J Clin Res Pediatr Endocrinol. Ahead of Print: JCRPE-92063 | DOI: 10.4274/jcrpe.galenos.2022.2021-12-3

A Novel Pathogenic IGSF1 Variant in a Patient with GH and TSH Deficiency Diagnosed by High IGF-I Values at Transition to Adult Care

Aslý Derya Kardelen¹, Esin Karakýlýç Özturan¹, Þükran Poyrazoðlu¹, Firdevs Baþ¹, Serdar Ceylaner², Sjoerd D Joustra³, Jan M Wit³, Feyza Darendeliler^1
1Istanbul University, Istanbul Faculty of Medicine, Department of Pediatric Endocrinology
²Intergen Genetic Research Center, Ankara, Turkey
³Willem-Alexander Children’s Hospital, Department of Pediatrics, Division of Pediatric Endocrinology, Leiden University Medical Center, the Netherlands

IGSF1 deficiency is a rare X-linked condition characterized by central hypothyroidism (CeH) and a wide variety of other clinical features with variable prevalence, including a delayed pubertal testosterone rise and growth spurt in contrast to normal or accelerated testicular growth, and adult macroorchidism with relatively low serum testosterone concentrations. Other features include increased waist circumference, attention deficit, prolactin deficiency and transient partial growth hormone (GH) deficiency in childhood in contrast to an increased GH secretion in adulthood. Patients with this disorder are not detected if neonatal screening programs are based on thyroid-stimulating hormone (TSH) concentrations. A 13.2-year-old male patient was referred to the pediatric endocrinology clinic for evaluation of short stature. He was born large for gestational age into a nonconsanguineous family. During work-up for short stature, deficiencies of TSH, prolactin and GH were detected, leading to treatment with levothyroxine and GH. At 16.9 years, GH treatment was stopped and during transition to adult care, his IGF-I level was above the normal range. This prompted an analysis of IGSF1, in which a novel hemizygous variant causing a stop codon at c.3559C>T (p.Q1187*) was found, confirming the diagnosis of the IGSF1 deficiency syndrome. In this report, we describe his clinical and hormonal characteristics at presentation and during longterm follow-up.

Keywords: IGSF1, central hypothyroidism, short stature, large for gestational age, growth hormone deficiency, prolactin deficiency

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