Edition 67 - 2018, March / Bibliographic Reviews

Bibliographic Reviews – Ed. 67

Marco A. Rivarola y Alicia Belgorosky

Servicio de Endocrinología, Hospital de Pediatria Garrahan, Buenos Aires, Argentina

For this issue of Endocrinologia Pediatrica On line, we have selected the following publications: 


European Journal of Endocrinology (2017) 177, R309–R321


Clinical and pharmacogenetic aspects of the growth hormone receptor polymorphism. Cesar L Boguszewski1, Edna J L Barbosa1, Per-Arne Svensson2,3, Gudmundur Johannsson4 and Camilla A M Glad2,4

1SEMPR, Endocrine Division, Department of Internal Medicine, Federal University of Parana, Curitiba, Brazil, 2Department of Molecular and Clinical Medicine, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, 3Institute of Health and Care Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, and 4Department of Endocrinology, Sahlgrenska University Hospital and Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 


Pharmacogenetics aims to maximize the beneficial effects of a medical therapy by identifying genetic finger prints from responders and non-responders and, thereby improving safety and efficacy profile of the drug. Most subjects who are deficient in growth hormone (GHD) are candidates for recombinant human GH (rhGH) therapy. To date, it is well established that even after adjustments for several clinical variables, such as age, gender, body composition and the age at onset of the GHD, response to rhGH treatment is highly variable among individuals, part of which is believed to be due to genetic factors within the GH system. As the first genetic variant to potentially influence the individual response to rhGH therapy in children with growth disorders, polymorphism in the GH receptor (GHR) has attracted a great interest as a target for pharmacogenetics. Studies have been conducted to compare the functional and molecular effects of the full-length GHR (fl-GHR) isoform with the exon 3 deleted (d3-GHR) isoform in children and adults treated with rhGH therapy. Additionally, the impact of the GHR polymorphism has been investigated in relation to the clinical status and response to medical treatment in acromegaly, especially to the GHR antagonist drug pegvisomant. Authors have performed a narrative review of the studies performed to date on the association of GHR polymorphism with rhGH response in children and adults, and its potential influence in the medical management of acromegaly. In addition, data from studies on the general population and in other chronic diseases examining a role of this genetic variant in the regulation of growth and metabolism were summarized.

Authors´ Summary and Conclusions.

Almost 30 years have passed since the first reports of the d3-GHR isoform and still the exact mechanisms by which its functional effect is conveyed are incompletely understood. One single experimental study, which has not been consistently replicated, found a 30% enhanced signal transduction in cells transfected with the d3-GHR, raising a large interest in using the GHR genotype to predict the response to rhGH in both children and adults. It is not possible, however, to estimate how a 30% improvement in in vitro GHR signal transduction would translate into clinical findings, as regulation of rhGH response in both children and adults is intriguingly complex and involves multiple factors other than the GHR signaling cascade. Epidemiologic studies have found associations of the d3-GHR isoform with longevity, anthropometric and metabolic parameters, in the general population. Previous systematic reviews and meta-analysis in GHD and non- GHD short children, as well as this narrative review including adults with GHD, show that the d3-GHR isoform may have a weak influence on the clinical phenotype and therapeutic response to rhGH, but data are heterogeneous and conflicting. However, it should be acknowledged that most studies involved a small number of observations, were not primarily designed to address the question of GHR genotype–phenotype relationships and, consequently, many issues on this association remain unsolved. In contrast, no influence of GHR polymorphism with major clinical significance has been found in acromegaly patients before or after treatment. For the next 30 years, it is hoped to see new experimental studies examining in more details the impact of d3-GHR isoform in relation to GH binding, GHR dimerization, rotation and signal transduction and, concomitantly, new clinical research on large series of patients specifically designed to clarify the physiological and pathological role of GHR polymorphism and its implication for pharmacogenetics.


J Clin Endocrinol Metab. 2017 Oct 1;102(10):3830-3838. doi: 10.1210/jc.2017-01192.

Nocturnal Urinary Excretion of FSH and LH in Children and Adolescents With Normal and Early Puberty. Kolby N1,2, Busch AS1,2, Aksglaede L1,2, Sørensen K1,2, Petersen JH1,2, Andersson AM1,2, Juul A1,2. 1 Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark. 2 International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.


CONTEXT: Clinical use of single serum gonadotropin measurements in children is limited by the pulsatile secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). However, first morning voided (FMV) urine may integrate the fluctuating gonadotropin serum levels. OBJECTIVE: We aimed to evaluate urinary and serum gonadotropin levels according to age, sex, and pubertal stage in healthy children and to assess the clinical use of FMV urinary gonadotropins in children with disordered puberty. DESIGN:

Cross-sectional part of the COPENHAGEN Puberty Study and longitudinal study of patients. SETTING: Population-based and outpatient clinic. PATIENTS OR OTHER PARTICIPANTS: Eight hundred forty-three healthy children from the COPENHAGEN Puberty Study and 25 girls evaluated for central precocious puberty (CPP). MAIN OUTCOME MEASURES: Clinical pubertal staging, including serum and urinary gonadotropin levels. RESULTS: Urinary gonadotropins increased with advancing age and pubertal development and were detectable in FMV urine before physical signs of puberty. FMV urinary LH correlated strongly with basal (r = 0.871, P < 0.001) and gonadotropin-releasing hormone (GnRH)-stimulated serum LH (r = 0.82, P < 0.001). Urinary LH was superior to urinary FSH in differentiating the pubertal stage. Receiver operating curve analysis revealed that a cut-off standard deviation (SD) score of 2 for urinary LH (IU/L) gave a sensitivity of 75% and a specificity of 92% in predicting a positive GnRH stimulation test (LHmax > 5 IU/L). Urinary concentrations of LH decreased after 3 months of GnRH treatment to levels below +2 SDs. CONCLUSIONS: Urinary gonadotropin levels increased before the onset of puberty and were elevated in girls with Central Precocious Puberty. They suggest urinary LH as an alternative noninvasive method to improve diagnosing and therapeutic management of children with disordered puberty.

Comments In conclusion, data suggest that first morning voided (FMV) urinary concentrations of LH can be used as a diagnostic marker in girls suspected of Central Precocious Puberty (CPP). Additionally, they suggest measurement of unadjusted FMV urinary concentrations of LH as a method for monitoring treatment with GnRHa in girls with CPP.


J Clin Endocrinol Metab (2016) Dec;101(12):4521-4531..

Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism with Gland-in-Situ. Nicholas AK1Serra EG1, Cangul H1Alyaarubi S1Ullah I1Schoenmakers E1Deeb A1Habeb AM1Almaghamsi M1Peters C1Nathwani N1, Aycan Z1Saglam H1Bober E1Dattani M1Shenoy S1Murray PG1Babiker A1Willemsen R1Thankamony A1Lyons G1Irwin R1Padidela R1Tharian K1Davies JH1Puthi V1Park SM1Massoud AF1Gregory JW1Albanese A1Pease-Gevers E1Martin H1Brugger K1Maher ER1Chatterjee VK1Anderson CA1Schoenmakers N1. 1University of Cambridge Metabolic Research Laboratories (A.K.N., E.S., G.L., V.K.K.C., N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom; Department of Human Genetics (E.G.S., C.A.A.), The Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Research Centre for Regenerative and Restorative Medicine (H.C.), Department of Medical Genetics Istanbul Medipol University, Kavacık, Istanbul, Turkey; Pediatric Endocrine Unit (S.A., I.U.), Department of Child Health, Sultan Qaboos University Hospital, Muscat, Oman; Paediatric Endocrinology Department (A.D.), Mafraq Hospital, AbuDhabi, United Arab Emirates; Pediatric Department Prince Mohamed Bin Abdulaziz Hospital (A.M.H.), Madinah, Kingdom of Saudi Arabia; Department of Paediatrics (M.A.), Madina Maternity & Children’s Hospital Madina Munawara, Saudi Arabia; 8. Department of Endocrinology (C.P.), Great Ormond St Hospital for Children, London, United Kingdom; Department of Paediatrics (N.N.), Luton and Dunstable University Hospital, Luton, United Kingdom; Division of Paediatric Endocrinology (Z.A.), Dr Sami Ulus Woman Health and Children Research Hospital Ankara, Turkey; Department of Paediatric Endocrinology (H.S.), Uludağ University, School of Medicine Bursa, Turkey; Department of Paediatric Endocrinology (E.B.), Dokuz Eylül University, Faculty of Medicine Izmir, Turkey; Developmental Endocrinology Research Group (M.D.), Section of Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme, University College London Institute of Child Health, London, United Kingdom; Department of Paediatrics (S.S.), Leicester Royal infirmary, Leicester United Kingdom; Centre for Paediatrics and Child Health (P.G.M.), Institute of Human Development University of Manchester, and Royal Manchester Children’s Hospital, Manchester, United Kingdom; Paediatric Endocrinology Division (A.B.), College of Medicine, King Saud University and King Saud University Medical City, Riyadh, Saudi Arabia; Department of Paediatrics (R.W., A.T.), University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; W Midlands Regional Genetics Laboratory (R.I.), Birmingham Women’s Hospital NHS Foundation Trust, Birmingham, United Kingdom; Department of Paediatric Endocrinology (R.P.), Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom; Department of Paediatrics (K.T.), Diana Princess of Wales Hospital, Grimsby, United Kingdom; Department of Paediatric Endocrinology (J.H.D.), University Hospital Southampton, Southampton, United Kingdom; Department of Paediatrics (V.P.), Peterborough and Stamford Hospitals NHS Foundation Trust, Peterborough, United Kingdom; Department of Clinical Genetics (S.-M.P.), Cambridge University Hospitals NHS Foundation Trust, Cambridge United Kingdom; London N W Healthcare NHS Trust (A.F.M.), Harrow, Middlesex, United Kingdom; Division of Population Medicine (J.W.G.), School of Medicine, Cardiff University, Heath Park Cardiff, UK; Department of Paediatric Endocrinology (A.A.), St George’s University Hospitals NHS Foundation Trust, London, United Kingdom; Centre for Endocrinology (E.P.-G.), William Harvey Research Institute, Queen Mary University London and Children’s Hospital, Barts Health NHS Trust, London, United Kingdom; Department of Medical Genetics (H.M., K.B., E.R.M.), University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom.


CONTEXT: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken. OBJECTIVE: the objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. PATIENTS, DESIGN, and SETTING: They screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. RESULTS: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases. CONCLUSIONS: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.


The thyroblobulin (TG), thyroid peroxidase (TPO), dual oxidase 2 (DUOX2), dual oxidase maturation factor 2 (DUOXA2), solute carrier family 5 member 5 (SLC5A5), solute carrier family 26 member 4 (SLC26A4), iodotyrosine deiodinase (IYD), and thyroid stimulating hormone receptor (TSHR) genes are considered potential candidates for etiology of CH; however around more than 60% of causes remain undefined.


Endocrine News from the Endocrine Society. December

2017: A progress report. Derek Bagley (Senior Editor).

2017 Highlights of Endocrine Research & Treatments.”

Potencial breakthrough for thyroid cancer patients. “A next-generation test is showing promising results in changing thyroid cancer diagnoses, allowing more patients with indeterminate thyroid nodules to avoid unnecessary surgeries, as this new version can more clearly distinguish between benign and malignant thyroid nodules.  This test, developed by Veracyte, is an upgrade of the company´s Afirma Gene Expression Classifier. Veracyte calls this new development the Afirma Genomics Sequencing Classifier (GSC), as it combines ribonucleic acid (RNA) sequencing and machines learning to leverage more enriched, previously undetectable genomic information.

“They are employing the same statistical methods that are being used in other fields such as social media and self-driving cars, buy applying them to thyroid cancer diagnosis”, says Endocrine Society member Giulia C. Kennedy, Ph.D., Veracyte´s chief scientific officer. “This approach uses RNA sequencing to interrogate the entire genome, and takes advantage of newer methods in machine learning to combine valuable features that provide a higher-resolution genomic picture of thyroid. This enables the Afirma GSC to recognize nuances that distinguish benign from malignant nodules, and which were previously not detectable”.

Increasing the number of benign nodules identified is important because increasing the number of benign nodules directly translates to patients avoiding unnecessary surgeries, Kennedy says. Before Afirma, unnecessary surgeries were a huge problem. The Afirma Gene Expression Classifier or, GEC, was the very first genome test that actually helped solve much of that problem, and now data suggest that the Afirma GSC, Genomic Expression Classifier, the next generation version, is going to save even more surgeries. Before Afirma, people with indeterminate nodules from fine-needle aspiration cytopathology had about 25% risk of having cancer. Therefore, doctors didn’t feel comfortable leaving those nodules in the patient. Even though it’s only a 25% risk, they would go on and have surgery, and of course, 75% of those patients would have benign nodules. Therefore, when Afirma came on the market, the test allowed 52% of those patients to be spared an unnecessary surgery. And now, this enhanced test has improved upon that by using some very sophisticated technology, both on the assay side and the algorithm side to raise that to 68%, which means even more patients can safely avoid surgery. You need a very high sensitivity and a high negative predictive value (NPV), in order to make sure that those patients you are calling benign are actually benign. The Afirma GSC has an excellent NVP and high sensitivity like the first test.              



Eur Thyroid J 2018 7:44-50. A Case Report of Syndromic Multinodular Goitre in Adolescence: Exploring the Phenotype Overlap between Cowden and DICER1 Syndromes. Bouron- Dal Soglio Da , de Kock L a , de Kock L.b,c, Gauci R.d, Sabbaghian N.b, Thomas E, Atkinson HCf, Pachter Nf,g,  Ryan Sh, Walsh JPf,I, Kumarasinghe MPj, Carpenter Kk, Aydoğan Al, Stewart CJR.g, Foulkes WDb,c,m, Choong CS. aDepartment of Pathology, CHU Sainte-Justine, Montreal, QC, Canada bThe Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montreal, QC, Canada
cDepartment of Human Genetics, McGill University, Montreal, QC, Canada dNuclear Medicine, Sir Charles Gairdner Hospital, Nedlands, WA, Australia eDepartment of Endocrinology and Diabetes, Princess Margaret Hospital for Children, Subiaco, WA, Australia fFaculty of Health and Medical Sciences, School of Medicine, The University of Western Australia, Crawley, WA, Australia gKing Edward Memorial Hospital, Perth, WA, Australia hDepartment of General Surgery, Sir Charles Gairdner Hospital, Nedlands, WA, Australia iDepartment of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, WA, Australia jPathWest, QEII Medical Centre, Perth, WA, Australia
kDepartment of Diagnostic Genomics, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia lDepartment of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
mDepartment of Medical Genetics, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.


BACKGROUND: Hereditary tumor predisposition syndromes may increase the risk for development of thyroid nodules at a young age. They present the case of an adolescent female with Cowden syndrome who had some atypical phenotypic features which overlapped with the DICER1 syndrome. MATERIAL AND METHODS: A 17-year-old female presented with a 3-month history of progressive right neck swelling. Fine needle cytology of the thyroid revealed a follicular neoplasm with features suggestive of follicular variant of papillary thyroid carcinoma and she underwent a hemi-thyroidectomy. Enlarging nodules in the remaining thyroid led to a completion thyroidectomy at 19 years of age. The patient’s past medical history included an ovarian mixed malignant germ cell tumour, pulmonary nodules and cysts, renal cysts, muco-cutaneous lesions, an arachnoid cyst, and a fibrous breast lesion. Macrocephaly was noted on physical examination. RESULTS:  Based on the patient’s complex phenotype and young age, a hereditary predisposition syndrome was suspected and genetic testing of PTEN (phosphatase and tensin gene) and DICER1 was undertaken. A heterozygous truncating germ-line PTEN mutation was identified, which combined with clinical findings, met criteria for the diagnosis of Cowden syndrome. Additional loss of heterozygosity of the wild-type PTEN allele was detected in the right thyroid lesion and ovarian tumour. No DICER1 mutations were identified. CONCLUSIONS: Genetic testing was crucial in elucidating this patient’s predisposition to the early development of neoplastic and non-neoplastic conditions. This report also highlights the phenotypic overlap between the Cowden and DICER1 syndromes and illustrates the importance of recognizing the variable phenotypic features of hereditary syndromes in order to enable timely implementation of therapy.


J Clin Endocrinol Metab. 2017 Dec 1;102 (12):4568-4577. Pharmacokinetics of IGF-1 in PAPP-A2-Deficient Patients, Growth Response, and Effects on Glucose and Bone Density.

Cabrera-Salcedo C1,2, Mizuno T2,3, Tyzinski L1, Andrew M1, Vinks AA2,3, Frystyk J4, Wasserman H1,2, Gordon CM1,2, Hwa V1,2, Backeljauw P1,2, Dauber A1,2. 1 Division of Endocrinology, Cincinnati Children’s Hospital Medical Center. 2 Department of Pediatrics, University of Cincinnati College of Medicine. 3 Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center. 4 Department of Clinical Medicine, Faculty of Health, Aarhus University Hospital, Denmark.


Context: The pregnancy-associated plasma protein A2 (PAPP-A2) cleaves insulin like growth factor binding proteins 3 and 5, releasing free insulin like growth factor 1 (IGF-1). Homozygous mutations in PAPP-A2 result in growth failure with elevated total but low free IGF-1.

Objective: To determine the 24-hour pharmacokinetic (PK) profile of free and total IGF-1 after a dose of recombinant human insulin like growth factor 1 (rhIGF-1). We describe the growth response and effects on glucose metabolism and bone mineral density (BMD) after 1 year of rhIGF-1 therapy. Design and Patients: Three affected siblings, their heterozygous parents, and two healthy controls participated. The subjects received a dose of rhIGF-1, followed by serial blood samples collected over 24 hours. The two younger siblings were started on rhIGF-1 treatment. An oral glucose tolerance test and dual-energy X-ray absorptiometry scans were obtained at baseline and after 1 year of treatment. Results:  Subcutaneous administration of rhIGF-1 increased the concentration of free and total IGF-1 in patients with PAPP-A2 deficiency. The PK profile was comparable in all participants. At baseline, all three subjects demonstrated insulin resistance and below-average BMD. Treatment with rhIGF-1 is ongoing in the youngest patient but was discontinued in his brother because of the development of pseudotumor cerebri. The treated patient had an increase in height velocity from 3.0 to 6.2 cm/y, resolution of insulin resistance, and an increase in total body BMD.

Conclusions: rhIGF-1 at standard dosages resulted in similar PK characteristics in patients with PAPP-A2 deficiency, heterozygous relatives, and healthy controls. The youngest affected patient experienced a modest growth response to therapy with rhIGF-1, as well as beneficial effects on glucose metabolism and bone mass.


These growth data suggest that the administered rhIGF-1 is not immediately captured into a ternary complex and thus made inaccessible by the PAPP-A2 deficiency. Furthermore, twice-daily administration of rhIGF-1 might be an appropriate dosing strategy for this patient population.  The free IGF-1 concentration remained above baseline for ~12 hours in all participants, achieving peak concentrations between 1 and 3.5 hours after the injection. Based on these observations, they determined that rhIGF-1 is a feasible approach to treat PAPP-A2 deficiency because it successfully increases the circulating free IGF-1 concentration, responsible for the growth failure observed in these patients. However, it is possible that patients with PAPP-A2 deficiency may be at increased risk for elevated intracranial pressure, but additional studies are needed to determine this risk. Their results emphasize that PAPP-A2 deficiency not only results in significant growth failure but also has important physiologic consequences for bone mass, body composition, and glucose homeostasis. In the current study, they demonstrate that rhIGF-1 at standard dosages is a reasonable treatment approach to improve linear growth in patients with PAPP-A2 deficiency. Moreover, rhIGF-1 therapy also appears to have beneficial effects on bone density, body composition, and glucose metabolism. Careful monitoring for adverse events, including elevated intracranial pressure, is critical.

The current study sought to expand the knowledge about the pharmacokinetic (PK) of rhIGF-1 in the setting of PAPP-A2 deficiency by directly assessing free IGF-1 levels and comparing them with those of the heterozygous parents and two healthy controls.

They present a clinical characterization of a family with three children with homozygous loss-of function mutations in PAPP-A2, focusing on glucose and bone metabolism at baseline and after 1 year of therapy with rhIGF-1. Additionally, they provide an analysis examining the PK of rhIGF-1 in affected patients compared with heterozygous relatives and healthy controls.

The SC administration of rhIGF-1 resulted in comparable PK parameters in PAPP-A2-deficient patients, their heterozygous relatives, and healthy adult controls. The free IGF-1 concentration remained above baseline for ~12 hours in all participants. This study adds to the sparse evidence that short-term treatment with rhIGF-1 might improve linear growth in PAPP-A2-deficient patients, as previously reported. However, it does raise a note of caution given that two of the three affected members had to discontinue rhIGF-1 therapy because of side effects.

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