Pendred syndrome among patients with congenital hypothyroidism detected by neonatal screening: identification of two novel PDS/SLC26A4 mutations.

Pendred syndrome is an autosomal recessive disorder characterised by sensorineural hearing loss and thyroid dyshormonogenesis. It is caused by mutations in the PDS/SLC26A4 gene (OMIM 605646) encoding for pendrin. Hypothyroidism in Pendred syndrome can be--although rarely--present from birth and therefore diagnosed by neonatal screening. The aim of our study was to identify patients with Pendred syndrome among a historical cohort of patients with congenital hypothyroidism (CH) identified by neonatal screening, and to find their mutations in the PDS/SLC26A4 gene. We investigated 197 Czech Caucasian children with CH detected by the neonatal screening between the years 1985 and 2005. The clinical diagnosis of Pendred syndrome was based on the laboratory and sonographic signs of thyroid dyshormonogenesis in association with sensorineural hearing loss. In subjects clinically diagnosed with Pendred syndrome, we sequenced all exons and exon-intron boundaries of the PDS/SLC26A4 gene. Hearing loss was present in 10/197 children with screening-detected CH. Of these, three fulfilled the diagnostic criteria of Pendred syndrome. Two patients were compound heterozygotes for PDS/SLC26A4 mutations: patient 1 carried c.2089+1G>A / c.3G>C and patient 2 carried p.Tyr530His / p.Val422Asp. Two of the four identified mutations were novel (c.3G>C in patient 1 and p.Val422Asp in patient 2). The third patient was free of mutations in the PDS/SLC26A4 gene, representing a phenocopy. In conclusion, our results indicate the rarity of Pendred syndrome as a cause of CH. The identification of two novel mutations expands the spectrum of mutations in the PDS/SLC26A4 gene and emphasizes their marked allelic heterogeneity.

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.

OBJECTIVE: Mutations in NKX2.1, NKX2.5, FOXE1 and PAX8 genes, encoding for transcription factors involved in the development of the thyroid gland, have been identified in a minority of patients with syndromic and non-syndromic congenital hypothyroidism (CH). DESIGN: In a phenotype-selected cohort of 170 Czech paediatric and adolescent patients with non-goitre CH, including thyroid dysgenesis, or non-goitre early-onset hypothyroidism, PAX8, NKX2.1, NKX2.5, FOXE1 and HHEX genes were analysed for mutations. METHODS: NKX2.1, NKX2.5, FOXE1 and HHEX genes were directly sequenced in patients with syndromic CH. PAX8 mutational screening was performed in all 170 patients by single-stranded conformation polymorphism, followed by direct sequencing of samples with abnormal findings. The R52P PAX8 mutation was functionally characterized by DNA binding studies. RESULTS: We identified a novel PAX8 mutation R52P, dominantly inherited in a three-generation pedigree and leading to non-congenital, early-onset, non-goitre, non-autoimmune hypothyroidism with gradual postnatal regression of the thyroid size and function. The R52P PAX8 mutation results in the substitution of a highly conserved residue of the DNA-binding domain with a loss-of-function effect. CONCLUSIONS: The very low frequency of genetic defects in a population-based cohort of children affected by non-goitre congenital and early-onset hypothyroidism, even in a phenotype-focussed screening study, suggests the pathogenetic role of either non-classic genetic mechanisms or the involvement of genes unknown so far. Identification of a novel PAX8 mutation in a particular variant of non-congenital early-onset hypothyroidism indicates a key function of PAX8 in the postnatal growth and functional maintenance of the thyroid gland.