Dr Sasha Howard

Profile

ORCID ID: 0000-0002-6698-903X

Dr Sasha Howard graduated in Medicine from the University of Cambridge (preclinical medicine, 1st class honors) and University College London (MBBS, distinction) in 2004. She trained in Paediatrics before sub-specialising in Paediatric Endocrinology at Barts Health, UCLH and Great Ormond Street Hospitals. She completed a PhD in Molecular Endocrinology at the William Harvey Research Institute, Barts and the London School of Medicine funded by a Wellcome Trust Research Training Fellowship and a Barts Charity Clinical Training Fellowship. She was awarded the 2015 Henning Andersen prize for Paediatric Endocrinology (ESPE) and 2016 1st Oral Plenary Prize at the Academy of Medical Sciences Spring Meeting for Clinician Scientists. In 2017 she won a 4-year NIHR clinical lectureship alongside an Academy of Medical Sciences starter grant to continue her research into disorders of human pubertal timing. She was awarded a Wellcome Trust Clinical Research Career Development Fellowship, stage 1 in 2021 and appointed Senior Lecturer at Queen Mary University of London and Honorary Consultant in Paediatric Endocrinology at Barts Health NHS Trust (Sept 2021). Dr Howard is member of the NIHR / BSPED Clinical Studies Group (CSG) and Co-PI of the Barts Pituitary Centre.

Memberships

• The Royal College of Paediatrics and Child Health (RCPCH)
• British Society of Paediatric Endocrinology and Diabetes (BSPED)
• British Society of Paediatric Endocrinology and Diabetes (BSPED) Clinical Studies Group (CSG)
• European Society of Paediatric Endocrinology (ESPE)
• The Society for Endocrinology (SfE)
• American Endocrine Society
• British Medical Association (BMA) 
  
  

Awards

• 2021   Wellcome Trust Clinical Research Career Development Fellowship Stage 1
• 2021   Barts Charity Large Programme Grant
• 2018   Academy of Medical Sciences CL Starter Grant
• 2018   Rosetrees Trust Award
• 2017   NIHR Academic Clinical Lectureship
• 2014   Wellcome Trust Pre-Doctoral Research Training Fellowship
• 2012   Rosetrees Trust Award
• 2012   Barts and the London Charity Clinical Training Fellowship 

Find out more about Endocrinology at the William Harvey Research Institute.

Research

Group members

• Dr Tansit Saengkaew, PhD Student

Close collaborators

• Dr Leonardo Guasti (Reader in Endocrinology)
• Professor Leo Dunkel (Professor of Paediatric Endocrinology).

Alumni

• Dr Alessandra Mancini (PhD student, now postdoc at Harvard University)
• Ms Matilde Ciaroni (Erasmus student, now in Industry)

Summary

Dr Howard’s research is focused on optimising the diagnosis and management of patients with pubertal disorders.

Puberty is the period of physical and psychological change from a child to an adult. Disorders of pubertal timing affect 4% of children, comprising significantly precocious (before 8yrs of age [>2 standard deviations below the mean population age]) or delayed (after 14yrs of age [>2 standard deviations above the mean age]) pubertal onset.

These common disorders are associated with adverse long-term health outcomes. Precocious puberty is associated with an increased risk of obesity, type 2 diabetes, and breast cancer, and delayed puberty is associated with psychosocial comorbidities and reduced bone density. Both are associated with early menopause or andropause.

While we know that these conditions are often inherited in families, we still understand very little about how they occur, and which gene changes are responsible. Currently, it can be difficult to distinguish which patients with early or late puberty need intensive treatment and follow up. 

Genetics of Disordered Puberty Project (CPMS ID 30730, PI Dr Sasha Howard): our aim is to identify genetic mutations that cause Central Precocious Puberty (CPP) and Delayed Puberty (DP). To achieve this, we utilise various genetic testing methods to diagnose patients that have been referred to us. So far, our cohort of referrals stands at >130 patients in whom we have found a genetic diagnosis in 28%.

If you have a patient with suspected CPP or DP please get in contact and we will endeavour to provide you with a genetic diagnosis completely free of charge. 

Important: We are a purely research-based group and therefore all genetic diagnoses may have to be validated by a NHS or nationally accredited facility.

Genetics of the timing of puberty

Figure 1. Genetics of the timing of puberty.  The precise genetic causes of the extreme tails of normal puberty are unclear, as is the basis of association of specific gene variants with pubertal timing in the general population (outside of families with GnRH deficiency or self-limited delayed puberty). Understanding the role(s) of gene variants influencing the timing of puberty, both precocious and delayed, is expected to contribute to the understanding of the biological control of human pubertal timing both in disease and in the general population. This knowledge could directly help patients through improved diagnostic ease and facilitate identification of gene-environmental interactions. Based on the observed inheritance pattern, we hypothesize that families with inherited self-limited delay in growth and puberty are enriched for genetic variants that have high-impact on pubertal timing and, that these variants are amenable to discovery using modern molecular genetic tools. Recently, we have discovered evidence that such high impact variants may influence the timing of puberty, significantly delaying the onset of puberty in a subset of families.

Figure 2. The genetic basis of delayed puberty. Previously identified genes implicated in the pathogenesis of self-limited delayed puberty are related to GnRH neuron development, up- and downstream GnRH function, and energy metabolism; KNDy - kisspeptin-neurokinin-dynorphin.

Figure 3. Working model of how mutations in genes such as IGSF10 led to delayed puberty. Reduced IGSF10 expression during embryogenesis in the corridor of nasal mesenchyme cells of the vomeronasal organ (VNO) leading to the olfactory bulbs delays the migration of gonadotropin-releasing hormone (GnRH) neurons to the hypothalamus. This reduction manifests in adolescence as a phenotype of delayed puberty due to abnormalities of GnRH neuronal network function.

Key Publications

• Saengkaew T and Howard SR. NGS Approach in the Diagnosis of Delayed Puberty, Current Opinion in Endocrine and Metabolic Research, 2020 doi: 10.1016/j.coemr.2020.05.003
• Mancini A, Howard SR et al. LGR4 deficiency results in delayed puberty through impaired Wnt-β-catenin signalling, JCI Insight 2020; 5(11), doi: 10.1172/jci.insight.133434
• Howard SR. Genetic Regulation in Pubertal Delay. J Mol Endocrinol 2019;63:37-9 doi: 10.1530/JME-19-0130
• Howard SR and Dunkel L. Delayed Puberty – Phenotypic Diversity, Molecular Genetic Mechanisms and Recent Discoveries. Endocrine reviews 2019 doi: 10.1210/er.2018-00248
• Mancini A, Howard SR, Cabrera CP et al. EAP1 regulation of GnRH promoter activity is important for human pubertal timing, Hum Mol Genet. 2019 Jan 4. doi: 10.1093/hmg/ddy451.
• Howard SR, Oleari R, Poliandri A, et al. HS6ST1 insufficiency causes self-limited delayed puberty in contrast with other GnRH deficiency genes. J Clin Endocrinol Metab. 2018 Jun 20. doi: 10.1210/jc.2018-00646.
• Howard SR and Dunkel L. Management of Hypogonadism From Birth to Adolescence. Best Practice & Research Clinical Endocrinology & Metabolism. 2018 doi: 10.1016/j.beem.2018.05.011
• Howard SR. Genes underlying delayed puberty. Mol Cell Endocrinol. 2018 May 4. pii: S0303-7207(18)30149-7. doi: 10.1016/j.mce.2018.05.001. 
• Cassatella D*, Howard SR*, Acierno J et al. Congenital Hypogonadotropic Hypogonadism and Constitutional Delay of Growth and Puberty Have Distinct Genetic Architectures Eur J Endocrinol. 2018 Feb. doi: 10.1530/EJE-17-0568. *joint first authorship
• Howard SR, Guasti L, Dunkel L et al. Contributions of function-altering variants in genes implicated in pubertal timing and body mass for self-limited delayed puberty J Clin Endocrinol Metab, 2017, Nov 16. doi: 10.1210/jc.2017-02147
• Howard SR and Dunkel L. The Genetic Basis of Delayed Puberty, Neuroendocrinology 2017 doi: 10.1159/000481569
• Howard SR, Guasti L, Ruiz-Babot G, et al. IGSF10 mutations dysregulate gonadotropin‐releasing hormone neuronal migration resulting in delayed puberty EMBO Mol Med 2016; 8(6) 626-642 doi.org/10.15252/emmm.201606250

Collaborators

Internal

• Dr Carles Gaston-Massuet (Endocrinology)
• Dr Helen Storr (Endocrinology)
• Prof Márta Korbonits (Endocrinology)
• Dr Evelien Gevers (Endocrinology)
• Prof Michael Barnes (Bioinformatics)
• Dr Claudia Cabrera (Bioinformatics)

External

• Anna Cariboni (Milan, Italy)
• Yee-Ming Chan (Boston, USA)
• Raja Brauner (Paris, France)
• Romina Grinspon and Rodolfo Rey (Buenos Aires, Argentina)
• Alexander Jorge and Ana Claudia Latronico (São Paolo, Brazil)
• Verónica Mericq and Paulina Merino (Santiago, Chile)
• Vincent Prevot (Lille France)
• Marco Bonomi (Milan, Italy)
• Alessia David (Imperial, London, UK)

News

• Paediatric Endcorinology - Expert Reviews (Medwire Newsfocus)
• Faulty 'delayed puberty' gene found (BBC News Online)
• Genetic causes of very late puberty (The Academy of Medical sciences)
• When breast is not best (Charlotte Philby)