Screening a large pediatric cohort with GH deficiency for mutations in genes regulating pituitary development and GH secretion: Frequencies, phenotypes and growth outcomes

Abstract

BackgroundPituitary development and GH secretion are orchestrated by multiple genes including GH1, GHRHR, GLI2, HESX1, LHX3, LHX4, PROP1, POU1F1, and SOX3. We aimed to assess their mutation frequency and clinical relevance in children with severe GH deficiency (GHD).MethodsThe Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS; Clinical Trial Registry Number: NCT01088412) was a prospective, open-label, observational research program for pediatric patients receiving GH treatment, conducted in 30 countries between 1999 and 2015. The study included a sub-study to investigate mutations in the genes listed above. PCR products from genomic blood cell DNA were analyzed by Sanger sequencing. DNA variants were classified as pathogenic according to the recommendations of the American College of Medical Genetics and Genomics. Demographic, auxologic, and endocrine data at baseline and during GH treatment were documented and related to the genotyping results.FindingsThe analysis comprised 917 patients. In 92 patients (10%) 33 mutations were found, 16 previously described and 17 novel (52%). Mutation carriers were significantly younger, shorter, and more slowly growing than non-carriers. In general, their peak values in GH stimulation tests were very low; however, in 15/77 (20%) patients with GH1, PROP1, and SOX3 mutations they were only moderately diminished (3-6 μg/L). Two patients with a GH1 mutation developed TSH deficiency and one ADH deficiency. Using logistic multi-regression analysis, significant indicators of a mutation were combined pituitary hormone deficiency, greater patient-parent height difference (SDS), low GH peak, and young age. Final height SDS gain in mutation carriers (mean ± SD 3.4 ± 1.4) was greater than in non-carriers (2.0 ± 1.4; P < .001) and in patients with non-GHD short stature.InterpretationDNA testing for mutations in children with severe GHD shows a positive finding in approximately 10%. Phenotypes of mutation carriers can be variable. The benefit for clinical practice justifies DNA testing as an important component in the diagnostic work-up of patients with severe GHD.FundEli Lilly and Company, Indianapolis, IN, USA.ClinicalTrials.com registration: NCT01088412.

Evolving pituitary hormone deficits in primarily isolated GHD: a review and experts’ consensus

“…Mutations of the developmental gene SOX2 can cause anophthalmia, esophageal atresia, and genital tract abnormalities associated with GH and gonadotropin deficiency [ 41 ]. The most frequent monogenic defect of pituitary development with recessive inheritance is caused by PROP1 mutations, which is characterized by the combination of GH, TSH, ACTH, and gonadotropin deficiency [ 42 ].…”

The Molecular Basis of Congenital Hypopituitarism and Related Disorders

“…Further variations on the phenotype, although rare, have been observed in human patients, and include, for example, aplasia of the AP with complete hypopituitarism and retinal coloboma (HESX1 insertion mutation c.385-386ins315) (22). Patients with HESX1 mutations (<1% of all cases) manifest variably penetrant phenotypes, ranging from IGHD, evolving hypopituitarism without midline and eye defects, to SOD and pituitary aplasia (6,13,23).…”

“…The transcription factor RAX is implicated in eye and forebrain development, with murine null mutants manifesting anophthalmia, cleft palate, and an abnormal hypothalamus resulting in perinatal lethality (30) The multifunctional LIM homeobox proteins LHX3 and LHX4 appear to be expressed at a later stage of pituitary development than the above genes and are involved in transactivation and protein-protein interactions (52)(53)(54). Mutations have been reported in <1% of all patients with CPHD in cohort studies (6,55,56). is thought to create a cryptic donor splice site predicted to lead to a loss of function (78).…”

“…Rare and unique forms of CH with accompanying midline abnormalities may be caused by mutations in two or more genes involved in the complex signaling pathways that are critical for HP embryonic development (5). The limited number of patients reported in cohort studies, the variable frequency of mutations in different ethnic backgrounds, and the marked phenotypic variability associated with different genes, all make genotypephenotype correlations difficult to establish (6). Additionally, very few studies have examined all of the patients within a cohort for mutations in all of the known genes implicated in CH.…”

High-throughput splicing assays identify missense and silent splice-disruptivePOU1F1variants underlying pituitary hormone deficiency

“…The first case of a recessive POU1F1 loss of function was described in a patient with CPHD born to consanguineous parents 16 , and since then thirty-seven unique variants in POU1F1 have been reported in patients with CPHD or IGHD [17][18][19][20][21][22][23] . A few dominant negative mutations have been reported: p.P76L alters the transactivation domain and causes completely penetrant IGHD 24 , p.K216E interferes with the ability of POU1F1 to interact with retinoic acid All rights reserved.…”