Edición 77 - Enero 2020 / Bibliographic Reviews

Bibliographic Review – Ed. 77

ENDOPEDONLINE – BIBLIOGRAPHIC REVIEWS – 77TH ISSUE.  JANUARY 2020
Marco A. Rivarola and Alicia Belgorosky. Hospital de Pediatria Garrahan, Buenos Aires, Argentina.

For this issue of Endocrinología Pediátrica On-Line, we have selected to comment on the following publications:
386
Nature Reviews Immunology, 2020, 20:4427-4440
Review Article Published: 06 August 2019
The Intestinal Microbiota Fueling Metabolic Inflammation.
Herbert Tilg, Niv Zmora, Timon E. Adolph, Eran Elinav
1 Department of Internal Medicine, Gastroenterology, Hepatology, Metabolism & Endocrinology, Medical University Innsbruck, Innsbruck, Austria. 2 Immunology Department, Weizmann Institute of Science, Rehovot, Israel. 3 Digestive Centre, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel. 4 Department of Internal Medicine, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel. 5 Department of Internal Medicine, Gastroenterology, Hepatology, Metabolism & Endocrinology, Medical University Innsbruck, Innsbruck, Austria. 6 Immunology Department, Weizmann Institute of Science, Rehovot, Israel. 7 Cancer-Microbiome Division, Deutsches Krebsforschungszentrum (DKFZ), Neuenheimer Feld 280, Heidelberg, Germany.
Abstract
Low-grade inflammation is the hallmark of metabolic disorders such as obesity, type 2 diabetes, and nonalcoholic fatty liver disease. Emerging evidence indicates that these disorders are characterized by alterations in the intestinal microbiota composition and its metabolites, which translocate from the gut across a disrupted intestinal barrier to affect various metabolic organs, such as the liver and adipose tissue, thereby contributing to metabolic inflammation. Here, we discuss some of the recently identified mechanisms that showcase the role of the intestinal microbiota and barrier dysfunction in metabolic inflammation. We propose a concept by which the gut microbiota fuels metabolic inflammation and dysregulation.
Excerpts selected from this article:
Strategies to combat metabolic inflammation. Interventions designed to control metabolic inflammation pose a compelling means to reduce the risk of developing metabolic syndrome. Dietary habits (for instance, composition, quantity, and timing) may impact metabolic inflammation. For instance, a high-fat diet promotes metabolic dysfunction in various organs, including the central nervous system, pancreas, liver, muscle, adipose tissue and vasculature, and dietary lipids drive a low-grade inflammatory state through upregulation of Toll-like receptor 4-mediated inflammation in human peripheral blood monocytes. Studies in mice have shown that dietary lipids can also drive adipose tissue inflammation and insulin resistance in a microbiome-dependent manner. In contrast, non-digestible carbohydrates (for example, dietary fiber) improve glucose homeostasis by enrichment of short-chain fatty acid-producing bacteria in the gut, although a study in humans found that weight reduction and anti-inflammatory effects mediated by dietary fibre was not associated with alterations in the gut microbiome. Similarly, diets restricted in carbohydrates reduced circulating proinflammatory cytokines and improved fat metabolism in humans with obesity and nonalcoholic fatty liver disease; omega-3 fatty acids and nicotinamide supplementation improved metabolic dysregulation in mice. Kynurenic acid reduced weight gain and promoted the expression of genes involved in lipid metabolism, thermogenesis and anti-inflammatory immune responses in adipose tissue and palmitic acid hydroxy stearic acids improved insulin sensitivity and reduced adipose tissue inflammation in mice. Experimental evidence also suggests that dietary timing impacts susceptibility to metabolic dysregulation. For example, time-restricted feeding ameliorated obesity and metabolic inflammation in mice. Additionally, exercise was associated with decreased levels of circulating proinflammatory cytokines and greater gut microbiota diversity in humans and ameliorated metabolic inflammation in mice. Finally, not only lifestyle modification but also bariatric surgery is considered an effective intervention to trigger weight loss and treat metabolic disorders in severely obese patients. The effect achieved by surgery is partially mediated by a reduction in calorie intake but may also be modulated by the intestinal microbiome, bile acid metabolism, and metabolic inflammation. A causal link between post-bariatric surgery microbiome alterations and attenuation of metabolic inflammation has been recently drawn in humans. Obese male human recipients with insulin resistance transplanted with faecal microbiota from human donors who underwent Roux-en-Y gastric bypass showed a decrease in insulin sensitivity and adipose inflammatory markers compared with recipients transplanted with microbiota from individuals with the metabolic syndrome.
Concept of microbiota-controlled metabolic inflammation. An array of bacterial components or pathogen-associated molecular patterns, such as lipopolysaccharides, flagellin, peptidoglycan, ADP-heptose, and lipoteichoic acid, elicit pro-inflammatory responses by innate and adaptive immune cells. Pathogen associated molecular patterns are detected by specialized immune cells, such as tissue-resident dendritic cells and macrophages, which are equipped with a large repertoire of pathogen-recognition receptors such as Toll-like receptors and NOD-like receptors. Receptor activation potently triggers the production of pro-inflammatory mediators (such as cytokines, chemokines, and oxidative perturbations) that fuel metabolic inflammation. Other immune cells, such as mucosa-associated invariant T cells, natural killer T cells, and regulatory T cells, can modulate metabolic inflammation. Immune cells may be primed in the intestine and migrate to distant organs (such as the liver and adipose tissue) or are directly recruited to metabolically active tissues to modulate metabolic inflammation. Besides microbial signals, the immune system may also respond to cellular stress and tissue injury with an inflammatory response in metabolic diseases. For example, DNA damage, endoplasmic reticulum stress or damage-associated molecular patterns (such as double-stranded DNA, mitochondrial DNA, and ATP) released during tissue injury can perturb immune functions and potentially lead to a chronic inflammatory condition in metabolic disorders. Bacterial signals may not only modulate the immune system, but also the function of the central nervous system. The study of the gut-brain axis has gained momentum in neurological diseases, which may also become relevant in behavioral sciences. For example, Escherichia coli proteins regulate host satiety in rats.

387
J Clin Endocrinol Metab 104: 4427–4440, 2019
Effect of Prebiotics on Microbiota, Intestinal Permeability, and Glycemic Control in Children with Type 1 Diabetes.
1Josephine Ho, 2Alissa C. Nicolucci, 3Heidi Virtanen,1Alana Schick, 3Jon Meddings, 4Raylene A. Reimer, 2,5 and 1,2 Carol Huang
Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada; 2 Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada; 3 International Microbiome Centre, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada; 4 Department of Internal Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada; and 5 Faculty of Kinesiology, University of Calgary, Calgary, Alberta T2N 1N4, Canada ORCiD numbers: 0000-0003-0379-4427 (J. Ho). Abstract
CONTEXT: Patients with type 1 diabetes (T1D) have lower microbiota diversity and distinct gut microbial profiles that have been linked to changes in intestinal permeability. Prebiotics are non-digestible carbohydrates that alter gut microbiota and could potentially improve glycemic control and reduce intestinal permeability and thereby insulin sensitivity. OBJECTIVE: To determine the effect of prebiotics on glycemic control, gut microbiota, and intestinal permeability in children with T1D. DESIGN: A randomized, placebo-controlled trial in children 8 to 17 years of age with T1D using placebo or prebiotic oligo-fructose-enriched inulin for 12 weeks. Baseline, 3-month, and 6-month assessments included HbA1c, C-peptide, gut microbiota, intestinal permeability, frequency of diabetic ketoacidosis (DKA), and severe hypoglycemia. RESULTS: Forty-three subjects were randomized and 38 completed the study. The groups were similar at baseline: prebiotic (N = 17), age 12.5 years (SD 2.8), HbA1c 8.02% (SD 0.82); placebo (N = 21), age 12.0 years (SD 2.6), HbA1c 8.08% (SD 0.91). No significant differences were found in the frequency of DKA or severe hypoglycemia. At 3-months, C-peptide was significantly higher (P < 0.029) in the group who received prebiotics, which was accompanied by a modest improvement in intestinal permeability. There was a significant increase in the relative abundance of Bifidobacterium within the prebiotic group at 3 months that was no longer present after the 3-month washout. The placebo group had a significantly higher relative abundance of Streptococcus, Roseburia inulinivorans, Terrisporobacter, and Faecalitalea compared with the prebiotic group at 3 months. CONCLUSION: Prebiotics are a potentially novel, inexpensive, low-risk treatment addition for T1D that may improve glycemic control. Further large-scale trials are needed.
Excerpts selected from this article:
The gut microbiota plays a key role in health and it is increasingly being recognized as a contributor to various disease states when an imbalance occurs. Both animal and human studies have reported a difference in microbial composition between those that develop diabetes from those that did not develop diabetes. In humans, gut microbiota composition differs between healthy controls, those with b-cell autoantibody [i.e. at risk for type 1 diabetes (T1D)], and patients with established T1D.
These studies suggest that gut leakiness may be modified by dietary factors. Our study showed that one-third of diabetes patients have a Lac/Man ratio .0.03 at baseline, which is abnormal. In comparison with the placebo group, the group who received prebiotic had improved gut permeability. More importantly, we observed a positive correlation between A1C and the Lac/Man ratio, suggesting that reducing the Lac/ Man ratio may reduce A1C and that intestinal permeability is a modifiable risk factor. Because there is wide variability in intestinal permeability among patients and it takes time for prebiotics to alter gut microbiota composition, which then may influence intestinal permeability, a larger study with prolonged duration of the prebiotic intervention will be necessary to determine the magnitude and duration of treatment effects. In the present study, we aimed to determine whether treatment with prebiotics could decrease intestinal permeability, which could, in turn, decrease endotoxemia and reduce insulin resistance, potentially leading to improved glycemic control. Although no significant differences were seen in A1C, there was higher C-peptide and an improvement in intestinal permeability in the prebiotic group. Prebiotic supplementation, specifically oligofructose-enriched inulin, is a potentially novel, inexpensive, low-risk treatment addition for T1D that may improve glycemic control. Further large-scale trials are needed.
 

388
J Clin Endocrinol Metab. 2019 Oct 21. pii: dgz101. doi: 10.1210/clinem/dgz101.
Circulating IGF-I independently predicts blood pressure in children with higher calcium-phosphorus product levels.
Xargay-Torrent S1, Dorado-Ceballos E2, Benavides-Boixader A1, Lizárraga-Mollinedo E1, Mas-Parés B3, Montesinos-Costa M4, De Zegher F5, Ibáñez L6,7, Bassols J3, López-Bermejo A1,2.
1Pediatric Endocrinology Research Group, [Girona Biomedical Research Institute] IDIBGI, Salt, Spain. 2Department of Pediatrics, Dr. Trueta University Hospital, Girona, Spain. 3Materno-Fetal Metabolic Research Group, [Girona Biomedical Research Institute] IDIBGI, Salt, Spain. 4Clinical Laboratory, Dr. Josep Trueta Hospital, Girona, Spain.5Department of Development & Regeneration, University of Leuven, Leuven, Belgium. 6Pediatric Endocrinology, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.7Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain.
Abstract
OBJECTIVE: To study the association between IGF-I and blood pressure in children, in particular, the potential interaction with the serum calcium-phosphorus product (Ca*P) in this association. METHODS: In a longitudinal study, 521 children (age 8.8 ± 0.1) from North-Eastern Spain were studied, of whom 158 were followed-up after 5 years. IGF-I, IGFBP-3, serum calcium and phosphorus were measured at baseline. Anthropometric [body-mass index (BMI) and waist] and cardio-metabolic [systolic (SBP) and diastolic blood pressure, pulse pressure, insulin, homeostatic model assessment of insulin resistance (HOMA-IR), HDL cholesterol and triglycerides] variables were assessed at baseline and at the end of follow-up. Statistical analysis included Pearson correlations followed by multivariable linear regression analyses. RESULTS: Baseline IGF-I and IGF-I/IGFBP-3 molar ratio positively correlated with baseline and follow-up BMI, waist, SBP, pulse pressure, insulin, HOMA-IR and triglycerides (r from 0.138 to 0.603; all p<0.05). The associations with SBP were stronger with increasing Ca*P (r from 0.261 to 0.625 for IGF-I; and r from 0.174 to 0.583 for IGF-I/IGFBP-3). After adjusting for confounding variables, baseline IGF-I and IGF-I/IGFBP-3 remained independently associated with both baseline and follow-up SBP in children in the highest Ca*P tertile (β from 0.245 to 0.381; p<0.01; model R2 from 0.246 to 0.566). CONCLUSIONS: These results suggest that IGF-I in childhood is an independent predictor of SBP in apparently healthy children, especially in those with high Ca*P levels.
Excerpts selected from this article:
According to the World Health Organization, cardiovascular diseases are the first cause of death globally. Increasing evidence suggests that such conditions may have their origins in childhood and progressively evolve. Indeed, high blood pressure in childhood is regarded as a risk factor for adult hypertension, a major contributor to cardiovascular diseases. However, elevated blood pressure is a modifiable risk factor. Thus, early diagnosis and prevention or treatment practices during childhood can potentially have a significant impact on future adverse outcomes.
The physiological function of IGF-I is to regulate cell metabolism, stimulate proliferation and inhibit apoptosis. It exerts a fundamental role in prenatal and postnatal development. Circulating levels of IGF-I are modulated by insulin-like growth factor-binding proteins (IGFBPs), which increase IGF-I half-life and reduce its bioavailability. Among them, the main carrier of IGF-I in the blood is IGFBP-3. The molar ratio between IGF-I and IGFBP-3 is considered clinically relevant to estimate the biologically active IGF-I.
Serum calcium-phosphorus product (Ca*P) has been associated with increased cardiovascular disease risk including vascular calcification and atherosclerosis. Bone metabolism is regulated by IGF-I, which increases bone resorption and bone deposition, suggesting a potential link among bone minerals, i.e. calcium and phosphorus, and IGF-I. Indeed, positive associations have been reported between circulating levels of IGF-I, and also IGFBP-3, and serum calcium.
In this context, our aim is to study, both cross-sectionally and longitudinally, the association between serum IGF-I concentrations and blood pressure in apparently healthy children. Secondly, the interaction of serum Ca*P in the association between IGF-I and blood pressure variation is also tested.
In adults, circulating Insulin-like growth factor-I (IGF-I) has been found to correlate with cardiovascular disease risk, including coronary artery disease, ischemic stroke or congestive heart failure, as well as the development of the metabolic syndrome. Also, a number of IGF1 gene polymorphisms have been linked to myocardial infarction risk, strengthening the connection between IGF-I and cardiovascular disease. However, discordant data exist in this area of study, with some reports showing positive and other negative associations between IGF-I levels and cardiovascular risk factors, especially with regard to blood pressure.
Currently, there are no longitudinal studies in apparently healthy children investigating the relationship between calcium and IGF-I which may involve complex interactions between them. One of the physiological roles of IGF-I is to adapt calcium and phosphorus metabolism to the augmented requirements during childhood and adolescent growth, a period of important bone formation. Also, acromegaly patients frequently have phosphate and calcium deviations, resulting in hyperphosphatemia or hypercalciuria. Elevated IGF-I triggers hypercalcemia through stimulating the production of vitamin D. In turn, vitamin D has been reported to increase circulating IGF-I and IGFBP-3. Taken together, these mechanisms could contribute to explain the observed interaction between IGF-I and Ca*P in the regulation of blood pressure.
Downloaded from https://academic.oup.com/jcem/advance-article-abstract
 

389
Horm Res Paediatr. 2019 Sep 11:1-13.
Current Insights into the Role of the Growth Hormone-Insulin-Like Growth Factor System in Short Children Born Small for Gestational Age.
Renes JS1, van Doorn J2, Hokken-Koelega ACS3,4.
1Department of Paediatrics, Subdivision of Endocrinology, Erasmus University Medical Centre, Sophia Children’s Hospital, Rotterdam, The Netherlands, 2Department of Genetics, Section of Metabolic Diagnostics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands. 3Department of Paediatrics, Subdivision of Endocrinology, Erasmus University Medical Centre, Sophia Children’s Hospital, Rotterdam, The Netherlands. 4Dutch Growth Research Foundation, Rotterdam, The Netherlands.
Abstract
BACKGROUND: The reason for the insufficient catch-up growth seen in 10% of children born small for gestational age (SGA) is poorly understood. Disturbances in the growth hormone (GH) – insulin-like growth factor (IGF) axis might underlie this failure to show sufficient catch-up growth. CONCLUSION: This review summarizes insights gained in the molecular and (epi) genetic mechanisms of the GH-IGF axis in short children born SGA. The most notable anomalies of the IGF system are the lowered IGF-I levels in both cord blood and the placenta, and the increased expression of IGF-binding proteins (IGFBP)-1 and IGFBP-2, which inhibit IGF-I, in the placenta of SGA neonates. These observations suggest a decreased bioactivity of IGF-I in utero. IGF-I levels remain reduced in SGA children with short stature, as well as IGFBP-3 and acid-labile subunit levels. The proteolysis of IGFBP-3 appears to be increased.
Excerpts selected from this article:
Most children born SGA show spontaneous catch-up growth during the first years of life. However, approximately 10% of all children born SGA fail to show enough catch-up growth and will continue to have a short stature throughout childhood and adolescence. Without growth hormone (GH) treatment, these children will reach an adult height well below the normal range and/or their target height range. The reason for this insufficient catch-up growth is poorly understood.
As the GH-IGF axis is involved in many physiological processes, understanding its molecular and (epi) genetic regulation is fundamental in optimizing our knowledge of the aetiology of the SGA phenotype. The most notable abnormalities of the IGF system in SGA neonates are the lowered levels of IGF-I in both cord blood and the placenta of SGA neonates. In contrast, the expression of the IGF-I inhibiting IGFBP-1 and IGFBP-2 in the placenta of SGA neonates is increased compared to AGA neonates. These observations suggest a decreased bioactivity of IGF-I in utero in SGA neonates. IGF-I levels remain reduced in SGA children with short stature, as well as those of IGFBP-3 and ALS. IGFBP-3 in the circulation of short SGA children appears to be subject to proteolysis to a higher degree than normal. Proteolyzed IGFBP-3 can, just like IGFBP-3, form ternary complexes with ALS and IGFs. However, it is assumed that the IGFs are bound in these complexes with a lower affinity and thus may be released easier. The biological significance of this remains uncertain but may indicate a compensatory mechanism for the lower IGF-I levels in short SGA children to enhance IGF-I bioavailability. However, in contrast, in 2 short SGA children an inactivating mutation in one of the IGFBP-3 proteases, PAPPA-2, has been found, leading to enhanced levels of IGF-I,
IGFBP-3, and ALS. It is not clear whether this concerns 2 exceptional cases of SGA. Further studying of IGFBP-3 proteolysis and the determination of the IGF bioactivity in the serum of short SGA children is needed. The lack of a clear identifiable cause of short stature in most SGA children renders an etiopathological approach to therapy difficult. Increasing our knowledge of the variability of the SGA phenotype is not only important for diagnosis but also for treatment options and expectations regarding the growth response. Pharmacogenetic studies might clarify some of the wide variations in growth response. Also, there is a necessity to optimize the GH dosage, since this will help to improve growth results. By using advanced growth prediction models, it might become feasible to decide on an individual GH dosage from the start of treatment, thereby aiming for the best treatment options for each individual child. Further research is needed, and clinical and basic researchers must continue working closely together to achieve advancements in this field. 

390
J Endocr Soc. 2019 Jul 31;3(10):1819-1824.
Whole-Exome Sequencing of Syndromic Adrenocortical Carcinoma (ACC) Reveals Distinct Mutational Profile From Sporadic ACC.
Nicolson NG1, Healy JM1,2, Korah R1, Carling T1,
1Yale Endocrine Neoplasia Laboratory, Department of Surgery, Yale School of Medicine, New Haven, Connecticut. 2Connecticut Children’s Medical Center, Hartford, Connecticut.
Abstract
Next-generation sequencing has provided genetic profiles of a large number of sporadic adrenocortical carcinomas (ACCs), but the applicability of these results to ACC cases associated with tumor predisposition syndromes is unclear. Although the germline features of these syndromes have been well described, the somatic mutational landscape of the tumors they give rise to is less clear. The group obtained germline and tumor tissue from a pediatric patient who developed ACC during her first year of life, which was treated successfully. She was subsequently diagnosed with additional tumors later in childhood. Whole exome sequencing analysis was performed followed by in silico protein function prediction, revealing a probably deleterious germline TP53 L265P mutation. The somatic mutational burden was comparable between the index case and a previously published cohort of 40 sporadic cases, but the mutational spectrum was distinct in terms of raw base-change frequency as well as in a trinucleotide context-specific analysis. No canonical somatic genetic drivers of ACC were identified in the reported case, suggesting that syndromic adrenocortical tumors may represent a genetically distinct entity from sporadic tumors.
Excerpts selected from this article:
A previous series has examined the landscape of pediatric ACC in a cohort with a high prevalence of a founder Brazilian TP53 R337H germline variant using whole-genome, whole-exome, and transcriptome profiling techniques, but did not examine mutational signature of syndromic cases specifically. Authors, therefore, performed whole-exome sequencing (WES) of both tumor and germline tissue from this pediatric patient with ACC, and suspected tumorigenic syndrome. The patient initially presented at five months of age when she developed progressive hemiparesis and was found to have a large left adrenal mass with apparent spinal metastasis. She had been noted previously to have some atypical developmental features at birth, including macroglossia and body hemihypertrophy. There was no family history in either parent or any other relatives of childhood cancers or other apparent tumor syndromes. The child underwent resection of the adrenal and spinal masses. Pathology revealed a 4.5 cm, 19.5 g adrenocortical tumor with increased mitotic rate, atypical mitoses, and nuclear pleomorphism without necrosis, vascular or capsular invasion or lymph node metastases; in light of the spinal metastasis, the tumor was noted to be a “European Network for the Study of Adrenal Tumors” stage IV adrenocortical carcinoma. The patient was treated postoperatively with adjuvant chemotherapy after which she was apparently cured of her ACC, which did not recur.
Unfortunately, she subsequently developed pelvic osteosarcoma at the age of 12 years, which was refractory to multiple resections and local and systemic therapies, and she ultimately died of that tumor four years later.
Comments. In this study, authors performed WES of an ACC occurring in a pediatric patient initially suspected to have Beckwith-Wiedemann syndrome. The genetic findings (and indeed the patient’s ultimate clinical course) would suggest that the more appropriate diagnosis was likely Li-Fraumeni syndrome. In any case, it was clear that the somatic genetic events in syndromic ACC are likely somewhat distinct from those events that occur in sporadic cases.
They identified a similar overall burden of somatic mutations, with a distinct mutational signature, in the syndromic case. In particular, the tumor carried relatively few Signature 1 mutation (associated with aging) and an unusually high number of Signature 25 mutations (a signature of unknown etiology that has been previously identified in Hodgkin lymphoma cells). Admittedly, the lack of Signature 1 mutations is possibly a consequence of the patient’s young age, rather than the tumor predisposition syndrome per se. Of course, many pediatric cases of ACC are associated with germline predisposition syndromes, so pediatric and syndromic ACC are overlapping categories.
Furthermore, despite the patient’s pathologically advanced disease, she experienced an apparent cure after aggressive treatment, with more than a decade ACC-free, which would be highly unusual in sporadic adult ACC. Indeed, prior reports of pediatric ACC have demonstrated superior survival in tumors presenting in the first few years of life, compared with those presenting in older children or in adults [Pinto EM et al Genomic landscape of paediatric adrenocortical tumors. Nat Commun. 2015;6(1):6302].
These molecular (and clinical) findings may call into question the appropriateness of taking a unique approach for the use of newer therapeutic agents in syndromic compared with sporadic ACC. It may, therefore, be particularly important to separate these patients from sporadic ACC in future studies in the field, as the carcinogenesis and progression of these tumors may likely proceed via different mechanisms than those found in sporadic ACC. Furthermore, an improved understanding of the somatic events leading to tumors, in the setting of germline predisposition disorders, may provide insight for early detection or even prevention of these life-limiting cancers in patients and families suffering from these diseases.

391
58th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE)
Vienna, Austria, September 19–21, 2019.
Novel insights into genetic disorders of growth
Symposium 5.1
Jesús Argente
University Hospital Niño Jesús. Universidad Autónoma de Madrid, Madrid, Spain.
Abstract
Human growth is a very complex phenomenon that is influenced by genetic, hormonal, nutritional and environmental factors from fetal life throughout puberty. Although the GH-IGF axis clearly has a central role in this process, with specific actions on longitudinal growth, numerous other genes are also involved in determining stature. Indeed, genome-wide association studies have identified >600 variants associated with human height, but this still only explains a small fraction of phenotypic variation. Since short stature in childhood is a common reason for clinical referral, pediatric endocrinologists must be aware of the multifactorial and polygenic contributions to height. Multiple disorders characterized by growth failure of prenatal or postnatal onset due to single gene defects have been described. Their early diagnosis, facilitated by advances in genomic technologies, is of utmost importance for their clinical management and to provide genetic counseling. In this conference the current clinical and genetic information and new taxonomic classification regarding isolated GH deficiency, combined pituitary hormone deficiency, GH insensitivity and primary peripheral deficiencies including IGF1, IGFALS, IGF1R, IGF2, and PAPP-A2 was reviewed. In addition, different syndromes with proportionate short stature as the main feature, including syndromes with short stature and microcephaly (Seckel syndrome spectrum disorders –SSSD-, microcephalic osteoplastic primordial dwarfism –types I and II-, 3M syndrome, Meier-Gorlin syndrome) was discussed. Special attention was given to the recently described abnormalities in the genes RNPC3 and PAPP-A2. Two important questions that should be discussed among pediatric endocrinologists and geneticists include: 1) Who should be tested for short stature and genetic alterations? and, 2) What genetic techniques should be used for the best diagnosis? This conference highlighted these questions.
Moreover, a recent publication on this subject by the Conferencist follows:
Front Endocrinol (Lausanne). 2019 Sep 6.
Genetics of Growth Disorders-Which Patients Require Genetic Testing?
Argente J1, Tatton-Brown K2, Lehwalder D3, Pfäffle R4.
1Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III and IMDEA Institute, Madrid, Spain. 2Institute of Cancer Research, St George’s University Hospital NHS Foundation Trust, London and St George’s University of London, London, United Kingdom. 3Global Medical Affairs, Merck Healthcare KGaA, Darmstadt, Germany.4Department of Pediatrics, University of Leipzig, Leipzig, Germany.
Abstract
The second 360° European Meeting on Growth Hormone Disorders, held in Barcelona, Spain, in June 2017, included a session entitled, Pragmatism vs.
Curiosity in Genetic Diagnosis of Growth Disorders, which examined current concepts of genetics and growth in the clinical setting, in terms of both growth failure and overgrowth. For patients with short stature, multiple genes have been identified that result in GH deficiency, which may be isolated or associated with additional pituitary hormone deficiencies, or in growth hormone resistance, primary insulin-like growth factor (IGF) acid-labile subunit deficiency, IGF-I deficiency, IGF-II deficiency, IGF-I resistance, and primary PAPP-A2 deficiency. While genetic causes of short stature were previously thought to primarily be associated with the GH-IGF-I axis, it is now established that multiple genetic anomalies not associated with the GH-IGF-I axis can result in short stature. A number of genetic anomalies have also been shown to be associated with overgrowth, some of which involve the GH-IGF-I axis. In patients with overgrowth in combination with an intellectual disability, two predominant gene families, the epigenetic regulator genes, and PI3K/AKT pathway genes, have now been identified. Specific processes should be followed for decisions on which patients require genetic testing and which genes should be examined for anomalies. The decision to carry out genetic testing should be directed by the clinical process, not merely for research purposes. The intention of genetic testing should be to direct the clinical options for the management of the growth disorder.


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