Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome

Abstract

X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 × 23.9 × 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 × 58.1 × 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome.

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

“…Among these, 15 were reported previously (Beckers et al 2015; Naves et al 2015; Trivellin et al 2014) although none was studied previously for somatic mosaicism. The three new XLAG syndrome patients (2 females, 1 male) were adult sporadic pituitary gigantism cases whose disease began as very young children.…”

“…Final height in pituitary gigantism, irrespective of genetic cause, is determined by a variety of factors, not least early control of hormonal hypersecretion (Rostomyan et al 2015). Two of the three sporadic mosaic males with XLAG syndrome did not undergo neurosurgery or effective medical therapy during childhood and hence have extreme gigantism (209 cm at 12 years in one case, Z-score >8.7, and >230 cm final height in the other) (Naves et al 2015). The other patient was controlled with surgery and medical therapy (growth hormone receptor antagonist, pegvisomant) during childhood and can be expected to have a normal final height (Beckers et al 2015).…”

“…This suggests that the pathological process is highly sensitive to even minor levels of increased copy number at the XLAG syndrome locus. The pituitary findings in cases of XLAG syndrome are quite uniform (mixed GH-prolactin secreting pituitary adenomas and/or hyperplasia) irrespective of the level of mosaicism of the patient (Beckers et al 2015; Naves et al 2015; Trivellin et al 2014). Moreover, as males and females are clinically similar, the impact of X-chromosome inactivation in females with XLAG syndrome should be considered, as this could hypothetically alter the level of duplication occurring in specific tissues, such as the hypothalamus.…”

“…The XLAG syndrome phenotype of early childhood onset gigantism is aggressive and difficult to treat; it can be differentiated clinically from other forms of pituitary gigantism due to younger age and more severe hormonal hypersecretion (Rostomyan, et al 2015). In the absence of multimodal neurosurgical and medical therapy XLAG syndrome is associated with relentless overgrowth due to GH hypersecretion (Naves, et al 2015). The etiology of the pituitary tumor/hyperplasia in XLAG appears to be linked to a central disorder of hypersecretion of growth hormone releasing hormone (GHRH), which is a unique causative feature for pituitary gigantism in humans (Daly, et al 2016).…”

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

“…In contrast, administration of pegvisomant can decrease IGF-1 levels and help to halt the growth rate [2,4,11,[25][26][27][28][29]. Results from larger studies in acromegaly using a combination of long acting SRL and pegvisomant have shown the utility of this approach.…”