Searchable abstracts of presentations at key conferences in endocrinology

ea0036P83 | (1) | BSPED2014

Congenital central hypothyroidism due to a TSHB mutation with uniparental inheritance

Nicholas Adeline K , Jaleel Safia , Schoenmakers Erik , Dattani Mehul , Roche Edna , Chatterjee V Krishna , Schoenmakers Nadia

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...

ea0028oc1.4 | Young Endocrinologists prize session | SFEBES2012

The thyroid hormone receptor-coactivator interface mediates negative feedback regulation of the human pituitary-thyroid axis

Moran Carla , Mitchell Catherine , Agostini Maura , Schoenmakers Erik , Gregory John , Gurnell Mark , Chatterjee Krishna

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...

ea0044oc3.1 | Thyroid and Neoplasia | SFEBES2016

Frequent Occurrence of DUOX2 and DUOXA2 Mutations in Cases with Borderline Bloodspot Screening TSH who Develop ‘True’ Congenital Hypothyroidism

Peters Catherine , Nicholas Adeline K , Lyons Greta , Langham Shirley , Serra Eva , Schoenmakers Erik , Muzza Marina , Fugazzola Laura , Schoenmakers Nadia

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...

ea0045oc5.7 | Oral Communications 5- Endocrine | BSPED2016

Frequent occurrence of DUOX2 and DUOXA2 mutations in cases with borderline bloodspot screening TSH who develop ‘True’ congenital hypothyroidism

Peters Catherine , Nicholas Adeline K. , Lyons Greta , Langham Shirley , Serra Eva G. , Schoenmakers Erik , Muzza Marina , Fugazzola Laura , Schoenmakers Nadia

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...

ea0044p241 | Thyroid | SFEBES2016

Contrasting phenotypes in Resistance to Thyroid Hormone α correlate with divergent properties of thyroid hormone receptor α1 mutant proteins

Moran Carla , Agostini Maura , McGowan Anne , Schoenmakers Erik , Fairall Louise , Lyons Greta , Rajanayagam Odelia , Watson Laura , Offish Amaka , Barton John , Price Susan , Schwabe John , Chatterjee Krishna

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...

ea0039oc5.5 | Oral Communications 5 | BSPED2015

A novel, missense, mutation (P81R) in the TRH receptor gene in congenital central hypothyroidism

Koulouri Olympia , Nicholas Adeline , Schoenmakers Erik , Mokrosinski Jacek , Lane Frances , Cole Trevor , Kirk Jeremy , Farooqi Sadaf , Chatterjee Krishna , Gurnell Mark , Schoenmakers Nadia

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...

ea0059p154 | Obesity & metabolism | SFEBES2018

Dominant-negative mutations in PPAR alpha are present in unselected human populations and have a metabolic signature

Melvin Audrey , Lam Brian , Langenberg Claudia , Agostini Maura , Schoenmakers Erik , Luan Jian'an , Rainbow Kara , Yeo Giles S , Wareham Nick , Savage David B , Chatterjee Krishna , O'Rahilly Stephen

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 ...

ea0038oc5.2 | Thyroid and parathyroid | SFEBES2015

A novel, missense, mutation (P81R) in the TRH receptor gene in congenital central hypothyroidism

Koulouri Olympia , Nicholas Adeline , Schoenmakers Erik , Mokrosinski Jacek , Lane Frances , Cole Trevor , Kirk Jeremy , Farooqi Sadaf , Chatterjee Krishna , Gurnell Mark , Schoenmakers Nadia

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...

ea0033oc2.9 | Oral Communications 2 | BSPED2013

A comprehensive next generation sequencing-based strategy for genetic diagnosis in congenital hypothyroidism

Schoenmakers Nadia , Cangul Hakan , Nicholas Adeline K , Schoenmakers Erik , Lyons Greta , Dattani Mehul , Peters Catherine , Langham Shirley , Habeb Abdelhadi M , Deeb Asma , Puthi Vijith , Park Soo-Mi , Muzza Marina , Persani Luca , Fugazzola Laura , Maher Eamonn , Chatterjee V Krishna

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 ...

ea0028oc1.5 | Young Endocrinologists prize session | SFEBES2012

Growth Retardation and Severe Constipation due to the first human, dominant negative Thyroid Hormone Receptor Alpha mutation

Schoenmakers Nadia , Bochukova Elena , Agostini Maura , Schoenmakers Erik , Rajanayagam Odelia , Keogh Julia , Henning Elana , Reinemund Jana , Gevers Evelien , Sarri Margarita , Downes Kate , Offiah Amaka , Albanese Assunta , Halsall David , Schwabe John , Bain Murray , Lindley Keith , Muntoni Francesco , Vargha-Khadem Faraneh , Dattani Mehul , Farooqi Sadaf , Gurnell Mark , Chatterjee Krishna

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...