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Volume 13.4

June 2016


Finding a Needle in a Haystack: the Advantages of Liquid Chromatography - Tandem Mass Spectrometry (LC-MS/MS) in Determination of Sex Hormones in Children

Shira Hirsh, PhD, Anat Ben-Dor, PhD



Determination of steroid sex hormones concentrations in children is very important for diagnosis of a wide range of pubertal, adrenal and sex development disorders. The majority of hormone measurements are carried out using traditional immunoassays, due to their technical simplicity, cost and availability of commercial reagents. But, due to limited specificity and sensitivity, traditional immunoassays often fail to determine low concentration analytes such as sex hormones in pediatric blood. In the last decade, the LC-MS/MS assay has risen as a new player in the analytic diagnostic field. The assay has proven appropriate for detection of very low hormones concentrations in blood, is quite easy to perform and can detect multiple steroids from a single sample. For the routine determination of an individual or panel of steroids, LC–MS/MS is now the recommended method for most diagnostic laboratories.


Ref: Ped. Endocrinol. Rev. 2016;13(4):714-719

Key words: Tandem mass spectrometry, Sex hormones, Hormone determination, Assay's specificity



Role of Nuclear Factor Kappa B (NF-κB) in Growth Plate Chondrogenesis

Francesco De Luca, MD



Nuclear Factor kappa B (NF-κB) is a group of seven transcription factors. Upon activation by a variety of stimuli, NF-κB translocates to the nucleus and modulates the expression of target genes involved in cell growth, survival, and death.

Previous evidence indicates that NF-κB regulates bone growth and development. We have shown that the NF-κB p65 is expressed in the growth plate and facilitates longitudinal bone growth by inducing chondrocyte proliferation and differentiation and by preventing apoptosis. Furthermore, we have demonstrated in rodents that NF-κB expressed in growth plate chondrocytes mediates the promoting effects of GH and IGF-1 on longitudinal bone growth and growth plate chondrogenesis. Lastly, functional studies carried out in two children with growth failure and GH insensitivity, and affected by two different mutations impairing NF-κB activation, indicate that NF-κB also mediates the growth-promoting effects of GH in humans.


Ref: Ped. Endocrinol. Rev. 2016;13(4):720-730

Key words: NF-κB, Growth plate, Chondrogenesis


Persistent Müllerian Duct Syndrome Caused by a Novel Mutation of an Anti- Müllerian Hormone Receptor Gene: Case Presentation and Literature Review

Ghadir Elias-Assad, MD, Marwan Elias, MD, Hannah Kanety, PhD, Asher Pressman, MD, Yardena Tenenbaum-Rakover, MD




Persistent Müllerian duct syndrome (PMDS) is a rare genetic disorder of male internal sexual development defined as lack of regression of Müllerian derivatives in the 46XY male with normally virilized external genitalia and unilateral or bilateral cryptorchidism. Approximately 85% of all cases are caused by mutations in genes encoding anti-Müllerian hormone (AMH) or its receptor (AMHR2) with autosomal recessive transmission. This condition is frequently diagnosed incidentally, during surgical repair of inguinal hernia or cryptorchidism. There is no consensus on surgical approach: malignancy risk in the Müllerian duct remnant or undescended testis encourages early removal of the former and bilateral orchiopexy; however, removal of Müllerian structures can impair testicular and vas deferens blood supply, potentially causing infertility. Herein, we report on a male infant with PMDS caused by a novel homozygous missense mutation in AMHR2 (c.928C>T; p.Q310X), review the literature, and discuss the diverse clinical and surgical approaches to this condition.


Ref: Ped. Endocrinol. Rev. 2016;13(4):731-740

Key words: Persistent Müllerian Duct Syndrome (PMDS), Anti- Müllerian Hormone (AMH), AMH Receptor (AMHR)


Polymorphism of the IGF-I System and Sports Performance

Sigal Ben-Zaken, PhD, Yoav Meckel, PhD, Dan Nemet2, MD, Nitzan Dror, MD, Alon Eliakim, MD



The potential use genetic polymorphism, and in particularly polymorphism of hormone genes, as a tool to predict athletic performance is currently very challenging. Recent studies suggest that single nucleotide polymorphisms in IGF-I and myostatin may be beneficial for endurance and short distance running, and may even be associated with elite performance. Polymorphism in IGF-I receptor may differentiate between the two edges of the endurance-power athletic performance running spectrum suggesting beneficial effects for endurance and prevent from success in power events. In contrast, and despite similar metabolic demands, the myostatin-IGF-I-IGF-IR system seems not to play an important role in swimming excellence. This suggests that combining different sport disciplines for sports genetic research purposes should be done with extreme caution. Finally, since any phenotype reflects a complex relationship between genes, environment, epigenetic factors, and the interactions between them, consulting the young athlete regarding future success cannot be based solely on genetic polymorphism.


Ref: Ped. Endocrinol. Rev. 2016;13(4):741-748

Key words: IGF, IGF receptor, Myostatin, Single nucleotide polymorphism, Sport


LHX4 Gene Alterations: Patient Report and Review of the Literature

Zoran Gucev, MD, PhD, Velibor Tasic, MD, PhD, Dijana Plaseska-Karanfilska, MD, PhD, Marina Krstevska Konstantinova, MD, PhD, Ana Stamatova, MD, Marija Dimishkovska, BA, Nevenka Laban, MD, PhD, Momir Polenakovic, MD, PhD



LHX4 mutations are rare in combined pituitary hormone deficiency, and even rarer in isolated GHD. We describe a 14 years old boy who was referred for investigation of short stature. Convergent strabismus, nystagmus was present. At the age of 5 years his gait was unstable. A progressive myopathy ensued. Tests of pituitary reserve showed partial IGHD (8.2 ng/ml). Other pituitary hormones were within normal range. Muscle biopsy showed congenital myopathy of undefined etiology. MRI of the brain revealed the empty sella syndrome. Targeted resequencing with a panel containing probe sets for enrichment and analysis of >4,800 clinically relevant genes, targeting 12Mb of the human genome revealed the c.250C>T (R84C) LHX4 mutation. His father is healthy, with no myopathy or pituitary deficiencies, but has the same LHX4 mutation. This report extends the range of phenotypes associated with LHX4 gene mutations. To the best of our knowledge, we are the first to report on congenital myopathy in an LHX4 gene mutation. Forthwith, we offer a comprehensive review of the patients published so far with their clinical and genetic characteristics.


Ref: Ped. Endocrinol. Rev. 2016;13(4):749-755

Key words: LHX4 mutation, Familial, Isolated growth hormone deficiency, Congenital myopathy, Empty sella


Stunted Growth. Proceedings of the 23rd Aschauer Soiree, Held at Aschauhof, Germany, November 7th 2015

Michael Hermanussen, MD, PhD, Josefin Ipsen, Rebekka Mumm, Christian Aßmann, PhD, Julia Quitmann5, PhD, Aleksandra Gomula, PhD, Andreas Lehmann, Isabelle Jasch, Vincent Tassenaar, PhD, Barry Bogin, PhD, Takashi Satake, PhD, Christiane Scheffler, PhD, Javier Núñez, PhD, Elena Godina, PhD, Rüdiger Hardeland, PhD, Jesper Boldsen, PhD, Mortada El-Shabrawi, MD, PhD, Mona Elhusseini, MD, PhD, Carmen Gabriela Barbu, MD, PhD, Ralucca Pop, MD, Jani Söderhäll, Andrea Merker, MD, James Swanson, PhD, Detlef Groth, PhD



Twenty-four scientists met at Aschauhof, Altenhof, Germany, to discuss the associations between child growth and development, and nutrition, health, environment and psychology. Meta-analyses of body height, height variability and household inequality, in historic and modern growth studies published since 1794, highlighting the enormously flexible patterns of child and adolescent height and weight increments throughout history which do not only depend on genetics, prenatal development, nutrition, health, and economic circumstances, but reflect social interactions. A Quality of Life in Short Stature Youth Questionnaire was presented to cross-culturally assess health-related quality of life in children. Changes of child body proportions in recent history, the relation between height and longevity in historic Dutch samples and also measures of body height in skeletal remains belonged to the topics of this meeting. Bayesian approaches and Monte Carlo simulations offer new statistical tools for the study of human growth.


Ref: Ped. Endocrinol. Rev. 2016;13(4):756-767

Key words: Adolescent growth, Peer group, Growth hormone, Community effect, Body height





The 49th Annual Meeting of the Japanese Society for Pediatric Endocrinology (JSPE), Funabori (Tokyo), Japan, 8-10 October, 2015

Tatsuhiko Urakami, MD


Ref: Ped. Endocrinol. Rev. 2016;13(4):768-769

Key words: Pediatric Endocrinology, Annual meeting 2015, JSPE, Year Book, English Session, Growth-promoting therapy, Congenital hypothyroidism, Neonatal screening, Ad4BP (NR5A1) , MIRAGE syndrome, Autoimmune endocrine disease, Type 1 diabetes


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