SomaticGPR101Duplication Causing X-Linked Acrogigantism (XLAG)—Diagnosis and Management

Abstract

Context:Recent reports have proposed that sporadic or familial germline Xq26.3 microduplications involving the GPR101 gene are associated with early-onset X-linked acrogigantism (XLAG) with a female preponderance.Case Description:A 4-year-old boy presented with rapid growth over the previous 2 years. He complained of sporadic headaches and had coarse facial features. His height Z-score was +4.89, and weight Z-score was +5.57. Laboratory testing revealed elevated serum prolactin (185 μg/L; normal, <18 μg/L), IGF-1 (745 μg/L; normal, 64–369 μg/L), and fasting GH > 35.0 μg/L. Magnetic resonance imaging demonstrated a homogenous bulky pituitary gland (18 × 15 × 13 mm) without obvious adenoma. A pituitary biopsy showed hyperplastic pituitary tissue with enlarged cords of GH and prolactin cells. Germline PRKAR1A, MEN1, AIP, DICER1, CDKN1B, and somatic GNAS mutations were negative. Medical management was challenging until institution of continuous sc infusion of short-acting octreotide combined with sc pegvisomant and oral cabergoline. The patient remains well controlled with minimal side effects 7 years after presentation. His phenotype suggested XLAG, but his peripheral leukocyte-, saliva-, and buccal cell-derived DNA tested negative for microduplication in Xq26.3 or GPR101. However, DNA isolated from the pituitary tissue and forearm skin showed duplicated dosage of GPR101, suggesting that he is mosaic for this genetic abnormality.Conclusions:Our patient is the first to be described with somatic microduplication leading to typical XLAG phenotype. This patient demonstrates that a negative test for Xq26.3 microduplication or GPR101 duplication on peripheral blood DNA does not exclude the diagnosis of XLAG because it can result from a mosaic mutation affecting the pituitary.

Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects

“…XLAG accounted for approximately 10 and 8% of cases in two large independent series of patients with pituitary gigantism, respectively (Rostomyan et al 2015, Iacovazzo et al 2016b. Different from other forms of gigantism, including those linked with AIP mutations and those without a known genetic predisposing factor, where most affected patients are males, XLAG is characterised by a female preponderance, and 24/33 reported XLAG patients are females carrying germline duplications, while somatic mosaic mutations have been identified in the only four reported cases of male patients with sporadic disease (Daly et al 2016b, Iacovazzo et al 2016b, Rodd et al 2016. In three independent families, motherto-son transmission has been described, in all cases with full penetrance (Trivellin et al 2014, Gordon et al 2016.…”

“…XLAG patients present with marked GH excess, in most cases with associated hyperprolactinaemia, caused by mixed somatotrophlactotroph adenomas associated, in some patients, with pituitary hyperplasia. In a minority of patients, the disease is due to pituitary hyperplasia in the absence of a PA. XLAG is very rare, with only 33 confirmed cases described so far in the medical literature (Trivellin et al 2014, Beckers et al 2015, Gordon et al 2016, Iacovazzo et al 2016b, Rodd et al 2016. XLAG accounted for approximately 10 and 8% of cases in two large independent series of patients with pituitary gigantism, respectively (Rostomyan et al 2015, Iacovazzo et al 2016b.…”

Somatic and germline mutations in the pathogenesis of pituitary adenomas

“…(13,125). It is a rare condition and less than 40 cases have been identified so far (13,125,126,127,128,129,130,131). Historically, some of the tallest humans bear clinical features suggestive of X-LAG (132).…”

“…In X-LAG the common duplicated region on chromosome Xq26.3 usually encompasses several genes, among which only GPR101 is differentially overexpressed in the affected pituitary adenoma (13). Indeed, in one X-LAG patient a duplication was identified in which only the GPR101 gene was duplicated (127). Duplications are germline in females and somatic in sporadic males with variable level of mosaicism in the latter (126,127,130).…”

Genetics of gigantism and acromegaly

“…While females present with germline mutations, male patients harbor the mutation in a mosaic state, which could be missed from a peripheral leukocyte-, saliva-, and buccal cell-derived DNA for microduplication in Xq26.3 or GPR101 . 28, 29 In such circumstances, DNA isolated from the pituitary tissue and forearm skin proved essential to show a duplicated dosage of GPR101 29 .…”