We have investigated two siblings, a sister and a brother, who presented at the age of 2 years, with central hypothyroidism, short stature and early onset obesity. The older sister presented at the age of 6 months with central hypothyroidism and was started on a low dose of thyroid hormone (25 ug l-thyroxine). Her growth continued to be poor and at the age of 2 years and 6 months her height was −3.98 SDS. She was started on growth hormone followed by a rapid catch-up growth and an improvement of body height. The younger brother presented at the age of 1 year and 4 months with a height of −3.81 SDS and was started on thyroid- and growth hormone. The BMI at start of therapy was 19,8 and 25.6 for the sister and brother, respectively, both numbers well above the 97.%ile. Leptin levels were not measurable and/or repeatedly below the normal range in both children but neither had an increased appetite. Polyuria and polydipsia is present in the boy, but CT-ProVasopressin in relation to serum osmolality was not reduced. We performed an MRI of the brain in the boy, which showed a small pituitary and a small stalk. The MRI in the girl was done abroad and reported to be normal. We performed genetic analysis and detected in both children a heterozygous mutation in the MAGEL2-gene (c.2909G>A, p.Trp970Ter) which led to a premature stop. Similar nonsense-mutations have been described in Schaaf-Young-syndome, a Prader-Willi-like syndrome and the MAGEL2-gene is one of the five protein-coding genes in the Prader-Willi-syndrome region on chromosome 15q11-13. The mutation described here is novel, meaning that is has not been reported before. We could not find this mutation in the parents, suggesting it to be de novo. In conclusion, we found as a cause of multiple pituitary hormone deficiencies a stop-codon mutation in the MAGEL2 gene. Both children had developmental delay, but no autistic features yet. The multiple hormone deficiencies are most likely due to a regulatory defect in the hormone secretion of wide variety of hypothalamic-pituitary hormones. The MAGEL2- gene seems to play an important role in the organization of central hormone secretion.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology