A patient with congenital hypothyroidism due to a PAX8 frameshift variant accompanying a urogenital malformation

Abstract

PAX8 is a transcription factor that is expressed in the thyroid gland and kidneys. Monoallelic loss-of-function PAX8 variants cause congenital hypothyroidism (CH), and urogenital malformations are infrequent complications seen in less than 10% of PAX8 variant carriers. Herein, we report the case of a 3-yr-old female patient with CH who was diagnosed during newborn screening. She was treated with levothyroxine, and she showed normal growth and development at a minimal dose (0.7 µg/kg/d of levothyroxine at 3 yr of age). At 5 mo of age, she visited an emergency department for fever and was incidentally found to have differently sized kidneys by ultrasonography, which was subsequently diagnosed as unilateral multicystic dysplastic kidney. Her serum creatinine and cystatin C levels were normal. Next-generation sequencing-based genetic analysis revealed that the patient was heterozygous for a PAX8 frameshift variant (p.Thr320ProfsTer106) and a DUOX2 missense variant (p.Arg885Gln). Our patient is the first truncating PAX8 variant carrier to have a urogenital malformation with CH. Genetic analysis for PAX8 should be considered in patients with CH and urogenital malformations.

Keywords: PAX8; congenital hypothyroidism; frameshift mutation; urogenital abnormality.

Fig. 1.

Clinical findings of the patient; A: Abdominal ultrasonography showing a dysplastic kidney with small cysts on the right (R, arrowheads) and compensatory hypertrophied left kidney (L, arrowheads). Bars indicate 1 cm. B: An ultrasonographic image of the thyroid showing a hypoplastic thyroid gland. A bar indicates 1 cm. C: Growth chart of the patient showing normal growth. The solid and dashed lines indicate the mean and ± 2 standard deviations in Japanese children, respectively (39). D: Daily levothyroxine requirement per kg body weight of the patient progressively decreased during follow-up. The dashed line and grey area represent the mean and ±2 standard deviations of the levothyroxine dose required in patients with atherosclerosis, respectively (40).

Fig. 2.

Identification of a novel truncating PAX8 variant; a schematic diagram of the PAX8 protein along with electropherograms of the identified variant is shown. The deleted nucleotides are shown by dashed lines. The black and grey areas represent the DNA-binding paired domain and transactivation domain, respectively. The location of previously described variants is indicated by black lines (upper, missense variants; lower, truncating variants).