ESPE Abstracts

Central hypothyroidism (CeH) is characterized by thyroid hormone deficiency due to impairment of pituitary TSH or hypothalamic TRH biosynthesis. CeH is often seen as a part of multiple pituitary hormone deficiencies, but it can also be seen as isolated. Diagnosis may be challenging. To date, some variants that can cause isolated CeH have been identified; although in a number of patients the cause has not been clarified. Recently, variants of the insulin receptor substrate 4 (IRS4) gene have been reported to be the cause of isolated CeH. Herein, we reported a patient with CeH due to a hemyzygous novel variant in IRS4.

Case: A 15-year-and-2-month male was referred to our clinic due to a low serum free thyroxin level, incidentally detected. Last four months, patient’s serum fT4 level was low without any symptoms. He was born as the second child of healthy nonconsanguineous parents. In his family history, his sister and a male-cousin were being treated for hypothyroidism. On physical examination, body weight was 70 kg (0.6 SDS), height was 178.1 cm (0.99 SDS). The thyroid gland was non-palpable. His bilateral testicular size was 20 mL, and pubic hair was Tanner stage 4. All systemic physical examination features were unremarkable. Initial laboratory investigations revealed normal blood count, electrolytes and liver-kidney functions. Hormonal evaluation revealed; TSH was 1.97 mIU/ml (N, 0.7-5.97), fT4 was 0.65 ng/dl (N, 0.96-1.77), fT3: 3.5 ng/dl (N, 1.58-3.9), Prolactin was 7.7 ng/ml (N, 4.79- 23.3), ACTH was 54 pg/mL and Cortisol was 9.7 µg/dL. Pituitary magnetic resonance imaging (MRI) was unremarkable. With the findings, isolated CeH was considered and then L-thyroxin treatment was started. Whole exome analysis revealed a hemizygous c.1772delG (p.G591fs*20) variant in IRS4, which was predicted to have ‘Likely Pathogenic’ according to American College of Medical Genetics (ACMG) criterias. Sanger sequencing in other family members revealed heterozygous variant in the mother. fT4 concentrations of the female carrier (mother) was 0.91 ng/dl (N, 0.7-1.4) and TSH was 1.1 mIU/ml (N, 0.35-4.94). The family members’, suspected for the disease, genetic analysis not completed yet. In conclusion we reported a novel IRS4 mutation in a patient with isolated CeH. Isolated CeH should kept in mind in insistent low fT4 levels without an increase in TSH levels. This study shows that the technique of WES could be an efficient diagnostic tool for congenital abnormalities.