Searchable abstracts of presentations at key conferences in endocrinology

ea0051oc4.1 | Oral Communications 4 | BSPED2017

Patients with self-limited delayed puberty harbour mutations in multiple genes controlling GnRH neuronal development

Howard Sasha , Andre Valentina , Guasti Leo , Cabrera Claudia , Barnes Michael , Cariboni Anna , Dunkel Leo

Objectives: Abnormal pubertal timing affects >4% of adolescents and is associated with adverse health outcomes. Up to 80% of variation in the timing of pubertal onset is genetically determined. Self-limited delayed puberty (DP) segregates in an autosomal dominant pattern, but in the majority the neuroendocrine pathophysiology and genetic regulation remain unclear. Mis-regulation of the embryonic migration of GnRH neurons has been implicated in the pathogenesis of DP (Howar...

ea0058oc4.5 | Oral Communications 4 | BSPED2018

Delayed or Absent? – use of next generation sequencing diagnostic tools in a UK puberty cohort

Howard Sasha R , Cabrera Claudia P , Barnes Michael R , Dunkel Leo

Objectives: Several different pathogenic mechanisms may converge on a final common pathway to produce the phenotype of delayed pubertal timing. Abnormal pubertal timing affects >4% of adolescents and is associated with adverse health outcomes. Up to 80% of variation in the timing of pubertal onset is genetically determined. Self-limited delayed puberty (DP) segregates in an autosomal dominant pattern, but in the majority the neuroendocrine pathophysiology and genetic regul...

ea0033oc1.5 | Oral Communications 1 | BSPED2013

Novel genes affecting the timing of puberty

Howard Sasha , Storr Helen , Metherell Lou , Barnes Michael , Cabrera Claudia , Gausti Leonardo , Wehkalampi Karoliina , Dunkel Leo

Background: Disturbances of pubertal timing affect >4% of the population and are associated with adverse health outcomes. Studies estimate 60–80% of variation in pubertal onset is genetically determined, but few genetic factors are known. We hypothesise that causal variants will be low-frequency, intermediate-impact variants and will be enriched in populations at the extremes of normal pubertal timing. Families with constitutional delay in growth and puberty (CDGP) ha...

ea0044p139 | Neuroendocrinology and pituitary | SFEBES2016

LGR4 and EAP1 mutations are implicated in the phenotype of self-limited delayed puberty

Mancini Alessandra , Howard Sasha R , Ruiz-Babot Gerard , Cabrera Claudia P , Barnes Michael R , Guasti Leonardo , Dunkel Leo

Background: Aberrations in the timing of puberty may result in significant adverse health outcomes, including cancers, cardiovascular and neurological pathologies. Self-limited delayed puberty (DP) (i.e. constitutional delay of puberty) runs in families with either autosomal dominant or complex inheritance patterns in >70% of families, indicating a strong genetic basis of the trait. However, only a few genes have been identified underlying DP so far....

ea0038oc6.3 | Advances in reproduction and signalling | SFEBES2015

Mutations in HS6ST1 are causal in self-limited delayed puberty as well as idiopathic hypogonadotropic hypogonadism

Howard Sasha , Poliandri Ariel , Storr Helen , Metherell Louise , Cabrera Claudia , Barnes Michael , Warren Helen , Wehkalampi Karoliina , Guasti Leo , Dunkel Leo

Background: Self-limited delayed puberty (DP) often segregates in an autosomal dominant pattern, suggesting that inheritance is conferred by a small number of genes. However, the underlying genetic background is mostly unknown. By comparison, many genes have been identified where loss-of-function mutations lead to hypogonadotropic hypogonadism (HH). Despite likely overlap between the pathophysiology of delayed puberty and conditions of GnRH deficiency, few studies have examine...

ea0034p158 | Growth and development | SFEBES2014

A novel gene affecting the timing of puberty

Howard Sasha , Guasti Leo , Storr Helen , Metherell Lou , Cariboni Anna , Barnes Michael , Cabrera Claudia , Wehkalampi Karoliina , Dunkel Leo

Background: Disturbances of pubertal timing affect >4% of the population and are associated with adverse health outcomes. Studies estimate 60–80% of variation in pubertal onset is genetically determined, but few genetic factors are known. We hypothesise that causal variants will be low-frequency, intermediate-impact variants and will be enriched in populations at the extremes of normal pubertal timing. Families with constitutional delay in growth and puberty (CDGP) ha...

ea0065cc1 | FEATURED CLINICAL CASE POSTERS | SFEBES2019

Double somatic mutations of CTNNB1 and GNA11 in aldosterone producing adenomas (APAs) presenting in puberty, pregnancy or menopause

Zhou Junhua , Storr Helen , Cottrell Emily , Cabrera Claudia , Argentesi Giulia , Wu Xilin , Goodchild Emily , Azizan Elena , Brown Morris J

Objective: We reported 3 patients with primary aldosteronism who presented at times of high plasma LH, and had somatic CTNNB1 mutations causing ˜100-fold elevation of LHCGR in their APAs (Teo et al. NEJM 2015). Subsequently we identified 4 further patients, but the association with pregnancy was not found by others. Whole exome sequencing (WES) of an APA diagnosed at onset of puberty suggests an explanation.Method: WES of tumour and blood w...

ea0066oc4.3 | Oral Communications 4 | BSPED2019

Defects in LGR4 Wnt-β-catenin signalling impair GnRH network development, leading to delayed puberty

Mancini Alessandra , Howard Sasha R , Cabrera Claudia P , Barnes Michael R , David Alessia , Wehkalampi Karoliina , Vassert Gilbert , Cariboni Anna , Garcia Maria Isabelle , Guasti Leonardo , Dunkel Leo

Background: The initiation of puberty is heralded by increasing gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus. During embryonic life the GnRH neuroendocrine network develops thanks to a coordinated migration of neurons from the nasal placode to the forebrain. Our group has previously demonstrated that dysregulation in GnRH neuronal migration leads to delayed pubertal onset. Late puberty affects up to 2% of the population and is associated with adverse h...

ea0039p1 | (1) | BSPED2015

Mutations in HS6ST1 cause self-limited delayed puberty (DP) in addition to idiopathic hypogonadotropic hypogonadism (IHH)

Howard Sasha , Poliandre Ariel , Storr Helen L , Metherell Louise A , Cabrera Claudia , Warren Helen , Barnes Michael , Wehkalampi Karoliina , Guasti Leonardo , Dunkel Leo

Background: Self-limited DP often segregates in an autosomal dominant pattern, but in the majority of patients the neuroendocrine pathophysiology and its genetic regulation remain unclear. By comparison, many genes have been identified where loss-of-function mutations lead to IHH. Despite likely overlap between the pathophysiology of DP and conditions of GnRH deficiency, few studies have examined the contribution of mutations in IHH genes to the phenotype of DP.<p class="a...

ea0065oc5.5 | Adrenal and Cardiovascular | SFEBES2019

Somatic transmembrane domain mutations of a cell adhesion molecule, CADM1, cause primary aldosteronism by preventing gap junction communication between adrenocortical cells

Wu Xilin , Garg Sumedha , Cabrera Claudia , Azizan Elena , Zhou Junhua , Mein Chaz , Takaoka Yutaka , Wozniak Eva , Zhao Wanfeng , Marker Alison , Buss Folma , Murakami Masanori , Beuschlein Felix , Reincke Martin , Ito Akihiko , Brown Morris

Background: Primary Aldosteronism (PA) is the commonest curable cause of hypertension. Whole exome sequencing (WES) of an aldosterone producing adenoma from a 46-year-old man with resistant hypertension revealed a novel somatic mutation (Val380Asp) of the single transmembrane domain of Cell Adhesion Molecule-1 (CADM1). A Gly379Asp mutation was identified by WES of a PA patient in Munich. Both patients were cured of hypertension by adrenalectomy.Method: A...