Context Rosai-Dorfman disease is an uncommon histiocytic disorder most frequently presenting as bilateral cervical lymphadenopathy in children and young adults Extranodal disease occurs in a significant proportion of patients It has been recently classified as part of the ‘R group’ of histiocytoses by the Histiocyte Society in 2016 Cutaneous Rosai-Dorfman disease is regarded as a separate disease entity that falls into the ‘C group’ of histiocytoses according to this classification system The pathogenesis was previously poorly understood; however, recent evidence demonstrating clonality in a subset of cases raises the possibility of a neoplastic process A possible association with IgG4-related disease remains controversial Objectives To provide a comprehensive review of Rosai-Dorfman disease, including nodal, extranodal and cutaneous forms, with a particular emphasis on new insights into the possible clonal nature of the disease; to discuss the recently revised classification of the histiocytoses by the Histiocyte Society; and to summarise the findings from the literature regarding the controversial association with IgG4-related disease Data sources This review is based on published peer-reviewed English literature Conclusions Classic Rosai-Dorfman disease, which may be sporadic or familial, is considered a separate entity from cutaneous disease, which is reflected in the revised classification of histiocytoses An increase in IgG4-positive plasma cells may be seen in Rosai-Dorfman disease This finding in isolation is of limited significance and should be interpreted with caution Studies investigating the molecular profile of the disease show that in at least a subset of cases the disease is a clonal process The classification of Rosai-Dorfman disease is therefore likely to change as our understanding of the aetiopathogenesis evolves

https://jcp.bmj.com/content/jclinpath/73/11/697.full.pdf

Rosai-Dorfman disease: an overview

Background H syndrome is an autosomal recessive genodermatosis with multisystem involvement caused by mutations in SLC29A3. Objective We sought to investigate the clinical and molecular findings in 79 patients with this disorder. Methods A total of 79 patients were included, of which 13 are newly reported cases. Because of the phenotypic similarity and molecular overlap with H syndrome, we included 18 patients with allelic disorders. For 31 patients described by others, data were gathered from the medical literature. Results The most common clinical features (>45% of patients) were hyperpigmentation, phalangeal flexion contractures, hearing loss, and short stature. Insulin-dependent diabetes mellitus and lymphadenopathy mimicking Rosai-Dorfman disease were each found in approximately 20%. Additional systemic features were described in less than 15% of cases. Marked interfamilial and intrafamilial clinical variability exists. Twenty mutations have been identified in SLC29A3, with no genotype-phenotype correlation. Limitations In the 31 patients described by others, data were collected from the medical literature. Conclusions H syndrome is a multisystemic disease with clinical variability. Consequently, all SLC29A3-related diseases should be considered a single entity. Recognition of the pleomorphic nature of H syndrome is important for diagnosis of additional patients.

H syndrome: the first 79 patients.

We investigated two siblings with granulomatous histiocytosis prominent in the nasal area, mimicking rhinoscleroma and Rosai-Dorfman syndrome. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous frameshift deletion in SLC29A3, which encodes human equilibrative nucleoside transporter-3 (hENT3). Germline mutations in SLC29A3 have been reported in rare patients with a wide range of overlapping clinical features and inherited disorders including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, and Faisalabad histiocytosis. With the exception of insulin-dependent diabetes and mild finger and toe contractures in one sibling, the two patients with nasal granulomatous histiocytosis studied here displayed none of the many SLC29A3-associated phenotypes. This mild clinical phenotype probably results from a remarkable genetic mechanism. The SLC29A3 frameshift deletion prevents the expression of the normally coding transcripts. It instead leads to the translation, expression, and function of an otherwise noncoding, out-of-frame mRNA splice variant lacking exon 3 that is eliminated by nonsense-mediated mRNA decay (NMD) in healthy individuals. The mutated isoform differs from the wild-type hENT3 by the modification of 20 residues in exon 2 and the removal of another 28 amino acids in exon 3, which include the second transmembrane domain. As a result, this new isoform displays some functional activity. This mechanism probably accounts for the narrow and mild clinical phenotype of the patients. This study highlights the ‘rescue’ role played by a normally noncoding mRNA splice variant of SLC29A3, uncovering a new mechanism by which frameshift mutations can be hypomorphic.

/pdf/a-mild-form-of-slc29a3-disorder-a-frameshift-deletion-leads-4m05fz4aml.pdf

A Mild Form of SLC29A3 Disorder: A Frameshift Deletion Leads to the Paradoxical Translation of an Otherwise Noncoding mRNA Splice Variant

The H syndrome: Two novel mutations affecting the same amino acid residue of hENT3

H syndrome (OMIM 612391) is a recently described autosomal recessive genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin and systemic manifestations including hepatosplenomegaly, cardiac anomalies, hearing loss, hypogonadism, low height, hypertriglyceridemia, hallux valgus, and flexion contractures. H syndrome results from mutations in the SLC29A3 gene, which encodes the human equilibrative nucleoside transporter hENT3. The cutaneous histopathology is characterized by a striking mononuclear cell infiltrate in the dermis consisting of CD68+ monocyte-derived cells and CD34+ and factor XIIIa+ dendrocytes. We describe a case of H syndrome in which the infiltrating mononuclear cells were CD68+, CD163+, S-100+, and CD1a-, thus simulating the immunophenotype observed in Rosai-Dorfman disease (RDD). The immunostaining for CD21, fascin, and CD34 were negative, and there were also many factor XIIIa+ dendrocytes interspersed within the dense mononuclear cell infiltrate. Recent findings of biallelic mutations in SLC29A3 in 2 families reported to have familial RDD and in a kindred with Faisalabad histiocytosis (OMIM 602782), which is an autosomal inherited form of histiocytosis with similarities to RDD, may explain the RDD-like immunophenotype in our H syndrome case.

A case of H syndrome showing immunophenotye similarities to Rosai-Dorfman disease.

:This study analyzes the histopathological findings in H syndrome, a recently recognized autosomal recessive genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin in well-defined anatomical areas accompanied by various systemic manifestations. So far, description

H Syndrome: Recently Defined Genodermatosis With Distinct Histologic Features. A Morphological, Histochemical, Immunohistochemical, and Ultrastructural Study of 10 Cases

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H Syndrome: Recently Defined Genodermatosis With Distinct Histologic Features. A Morphological, Histochemical, Immunohistochemical, and Ultrastructural Study of 10 Cases