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Faisalabad histiocytosis

MIM.602782 11q25

Saturday 18 March 2006

Definition: Faisalabad histiocytosis is a form of histiocytosis associated with sensorineural deafness and joint contractures.

Faisalabad histiocytosis (MIM.602782) was first described as a novel autosomal recessive form of histiocytosis in a highly consanguineous family originating from Pakistan.

Affected individuals were born with joint deformities, sensorineural hearing loss and subsequently developed a generalized lymphadenopathy and swellings in their eyelids that were shown to contain histiocytes.

The phenotype of Faisalabad histiocytosis overlaps with that of Rosai-Dorfman disease (RDD or sinus histiocytosis with massive lymphadenopathy (SHML)), a histiocytic disorder characterized by painless but protracted lymphadenopathy with lymph node histology showing large histiocytes with voluminous clear cytoplasm, rounded nuclei and emperipolesis.

Rosai-Dorfman disease is mostly sporadic but inherited cases can occur. There is a phenotypic similarity between familial Rosai-Dorfman disease and FHC.


- Mutations in SLC29A3, Encoding an Equilibrative Nucleoside Transporter ENT3, Cause a Familial Histiocytosis Syndrome (Faisalabad Histiocytosis) and Familial Rosai-Dorfman Disease (PLOs Genetics)

  • 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.


Although the Faisalabad histiocytosis gene was previously mapped to chromosome 11q25, reinvestigation of the family using high-density SNP arrays excluded the original locus and identified a novel locus at chromosome 10q22.1.

Grmline SLC29A3 mutations were identified in patients diagnosed with syndromic forms of histiocytosis (Faisalabad histiocytosis and familial RDD/SHML (fRDD)).

RDD is classified as a reactive macrophage histiocytosis. Histopathological analysis of lymph nodes in patients with SLC29A3-associated FHC/RDD demonstrate prominent sinus histiocytes with large vesicular nuclei and abundant pale staining cytoplasm and emperipolesis.

Langerhans cell-type histiocytes are absent, and eosinophils are rare. Affected patients have a polyclonal gammopathy.

A study has also described germline SLC29A3 mutations in H syndrome. This autosomal recessive disorder is characterized by cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature, hallux valgus, and fixed flexion contractures of the toe joints and the proximal interphalangeal joints.

Additionally, 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.

Comparison of the clinical features of families with germline SLC29A3 mutations demonstrates overlapping features. Thus hyperpigmented skin lesions (histological examination demonstrates polyclonal perivascular lymphohistiocytic infiltration with numerous plasma cells in the dermis and subcutis) are common to PHID and H syndrome.

Hearing loss and short stature is found in H syndrome and in FHC/RDD. However deafness is not a feature of PHID and diabetes mellitus and pancreatic insufficiency is restricted to PHID.

Patients with H syndrome and PHID may have lymphadenopathy but do not have the life-threatening lymph node enlargement seen in FHC/fRDD.

FHC/familial RDD, H and PHID syndromes share some common features and the phenotype of each disorder may vary between families. At present, the reason for the phenotypic variability associated with SLC29A3 mutations is unclear.

In particular the p.Gly437Arg mutation has been detected in H syndrome, PHID and FHC patients suggesting that genetic and/or environmental modifiers may be implicated.

These related diseases might be viewed as manifestations of a “SLC29A3 spectrum disorder” (akin to the use of the “PTEN hamartoma tumour syndrome” to cover several clinical diagnoses caused by PTEN mutations).

Further studies to determine the inter- and intrafamilial phenotypic variability of “SLC29A3 spectrum disorder” should provide insights into the molecular basis for variations in clinical phenotype and the extent to which different types of SLC29A3 spectrum disorder should be considered as clinically distinct but related disorders or as a single entity with variable expression.

There is a widespread expression of slc29a3. It is interesting that some of the organs with prominent expression (e.g. ear, testis and skin) are affected in patients with FHC and/or H syndrome.

However, the clinical phenotype of SLC29A3 spectrum disorder is more restricted than might be predicted from the expression pattern as some tissues with high expression of slc29a3 are clinically unaffected. (Morgan MV et al., Plos Genetics)


- Cline, M. J. : Histiocytes and histiocytosis. Blood 84: 2840-2853, 1994. PubMed ID : 7524755

- Moynihan, L. M.; Bundey, S. E.; Heath, D.; Jones, E. L.; McHale, D. P.; Mueller, R. F.; Markham, A. F.; Lench, N. J. : Autozygosity mapping, to chromosome 11q25, of a rare autosomal recessive syndrome causing histiocytosis, joint contractures, and sensorineural deafness. Am. J. Hum. Genet. 62: 1123-1128, 1998. PubMed ID : 9545394