Endocrine Abstracts

Background: PHID syndrome has been recently described as a unique syndrome characterised by pigmented hypertrichosis; non immune mediated insulin depended diabetes mellitus (DM). Other associated features of the syndrome include pancreatic exocrine insufficiency, short stature and hypogonadism.

Aims: To identify the genetic basis of PHID syndrome in six patients from five unrelated families and to characterise the endocrine features associated with this syndrome.

Methods: Homozygosity mapping was performed in all five families followed by candidate gene sequencing in our cohort of six patients. Functional studies were performed on the diseased fibroblasts. Combined pituitary function test was performed to assess GH and pituitary–gonadal axis in 2 patients.

Results: Homozygosity mapping identified a single common 1.4 Mb region of shared homozygosity within cytogenetic band 10q22.1. Five loss of function mutations were found in SLC29A3 gene (three missense, one frameshift and one nonsense). Functional studies from the diseased fibroblasts revealed a 34% reduction in the hENT3 mRNA and defect in cellular trafficking of residual protein. Oral glucose tolerance test showed undetectable insulin secretion in the face of high blood glucose concentration. Investigation of short stature revealed adequate GH response to glucagon stimulation test however patients failed to generate an IGF1/BP3 response to GH treatment suggestive of GH resistance. GnRH test revealed features of hypogonadotropic hypogonadism in a female with failure to attain puberty at 16 years of age.

Conclusion: Inactivating mutations in the human SLC29A3 gene causes a novel Mendelian disorder associated with insulin dependent DM; pigmented hypertrichosis; short stature and hypogonadism. Mutations in SLC29A3 lead to alterations in cell size/number possibly via the insulin signalling pathway. Further studies are required to understand the role of hENT3 protein in pancreatic endocrine and exocrine tissues and in the pituitary gland.