Endocrine Abstracts

Introduction: Congenital central hypothyroidism (CH), is characterized by low levels of thyroid hormones and TSH. It is not possible to diagnose this condition by neonatal screening programs based on TSH measurements, hence it is often missed. The assumption that CH is usually a mild condition has been refuted, and more than 50% of all newborns with CH have moderate to severe disease. Early diagnosis and treatment lead to better neurodevelopmental outcomes. Isolated CH is a rare condition with an estimated prevalence of 1:13000. More than 90% of cases are due to pathogenic mutations in five known genes: thyroid releasing hormone receptor (TRHR), thyroid stimulating hormone beta subunit (TSHB), immunoglobulin superfamily member 1 (IGSF1), transducin (beta)-like 1X-linked (TBL1X) and in insulin receptor substrate 4 (IRS4) genes. Mutations in both IGSF1 and TBL1X can lead to X-linked isolated CH. IGSF1 mutations are also associated with low PRL, variable GH deficiency, metabolic syndrome, and postpubertal macroorchidism.

Case description: A 40-year-old pregnant woman with a past medical history of hemithyroidectomy due to goiter, was diagnosed with CH at the age of 20 years. Prolactin levels were low, adrenal function was preserved and pituitary imaging was normal. She reported having had lactation problems after her first pregnancy. The family history was unremarkable and there is no known consanguinity. Genetic evaluation: A prenatal CMA (chromosomal microarray) revealed a normal male karyotype 46XY with a 250kb deletion on chromosome X :arr (hg19) Xq26.1- Xq26.2 (130.181.100-130.431.733)*0. This deletion encompasses two omim genes: ARHGAP36, IGSF1 and was later confirmed to be inherited from the patient. Central congenital hypothyroidism was diagnosed clinically in the newborn baby, and treatment with thyroid hormone replacement was initiated, there was no need for steroid replacement therapy.

Discussion: X linked IGSF1 deficiency syndrome is the main etiology for Congenital CH. As far as we know, this is the first described case of a molecular diagnosis made in utero. Such early diagnosis enables focused surveillance of the fetus, regarding thyroid size, bone age and heart rate. Hypocortisolism was described in 20% of neonates with CH. Prenatal diagnosis enables early treatment with thyroid hormones and steroids if needed, and reduces the risk of neurodevelopmental problems.