Adrian F. Daly

CONTEXT: An association between germline aryl hydrocarbon receptor-interacting protein (AIP) gene mutations and pituitary adenomas was recently shown. OBJECTIVE: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA). DESIGN: This was a multicenter, international, collaborative study. SETTING: The study was conducted in 34 university endocrinology and genetics departments in nine countries. PATIENTS: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis. MAIN OUTCOME MEASURES: Presence/absence and description of AIP gene mutations were the main outcome measures. INTERVENTION: There was no intervention. RESULTS: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. CONCLUSIONS: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.

Structural variants (SVs) that disrupt topologically associating domains can cause disease by rewiring enhancer-promoter interactions. Duplications involving GPR101 are known to cause X-linked acrogigantism (X-LAG) through ectopic GPR101 expression, but not all of these duplications are pathogenic. This presents a diagnostic challenge, especially in the prenatal setting. We evaluated POSTRE, a tool that predicts the regulatory impact of SVs, to distinguish pathogenic from benign GPR101 duplications. We analyzed seven non-pathogenic duplications and 27 known X-LAG-associated duplications. To enable predictions in an X-LAG-relevant tissue, enhancer maps built using H3K27ac ChIP-seq, ATAC-seq, and RNA-seq data derived from human anterior pituitary samples (NIH research protocol 97-CH-0076, Clinicaltrials.gov Identifier NCT00001595, submitted on 11 March 1999) were integrated into POSTRE. POSTRE correctly classified all 34 duplications as benign or pathogenic. In addition, one X-LAG case with mild clinical features (i.e. severe growth hormone hypersecretion without pituitary tumorigenesis) was found to include only 2/5 VGLL1 enhancers, whereas all typical X-LAG cases had ≥4 enhancers duplicated. This suggests that partial enhancer hijacking at VGLL1 could explain the different clinical features in this individual. These findings support the utility of POSTRE to support diagnostic pipelines when interpreting SVs affecting chromatin architecture in pituitary disease and highlight its potential to reduce uncertainty in genetic counseling without requiring chromatin conformation capture assays.

We describe for the first time the case of a woman presenting with Tatton-Brown-Rahman syndrome (TBRS) and multiple endocrine neoplasia (MEN). She developed primary hyperparathyroidism at age 13, a pituitary cyst at age 14, adrenal tumor at age 21, and metastatic insulinoma at age 34. In addition, she showed intellectual disability, obesity, multiple lipomas, facial dysmorphia, hemihypertrophy and kyphoscoliosis. At age 35, genome analysis revealed a pathogenic de-novo heterozygous germline DNMT3A variant, while classic MEN syndromes were ruled out by targeted somatic and germline genetic testing. This case highlights not only the importance of genomic analysis in patients with multiple and atypical conditions, but also the need for a multidisciplinary approach for TBRS patients, including in adulthood, involving endocrinologists to enhance understanding and optimize monitoring of this syndrome.