ESPE Abstracts

Case report: We describe a 4-year-old girl, born by vaginal delivery after 41 weeks gestational (length: 55 cm, 99^thcentile, weight: 4.8 kg, 99^th centile). TSH on newborn screen was normal. Evaluated in the first month of life by gastroenterologists for severe constipation required several hospitalizations and investigation by endoscopy, biopsy, and rectal manometry. Constipation was treated by continuous polyethylene glycol administration. When she first came to our observation, she showed facial dysmorphisms, (macrocephaly, large eyes, epicanthus, arched and everted upper lip, wide mouth, dorsal hypertrichosis, and sunken bridge of the nose). She also displayed modest psychomotor delay, dyslalia, easy fatigability and poor growth. Tests revealed modest normocytic normochromic anemia (Hb 10.8 mg/dl), TSH of 3.0 mU/L (0.67-4.16) fT4 of 1.02 ng/dL (0.86-1.4), and fT3 of 7.04 pg/mL (3.3-4.8). Neuropsychiatric evaluation revealed ideational and motor slowing, delayed verbal comprehension and underdeveloped language, with normal IQ of 109.

Diagnosis: A de novo heterozygous thyroid hormones receptor alpha (THRA) gene mutation was identified: c.869G>A replacing the normal glycine 290 with asparagine (G290S) in the corresponding protein product, TRa. This missense variant according to tACMG guidelines is probably pathogenic (class 4).

Discussion: THRA gene alterations cause impaired sensitivity to thyroid hormones in gut, bone, heart and brain. The elevated T3/T4 ratio was expected, as THRA positively regulates deiodinase 3 that inactivates T4 and T3 by conversion reverse T3 and T2, respectively. TSH is not affected being regulated by thyroid hormone receptor beta (TRß). The mutant THRA was not previously reported but presence of an equivalent pathogenic mutation in the THRB gene together with the clinical and laboratory findings support pathogenicity of the newly identified TRa G290S. The only treatment available is high doses of levothyroxine. Our patient started with 50 mg per day with planned increments of 50 until the dose of 300 mg is reached. Now, two months later, at the dose of 100 mg per day, constipation is significantly reduced, and her growth rate slightly improved (from -0.8 to -0.60 SDS). TSH was suppressed (0.01 mU/L), and FT4 and FT3 increased (4.42 and 17.8 pg/mL, respectively). The patient experienced no side effects and the normocytic anemia did not abate.

Conclusions: TRa defects should be suspected in infants with severe constipation, growth delay, normal TSH levels and high T3/T4 ratio. Following confirmation of THRA gene mutation, close follow up of treatment with high doses of levothyroxine is recommended.