A Study Of Treatment, Neurodevelopmental Outcome And Thyroid Transcription Factor-1 Gene In Chinese Children With Congenital Hypothyroidism

IntroductionCongenital hypothyroidism (CH) is a common neonatal metabolic disorder and may result in severe neurodevelopmental impairment. The neonatal screening program enables the early identification of affected patients and helps to prevent mental retardation. The outcome of the patients is affected by the endogenous factors such as the etiology and severity of the disease, and the exogenous ones including the timing and effectiveness of hormonal replacement. Thyroid dysgenesis (TD) accounts for about 85% of all cases with CH. There is a possible genetic mechanism in the pathogenesis of TD. Thyroid transcription factor-1 (TTF-1) is involved in the development of the gland and in the transcriptional control of the thyroglobulin, thyroperoxidase, and thyrotropin receptor genes. It is possible that mutations in TTF-1 gene encoding TTF-1 could result in failure of the thyroid gland to develop. Some screenings for mutations in TTF-1 gene have been done in Caucasian individuals, but the mutant TTF-1 in Chinese population with CH (or TD) has not been reported. In the present study, we followed up 75 Chinese children with CH until the age of two years and performed genetic analysis of the TTF-1 gene in thesechildren.Subjects and MethodsSubjectsA total of 75 children with CH, born between October 1999 and December 2004, were diagnosed at the Zhejiang Neonatal Screening Center in China. The patients were divided into two subgroups according to the morphogenesis of the thyroid on the basis of thyroid scan and ultrasound investigation: TD (n=46) and normal thyroid gland (TN, n=29). Meanwhile, the genomic DNA from 100 normal children was collected for genetic analysis, which served as controls.MethodsTreatment and biochemical (Serum TSH, total T4 and total T3) follow-up were scheduled at the day of starting treatment, then at 2, 3, 6, 9, 12,18 and 24 months of age. The results were documented. Thirty children had their development evaluated with the Gesell Developmental Scales at 2 years of age.The coding region of the TTF-1 gene was amplified by polymerase chain reaction (PCR) with 4 pairs of primers. The PCR products were directly sequenced using a cycle sequencing method. ResultsMedian serum TSH levels were higher (P < 0.01) and total T4 and total T3 levels were lower in the TD group than in the TN group (T4: P = 0.01;T3: P < 0.01). Moreover, TSH levels in the TN groups were normalized earlier, and the TD group received higher dose of levothyroxine. At the age of two years, the children with TD had lower values of the median development quotient (DQ), which was not statistically significant.The entire coding region of the TTF-1 gene was analyzed in all patients and normal individuals and no mutation were detected. In a patient with TN, one heterozygous G-to-A transversion at position 858 (G858A) from the coding region was found (reference sequence NM₀03317), but the amino acid did not change. The same nucleotidesubstitution was not detected in the parents of the patient and the 100 normal subjects. Conclusions(1) The treatment and follow-up schedules for CH may differ in the two groups based on the morphogenesis of the thyroid. The children with TD need closer monitoring particularly in early life and higher dose of levothyroxine.(2) The absence of mutations in the TTF-1 gene in our samples indicates that the TTF-1 gene might not be a frequent cause of CH (or TD) in the Chinese population.