ESPE Abstracts

Abstract: Combined Pituitary Hormone Deficiency (CPHD) is characterized by growth hormone and at least one other pituitary hormone deficiency. It is of varying etiology, extent and severity and it usually occurs sporadically with only 10% of cases being familial. Although pathogenic variants in more than 30 genes expressed during the development of the head, hypothalamus and/or pituitary have been identified so far to cause genetic forms of CPHD, the aetiology of around 85% of the cases remains unknown.

Patient and Methods: A full-term male (46,XY) newborn, with gestational age 37+6 weeks and birth weight 3220g, was admitted in the 2nd day of life for investigation of dysmorphic facial features and episodes of hypoglycemia. Clinical examination revealed cleft palate, cleft lip, micrognathia/retrognathia, hypotonia, micropenis (0.7cm), hypospadias with bilaterally palpable small testes (testicular volume <1mL). Hormonal assessment revealed central hypothyroidism, adrenal insufficiency, hypogonadotropic hypogonadism and growth hormone deficiency. The MRI showed hypoplastic anterior pituitary with normal posterior pituitary and pituitary stalk. The patient was immediately placed on replacement therapy with hydrocortisone and levothyroxine. Molecular genetic analysis was carried out employing Whole Exome Sequencing (WES) on an Illumina NextSeq 500. Sanger sequencing was undertaken in order to verify the mode of inheritance of the variants identified to be related to the patient’s phenotype.

Results: WES revealed the presence of two ROBO1 gene rare variants, p.Ala972Thr and p.Val1253Met, maternally and paternally inherited. Both were categorized as VUS according to the ACMG criteria. Variant p.Ala972Thr has been reported in a patient with developmental disorders and pontine hypoplasia, thinning of the anterior commissure and corpus callosum, and absence of the transverse pontine fibers. Two secondary findings, GPR161 p.His373Tyr and NOTCH3 p.Ser502Phe, were also identified, both of paternal inheritance and categorized as VUS.

Conclusion: To date mutations in ROBO1 gene have been reported in a few cases of CPHD and PSIS, inherited in an autosomal dominant manner usually from unaffected parents, whereas our patient was found to be compound heterozygote for two rare ROBO1 gene variants. It is not clear whether both ROBO1 variants are the cause of the phenotype or this is a case of recessive inheritance. Furthermore, it is possible that the secondary findings, particularly the NOTCH3 gene variant, are pointing to a digenic defect. Correlating the phenotype of patients with CPHD and midline defects with novel genes enhances our understanding of pituitary development, and the genetic basis of the disorder.