Introduction: Pituitary gigantism is a rare disorder caused by GH-secreting lesions.
Aim: We studied gigantism for genetic defects.
Methods: We performed genome-wide analyses in 46 patients with gigantism and 248 patients with acromegaly.
Results: We detected a novel microduplication at chromosome Xq26.3 in two unrelated kindreds and 13 sporadic cases de novo. All patients had disease onset before five years of age and presented with mixed GH/prolactin-secreting macroadenomas and/or hyperplasia. All sporadic cases harbored non-recurrent duplications, whereas familial cases inherited the duplications from their mothers. Breakpoint junctions revealed microhomology, suggesting a replicative mechanism for their formation. Patients shared a common duplicated region of ~500 kb containing four protein-coding genes, of which only GPR101, a G-protein coupled receptor (GPCR) that activates cAMP signaling, was consistently over-expressed in patients pituitary lesions. Low GPR101 expression levels were seen in non-duplicated GH-secreting tumors and in most normal adult human tissues, including the pituitary. On the contrary, high expression was observed in human fetal pituitary. Adult pituitaries of both rhesus monkey and rat expressed GPR101 but in different cell types. In the developing zebrafish embryo a strong and brain-specific GPR101 staining (including in the hypothalamus and pituitary) was seen.
Conclusions: We describe a new genomic disorder caused by Xq26.3 microduplications (X-LAG for X-linked Acro-Gigantism) and characterized by early-onset gigantism. This syndrome is likely caused by overexpression of GPR101, a dosage-sensitive GPCR that activates the cAMP pathway, whose mitogenic effects in pituitary somatotropes are well established. The brain is the major site of GPR101 expression across different species, although divergent species- and developmental stage-specific expression patterns are evident, especially concerning the pituitary. These differences might reflect the very different growth, development and maturation patterns among species. GPR101 may also be mutated in adult patients with acromegaly.
Disclosure: This work was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.