Is Your Pituitary Tumor Genetic? Key Signs and Testing Guidelines

We’re delighted to share this article by Dr. Jennifer Perkins on genetics and pituitary disease, a subject of great interest to our community. If you follow our work, you know we’ve published extensively on this topic, including articles and interviews featuring the breakthrough research of Dr. Marta Korbonits. If you’re new to PWN, you can explore those articles here.

From Jennifer Perkins, MD, MBA,  Co-director of UCSF’s endocrine neoplasia program, Executive Medical Director ambulatory, and PWN contributor –  Genetic Syndromes Associated with Pituitary Tumors  –  Pituitary adenomas are benign and make up about 10% of all intracranial tumors and are seen in 10-20% of people when looking at MRI (Magnetic Resonance Imaging) or autopsy studies. However, pituitary adenomas only become clinically significant in about 1 in 1,000 people (0.1%) with an annual incidence of 3-5 cases per 100,000 persons per year. Most, about 95% are sporadic meaning there is no genetic cause however, some arise due to genetic reasons. The section below outlines several genetic causes, what type of pituitary tumors are typically seen in these conditions, what are the associated features, and when testing is indicated. In general, genetic testing should be considered in patients with,

• Pituitary adenoma diagnosed <30 years of age
• Macroadenomas that are aggressive or tumors that are treatment resistant
• Family history of pituitary tumors or endocrine neoplasia syndromes
• Syndromic features suggestive of a genetic cause such as hyperparathyroidism, NETs (neuroendocrine tumors), gigantism, etc.

MEN1 and AIP-related disease account for the majority of heritable causes.

Multiple Endocrine Neoplasia Type 1 (MEN 1)

• Gene: MEN1
• Pituitary tumors: Prolactinomas most common; GH (Growth hormone) and ACTH-secreting tumors (Cushing’s) also occur
• Associated features: Primary hyperparathyroidism (hallmark feature seen in >98% and often early in the disease expression), pancreatic neuroendocrine tumors (gastrinomas, insulinomas), adrenal tumors, and facial angiofibromas
• Testing indication: Any pituitary adenoma with hyperparathyroidism, pancreatic NETs, or family history
• Recommended test: Germline MEN1 sequencing ± deletion/duplication analysis

Familial Isolated Pituitary Adenoma (FIPA)

• Gene: AIP (most common); GPR101 (X-linked gigantism subset)
• Pituitary tumors: GH-secreting adenomas (often large, aggressive tumors), prolactinomas
• Associated features: Young age of onset (<30 years old), macroadenomas, resistance to somatostatin analogs, family history of pituitary tumors without other MEN features
• Testing indication: Young patients with macroadenomas or familial pituitary tumors
• Recommended test: AIP sequencing; GPR101 if gigantism/early-onset acromegaly

X-Linked Acrogigantism (XLAG)

• Gene: GPR101 duplication on the X chromosome
• Pituitary tumors: GH and PRL (prolactin) secreting adenomas or pituitary hyperplasia
• Associated features: Gigantism in infancy or early childhood typically less than 2 years of age, rapid linear growth, elevated GH/IGF-1. More severe of a presentation than that seen in AIP related GH tumors.
• Testing indication: Childhood-onset gigantism
• Recommended test: GPR101 duplication analysis

Carney Complex

• Gene: PRKAR1A (most common)
• Pituitary tumors: GH-secreting adenomas or hyperplasia
• Associated features: Spotty skin pigmentation (lentigines), cardiac myxomas, primary pigmented nodular adrenal disease (PPNAD leading to Cushing syndrome), testicular tumors
• Testing indication: Acromegaly with lentigines, myxomas, or adrenal Cushing syndrome
• Recommended test: PRKAR1A sequencing

McCune–Albright Syndrome

• Gene: Somatic activating mutations in GNAS (mosaic; not inherited)
• Pituitary tumors: GH-secreting adenomas or hyperplasia
• Associated features: Café-au-lait macules (coast of Maine), polyostotic fibrous dysplasia, precocious puberty, hyperthyroidism (overactive thyroid)
• Testing indication: Acromegaly with fibrous dysplasia or café-au-lait lesions
• Recommended test: GNAS mutation testing on affected tissue (blood often negative)

Multiple Endocrine Neoplasia Type 4 (MEN4)

• Gene: CDKN1B
• Pituitary tumors: Similar to MEN1 (prolactinomas, GH adenomas)
• Associated features: Hyperparathyroidism, neuroendocrine tumors; MEN1-like phenotype but MEN1-negative
• Testing indication: MEN1 phenotype with negative MEN1 testing
• Recommended test: CDKN1B sequencing

Succinate Dehydrogenase–Related Tumor Syndromes

• Genes: SDHA, SDHB, SDHC, SDHD, SDHAF2
• Pituitary tumors: Rare; often aggressive adenomas (GH or PRL)
• Associated features: Paragangliomas, pheochromocytomas, renal cell carcinoma, gastrointestinal stromal tumors
• Testing indication: Pituitary adenoma plus personal or family history of paraganglioma/pheochromocytoma
• Recommended test: SDHx gene panel

DICER1 Syndrome (Rare)

• Gene: DICER1
• Pituitary tumors: Rare pituitary blastoma (infancy/early childhood)
• Associated features: Pleuropulmonary blastoma, ovarian Sertoli–Leydig tumors, thyroid nodules/cancer
• Testing indication: Pediatric pituitary tumors with syndromic features
• Recommended test: DICER1 sequencing

About Jennifer Perkins, MD, MBA – Dr. Jennifer Perkins is an endocrinologist who specializes in endocrine neoplasia (tumors of hormone-producing glands, such as adrenal, thyroid and parathyroid tumors) with a focus in thyroid cancers and familial adrenal tumors. As co-director of UCSF’s endocrine neoplasia program, she works with surgeons, radiation oncologists, medical oncologists and other endocrinologists to care for her patients.  Read more about Dr. Perkins here.

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