Edition 71 - December 2018 / Bibliographic Reviews

Bibliographic Reviews – Ed. 71

Marco A. Rivarola y Alicia Belgorosky. Servicio de Endocrinología, Hospital de Pediatría Garrahan, Buenos Aires, Argentina. 

For the present Bibliographic Reviews we have selected one Meet the Expert abstract and some Free Communications from the 57th European Society for Paediatric Endocrinology, Annual Meeting, which convened in Athens. Greece, September 2018.

Additionally, we are transcribing the abstract of a recent publication in the J Endocrinol, proposing an interesting stimulating effect of leptin on the aromatase expression in the rat growth plate, limiting catch-up growth efficiency.



Gonadal Function in Congenital Adrenal Hyperplasia (CAH).
Hedi Claahsen – van der Grinten E.
Radboud University, NIjmegen Medical Centre, Nijmegen, Netherlands

Abstract: Congenital adrenal hyperplasia (CAH) is a group of rare congenital disorders of the adrenal cortex due to a defect in one of the enzymes involved in steroid synthesis leading to cortisol deficiency and overproduction of adrenal androgens. In the most severe forms CAH is a life threatening disease due to the risk of Addisonian and salt wasting crisis. In the last 50 years diagnostics and treatment improved significantly. Patients are treated with lifelong replacement of glucocorticoids and, in aldosterone deficieny, also mineralocorticoids. Nowadays, most children reach puberty and adulthood without severe complications and a good quality of life. Therefore, long term complications of CAH become more important also for pediatric endocrinologist as some of these complications may have their origin already in childhood. One of the most severe complications in adult male and female CAH patients is infertility due to primary (hypergonadotropic) or secondary (hypogonadotropic) gonadal dysfunction. The most important cause of infertility in male CAH patients is the presence of testicular adrenal rest tumours (TART) leading to obstruction of the seminiferous tubule and obstructive azoospermia. Longstanding TART can lead to irreversible damage of testicular tissue. This complication already occurs during childhood and puberty. Another important factor contributing to infertility is the suppression of the hypothalamic-pituitary-gonadal axis due to high circulating levels of androgens resulting in secondary gonadal failure. In female CAH patients fertility can be impaired due to adrenal overproduction of androgens and progestins (17-hydroxyprogesterone and progesterone), ovarian hyperandrogenism (polycystic ovary syndrome), ovarian adrenal rest tumors, genital surgery, and psychological factors such as delayed psychosexual development and reduced sexual activity. In this expert meeting, the speaker discussed different causes of gonadal dysfunction in male and female CAH patients with a special focus on their occurrence during adolescence.




Monogenic and Digenic Gene Mutations are Present in Children with Idiopathic Short Stature (ISS).
Nora María Sanguinetia, Laura Ramıíreza, Ana Claudia Keselmana,
Paula Alejandra Scagliaa, María Gabriela Ropelatoa, María Gabriela Ballerinia, Liliana Karabatasa, Sabina Domenéa, Lucía Martuccia, Débora Braslavskya, Estefania Landia, Hamilton Cassinellia, Bárbara Casalia, Graciela Del ReyaPatricia Pennisia, Héctor Jaspera, Martín Vázquezb, Rodolfo Reya, Horacio Domenéa, Mariana Gutiérreza, Ignacio Bergadáa.

aCentro de Investigaciones Endocrinológicas ‘Dr. César Bergadá’ (CEDIE) CONICET – FEI – División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina; bInstituto de Agrobiotecnología de Rosario (INDEAR), CONICET, Rosario, Argentina

BACKGROUND: Several genetic defects (GHR, SHOX, GHSR, NPR2, IGFALS) have been reported in children classified as ISS. ISS children are GH sufficient and about one third of them show low IGF-I levels, suggesting some degree of GH insensitivity. OBJECTIVE: To explore potential genetic defects in ISS children suspicious of GH insensitivity, selected by low IGF-I levels and low response to IGF generation test. Subjects and Methods: Levels of IGF-I, IGFBP-3, and ALS were determined in 42 ISS children (34 males; 2.1–9.4 years old, height < -2.5 S.D., stimulated GH >4.8 mg/l). Those presenting IGF-I


Molecular Characterization of TNXA/TNXB Chimeras in CYP21A2 Gene Deletions: High Frequency of Undiagnosed Ehlers-Danlos Syndrome in Congenital Adrenal Hyperplasia Patients.
Roxana Marino, Guillermo Notaristéfano, Natalia Pérez Garrido,  Pablo Ramirez, Maria Sol Touzon, Matías Pujana, Angélica Moresco,  Gabriela Finkielstain, Gabriela Obregón, Marco A Rivarola, Alicia Belgorosky. Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.

The contiguous gene deletion syndrome, CAH-X, was reported in an 8.5% of Congenital Adrenal Hyperplasia (CAH) patients with a TNXA/TNXB chimera. This results in deletions of CYP21A2 gene, encoding 21-hydroxylase necessary for cortisol biosynthesis, and TNXB, encoding the extracellular matrix glycoprotein tenascin-X (TNX). There are three TNXA/TNXB chimeras (CH1, CH2, CH3) that differ in the junction site, resulting in TNXB haplo-insufficiency or dominant negative effect and an Ehlers Danlos Syndrome (EDS) phenotype. Recently, it has been described a biallelic form of CAH-X syndrome.
The aim of this study was to analyze copy number variations and genetic status of TNXB gene in 58 CAH patients due to CYP21A2 deletion, to determine the frequency of TNXB alterations in our population. A total of 58 unrelated CAH patient carriers of CYP21A2 gene deletion (65 alleles) were screened for TNXB defects. All the patients were analyzed for the presence of CH1 by MLPA technique evidenced by a 120 bp deletion in TNXB exon 35, and confirmed by exon 35 Sanger sequencing. In addition, all of them were screened for other TNXB alterations related to CH2 and CH3 by exon 40, 41 and 43 Sanger sequencing. Results: The presence of TNXB deletion due to CH1 was found in 28/65 (43%) alleles carriers of CYP21A2 gene deletion. Moreover, when they analyzed the presence of other chimeras (CH2 and CH3) 47/65 (75%) alleles were found to carry a contiguous deletion that extended into the TNXB gene. Of 58 patients evaluated for copy number variations, haplo-insufficiency of TNXB was found in 39 patients, two patients were homozygous for CH1 (biallelic form) and two patients were compound heterozygous for CH1 and CH2 (biallelic form).
Conclusion: A high frequency of TNXB alterations was found in CYP21A2 deletion carrier alleles in this population. MLPA and Sanger sequencing techniques resulted useful to characterize TNXB deletion. Accurate genotype-phenotype correlation remains to be elucidated in this cohort. Nevertheless, based on the high frequency of TNXB alterations in CYP21A2 deletion carrier alleles found in this study, it is recommended to evaluate TNXB status in these patients, warranting assessment of connective tissue dysplasia, including cardiologic alterations in positive cases.


Improved Mental and Motor Development During 3 Years of GH Treatment in Very Young Children with Prader-Willi Syndrome.
Stephany Donzea,b, Layla Damena,b, Eva Mahabiera,b, Anita Hokken-Koelegaa,b aDutch Growth Research Foundation, Rotterdam, Netherlands;
bErasmus University Medical Center-Sophia Children’s Hospital, Rotterdam, Netherlands

Context: Infants and toddlers with Prader-Willi Syndrome (PWS) have a mental and motor developmental delay. Short-term data suggest a positive effect of growth hormone (GH) on mental and motor development in infants and children with PWS. There are, however, no longer-term results about the effects of GH treatment on mental and motor development. Objective: To investigate the longer-term effects of GH on psychomotor development in infants and toddlers with PWS and the effect of age at start of GH treatment on psychomotor development. Methods: Prospective cohort study in 63 young children with PWS. All patients were naıve to GH treatment at time of enrolment and started GH in a dose of 1 mg/m2/day (z0.035 mg/kg/day). Main outcome measures were mental and motor.
Developmental age assessed with Bayleys Scales of Infant Development II (BSID-II) and expressed as % of the expected development (100%). Results: Thirthy-five boys and 28 girls participated in the evaluation of psychomotor development. GH treatment was started at a median (IQR) age of 1.0 year (0.7-1.6). During 3 years of GH, mean (SEM) mental development increased from 58.1% (2.8) at baseline to 79.6% (3.7), and motor development from 41.9% (2.9) to 78.2% (3.9; both P!0.01). In spite of this improvement, the average mental and motor development after 3 years of GH was still significantly lower compared to healthy references (both P<0.001). A lower baseline psychomotor development and a younger age at start of GH treatment were associated with a higher increase in mental and motor development (all P<0.01). Conclusion: Mental and motor development increased significantly during 3 years of GH treatment, reducing the gap between infants with PWS and healthy peers. Infants with a lower baseline psychomotor development advanced more than infants with a higher baseline psychomotor development. Currently, the increased awareness of PWS and the improved genetic tests have made it possible to diagnose PWS during early infancy. As starting GH treatment at a younger age results in a better psychomotor development, we nowadays start GH treatment in very young infants with PWS.


Identification of ADAMTS6 as a Novel Candidate Gene for Idiopathic Short Stature with Advanced Bone Maturation
Diana M. Warman, Pablo Ramirez, Roxana Marino, Natalia Perez Garrido, Maria Sol Touzon, Matias Pujana Pentreath, Maria Celeste Mattone, Marco Rivarola, Alicia Belgorosky.
Hospital Garrahan, Buenos Aires, Argentina.

Aggrecan (ACAN) is the major proteoglycan in the articular cartilage, critical for the structure and function of the growth plate cartilage. Case Report: 11-year-old (y) boy admitted at 1.8 y of chronological age (CA), due to poor growth rate. Height (H): 76 cm (



Induction of Pancreatic Beta-Cell Neogenesis.
Patrick Collombat
INSERM, Nice, France

BACKGROUND: The recent discovery that genetically-modified pancreatic alpha-cells can regenerate and convert into beta-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. RESULTS: Authors recently identified GABA as an inducer of alpha-to-beta-like cell conversion in vivo. This conversion induces alpha-cell replacement mechanisms through the mobilization of duct-lining precursor cells that adopt an alpha-cell identity prior to being converted into beta-like cells, solely upon sustained GABA exposure. Importantly, these neo-generated beta-like cells are functional and can repeatedly reverse chemically-induced diabetes in vivo. Similarly, the treatment of transplanted human islets with GABA results in a loss of alpha-cells and a concomitant increase in beta-like cell counts, suggestive of alpha-to-beta-like cell conversion processes also in humans. The latest advances were discussed. CONCLUSIONS: This newly discovered GABA-induced alpha-cell-mediated beta-like cell neogenesis could therefore represent an unprecedented hope towards improved therapies for diabetes.



SHOX – From Gene to Growth Plate
Gudrun Rappold. Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
SHOX deficiency is the most frequent genetic growth disorder associated with isolated and syndromic forms of short stature. Caused by mutations in the homeobox gene SHOX, its varied clinical manifestations include isolated short stature, Leri-Weill dyschondrosteosis, and Langer mesomelic dysplasia. In addition, SHOX deficiency contributes to the skeletal features in Turner syndrome. Causative SHOX mutations have allowed downstream pathology to be linked to defined molecular lesions. Expression levels of SHOX are tightly regulated, and almost half of pathogenic mutations have affected enhancers. Clinical severity of SHOX deficiency varies between genders and ranges from normal stature to profound mesomelic skeletal dysplasia. Zebrafish and chicken animal models together with micromass cultures and primary cell lines have been used to address SHOX function. Pathway and network analysis have identified interacting molecules, target genes, and regulators. SHOX is one of several critical factors regulating chondrocyte hypertrophy and chondrocyte maturation in the growth plate. Two decades of research support the concept of SHOX as a transcription factor that integrates diverse aspects of bone development, growth plate biology, and apoptosis.



J Endocrinol. 2018 Jun; 237(3):229-242.
Leptin Stimulates Aromatase in the Growth Plate: Limiting Catch-up Growth Efficiency. Masarwi M1,2Shamir R1,2,3Phillip M1,2,4Gat-Yablonski G5,2,4.
1Sackler Faculty of MedicineTel Aviv University, Tel Aviv, Israel. 2Felsenstein Medical Research CenterPetach Tikva, Israel, 3Institute of Gastroenterology Nutrition and Liver Diseases, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel. 4The Jesse Z and Sara Lea Shafer Institute for Endocrinology and DiabetesNational Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel. 5Sackler Faculty of MedicineTel Aviv University, Tel Aviv, Israel

Catch-up growth (CUG) in childhood is defined as periods of growth acceleration, after the resolution of growth attenuation causes, bringing the children back to their original growth trajectory. Sometimes, however, CUG is incomplete, leading to permanent growth deficit and short stature. The aim of this study was to investigate the mechanisms that limit nutritional-CUG. Specifically, we focused on the crosstalk between leptin, increased by re-feeding, and sex hormones, which increase with age. In vivo studies were performed in young male Sprague Dawley rats fed ad libitum or subjected to 10/36 days of 40% food restriction followed by 90-120 days of re-feeding. In vitro studies were performed on ATDC5 cells. Analyses of mRNA and protein levels were done using qPCR and Western blot, respectively. CUG was complete in body weight and humerus length in animals that were food-restricted for 10 days but not for those food-restricted for 36 days. In vitro studies showed that leptin significantly increased aromatase gene expression and protein level as well as the expression of estrogen and leptin receptors in a dose- and time-dependent manner. The effect of leptin on aromatase was direct and was mediated through the MAPK/Erk, STAT3 and PI3K pathways. The crosstalk between leptin and aromatase in the growth plate suggests that re-feeding during puberty may lead to increased estrogen level and activity, and consequently, irreversible premature epiphyseal growth plate closure. These results may have important implications for the development of novel treatment strategies for short stature in children.

Posted in Edition 71 - December 2018, Bibliographic Reviews
Previous Editions
Instructivo para mandar imágenes
RSS Feed