Endocrine Abstracts

Background: PHID is a novel syndrome caused by mutations in SLC29A3, which encodes for the nucleoside transporter protein hENT3. It is associated with multiple endocrine manifestations including severe short stature, pubertal delay and pancreatic exocrine insufficiency. Mutations in SLC29A3 have also been linked to H syndrome and familial Rosai Dorfman Disease (RDD). A key feature of these syndromes is persistent inflammation. Currently there is no treatment for these patients.

Aims: To study the mechanism of the inflammatory response in patients with PHID.

Methods: Serum amyloid A protein (SAA) is a marker of the inflammatory response and was measured at the National Amyloidosis Centre at the Royal Free Hospital in London in 2 patients with mutations in SLC29A3. Immunohistochemistry determined the subcellular localisation of hENT3. As the inflammatory response activates the interleukin-1 beta (IL-1b) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, the effect of SLC29A3 knockdown was investigated on inflammation by observing the activation of the downstream transcription factor NF-κB.

Results: In both patients SAA was significantly elevated (99.1 and 30 mg/dl respectively, control <10 mg/dl). hENT3 was localised to the mitochondrion in cultured placental cell lines (TC1) while in fibroblasts it was observed in the endosome. NF-κB was activated when SLC29A3 was silenced.

Conclusions: PHID syndrome is associated with significant elevation of SAA which reflects the underlying inflammatory response. The persistent inflammation might explain the multiple endocrine manifestations observed in patients with PHID syndrome. Our preliminary data suggests that the inflammatory response involves activation of NF-κB. These observations might allow patients with PHID syndrome to be treated with drugs which block the IL-1b and NF-κB pathways (such as anakinra).