E-ISSN: 2791-8823
Volume: 1 Issue: - Year: 2021
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Turkish Pediatric Endocrinology and Diabetes Society
The IGSF1 Deficiency Syndrome May Present with Normal Free T4 Levels, Severe Obesity, or Premature Testicular Growth [J Clin Res Pediatr Endocrinol]
J Clin Res Pediatr Endocrinol. 2021; 13(4): 461-467 | DOI: 10.4274/jcrpe.galenos.2020.2020.0125

The IGSF1 Deficiency Syndrome May Present with Normal Free T4 Levels, Severe Obesity, or Premature Testicular Growth

Steven Ghanny1, Aliza Zidell1, Helio Pedro1, Sjoerd D. Joustra2, Monique Losekoot3, Jan M. Wit2, Javier Aisenberg1
1Hackensack University Medical Center, Department of Pediatrics, Hackensack, United States
2Leiden University Medical Center, Department of Pediatrics, Leiden, The Netherlands
3Leiden University Medical Center, Department of Clinical Genetics, Leiden, The Netherlands

Our objective was to further expand the spectrum of clinical characteristics of the IGSF1 deficiency syndrome in affected males. These characteristic include almost universal congenital central hypothyroidism (CeH) with disharmonious pubertal development (normally timed testicular growth, but delayed rise of serum testosterone), macroorchidism, increased body mass index (BMI), and decreased attentional control. In addition, a subset of patients show prolactin deficiency, transient partial growth hormone deficiency in childhood and increased growth hormone secretion in adulthood. We present a family in which the proband was diagnosed with CeH and low serum prolactin. Severe weight gain started at two years old, with a BMI of 42.3 at 13.9 years. Testicular enlargement (5-6 mL, 3.8-4.3 standard deviation score) started aged three years. A pathogenic variant was found in the IGSF1 gene: c.3411_3412del, p.(Tyr1137*). His brother was referred for short stature at age 13 years and was diagnosed with CeH, normal serum prolactin and IGF-1, and disharmonious puberty. In four male relatives (the proband’s brother and three cousins) with the variant (one adult), free thyroxine (fT4) was below the lower limit of the reference range in two, and just above this limit in the other two. Three were overweight or obese, adolescents had disharmonious pubertal development and the adult had profound macroorchidism. In conclusion, male hemizygous carriers of a pathogenic IGSF1 variant can present with fT4 concentration above the lower limit of the reference range while severe early onset obesity or premature testicular growth are part of the phenotypic spectrum.

Keywords: IGSF1 deficiency, hypothyroidism, macroorchidism, obesity, prolactin

Steven Ghanny, Aliza Zidell, Helio Pedro, Sjoerd D. Joustra, Monique Losekoot, Jan M. Wit, Javier Aisenberg. The IGSF1 Deficiency Syndrome May Present with Normal Free T4 Levels, Severe Obesity, or Premature Testicular Growth. J Clin Res Pediatr Endocrinol. 2021; 13(4): 461-467
Manuscript Language: English
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