Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects

Abstract

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101. We studied XLAG syndrome patients (N=18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome were identified with Xq26.3 duplications using high definition array comparative genome hybridization (HD-aCGH). We noted males with XLAG had a decreased log2 ratio compared with expected values, suggesting potential mosaicism, while females showed no such decrease. As compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1-53.8%. These characteristics were replicated using a novel, personalized breakpoint-junction specific quantification droplet digital PCR (ddPCR) technique. Using a separate ddPCR technique we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism and identified one female gigantism patient that had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.

Characterization of GPR101 transcript structure and expression patterns

“…We have shown that microduplications in X-LAG patients can occur constitutionally or as somatic mosaicism (Daly, et al 2016b). Patients with X-LAG present with mixed growth hormone (GH) and prolactin (PRL)-secreting pituitary macroadenomas and/or hyperplasia before five years of age (Beckers, et al 2015).…”

Childhood acromegaly due to X-linked acrogigantism: long term follow-up

“…Dysregulation of GH secretion may explain why the patient grew normally for years, but had repeated testing consistent with GH deficiency. Additionally, somatic mosaicism has been identified in the pathogenesis of X-LAG syndrome in males, with sporadic cases more affected than familial cases [8]. …”

Combined treatment with octreotide LAR and pegvisomant in patients with pituitary gigantism: clinical evaluation and genetic screening

“…Recently another genetic cause of pituitary adenomas-X-LAG due to a microduplication on Xq26.3-was described in cases with a phenotype of infant-onset gigantism. X-LAG is distinct from AIP mutation-related somatotropinomas in terms of greater female predominance and a significantly younger age at presentation, but is also SRL resistant [2, 4,10,11].…”

“…Patients also underwent high density-array comparative genomic hybridization (HD-aCGH) to search for constitutive or somatic mosaic Xq26.3 duplications, as previously described [2,10]. Disease control was defined as an age/-sex-adjusted IGF1 level less than upper limit of normal (ULN) and a GH level less than 1 ng/ml at last follow-up (for those patients who were not treated with pegvisomant), and shrinkage or unchanged size of the pituitary lesion on MRI.…”