Genetic Etiology in Congenital Hypothyroidism

Gözde Gürpınar; Koçer Gizem Böke; Esra Koçyiğit; Közler Selen Hürmüzlü; Erhan Parıltay; Haluk Akın; Jones Jeremy Huw; Çizmecioğlu Jones Filiz Mine

Introduction: Numerous genetic defects have been identified in relation to congenital hypothyroidism (CH). In recent years, with the increased accessibility of molecular genetic analysis, CH etiology is better understood. We evaluated patients followed with a diagnosis of CH who were diagnosed using next-generation sequencing analysis.

Methods: The study included 19 cases (10 females,52.6%). Patients with thyroid gland in situ (GIS), taking Na L-thyroxine (discontinued/continued follow-up), with persistently elevated TSH, and positive molecular genetic analysis results were included.

Results: Seventeen (89.5%) were referred from the newborn screening program, while two were referred due to prolonged jaundice. The rate of consanguineous marriages was 42%, with four (21%) being siblings. The median (range) age of starting treatment was 30 (11-330) days, median venous TSH was 28.8 (8.4-594)mIU/L, fT4 was 0.91 (0.2-1.5)ng/dL. The median duration of treatment was 6 (0.01-10.9) years, median follow-up was 7.3(1.8-14.2) years. Six (32%) discontinued medication during follow-up, at a median age of 21 (3-36) months, when TSH was 5.45 (0.34-11.40)mIU/L and fT4 was 1.41 (1.27-1.70)ng/dL. Two siblings with same TPO variants had significantly different clinical presentations. One had severe hypothyroidism (TSH:451mIU/L, fT4 <0.25ng/dL) while the other had TSH 9.2mIU/L, fT4 0.97ng/dL (Table1).

Table 1: Molecular genetics of patients
Gene n = 19	Variant	Inheritance	ACMG
TSHR	c.1532C>T	Homozygous	VUS (variant of uncertain significance)
	c.2066T>G	Heterozygous	LP (Likely pathogenic)
	c.1957C>G	Heterozygous	LP
	c.484C>T	Homozygous	LP
	c.484C>G/ c.467+1G>A (n = 2)	Compound heterozygous	LP/LP
TPO	c.1618C>T (n = 2)	Homozygous	P (pathogenic)
	c.955G>A	Homozygous	VUS
	c.2212C>T	Heterozygous	LP
TG	c.3333A>G	Heterozygous	VUS
DUOX2	c.2056C>T	Homozygous	P
DUOX2	c.1873C>T/c.3509A>C	Compound heterozygous	P/VUS
DUOXA2/DUOX2	c.738C>G/c.716-374G>T	Heterozygous	P/VUS
DUOX2/TPO/TSHR	c.2895_2898del/ c.1184_1187dup/ c.122G>C	Heterozygous	P/P/LP
TSHB	c.*64T>C	Heterozygous	VUS
IRS4	c.1324C>T	Hemizygous	VUS
AKT1	c.440T>C	Heterozygous	VUS
NKX2-5	c.876C>G	Heterozygous	VUS

Discussion: The rate of identifying molecular etiology in GIS cases is higher in the literature, and genetic variants associated with thyroid disorders other than dyshormonogenesis can be identified, as shown in our cases. Studies have linked the AKT1 gene to non-medullary thyroid cancer and the IRS4 gene to central hypothyroidism. Furthermore, similar to our cases, cases with elevated TSH levels related to thyroid disorders other than dyshormonogenesis have been reported in the literature in the presence of a mutation in the TSHB gene associated with central hypothyroidism. Siblings sharing identical TPO variants may show different symptoms. Genetic analysis in GIS cases with CH can help personalize treatment.

ESPE Abstracts

P1-293