Endocrine Abstracts (2017) 49 EP904 | DOI: 10.1530/endoabs.49.EP904

Study of CHD7 gene in KAL 1-negative patients previously diagnosed with congenital hypogonadotropic hypogonadism that develop new pituitary deficiencies

Beatriz Lecumberri1,2, Francisco Javier Rodríguez2, Óscar Moreno1, Manuel de Santiago1, Manuel Nistal2,4, Elena Vallespin2,3, Angel Campos2,3 & Karen Heath2,3

1Endocrinology Department, La Paz University Hospital, Madrid, Spain; 2IdiPAZ, Madrid, Spain; 3INGEMM; La Paz University Hospital, Madrid, Spain; 4Pathology Department, La Paz University Hospital, Madrid, Spain.

Introduction: Recent studies suggest that some patients initially diagnosed with congenital hypogonadotropic hypogonadism (CHH), may evolve towards a combined pituitary hormonal deficiency (CPHD). Heterozygous pathogenic CHD7 variants impair neural cell crest guidance causing CHARGE syndrome and have been associated with abnormal pituitary development/function/structure and isolated CHARGE features, including HH. We aimed to genotype CHD7 and phenotype thoroughly those adult patients previously diagnosed with CHH that developed new pituitary deficiencies during the follow-up.

Patients: From 20 unrelated KAL 1-negative patients with a past CHH diagnosis followed in our adult endocrinology clinic during an average of 21.2 years (13–37), we selected those with new pituitary deficiencies – 7/20, all males, mean age 37.2 years (29–53) – and studied CHD7 using a targeted NGS panel (HYPOPIT.V1). Markedly low IGF-1 levels were detected in 6/7 (85%) and of TSH in 4/7 (57.4%).

Results: 2/7 patients (28.6%) harboured heterozygous CHD7 rare variants. The variant of unknown significance NM_017780:exon31:c.G6255T:p.L2085F that suggests pathogenicity but lacks functional sudy, was found in a 53-year-old male, that has a left temporal arachnoid cyst, a pars intermedia cyst, low IGF-1 levels, a pigmentary glaucoma treated with iridotomy, aortic elongation and a “Sertoli-cell-only syndrome” diagnosis based on testicular biopsy performed at 38 years. Another 37-year-old-male, that was hormonally and surgically treated for bilateral cryptorchidism during childhood, and currently shows a partial empty sella, absence of neurohypophysis and low TSH and IGF-1 levels, had the rare pathogenic heterozygous variant NM_017780.3:c.8416C>G:p.Leu2806Val, involved in CHARGE, isolated HH, and in a few CPHD cases with atypical CHARGE features. Curiously both fathers of these two patients died before 65 years of age due to lung diseases (the first being cancer).

Conclusions: Our results suggest that CHD7 should be included in the genetic study of CHH patients, especially in those that develop new pituitary deficiencies over time.