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

Abstract

Purpose Acromegaly in infancy is extremely rare. We describe a 32 year old woman who presented at 6 months of age with isolated macrocephaly, followed by accelerated linear growth. At 21 months of age, her head circumference was 55 cm (+5.5 SD), height was 97.6 cm (+4.4 SD) and weight was 20.6 kg (+6.2 SD). She had markedly elevated levels of growth hormone (GH) (135 ng/ml), IGF-1 (1540 ng/ml) and prolactin (370 ng/ml). A pituitary macroadenoma was surgically resected. Immunohistochemical staining was positive for GH. Post-operatively, she developed ACTH and TSH deficiency and diabetes insipidus. Methods Long term clinical follow-up and genetic testing with chromosomal microarray analysis. Results Despite GH deficiency, she grew well until 7 ½ years old, with subsequent decline in growth velocity, and received GH therapy for 5 years. Puberty was initiated with estrogen therapy. As an adult, she has no stigmata of acromegaly, with a height of 164.5 cm and non-acromegalic features. IGF-1 has remained in the low normal range. Prolactin has been mildly elevated. Serial MRIs have shown no evidence of tumor recurrence. She receives replacement therapy with hydrocortisone, levothyroxine and DDAVP. Chromosomal microarray analysis revealed that she has X-linked acrogigantism (X-LAG) due to a de novo duplication of Xq26.3 (516 kb). She recently became pregnant following ovarian stimulation and chorionic villus sampling revealed that she is carrying a male with the same duplication. Conclusion This report provides detailed long term clinical follow-up of a patient with X-LAG syndrome.

Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects

“…Owing to the low penetrance of the disease, AIP mutations can also be identified in subjects with early-onset PAs, and typically among those with gigantism and early-onset acromegaly (Tichomirowa et al 2011, Cuny et al 2013, Hernandez-Ramirez et al 2015. Very rarely, duplications of Xq26.3 involving the GPR101 gene have been identified in families with XLAG (Trivellin et al 2014, Gordon et al 2016. To this date, most of the reported XLAG patients presented as isolated cases due to de novo germline or somatic mosaic mutations, and only three cases of familial XLAG have been so far described (Trivellin et al 2014, Gordon et al 2016.…”

“…Very rarely, duplications of Xq26.3 involving the GPR101 gene have been identified in families with XLAG (Trivellin et al 2014, Gordon et al 2016. To this date, most of the reported XLAG patients presented as isolated cases due to de novo germline or somatic mosaic mutations, and only three cases of familial XLAG have been so far described (Trivellin et al 2014, Gordon et al 2016.…”

“…XLAG patients present with marked GH excess, in most cases with associated hyperprolactinaemia, caused by mixed somatotrophlactotroph adenomas associated, in some patients, with pituitary hyperplasia. In a minority of patients, the disease is due to pituitary hyperplasia in the absence of a PA. XLAG is very rare, with only 33 confirmed cases described so far in the medical literature (Trivellin et al 2014, Beckers et al 2015, Gordon et al 2016, Iacovazzo et al 2016b, Rodd et al 2016. XLAG accounted for approximately 10 and 8% of cases in two large independent series of patients with pituitary gigantism, respectively (Rostomyan et al 2015, Iacovazzo et al 2016b.…”

“…Different from other forms of gigantism, including those linked with AIP mutations and those without a known genetic predisposing factor, where most affected patients are males, XLAG is characterised by a female preponderance, and 24/33 reported XLAG patients are females carrying germline duplications, while somatic mosaic mutations have been identified in the only four reported cases of male patients with sporadic disease (Daly et al 2016b, Iacovazzo et al 2016b, Rodd et al 2016. In three independent families, motherto-son transmission has been described, in all cases with full penetrance (Trivellin et al 2014, Gordon et al 2016. As no other clinical manifestations have been described in these kindreds, XLAG is considered as a rare cause of FIPA.…”

Paleogenetic study of ancient DNA suggestive of X-linked acrogigantism

“…X-LAG is characterized by of mixed GH/prolactin-secreting pituitary macroadenomas 47 and/or hyperplasia in early childhood (Beckers et al 2015). X-LAG typically occurs 48 sporadically in females, but somatic mosaicism also occurs in males; familial mother-to-son 49 transmission of the Xq26.3 duplication has been reported in three familial isolated pituitary 50 adenoma families (Trivellin et al 2014;Daly et al 2016;Gordon et al 2016;Iacovazzo et al 51 2016). The clinical presentation of X-LAG syndrome differs from other genetic forms of 52 pituitary gigantism (Rostomyan et al 2015) and many well-known historical cases of gigantism 53…”