PITUITARY ADENOMA, FAMILIAL ISOLATED, INCLUDED
SOMATOSTATIN ANALOG, RESISTANCE TO, INCLUDED
ACROMEGALY DUE TO PITUITARY ADENOMA PITUITARY ADENOMA PREDISPOSITION, INCLUDED
ISOLATED FAMILIAL SOMATOTROPINOMA
SOMATOTROPHINOMA, FAMILIAL
SOMATOTROPINOMA, FAMILIAL ISOLATED
FIPA, INCLUDED
PAP, INCLUDED
FIS
IFS
Somatotropinoma
Pituitary adenomas are benign monoclonal neoplasms of the anterior pituitary gland, accounting for approximately 15% of intracranial tumors. Growth hormone (GH; 139250)-secreting tumors, which clinically result in acromegaly, comprise about 20% of all pituitary tumors and are the ... Pituitary adenomas are benign monoclonal neoplasms of the anterior pituitary gland, accounting for approximately 15% of intracranial tumors. Growth hormone (GH; 139250)-secreting tumors, which clinically result in acromegaly, comprise about 20% of all pituitary tumors and are the second most common hormone-secreting pituitary tumor after prolactin (176760)-secreting tumors (600634), which account for 40 to 45% of pituitary tumors. ACTH-secreting tumors, resulting in Cushing disease (219090), and thyrotropin (TSHB; 188540)-secreting tumors are much less common. Nonsecreting pituitary tumors, which account for about 33%, can cause symptoms due to local compressive effects of tumor growth (Vierimaa et al., 2006; Georgitsi et al., 2007; Horvath and Stratakis, 2008). Acromegaly is characterized by coarse facial features, protruding jaw, and enlarged extremities (Vierimaa et al., 2006). Familial isolated somatotropinoma (FIS) is defined as the occurrence of at least 2 cases of acromegaly or gigantism in a family that does not exhibit features of other endocrine syndromes. FIS patients tend to have onset about 4 to 10 years earlier than patients with sporadic disease (Gadelha et al., 1999; Horvath and Stratakis, 2008). Familial isolated pituitary adenoma (FIPA) and pituitary adenoma predisposition (PAP) are terms referring to families in which 2 or more individuals develop pituitary tumors. Within a family, tumor types can be heterogeneous, with members of the same family having GH-secreting, prolactin-secreting, ACTH-secreting, or nonsecreting adenomas; in contrast, some families are homogeneous with regard to tumor type. Familial isolated somatotropinoma refers specifically to GH-secreting tumors and is usually associated with an acromegaly phenotype. Thus, FIS is a subset of FIPA or PAP (Toledo et al., 2007). Familial acromegaly can also occur in association with multiple endocrine neoplasia type I (MEN1; 131100), Carney complex (CNC1; 160980), and the McCune-Albright syndrome (174800).
Levin et al. (1974) reported 2 brothers with acromegaly confirmed by elevated serum GH levels and the finding of pituitary tumors. Both also had acanthosis nigricans.
Jones et al. (1984) reported an uncle and nephew with ... Levin et al. (1974) reported 2 brothers with acromegaly confirmed by elevated serum GH levels and the finding of pituitary tumors. Both also had acanthosis nigricans. Jones et al. (1984) reported an uncle and nephew with acromegaly. The authors considered MEN type I to be unlikely because of the absence of other endocrine disease at an advanced age. Abbassioun et al. (1986) and McCarthy et al. (1990) also reported familial acromegaly. Pestell et al. (1989) described a family in which 5 members over 3 generations had isolated functional pituitary adenomas. Four patients had acromegaly and 1 had galactorrhea from prolactin excess. Affected individuals were related as uncle and nephew or uncle and niece or as second cousins; no parent-child transmission was observed and there was no consanguinity. Pestell et al. (1989) proposed autosomal dominant inheritance with reduced penetrance. The authors considered the disorder in this family to be distinct from MEN1. Links et al. (1993) reported a father and son with acromegaly associated with pituitary adenoma. The adenoma from the son was also found to secrete thyrotropin (see TSHB; 188540) and prolactin. The father was deceased at the time of the report. Gadelha et al. (1999) reported 2 unrelated families with isolated acromegaly/gigantism. In one family, 3 of 4 sibs were affected, with ages at diagnosis of 19, 21, and 23 years. In the other family, 5 of 13 sibs were diagnosed as affected at 13, 15, 17, 17, and 24 years of age. There was no history of consanguinity in either family, and the medical histories and laboratory results excluded MEN1 and the Carney complex. Verloes et al. (1999) reported 3 unrelated families in which 2 members each had acromegaly not associated with other clinical features of MEN1. Two of the 6 patients also had galactorrhea due to prolactin secretion. Age at onset was usually in the twenties. After a review of similar families that had been published, Verloes et al. (1999) concluded that the disorder was a unique entity and showed autosomal dominant inheritance with reduced penetrance. Jorge et al. (2001) reported a Brazilian family with acromegaly due to pituitary adenomas. The proband was a 24-year-old woman who presented with headaches, galactorrhea, menstrual irregularities, and progressive enlargement of hands and feet. Physical examination revealed evident acromegalic facial and acral features. Serum GH (139250) and prolactin were increased. The proband's brother presented at age 29 years with a 10-year history of progressive enlargement of hands, feet, and mandible. Serum growth hormone and insulin-like growth factor-1 (IGF1; 147440) were increased, but prolactin was normal. Other endocrine values were normal in both patients, excluding endocrine syndromes. Their father had acromegalic features confirmed by family pictures; he had died of an unrelated cause at the age of 40 years without endocrine evaluation. Molecular analysis of the sibs excluded germline mutations in the MEN1, GNAS1, GNAI2 (139360), and GHRHR (139191) genes. Vierimaa et al. (2006) described a very large kindred in northern Finland in which multiple individuals had pituitary adenomas, secreting either prolactin (176760) (5) or growth hormone (4); 2 individuals had a mixed tumor secreting both hormones. There were 3 clear cases of acromegaly or gigantism. Genealogy could be traced to the 1700s. Vierimaa et al. (2006) postulated that the phenotype represented a hereditary predisposition to pituitary adenomas (PAP) with very low penetrance. A second family had 2 individuals in 2 generations with somatotropinomas. Compared to patients with sporadic pituitary tumors, those with PAP had a significantly younger age at time of diagnosis (24.7 vs 43.6 years, P = 0.0003), but there were no differences in tumor size or sex distribution. Six of the 15 patients diagnosed under 35 years of age (40%) in the population-based series had PAP.
In affected individuals from a large Finnish family with pituitary adenoma predisposition, Vierimaa et al. (2006) identified a heterozygous germline mutation in the AIP gene (Q14X; 605555.0001). Further screening ... - Germline Mutations in the AIP Gene In affected individuals from a large Finnish family with pituitary adenoma predisposition, Vierimaa et al. (2006) identified a heterozygous germline mutation in the AIP gene (Q14X; 605555.0001). Further screening identified this mutation in 6 of 45 patients from a population-based cohort with acromegaly. Affected Italian sibs were found to have an R304X mutation (605555.0003). Loss of heterozygosity at the AIP locus was detected in all 8 pituitary tumors analyzed, including somatotropinomas, prolactinomas, and mixed-type tumors. In the Brazilian sibs with acromegaly and GH (139250)-secreting pituitary adenomas reported by Jorge et al. (2001), Toledo et al. (2007) identified a heterozygous mutation in the AIP gene (605555.0007). A 41-year-old brother with the mutation was clinically unaffected, but was found on imaging to have a small, apparently nonsecreting pituitary nodule. A 3-year-old boy with the mutation was also unaffected, but was younger than the average age at symptom onset. In 9 of 460 patients from Europe and the U.S. with pituitary adenomas, Georgitsi et al. (2007) identified 9 different germline mutations in the AIP gene (see, e.g., 605555.0004-605555.0006). Eight patients had GH-secreting tumors and acromegaly, and 1 had Cushing syndrome due to an ACTH-secreting tumor (219090). Age at diagnosis ranged from 8 to 41 years. Daly et al. (2007) studied the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma from 9 different countries. 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; 9 of the mutations were novel. Tumors were significantly larger (p = 0.0005) and diagnosed at a younger age (p = 0.0006) in AIP mutation-positive versus mutation-negative subjects. Although somatotropinomas predominated among FIPA families with AIP mutations, mixed GH/prolactin-secreting tumors (600634), prolactinomas, and nonsecreting adenomas were also found. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations. Barlier et al. (2007) did not identify mutations in the AIP gene in 107 European patients with sporadic pituitary adenomas, including prolactinomas (49), somatotropinomas (26), ACTH-secreting tumors (2), TSH-secreting tumors (1), and nonfunctioning tumors (29). One additional patient with a somatotropinoma was found to have a germline mutation in the AIP gene (R22X; 605555.0009). Barlier et al. (2007) concluded that germline AIP mutations are infrequent in patients with sporadic pituitary adenomas. Igreja et al. (2010) analyzed the AIP gene in 38 families with FIPA, in which at least 2 family members had pituitary adenoma without features of MEN1 (131100) or Carney complex (see 160980), and identified mutations in 11 of the families, including 3 with large deletions. The authors reviewed the clinical characteristics of these 38 families and 26 previously reported families (Leontiou et al., 2008), confirming that patients with AIP mutations had a lower mean age at diagnosis. Igreja et al. (2010) noted that overall, AIP mutations were implicated in 20 (31%) of the 64 families in their FIPA cohort. - Somatic Mutations in the GNAS1 Gene Thakker et al. (1993) found somatic mutations in the GNAS1 gene in 2 non-MEN1 somatotropinomas, one of which also demonstrated allele loss of chromosome 11 (see, e.g., 139320.0009). Hayward et al. (2001) noted that approximately 40% of growth hormone-secreting pituitary adenomas harbor somatic mutations in the GNAS1 gene. Mutations at arg201 or glu227 (see, e.g., 139320.0008 and 139320.0010, respectively) constitutively activate the alpha subunit of GNAS1.