Clinically relevant pituitary adenomas are present in about 1 per 1,000 of the general population and prolactinomas are by far the most common clinical subtype of pituitary adenomas. Usually ...prolactinomas affect premenopausal women and present with typical symptoms of menstrual disturbance and/or galactorrhea. They are generally managed with dopamine agonists to restore fertility and to control symptoms and tumor size. In a subset of prolactinomas, however, management remains challenging. Studies in recent years have identified the factors related to dopamine agonist resistance, such as male sex, genetic features, and aggressive tumor behavior. Certain other patient groups represent particular challenges for management, such as pediatric patients and pregnant women. Treatment with dopamine agonists is usually safe and effective, and adverse effects such as clinically relevant cardiac valvular complications and impulse control disorders may occur in isolated instances. A number of important disease characteristics of prolactinomas remain to be explained, such as the difference in sex prevalence before and after menopause, the higher prevalence of macroadenomas in older males, and the biochemical mechanisms of resistance to dopaminergic agonists.
Pituitary adenomas are one of the most frequent intracranial tumors and occur with a prevalence of approximately 1:1000 in the developed world. Pituitary adenomas have a serious disease burden, and ...their management involves neurosurgery, biological therapies, and radiotherapy. Early diagnosis of pituitary tumors while they are smaller may help increase cure rates. Few genetic predictors of pituitary adenoma development exist. Recent years have seen two separate, complimentary advances in inherited pituitary tumor research. The clinical condition of familial isolated pituitary adenomas (FIPA) has been described, which encompasses the familial occurrence of isolated pituitary adenomas outside of the setting of syndromic conditions like multiple endocrine neoplasia type 1 and Carney complex. FIPA families comprise approximately 2% of pituitary adenomas and represent a clinical entity with homogeneous or heterogeneous pituitary adenoma types occurring within the same kindred. The aryl hydrocarbon receptor interacting protein (AIP) gene has been identified as causing a pituitary adenoma predisposition of variable penetrance that accounts for 20% of FIPA families. Germline AIP mutations have been shown to associate with the occurrence of large pituitary adenomas that occur at a young age, predominantly in children/adolescents and young adults. AIP mutations are usually associated with somatotropinomas, but prolactinomas, nonfunctioning pituitary adenomas, Cushing disease, and other infrequent clinical adenoma types can also occur. Gigantism is a particular feature of AIP mutations and occurs in more than one third of affected somatotropinoma patients. Study of pituitary adenoma patients with AIP mutations has demonstrated that these cases raise clinical challenges to successful treatment. Extensive research on the biology of AIP and new advances in mouse Aip knockout models demonstrate multiple pathways by which AIP may contribute to tumorigenesis. This review assesses the current clinical and therapeutic characteristics of more than 200 FIPA families and addresses research findings among AIP mutation-bearing patients in different populations with pituitary adenomas.
Pituitary gigantism is a rare manifestation of chronic growth hormone (GH) excess that begins before closure of the growth plates. Nearly half of pituitary gigantism patients have an identifiable ...genetic cause. X-linked acrogigantism (X-LAG; 10% of pituitary gigantism) typically begins during infancy and can lead to the tallest individuals described. In the 10 years since its discovery, about 40 patients have been identified. Patients with X-LAG usually develop mixed GH and prolactin macroadenomas with occasional hyperplasia that secrete copious amounts of GH, and frequently prolactin. Circulating GH releasing hormone (GHRH) is also elevated in a proportion of patients. X-LAG is caused by constitutive or sporadic mosaic duplications at chromosome Xq26.3 that disrupt the normal chromatin architecture of a topologically associating domain (TAD) around the orphan G protein coupled receptor (GPCR), GPR101. This leads to the formation of a neoTAD in which GPR101 over-expression is driven by ectopic enhancers ("TADopathy"). X-LAG has been seen in three families due to transmission of the duplication from affected mothers to sons. GPR101 is a constitutively active receptor with an unknown natural ligand that signals via multiple G proteins and protein kinases A and C to promote GH/prolactin hypersecretion. Treatment of X-LAG is challenging due to the young patient population and resistance to somatostatin analogs; the GH receptor antagonist pegvisomant is often an effective option. GH, insulin-like growth factor 1 (IGF-1) and prolactin hypersecretion and physical overgrowth can be controlled before definitive adult gigantism occurs, often at the cost of permanent hypopituitarism.
In the general population, height is determined by a complex interplay between genetic and environmental factors. Pituitary gigantism is a rare but very important subgroup of patients with excessive ...height, as it has an identifiable and clinically treatable cause. The disease is caused by chronic growth hormone and insulin-like growth factor 1 secretion from a pituitary somatotrope adenoma that forms before the closure of the epiphyses. If not controlled effectively, this hormonal hypersecretion could lead to extremely elevated final adult height. The past 10 years have seen marked advances in the understanding of pituitary gigantism, including the identification of genetic causes in ~50% of cases, such as mutations in the AIP gene or chromosome Xq26.3 duplications in X-linked acrogigantism syndrome. Pituitary gigantism has a male preponderance, and patients usually have large pituitary adenomas. The large tumour size, together with the young age of patients and frequent resistance to medical therapy, makes the management of pituitary gigantism complex. Early diagnosis and rapid referral for effective therapy appear to improve outcomes in patients with pituitary gigantism; therefore, a high level of clinical suspicion and efficient use of diagnostic resources is key to controlling overgrowth and preventing patients from reaching very elevated final adult heights.
Abstract
Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary ...tumors over-expressing the orphan G-protein coupled receptor, GPR101. The role of GPR101 in GH secretion remains obscure. We studied GPR101 signaling pathways and their effects in HEK293 and rat pituitary GH3 cell lines, human tumors and in transgenic mice with elevated somatotrope Gpr101 expression driven by the rat
Ghrhr
promoter (
Ghrhr
Gpr101
)
. Here, we report that Gpr101 causes elevated GH/prolactin secretion in transgenic
Ghrhr
Gpr101
mice but without hyperplasia/tumorigenesis. We show that GPR101 constitutively activates not only G
s
, but also G
q/11
and G
12/13
, which leads to GH secretion but not proliferation. These signatures of GPR101 signaling, notably PKC activation, are also present in human pituitary tumors with high GPR101 expression. These results underline a role for GPR101 in the regulation of somatotrope axis function.
Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors is a matter of interest as ...it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes were known to predispose to pituitary tumor formation. In the last decade, several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggests that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin-specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview of the genetic pathophysiology of pituitary adenomas and their clinical relevance.
Pituitary adenomas occur in a familial setting in multiple endocrine neoplasia type 1 (MEN1) and Carney’s complex (CNC), which occur due to mutations in the genes MEN1 and PRKAR1A respectively. ...Isolated familial somatotropinoma (IFS) is also a well-described clinical syndrome related only to patients with acrogigantism. Pituitary adenomas of all types – not limited to IFS – can occur in a familial setting in the absence of MEN1 and CNC; this phenotype is termed familial isolated pituitary adenomas (FIPA). Over the past 7 years, we have described over 90 FIPA kindreds. In FIPA, both homogeneous and heterogeneous pituitary adenoma phenotypes can occur within families; virtually all FIPA kindreds contain at least one prolactinoma or somatotropinoma. FIPA differs from MEN1 in terms of a lower proportion of prolactinomas and more frequent somatotropinomas in the FIPA cohort. Patients with FIPA are significantly younger at diagnosis and have significantly larger pituitary adenomas than matched sporadic pituitary adenoma counterparts. A minority of FIPA families overall (15%) exhibit mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene; AIP mutations are present in only half of IFS kindreds occurring as part of the FIPA cohort. In families with AIP mutations, pituitary adenomas have a penetrance of over 50%. AIP mutations are extremely rare in patients with sporadic pituitary adenomas. This review deals with pituitary adenomas that occur in a familial setting, describes in detail the clinical, pathological, and genetic features of FIPA, and addresses aspects of the clinical approach to FIPA families with and without AIP mutations.
Abstract
Pituitary adenomas are benign tumors with variable functional characteristics
that can have a significant impact on patients. The majority arise sporadically,
but an inherited genetic ...susceptibility is increasingly being recognized. Recent
advances in genetics have widened the scope of our understanding of pituitary
tumorigenesis. The clinical and genetic characteristics of pituitary adenomas
that develop in the setting of germline-mosaic and somatic
GNAS
mutations
(McCune–Albright syndrome and sporadic acromegaly), germline
MEN1
mutations (multiple endocrine neoplasia type 1), and germline
PRKAR1A
mutations (Carney complex) have been well described. Non-syndromic familial
cases of isolated pituitary tumors can occur as familial isolated pituitary
adenomas (FIPA); mutations/deletions of the
AIP
gene have been
found in a minority of these. Genetic alterations in
GPR101
have been
identified recently as causing X-linked acro-gigantism (X-LAG) leading to very
early-onset pediatric gigantism. Associations of pituitary adenomas with other
tumors have been described in syndromes like multiple endocrine neoplasia type
4, pheochromocytoma-paraganglioma with pituitary adenoma association (3PAs)
syndrome and some of their genetic causes have been elucidated. The genetic
etiologies of a significant proportions of sporadic corticotropinomas have
recently been identified with the discovery of
USP8
and
USP48
mutations. The elucidation of genetic and molecular pathophysiology in pituitary
adenomas is a key factor for better patient management and effective
follow-up.
PDF
