Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood.
Researchers performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly.
Microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism was observed; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases.
All the patients had disease onset during early childhood.
Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years.
Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein–coupled receptor, was overexpressed in patients' pituitary lesions.
A recurrent GPR101 mutation ( p.E308D ) in 11 of 248 patients with acromegaly was identified, with the mutation found mostly in tumors.
When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone–producing cells.
Researchers have described a pediatric disorder ( which they have termed X-linked acrogigantism [ X-LAG ] ) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone.
Duplication of GPR101 probably causes X-LAG.
A recurrent mutation in GPR101 in some adults with acromegaly was also found. ( Xagena )
Trivellin G et al, N Engl J Med 2014; 371:2363-2374