CONTEXT:Congenital hypothyroidism (CH) is a common endocrine disorder with an incidence of 1:3000-4000 at birth. In 80-85% of cases, CH is caused by defects in thyroid organogenesis, resulting in absent, ectopically located, and/or severely reduced gland [thyroid dysgenesis (TD)]. Mutations in genes controlling thyroid development have demonstrated that in a few cases, TD is a Mendelian trait. However, accumulating evidence supports the view that the genetics of TD are complex, possibly with a polygenic/multifactorial basis. A higher prevalence of congenital heart disease has been documented in children with CH than in the general population. Such an association suggests a possible pathogenic role of genes involved in both heart and thyroid development. NKX2-5 encodes a homeodomain-containing transcription factor with a major role in heart development, and mutations affecting this gene have been reported in individuals with congenital heart disease.OBJECTIVE:In the present work we investigated the possible involvement of NKX2-5 mutations in TD.RESULTS:Our results indicate that Nkx2-5(-/-) embryos exhibit thyroid bud hypoplasia, providing evidence that NKX2-5 plays a role in thyroid organogenesis and that NKX2-5 mutations contribute to TD. NKX2-5 mutational screening in 241 patients with TD allowed the identification of three heterozygous missense changes (R25C, A119S, and R161P) in four patients with TD. Functional characterization of the three mutations demonstrated reduced DNA binding and/or transactivation properties, with a dominant-negative effect on wild-type NKX2-5.CONCLUSION:Our results suggest a previously unknown role of NKX2-5 in the pathogenesis of TD.

OBJECTIVE:To identify risk factors for permanent and transient congenital hypothyroidism (CH).DESIGN:A population-based case-control study was carried out by using the network created in Italy for the National Register of Infants with CH.METHODS:Four controls were enrolled for each new CH infant; 173 cases and 690 controls were enrolled in 4 years. In order to distinguish among risk factors for permanent and transient CH, diagnosis was re-evaluated 3 years after enrollment when there was a suspicion of transient CH being present. Familial, maternal, neonatal and environmental influences were investigated.RESULTS:An increased risk for permanent CH was detected in twins by a multivariate analysis (odds ratio (OR) = 12.2, 95% confidence interval (CI): 2.4-62.3). A statistically significant association with additional birth defects, female gender and gestational age >40 weeks was also confirmed. Although not significant, an increased risk of CH was observed among infants with a family history of thyroid diseases among parents (OR = 1.9, 95% CI: 0.7-5.2). Maternal diabetes was also found to be slightly associated with permanent CH (OR = 15.7, 95% CI: 0.9-523) in infants who were large for gestational age. With regard to transient CH, intrauterine growth retardation and preterm delivery were independent risk factors for this form of CH.CONCLUSION:This study showed that many risk factors contribute to the aetiology of CH. In particular, our results suggested a multifactorial origin of CH in which genetic and environmental factors play a role in the development of the disease.

Homozygous null mice for thyroid transcription factor (TTF)-2 gene exhibit cleft palate and thyroid malformation. We performed a genetic analysis of the TTF-2 gene in 2 children with congenital hypothyroidism (CH) and cleft palate, 45 children with thyroid dysgenesis, 19 children with isolated cleft palate or cleft lip, 4 patients with thyroid hemiagenesis. The entire coding-region of the TTF-2 gene was analyzed by direct sequencing. Direct sequencing of the TTF-2 gene revealed polymorphisms in the length of the polyalanine tract. The most frequent stretch length was 14 residues and it was found in 50 of 70 (71%) and in 45 of 53 (85%) normal healthy controls. A polyalanine tract of 16 residues in the heterozygous state was seen in 18 of 70 (26%) cases and in 4 of 53 (7%) normal subjects. In 1 of 4 (25%) case of hemiagenesis a polyalanine tract of 16 residues in the homozygous state was observed. In 1 of 26 agenesis the polyalanine tract consisted of 12 residues in the heterozygous state. Direct sequencing also revealed the presence of two silent polymorphisms. No mutations were identified in the TTF-2 gene. In conclusion, our results show that no genetic alteration was present in the TTF-2 gene of these patients, suggesting that defects in the TTF-2 gene are a rare event.

Newborn screening for congenital hypothyroidism (CH) has become routine in Italy. It provided new information regarding the epidemiology, diagnosis and treatment of CH infants and allowed to identify transient disorders of thyroid function in infancy. In fact, when the permanence of hypothyroidism has not been established in the newborn period, a confirmation of the diagnosis at 2-3 years of life should be performed. In this study results regarding the diagnosis reevaluation performed in 23 out of 184 CH children followed at the follow-up center for CH of the University of Rome "La Sapienza", are reported. Eleven of 23 reevaluated children had transient hypothyroidism (TH) and permanent CH was confirmed in the others. Four of the 11 TH children had law gestational age at birth, 1 had high antithyroid peroxidase titre due to maternal autoimmune thyroiditis and 2 were resident in iodine deficient areas. Our results show the importance of diagnosis reevaluation to identify transient disorders of thyroid function in infancy and confirm the role of neonatal, maternal and environmental factors in the etiopathogenesis of TH.

Permanent congenital hypothyroidism (CH) has an incidence of 1/3000-4000 newborns and is among the most frequent cause of mental retardation and neurological alterations in children. In 80% to 85% of cases CH is associated with thyroid dysgenesis. A group of 61 patients with CH (22 with agenesis, 18 with ectopy, 1 with hypoplasia, and 20 cases with CH without thyroid enlargement but not further characterized) and 30 normal subjects were examined for the presence of mutations in the gene encoding the thyroid transcription factor 1 (TTF-1). The coding-region of the TTF-1 gene was analyzed in all cases by the single stranded conformational polymorphism (SSCP) and no mutations were detected. Direct sequencing also carried out in patients with thyroid agenesis confirmed the absence of mutations or polymorphisms in the TTF-1 gene. The absence of mutations in the TTF-1 gene in our samples indicates that the mutations in the TTF-1 gene are not a frequent cause of CH.

Introduction: Early diagnosis by neonatal thyroid screening is crucial for intellectual and neuropsychological outcome of children with congenital hypothyroidism (CH). Nevertheless, numerous reports have shown that some CH children, even if early treated, still have neuropsychological sequelae at a later age. In this study, we investigate whether the occurrence of a delayed onset of therapy, despite newborn screening, can be responsible for psychomotor abnormalities. Subject and methods: Intellectual and neuropsychological development was assessed in a group of 29 CH children diagnosed by screening in a defined Italian region, in 3 CH children detected on the basis of clinical symptoms and in 11 CH adults born before the screening program was introduced. Thyroid assessment and clinical examination were also performed in these patients. Results: The screened CH children with delayed therapy onset (range:40–70 days) had mostly ectopic and eutopic thyroids and showed significantly lower mean intelligence quotients (90.8 ± 16 vs 106.2 ± 13) and lower mean scores on neuropsychological tests than earlier treated CH children (range: 7–30 days). Discussion: Our study points out that children with ectopic thyroid and dyshormonogenesis, although showing a milder thyroid deficit at screening, may be at risk for delayed onset of therapy and consequent cognitive damage prompt, and adequate treatment should be given in all types of primary CH to prevent mental disturbances in CH children.

Congenital hypothyroidism (IC) is the most frequent endocrine disease of the infancy and it is caused by primary deficiency of thyroid hormones. The damages derived by protracted hormone deficiency are diffused to all organs and systems and particularly severe for the development of central nervous system. Mental retardation can be prevented by early diagnosis and therapy. Early diagnosis is assured by neonatal thyroid screening performed on all newborns in the first days of life. The progress report on the screening situation in Italy as well as the national coordination realized in this field are presented.

Clinical and laboratory data from 42 children (31 females and 11 males) with primary congenital hypothyroidism (CH) diagnosed by neonatal screening over a six-year period are reported. The mean age at onset of thyroid hormone therapy was 33 days. The adequacy of replacement therapy was assessed by repeated TT4, FT4, T3 and TSH serum determinations. The high serum TT4 concentrations frequently observed were not accompanied by clinical evidence of hyperthyroidism. rT3 levels determined in 28 CH children with TT4 greater than 15 micrograms/dl were clearly higher than in the controls. The mean weight, length and head circumference remained always between the 50th and 75th centile. The radiological assessment of the knee, mainly the distal femoral surface, has been considered as an important clinical value in the initial diagnosis and in the evaluation of both severity and duration of disease. The psychomotor development was assessed using Brunet-Lezine's test until age 36 months, Stanford-Binet at 4 and 5 and WISC at 6 years of age. The mean global developmental quotients (GDQ) were always between 85 and 97 at 6 to 72 months of age, only eight children were below 85. A significant correlation was found between GDQ at 6 months and the bone age. The neurological examination showed an impairment of posture, coordination and subtle deficits in motor and perceptual abilities in a small percentage of children.

Acta PaediatricaVolume 61, Issue 5 p. 609-611 SOME EFFECTS OF RUBELLA VACCINATION ON IMMUNOLOGIC RESPONSIVENESS1 MARIO MIDULLA, MARIO MIDULLA Institute of Paediatrics, University of Rome, Rome, ItalySearch for more papers by this authorLUISA BUSINCO, LUISA BUSINCO Institute of Paediatrics, University of Rome, Rome, ItalySearch for more papers by this authorLIDIA MOSCHINI, LIDIA MOSCHINI Institute of Paediatrics, University of Rome, Rome, ItalySearch for more papers by this author MARIO MIDULLA, MARIO MIDULLA Institute of Paediatrics, University of Rome, Rome, ItalySearch for more papers by this authorLUISA BUSINCO, LUISA BUSINCO Institute of Paediatrics, University of Rome, Rome, ItalySearch for more papers by this authorLIDIA MOSCHINI, LIDIA MOSCHINI Institute of Paediatrics, University of Rome, Rome, ItalySearch for more papers by this author First published: September 1972 https://doi.org/10.1111/j.1651-2227.1972.tb15954.xCitations: 15AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Aceto, T., Mattimore, J. M. & Beckhorn, G. D.: Cortisol metabolites in children with varicella or rubcola. Abst Society for Pediatric Research, 1965. 2 Belsey, M. A.: The effect of varicella on tuberculosis. Southern M J, 58: 1584, 1965. 3 Berkovich, S. & Starr, S.: Effects of live type I poliovirus vaccine and other viruses on the tuberculin test. New Engl J Med, 274: 67, 1966. 4 Colarizi, A., Midulla, M. & Pediconi, M.: Indagini sullo stato immunitario verso la rosolia di bambini e madri nell'area di Roma. Risultati di un primo esperimento di vaccinazione. Minerva Med, 61: 1578, 1970. 5 Debrè, R. & Papp, K.: Sur la cuti-réaction tuberculinique au cours de la rougéole. Compt Rend Soc Biol, 95: 29, 1926. 6 Fiaschi, E., Naccarato, R., Fagiolo, U. & Farini, R.: Alcuni aspetti di immunità cellulare e umorale nell'epatite acuta virale. Gazz San, 41: 157, 1970. 7 Fireman, P., Friday, G. & Kumate, J.: Effect of measles vaccine on immunologic responsiveness. Pediatrics, 43: 264, 1969. 8 Lamb, G. A.: Effect of HPV-80 rubella vaccine on the tuberculin reaction. Amer J Dis Child, 118: 261, 1969. 9 Kadowaki, J., Nihira, M. & Nakao, T.: Reduction of phytohemagglutinin-induced lymphocyte transformation in patients with measles. Pediatrics, 45: 508, 1970. 10 Kravis, L. P., Gordon, J. D., Leeks, H. I. & Bhagwat, S.: Detection of tuberculin sensitivity in children by leukocyte culture. Amer J Dis Child, 115: 247, 1968. 11 Montgomery, J. R., South, M. A., Rawls, W. E., Melnick, J. L., Olson, G. R., Dent, P. B. & Good, R. A.: Viral inhibition of lymphocyte response to phytohemagglutinin. Science, 157: 1068, 1967. 12 Simons, M. J. & Jack, I.: Lymphocyte viraemia in congenital rubella. Lancet, II: 953, 1968. 13 Stewart, G. L., Parkman, P., Hopps, H. E., Douglas, R. D., Hamilton, J. P. & Meyer, H. M.: Rubella virus hemagglutination-inhibition test. New Engl J Med, 276: 554, 1967. 14 von Pirquet, C.: Das verhalten der kutane tuberkulin reaktion während der Masern. Deutsch Med Wschr, 34: 1297, 1908. Citing Literature Volume61, Issue5September 1972Pages 609-611 ReferencesRelatedInformation