Publications by authors named "Martin O Savage"

93 Publications

Growth Hormone Receptor (GHR) 6Ω Pseudoexon Activation: a Novel Cause of Severe Growth Hormone Insensitivity.

J Clin Endocrinol Metab 2021 Jul 28. Epub 2021 Jul 28.

Centre for Endocrinology, William Harvey Research Institute: Barts and The London School of Medicine and Dentistry William Harvey Research Institute, London EC1M 6BQ, UK.

Context: Severe forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies.

Objective: This work aims to identify the genetic cause of growth failure in 3 "classical" GHI individuals.

Methods: A novel intronic growth hormone receptor gene (GHR) variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.

Results: We identified a novel homozygous intronic GHR variant (g.5:42700940T > G, c.618+836T > G), 44 bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C > T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation.

Conclusion: Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.
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http://dx.doi.org/10.1210/clinem/dgab550DOI Listing
July 2021

Digital Health for Supporting Precision Medicine in Pediatric Endocrine Disorders: Opportunities for Improved Patient Care.

Front Pediatr 2021 29;9:715705. Epub 2021 Jul 29.

Department of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, London, United Kingdom.

Digitalization of healthcare delivery is rapidly fostering development of precision medicine. Multiple digital technologies, known as telehealth or eHealth tools, are guiding individualized diagnosis and treatment for patients, and can contribute significantly to the objectives of precision medicine. From a basis of "one-size-fits-all" healthcare, precision medicine provides a paradigm shift to deliver a more nuanced and personalized approach. Genomic medicine utilizing new technologies can provide precision analysis of causative mutations, with personalized understanding of mechanisms and effective therapy. Education is fundamental to the telehealth process, with artificial intelligence (AI) enhancing learning for healthcare professionals and empowering patients to contribute to their care. The Gulf Cooperation Council (GCC) region is rapidly implementing telehealth strategies at all levels and a workshop was convened to discuss aspirations of precision medicine in the context of pediatric endocrinology, including diabetes and growth disorders, with this paper based on those discussions. GCC regional investment in AI, bioinformatics and genomic medicine, is rapidly providing healthcare benefits. However, embracing precision medicine is presenting some major new design, installation and skills challenges. Genomic medicine is enabling precision and personalization of diagnosis and therapy of endocrine conditions. Digital education and communication tools in the field of endocrinology include chatbots, interactive robots and augmented reality. Obesity and diabetes are a major challenge in the GCC region and eHealth tools are increasingly being used for management of care. With regard to growth failure, digital technologies for growth hormone (GH) administration are being shown to enhance adherence and response outcomes. While technical innovations become more affordable with increasing adoption, we should be aware of sustainability, design and implementation costs, training of HCPs and prediction of overall healthcare benefits, which are essential for precision medicine to develop and for its objectives to be achieved.
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http://dx.doi.org/10.3389/fped.2021.715705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358399PMC
July 2021

Growth Hormone Receptor (Ghr) 6ω Pseudoexon Activation: A Novel Cause Of Severe Growth Hormone Insensitivity (Ghi).

J Clin Endocrinol Metab 2021 Jul 28. Epub 2021 Jul 28.

Centre for Endocrinology, William Harvey Research Institute: Barts and The London School of Medicine and Dentistry William Harvey Research Institute.

Context: Severe forms of Growth Hormone Insensitivity (GHI) are characterized by extreme short stature, dysmorphism and metabolic anomalies.

Objective: Identification of the genetic cause of growth failure in 3 'classical' GHI subjects.

Design: A novel intronic GHR variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.

Results: We identified a novel homozygous intronic GHR variant (g.5:42700940T>G, c.618 + 836T> G), 44bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C>T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a non-functional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following growth hormone stimulation.

Conclusion: Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.
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http://dx.doi.org/10.1210/clinem/dgab550DOI Listing
July 2021

Genetic characterization of short stature patients with overlapping features of growth hormone insensitivity syndromes.

J Clin Endocrinol Metab 2021 Jun 16. Epub 2021 Jun 16.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Context And Objective: Growth hormone insensitivity (GHI) in children is characterized by short stature, functional IGF-I deficiency and normal or elevated serum GH concentrations. The clinical and genetic etiology of GHI is expanding. We undertook genetic characterization of short stature patients referred with suspected GHI and features which overlapped with known GH-IGF-I axis defects.

Design And Methods: Between 2008 and 2020, our center received 149 GHI referrals for genetic testing. Genetic analysis utilized a combination of candidate gene sequencing (CGS), whole exome sequencing (WES), array comparative genomic hybridization (aCGH) and a targeted whole genome short stature gene panel.

Results: Genetic diagnoses were identified in 80/149 subjects (54%) with 45/80 (56%) having known GH-IGF-I axis defects (GHR n=40, IGFALS n=4, IGFIR n=1). The remaining 35/80 (44%) had diagnoses of 3M syndrome (n=10) (OBSL1 n=7, CUL7 n=2 and CCDC8 n=1), Noonan syndrome (n=4) (PTPN11 n=2, SOS1 n=1 and SOS2 n=1), Silver-Russell syndrome (n=2) (Loss of methylation on chromosome 11p15 and uniparental disomy for chromosome 7), Class 3-5 copy number variations (n=10) and disorders not previously associated with GHI (n=9) (Barth syndrome, Autoimmune lymphoproliferative syndrome, Microcephalic osteodysplastic primordial dwarfism Type II, Achondroplasia, Glycogen storage disease Type IXb, Lysinuric protein intolerance, Multiminicore Disease, MACS syndrome and Bloom syndrome).

Conclusion: We report the wide range of diagnoses in 149 patients referred with suspected GHI, which emphasizes the need to recognize GHI as a spectrum of clinical entities in undiagnosed short stature patients. Detailed clinical and genetic assessment may identify a diagnosis and inform clinical management.
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http://dx.doi.org/10.1210/clinem/dgab437DOI Listing
June 2021

Digital technologies to improve the precision of paediatric growth disorder diagnosis and management.

Growth Horm IGF Res 2021 Aug 4;59:101408. Epub 2021 Jun 4.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK. Electronic address:

Paediatric disorders of impaired linear growth are challenging to manage, in part because of delays in the identification of pathological short stature and subsequent referral and diagnosis, the requirement for long-term therapy, and frequent poor adherence to treatment, notably with human growth hormone (hGH). Digital health technologies hold promise for improving outcomes in paediatric growth disorders by supporting personalisation of care, from diagnosis to treatment and follow up. The value of automated systems in monitoring linear growth in children has been demonstrated in Finland, with findings that such a system is more effective than a traditional manual system for early diagnosis of abnormal growth. Artificial intelligence has potential to resolve problems of variability that may occur during analysis of growth information, and augmented reality systems have been developed that aim to educate patients and caregivers about growth disorders and their treatment (such as injection techniques for hGH administration). Adherence to hGH treatment is often suboptimal, which negatively impacts the achievement of physical and psychological benefits of the treatment. Personalisation of adherence support necessitates capturing individual patient adherence data; the use of technology to assist with this is exemplified by the use of an electronic injection device, which shares real-time recordings of the timing, date and dose of hGH delivered to the patient with the clinician, via web-based software. The use of an electronic device is associated with high levels of adherence to hGH treatment and improved growth outcomes. It can be anticipated that future technological advances, coupled with continued 'human interventions' from healthcare providers, will further improve management of paediatric growth disorders.
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http://dx.doi.org/10.1016/j.ghir.2021.101408DOI Listing
August 2021

Growth failure: 'idiopathic' only after a detailed diagnostic evaluation.

Endocr Connect 2021 Mar;10(3):R125-R138

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, London, UK.

The terms 'idiopathic short stature' (ISS) and 'small for gestational age' (SGA) were first used in the 1970s and 1980s. ISS described non-syndromic short children with undefined aetiology who did not have growth hormone (GH) deficiency, chromosomal defects, chronic illness, dysmorphic features or low birth weight. Despite originating in the pre-molecular era, ISS is still used as a diagnostic label today. The term 'SGA' was adopted by paediatric endocrinologists to describe children born with low birth weight and/or length, some of whom may experience lack of catch-up growth and present with short stature. GH treatment was approved by the FDA for short children born SGA in 2001, and by the EMA in 2003, and for the treatment of ISS in the US, but not Europe, in 2003. These approvals strengthened the terms 'SGA' and 'ISS' as clinical entities. While clinical and hormonal diagnostic techniques remain important, it is the emergence of genetic investigations that have led to numerous molecular discoveries in both ISS and SGA subjects. The primary message of this article is that the labels ISS and SGA are not definitive diagnoses. We propose that the three disciplines of clinical evaluation, hormonal investigation and genetic sequencing should have equal status in the hierarchy of short stature assessments and should complement each other to identify the true pathogenesis in poorly growing patients.
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http://dx.doi.org/10.1530/EC-20-0585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052574PMC
March 2021

Paediatric Cushing's disease: Epidemiology, pathogenesis, clinical management and outcome.

Rev Endocr Metab Disord 2021 Jan 30. Epub 2021 Jan 30.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, London, UK.

Cushing's disease (CD) is rare in paediatric practice but requires prompt investigation, diagnosis and therapy to prevent long-term complications. Key presenting features are a change in facial appearance, weight gain, growth failure, virilization, disturbed puberty and psychological disturbance. Close consultation with an adult endocrinology department is recommended regarding diagnosis and therapy. The incidence of CD, a form of ACTH-dependent Cushing's syndrome (CS), is equal to approximately 5% of that seen in adults. The majority of ACTH-secreting adenomas are monoclonal and sporadic, although recent studies of pituitary tumours have shown links to several deubiquitination gene defects. Diagnosis requires confirmation of hypercortisolism followed by demonstration of ACTH-dependence. Identification of the corticotroph adenoma by pituitary MRI and/or bilateral inferior petrosal sampling for ACTH may contribute to localisation before pituitary surgery. Transsphenoidal surgery (TSS) with selective microadenomectomy is first-line therapy, followed by external pituitary irradiation if surgery is not curative. Medical therapy to suppress adrenal steroid synthesis is effective in the short-term and bilateral adrenalectomy should be considered in cases unfit for TSS or radiotherapy or when urgent remission is needed after unsuccessful surgery. TSS induces remission of hypercortisolism and improvement of symptoms in 70-100% of cases, particularly when performed by a surgeon with experience in children. Post-TSS complications include pituitary hormone deficiencies, sub-optimal catch-up growth, and persisting excess of BMI. Recurrence of hypercortisolism following remission is recognised but infrequent, being less common than in adult CD patients. With experienced specialist medical and surgical care, the overall prognosis is good. Early referral to an experienced endocrine centre is advised.
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http://dx.doi.org/10.1007/s11154-021-09626-4DOI Listing
January 2021

The continuum between GH deficiency and GH insensitivity in children.

Rev Endocr Metab Disord 2021 03 6;22(1):91-99. Epub 2020 Oct 6.

Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA.

The continuum of growth hormone (GH)-IGF-I axis defects extends from severe to mild GH deficiency, through short stature disorders of undefined aetiology, to GH insensitivity disorders which can also be mild or severe. This group of defects comprises a spectrum of endocrine, biochemical, phenotypic and genetic abnormalities. The extreme cases are generally easily diagnosed because they conform to well-studied phenotypes with recognised biochemical features. The milder cases of both GH deficiency and GH insensitivity are less well defined and also overlap with the group of short stature conditions, labelled as idiopathic short stature (ISS). In this review the continuum model, which plots GH sensitivity against GH secretion, will be discussed. Defects causing GH deficiency and GH insensitivity will be described, together with the use of a diagnostic algorithm, designed to aid investigation and categorisation of these defects. The continuum will also be discussed in the context of growth-promoting endocrine therapy.
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http://dx.doi.org/10.1007/s11154-020-09590-5DOI Listing
March 2021

GHR gene transcript heterogeneity may explain phenotypic variability in GHR pseudoexon (6Ψ) patients.

Endocr Connect 2020 Feb 1. Epub 2020 Feb 1.

H Storr, Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, EC1M 6BQ, United Kingdom of Great Britain and Northern Ireland.

Objectives: The homozygous GH receptor (GHR) pseudoexon (6Ψ) mutation leads to growth hormone insensitivity (GHI) with clinical and biochemical heterogeneity. We investigated whether transcript heterogeneity (6Ψ-GHR to WT-GHR transcript ratio) and/or concurrent defects in other short stature (SS) genes contribute to this.

Methods: 6Ψ-GHR and WT-GHR mRNA transcripts of 4 6Ψ patient (height SDS -4.2 to -3.1) and 1 control fibroblasts were investigated by RT-PCR. Transcripts were quantified by qRT-PCR and delta delta CT analysis and compared using ANOVA with Bonferroni correction. In eleven 6Ψ patients, 40 genes known to cause GHI/SS were analysed by targeted next generation sequencing.

Results: RT-PCR confirmed 6Ψ-GHR transcript in the 6Ψ patients but not control. 6Ψ-GHR transcript levels were comparable in patients 1 and 3 but significantly different among all other patients. The mean 6Ψ:WT transcript ratios ranged from 29-71:1 for patients 1-4 and correlated negatively with height SDS (R=-0.85; p<0.001). Eight deleterious variants in 6 genes were detected but the number of gene hits did not correlate with the degree of SS in individual 6Ψ patients.

Conclusion: Variable amounts of 6Ψ- and WT-GHR transcripts were identified in 6Ψ patients but no 6Ψ transcript was present in the control. Higher 6Ψ:WT GHR transcript ratio correlated with SS severity and may explain the phenotypic variability. Analysis of known SS genes suggested that phenotypic variation is independent of the genetic background. This is the first report of transcript heterogeneity producing a spectrum of clinical phenotypes in different individuals harbouring an identical homozygous genetic mutation.
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http://dx.doi.org/10.1530/EC-20-0026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077524PMC
February 2020

Abnormal linear growth in paediatric adrenal diseases: Pathogenesis, prevalence and management.

Clin Endocrinol (Oxf) 2020 02 5;92(2):98-108. Epub 2019 Dec 5.

Endocrinology Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK.

Abnormal adrenal function can interfere with linear growth, potentially causing either acceleration or impairment of growth in paediatric patients. These abnormalities can be caused by direct effects of adrenal hormones, particularly glucocorticoids and sex steroids, or be mediated by indirect mechanisms such as the disturbance of the growth hormone-insulin-like growth factor-1 axis and aromatization of androgens to oestrogens. The early diagnosis and optimal treatment of adrenal disorders can prevent or minimize growth disturbance and facilitate improved height gain. Mechanisms of growth disturbance in the following abnormal states will be discussed; hypercortisolaemia, hyperandrogenaemia and obesity. Prevalence and features of growth disturbance will be discussed in ACTH-dependent and ACTH-independent Cushing's syndrome, adrenocortical tumours, premature adrenarche, congenital adrenal hyperplasia and adrenal insufficiency disorders. Recommendations for management have been included.
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http://dx.doi.org/10.1111/cen.14131DOI Listing
February 2020

Managing Paediatric Growth Disorders: Integrating Technology Into a Personalised Approach

J Clin Res Pediatr Endocrinol 2020 09 20;12(3):225-232. Epub 2019 Nov 20.

Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Centre of Endocrinology, London, UK

Long-term growth management can be challenging for patients, families and healthcare professionals (HCP). Personalised optimal responses to growth hormone (GH) therapy depend on the creation of a good working relationship between the patient and family and the HCPs responsible for care. Current unmet needs in growth management will be discussed, focusing on the likelihood of a poor growth response and its identification and management with emphasis on the importance of good adherence to GH therapy. Digital tools are now available to record injections and communicate accurate adherence data to the HCP and patient. Psychological barriers to good adherence will be covered, with techniques identified to change behaviour and improve outcome. Motivational interviewing is a valuable skill in this respect and should be taught to both medical and nursing HCPs to enhance the quality of the relationship with the patient and family. Key messages are, firstly, the importance of personalised care with the HCP using acquired psychological skills to prevent and manage poor adherence. Secondly, a human-eHealth partnership is necessary to maximise the benefit of new digital tools to aid in successful growth management.
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http://dx.doi.org/10.4274/jcrpe.galenos.2019.2019.0153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499133PMC
September 2020

Achieving Optimal Short- and Long-term Responses to Paediatric Growth Hormone Therapy

J Clin Res Pediatr Endocrinol 2019 11 9;11(4):329-340. Epub 2019 Jul 9.

William Harvey Research Institute, Barts and the London Faculty of Medicine and Dentistry, London, United Kingdom

It is over sixty years since the first administration of human growth hormone (GH) to children with GH deficiency, and over thirty years since recombinant human GH has been available for treatment of GH deficiency and a wider range of non-GH deficiency disorders. From a diagnostic perspective, genetic analysis, using single gene or Sanger sequencing and more recently next generation or whole exome sequencing, has brought advances in the diagnosis of specific causes of short stature, which has enabled therapy to be targeted more accurately. Genetic discoveries have ranged from defects of pituitary development and GH action to abnormalities in intracellular mechanisms, paracrine regulation and cartilage matrix formation. The strategy of GH therapy using standard doses has evolved to individualised GH dosing, depending on diagnosis and predictors of growth response. Evidence of efficacy of GH in GH deficiency, Turner syndrome and short children born small for gestational age is reviewed. The importance of critical assessment of growth response is discussed, together with the recognition and management of a poor or unsatisfactory growth response and the organisational issues related to prevention, detection and intervention regarding suboptimal adherence to GH therapy.
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http://dx.doi.org/10.4274/jcrpe.galenos.2019.2019.0088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878339PMC
November 2019

Nonclassical GH Insensitivity: Characterization of Mild Abnormalities of GH Action.

Endocr Rev 2019 04;40(2):476-505

Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio.

GH insensitivity (GHI) presents in childhood with growth failure and in its severe form is associated with extreme short stature and dysmorphic and metabolic abnormalities. In recent years, the clinical, biochemical, and genetic characteristics of GHI and other overlapping short stature syndromes have rapidly expanded. This can be attributed to advancing genetic techniques and a greater awareness of this group of disorders. We review this important spectrum of defects, which present with phenotypes at the milder end of the GHI continuum. We discuss their clinical, biochemical, and genetic characteristics. The objective of this review is to clarify the definition, identification, and investigation of this clinically relevant group of growth defects. We also review the therapeutic challenges of mild GHI.
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http://dx.doi.org/10.1210/er.2018-00146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607971PMC
April 2019

The growth hormone-insulin-like growth factor-I axis in the diagnosis and treatment of growth disorders.

Endocr Connect 2018 Jun 3;7(6):R212-R222. Epub 2018 May 3.

William Harvey Research InstituteBarts and the London School of Medicine & Dentistry, London, UK

The growth hormone (GH)-insulin-like growth factor (IGF)-I axis is a key endocrine mechanism regulating linear growth in children. While paediatricians have a good knowledge of GH secretion and assessment, understanding and use of measurements of the components of the IGF system are less current in clinical practice. The physiological function of this axis is to increase the anabolic cellular processes of protein synthesis and mitosis, and reduction of apoptosis, with each being regulated in the appropriate target tissue. Measurement of serum IGF-I and IGF-binding protein (IGFBP)-3 concentrations can complement assessment of GH status in the investigation of short stature and contribute to prediction of growth response during GH therapy. IGF-I monitoring during GH therapy also informs the clinician about adherence and provides a safety reference to avoid over-dosing during long-term management.
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http://dx.doi.org/10.1530/EC-18-0099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987361PMC
June 2018

Phenotypic spectrum and responses to recombinant human IGF1 (rhIGF1) therapy in patients with homozygous intronic pseudoexon growth hormone receptor mutation.

Eur J Endocrinol 2018 May 2;178(5):481-489. Epub 2018 Mar 2.

Centre for EndocrinologyWilliam Harvey Research Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, UK

Background: Patients with homozygous intronic pseudoexon GH receptor () mutations (6Ψ) have growth hormone insensitivity (GHI) (growth failure, IGF1 deficiency and normal/elevated serum GH). We report 9 patients in addition to previously described 11 6Ψ patients and their responses to rhIGF1 therapy.

Methods: 20 patients (12 males, 11 families, mean age 4.0 ± 2.2 years) were diagnosed genetically in our centre. Phenotypic data and responses to rhIGF1 treatment were provided by referring clinicians. Continuous parametric variables were compared using Student -test or ANOVA.

Results: 10/20 (50%) had typical facial features of GHI, 19/20 (95%) from consanguineous families and 18/20 (90%) of Pakistani origin. At diagnosis, mean height SDS: -4.1 ± 0.95, IGF1 SDS: -2.8 ± 1.4; IGFBP3 SDS: -3.0 ± 2.1 and mean basal and peak GH levels: 11.9 µg/L and 32.9 µg/L, respectively. 1/12 who had IGF1 generation test, responded (IGF1: 132-255 ng/mL). 15/20 (75%; 11M) received rhIGF1 (mean dose: 114 µg/kg twice daily, mean duration: 5.3 ± 2.5 years). Mean baseline height velocity of 4.7 ± 1.1 cm/year increased to 7.4 ± 1.8 cm/year ( = 0.001) during year 1 of therapy. Year 3 mean height SDS (-3.2 ± 1.0) was higher than pre-treatment height SDS (-4.3 ± 0.8) ( = 0.03). Mean cumulative increase in height SDS after year 5 was 1.4 ± 0.9. Difference between target height (TH) SDS and adult or latest height SDS was less than that of TH SDS and pre-treatment height SDS (2.1 ± 1.2 vs 3.0 ± 0.8;  = 0.02).

Conclusion: In addition to phenotypic heterogeneity in the cohort, there was mismatch between clinical and biochemical features in individual patients with 6Ψ mutations. rhIGF1 treatment improved height outcomes.
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http://dx.doi.org/10.1530/EJE-18-0042DOI Listing
May 2018

Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency.

J Endocr Soc 2017 Apr 8;1(4):345-358. Epub 2017 Mar 8.

Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.

Context: Autosomal-recessive mutations in the growth hormone receptor (GHR) are the most common causes for primary growth hormone insensitivity (GHI) syndrome with classical GHI phenotypically characterized by severe short stature and marked insulin-like growth factor (IGF)-I deficiency. We report three families with dominant-negative heterozygous mutations in the intracellular domain of the causing a nonclassical GHI phenotype.

Objective: To determine if the identified heterozygous variants exert potential dominant-negative effects and are the cause for the GHI phenotype in our patients.

Results: All three mutations (c, and >C) are predicted to result in frameshift and early protein termination. functional analysis of variants c and suggests that these variants are expressed as truncated proteins and, when coexpressed with wild-type mimicking the heterozygous state in our patients, exert dominant-negative effects. Additionally, we provide evidence that a combination therapy of recombinant human growth hormone (rhGH) and rhIGF-I improved linear growth to within normal range for one of our previously reported patients with a characterized, dominant-negative () mutation.

Conclusion: Dominant-negative mutations are causal of the mild GHI with substantial growth failure observed in our patients. Heterozygous defects in the intracellular domain of should, therefore, be considered in cases of idiopathic short stature and IGF-I deficiency. Combination therapy of rhGH and rhIGF-I improved growth in one of our patients.
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http://dx.doi.org/10.1210/js.2016-1119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686656PMC
April 2017

Whole-exome sequencing gives additional benefits compared to candidate gene sequencing in the molecular diagnosis of children with growth hormone or IGF-1 insensitivity.

Eur J Endocrinol 2017 Dec 4;177(6):485-501. Epub 2017 Sep 4.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Background: GH insensitivity (GHI) is characterised by short stature, IGF-1 deficiency and normal/elevated serum GH. IGF-1 insensitivity results in pre- and post-natal growth failure with normal/high IGF-1 levels. The prevalence of genetic defects is unknown.

Objective: To identify the underlying genetic diagnoses in a paediatric cohort with GH or IGF-1 insensitivity using candidate gene (CGS) and whole-exome sequencing (WES) and assess factors associated with the discovery of a genetic defect.

Methods: We undertook a prospective study of 132 patients with short stature and suspected GH or IGF-1 insensitivity referred to our centre for genetic analysis. 107 (96 GHI, 88 probands; 11 IGF-1 insensitivity, 9 probands) underwent CGS. WES was performed in those with no defined genetic aetiology following CGS.

Results: A genetic diagnosis was discovered 38/107 (36%) patients (32% probands) by CGS. WES revealed 11 patients with genetic variants in genes known to cause short stature. A further 2 patients had hypomethylation in the H19/IGF2 region or mUPD7 consistent with Silver-Russell Syndrome (total with genetic diagnosis 51/107, 48% or 41/97, 42% probands). WES also identified homozygous putative variants in and in 2 patients. Low height SDS and consanguinity were highly predictive for identifying a genetic defect.

Conclusions: Comprehensive genetic testing confirms the genetic heterogeneity of GH/IGF-1 insensitivity and successfully identified the genetic aetiology in a significant proportion of cases. WES is rapid and may isolate genetic variants that have been missed by traditional clinically driven genetic testing. This emphasises the benefits of specialist diagnostic centres.
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http://dx.doi.org/10.1530/EJE-17-0453DOI Listing
December 2017

Cushing's syndrome in infancy due to ectopic ACTH secretion by a sacro-coccygeal teratoma.

J Pediatr Endocrinol Metab 2017 Apr;30(4):475-478

Department of Pediatrics, Endocrinology and Diabetes with a Cardiology Unit, Medical University in Bialystok, ul. Waszyngtona 17, 15-274 Białystok.

Background: Adenocorticotropic hormone (ACTH)-dependent Cushing's syndrome in infancy is extremely rare. We describe the case of a sacro-coccygeal ectopic ACTH-secreting immature teratoma in an infant who also presented the triad of defects characteristic of Currarino syndrome.

Case Presentation: A girl was born with a large immature teratoma in the sacro-coccygeal region associated with anal atresia. At the age of 7 days, the concentration of α-fetoprotein (AFP) was above the age-specific normal range. Two non-radical surgical excisions of the tumour were performed. At the age of 7 months, she developed polyphagia, acne, hirsutism, hypertension and hypokalemia with elevated ACTH and absence of serum cortisol circadian rhythm. Immunostaining of tumour tissue showed ACTH-immunoreactive cells. Due to unsuccessful therapy with ketoconazole and resistance to antihypertensive medications [blood pressure (BP) 210/160 mmHg], metyrapone was administered, which controlled her ACTH and cortisol levels in the normal range. Following further removal of tumour bulk after three operations during the first year of life, there was a decrease of BP to normal values.

Conclusions: A rare case of ectopic ACTH syndrome causing Cushing's syndrome in infancy in the context of Currarino syndrome is reported. Radical surgery has resulted in excision of the tumour and current control of Cushing's syndrome.
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http://dx.doi.org/10.1515/jpem-2016-0339DOI Listing
April 2017

Long-term outcomes of children treated for Cushing's disease: a single center experience.

Pituitary 2016 Dec;19(6):612-624

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, First Floor, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK.

Purpose: Pediatric Cushing's disease (CD) is rare and there are limited data on the long-term outcomes. We assessed CD recurrence, body composition, pituitary function and psychiatric comorbidity in a cohort of pediatric CD patients.

Methods: Retrospective review of 21 CD patients, mean age at diagnosis 12.1 years (5.7-17.8), managed in our center between 1986 and 2010. Mean follow-up from definitive treatment was 10.6 years (2.9-27.2).

Results: Fifteen patients were in remission following transsphenoidal surgery (TSS) and 5 were in remission following TSS + external pituitary radiotherapy (RT). One patient underwent bilateral adrenalectomy (BA). CD recurrence occurred in 3 (14.3 %) patients: 2 at 2 and 6 years after TSS and 1 7.6 years post-RT. The BA patient developed Nelson's syndrome requiring pituitary RT 0.6 years post-surgery. Short-term growth hormone deficiency (GHD) was present in 14 patients (81 % patients tested) (11 following TSS and 3 after RT) and 4 (44 % of tested) had long-term GHD. Gonadotropin deficiency caused impaired pubertal development in 9 patients (43 %), 4 requiring sex steroid replacement post-puberty. Four patients (19 %) had more than one pituitary hormone deficiency, 3 after TSS and 1 post-RT. Five patients (24 %) had long-term psychiatric co-morbidities (cognitive dysfunction or mood disturbance). There were significant long-term improvements in growth, weight and bone density but not complete reversal to normal in all patients.

Conclusions: The long-term consequences of the diagnosis and treatment of CD in children is broadly similar to that seen in adults, with recurrence of CD after successful treatment uncommon but still seen. Pituitary hormone deficiencies occurred in the majority of patients after remission, and assessment and appropriate treatment of GHD is essential. However, while many parameters improve, some children may still have mild but persistent defects.
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http://dx.doi.org/10.1007/s11102-016-0756-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080319PMC
December 2016

Diagnosis and management of growth disorders in Gulf Cooperation Council (GCC) countries: Current procedures and key recommendations for best practice.

Int J Pediatr Adolesc Med 2016 Sep 10;3(3):91-102. Epub 2016 Aug 10.

William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, UK.

Diagnosis and management of growth disorders comprises an important area of pediatric practice. Current procedures in the different stages of the identification, referral, investigation, and treatment of growth disorders in the Gulf Cooperation Council (GCC) countries have been summarized. Evidence-based procedures, relating specifically to height screening for identification of short stature, auxological criteria for patient referral from primary to secondary pediatric care, and general and endocrine investigations and diagnosis have been discussed and outlined. The management issues related to key disorders that are licensed for growth hormone (hGH) therapy, namely GH deficiency, Turner syndrome, short stature related to birth size small for gestational age (SGA), and idiopathic short stature are discussed with recommendations described for best practice. Finally, two key components of short stature management, namely transitional care for the transfer of patients from pediatric to adult endocrinology services and adherence to recommended therapy with hGH, have been addressed with current practice outlines and recommendations presented.
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http://dx.doi.org/10.1016/j.ijpam.2016.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372455PMC
September 2016

Investigation for Paediatric Cushing's Syndrome Using Twenty-Four-Hour Urinary Free Cortisol Determination.

Horm Res Paediatr 2016 10;86(1):21-6. Epub 2016 Jun 10.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Objective: Paediatric Cushing's syndrome (CS) remains a challenge to diagnose and exclude. We assessed the accuracy of 24-hour urinary free cortisol (UFC) determination in children referred for suspected CS.

Design: We conducted a retrospective study of paediatric patients referred to our centre with suspected CS between 1982 and 2014.

Patients: Of 66 subjects (mean age 12.9 years; range 4.4-16.9), there were 47 cases of CS (29 males), which included Cushing's disease (CD; 39 patients, 25 males), primary pigmented nodular adrenocortical disease (8 patients, 4 males) and 19 'controls' (6 males) in whom the diagnosis of CS was excluded.

Measurements: The subjects had between one and five 24-hour UFC collections analysed by radioimmunoassay, chemiluminescent immunoassay or liquid chromatography-mass spectrometry. The data were normalised, corrected for body surface area (m2) and assessed using receiver operating characteristic analysis and an independent two-tailed t test.

Results: The diagnostic accuracy of 24-hour UFC for CS was excellent (area under the curve 0.98, 95% CI 0.946-1.00, sensitivity 89%, specificity 100%).

Conclusions: Twenty-four-hour UFC is a reliable and practical investigation with high diagnostic accuracy for paediatric CS. However, further investigations may be required if the UFC is normal but there is a high diagnostic suspicion of CS.
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http://dx.doi.org/10.1159/000446913DOI Listing
April 2017

Early Detection, Referral, Investigation, and Diagnosis of Children with Growth Disorders.

Horm Res Paediatr 2016 8;85(5):325-32. Epub 2016 Apr 8.

Department of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK.

Early diagnosis is a key objective in clinical medicine, and early detection of pathological short stature has tangible benefits for growth prognosis and the well-being of the child. Despite late diagnosis being common in growth disorders, programmes of height screening in primary care are not universal in developed countries and may be random or non-existent. A notable exception is automated growth monitoring in Finland, where an algorithm to detect abnormal growth is integrated into children's electronic health records, resulting in increased diagnoses of pathological short stature. Evidence-based anthropometric criteria for referral of short stature to secondary or tertiary care are now published, due largely to excellent studies in the Netherlands. Following referral of the short child, the protocol for laboratory investigations remains somewhat controversial because in healthy children their diagnostic yield can be too low for cost-effectiveness. However, outside of tertiary academic paediatric endocrinology centres, baseline screening tests are considered worthwhile and may speed up diagnosis and treatment. Finally, auxological cut-offs cannot replace good clinical practice, and the understanding that early and effective management depends on commitment to a diagnosis and individualisation of therapy in the short child cannot be overemphasised.
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http://dx.doi.org/10.1159/000444525DOI Listing
April 2017

Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline.

J Clin Endocrinol Metab 2015 Aug 29;100(8):2807-31. Epub 2015 Jul 29.

Program in Reproductive and Adult Endocrinology (L.K.N.), The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Neuroendocrine Unit (B.M.K.B.), Massachusetts General Hospital, Boston, Massachusetts 02114; Medical College of Wisconsin (J.W.F.), Milwaukee, Wisconsin 53226; Mayo Clinic (M.H.M.), Division of Preventive Medicine, Rochester, Minnesota 55905; Department of Human Metabolism (J.N.-P.), School of Medicine and Biomedical Science, University of Sheffield, Sheffield S10 2RX, United Kingdom; William Harvey Research Institute (M.O.S.), Barts and the London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom; and Department of Endocrinology (A.T.), Centre Hospitalier Universitaire de Bordeaux and Inserm 862, University of Bordeaux, 33077 Bordeaux, France.

Objective: The objective is to formulate clinical practice guidelines for treating Cushing's syndrome.

Participants: Participants include an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. The European Society for Endocrinology co-sponsored the guideline.

Evidence: The Task Force used the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews and used the best available evidence from other published systematic reviews and individual studies.

Consensus Process: The Task Force achieved consensus through one group meeting, several conference calls, and numerous e-mail communications. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines.

Conclusions: Treatment of Cushing's syndrome is essential to reduce mortality and associated comorbidities. Effective treatment includes the normalization of cortisol levels or action. It also includes the normalization of comorbidities via directly treating the cause of Cushing's syndrome and by adjunctive treatments (eg, antihypertensives). Surgical resection of the causal lesion(s) is generally the first-line approach. The choice of second-line treatments, including medication, bilateral adrenalectomy, and radiation therapy (for corticotrope tumors), must be individualized to each patient.
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http://dx.doi.org/10.1210/jc.2015-1818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525003PMC
August 2015

MANAGEMENT OF ENDOCRINE DISEASE: Paediatric Cushing's disease.

Eur J Endocrinol 2015 Jul;173(1):R35-45

Barts and the London School of Medicine and DentistryWilliam Harvey Research Institute, Centre for Endocrinology, Queen Mary University of London, 1st Floor, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.

Cushing's disease (CD) is the commonest form of ACTH-dependent Cushing's syndrome and is a rare clinical diagnosis in paediatric and adolescent patients. CD is caused by an ACTH-secreting pituitary corticotroph adenoma and is associated with significant morbidity in children; therefore, early diagnosis and treatment are critical for optimal therapeutic outcome. This review highlights the key clinical and biochemical features of paediatric CD and appraises current practices in diagnosis and management. A close liaison with adult endocrinology colleagues, particularly, for interpretation of investigations and definition of therapeutic strategy is strongly advised.
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http://dx.doi.org/10.1530/EJE-15-0013DOI Listing
July 2015

Genetic characterisation of a cohort of children clinically labelled as GH or IGF1 insensitive: diagnostic value of serum IGF1 and height at presentation.

Eur J Endocrinol 2015 Feb 19;172(2):151-61. Epub 2014 Nov 19.

Barts and the London School of Medicine and DentistryWilliam Harvey Research Institute, Centre for Endocrinology, Queen Mary University of London, London, UK.

Objective And Design: GH insensitivity (GHI) encompasses growth failure, low serum IGF1 and normal/elevated serum GH. By contrast, IGF1 insensitivity results in pre- and postnatal growth failure associated with relatively high IGF1 levels. From 2008 to 2013, 72 patients from 68 families (45M), mean age 7.1 years (0.4-17.0) with short stature (mean height SDS -3.9; range -9.4 to -1.5), were referred for sequencing.

Methods: As a genetics referral centre, we have sequenced appropriate candidate genes (GHR, including its pseudoexon (6Ψ), STAT5B, IGFALS, IGF1, IGF1R, OBSL1, CUL7 and CCDC8) in subjects referred with suspected GHI (n=69) or IGF1 insensitivity (n=3).

Results: Mean serum IGF1 SDS was -2.7 (range -0.9 to -8.2) in GHI patients and 2.0, 3.7 and 4.4 in patients with suspected IGF1 insensitivity. Out of 69 GHI patients, 16 (23%) (19% families) had mutations in GH-IGF1 axis genes: homozygous GHR (n=13; 6 6Ψ, two novel IVS5ds+1 G to A) and homozygous IGFALS (n=3; one novel c.1291delT). In the GHI groups, two homozygous OBSL1 mutations were also identified (height SDS -4.9 and -5.7) and two patients had hypomethylation in imprinting control region 1 in 11p15 or mUPD7 consistent with Silver-Russell syndrome (SRS) (height SDS -3.7 and -4.3). A novel heterozygous IGF1R (c.112G>A) mutation was identified in one out of three (33%) IGF1-insensitive subjects.

Conclusion: Genotyping contributed to the diagnosis of children with suspected GHI and IGF1 insensitivity, particularly in the GHI subjects with low serum IGF1 SDS (<-2.0) and height SDS (<-2.5). Diagnoses with similar phenotypes included SRS and 3-M syndrome. In 71% patients, no diagnosis was defined justifying further genetic investigation.
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http://dx.doi.org/10.1530/EJE-14-0541DOI Listing
February 2015

Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD).

J Clin Endocrinol Metab 2014 Aug 6;99(8):E1556-63. Epub 2014 Mar 6.

Centre for Endocrinology (R.P., L.F.C., C.R.H., J.C.K., M.O.S., A.J.L.C., H.L.S., L.A.M.), Queen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom; Inherited Cardiovascular Diseases Unit (J.P.K.), Department of Cardiology, Great Ormond St Hospital for Children, and Department of Paediatric Endocrinology (C.J.P.), Great Ormond St Hospital for Children, London WC1N 3JH, United Kingdom; and Department of Paediatric Endocrinology (N.N.), Luton and Dunstable University Hospital, Luton LU4 0DZ, United Kingdom.

Context: Classic ACTH resistance, due to disruption of ACTH signaling, accounts for the majority of cases of familial glucocorticoid deficiency (FGD). Recently FGD cases caused by mutations in the mitochondrial antioxidant, nicotinamide nucleotide transhydrogenase, have highlighted the importance of redox regulation in steroidogenesis.

Objective: We hypothesized that other components of mitochondrial antioxidant systems would be good candidates in the etiology of FGD.

Design: Whole-exome sequencing was performed on three related patients, and segregation of putative causal variants confirmed by Sanger sequencing of all family members. A TXNRD2-knockdown H295R cell line was created to investigate redox homeostasis.

Setting: The study was conducted on patients from three pediatric centers in the United Kingdom.

Patients: Seven individuals from a consanguineous Kashmiri kindred, six of whom presented with FGD between 0.1 and 10.8 years, participated in the study.

Interventions: There were no interventions.

Main Outcome Measure: Identification and functional interrogation of a novel homozygous mutation segregating with the disease trait were measured.

Results: A stop gain mutation, p.Y447X in TXNRD2, encoding the mitochondrial selenoprotein thioredoxin reductase 2 (TXNRD2) was identified and segregated with disease in this extended kindred. RT-PCR and Western blotting revealed complete absence of TXNRD2 in patients homozygous for the mutation. TXNRD2 deficiency leads to impaired redox homeostasis in a human adrenocortical cell line.

Conclusion: In contrast to the Txnrd2-knockout mouse model, in which embryonic lethality as a consequence of hematopoietic and cardiac defects is described, absence of TXNRD2 in humans leads to glucocorticoid deficiency. This is the first report of a homozygous mutation in any component of the thioredoxin antioxidant system leading to inherited disease in humans.
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http://dx.doi.org/10.1210/jc.2013-3844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207928PMC
August 2014

Paediatric pituitary adenomas: a decade of change.

Horm Res Paediatr 2014 11;81(3):145-55. Epub 2014 Feb 11.

Division of Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy.

Pituitary adenomas, although rare in the paediatric age range and mostly benign, represent very challenging disorders for diagnosis and management. The recent identification of genetic alterations in young individuals with pituitary adenomas has broadened the scope of molecular investigations and contributed to the understanding of mechanisms of tumorigenesis. Recent identification of causative mutations of genes such as GNAS, PRKAR1A, MEN1 and AIP has introduced the concept of molecular screening of young apparently healthy family members. Population-based studies have reported a significantly higher number of affected subjects and genetic variations than expected. Radiological techniques have advanced, yet many microadenomas remain undetectable on scanning. However, experience with transsphenoidal and endoscopic pituitary surgery has led to higher rates of cure. Prolactinomas, corticotroph and somatotroph adenomas remain the most prevalent, with each diagnosis presenting its own challenges. As paediatric pituitary adenomas occur very infrequently within the paediatric age range, paediatric endocrine units cannot provide expert management in isolation. Consequently, close co-operation with adult endocrinology colleagues with experience of pituitary disease is strongly recommended.
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http://dx.doi.org/10.1159/000357673DOI Listing
December 2014

Endonasal endoscopic transsphenoidal pituitary surgery: early experience and outcome in paediatric Cushing's disease.

Clin Endocrinol (Oxf) 2014 Feb 19;80(2):270-6. Epub 2013 Jul 19.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Background: Selective adenomectomy remains the first-line treatment for Cushing's disease (CD), until recently by microscopic transsphenoidal pituitary surgery. Endonasal transsphenoidal endoscopic surgery (ETES) is emerging as a novel, less invasive treatment for pituitary adenomas and has become the optimal surgical approach.

Objective: There are no published series for the treatment of paediatric CD by ETES, and we report our centre's preliminary results.

Design: Retrospective analysis.

Patients: Six paediatric patients (median age 15·8 years; range 11·7-17·0 years) fulfilled standard diagnostic criteria for CD. Preoperatively, no abnormality was identified on pituitary MR scanning in 3 (50%) patients, one had a macroadenoma. Bilateral petrosal sinus sampling demonstrated central ACTH secretion (IPS/P ACTH ratio ≥3·0, post-CRH) in 3/6 (50%) patients. The same neurosurgeon and endoscopic nasal surgeon undertook all the operations.

Outcome Measures: Therapeutic outcome and rate of complications.

Results: Clinical recovery and biochemical 'cure' were achieved in 5 (83%) patients, and a corticotroph adenoma was confirmed histologically in all cured cases. One case developed post-operative CSF leak requiring lumbar drain insertion and patching. At a mean interval of 4·7 years (0·1-10·8 years) post-operatively, cured patients have shown no recurrence. One patient, with a large diffuse adenoma requiring more extensive surgery, has panhypopituitarism, and another patient has GH and gonadotrophin deficiencies.

Conclusions: Our experience shows that ETES for removing corticotroph adenomas in children, in most cases not visualized on MRI, is minimally invasive and gave excellent post-operative recovery/results. In skilled hands, this technique provides an alternative to conventional transsphenoidal microscopic surgery in managing paediatric CD.
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http://dx.doi.org/10.1111/cen.12275DOI Listing
February 2014

The variability of responses to growth hormone therapy in children with short stature.

Indian J Endocrinol Metab 2012 Dec;16(Suppl 2):S178-84

Department of pediatric endocrinology William Harvey Research Institute, Barts and The London School of Medicine & Dentistry, London, UK.

Growth hormone (GH) is widely prescribed for children with short stature across a range of growth disorders. We describe the variability of responses seen in conditions approved for GH therapy. Although responses in different growth disorders are satisfactory, evidence is increasing for an unacceptably high rate of poor or unsatisfactory response (i.e., not leading to significant catch-up growth) in terms of change in height standard deviation score and height velocity. Consequently, there is a need to define a poor response and to prevent or correct it by optimizing treatment regimens. This review discusses the optimal investigation of the child who is a candidate for GH therapy so that a diagnosis-based guide to therapy and dosage can be made. The relevant parameters in the evaluation of growth response are described together with the definitions of a poor response.
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http://dx.doi.org/10.4103/2230-8210.104034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603021PMC
December 2012
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