Neurofibromatosis Type 1 Has a Wide Spectrum of Growth Hormone Excess

Authors

Fady Hannah-Shmouni
Giampaolo Trivellin
Pablo Beckers
Lefkothea P Karaviti
Maya Lodish
Christina Tatsi
Adekunle M Adesina
Fotini Adamidou
Gesthimani Mintziori
Jami L Josefson
Martha Quezado
Constantine A Stratakis

Publication Date

4-13-2022

Journal

Journal of Clinical Medicine

DOI

10.3390/jcm11082168

PMID

35456261

PMCID

PMC9029762

PubMedCentral® Posted Date

4-13-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

acromegaly, gigantism, GH excess, neurofibromatosis type 1, overgrowth, optic pathway glioma, X-LAG, GPR101, pituitary tumor

Abstract

Overgrowth due to growth hormone (GH) excess affects approximately 10% of patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). Our aim is to describe the clinical, biochemical, pathological, and genetic features of GH excess in a retrospective case series of 10 children and adults with NF1 referred to a tertiary care clinical research center. Six children (median age = 4 years, range of 3−5 years), one 14-year-old adolescent, and three adults (median age = 42 years, range of 29−52 years) were diagnosed with NF1 and GH excess. GH excess was confirmed by the failure to suppress GH (/mL) on oral glucose tolerance test (OGTT, n = 9) and frequent overnight sampling of GH levels (n = 6). Genetic testing was ascertained through targeted or whole-exome sequencing (n = 9). Five patients (all children) had an OPG without any pituitary abnormality, three patients (one adolescent and two adults) had a pituitary lesion (two tumors, one suggestive hyperplasia) without an OPG, and two patients (one child and one adult) had a pituitary lesion (a pituitary tumor and suggestive hyperplasia, respectively) with a concomitant OPG. The serial overnight sampling of GH levels in six patients revealed abnormal overnight GH profiling. Two adult patients had a voluminous pituitary gland on pituitary imaging. One pituitary tumor from an adolescent patient who harbored a germline heterozygous p.Gln514Pro NF1 variant stained positive for GH and prolactin. One child who harbored a heterozygous truncating variant in exon 46 of NF1 had an OPG that, when compared to normal optic nerves, stained strongly for GPR101, an orphan G protein-coupled receptor causing GH excess in X-linked acrogigantism. We describe a series of patients with GH excess and NF1. Our findings show the variability in patterns of serial overnight GH secretion, somatotroph tumor or hyperplasia in some cases of NF1 and GH excess. Further studies are required to ascertain the link between NF1, GH excess and GPR101, which may aid in the characterization of the molecular underpinning of GH excess in NF1.