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Background: In the last couple of years, different genes that play major roles in embryonic thyroid development have been identified. Several mutations, e.g., NKX2.1, FOXE1 and PAX8, were identified in patients with congenital hypothyroidism due to thyroid dysgenesis. However, the pathophysiology of most cases of thyroid dysgenesis remains unknown. Due to the sporadic occurrence and discordance observed in monozygotic twins, a classic genetic hypothesis for thyroid dysgenesis is improbable. Case Report: We present two pairs of monozygotic twins discordant for thyroid dysgenesis that exemplify these conceptual difficulties. Conclusions: Identification of the epigenetic differences observed in monozygotic twins discordant for thyroid dysgenesis may be crucial in discovering the pathogenesis of thyroid dysgenesis. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aims: To investigate the frequency of thyroid dysgenesis (TD) in first-degree relatives of TD cases. Methods: 244 first-degree relatives of 82 TD cases were screened by thyroid ultrasound (USG), T4, fT4 and TSH. USG was also performed in 220 unrelated, age- and sex-matched healthy controls to obtain normative data for thyroid volumes. Results: Specific diagnoses of indexes were 35 ectopia, 22 athyreosis, 14 severe hypoplasia, 8 hypoplasia, and 3 hemiagenesis/asymmetric hypoplasia. In 5 of 77 families (6.5%), there were 2 cases with known symptomatic TD. A total of 10 cases made familial symptomatic TD ratio 12% (10/82) in our cohort. Screening of 244 asymptomatic family members did not reveal new cases with overt hypothyroidism. However, low thyroid volume in 15 and slightly elevated TSH in 6 family members and both in 1 family member were detected (7.4% for low thyroid volume, 3.2% for high TSH). Thus, the ratio of affected (symptomatic and asymptomatic) family members among families of TD cases was found to be 8.7%. Conclusions: 12% of TD cases are familial in our cohort. Screening of asymptomatic family members of TD revealed an additional 7.4% mild hypoplasia and 3.2% hyperthyrotropinemia without overt hypothyroidism which points out the importance of genetic factors in pathogenesis. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In the last decade a high frequency of extrathyroidal congenital anomalies has been reported in infants with congenital hypothyroidism (CH) detected by neonatal screening. In the present study the occurrence of additional congenital malformations (CM) in a cohort of children with confirmed primary CH due to thyroid dysgenesis was investigated. A high prevalence of extrathyroidal major congenital anomalies (15.9%), more than 5-fold higher than that reported in the Egyptian population (2.7%), was found. The cardiac and musculoskeletal systems were the most commonly involved, comprising 9.09 and 47.72% of all anomalies, respectively. The high prevalence of musculoskeletal anomalies in this study was mostly due to minor anomalies as brachydactyly and digitalization of thumbs. The type of dysgenesis (i.e. aplastic, ectopic or hypoplastic) as well as the severity of hypothyroidism, as assessed by TSH and T4 levels at diagnosis, had no relation with the occurrence of extrathyroidal abnormalities. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Thyroid dysgenesis (TD) is the most prevalent form of congenital hypothyroidism. Ttf-1, Ttf-2, Pax8 and the Tshr are expressed at early stages of thyroid development and are implicated in thyroid ontogeny. Mutations in these genes have been found in some cases of TD. The prevalence of familial forms of TD is significantly higher than expected if the disease was only sporadic, allowing to postulate a genetic basis of the disease. Linkage analysis and mutational screening of the four above-mentioned genes in familial forms of TD showed their exclusion as contributors to the disease in some families, implicating genetic heterogeneity and involving other genetic mechanisms. Strategies to uncover new genes involved in TD are therefore needed. We underscore differences in the temporal expression patterns during the human thyroid development with those in animal models. Further, the extrathyroid expression of these genes during human development enables to define the gene-specific malformations that may be present in patients bearing mutations. The data gathered on molecular thyroid development enable precise genetic counselling of affected families. By increasing our knowledge of thyroid development, we hope to uncover new perspectives of genetic screening and eventually of early in utero treatment. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In patients with congenital hypothyroidism (CH), the autosomal recessive inheritance of mutations of thyroid peroxidase, thyroglobulin and the NIS and pendrin genes encoding for sodium iodide transporters has been identified. CH due to thyroid dysgenesis was considered to be a sporadic disease, but recently, inheritable defects of thyroid development have been described. The autosomal recessive inheritance of mutations of the thyroid-stimulating hormone receptor gene was recognized in patients with CH and thyroid hypoplasia, while autosomal dominant mutations of the Pax-8 gene were described in patients with thyroid dysgenesis. In addition, analysis of mutations of the β-thyrotropin gene has resulted in a new understanding of the pathogenesis of central CH. Molecular genetic studies in patients with CH detected by newborn screening will provide the information necessary for genetic counselling and may help to explain the less favourable outcome present in 5–10% of the patients.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]