Reply

Abstract

To the Editors: In response to the Letter to the Editor by Pharoah, we mention in our article that one of the potential causes for multiple organ system malformations seen in children with congenital hypothyroidism may be the role of thyroid hormones during early embryogenesis, and this is probably the most likely and attractive of all explanations. However, we could not find any study that conclusively demonstrated deficiency of thyroid hormones alone to be responsible for all the anomalies. Thyroid hormone deficiency in the antenatal period has been shown to affect neurologic development quite conclusively, as suggested by Pharoah. The possibility of monochorionic twinning with feto-fetal transfusion perturbations as an explanation for multiple congenital anomalies is fascinating. However, our concern is: “Are monochorionic twin pregnancies so common that they can account for all the cases of multiple malformations that are seen in children with congenital hypothyroidism?” Are there any studies showing this to be more than a plausible explanation? Development of the embryonic thyroid gland is affected by many transcription factors, such as TTF-1, TTF-2 and Pax-8. The target genes of these transcription factors are thyroglobulin and thyroid peroxidase genes. Pax -8 mutations were found to be involved in syndromic cases of congenital hypothyroidism that involved only the thyroid and renal systems and not multiple organ systems.1Krude H. Macchia P.E. DiLauro R. Grüters A. Familial hypothyroidism due to thyroid dysgenesis caused by dominant mutations of the PAX8 gene. Proc 37th Annual Meeting of the European Society for Pediatric Endocrinology.Horm Res. 1998; 50 (17)Google Scholar, 2Meeus L. Gilbert B. Rydlewski C. Parma J. Roussie A.L. Abramowicz M. et al.Characterization of a novel loss of function mutation of PAX8 in a familial case of congenital hypothyroidism with in-place, normal-sized thyroid.J Clin Endocrinol Metab. 2004; 89: 4285-4291Crossref PubMed Scopus (99) Google Scholar, 3Al Taji E. Biebermann H. Límanová Z. Hníková O. Zikmund J. Dame C. et al.Screening for mutations in transcription factors in a Czech cohort of 170 patients with congenital and early-onset hypothyroidism: identification of a novel PAX8 mutation in dominantly inherited early-onset non-autoimmune hypothyroidism.Eur J Endocrinol. 2007; 156: 521-529Crossref PubMed Scopus (88) Google Scholar In our matched data, 8 subjects had only renal anomalies along with the congenital hypothyroidism. Finally, ours is an observational study and by no means proves causality. Because it is difficult to prove what really causes multiple anomalies in children with congenital hypothyroidism, we still believe that involvement of common genes in thyroid and kidney development as a potential cause needs to be investigated further. In response to the Letter to the Editor by Nebesio, congenital renal anomalies are leading causes of pediatric end-stage kidney disease.4Warady B. Chadha V. Chronic kidney disease in children: the global perspective.Pediatr Nephrol. 2007; 22: 1999-2009Crossref PubMed Scopus (313) Google Scholar Hydronephrosis might be a clinically silent yet significant renal abnormality, especially if it is associated with urinary outflow obstruction or vesicoureteral reflux.5Sidhu G. Beyene J. Rosenblum N.D. Outcome of isolated antenatal hydronephrosis as a predictor of postnatal outcome: a meta-analysis.Pediatrics. 2006; 118: 586-593Crossref PubMed Scopus (316) Google Scholar Our data indicate that more than 3 in 100 children with congenital hypothyroidism (CHT) may have hydronephrosis, so we are not surprised that Tonacchera et al did not observed any renal anomalies in 43 children who had abdominal USG. Because it is difficult to prove what really causes multiple anomalies in children with CHT, we still believe that involvement of common genes in thyroid and kidney development, as a potential cause needs to be investigated further. We believe that cardiac anomalies may be less clinically silent than kidney anomalies and may present earlier to physician attention. Our recommendation for early renal ultrasonographic evaluation of children with CHT is not endorsed by any society and is based on our clinical data. Calculated by Nebesio, yearly cost of $800000 for routine renal ultrasonography is indeed steep; however, cost of dialysis and kidney transplantation for patients with obstructive and reflux uropathy associated with CHT is unknown. It is our belief that we can detect early and in a noninvasive way the children with CHT who are at risk of renal anomalies.