History of Familial Pituitary Adenomas


Reports of familial pituitary adenomas date back to more than a century ago, though information is sparse. The term acromegaly was first used by Pierre Marie in 1886 but patients with acromegaly have been described much earlier. It was only at the beginning of the 20th century with post-mortem examinations of patients with acromegaly that it became clear that the cause of acromegaly was associated with pituitary adenomas and that gigantism had a similar cause with onset of the disease during childhood (de Herder, 2008). The first recorded patients with isolated familial acromegaly, as far as we understand, are Baptiste and Antoine Hugo in the early 20th century. Their heights were 2.30 m and 2.25 m and they had 3 brothers and 2 sisters of normal height (Figure 1). The report describes typical features of acromegaly including hypogonadism, osteoporosis, frontal bossing, prognathism and enlarged internal organs. Post-mortem examination of Antonio Hugo revealed a huge pituitary adenoma (50 x 25 x 23 mm) with suprasellar, retrosellar and left parasellar expansion (de Herder, 2008).

Familial isolated (i.e. no other organ's tumour is associated) pituitary adenomas were not formally described until 1967, when a prolactinoma family was reported (Linquette et al., 1967). This was followed by a description of two acromegaly family (Levin et al., 1974; Himuro et al., 1976) and later a corticotroph adenoma family (Salti & Mufarrij, 1981) and slowly isolated familial pituitary adenomas became appreciated as a new clinical disease (Pestell et al., 1989; McCarthy et al., 1990). Currently over 200 families have been described with familial isolated pituitary adenomas, however, this number will increase as this condition is being more recognised.

In 1995 a family with 3 patients affected by gigantism or acromegaly was described with no association to the immediate vicinity of the MEN1 gene locus (Benlian et al., 1995). In 1997, loss of heterozygosity (LOH) on chromosome 11q13 was reported in pituitary adenomas of 2 siblings with familial acromegaly. This locus comprised the MEN1 gene, so it was suggested that familial acromegaly was either an alternative form of the MEN1 syndrome, or there was an independent gene at the locus nearby which was involved in the pathogenesis (Yamada et al., 1997). A study on 2 additional families confirmed the involvement of the 11q13 locus (Gadelha et al., 2000). The hypothesis of an independent gene was later confirmed by a study on 8 novel families (Soares et al., 2005). Subsequently the original 4 families with association to the 11q13 area (Benlian et al., 1995; Yamada et al., 1997; Gadelha et al., 2000) as well as 4 of the 8 subsequent families with LOH at 11q13 were shown to harbor an AIP mutation (Figure 2) (Iwata et al., 2007; Leontiou et al., 2008) following the identification of the AIP gene (Vierimaa et al., 2006).

Recently a number of IRISH FAMILIES have been genetically linked to a patient in the 18th century. If you would like to read further on this topic, please click here.


Erdheim was the first to describe familial pituitary tumors to occur in the setting of MEN in 1903 (Erdheim J., 1903). Wermer later described a family with four sisters affected with pituitary adenomas, hypercalcemia and adenomatosis of the pancreas and gut. He suggested that the condition was inherited in an autosomal dominant pattern (Wermer P., 1954). In 1989 the MEN1 locus was assigned to Chromosome 11 (11q13) (Thakker, NEJM, 1989). In 1997 the MEN1 gene was cloned (Chandrasekharappa, Science, 1997 and Lemmens, Human Molecular Genetics, 1997).

Carney complex

This syndrome was first described by Aidan Carney in 1985, as "the complex of myxomas, spotty pigmentation and endocrine overactivity" after a thorough study of 40 patients, among whom 10 were familial. Additional evidence for unifying this coexistence of otherwise rare conditions in a unique syndrome was the young age at presentation and the unusual type of involvement of most affected sites, that tended to be multicentric (heart and skin) and bilateral in paired organs (adrenal, breast, and testis). One year later Carney reported observations consistent with a Mendelian dominant inheritance of the syndrome that was designated as Carney complex (CNC) by Bain. This new entity allowed the inclusion of patients presenting cardiocutaneous lesions previously characterized as LAMB (lentigines, atrial myxoma, mucocutaneous myxoma, blue nevi) or NAME (nevi, atrial myxoma, myxoid neurofibroma, ephelide). In 1996 Stratakis et al. using linkage analysis reported a locus potentially linked to CNC on chromosome 2p16, close to the gene encoding proopiomelanocortin and the DNA-mismatch repair genes hMSH2 and hMSH6. However, in 1997, the syndrome was shown to be genetically heterogeneous, and in 1998, a second possible locus located on chromosome 17q2 was also detected. In 2000, two different groups demonstrated that germline mutations in the gene coding the protein kinase A R1alpha regulatory subunit (PKAR1A) located on the locus 17q22-24 were responsible for several phenotypes of CNC. (source: http://www.endotext.org/adrenal/adrenal21/adrenal21.htm)

Figure 1. The Hugo brothers, Baptiste (2.30m, 1887-1914) and Antoine Hugo (2.25m, 1876-1916). The first documented case of possible isolated familial acromegaly. Baptiste and Antoine Hugo tower in height above the rest of their immediate family.