Two Cases of Thyroid Dysgenesis Caused by Different Novel <i>PAX8</i> Mutations in the DNA-Binding Region: <i>In Vitro</i> Studies Reveal Different Pathogenic Mechanisms

Hermanns, Pia; Grasberger, Helmut; Cohen, Ronald N.; Freiberg, Clemens; Dörr, Helmuth-Günther; Refetoff, Samuel; Pohlenz, Joachim

doi:10.1089/thy.2012.0141

Cited by 28 publications

(12 citation statements)

References 21 publications

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“…To date, 16 PAX8 mutations and four PAX8 variants have been described in familial and sporadic forms of thyroid dysgenesis (1, 2, 3, 9, 10, 13,14,15,16,17,18,22,23,24,25,26,27,28). Mutation frequencies differ markedly among affected transcription factor genes, suggesting regional and/or ethnic differences.…”

Section: Discussionmentioning

confidence: 99%

Extreme phenotypic variability of thyroid dysgenesis in six new cases of congenital hypothyroidism due to PAX8 gene loss-of-function mutations

Ramos

Carré

Chevrier

et al. 2014

European Journal of Endocrinology

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Context: Within the last two decades, heterozygous loss-of-function PAX8 mutations have been reported in patients with a wide degree of thyroid gland dysfunction and growth despite the presence of identical mutations. Objectives: To search for PAX8 mutations in a cohort of patients with congenital hypothyroidism (CH) and various types of thyroid gland defects. Design: A cross-sectional study was conducted in a cohort of patients. Setting: The French neonatal screening program was used for recruiting patients. Patients: A total of 118 patients with CH, including 45 with familial and 73 with sporadic diseases, were included in this study. The thyroid gland was normal in 23 patients had hypoplasia, 25 had hemithyroid agenesis, 21 had athyreosis, and 21 had ectopy. Results: We found four different PAX8 mutations (p.R31C, p.R31H, p.R108X, and p.I47T) in ten patients (six patients with CH and four family members), two with sporadic and eight with familial diseases. Imaging studies performed in the index cases showed ectopic thyroid gland (nZ2), hypoplasia (nZ2), eutopic lobar asymmetry (nZ1), and eutopic gland compatible with dyshormonogenesis (nZ1). The previously reported p.R31C and the novel p.I47T PAX8 mutations are devoid of activity. Conclusion: Four different PAX8 mutations were detected in six index patients with CH (ten total subjects). The p.R31C, p.R31H, and p.R108X mutations have been reported. The novel p.I47T PAX8 mutation presented loss of function leading to CH. Thyroid ectopy was observed in two cases of PAX8 (p.R31H) mutation, a finding that has not been reported previously. We observed a high inter-individual and intra-familial variability of the phenotype in PAX8 mutations, underlining that population genetic studies for CH should include patients with various clinical presentations.

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Section: Discussionmentioning

confidence: 99%

Extreme phenotypic variability of thyroid dysgenesis in six new cases of congenital hypothyroidism due to PAX8 gene loss-of-function mutations

Ramos

Carré

Chevrier

et al. 2014

European Journal of Endocrinology

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“…Twenty-nine heterozygous loss-of-function PAX8 mutations defined as 'disease causing' are reported in HGMD (Human Gene Mutation Database (HGMD) Professional 2018.1), the majority comprising substitutions affecting the DNA-binding domain. Inheritance is autosomal dominant with variable expressivity and penetrance and both dominant negative effects and haploinsufficiency may mediate disease phenotype (33,34). Affected patients predominantly exhibit thyroid hypoplasia; however, GIS, ectopy and athyreosis may also occur ( Fig.…”

Section: Pax8mentioning

confidence: 99%

DIAGNOSIS OF ENDOCRINE DISEASE: Congenital hypothyroidism: update and perspectives

Peters

Trotsenburg

Schoenmakers

2018

European Journal of Endocrinology

115

103

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Congenital hypothyroidism (CH) may be primary, due to a defect affecting the thyroid gland itself, or central, due to impaired thyroid-stimulating hormone (TSH)-mediated stimulation of the thyroid gland as a result of hypothalamic or pituitary pathology. Primary CH is the most common neonatal endocrine disorder, traditionally subdivided into thyroid dysgenesis (TD), referring to a spectrum of thyroid developmental abnormalities, and dyshormonogenesis, where a defective molecular pathway for thyroid hormonogenesis results in failure of hormone production by a structurally intact gland. Delayed treatment of neonatal hypothyroidism may result in profound neurodevelopmental delay; therefore, CH is screened for in developed countries to facilitate prompt diagnosis. Central congenital hypothyroidism (CCH) is a rarer entity which may occur in isolation, or (more frequently) in association with additional pituitary hormone deficits. CCH is most commonly defined biochemically by failure of appropriate TSH elevation despite subnormal thyroid hormone levels and will therefore evade diagnosis in primary, TSH-based CH-screening programmes. This review will discuss recent genetic aetiological advances in CH and summarize epidemiological data and clinical diagnostic challenges, focussing on primary CH and isolated CCH.

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“…Congenital hypothyroidism (CH) is one of the most common causes of intellectual disability and growth retardation with worldwide incidence ranging from 1:2000 to 1:4000 newborns ( 1 , 2 , 3 ). Newborn screening allows for early detection and treatment of CH, thus effectively preventing intellectual disability and short stature due to lack of thyroid hormone.…”

Section: Introductionmentioning

confidence: 99%

The incidence of congenital hypothyroidism (CH) in Guangxi, China and the predictors of permanent and transient CH

Luo

et al. 2017

Endocrine Connections

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BackgroundThe incidence of congenital hypothyroidism (CH) differs significantly among different ethnicities and regions, and early differentiation of transient CH is important to avoid unnecessary prolonged treatment with L-T4.ObjectiveTo investigate the incidence of CH based on the newborn screening program in Guangxi Zhuang Autonomous Region, China, and to analyze the predictors that might allow for an early differentiation between permanent (P) and transient (T) CH.Design and methodsData from newborn screening program over a seven-year period (January 2009 to January 2016) at Guangxi Maternal and Child Health Hospital are analyzed. Blood samples were collected on filter paper between 3 and 7 days after birth, and TSH level was measured by time-resolved fluorescence assay. Individuals with increased TSH (TSH ≥ 8 IU/L) levels detected by newborn screening were recalled for further evaluation. Serum TSH, FT3 and FT4 were determined by electrochemiluminescence assay using venous blood samples. Diagnosis of CH is based on elevated TSH levels (>10 IU/L) and decreased FT4 levels (<12 pmol/L). Patients with elevated TSH levels and normal FT4 levels were diagnosed as hyperthyrotropinemia. Permanent or transient CH was determined by using the results of thyroid function tests after temporary withdrawal of L-T4 therapy at approximately 2–3 years of age.ResultsAmong 1,238,340 infants in the newborn screening program, 14,443 individuals were recalled for reevaluation (re-call rate 1.18%), 911 and 731 individuals were subsequently determined to have hyperthyrotropinemia and CH respectively; thus, a prevalence of 1:1359 and 1:1694 for hyperthyrotropinemia and CH. Of the 731 patients with CH, 161 patients were diagnosed with permanent CH (PCH), and 159 patients were diagnosed with transient CH (TCH), the other 411 patients are too young to determine their subtypes. Patients with PCH required an increasing dose of L-T4 during the first few years, whereas patients with TCH required a decreased dose of L-T4. The TSH levels at diagnosis and the dose of L-T4 used were significantly higher in PCH cases than in transient cases. The FT4 levels at diagnosis were significantly lower in PCH cases than in TCH cases. The TSH levels at diagnosis, FT4 levels at diagnosis and L-T4 doses at 90 days were evaluated as predictors for differentiating PCH and TCH, and their accuracy at their respective optimal cutoffs were determined to be 60.6%, 66.7% and 93.9%, respectively.ConclusionsThe CH incidence in Guangxi Zhuang Autonomous Region is slightly higher (1:1694) compared to the worldwide levels (1/2000–1/4000). The PCH and TCH ratio is close to 1; thus, the estimated PCH incidence is 1/3388, which is similar to reported worldwide average incidence (1/3000). The L-T4 dose required at 90 days (>30 μg/day) has the highest predictive value for PCH. Earlier differentiation of PCH and TCH helps to determine appropriate treatment course.

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Two Cases of Thyroid Dysgenesis Caused by Different Novel PAX8 Mutations in the DNA-Binding Region: In Vitro Studies Reveal Different Pathogenic Mechanisms

Cited by 28 publications

References 21 publications

Extreme phenotypic variability of thyroid dysgenesis in six new cases of congenital hypothyroidism due to PAX8 gene loss-of-function mutations

Extreme phenotypic variability of thyroid dysgenesis in six new cases of congenital hypothyroidism due to PAX8 gene loss-of-function mutations

DIAGNOSIS OF ENDOCRINE DISEASE: Congenital hypothyroidism: update and perspectives

The incidence of congenital hypothyroidism (CH) in Guangxi, China and the predictors of permanent and transient CH

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