Introduction: CPHD is characterized by GH and at least one other pituitary hormone deficiency. Mutations in genes expressed in the developing head, hypothalamus, and/or pituitary cause CPHD. To date around 30 genes have been identified to be related to CPHD, however the 85% of the cases remain with unknown aetiology. Whole Exome Sequencing (WES) enables parallel searching for pathogenic variants of CPHD in targeted known gene panels as well as the identification of novel genes related to CPHD thus allowing genetic diagnosis, prognosis and genetic counseling.
Patient and Methods: A newborn boy (46, XY) delivered by CS due to IUGR with a birthweight of 2200gr, presented with refractory hypoglycemia and mild hypotonia. On physical examination he had micropenis with bilaterally pulpable small testes. Endocrinological work up revealed secondary hypothyroidism, secondary adrenal insufficiency and hypogonadotropic hypogonadism (HH). MRI scan of the hypothalamic pituitary region depicted hypoplastic anterior pituitary and ectopic posterior pituitary lobe with absence of pituitary stalk. WES was carried out on an Ion Torrent S5 platform and the data was aligned to the human genome reference hg19 with Torrent Mapping Alignment Program (TMAP) and annotated by the Ion Reporter software and Varaft. An in silico panel of 80 genes related to CPHD was employed to search for variants with MAF values <1%. The pathogenic variants selected were verified by Sanger sequencing.
Results: Three heterozygous pathogenic variants were detected to be related to the patient's phenotype in three genes: BMP4; p.A42P (maternally inherited) related to CPHD, GNRH1; p.Arg73X (paternally inherited) related to HH and SRA1 p.Q32E related to HH and secondary adrenal insufficiency.
Conclusions: We speculate that a synergistic action of several gene mutations may underlie our patient's phenotype. BMP4 plays significant role in early organogenesis, pituitary development and function. The variant p.A42P, has been previously described in a patient with tooth agenesis, however a heterozygous BMP4 mutation (p.R300P) has been reported in a case with CPHD and hypoplastic pituitary gland. The pathogenic variant p.Arg73X of the GNRH1 gene has been previously described in a patient with HH. SRA1 (Steroid Receptor Activator) is a functional ncRNA which among its other functions regulate steroid receptors-dependent gene expression. The pathogenic variant p.Q32E has previously been identified in a patient with HH and could probably explain the secondary adrenal insufficiency of our patient, since SRA1 regulates SF1 target gene expression by functioning as a coactivator in association with DAX1.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology