This document summarizes several genetic diseases and syndromes associated with pituitary tumors, including their underlying molecular pathways. It discusses Multiple Endocrine Neoplasia Type 1 caused by MEN1 mutations; Carney complex caused by PRKAR1A mutations impacting G-protein signaling; familial isolated pituitary adenoma potentially caused by AIP mutations in the aryl hydrocarbon receptor pathway; and succinate dehydrogenase-related familial pituitary adenoma impacting mitochondrial metabolism. It also outlines X-linked acrogigantism caused by GPR101 duplications, McCune-Albright syndrome from GNAS mutations, and DICER1 syndrome altering microRNA processing.

1. Genetic Diseases & Syndromes Associated With
Pituitary Tumors

2. In an effort to leverage CCR’s expertise in basic and clinical
research studies of rare tumors, CCR launched the NCI Rare
Tumor Initiative in 2013.

4. Pituitary Tumors
GNAS: G-protein alpha subunit (Gs-α), key component of many signal pathways. MEN1 – menin protein.
PRKAR1A: Protein Kinase 1-Regulatory Subtype-1α. SDH (Succinate dehydrogenase)-related familial
pituitary adenoma = Pituitary adenoma/paraganglioma pheochromacytoma syn.). DICER cleaves dsRNA
and pre-miRNA into siRNA and microRNA. AIP: Aryl-hydrocarbon receptor-interacting protein

5. Pituitary Tumors

6. X-linked acrogigantism
(X-LAG): Early-onset
pediatric gigantism
associated with micro-
duplications in Xq26.3.
SDH-related familial pituitary adenoma = Paraganglioma/
Phaeochromocytoma/Pituitary Adenoma Synd. SDH: Inner
mitochondrial membrane proteins; Human: 4 genes
Involve in oxidative phosphorylation & citric acid cycle.
DICER1
Syndrome:
Pituitary
Blastoma

7. • Multiple Endocrine Neoplasia Type-1:
Wermer’s Syndrome: Rare, 1 in
30,000. Autosomal dominant, MEN1
mutation at 11q13.
• Pancreatic endocrine tumors: 40%
insulinoma.
• Zollinger-Ellison Syndrome: Non–β-cell
tumors may secrete gastrin and can
cause peptic ulcers. About 20-60%
percent of ZES is caused by MEN1.
Pituitary tumors: 15 to 42% of MEN1 patients. 25 to 90%: Prolactinomas. 25%
secrete GH or GH+Prolactin. Acromegaly & Galactorrhea

8. Menin activates genes of cell differentiation and represses proliferative and anti-
apoptotic proteins. Its defect causes apoptosis-resistance, cell proliferation and
loss of cell differentiation.
Menin is a
tumor
suppressor
protein in
cell nucleus
and inhibits
transcription
factor junD.

9. Carney Complex: Autosomal
dominant. Mutation in
PRKAR1A encoding PKA-
Regulatory subunit type 1-
alpha at 17q23-q24.
PPNAD: Primary Pigmented
Nodular Adrenocortical Disease –
high cortisol.
LAMB: Lentigines (flat skin
pigmentations),
Atrial myxomas, Blue nevi.
NAME: Nevi, Atrial myxoma,
Myxoid neurofibroma,
Ephelides (freckles).

10. (A) Family Pedigree of Carney
Complex Arrow: Proband. (B)
Moon face. (C) Abdominal
obesity & red striae. (D) Earlobe
Skin myxoma. (E) Spotty
pigmentations on the legs.
(A) Ephelids, (B) Lentigines, (C)
Cutaneous & (D, E) Mammary
myxomas, (F) Nevus

11. PRKAR1 is downstream of GCR and G-Protein Signaling. G-Protein: Guanin
Nucleotide Binding Protein, composed of 3 subunits. Transmits membrane stimuli
to cytosol via hydrolizing GTP and activating adenylate cyclase.

12. Familial – Isolated (No
pheochr & paragangliom).
In 20% of families, a
responsible gene has been
identified causing the
disease, called Aryl
hydrocarbon receptor
Interacting Protein, AIP.
Autosomal dominant. AIP
gene localizes at 11q13.3.
Mostly somatotropinomas
± prolactinomas.
In 80% of FIPA-families, the responsible gene is not
known. Tumors in these families most commonly
secrete GH or prolactin. They may also be non-
functional or very rarely secrete ACTH and cause
Cushing’s Disease.

13. AIP interacts with the aryl hydrocarbon receptor, peroxisome proliferator-activated receptor
alpha and the aryl hydrocarbon receptor nuclear translocator.

14. McCune–Albright syndrome is suspected when two of these features are present:
Autonomous endocrine hormone excess, such as in precocious puberty.
Polyostotic fibrous dysplasia. Unilateral café au lait spots
GNAS gene 20q12.3-q-13.3. GNAS encodes G-Protein Subunit-α. One child
with MAS may be entirely healthy, with no bone or endocrine problems, enter
puberty at normal age, and have no unusual skin pigmentation.

15. G protein-coupled
receptors (GPCRs) have 7
transmembrane
domains and transduce
extracellular signals
through heterotrimeric
G-proteins.
GNAS-gene encoded
GNAS protein is the
stimulatory G-protein
subunit (Gs-α), a key
component of many
signal transduction
pathways.

16. Phaeochromocytoma/paraganglioma
and pituitary adenoma – Succinate
dehydrogenase related familial
pituitary adenoma.
PHD is HIF-α prolyl hydroxylase.
During normal oxygen supply, pVHL
and PHD triggers degradation of HIF1-
α.
Native and metabolic hypoxia
activates HIF dimerization, its
translocation to nucleus and
activation of proliferative &
angiogenic genes.
Heterogenous genetic background: 4
different SDH proteins & 4-different
encoding genes (B, C, D were found
mutant)

17. SDH mutations cause depletion
of fumarate…
thereby; relieves the inhibition
on α-ketoglutarate.
α-ketoglutarate stimulates
tumorigenesis
A) By blocking prolylhydroxylase
(PHD)-mediated degradation
of HIF-1α.
B) By epigenetic changes
involving demethylation of
DNA and histones.

18. DICER-1 Syndrome: Pituitary Blastoma
DICER1 syndrome is an inherited disorder that increases the risk of a variety of benign and
malignant tumors, commonly tumors in lungs, kidneys, ovaries, and thyroid. DICER1 gene
(14q32.13)-encoded protein Dicer (also known as helicase with RNase motif) cleaves dsRNA and
pre-miRNA into short double-stranded RNA fragments called small interfering RNA and
microRNA. Dicer facilitates the activation of the RNA-induced silencing complex (RISC), which is
essential for RNA interference.

20. X-Linked Acrogigantism: X-LAG Syndrome
• X-LAG is a new syndrome of
pituitary gigantism, caused by
microduplications on
chromosome Xq26.3,
encompassing a GPCR
gene GPR101, which is highly
upregulated in pituitary tumor.
• Patients had hypersecretion of
GH/IGF-1 and prolactin, usually
due to a pituitary macroadenoma
or hyperplasia.

21. Representative cases: (A) Patient age: 32 mo, height >4 SDS (age of onset of
abnormal growth – AOAB: 11 mo). Large hands & feet. Facial features moderately
coarsened but proportioned. (B) Spaced teeth and acanthosis nigricans on neck. (C)
Patient age: 33 mo. – AOAB: 3 mo, height>5 SDS. Large hands & feet. (D) Her facial
features: Large nose, prominent mandible, hypertelorism.
X-Linked Acrogigantism: X-LAG Syndrome

22. • Pathways Associated with Menin: Multiple Endocrine Neoplasia, Type-1
• Pathways associated with G-Protein and GPCR
A) GNAS – G Protein Subunit Alpha: McCune Albright Syndrome
B) GPCR – GPR101 mutation: X-Linked Acrogigantism
C) PRKAR1A: Downstream of G-Protein – GPCR Interaction: Carney Complex
• Pathways Associated with Aryl Hydrocarbon Receptor Signaling: FIPA, Familial Isolated
Pituitary Adenoma
• Pathway Associated with Mitochondrial Metabolism
A) Succinic Acid Dehydrogenase: Paraganglioma/ Phaeochromocytoma/Pituitary Adenoma
Syndrome
• Pathway Associated with mi-RNA Processing: DICER1 Syndrome
AN OVERVIEW OF MOLECULAR PATHWAYS IN PITUITARY TUMORIGENESIS
ILLUMINATED VIA RESEARCH ON GENETIC DISEASES