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

Abstract

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.

Co-occurrence ofMEN1p.Gly111fs andAIPp.Arg16His Variants in Familial MEN1 Phenotype

“…However, despite suggestive data as to the pathogenicity of this AIP variant, it has been regarded as a rare polymorphism (15,18,19), in part due to its detection in unaffected controls (16,18,20), in agreement with the data reported herein and also the lack of co-segregation of the p.Arg16His variant with disease phenotype in some familial cases (21). Of note, results from a recent study regarding p.Arg16His functional impact on AIP protein demonstrated that this alteration is sufficient to disturb cAMP signaling and growth hormone secretion, suggesting that the p.Arg16His variant alone may not be sufficient to produce a pathological effects but along with other mutations may be associated with the pathological mechanism (22).…”

Low rate of germline AIP mutations in patients with apparently sporadic pituitary adenomas before the age of 40: a single-centre adult cohort

“…While non-functioning adenomas constitute the majority of tumours in patients presenting to our clinic out of the w100-120 new referrals per annum, most such patients fall into an older age group; in this series the majority of patients presented with macroadenomas and a clinical presentation of acromegaly-gigantism rather than non-functioning tumours (24). In our patient group, no AIP variants were identified in any patient other than those with acromegaly; in two cases they were deemed to be definitely pathological, while in another two cases the issue regarding the pathogenicity of the variants is debated (23,25). The missense variant c.47GOA in patient 4 has been described and reviewed recently in the literature in association with an aggressive non-functioning adenoma; our patient showed the clinical picture of a macroadenoma, with aggressive features of increased MIB1 and a sparse granulation pattern.…”

“…The pathology demonstrated a sparsely granulated somatotroph macroadenoma with expression of GH staining in 40% of cells. She was found to be heterozygous for missense variant c.47GOA, in exon 1 of AIP, a variant of uncertain pathogenic significance (23).…”

“…Patient 4 was found to be heterozygous for a missense variant c.47GOA, in exon 1 of AIP, a variant of uncertain pathogenic significance. This could be a SNP based on current functional classification data, as has been shown in a recent paper associated with an aggressive clinical course in a NFA (23).…”

Spontaneous Conception and Term Delivery in a Woman with Ucontrolled Acromegaly and Hypogonadotropic Hypogonadism

“…Despite the severe clinical, biochemical and imaging picture, our patient did not harbor an AIP mutation (AIP -related pituitary adenomas, frequently somatotroph, either familial or sporadic are usually diagnosed in younger patients and are larger and more invasive) (26).…”