ESPE Abstracts

Congenital Central Hypothyroidism (CeH) is a rare and heterogenous disease that can be part of a combined pituitary hormone deficit (CPHD) condition. The immunoglobulin superfamily member 1 (IGSF1) is the gene more frequently involved in these inherited forms and responsible for the so called X-linked IGSF1 deficiency syndrome, characterized by an estimated incidence of 1: 100.000. The main features are CeH, delayed/disharmonic pubertal development, macroorchidism, variable prolactin and occasionally transient/partial GH deficiencies.Here we report the case of two siblings affected by this peculiar form of CeH. The younger brother was referred to our center at 7 years of age with a previous diagnosis of CeH and treated with Levothyroxine (L-T4). He presented suggestive phenotypic features including a relative macrocrania, disharmonic growth, BMI of 21 kg/mq (+1.55SDS), 3-4 cc testicles (+1.3-2.2SDS) with infant penis.Blood tests showed an inhibited TSH with normal FT4 values (1.02 ng/dl, vn 0.93-1.7ng/dl) on treatment with 1.79 mcg/kg/day L-T4;testosterone and basal gonadotropins were compatible with pre-pubertal stage. IGF1 and prolactin values resulted within normal range. Genetic analysis for CeH-related genes revealed the presence of a p.T614A (c.1804A> G) hemizygote genetic variant on exon 12 of IGSF1 gene. This is a newly described allelic variant of uncertain significance (VUS) inherited from the mother. The older brother was evaluated at our center at the age of 8. He had a BMI of 20.8 kg/mq (1.27 SDS), 4-5 cc testicles (+2.2-2.8 SDS) with infantile penis. Blood tests showed: TSH 1.98 mU/l,FT4 0.96 ng/dl (vn 0.93-1.7ng/dl), prolactin and IGF-1 within normal limits, basal gonadotropins and testosterone values as in pre-pubertal stage. The TRH test documented a valid response in TSH and FT4 values after specific stimulus. Brain MRI was normal. After the discharge, he presented persistently low FT4 levels, therefore L-T4 treatment was started at a dose of 1.6 mcg/kg/day. The therapy was progressively increased (up to 2 mcg/kg/day) maintaining free hormones in the upper part of the reference range.Patients with CeCH typically present with mild symptoms and biochemical diagnosis can be challenging. We advise genetic evaluation of IGSF1 gene in all patients with CeH of unknown cause especially in presence of a typical X-linked inheritance and/or peculiar clinical signs such as macrocrania and/or macroorchidism. Indeed, genetic analysis may allowan early diagnosis and a promt therapeutic approach in order to avoid possible sequelae of untreated CeH.