RF17 | PMON24 The paradox of combined pituitary hormone deficiency and tall stature: a glimpse from exome sequencing

INTRODUCTION: An intact GH-IGF-1 axis is known to be essential for proper growth. However, cases in which individuals with growth hormone deficiency (GHD) reach target height without the use of GH suggest that other mechanisms may play a role in the growth process. Out of 209 patients with hypopituitarism followed in the endocrinology clinic at HCFMUSP, 9 presented with normal stature despite GHD and hypogonadotropic hypogonadism. Among them, 1 male patient presented with tall stature. The mechanisms under growth without growth hormone are poorly understood, so we hypothesized that genetic mutations in genes related to tall stature could be a plausible explanation. The aim of the present work was to look for allelic variants in the exome that could be associated with tall stature, combined pituitary hormone deficiency and/or skeletal deformities. The index male patient presented at the age of 28 to a medical assistance due to the lack of pubertal development, leading to the diagnosis of FSH/LH and TSH deficiencies and thus treated accordingly. He was still growing even under testosterone replacement and noticed that his hand and fingers also got bigger in this period. At 32-year-old he presented to our service with a stature of 193.5cm (z score of +2.40) being out of his target height range. An arm span of 195cm was notice together with skeletal deformities such as claw toes, trigger fingers in hands and a barrel chest. At this time ACTH and GH deficiencies were diagnosed and an adult dose of GH was initiated. Over one year treatment he grew 1 cm even presenting complete closed epiphyses in hands but incomplete epiphyseal fusion in the iliac crest (Risser 4). In the skeletal X ray scoliosis, deformities in hands and feet were noticed. Pituitary MRI revealed an ectopic neurohypophysis and a reduced adenohypophysis. Whole exome sequencing was performed and allelic variants in exonic or splice site regions with frequency of less than 1% were prioritized. Out of 26 variants, 13 were classified as VUS or pathogenic in the genes PSG4, ZGPAT, LRP2, LRP5, LRP6, RYR1, REL SPAST, SDHC, EGFR, ARID3B and TGFB2, being the last 5 genes never described in 4 different populational databases (gnomAD, 1000G, ABraOM and SELAdb). Allelic variant in TGFB2 gene has been related to Marfan syndrome. Family members are having these genes in the process of being segregated. CONCLUSION: Mutations in genes related to tall stature may be a mechanism that could explains normal growth among individuals with GHD. Presentation: Sunday, June 12, 2022 12:42 p.m. - 12:47 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.