Congenital hypothyroidism affects 1/3000-4000 newborns. The causes of this group of disorders are still largely unknown. Although most cases are sporadic some families have several affected children and/or consanguineous parents, suggesting autosomal recessive inheritance. Furthermore, there is a murine strain (hyt) with congenital hypothyroidism and autosomal recessive inheritance, whose phenotype appears to be identical with the corresponding human disease. In the hyt mouse, the disease is caused by a mutation in the thyroid-stimulating hormone receptor (TSHR) gene, making this gene a likely candidate also for the human disease. The human TSHR gene was mapped on radiation hybrid panels and closely linked flanking markers D14S287 and D14S616 were identified. On the Genebridge 4 panel, D14S287 was found to be located 8.5 cR (corresponding to 2.3 cM) proximal to the TSHR gene, and D14S616 was found to be located 4.4 cR (1.2 cM) distal to the TSHR gene. These markers were analyzed in 23 families, most of them with two or more children affected by congenital hypothyroidism and some with appreciable consanguinity of the parents. Assuming homogeneity, the two-point lod score at theta = 0.1 was -4.8 for D14S287 and -5.8 for D14S616, and thus linkage to the TSHR gene was excluded. Even when the data were analyzed with allowance for heterogeneity, there was no evidence of linkage. Our conclusion is that if mutation of the TSHR gene causes familial congenital hypothyroidism in humans, it affects only a small proportion of the cases.
Congenital hypothyroidism affects 1/3000-4000 newborns and it has been estimated that 10-20% are familial cases with an autosomal recessive mode of inheritance. Previous studies of mostly individual cases have led to the identification of mutations in a number of genes, indicating that it is a genetically heterogeneous disease, but no major gene has been identified. In the present investigation, a population-based sample of 23 families with autosomal recessive congenital hypothyroidism, but no signs of goitre, were subject to linkage analysis. When markers located close to the thyroglobulin gene on chromosome 8q24 were used in a two-point analysis allowing for heterogeneity, a Z(max) of 4.10 was obtained with the microsatellite marker D8S557, indicating heterogeneity with 43% of the families being linked. A multipoint analysis using the markers D8S557 and D8S1835 gave a Z(max) of 3.51, assuming homogeneity. There was significant evidence of heterogeneity with 44.5% of the families being linked. The results indicate that a gene in 8q24 is a common cause of familial congenital hypothyroidism. Since thyroglobulin is essential for thyroid physiology, the gene encoding this protein is the obvious candidate for mutation analysis in the linked families.
Noonan syndrome, multiple lentigines syndrome (LEOPARD syndrome), Watson syndrome and neurofibromatosis type 1 share certain clinical manifestations. We present a linkage analysis using microsatellite markers located in the neurofibromatosis type 1 region at 17q11 in a family with Noonan syndrome and café‐au‐lait spots and in another family with multiple lentigines syndrome. No linkage of the disease to the neurofibromatosis type 1 locus was found in the families investigated. On the basis of our results, we suggest that neither familial multiple lentigines syndrome nor Noonan syndrome is caused by a defect in the neurofibromatosis type 1 gene.
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