Familial Rosai Dorfman disease with a previously undescribed cutaneous RDD presenting as erythematous nodular plaques on the face. This report underlines the clinical variability of SLC29A3 disorders even with an identical mutation in the same family.ConclusionWe report a rare event of 5 Tunisian family Members' found to be homozygous for SLC29A3 gene mutations but showing a different phenotype severity. Our study reveals that despite a single mutation, the clinical expression of the SLC29A3 disorders may be significantly heterogeneous suggesting a poor genotype-phenotype correlation for the disease.

Nucleosides drive histiocytosis in SLC29A3 disorders by activating TLR7

A lysosomal transmembrane protein SLC29A3 transports nucleosides from lysosomes to the cytoplasm. Loss-of-function mutations of the SLC29A3 gene cause lysosomal nucleoside storage in monocyte/macrophages, leading to their accumulation called histiocytosis in humans and mice. Little is known, however, about a mechanism behind nucleoside-dependent histiocytosis. TLR7, an innate immune sensors for single stranded RNA, bind and respond to nucleosides. We here show that they drive nucleoside-mediated histiocytosis. Patrolling monocyte/macrophages accumulate in the spleen of Slc29a3−/− mice but not Slc29a3−/−Tlr7−/− mice. Accumulated patrolling monocyte/macrophages stored nucleosides derived from cell corpse. TLR7 was recruited to phagosomes and activated as evidenced by TLR7-dependent phagosomal maturation. TLR7 induced hyper-responsiveness to M-CSF in Slc29a3−/− monocyte/macrophages. These results suggest that TLR7 drives histiocytosis in SLC29A3 disorders.One Sentence SummarySLC29A3 disorders are caused by activation of TLR7 with accumulated nucleosides in lysosomes.

P52 Bilateral sacroiliitis in a patient with H syndrome

Background Introduction H syndrome is a rare inherited form of histiocytosis. It is an autosomal recessive disorder caused by a mutation in SLC29A3 gene resulting in histiocytic infiltration of numerous organs. It becomes clinically apparent mostly during childhood with characteristic hyperpigmented hypertrichotic indurated skin lesions that mainly involve the lower limbs. Other reported features include Sensorineural hearing loss, heart anomalies, hepatosplenomegaly, lymphadenopathy, insulin dependent diabetes mellitus and flexion contractions of interphalangeal joints. We report sacroiliitis, a possible new feature, in a young girl diagnosed with H syndrome. Methods We report the case of a 16 year-old Syrian girl diagnosed to have H syndrome presented with inflammatory polyarthritis, bilateral sacroiliitis and bilateral anterior uveitis. She was managed with methotrexate and adalimumab with significant improvement. Results The findings in our patient raise the question whether she truly has a rheumatic illness beside H syndrome, or merely represent newly recognized manifestation of H syndrome. Conclusion H syndrome is a recently recognised autosomal recessive condition with characteristic dermatologic and systemic manifestation. Along with arthritis, sacroiliitis and uveitis could represent part of the phenotypic description of this rare entity. Conflicts of Interest The authors declare no conflicts of interest.

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

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.