Endocrine Abstracts

Background: Compound heterozygous POLE1 mutations have previously been described as a cause of IMAGe syndrome. The severity of the adrenal insufficiency (AI) at initial presentation has been a subject of ongoing debate.

Case report: At 22 weeks gestation the proband’s mother was referred to paediatric endocrinology for low oestriol on antenatal quadruple testing. The pregnancy was complicated by severe growth restriction leading to emergency caesarean section at 34 weeks. The baby weighed 1.3 kg and was admitted to NICU with respiratory distress, hypoglycemia and jaundice. Synacthen testing on day 4 confirmed primary AI. Cortisol concentrations were 149nmol/l at 0 minutes and 152 nmol/l at 30 minutes, with baseline ACTH of 1250ng/l. USP demonstrated low concentrations of all cortisol metabolites. Ultrasound and MRI abdomen did not visualise the adrenals. USS hips showed bilateral dysplastic hips. Karyotype was XX. No abnormalities were identified on adrenal gene panel (AAAS, AIRE, CDKN1C, CYP11A1, MC2R, MRAP, NNT, NR0B1, NR5A1, SAMD9, SGPL1, STAR, TBX19). Targeted trio exome sequencing identified the presence of compound heterozygous POLE1 pathogenic variants; a frameshift variant c.4260_4261insACAG and a recurrent splicing variant, c.1686+32C>G. The patient is currently on adrenal replacement therapy (hydrocortisone and fludrocortisone) and sodium chloride supplements. She continues to require NGT feeds; height and weight remain -4SD. Initial immune workup demonstrates low immunoglobulins and T cell concentrations.

Discussion: This case report demonstrates the importance of early investigation for AI in babies born to mothers with low oestriol on antenatal quadruple testing. It highlights that current adrenal panels do not include all genes associated with AI. Making a rapid diagnosis in this infant led to early assessment of immune function and enabled discharge home as extreme growth failure is an expected finding in IMAGe.