Publications by authors named "Helen L Storr"

50 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

Genetic Evaluation Supports Differential Diagnosis in Adolescent Patients with Delayed Puberty.

Eur J Endocrinol 2021 Aug 1. Epub 2021 Aug 1.

S Howard, Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, United Kingdom of Great Britain and Northern Ireland.

Context: Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents.

Objective: To assess whether gene panel testing can assist with clinical differential diagnosis, to allow accurate and timely management of delayed puberty patients.

Design: Retrospective study Methods: Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rare, predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed.

Results: Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only 3 patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP.

Conclusion: This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately.
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http://dx.doi.org/10.1530/EJE-21-0387DOI Listing
August 2021

Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause.

Nat Genet 2021 Sep 12;53(9):1360-1372. Epub 2021 Aug 12.

Department of Surgery, St Bartholomew's Hospital, London, UK.

Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant APAs led to a total of 16 of 27 (59%) with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11 or GNAQ. Solitary GNA11 mutations were found in hyperplastic zona glomerulosa adjacent to double-mutant APAs. Nine of ten patients in our UK/Irish cohort presented in puberty, pregnancy or menopause. Among multiple transcripts upregulated more than tenfold in double-mutant APAs was LHCGR, the receptor for luteinizing or pregnancy hormone (human chorionic gonadotropin). Transfections of adrenocortical cells demonstrated additive effects of GNA11 and CTNNB1 mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Q mutations appear clinically silent without a codriver mutation of CTNNB1.
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http://dx.doi.org/10.1038/s41588-021-00906-yDOI Listing
September 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

Bedtime Salivary Cortisol as a Screening Test for Cushing Syndrome in Children.

J Endocr Soc 2021 May 4;5(5):bvab033. Epub 2021 Mar 4.

Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, 5021 Bergen, Norway.

Background: Diagnosing Cushing syndrome (CS) can be challenging. The 24-hour urine free cortisol (UFC) measurement is considered gold standard. This is a laborious test, dependent on correct urine collection. Late-night salivary cortisol is easier and is used as a screening test for CS in adults, but has not been validated for use in children.

Objective: To define liquid chromatography tandem mass spectrometry (LC-MS/MS)-based cutoff values for bedtime and morning salivary cortisol and cortisone in children, and validate the results in children with and without CS.

Methods: Bedtime and morning salivary samples were collected from 320 healthy children aged 4 to 16 years. Fifty-four patients from the children's outpatient obesity clinic and 3 children with pituitary CS were used for validation. Steroid hormones were assayed by LC-MS/MS. Cutoff levels for bedtime salivary cortisol and cortisone were defined by the 97.5% percentile in healthy subjects.

Results: Bedtime cutoff levels for cortisol and cortisone were 2.4 and 12.0 nmol/L, respectively. Applying these cutoff levels on the verification cohort, 1 child from the obesity clinic had bedtime salivary cortisol exceeding the defined cutoff level, but normal salivary cortisone. All 3 children with pituitary CS had salivary cortisol and cortisone far above the defined bedtime cutoff levels. Healthy subjects showed a significant decrease in salivary cortisol from early morning to bedtime.

Conclusions: We propose that bedtime salivary cortisol measured by LC-MS/MS with a diagnostic threshold above 2.4 nmol/L can be applied as a screening test for CS in children. Age- and gender-specific cutoff levels are not needed.
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http://dx.doi.org/10.1210/jendso/bvab033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064046PMC
May 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

Rare CNVs provide novel insights into the molecular basis of GH and IGF-1 insensitivity.

Eur J Endocrinol 2020 Dec;183(6):581-595

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

Objective: Copy number variation (CNV) has been associated with idiopathic short stature, small for gestational age and Silver-Russell syndrome (SRS). It has not been extensively investigated in growth hormone insensitivity (GHI; short stature, IGF-1 deficiency and normal/high GH) or previously in IGF-1 insensitivity (short stature, high/normal GH and IGF-1).

Design And Methods: Array comparative genomic hybridisation was performed with ~60 000 probe oligonucleotide array in GHI (n = 53) and IGF-1 insensitivity (n = 10) subjects. Published literature, mouse models, DECIPHER CNV tracks, growth associated GWAS loci and pathway enrichment analyses were used to identify key biological pathways/novel candidate growth genes within the CNV regions.

Results: Both cohorts were enriched for class 3-5 CNVs (7/53 (13%) GHI and 3/10 (30%) IGF-1 insensitivity patients). Interestingly, 6/10 (60%) CNV subjects had diagnostic/associated clinical features of SRS. 5/10 subjects (50%) had CNVs previously reported in suspected SRS: 1q21 (n = 2), 12q14 (n = 1) deletions and Xp22 (n = 1), Xq26 (n = 1) duplications. A novel 15q11 deletion, previously associated with growth failure but not SRS/GHI was identified. Bioinformatic analysis identified 45 novel candidate growth genes, 15 being associated with growth in GWAS. The WNT canonical pathway was enriched in the GHI cohort and CLOCK was identified as an upstream regulator in the IGF-1 insensitivity cohorts.

Conclusions: Our cohort was enriched for low frequency CNVs. Our study emphasises the importance of CNV testing in GHI and IGF-1 insensitivity patients, particularly GHI subjects with SRS features. Functional experimental evidence is now required to validate the novel candidate growth genes, interactions and biological pathways identified.
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http://dx.doi.org/10.1530/EJE-20-0474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592635PMC
December 2020

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

Time to Diagnosis in Cushing's Syndrome: A Meta-Analysis Based on 5367 Patients.

J Clin Endocrinol Metab 2020 03;105(3)

Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany.

Context: Signs and symptoms of Cushing's syndrome (CS) overlap with common diseases, such as the metabolic syndrome, obesity, osteoporosis, and depression. Therefore, it can take years to finally diagnose CS, although early diagnosis is important for prevention of complications.

Objective: The aim of this study was to assess the time span between first symptoms and diagnosis of CS in different populations to identify factors associated with an early diagnosis.

Data Sources: A systematic literature search via PubMed was performed to identify studies reporting on time to diagnosis in CS. In addition, unpublished data from patients of our tertiary care center and 4 other centers were included.

Study Selection: Clinical studies reporting on the time to diagnosis of CS were eligible. Corresponding authors were contacted to obtain additional information relevant to the research question.

Data Extraction: Data were extracted from the text of the retrieved articles and from additional information provided by authors contacted successfully. From initially 3326 screened studies 44 were included.

Data Synthesis: Mean time to diagnosis for patients with CS was 34 months (ectopic CS: 14 months; adrenal CS: 30 months; and pituitary CS: 38 months; P < .001). No difference was found for gender, age (<18 and ≥18 years), and year of diagnosis (before and after 2000). Patients with pituitary CS had a longer time to diagnosis in Germany than elsewhere.

Conclusions: Time to diagnosis differs for subtypes of CS but not for gender and age. Time to diagnosis remains to be long and requires to be improved.
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http://dx.doi.org/10.1210/clinem/dgz136DOI Listing
March 2020

An analysis of surveillance screening for SDHB-related disease in childhood and adolescence.

Endocr Connect 2019 Mar;8(3):162-172

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

Objective Phaeochromocytomas (PCC) and paragangliomas (PGL) are rare in children. A large proportion of these are now understood to be due to underlying germline mutations. Here we focus on succinate dehydrogenase subunit B (SDHB) gene mutation carriers as these tumours carry a high risk of malignant transformation. There remains no current consensus with respect to optimal surveillance for asymptomatic carriers and those in whom the presenting tumour has been resected. Method We undertook a retrospective analysis of longitudinal clinical data of all children and adolescents with SDHB mutations followed up in a single UK tertiary referral centre. This included index cases that pre-dated the introduction of surveillance screening and asymptomatic carriers identified through cascade genetic testing. We also conducted a literature review to inform a suggested surveillance protocol for children and adolescents harbouring SDHB mutations. Results Clinical outcomes of a total of 38 children are presented: 8 index cases and 30 mutation-positive asymptomatic carriers with 175 patient years of follow-up data. Three of the eight index cases developed metachronous disease and two developed metastatic disease. Of the 30 asymptomatic carriers, 3 were found to have PGLs on surveillance screening. Conclusions Surveillance screening was well tolerated in our paediatric cohort and asymptomatic paediatric subjects. Screening can identify tumours before they become secretory and/or symptomatic, thereby facilitating surgical resection and reducing the chance of distant spread. We propose a regular screening protocol commencing at age 5 years in this at-risk cohort of patients.
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http://dx.doi.org/10.1530/EC-18-0522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391899PMC
March 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

Emergence of Pituitary Adenoma in a Child during Surveillance: Clinical Challenges and the Family Members' View in an Mutation-Positive Family.

Int J Endocrinol 2018 4;2018:8581626. Epub 2018 Apr 4.

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

Introduction: Germline aryl hydrocarbon receptor-interacting protein () mutations are responsible for 15-30% of familial isolated pituitary adenomas (FIPAs). We report a FIPA kindred with a heterozygous deletion in , aiming to highlight the indications and benefits of genetic screening, variability in clinical presentations, and management challenges in this setting.

Patients: An 18-year-old male was diagnosed with a clinically nonfunctioning pituitary adenoma (NFPA). Two years later, his brother was diagnosed with a somatolactotrophinoma, and a small Rathke's cleft cyst and a microadenoma were detected on screening in their 17-year-old sister. Following amenorrhoea, their maternal cousin was diagnosed with hyperprolactinaemia and two distinct pituitary microadenomas. A 12-year-old niece developed headache and her MRI showed a microadenoma, not seen on a pituitary MRI scan 3 years earlier.

Discussion: Out of the 14 members harbouring germline mutations in this kindred, 5 have pituitary adenoma. Affected members had different features and courses of disease. Bulky pituitary and not fully suppressed GH on OGTT can be challenging in the evaluation of females in teenage years. Multiple pituitary adenomas with different secretory profiles may arise in the pituitary of these patients. Small, stable NFPAs can be present in mutation carriers, similar to incidentalomas in the general population. Genetic screening and baseline review, with follow-up of younger subjects, are recommended in mutation-positive families.
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http://dx.doi.org/10.1155/2018/8581626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904812PMC
April 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

Modeling Congenital Adrenal Hyperplasia and Testing Interventions for Adrenal Insufficiency Using Donor-Specific Reprogrammed Cells.

Cell Rep 2018 01;22(5):1236-1249

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

Adrenal insufficiency is managed by hormone replacement therapy, which is far from optimal; the ability to generate functional steroidogenic cells would offer a unique opportunity for a curative approach to restoring the complex feedback regulation of the hypothalamic-pituitary-adrenal axis. Here, we generated human induced steroidogenic cells (hiSCs) from fibroblasts, blood-, and urine-derived cells through forced expression of steroidogenic factor-1 and activation of the PKA and LHRH pathways. hiSCs had ultrastructural features resembling steroid-secreting cells, expressed steroidogenic enzymes, and secreted steroid hormones in response to stimuli. hiSCs were viable when transplanted into the mouse kidney capsule and intra-adrenal. Importantly, the hypocortisolism of hiSCs derived from patients with adrenal insufficiency due to congenital adrenal hyperplasia was rescued by expressing the wild-type version of the defective disease-causing enzymes. Our study provides an effective tool with many potential applications for studying adrenal pathobiology in a personalized manner and opens venues for the development of precision therapies.
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http://dx.doi.org/10.1016/j.celrep.2018.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809617PMC
January 2018

Kisspeptin Is a Novel Regulator of Human Fetal Adrenocortical Development and Function: A Finding With Important Implications for the Human Fetoplacental Unit.

J Clin Endocrinol Metab 2017 09;102(9):3349-3359

Centre for Endocrinology, William Harvey Research Institute, London, EC1M 6BQ, United Kingdom.

Context: The human fetal adrenal (HFA) is an integral component of the fetoplacental unit and important for the maintenance of pregnancy. Low kisspeptin levels during pregnancy are associated with miscarriage, and kisspeptin and its receptor are expressed in the HFA. However, the role of kisspeptin in fetal adrenal function remains unknown.

Objective: To determine the role of kisspeptin in the developing HFA.

Design: Experiments using H295R and primary HFA cells as in vitro models of the fetal adrenal. Association of plasma kisspeptin levels with HFA size in a longitudinal clinical study.

Setting: Academic research center and tertiary fetal medicine unit.

Participants: Thirty-three healthy pregnant women were recruited at their 12-week routine antenatal ultrasound scan.

Main Outcome Measures: The spatiotemporal expression of Kiss1R in the HFA. The production of dehydroepiandrosterone sulfate (DHEAS) from HFA cells after kisspeptin treatment, alone or in combination with adrenocorticotropic hormone or corticotropin-releasing hormone. Fetal adrenal volume (FAV) and kisspeptin levels at four antenatal visits (∼20, 28, 34, and 38 weeks' gestation).

Results: Expression of Kiss1R was present in the HFA from 8 weeks after conception to term and was shown in the inner fetal zone. Kisspeptin significantly increased DHEAS production in H295R and second-trimester HFA cells. Serial measurements of kisspeptin confirmed a correlation with FAV growth in the second trimester, independent of sex or estimated fetal weight.

Conclusions: Kisspeptin plays a key role in the regulation of the HFA and thus the fetoplacental unit, particularly in the second trimester of pregnancy.
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http://dx.doi.org/10.1210/jc.2017-00763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587078PMC
September 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

Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.

J Clin Invest 2017 Mar 6;127(3):942-953. Epub 2017 Feb 6.

Primary adrenal insufficiency is life threatening and can present alone or in combination with other comorbidities. Here, we have described a primary adrenal insufficiency syndrome and steroid-resistant nephrotic syndrome caused by loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1). SGPL1 executes the final decisive step of the sphingolipid breakdown pathway, mediating the irreversible cleavage of the lipid-signaling molecule sphingosine-1-phosphate (S1P). Mutations in other upstream components of the pathway lead to harmful accumulation of lysosomal sphingolipid species, which are associated with a series of conditions known as the sphingolipidoses. In this work, we have identified 4 different homozygous mutations, c.665G>A (p.R222Q), c.1633_1635delTTC (p.F545del), c.261+1G>A (p.S65Rfs*6), and c.7dupA (p.S3Kfs*11), in 5 families with the condition. In total, 8 patients were investigated, some of whom also manifested other features, including ichthyosis, primary hypothyroidism, neurological symptoms, and cryptorchidism. Sgpl1-/- mice recapitulated the main characteristics of the human disease with abnormal adrenal and renal morphology. Sgpl1-/- mice displayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes as well as renal histology in keeping with a glomerular phenotype. In summary, we have identified SGPL1 mutations in humans that perhaps represent a distinct multisystemic disorder of sphingolipid metabolism.
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http://dx.doi.org/10.1172/JCI90171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330744PMC
March 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

Outcomes of annual surveillance imaging in an adult and paediatric cohort of succinate dehydrogenase B mutation carriers.

Clin Endocrinol (Oxf) 2017 Feb 24;86(2):286-296. Epub 2016 Oct 24.

Department of Endocrinology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.

Objective: For 'asymptomatic carriers' of the succinate dehydrogenase subunit B (SDHB) gene mutations, there is currently no consensus as to the appropriate modality or frequency of surveillance imaging. We present the results of a surveillance programme of SDHB mutation carriers.

Design: Review of clinical outcomes of a surveillance regimen in patients identified to have an SDHB gene mutation, based on annual MRI, in a single UK tertiary referral centre.

Patients: A total of 92 patients were identified with an SDHB gene mutation. a total of 27 index patients presented with symptoms, and 65 patients were identified as asymptomatic carriers.

Measurements: Annual MRI of the abdomen, with alternate year MRI of the neck, thorax and pelvis. Presence of an SDHB-related tumour included paraganglioma (PGL), phaeochromocytoma (PCC), renal cell carcinoma (RCC) and gastrointestinal stromal tumour (GIST).

Results: A total of 43 PGLs, eight PCCs and one RCC occurred in the 27 index patients (23 solitary, four synchronous, five metachronous). A further 15 SDHB-related tumours (11 PGLs, three RCCs, one GIST) were identified in the asymptomatic carriers on surveillance screening (25% of screened carriers): 10 on the first surveillance imaging and five on subsequent imaging 2-6 years later. A total of 11 patients had malignant disease.

Conclusions: SDHB-related tumours are picked up as early as 2 years after initial negative surveillance scan. We believe the high malignancy rate and early identification rate of tumours justifies the use of 1-2 yearly imaging protocols and MRI-based imaging could form the mainstay of surveillance in this patient group thereby minimizing radiation exposure.
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http://dx.doi.org/10.1111/cen.13246DOI Listing
February 2017

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

IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty.

EMBO Mol Med 2016 06 1;8(6):626-42. Epub 2016 Jun 1.

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

Early or late pubertal onset affects up to 5% of adolescents and is associated with adverse health and psychosocial outcomes. Self-limited delayed puberty (DP) segregates predominantly in an autosomal dominant pattern, but the underlying genetic background is unknown. Using exome and candidate gene sequencing, we have identified rare mutations in IGSF10 in 6 unrelated families, which resulted in intracellular retention with failure in the secretion of mutant proteins. IGSF10 mRNA was strongly expressed in embryonic nasal mesenchyme, during gonadotropin-releasing hormone (GnRH) neuronal migration to the hypothalamus. IGSF10 knockdown caused a reduced migration of immature GnRH neurons in vitro, and perturbed migration and extension of GnRH neurons in a gnrh3:EGFP zebrafish model. Additionally, loss-of-function mutations in IGSF10 were identified in hypothalamic amenorrhea patients. Our evidence strongly suggests that mutations in IGSF10 cause DP in humans, and points to a common genetic basis for conditions of functional hypogonadotropic hypogonadism (HH). While dysregulation of GnRH neuronal migration is known to cause permanent HH, this is the first time that this has been demonstrated as a causal mechanism in DP‡.
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http://dx.doi.org/10.15252/emmm.201606250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888853PMC
June 2016

STAG3 truncating variant as the cause of primary ovarian insufficiency.

Eur J Hum Genet 2016 Jan 10;24(1):135-8. Epub 2015 Jun 10.

Reproductive Medicine Unit, Institute for Women's Health, University College London Hospitals, London, UK.

Primary ovarian insufficiency (POI) is a distressing cause of infertility in young women. POI is heterogeneous with only a few causative genes having been discovered so far. Our objective was to determine the genetic cause of POI in a consanguineous Lebanese family with two affected sisters presenting with primary amenorrhoea and an absence of any pubertal development. Multipoint parametric linkage analysis was performed. Whole-exome sequencing was done on the proband. Linkage analysis identified a locus on chromosome 7 where exome sequencing successfully identified a homozygous two base pair duplication (c.1947_48dupCT), leading to a truncated protein p.(Y650Sfs*22) in the STAG3 gene, confirming it as the cause of POI in this family. Exome sequencing combined with linkage analyses offers a powerful tool to efficiently find novel genetic causes of rare, heterogeneous disorders, even in small single families. This is only the second report of a STAG3 variant; the first STAG3 variant was recently described in a phenotypically similar family with extreme POI. Identification of an additional family highlights the importance of STAG3 in POI pathogenesis and suggests it should be evaluated in families affected with POI.
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http://dx.doi.org/10.1038/ejhg.2015.107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795223PMC
January 2016

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

Use of continuous glucose monitoring to identify glucose dysregulation in growth hormone insensitivity syndrome.

Horm Res Paediatr 2014 16;82(6):394-8. Epub 2014 Dec 16.

Newborn Intensive Care Unit, St. Mary's Hospital, Central Manchester Foundation Trust, Manchester, UK.

Background/aims: Monogenic forms of growth hormone insensitivity (GHI) and its treatment with recombinant insulin-like growth factor-1 (rIGF-1) are both associated with glucose dysregulation. We used the information provided by continuous glucose monitoring systems (CGMS) for the clinical management of two children with monogenic GHI prior to the commencement of therapy as well as during the years when they received rIGF-1 treatment and continued to do so after the cessation of therapy.

Methods: We evaluated the extent of hyper- and hypoglycaemia with CGMS.

Results: In one patient, before treatment CGMS identified self-limiting nocturnal hypoglycaemia. Initiation of rIGF-1 treatment resulted in severe and persistent hypoglycaemia with an absence of spontaneous recovery. Corrective dietary measures were instituted. In a second patient, who had a poor growth response to rIGF-1 therapy, CGMS identified significant fluctuations in daytime glucose levels whilst on treatment with evidence of postprandial hyperglycaemia and both rebound and nocturnal hypoglycaemia. Given the lack of improved growth and the documented glucose dysregulation, treatment was stopped and repeat measurements with CGMS 1 month afterwards showed complete resolution.

Conclusions: We have demonstrated that CGMS is an effective tool to assess glucose dysregulation in patients with GHI and alters clinical management.
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http://dx.doi.org/10.1159/000369096DOI Listing
October 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

Clinical experience in the screening and management of a large kindred with familial isolated pituitary adenoma due to an aryl hydrocarbon receptor interacting protein (AIP) mutation.

J Clin Endocrinol Metab 2014 Apr 1;99(4):1122-31. Epub 2013 Jan 1.

Regional Center for Endocrinology and Diabetes (F.W., S.H., A.B.A.), Royal Victoria Hospital, Belfast BT12 6BA, Northern Ireland, United Kingdom; Department of Medical Genetics (L.B., P.J.M.), Belfast Health and Social Care Trust, Belfast BT9 7AB, Northern Ireland, United Kingdom; Department of Endocrinology (H.S.C., H.L.S., S.A.A., M.K.), Barts and London School of Medicine, Queen Mary University of London, London EC1A 6BQ, United Kingdom; North East Thames Regional Genetics Service (A.V.K.), Great Ormond Street Hospital, London WC1N 3JH, United Kingdom; Department of Endocrinology (S.M.O.), St James University Hospital, Leeds LS9 7TF, United Kingdom; Department of Radiology (J.E.), St Bartholomew Hospital, London EC1A 7BE, United Kingdom; and Department of Endocrinology (N.A.), Royal Belfast Hospital for Sick Children, Belfast, BT12 6BA, United Kingdom.

Context: Germline AIP mutations usually cause young-onset acromegaly with low penetrance in a subset of familial isolated pituitary adenoma families. We describe our experience with a large family with R304* AIP mutation and discuss some of the diagnostic dilemmas and management issues.

Objective: The aim of the study was to identify and screen mutation carriers in the family.

Patients: Forty-three family members participated in the study.

Setting: The study was performed in university hospitals.

Outcome: We conducted genetic and endocrine screening of family members.

Results: We identified 18 carriers of the R304* mutation, three family members with an AIP-variant A299V, and two family members who harbored both changes. One of the two index cases presented with gigantism and pituitary apoplexy, the other presented with young-onset acromegaly, and both had surgery and radiotherapy. After genetic and clinical screening of the family, two R304* carriers were diagnosed with acromegaly. They underwent transsphenoidal surgery after a short period of somatostatin analog treatment. One of these two patients is in remission; the other achieved successful pregnancy despite suboptimal control of acromegaly. One of the A299V carrier family members was previously diagnosed with a microprolactinoma; we consider this case to be a phenocopy. Height of the unaffected R304* carrier family members is not different compared to noncarrier relatives.

Conclusions: Families with AIP mutations present particular problems such as the occurrence of large invasive tumors, poor response to medical treatment, difficulties with fertility and management of pregnancy, and the finding of AIP sequence variants of unknown significance. Because disease mostly develops at a younger age and penetrance is low, the timing and duration of the follow-up of carriers without overt disease requires further study. The psychological and financial impact of prolonged clinical screening must be considered. Excellent relationships between the family, endocrinologists, and geneticists are essential, and ideally these families should be managed in centers with specialist expertise.
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http://dx.doi.org/10.1210/jc.2013-2868DOI Listing
April 2014
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