Endocrine Abstracts

Background

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 85% of the cases remain with unknown molecular aetiology.

Patient and methods

A newborn boy (46, XY) delivered by CS due to IUGR with a birthweight of 2200 g, presented with refractory hypoglycemia and mild hypotonia. On physical examination he had micropenis with bilaterally palpable 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, aligned to hg19 and annotated by Varaft. An in silico panel of 120 genes related to CPHD was employed to select variants (MAF values <1%). The pathogenic variants selected were verified by Sanger sequencing.

Results

Four heterozygous variants were found to be related to the patient’s phenotype in four genes. Two of them were maternally inherited: BMP4; p.A42P and NR4A1; p.P148L and 2 paternally inherited: GNRH; p.Arg73X and SRA1; p.Q32E.

Conclusions

We speculate that a synergistic action of these gene variants may underlie our patient’s phenotype. BMP4 plays significant role in early organogenesis, pituitary development and function. BMP4; p.A42P has been described in a patient with tooth agenesis, however the BMP4; p.R300P has been reported in a CPHD and hypoplastic pituitary gland patient. GNRH1; p.Arg73X, has been described in a patient with HH. The SRA1; p.Q32E has 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. NR4A1 gene encodes for a protein, member of the steroid–thyroid hormone-retinoid receptor superfamily, which acts as a nuclear transcription factor and is highly expressed in the adrenals.