Chromosome Xq26.3 Duplication Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene duplication syndrome (chrX:135.6-136.1, GRCh37).

Description

X-linked acrogigantism (XLAG), due to microduplications of chromosome Xq26.3, is characterized by excessive growth, usually beginning during the first year of life in previously normal infants. The overgrowth is caused by growth hormone (GH1; 139250) hypersecretion from pituitary hyperplasia and/or a pituitary macroadenoma. XLAG can occur as a sporadic condition or present as familial isolated pituitary adenomas (FIPAs) in acrogigantism kindreds (Beckers et al., 2015).

Clinical Features

Bergamaschi et al. (2010) reported the clinical features of a 3.4-year-old girl with gigantism due to a growth hormone/prolactin-secreting adenoma.

Glasker et al. (2011) reported a mother and 2 sons with early-onset gigantism and high levels of growth hormone and prolactin. The mother and older son had pituitary adenoma, while the younger son had diffuse hyperplasia of mammosomatotrophs with no evidence of adenoma. The mother had been reported by Espiner et al. (1981) as 'the youngest example of verified pituitary gigantism on record.'

Trivellin et al. (2014) studied 43 patients with nonsyndromic gigantism without abnormalities in genes associated with pituitary tumors. Genetic analyses delineated 2 phenotypes: an early-childhood form of gigantism with a typical onset in late infancy, and a second form with a typical onset in adolescence. Microduplications on chromosome Xq26.3 were detected in 14 patients (including the patients reported by Bergamaschi et al. (2010) and Glasker et al. (2011)) with the early-childhood form; 5 patients, including 1 mother who was deceased, were from 2 unrelated kindreds, and 9 patients were sporadic cases. The median age of onset for patients carrying the microduplication was 1 year, with a range of 0.5 to 2 years. The median age at diagnosis was 3 years, with a range of 1 to 22 years. Median height at diagnosis was 116 cm (+3.8 SD, range = +1.9 to +7.1 SD). All had elevated levels of growth hormone and insulin-like growth factor-1 (IGF1; 147440) at diagnosis; none showed suppression of growth hormone during oral glucose tolerance test. Ninety-three percent showed elevated prolactin (176760) levels at diagnosis. Ten patients had adenoma only; 2 patients had both adenoma and hyperplasia; and 1 had hyperplasia only. Ten of the 14 patients with microduplication were female and were of normal size at birth. Precocious puberty was not observed in microduplication carriers. Hormonal control was not achieved in any of the patients by medical therapy alone. Such control required either radical or repeated neurosurgery alone alone (in 4 patients) or in combination with the administration of the growth hormone receptor antagonist pegvisomant (in 3 patients) or radiotherapy (in 2 patients). Seven patients had permanent hypopituitarism at the time of the study.

Beckers et al. (2015) reported 18 patients with XLAG syndrome, including 13 previously studied by Trivellin et al. (2014). There were 2 families with 3 and 2 affected members, and 13 sporadic cases. All patients had pituitary abnormalities at diagnosis, 14 of which appeared to be a macroadenoma on MRI, whereas the remaining cases showed pituitary enlargement without an identifiable adenoma. Tumor extension to the optic chiasm was frequent (12 cases), whereas invasion of the cavernous sinus was present in only 2 patients at diagnosis. Beckers et al. (2015) stated that a unifying feature of XLAG syndrome is the strikingly early age at onset, given that the children appear clinically normal at birth.

Pathogenesis

Daly et al. (2016) analyzed tissue from a pituitary tumor resected from a 2-year-old girl with XLAG syndrome. The tumor was determined to be a combination of extensive GH/prolactin-positive hyperplasia of the anterior pituitary with an atypical mixed GH/prolactin adenoma, and staining for somatostatin receptor subtypes 2 (SSTR2; 182452) and 5 (SSTR5; 182455) was moderate to high. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Coincubation with GHRH and a GHRH receptor antagonist blocked the GHRH-induced GH stimulation, and the GHRH receptor antagonist alone significantly reduced GH release. The multi-receptor somatostatin analog pasireotide, but not octreotide, which mainly targets SSTR2, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. Daly et al. (2016) concluded that GHRH hypersecretion can accompany the pituitary abnormalities seen in XLAG syndrome, and suggested that the pathology of the disorder may include hypothalamic dysregulation of GHRH secretion, consistent with localization of GPR101 (300393) in the hypothalamus.

Iacovazzo et al. (2016) studied 12 patients with XLAG, including 10 female patients with germline duplications and 2 male patients who exhibited mosaicism for duplications at Xq26.3 (see CYTOGENETICS). In 9 (75%) of the patients, macroadenomas were present, all of which showed suprasellar extension. However, MRI in 3 (25%) of the patients showed diffuse enlargement of the gland, suggestive of pituitary hyperplasia rather than a distinct adenoma. The authors noted that features of the XLAG-related pituitary adenomas were remarkably similar, with most patients developing mixed somatotroph/lactotroph adenomas showing a characteristic sinusoidal and lobular architecture and containing both densely granulated and sparsely granulated somatotroph cells. Microcalcifications and follicle-like structures were common, and mitotic activity was generally low.

Somatic Mosaicism

Daly et al. (2016) studied 18 patients with XLAG, including 15 previously reported patients (Trivellin et al., 2014; Beckers et al., 2015; Naves et al., 2016). The patients' duplications were all unique, ranging in size from 554 to 674 kb, with variable boundaries; all included the GPR101 gene. High-density array comparative genomic hybridization revealed decreased log(2) ratios in all 6 male patients, consistent with somatic mosaicism, whereas none of the female XLAG patients showed evidence of mosaicism. The levels of duplication were lower in 3 sporadic cases than in 3 familial cases. Quantitative droplet digital PCR (ddPCR) confirmed low-level mosaicism in the sporadic cases (approximately 59%, 29%, and 18%, respectively) compared to the familial cases, in whom the mosaicism level was intermediate between that of the sporadic cases and the lack of mosaicism in the female XLAG patients. Daly et al. (2016) concluded that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at Xq26.3 in male patients. Noting that the clinical characteristics of the disease were similarly severe in both sexes, they suggested that the impact of X-chromosome inactivation in female XLAG patients should be considered.

Clinical Management

Beckers et al. (2015) analyzed the clinical management of 18 patients with XLAG syndrome, including 13 previously studied by Trivellin et al. (2014), noting that although somatostatin analogs (SSAs) are the mainstay of medical treatment of GH excess, their efficacy is poor in the setting of XLAG. None of the patients achieved primary or secondary control of their disease or GH/IGF1 secretion with SSAs, even when using adult doses in young children. Beckers et al. (2015) stated that the poor SSA response was not due to low expression of somatostatin receptors, since analysis of the 6 cases in which there was adequate tissue for immunohistochemistry demonstrated moderate to high expression of SSTR2, the main target of octreotide and lanreotide, the SSAs administered to these patients. In addition, 5 of the 6 tumors stained positively for SSTR5, 4 showed high expression of SSTR3 (182453), and 3 were also positive for SSTR1 (182451). Neurosurgery was performed or planned in all cases, but was frequently associated with significant pituitary dysfunction, including GH deficiency. Conversely, very small residual tumor was capable of maintaining levels of GH/IGF1 above normal for many years, thereby necessitating chronic medical therapy. However, these residual tumor tissues did not regrow significantly, which Beckers et al. (2015) suggested might be due to the low proliferative index observed in most cases.

Naves et al. (2016) reported an 11.5-year-old boy with XLAG, in whom excessive growth was established by 2.5 years of age. He was diagnosed with pituitary gigantism at 5.75 years of age, at which time MRI showed a very large intra- and suprasellar mass with compression of the chiasma but no cavernous sinus invasion. The family declined treatment and the patient was lost to follow-up, until he presented again at age 10.5 years with headaches, seizures, and visual disturbances. Visual examination showed bitemporal hemianopsia. He had GH/IGF1 hypersecretion, marked hyperprolactinemia, and hypopituitarism of the thyrotrope, corticotrope,and gonadotrope axes. Repeat MRI showed an invasive intra- and suprasellar mass that had grown markedly, with compression of optic chiasma, cystic degeneration of the suprasellar portion, bilateral cavernous sinus invasion, and encasement of the internal carotid arteries, as well as hydrocephalus. Despite debulking and treatment with SSAs, GH levels remained elevated, IGF1 was in the high normal range, and his vertical growth continued; further resection and radiotherapy were planned. Immunohistochemical analysis confirmed the tumor as a typical XLAG mixed GH- and PRL-secreting adenoma; however, Ki-67 (see 176741) was 3.5% and there were more than 2 mitoses per high-powered field, indicating higher proliferation than in other XLAG syndrome cases. Naves et al. (2016) stated that this case illustrated the aggressive nature of tumor evolution and the challenging clinical management in XLAG syndrome, emphasizing the importance of early intervention.

Inheritance

Trivellin et al. (2014) reported 1 family with familial isolated pituitary adenomas that included an affected mother and 2 affected sons, described previously by Glasker et al. (2011), who carried the same Xq26.3 microduplication; the unaffected father did not have the duplication. In another family with this condition, the mother had childhood-onset gigantism and a histologically confirmed pituitary macroadenoma but had died of complications of hypopituitarism. She had 2 children: the son carried the Xq26.3 microduplication and had childhood-onset gigantism, and the healthy daughter did not have the duplication. Trivellin et al. (2014) concluded that Xq26.3 microduplications can be a pathogenic explanation in kindreds with familial isolated pituitary adenomas and acrogigantism without AIP (605555) mutations.

Cytogenetics

Using array comparative genomic hybridization, Trivellin et al. (2014) found 10 different microduplications of chromosome Xq26.3 in 12 patients with familial or sporadic gigantism. All sporadic duplications were nonrecurrent. The same duplication was transmitted from an affected mother to her 2 affected offspring. The common duplicated genomic segment was approximately 500 kb in length, from position 135,627,637 to 136,118,269 (GRCh37). One patient had a complex genomic rearrangement with 2 duplicated segments that were separated by a short region of genomic sequence. This allowed the delineation of 2 smallest regions of overlap (SROs), one (SRO1) a 359-kb region (chrX:135,627,637-135,986,830, GRCh37) that encompasses 3 genes (CD40LG, 300386; ARHGEF6, 300267; and RBMX, 300199) and the other (SRO2) a 73-kb region (chrX:136,045,310-136,118,269, GRCh37) encompassing the GPR101 gene (300393). Of all the genes in the duplicated segments, only GPR101 had markedly increased expression in the pituitary tumors of patients carrying the microduplication.

From a cohort of 153 patients diagnosed with pituitary gigantism, Iacovazzo et al. (2016) identified 12 patients with microduplications at Xq26.3, including 10 female patients with germline duplications, 1 of whom (case IV) was originally described by Moran et al. (1990). In addition, 2 male patients harbored a duplication in mosaic state, 1 of whom (case IX) was previously reported by Rodd et al. (2016). In 7 of the patients, the CNVs encompassed 4 genes (CD40LG, ARHGEF6, RBMX, and GPR101), but in 1 patient (case I), the distal duplication narrowed the smallest region of overlap to an interval encompassing only the GPR101 gene. Most of the duplications occurred due to the fork-stalling and template-switching/microhomology-mediated break-induced replication mechanism, but in 1 patient (case III) the duplication was generated via an Alu-Alu mediated rearrangement. There was no history of pituitary disease in any of the families, and in the 4 germline cases in which DNA samples were available from both parents, the duplication was shown to have arisen de novo in the proband. The authors concluded that GPR101 is the causative gene in the Xq26.3 region, since duplication of GPR101 alone was sufficient to cause the XLAG phenotype.