Volume 17.2

December 2019



In Memoriam:

Hans K. Åkerblom, Professor Emeritus (1934-2019) 

Mikael Knip, MD, PhD, Johanna Vesterinen, D.Sc. (Econ.) 


Ref: Ped. Endocrinol. Rev. 2019;17(2):76-77



For Debate: Programing of the Autoimmune Diabetogenic Response in the Thymus during Fetal and Perinatal Life

Vincent Geenen, MD, PhD, Didier Hober, MD, PhD



The presentation of self-peptides in the thymus is responsible both for negative selection of selfreactive T cells emerging during stochastic TCR recombination in fetal life, as well as positive selection of self-specific regulatory thymic T (tTreg) cells during
and after perinatal life. The combination of these two sequential processes programs central self-tolerance, a
fundamental property of the adaptive immune system. A defect in intrathymic self-presentation, either genetic
or acquired, is the earliest event in the pathogenesis of autoimmunity already during fetal development. This
defect is necessary but not sufficient for the appearance of a classical autoimmune disease like type 1 diabetes
(T1D). Environmental factors are required for activation of the diabetogenic autoimmune response that targets
insulin-secreting β cells in pancreatic Langerhans’ islets. Based on epidemiological studies, viral infections
have been suspected for a long time to be one of those environmental factors. In this Debate article, we present
a series of experimental data that support the hypothesis that, following vertical transplacental transfer, viruses
might infect the fetal thymus and disturb already in utero central self-tolerance orchestrated by this organ.
“It is with logic that we prove but it is with intuition that we discover.” Henri Poincaré (1854-1912)


Ref: Ped. Endocrinol. Rev. 2019;17(2):78-83
doi: 10.17458/per.vol17.2019.gh.fd.autoimmunediabetogenicthymus
Key words: Thymus, Self-tolerance, Autoimmunity, Type 1 diabetes, Fetal and perinatal life, Viruses, Enterovirus,
Coxsackievirus B




Osteoclasts in Health and Disease

Ulf H. Lerner, DDS, PhD



Osteoclasts are multinucleated, giant cells originating from myeloid hematopoetic stem cells. These are the only cells in nature which
can resorb bone. Differentiation of mononucleated osteoclast progenitor cells requires stimulation with M-CSF
(macrophage colony-stimulating factor) for the cells to proliferate and survive and with RANKL (receptor activator
of nuclear factor kappa B ligand) for differentiation along the osteoclastic lineage to cells which eventually fuse to
the mature, multinucleated osteoclasts. Therefore, most hormones and cytokines stimulating osteoclastogenesis do
so indirectly by regulating the expression in osteoblasts of RANKL and its inhibitory decoy receptor OPG. Antibodies neutralizing RANKL is a common therapy to inhibit excessive osteoclast formation in diseases such as osteoporosis and malignant tumors with skeletal
metastasis. Mature osteoclasts resorb bone by stimulating acid release into the resorption lacunae, followed by
proteolytic degradation of bone matrix proteins. Loss-offunction mutations of proteins involved in acidification and
proteolysis cause osteopetrosis, a disease with sclerotic bone due to non-functional osteoclasts. Osteoclasts are
important for a healthy skeleton by removing damaged bone during remodeling of the skeleton, but are also
important for modeling of bone, calcium homeostasis and tooth eruption, and possibly also for glucose and
fat metabolism. Loss of bone in inflammatory disease, metastasizing tumors and osteoporosis is due to increased
RANKL expression and enhanced osteoclast formation. The present overview aims to summarize how osteoclasts are
formed and resorb bone in health and disease. 


Ref: Ped. Endocrinol. Rev. 2019;17(2):88-99
doi: 10.17458/per.vol17.2019.l.osteoclastshealthdisease
Key words: Osteoclast, Bone resorption, RANKL, Osteoporosis, Rheumatoid arthritis



Pediatric Cushing Syndrome; an Overview

Christina Tatsi, MD, PhD, Constantine A. Stratakis, MD, D (Med)Sc



Endogenous Cushing syndrome (CS) is a rare entity in the pediatric population. Patients usually present with height deceleration and continuous weight gain, along with other classic stigmata of CS, such as acne, striae, hirsutism and others. The diagnosis of CS
involves documentation of abnormal cortisol secretion with measurement of urinary free cortisol and midnight serum
or salivary cortisol, and the use of the 1mg dexamethasone suppression test. After confirmation of CS, localization of
the source of hypercortisolemia, involves differentiation of ACTH-dependent versus ACTH-independent causes of
CS. Surgical resection of the identified source of CS is the preferred method of treatment whenever possible.


Ref: Ped. Endocrinol. Rev. 2019;17(2):100-109
doi: 10.17458/per.vol17.2019.ts.pediatriccushingsyndrome
Key words: Cushing, Children, Pituitary adenoma, Adrenal




Endocrine Management of Ovotesticular DSD, an Index Case and Review of the Literature

Marissa J. Kilberg, MD, Michelle McLoughlin, MSN, CRNP, CPNP-AC, Louisa C. Pyle, MD, PhD, Maria G Vogiatzi, MD



Ovotesticular Differences in Sexual Development (OT-DSD) is a rare subset of DSD with great phenotypic variability characterized by the
presence of both testicular and ovarian tissue in the same individual. Here, we describe the case of 46,XX, SRYnegative
baby with ambiguous genitalia and ovotestis discovered during laparoscopy. As the family decided on female gender of rearing, the testicular component of the ovotestis was removed while the ovarian component was preserved. Stemming from this case, we review the
clinical presentation of OT-DSD throughout ages, the role of genetics and risk for gonadal tumors when making
decisions about prophylactic gonadectomy. Finally, we summarize the most recent information of the spontaneous
endocrine function, with or without conservative therapy, and fertility potential of people with OT-DSD.


Ref: Ped. Endocrinol. Rev. 2019;17(2):110-116
doi: 10.17458/per.vol17.2019.kmv.endocrineovotesticulardsd
Key words: Ovotestis, Puberty, Fertility, Gonadectomy, Gonadoblastoma


Primary School Performance of Girls with Turner Syndrome: A Transcultural Assessment

Jan Lebl, MD, PhD, Rasha Tarif Hamza, MD, PhD, Judith Stoklasova, MD, Jirina Zapletalova, MD, PhD, Stanislava Kolouskova, MD, PhD, Ondrej Soucek, MD, PhD, Barbora Obermannova, MD, PhD, Marta Snajderova, MD, PhD, Shenali Anne Amaratunga, MD, Zdenek Sumnik, MD, PhD, Marketa Pavlikova, Mgr, Stepanka Pruhova, MD, PhD


Objectives: We analyzed primary school performance of girls with Turner syndrome (TS) in two distinct countries to ascertain if the cognitive phenotype of TS causes selective learning difficulties. Methods: The cohort comprised of 44 Czech and 50 Egyptian girls with TS who attended public schools. School reports from grades 1 to 9 were obtained retrospectively from Czech participants with TS. Only recent school reports were obtained from Egyptian participants. Two controls per participant were requested - biological sisters
and/or female classmates. The results were converted into a 5-point scale (1-excellent; 5-unsatisfactory). Results: Analysis of longitudinal Czech data displayed a strong time component in both subjects and controls. Showing better points in lower grades with its gradual
worsening as the education complexity increased. In contrast, there was a strong statistically significant difference between groups in Mathematics (p=0.0041, p=0.0205 after Bonferroni correction) and this difference increased over time. The points for Mathematics did not differ in grades 1+2 (0.05 difference in mean grade between the two groups), however, they differed by 0.28 in grades
6+7 and by 0.32 in grades 8+9. While slightly different in character (cross-sectional vs. longitudinal), the Egyptian
cohort data confirmed our findings, showing no difference in general school performance but having similar trends in
Mathematics (grades 1+2: 0.11, grades 6+7: 0.54, grades 8+9: 0.68; p=0.0058, p=0.029 after Bonferroni correction).
Conclusion: Excluding results in Mathematics, which showed pronounced worsening in relation to age in comparison with
unaffected controls, girls with TS performed similarly to their controls.

Ref: Ped. Endocrinol. Rev. 2019;17(2):117-124
doi: 10.17458/per.vol17.2019.lhs.gilrsturnersyndrome
Key words: Turner syndrome, Primary school, School performance, Cognitive phenotype, Learning disability

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Pediatric Endocrinology Reviews (PER) is the most respected international peer reviewed journal in Pediatric Diabetes, Nutrition Metabolism and Genetics. Hypothyriodism, Hyperthyriodism, Glycemic Management for Children with Diabetes Glucose Monitoring Adrenal Insufficiency Turner Syndrome Late Adolescence Klinefelter Syndrome Children with Short Stature and Growth Failure: Heightism Type 1 Diabetes in Children Growth Hormone Treatment for GHD Insulin-like Growth Factor-I Growth Hormone Deficiency SGA Children with Short Stature Receiving GH Treatment Hypothalamic Obesity Adolescent Gynecomastia Hematospermia in Adolescents Gain-of-Function CDKN1C Mutations Craniopharyngioma Succinate-Dehydrogenase Deficient Paragangliomas/Pheochromocytomas Adrenal Steroidogenesis: Impact on Gonadal Function Focal Congenital Hyperinsulinism (CHI)  Longevity Hormone Klotho Pediatric Congenital Hypothyroid Lysosomal Storage Diseases Juvenile NCL (CLN3 Disease) GM1 and GM2 Gangliosidoses Types A and B Niemann-Pick Disease CLN2 Disease (Classic Late Infantile Neuronal Ceroid Lipofuscinosis) Krabbe Disease Fucosidosis Nuclear Factor Kappa B (NF-κB) in Growth Plate Chondrogenesis Persistent Müllerian Duct Syndrome LHX4 Gene Alterations Stunted Growth 45,X/46,XY Gonadal Dysgenesis Thyroid Hemiagenesis Nutrimetabolomics and Adipocitokines Chromosomal Microarray Analysis (CMA) Chromosomal microarray, Copy Number Variant (CNV), Prenatal, Amniocentesis, Comparative genomic hybridization, SNP array, Diagnosis, Clinical Abreviations: aCGH – array-based comparative genomic hybridization, ASD – autism spectrum disorder, BAC – bacterial artificial chromosome, CHD – congenital heart disease, CMA – chromosomal microarray analysis, CNV – copy number variant, CVS – chorionic villus sampling, DD – developmental delay, DNA – deoxyribonucleic acid, FISH – fluorescent in situ hybridization, GABA - gammaaminobutyric acid, ID – intellectual disability, LOH – loss of heterozygosity, NGS – next generation sequencing, NIPT – noninvasive prenatal testing, NOS – not otherwise specified, PGD - preimplantation genetic diagnosis, SNP – single nucleotide polymorphism, VUS – variant of unclear clinical significance Central precocious puberty, Traumatic brain injury, Pathophysiology Nephrolithiasis, Nephrocalcinosis, Hypercalciuria, Hyperoxaluria, Hypouricemia, Cystinuria, Genetics