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Case Report and Methods Clinical caseĬlinical, laboratory, and radiological data were collected from the time of the infant’s prenatal diagnosis to his most recent clinic visit. These observations help elucidate the pathophysiology, tumorigenesis, and clinical presentation of pediatric pituitary adenomas. This report follows a patient with familial X-LAG prospectively starting at prenatal diagnosis and affords the unique opportunity to compare clinical courses and histopathology findings. Additionally, we compare the mother and son’s pathology that provides further insight into the tumors of X-LAG. We now describe the clinical course for the son of a previously described case of X-LAG ( 10, 11). The pituitary adenomas are thought to be mixed somatotroph-lactotroph adenomas with pituitary-specific transcription factor-1 (PIT1) expression ( 2, 6). Resection of the tumor reveals characteristic histologic features including sinusoidal and lobular architectures with scattered follicles and calcifications. Treatment is challenging, with a combination of therapeutic approaches necessary to achieve suppression of elevated hormone effects and control of tumor size ( 2, 3, 8, 9). In contrast to other causes of gigantism for which male predominance is observed, X-LAG is female-predominant (78%), with median age of onset of 1.0 years (0.5 to 2.0), much younger than the median of 16.0 years (5.0 to 18.0) in other gigantism cases ( 1–4, 6, 8). GPR101 is thought to play a role in the development of the GHRH–GH axis and encodes a G-protein coupled receptor that strongly activates the cAMP pathway and stimulates proliferation of pituitary cells and secretion of PRL and GH ( 2, 5, 8).
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X-LAG is caused by a microduplication of GPR101 on chromosome Xq26.3 ( 2, 3, 6, 7). In most cases, prolactin (PRL) concentrations are also markedly elevated ( 2, 7). It is characterized by GH and IGF-1 excess leading to acromegaly, accelerated growth velocity, and increased height/weight deviation from the standard growth curve prior to epiphyseal closure ( 1, 2, 4, 6). In the 28 reported patients with X-LAG who have been analyzed by array comparative genomic hybridization, there are 24 nonrecurrent duplications with unique breakpoint junctions these comprise 21 sporadic cases and 7 familial cases from 3 kindreds ( 4).įirst described in 2014, X-LAG is pituitary gigantism occurring as early as the first few months of life ( 6). In familial isolated pituitary adenoma with two or more affected family members, the major known genetic cause is an AIP mutation (20%) followed by X-LAG ( 1–3, 5). The leading cause of nonsyndromic disease is a mutation of aryl hydrocarbon receptor interacting protein ( AIP) (29% to 41%), followed by X-linked acrogigantism (X-LAG) resulting from G-protein coupled receptor 101 ( GPR101) mutations (8% to 10%) ( 1–4). In roughly one-half of childhood-onset cases, there is an identifiable genetic cause ( 1–3). Pituitary gigantism is extremely rare in infancy and childhood. Both showed an elevated Ki-67 proliferation index, 5.6% in the mother and 8.5% in the infant, the highest reported in X-LAG.
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Furthermore, the tumor expressed other lineage-specific transcription factors, as well as SOX2 and octamer-binding transcription factor 4, demonstrating the multipotentiality of X-LAG tumors. In both cases, many tumor cells expressed PRL, GH, and pituitary-specific transcription factor-1. The pituitary adenoma resembled the mother’s pituitary adenoma, with tumor cells arranged in trabeculae and glandular structures. At 15 months, he underwent tumor resection. The infant grew rapidly with rising PRL, GH, and IGF-1 concentrations and an enlarging suprasellar pituitary mass, despite treatment with bromocriptine. After conception, single-nucleotide polymorphism microarray on a chorionic villus sample showed the same microduplication in the fetus, confirming familial X-LAG. During preconception planning, X-LAG was diagnosed: single-nucleotide polymorphism microarray showed chromosome Xq26.3 microduplication.
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For more than 30 years, stable PRL, GH, and IGF-1 concentrations and serial imaging studies indicated no tumor recurrence. The patient’s mother, diagnosed with acrogigantism at 21 months, underwent pituitary tumor excision at 24 months.