Correspondence

Familial Forms of Thyroid Dysgenesis among Infants with Congenital Hypothyroidism

N Engl J Med 2000; 343:441-442August 10, 2000

Article

To the Editor:

Thyroid dysgenesis (thyroid aplasia or an ectopic thyroid gland) is responsible for 85 percent of cases of congenital hypothyroidism. The pathogenesis of thyroid dysgenesis is not known. Although a few familial cases have been reported,1,2 the disorder is considered to be sporadic. Some cases caused by mutations of several genes involved in thyroid organogenesis (the thyroid transcription factor 1 and 2 genes and PAX 8) and the gene for the thyrotropin receptor have been reported.3-5 However, among cases of congenital hypothyroidism, the proportion of familial cases caused by thyroid dysgenesis is not known.

In a study supported by the French Association for the Diagnosis and Prevention of Child Handicap, we sent a questionnaire to all 592 pediatricians who provided ongoing clinical care for the 4049 infants with congenital hypothyroidism detected during the first 19 years of the French screening program for newborn infants, during which 14,416,428 infants were tested. The results of biochemical and imaging studies of the infants and information about the family pedigree were requested. We received replies from 435 pediatricians (73 percent) who followed a total of 2472 infants with congenital hypothyroidism caused by thyroid dysgenesis. The pediatricians reported 67 cases in infants from 32 multiplex families: 48 cases in infants born after the start of the screening program and 19 in infants born before the start of the program. Thus, since 1979, the overall proportion of familial cases of congenital hypothyroidism with thyroid dysgenesis was 2 percent (48 of 2472). Among the 32 families, there were 23 with affected first-degree relatives — 15 times the number that would be expected on the basis of chance alone (1.5) — indicating the existence of a strong familial component.

There were at least two affected siblings in 13 families, affected parents and offspring in 10 families, and more distant affected relatives in 9 families (Figure 1Figure 1Representative Pedigrees and Phenotypes among 32 Families with Congenital Hypothyroidism Caused by Thyroid Dysgenesis.). Of the 67 infants, 38 had ectopic thyroid glands and 29 had thyroid aplasia. In 12 families all the affected members had ectopic thyroid tissue, in 7 families all the affected members had thyroid aplasia, and in 13 families both types of thyroid dysgenesis were present.

Although common unidentified environmental factors cannot be ruled out, the involvement of genetic factors is strongly suggested, with common underlying mechanisms for both types of thyroid dysgenesis. According to the hypothesis of genetic homogeneity, transmission of thyroid dysgenesis is compatible with an autosomal dominant mode of inheritance with incomplete penetrance. However, the marked clinical variability both within and between families may reflect genetic heterogeneity.

Mireille Castanet, M.D.
Hôpital Robert Debré, 75019 Paris, France

Stanislas Lyonnet, M.D., Ph.D.
Hôpital Necker Enfants-Malades, 75015 Paris, France

Catherine Bonaïti-Pellié, M.D., Ph.D.
Institut Gustave Roussy, 94800 Villejuif, France

Michel Polak, M.D., Ph.D.
Paul Czernichow, M.D.
Juliane Léger, M.D.
Hôpital Robert Debré, 75019 Paris, France

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Citing Articles (10)

Citing Articles

1. 1

   Aurore Carré, Mireille Castanet, Sylvia Sura-Trueba, Gabor Szinnai, Guy Vliet, Delphine Trochet, Jeanne Amiel, Juliane Léger, Paul Czernichow, Virginie Scotet, Michel Polak. (2007) Polymorphic length of FOXE1 alanine stretch: evidence for genetic susceptibility to thyroid dysgenesis. Human Genetics 122:5, 467-476
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2. 2

   Keisuke Kanda, Haruo Mizuno, Yukari Sugiyama, Hiroki Imamine, Hajime Togari, Kazumichi Onigata. (2006) Clinical significance of heterozygous carriers associated with compensated hypothyroidism in R450H, a common inactivating mutation of the thyrotropin receptor gene in Japanese. Endocrine 30:3, 383-388
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3. 3

   D. Carranza, G. Van Vliet, M. Polak. (2006) Hypothyroïdie congénitale. Annales d'Endocrinologie 67:4, 295-302
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4. 4

   Stefan Höpfner, Bernhard Höpfner, Ernst W. Rauterberg. (2005) Neonatal screening for congenital hypothyroidism in Hessen, Germany: efficiency of the screening program and school achievement of 129 children at an age of 8–12 years. Journal of Perinatal Medicine 33:6, 543-548
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5. 5

   MIREILLE CASTANET, LAURENCE LEENHARDT, JULIANE L??GER, AURORE SIMON-CARR??, STANISLAS LYONNET, ANNA PELET, PAUL CZERNICHOW, MICHEL POLAK. (2005) Thyroid Hemiagenesis Is a Rare Variant of Thyroid Dysgenesis with a Familial Component but without Pax8 Mutations in a Cohort of 22 Cases. Pediatric Research 57:6, 908-913
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   Massimo Tonacchera, Mariaelena Banco, Paola Lapi, Caterina Di Cosmo, Anna Perri, Lucia Montanelli, Lidia Moschini, Gianluca Gatti, Daniele Gandini, Alessandro Massei, Patrizia Agretti, Giuseppina De Marco, Paolo Vitti, Luca Chiovato, Aldo Pinchera. (2004) Genetic Analysis of TTF-2 Gene in Children with Congenital Hypothyroidism and Cleft Palate, Congenital Hypothyroidism, or Isolated Cleft Palate. Thyroid 14:8, 584-588
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7. 7

   Henrik Fagman, Mats Grände, Amel Gritli-Linde, Mikael Nilsson. (2004) Genetic Deletion of Sonic Hedgehog Causes Hemiagenesis and Ectopic Development of the Thyroid in Mouse. The American Journal of Pathology 164:5, 1865-1872
   CrossRef

8. 8

   S.-M. Park, R. J. Clifton-Bligh, P. Betts, V. K. K. Chatterjee. (2004) Congenital hypothyroidism and apparent athyreosis with compound heterozygosity or compensated hypothyroidism with probable hemizygosity for inactivating mutations of the TSH receptor. Clinical Endocrinology 60:2, 220-227
   CrossRef

9. 9

   Michel Polak, Sylvia Sura-Trueba, Anne Chauty, Gabor Szinnai, Aurore Carré, Mireille Castanet. (2004) Molecular Mechanisms of Thyroid Dysgenesis. Hormone Research 62:Suppl. 3, 14-21
   CrossRef

10. 10

    P. Bretones, L. Duprez, J. Parma, M. David, G. Vassart, P. Rodien. (2001) A Familial Case of Congenital Hypothyroidism Caused by a Homozygous Mutation of the Thyrotropin Receptor Gene. Thyroid 11:10, 977-980
    CrossRef