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Dr Sasha Howard

Sasha

Wellcome Trust Clinical Research Career Development Fellow, Senior Lecturer and Honorary Consultant in Paediatric Endocrinology

Centre: Endocrinology

Email: s.howard@qmul.ac.uk
Telephone: +44(0) 20 7882 6235
Twitter: @drsashahoward

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

  • 2023 Rosetrees Trust Major Project grant 
  • 2023 ESPE Research Unit      
  • 2023 ESPE Early Career Scientific Development Grant Dr F D’Aniello
  • 2023 Society for Endocrinology, Early Career Grant  to Dr J Read
  • 2023 British Society of Neuroendocrinology, Project Grant to Dr J Read
  • 2023 Isaac Shapera Medical Trust, IAT award for SFP to Dr Y Aung
  • 2023 NIHR IAT award for ACF to Dr E Alexander 
  • 2023 FinRett Project Grant  
  • 2022 British Society of Neuroendocrinology, Student Project Grant
  • 2021 British Society of Paediatric Endocrinology and Diabetes Research and Development Award
  • 2021 British Society of Neuroendocrinology, Project Grant
  • 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 Jordan Read (PDRA); Dr Yasmin Al-Sayed (PDRA); Dr Charlotte Hall (Bioinformatician); Dr Elena Tsisanova (PDRA); Mr Saleh Momeni (MSc student); Dr Emma Alexander (Academic Clinical Fellow); Dr Francesco D'Aniello (ESPE Early Scientific Career Fellow); Dr Sophie Rhys-Evans (Specialist Foundation Programme Fellow)

Close collaborators
Dr Leonardo Guasti (Reader in Endocrinology); Professor Leo Dunkel (Professor of Paediatric Endocrinology); Dr Alessia David (Imperial College London); Dr Ali Abbara (Imperial College London); Professor Mehul Dattani (Great Ormond Street Hospital for Children and ICH-UCL)

Alumni
Dr Tansit Saengkaew, (PhD Student, now Assistant Professor of Paediatric Endocrinology and Medical instructor, Prince of Songkla University, Thailand); Dr Alessandra Mancini (PhD student, now postdoc at Harvard University); Ms Matilde Ciaroni (Erasmus student, now in Industry); Dr Yuri Aung (SFP); Dr Kyla Ng Yin (SFP)

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.

Management of Central Hypogonadism in Children

The management of male infertility is very challenging, particularly in severe forms of hormone deficiency. These hormones are specific signals produced by the brain, which direct development of the testicles or ovaries. Patients who are unable to produce these signals (named ‘gonadotropin hormones’) have a condition called gonadotropin deficiency (GD).
For males with GD medical therapy for fertility is often unsuccessful. This is because hormones drive the development of the testicles in infancy and at puberty, a process vital to enable later sperm production. Despite adult hormone replacement, individuals may suffer infertility, in addition to chronic health and psychological issues.

Standard treatment for lack of puberty in adolescent males with GD is with testosterone. This helps with physical development, but not with testicular development or sperm production. Views of patient and their carers highlights the importance for young men with GD of adequate pubertal development, testicular maturity and the ability to make sperm.
In contrast, replacement of gonadotropin hormones enables physical maturity and the growth spurt, as well as specific testicular growth, to occur during puberty. These medications are currently used in adult patients with GD within fertility services, but can be used in puberty to allow reproductive development at the appropriate age.

Our team are leading on a proposal for the PinG study, to assess the clinical effectiveness of Pubertal Induction with Gonadotropins in Adolescent and Young Adult Males with Gonadotropin Deficiency (grant applications in progress 2023).

Key Publications

  1. Alexander EC, Faruqi D, et al and Howard SR Gonadotropins for pubertal induction in males with hypogonadotropic hypogonadism: systematic review and meta-analysis. Eur J Endocrinol, in press 2023
  2. Lettieri A, Oleari R, van den Munkhof MH, van Battum E et al,.. Howard SR, Fantin A, Pasterkamp RJ and Cariboni A. SEMA6A drives GnRH neuron-dependent puberty onset by tuning median eminence vascular permeability Nat Commun, 2023 doi: 10.1038/s41467-023-43820-z
  3. Hoskyns RB and Howard SR. Effects of the COVID-19 Pandemic on the Incidence of Central Precocious Puberty; a narrative review J Ped Endocrinol Metab in press 2023
  4. Howard SR and Quinton R. Outcomes and experiences of adults with congenital hypogonadism can inform improvements in the management of delayed puberty. J Ped Endocrinol Metab 2023.  doi: 10.1515/jpem-2023-0407.
  5. Aung Y, Kokotsis V, Yin KN, Banerjee K, Butler G, Dattani MT, Dimitri P, Dunkel L, Hughes C, McGuigan M, Korbonits M, Paltoglou G, Sakka S, Shah P, Storr HL, Willemsen RH and Howard SR Key features of puberty onset and progression can help distinguish self-limited delayed puberty from congenital hypogonadotrophic hypogonadism. Front. Endocrinol. 2023. doi: 10.3389/fendo.2023.1226839
  6. Canton APM, Tinano FR, Guasti L,,, Howard SR*, Latronico AC*. Rare Variants in the MECP2 Gene in Girls with Central Precocious Puberty. Lancet Diabetes and Endocrinology 2023, doi:10.1016/S2213-8587(23)00131-6 *co-senior author
  7. K Duckett, A Williamson, JWR Kincaid, K Rainbow, LJ Corbin, HC Martin, ...Howard SR…. Ken K Ong, Stephen O’Rahilly. Prevalence of deleterious variants in MC3R in patients with constitutional delay of growth and puberty. J Clin Endocrinol Metab, 2023 doi:10.1210/clinem/dgad373
  8. Mistry JN,…Howard SR, Dunkel L, Sankilampi U, Guasti L, The crosstalk between FGF21 and GH leads to weakened GH receptor signaling and IGF1 expression and is associated with growth failure in very preterm infants. Frontiers Endo, 2023 doi: 10.3389/fendo.2023.1105602
  9. Howard SR, Fanis P, Nicolaides N, Grandone A. Editorial: Genetic, Epigenetic and Molecular Landscaping of Puberty. Frontiers Endo, 2023 doi: 10.3389/fendo.2023.1178888
  10. Oleari R, Lettieri A, Manzini S, Paganoni A, André V, Grazioli P, Busnelli M, Duminuco P, Vitobello A, Philippe C, Bizaoui V, Storr HL, Amoruso F, Memi F, Vezzoli V, Massa V, Scheiffele P, Howard SR* and Cariboni A*. Combined omic analyses reveal novel loss-of-function NLGN3 variants in GnRH deficiency and autism, MedRxiv, 2022 doi.org/10.1101/2022.05.24.22275221 *co-senior author
  11. Howard SR, Kurzanwinski T and Gaze M. New UK Guidelines for Differentiated Thyroid Cancer in Children, British J Surgery 2022, doi.org/10.1093/bjs/znac281
  12. Howard SR, Freeston S, Harrison B, Izatt L, Natu S, Newbold K, Pomplun S, Spoudeas HA, Wilne S, Kurzawinski TR, Gaze MN. Paediatric Differentiated Thyroid Carcinoma: A UK National Clinical Practice Consensus Guideline, Endocrine Related Cancer 2022, doi.org/10.1530/ERC-22-0035
  13. Saengkaew T, Ruiz-Babot G, David A, Mancini A, Mariniello K, Cabrera CP, Barnes MR, Dunkel L, Guasti L, Howard SR Whole exome sequencing identifies deleterious rare variants in CCDC141 in familial self-limited delayed puberty, Genomic Medicine 2021 Dec, doi:10.1038/s41525-021-00274-w
  14. Saengkaew T and Howard SR Genetics of Pubertal Delay, Clinical Endocrinology 2021, doi:10.1111/cen.14606
  15. Saengkaew T, Patel HR, Banerjee K, Butler G, Dattani MT, McGuigan M, Storr HL, Willemsen RL, Dunkel L, Howard SR Genetic Evaluation Supports Differential Diagnosis in Adolescent Patients with Delayed Puberty, European Journal of Endocrinology, 2021 Aug, doi:10.1530/EJE-21-0387
  16. Howard SR. Interpretation of reproductive hormones before, during and after the pubertal transition – identifying health and disordered puberty, Clinical Endocrinology 2021 doi:10.1111/cen.14578
  17. 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
  18. 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
  19. Howard SR. Genetic Regulation in Pubertal Delay. J Mol Endocrinol 2019;63:37-9 doi: 10.1530/JME-19-0130
  20. Howard SR and Dunkel L. Delayed Puberty – Phenotypic Diversity, Molecular Genetic Mechanisms and Recent Discoveries. Endocrine Reviews 2019 doi: 10.1210/er.2018-00248
  21. 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.
  22. 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.
  23. 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
  24. 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.
  25. 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
  26. 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
  27. Howard SR and Dunkel L. The Genetic Basis of Delayed Puberty, Neuroendocrinology 2017 doi: 10.1159/000481569
  28. 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

Clinical guidelines

  1. Protocol for Induction of Puberty in Males with Gonadotropin Deficiency, BSPED Local guideline 2022, L Dunkel, R Prasad, S Senniappan, G Butler, SR Howard https://www.bsped.org.uk/media/1989/protocol-for-induction-of-puberty-with-gonadotropins-in-males-with-gnrh-or-gonadotropin-deficiency_bsped_website-002.pdf
  2. UK Guidelines for Differentiated Thyroid Cancer in Children 2022, Howard SR, Freeston S, Harrison B, Izatt L, Natu S, Newbold K, Pomplun S, Spoudeas HA, Wilne S, Kurzawinski TR, Gaze MN https://www.cclg.org.uk/guidelines/endocrine/thyroid-carcinoma 
  3. GnRH Analogue Stimulation Testing to Investigate Precocious Puberty, BSPED Approved guideline 2021, SR Howard, R Ghauri, R El-Khairi https://www.bsped.org.uk/media/1907/gnrh-analogue-stimulation-testing-in-cpp.pdf 

Sponsors

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

Teaching

QMUL

  • Primary Supervisor for ACF and SFP doctors (2021-2024)
  • Primary Supervisor for SSC4/ MSc students (2021-2024)                                         
  • Academic Advisor MBBS (2023-2024)                                                                         
  • PGDip/MSc Endocrinology, Lecturer (2016-2024)                                                     
  • OSCE examiner/ MBBS & GEP interviewer (2016-2024)                                             
  • Undergraduate Endocrine physiology and biochemistry, Lecturer (2017-2024)     

Ex-QMUL

  • ESPE Connect Webinar Dec (2023)
  • MedEA Webinar series Oct (2023)
  • Anne Klibanski Visiting Lecture Series, Massachusetts General Hospital, USA (May 2023)
  • Invited symposium speaker, ESPE Rome Italy (2022)
  • Invited symposium speaker, BSPED, (November 2021)

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