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Mutant gene linked to acromegalic gigantism
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Four Irish families with histories of acromegalic gigantism may share more than a condition with the famous 18th-century Irish giant Charles Byrne: They may have a common ancestor as well.
In a study conducted in the United Kingdom, Charles Byrne was shown to have a mutation of the aryl-hydrocarbon-interacting protein gene (AIP): c.910→T, p.R304X. Four of 140 families with familial isolated pituitary adenoma also exhibited the same mutation, and all four families were based in Ireland. Overall, the researchers identified 51 carriers of the disease, although only 14 had adenomas. Of these, eight cases experienced childhood onset of the disease.
“We know that AIP mutation can occur in seemingly sporadic patients with childhood-onset acromegaly,” Márta Korbonits, MD, PhD, who led the study, told Endocrine Today. “However, if there is also a family history of childhood-onset acromegaly, then an AIP mutation is almost certainly the cause.”
What prompted Korbonits, of the Barts and The London School of Medicine at Queen Mary University of London, and colleagues to investigate the four families’ potential connection to Byrne was their proximity to his birthplace.
Byrne was born in 1761 in Northern Ireland, and experienced rapid growth during adolescence. By age 19 years, he regularly used his considerable height of 231 cm to attract attention in street shows and eventually traveled to London to perform in similar venues. Byrne’s health, however, soon deteriorated, and he died at the age of 22 years.
A historical sketch shows Byrne alongside twin brothers — also giants — who were reportedly born in a village near his birthplace. Sources indicate that they were Byrne’s cousins, a fact that alone suggested a genetic cause for the condition, according to Korbonits.
Eventually, Byrne’s body fell into the hands of surgeon John Hunter and was exhibited in the Hunterian Museum. In 1909, curator Sir Arthur Keith and renowned American neurosurgeon Harvey Cushing, MD, opened the skull and concluded that Byrne’s gigantism was related to a pituitary adenoma. Radiography performed in 1980 revealed unfused epiphyses at the time of Byrne’s death, with his bone age only appearing to be approximately 17 years, suggesting that this patient suffered from hypogonadism and this allowed his ongoing growth.
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Source: Márta Korbonits, MD,
PhD |
For the current study, two teeth from Byrne’s skull yielded enough DNA for analysis, and sequencing results indicated that the four Irish families and Byrne shared a common haplotype spanning 2.68 megabases of a region on chromosome 11q13. The researchers noted, however, that a sporadic case of gigantism in a patient from India, who also harbored the same mutation but not the haplotype around the gene, is suggestive that not all cases of R304X mutation have the same common ancestor.
Supposing that a generation is 25 years, the researchers estimated that the most recent common ancestor lived about 57 to 66 generations ago, or between 1,425 and 1,650 years ago. Now, they said, living carriers of this mutant allele could number in the hundreds.
At the end of the 19th century, some physicians suggested that acromegaly is an acquired condition whereas gigantism is congenital.
“With data emerging on AIP mutations in patients with familial acromegaly, it appears that this old dogma might, ultimately, have some truth, since we have now shown that one of the most famous giants in the medical literature did indeed harbor an inherited predisposition to the disease, and that the mutation responsible for this predisposition persists in the contemporary population of Ireland,” the researchers wrote.
These findings, Korbonits said, have significant clinical potential. She pointed out that physicians may now prevent the development of gigantism in the future.
“If there is childhood-onset pituitary adenoma or a family history
of pituitary adenoma, then genetic testing should be considered,” she
said. “Families should be screened and followed.”
– by
Melissa Foster
For more information:
- Chahal HS. N Engl J Med. 2011;364:43-50.
- For more information on familial isolated pituitary adenoma, visit www.fipapatients.org
Disclosure: Dr. Korbonits reports no relevant financial disclosures.
Dr. Korbonits and her colleagues have conducted an elegant study demonstrating the heritability of a gene mutation harbored in Irish families with gigantism. The historical interest of this study underscores the advances made in genetics, as well as understanding pituitary disease pathogenesis. Hopefully, increasing numbers of gene mutations will become manifest and enable comprehensive future screening of patients predisposed to endocrine tumors.
– Shlomo Melmed, MD, FRCP
Endocrine Today Editorial Board member
Disclosure: Dr. Melmed reports no relevant disclosures.