Abstract
Pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene are increasingly recognised as a cause of familial isolated pituitary adenoma. AIP-associated tumours are most commonly growth hormone (GH) producing. In our cohort of 175 AIP mutation positive patients representing 93 kindreds, 139 (79%) have GH excess, 19 have prolactinoma (17 familial and 2 sporadic cases) and out of the 17 clinically non-functioning tumours 4 were subsequently operated and found to be GH or GH & prolactin immunopositive adenoma. Here we report a family with an AIP variant, in which multiple family members are affected by prolactinoma, but none with GH excess. To our knowledge this is the first reported family with an AIP pathogenic variant to be affected solely by prolactinoma. These data suggest that prolactinoma families represent a small subset of AIP mutation positive kindreds, and similar to young-onset sporadic prolactinomas, AIP screening would be indicated.
Highlights
Most pituitary tumours arise sporadically, in around 5% of cases there is a familial presentation
A number of genetic syndromes are implicated in hereditary pituitary tumours, including Multiple Endocrine Neoplasia Types 1 and 4, Carney Complex, X-linked acrogigantism and McCune-Albright syndrome
Pathogenic variants in the aryl hydrocarbon-interacting protein gene (AIP) gene are increasingly recognised in families with isolated pituitary tumour syndrome, typically causing gigantism, with children as young as 4 years being reported to be affected
Summary
Most pituitary tumours arise sporadically, in around 5% of cases there is a familial presentation. A family history of pituitary disease was elicited in 2017, and targeted sequencing of the AIP gene identified a heterozygous nonsense variant, NM_003977.3:c.910C>T p.(Arg304Ter), in exon 6 His sister, at the age of 36 years, was referred to a different endocrine clinic in the same city in 2006 with a 9-month history of secondary amenorrhoea and galactorrhoea, which persisted after stopping citalopram. Prolactin was elevated at 2,131 mU/l in 2018 with morning testosterone of 7.7 nmol/l (reference > 10 nmol/l), IGF-1 was 210 μg/l (age adjusted reference range 105–410) and MRI showed a 7 mm left-sided pituitary adenoma. He was treated with cabergoline initially 0.5 mg 0.75 mg weekly. There are two remaining female siblings (Fig. 3); one did not have the AIP variant, the other has not given her consent for genetic testing but has a serum prolactin within the reference range and she is of normal height
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