ESPE Abstracts

Recently, pathogenic biallelic variants in the gene encoding DNA polymerase epsilon catalytic subunit 1 (POLE1), have been described in 15 individuals from 12 families, including members of 3 Irish families. These loss-of-function mutations cause POLε deficiency, thus impairing DNA replication. All reported cases share the same heterozygous intronic variant (c.1686þ32C>G) as part of a common haplotype, in addition to a different loss-of-function variant in the other allele. Phenotypically, these individuals have clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies [in males]). In addition, these mutations also display distinctive facial features and immunodeficiency characterised by lymphocyte depletion. In Ireland to date, there are 6 reported cases of POLE1. We report on the 3 cases who are now adolescents or adults; two females aged 44 and 14.5 years respectively, and one male aged 15 years (cases 1, 2 and 3 respectively). All cases were born to Irish parents. In each case, the intronic POLE gene variant c.1686+32C>G was detected, with a loss-of-function mutation identified on the alternative allele. All presented with severe prenatal growth failure and postnatal short stature. There is subtle but clinically insignificant immunodeficiency in our cases. Clinical features are summarised in Table 1. Pubertal delay has universally been reported in our cohort with case 1 reaching menarche age 22 years following a normal LHRH stimulation test. Case 2, now 14.5 years, has pubic hair Tanner stage III, breast I, premenarchal. She has normal gonadotrophins and oestradiol levels (83pmol/L at age 13.5 years), pelvic ultrasound is pre-pubertal and bone age appropriate for age. Puberty was delayed in case 3 resulting in pubertal induction at age 15. Insulin resistance was found in cases 1 and 3, the latter is treated with metformin. POLE1 is a newly described condition of primordial dwarfism and adrenal insufficiency. In our case series, severe delayed puberty despite an apparently normal hypothalamic pituitary gonadal axis, and insulin resistance, are features which have not been previously described.