ESPE Abstracts

Introduction: Transient congenital hypothyroidism (TCH) refers to a temporary deficiency of thyroid hormone identified after birth, with low thyroxine (T4) and elevated thyrotropin (TSH). Approximately 17%-40% of children diagnosed with CH by newborn screening (NBS), have transient hypothyroidism. Levo-thyroxine (L-T4) early treatment is recommended at the dose 10-15 µg/kg/day. Children with thyroid gland in situ should be re-evaluated after the age of 3 in order to differentiate a transient from a permanent form. Several genetic variants, including dual oxidase 2 (DUOX2), have been described in patients with TCH. DUOX2 (15q15.3) encodes for a glycoprotein member of the NADPH oxidase family required for iodine organification and thyroid hormone synthesis. NPTX1 (Neuronal Pentraxin 1, 17q25.3) is exclusively localized to the nervous system, and probably regulates neural lineage specification from pluripotent stem cells. To date, no association has been reported between NPTX1 and CH.

Case report: Two sisters were born in 2013 and 2017 from uneventful pregnancies. Prenatal, neonatal medical history were unremarkable. No consanguinity, no other family members affected. CH has diagnosed by NBS. Serum thyroglobulin was normal and the thyroid ultrasound showed a normal gland in situ. Thyroid scintigraphy was not performed. They required small doses of L-T4 (≈2 µg/kg/die) to maintain normal serum fT4 and TSH. Next generation sequencing revealed a homozygous DUOX2 missense variant p.A297S (c-G889T) in exon 8 (rs 755241413, MAF<0.01), and a heterozygous NPTX1 missense variant p.L95V (c.C283G) in exon 1 (rs371219313, MAF<0.01). After withdrawal from therapy the older sister presented slightly elevated serum TSH (<10 µUI/ml) with normal fT4. The youngest sister, now 3.2 year old, has just stopped treatment.

Conclusion: Novel missense variants of DUOX2 gene and NPTX1 gene were found in two sisters with CH. While DUOX2 variants are known to be associated with TCH, the significance of the NPTX1 variant and its pathogenic activity are not known and need further investigation.