SLC29A3 mutation in a patient with syndromic diabetes with features of pigmented hypertrichotic dermatosis with insulin-dependent diabetes, H syndrome and Faisalabad histiocytosis.

AIMS: Atypical forms of diabetes may be caused by monogenic mutations in key genes controlling beta-cell development, survival and function. This report describes an insulin-dependent diabetes patient with a syndromic presentation in whom a homozygous SLC29A3 mutation was identified. METHODS: SLC29A3 was selected as the candidate gene based on the patient's clinical manifestations, and all exons and flanking regions in the patient's genomic DNA were sequenced. RESULTS: A homozygous splice mutation (c.300+1G>C) resulting in a frameshift and truncated protein (p.N101LfsX34) was identified. The patient had insulin-dependent diabetes, congenital deafness, short stature, hyperpigmented patches on the skin, dysmorphic features, cardiomegaly, arthrogryposis, hepatosplenomegaly, anaemia with erythroblastopenia, and an inflammatory syndrome with fever and arthritis; she also presented with a fibrotic mediastinal mass. These clinical features overlapped with pigmented hypertrichosis with insulin-dependent diabetes (PHID), H syndrome, Faisalabad histiocytosis and sinus histiocytosis with massive lymphadenopathy (SHML), all of which are also caused by SLC29A3 mutations. CONCLUSION: This is the most severe case reported of SLC29A3 mutations with cumulative features of all these syndromes. This extreme severity coincides with the most N-terminal location of the truncation mutation, thereby affecting all alternative transcripts of the gene. This case report extends the clinical variability of homozygous SLC29A3 mutations that result in a spectrum of multisystemic manifestations.

Abnormal FGFR 3 expression in cartilage of thanatophoric dysplasia fetuses.

Thanatophoric dysplasia (TD), the commonest lethal skeletal dysplasia in humans, is accounted for by recurrent mutations in the fibroblast growth factor receptor 3 gene (FGFR 3), causing its constitutive activation in vitro. Taking advantage of medical abortion of 18 TD fetuses, cartilage sections were studied for FGFR 3 gene expression by in situ hybridization and immunohistochemistry. Specific antibodies revealed high amounts of FGFR 3 in cartilage of TD fetuses with no increased level of the corresponding mRNA. The specific signal was mainly detected in the nucleus of proliferative and hypertrophic chondrocytes. Based on this observation and the abnormal expression of collagen type X in hypertrophic TD chondrocytes, we suggest that constitutive activation of the receptor through formation of a stable dimer increases its stability and promotes its translocation into the nucleus, where it might interfere with terminal chondrocyte differentiation.