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.
Highlights
X-linked acrogigantism (XLAG) is a recently identified cause of early-onset pituitary gigantism [1, 2]
We aimed to evaluate the prevalence of Xq26.3 microduplication, a copy number variation (CNV) gain including GPR101, in a large cohort of 153 patients with non-syndromic pituitary gigantism, who were all screened for aryl hydrocarbon receptor-interacting protein (AIP) mutations
Mixed adenomas contain either densely granulated (DG) or sparsely granulated (SG) somatotrophs admixed with lactotroph cells [17, 22]; the coexistence of DG and SG somatotroph cells observed in XLAG-related adenomas has never been formally described to the best of our knowledge
Summary
X-linked acrogigantism (XLAG) is a recently identified cause of early-onset pituitary gigantism [1, 2]. All previously published patients harbor Xq26.3 microduplications encompassing a region of approximately 500Kb [1, 2]. This region contains the locus of the GPR101 gene, encoding an orphan G protein-coupled receptor (GPCR) that is significantly overexpressed in the pituitary samples of XLAG patients. The c.924G > C (p.E308D) GPR101 missense variant was identified in 4.4 % of a series of patients with sporadic acromegaly. This variant was suggested to represent a disease-associated mutation, as it increases cell proliferation and GH release in vitro [1]
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