January - March 2013, Volume 9, Issue 1

Baciu I, Radian S.,Capatina C., Botusan I., Aflorei D, Stancu C., Dumitrascu A., Ciubotaru V., Coculescu M

The p.R16H (C.47G>A) AIP gene variant in a case with invasive non-functioning pituitary macroadenoma and Screening of a Control Cohort

Acta Endo (Buc) 2013, 9 (1): 97-108
doi: 10.4183/aeb.2013.97

Background: Germline aryl hydrocarbon receptor-interacting protein (AIP) mutations are found in familial isolated pituitary adenoma syndrome (FIPA) families and in a small number of sporadic pituitary adenoma (PA) patients. Although the tumorigenic mechanisms of AIP mutations are unclear, truncating mutations are considered pathogenic, but missense mutations are difficult to evaluate. p.R16H (c.47G>A) is a controversial AIP variant of unknown significance. Aim: To describe a new PA case associated with AIP p.R16H. Patients and methods: One AIP p.R16H non-functioning pituitary adenoma (NFPA) case identified by mutation sequencing screening of sporadic PA patients; 108 controls were screened for p.R16H. Results: The 38 yrs. old male NFPA patient had no family history of PA and harboured a heterozygous p.R16H variant. The proband and two brothers presented severe intellectual disability. Severe visual impairment was the initial symptom and clinical, biochemical and imaging examination demonstrated a large NFPA invading the right cavernous sinus. After transsphenoidal debulking, the remaining tumor continued growth. One of proband’s sisters was negative for p.R16H. Among controls, we identified one heterozygous p.R16H carrier, presenting a thyroid follicular neoplasm. Loss of heterozygosity analysis of the pituitary and thyroid tumors was not performed. Conclusions: We report two new occurrences of AIP p.R16H, associated with a NFPA and with a thyroid tumor. The NFPA patient was young and presented an invasive macroadenoma, features typical of AIP-mutated patients. Because the association between p.R16H and PAs has not been conclusively established, further research of p.R16H is warranted, in view of its implications for AIP genetic testing.

Keywords: pituitary adenoma, AIP, genetics, genetic counseling, penetrance

Correspondence: Serban Radian, MD, PhD, Department of Endocrinology, “Carol Davila” University of Medicine and Pharmacy and “Constantin I. Parhon” National Institute of Endocrinology, Bd. Aviatorilor 34-36, sector 1, Bucharest 011863, Romania, e-mail: serban.radian@parhon.ro