Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study

Abstract

Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0328-1) contains supplementary material, which is available to authorized users.

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

“…XLAG is a condition of early-onset pituitary gigantism due to the germline or somatic mosaic duplication of the GPR101 gene (Trivellin et al 2014, Iacovazzo et al 2016b, Iacovazzo & Korbonits 2018. 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.…”

“…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.…”

Clinical genetic testing in endocrinology: Current concepts and contemporary challenges

“…aCGH detects the majority of structural abnormalities (with the potential exception of balanced translocations) and is commonly used as the first‐line genetic investigation for the children with neurodevelopmental delay or congenital abnormalities, and includes evaluation for the 22q11.2 deletion syndrome and Prader‐Willi syndrome (Table ). Additional methods to detect structural changes include fluorescence in situ hybridization (FISH), which can be designed to identify abnormalities located to specific chromosomal regions (eg translocations); whole‐genome SNP array and droplet digital PCR (ddPCR) to detect CNVs; and multiplex‐ligation dependent probe amplification (MLPA), which is commonly used to detect partial or whole gene deletions associated with several monogenic disorders (eg MEN1 and VHL) (Table ).…”

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 .…”

“…30,31 In one study, patients with sporadic familial acromegaly did not show an increased prevalence of the c.924G > C (p.E308D) GPR101 variant when compared to public databases. 28 Although the specific role of GPR101 in stimulating GH secretion remains elusive, recent evidence supports an effect on GHRH secretion. 7,32 Whether this is the main mechanism leading to pituitary tumorigenesis in XLAG, or that there are additional roles of GPR101 in the pituitary somatomammotroph cells remains to be seen.…”