Abstract
The histiocytoses are a heterogeneous group of disorders characterised by an excessive number of histiocytes. In most cases the pathophysiology is unclear and treatment is nonspecific. Faisalabad histiocytosis (FHC) (MIM 602782) has been classed as an autosomal recessively inherited form of histiocytosis with similarities to Rosai-Dorfman disease (RDD) (also known as sinus histiocytosis with massive lymphadenopathy (SHML)). To elucidate the molecular basis of FHC, we performed autozygosity mapping studies in a large consanguineous family and identified a novel locus at chromosome 10q22.1. Mutation analysis of candidate genes within the target interval identified biallelic germline mutations in SLC29A3 in the FHC kindred and in two families reported to have familial RDD. Analysis of SLC29A3 expression during mouse embryogenesis revealed widespread expression by e14.5 with prominent expression in the central nervous system, eye, inner ear, and epithelial tissues including the gastrointestinal tract. SLC29A3 encodes an intracellular equilibrative nucleoside transporter (hENT3) with affinity for adenosine. Recently germline mutations in SLC29A3 were also described in two rare autosomal recessive disorders with overlapping phenotypes: (a) H syndrome (MIM 612391) that is characterised by cutaneous hyperpigmentation and hypertrichosis, hepatomegaly, heart anomalies, hearing loss, and hypogonadism; and (b) PHID (pigmented hypertrichosis with insulin-dependent diabetes mellitus) syndrome. Our findings suggest that a variety of clinical diagnoses (H and PHID syndromes, FHC, and familial RDD) can be included in a new diagnostic category of SLC29A3 spectrum disorder.
Highlights
Histiocytosis encompasses a group of diverse disorders characterised by the accumulation and infiltration of monocytes, macrophages, and dendritic cells in the affected tissues
We identified germline SLC29A3 mutations in patients diagnosed with syndromic forms of histiocytosis (Faisalabad histiocytosis and familial Rosai-Dorfman disease (RDD)/sinus histiocytosis with massive lymphadenopathy (SHML))
Another study has recently described germline SLC29A3 mutations in an autosomal recessive disorder, PHID (Pigmented Hypertrichosis with Insulin dependent Diabetes mellitus) syndrome, which is characterized by the childhood onset of pigmented hypertrichotic skin lesions associated with a high risk of insulin-dependent diabetes mellitus [11]
Summary
Histiocytosis encompasses a group of diverse disorders characterised by the accumulation and infiltration of monocytes, macrophages, and dendritic cells in the affected tissues. The identification of SLC29A3 mutations as the molecular basis for a familial form of syndromic histiocytosis (FHC/RDD) confirms a direct link between Faisalabad histiocytosis and Rosai-Dorfman disease and links these disorders to other SLC29A3-associated phenotypes. Class II consists of macrophage-related disorders including hemophagocytic lymphohistiocytosis (HLH) which is characterised by inherited (Familial haemophagocytic lymphohistiocytosis) (FHLH) (MIM 267700) and sporadic forms of the disease. Class III comprises malignant disorders involving histiocytic lineage cells including histiocytic lymphoma and acute monocytic leukaemia. Additional, less common, histiocytic disorders included in class II are Sinus histiocytosis with massive lymphadenopathy (SHML, Rosai-Dorfman syndrome), Xanthogranuloma, Reticulohistiocytoma and a familial form previously designated as Faisalabad histiocytosis [4]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.