Two-Hit Germline and Somatic AIP Mutations in a Pediatric Growth Hormone-Secreting Pituitary Adenoma

Background: Gigantism is an extremely rare pediatric disorder caused by a growth hormone (GH)-secreting pituitary adenoma. While most cases of acromegaly are caused by somatic mutations, ∼50% of gigantism cases have a germline mutation. We present the case an 11-year-old patient found to have a GH-secreting pituitary macroadenoma that was successfully cured with a transsphenoidal resection. Molecular characterization showed a pathogenic heterozygous germline mutation in the AIP gene. Somatic analysis of the tumor tissue revealed a large-scale deletion on chromosome 11 overlapping with AIP leading to biallelic AIP loss.

Case Report: A healthy 11-year-old male presented with symptoms of excessive growth spurt, weight gain, appetite change, behavioral change (aggression, anxiety, and fatigue), and frontal headaches. He was initially referred to a psychiatrist for behavioral issues and started on anxiolytics. Worsening frontal headaches prompted a neurological consult. A 1.1 × 1.9 × 1.8 cm subtly enhancing sellar mass was seen on MRI causing mass effect on the optic chiasm, indicative of a pituitary macroadenoma. Laboratory results showed elevated IGF-1 (864 ng/mL, +4.9 SD) and random GH (19.20 ng/mL) levels. At presentation, patient height was at the 75th percentile, inappropriately high relative to the mid-parental height prediction of 10th-percentile. On exam, he was non-dysmorphic and appeared generally healthy. Endocrine workup was consistent with nonsyndromic GH-secreting adenoma. The mass was resected via an endonasal endoscopic approach. Postoperative MRI confirmed gross-total resection.

Pathology showed an intermediate-grade adenoma with K_i-67 of 3 to 6%. Postoperatively, IGF-1 and GH levels returned to within normal limits within 1 month. Whole-exome sequencing of the peripheral blood revealed a deleterious germline heterozygous mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene, a rare (1/246,000) in-frame variant resulting in the deletion of 8 amino acid residues in a highly conserved functional domain of the AIP protein. This AIP variant is known to cause familial isolated pituitary adenomas (FIPA) with incomplete penetrance (20–23%). Whole-exome somatic sequencing of the tumor tissue revealed a large-scale deletion on chromosome 11, leading to biallelic loss of wild-type AIP. At 4-month follow-up, no evidence of recurrent tumor was seen on MRI. Due to the rare and aggressive genetic and pathologic profile of the tumor, the patient is closely monitored by MRI and serial laboratory testing.

Discussion: GH-secreting pituitary adenomas are known to occur at a higher rate in individuals with genetic syndromes including neurofibromatosis, McCune-Albright, MEN-1 or 4, or Carney complex. Our patient had no findings suggestive of an underlying syndrome. Tumors with AIP mutations are often seen with predisposition for pituitary adenoma (PAP) and FIPA; they can result in adenomas that secrete GH (most common), prolactin, or both. We postulate the intermediate grade of this tumor may be due in part to the two hits of both somatic and germline mutations.

Conclusion: We present a rare and aggressive case of pituitary gigantism with biallelic AIP loss, through a germline heterozygous mutation and somatic deletion, review the case history and pathogenetic aspects of the case, and present a hypothesis for the tumor’s uncommon intermediate mitotic profile.