ESPE Abstracts

Background: Congenital hypothyroidism (CH) caused by DUOX2 deficiency has a wide range of clinical presentations and phenotype-genotype correlations are not always straightforward.

Objective: To describe four children from Quebec with biallelic DUOX2 variants and widely variable phenotypes.

Design/Methods: Case series of four children seen for evaluation of thyroid function at the endocrinology service of two university hospitals in the Province of Quebec. Clinical and biochemical data were analyzed and molecular genetic studies were performed.

Results: Patient 1 presented at 13 weeks with a rapidly developing goiter resulting in severe tracheal compression and overt hypothyroidism (TSH 183 mU/l, fT₄ 4.2 pmol/l) of recent onset. Respiratory distress was successfully managed with levothyroxine replacement. DUOX2 analysis revealed he had inherited the known p.G1518S mutation from his mother and a novel deletion of 540 base pairs (c.513+53_818del) from his father. Patients 2 and 3 are siblings who are compound heterozygotes for known mutations (p.M866R[pat]/p.F966SfsX29[mat]) in DUOX2, yet presented with greatly discordant phenotypes: the sister had overt hypothyroidism at 14 months (TSH 93 mU/l, fT₄ 3.96 pmol/l) but only mild hyperthyrotropinemia at 15 years (TSH 7.22 mU/l, fT₄ 8.12 pmol/l) while the brother has lifelong euthyroidism; iodine exposure could not account for this discrepancy. Patient 4, the only one with a positive newborn screening (NBS) result (TSH 22 mU/l), is a compound heterozygote for known mutations (p.P303R[pat]/p.F966SfsX29[mat]); he had mild persistent CH, as typically associated with biallelic DUOX2 variants. All parents were heterozygous and euthyroid.

Conclusion: The clinical expression of biallelic DUOX2 variants is very heterogeneous. Patient 1 is the first reported case of DUOX2 deficiency with life-threatening compressive goiter in infancy, the prompt recognition and treatment of which allowed to avoid surgical decompression. Genetic modifiers of DUOX2 deficiency that may account for the wide variation in phenotype between and within pedigrees are being studied.