Endocrine Abstracts

Introduction: Biallelic mutations in the TSHB gene are a recognized cause of isolated congenital central hypothyroidism (CH), with autosomal recessive inheritance. In countries where neonatal CH screening relies on detection of an elevated TSH, such cases are missed, with the potential for delayed diagnosis and subsequent developmental impairment.Case: A female infant presented aged 8 weeks with prolonged jaundice, poor weight gain, constipation...

Corepressors and coactivators of thyroid hormone receptor-mediated function facilitate repression and transactivation of positively-regulated target genes respectively, but their role in negative regulation is not understood. A 13 yr old boy, born at 31 weeks gestation, was jittery at birth, with neonatal respiratory distress. Childhood features included poor weight gain, heat intolerance, tachycardia and hyperactivity. Ongoing problems are low frequency hearing loss, poor sig...

The UK newborn screening programme for congenital hypothyroidism (CH) facilitates prevention of neurodevelopmental delay in CH by enabling prompt diagnosis and treatment. Although the UK Newborn Screening Programme Centre (UKNSPC) defines a borderline bloodspot screening TSH (bsTSH) concentration as 10–20 mU/l, the lower cutoff used at Great Ormond Street Hospital (6 mU/l), enables diagnosis of true and transient CH in cases missed using UKNSPC criteria. We hypothesised t...

The UK newborn screening programme for congenital hypothyroidism (CH) facilitates prevention of neurodevelopmental delay in CH by enabling prompt diagnosis and treatment. Although the UK Newborn Screening Programme Centre (UKNSPC) defines a borderline bloodspot screening TSH (bsTSH) concentration as 10–20 mU/l, the lower cutoff used at Great Ormond Street Hospital (6 mU/l), enables diagnosis of true and transient CH in cases missed using UKNSPC criteria. We hypothesised t...

Resistance to Thyroid Hormone alpha (RTHα) is characterised by tissue-selective hypothyroidism with near-normal thyroid function tests, and is due to thyroid receptor α gene mutations. We sought to correlate the clinical characteristics and response to thyroxine treatment of two RTHα patients with the properties of their defective TRα proteins.Clinical, biochemical and physiological parameters were assessed in each patient at baseline...

Background: Congenital, isolated, central, hypothyroidism (CCH), is rare and evades diagnosis on TSH-based congenital hypothyroidism screening programmes in the UK. Genetic ascertainment is therefore paramount in enabling prompt diagnosis and treatment of familial cases. Recognised causes include TSHB and IGSF1 gene defects, with only two previous reports of biallelic, highly disruptive (nonsense; R17X, in-frame deletion and missense; p.S115-T117del+T118), mu...

The study of humans carrying dominant negative mutations in PPAR gamma has contributed significantly to our understanding of its role in human physiology. To date, comparable studies of PPAR alpha have not been reported. Using a pooled approach, we undertook exon sequencing of PPARA in 11,848 adult participants of the Fenland study, a population-based cohort study with detailed metabolic phenotyping. Twenty-nine PPARA missense variants were detected (allelic ...

Background: Congenital, isolated, central, hypothyroidism (CCH), is rare and evades diagnosis on TSH-based congenital hypothyroidism screening programmes in the UK. Genetic ascertainment is therefore paramount in enabling prompt diagnosis and treatment of familial cases. Recognised causes include TSHB and IGSF1 gene defects, with only two previous reports of biallelic, highly disruptive (nonsense; R17X, in-frame deletion and missense; p.S115-T117del+T118), mu...

Introduction: Less than 20% of congenital hypothyroidism (CH) has a known genetic aetiology; thyroid transcription factor mutations (PAX8, Nkx2.1, Nkx2.5, FOXE1) or biallelic TSHR mutations cause <5% of thyroid dysgenesis (TD), whereas mutations in genes mediating thyroid hormone biosynthesis (TPO, TG, DUOX2, DUOXA2, IYD, SLC5A5, SLC26A4) account for most dyshormonogenesis cases. Increased CH frequency in consanguineous populations, relatives of ...

Introduction: Thyroid hormones act via receptors encoded by different genes (THRA and THRB) generating receptor subtypes (TRα1, TRβ1, TRβ2) with differing, tissue-specific expression. Resistance to Thyroid Hormone due to THRB defects is well recognised, but no THRA mutations have yet been reported. We describe the first case of human TRα-mediated thyroid hormone resistance due to a dominant negative THRA mutation.Results: A 6-year-old...