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Volume 13.1

September 2015


For Debate: Bone Age Estimation for Whom by Whom? By Which Method?

Zvi Laron, MD, PhD (h.c.)



Bone (skeletal) age determination is the simplest and most used index for the assessment of developmental and physiological age in healthy children and those with growth disorders. At present the test is done by manual or automated reading of the hand and wrist X-rays, necessitating two visits by the child: to the pediatrician and radiology departments. A newly developed simple quantitative ultrasound technique (QUST) using several hand and wrist bones, which can be performed in the pediatrician’s office could combine the child’s growth and biological age evaluation in one visit.


Ref: Ped. Endocrinol. Rev. 2015;13(1):444-447

Key words: Growth, Bone (skeletal) age, Bone age/ Chronological age ration, Methods of bone age determination, Developmental age, Physiological age


Chromosomal Microarray Analysis (CMA) a Clinical Diagnostic Tool in the Prenatal and Postnatal Settings

Nurit Assia Batzir, MD, Mordechai Shohat, MD, Idit Maya, MD



Chromosomal microarray analysis (CMA) is a technology used for the detection of clinically-significant microdeletions or duplications, with a high sensitivity for submicroscopic aberrations. It is able to detect changes as small as 5-10Kb in size – a resolution up to 1000 times higher than that of conventional karyotyping. CMA is used for uncovering copy number variants (CNVs) thought to play an important role in the pathogenesis of a variety of disorders, primarily neurodevelopmental disorders and congenital anomalies. CMA may be applied in the prenatal or postnatal setting, with unique benefits and limitations in each setting. The growing use of CMA makes it essential for practicing physicians to understand the principles of this technology and be aware of its powers and limitations.


Ref: Ped. Endocrinol. Rev. 2015;13(1):448-454


Key words: 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


Association of Turner Syndrome and Growth Hormone Deficiency: A Review

Jorge Sales Marques, MD, Sónia Aires, MD



Turner syndrome (TS) is an important cause of short stature in girls. Patients with TS most often do not have growth

hormone deficiency (GHD). Testing GH secretion is not indicated despite the presence of short stature. In the last 20 years only three cases were reported with this association in Pubmed. We describe a case of an 11 year old girl with short stature and karyotype confirmed TS: 45,X(16)46,X,i(X)(q10)(13). Because her growth velocity was low (-3 SD), we evaluated the GH response with stimulating tests and the results were under the normal range. These findings were

compatible with GHD. It is important to check for GHD in patients with TS whenever the growth velocity is low for age and sex.


Ref: Ped. Endocrinol. Rev. 2015;13(1):455-457

Key words: Turner syndrome, Growth hormone deficiency, Growth velocity


Precocious Puberty Following Traumatic Brain Injury in Early Childhood: A Review of the Literature

Vincenzo De Sanctis, MD, Ashraf T. Soliman, MD, PhD, FRCP, Heba Elsedfy, MD, Nada A. Soliman, MD, Rania Elalaily, MD, Mohamed El Kholy, MD



Aims of the review: The intent of the current manuscript is to review the cases of central precocious puberty (CPP) in early childhood following traumatic brain injury (TBI). Search of the literature: The MEDLINE database was accessed through PubMed in April 2015. Results were not restricted to the date and language of the articles. For the first search we utilized MeSH terms “precocious puberty” in conjunction with “traumatic brain injury” and with “endocrine consequences”. Reference lists were reviewed and relevant papers were also consulted to find additional studies and data. In selected cases the corresponding author was contacted by email. Results: In our systematic review, only a few case reports or small case series have highlighted a link between TBI and hypothalamic-pituitary hormone abnormalities.

Fourteen reported children were females and 8 were males. The majority of patients reported had severe TBI, assessed by Glasgow Coma Scale or structural injury (skull fractures, intracranial hemorrhage or cerebral injury) reported on computerized tomography or magnetic resonance imaging scans. The pathogenic mechanism of precocious puberty has not yet been determined. An increased pressure on the hypothalamic-pituitary area with loss of normal childhood hypothalamic inhibition of pituitary gonadotropins could be one of the factors responsible for CPP after TBI.

Conclusions: The current review highlights the importance of close clinical follow-up to evaluate the rate of linear growth and pubertal development after TBI. Although, precocious puberty appears to be rare after TBI, prevalence should ideally be assessed by longitudinal follow-up of a large population. Therefore, further multicenter and multidisciplinary studies are required to explore in detail the true incidence and the possible mechanisms of CPP after TBI. Because precocious puberty can be detected on clinical assessment during childhood, a pragmatic approach would be for family physicians to monitor growth and development in children after TBI. Inasmuch as precocity is mediated through the hypothalamic-pituitary pathways, use of LH-RH analogue therapy should be effective in arresting pubertal progression.


Ref: Ped. Endocrinol. Rev. 2015;13(1):458-464

Key words: Central precocious puberty, Traumatic brain injury, Pathophysiology


Should Patients with Trichorhinophalangeal yndrome be Tested for Growth Hormone Deficiency?

Jorge Sales Marques, MD, Catarina Maia, MD, Raquel Almeida, MD, Lara Isidoro, MD, Catarina Dias, MD



Type 1 Trichorhinophalangeal syndrome (TRPS) is characterized by typical facial and skeletal abnormalities. These patients frequently exhibit short stature; however, only one case with growth hormone (GH) deficiency can be found in the literature. Our patient is a 10-year-old girl with two novel nonsense pathogenic mutations in the TRPS1 gene, both in heterozygosity: c.1198C>T (p. Gln400X) and c.2086C>T (p. Arg696X). She has an additional GH deficiency. The patient is short in stature, with a growth velocity of 1.5 cm per year (SDS – 4.07), a bone age of 4.5 years, and she shows no response to the GH stimulation tests. According to a previous report of an identical case, catch-up growth will occur after beginning GH treatment. We believe that GH stimulation tests should be performed on patients with TRPS1 exhibiting a growth velocity below the normal range expected for their age and sex. If the result is subnormal, then GH therapy should be attempted.


Ref: Ped. Endocrinol. Rev. 2015;13(1):465-467

Key words: Growth hormone deficiency, Type 1 Trichorhinophalangeal Syndrome


Nephrolithiasis and Nephrocalcinosis in Children – Metabolic and Genetic Factors

Velibor Tasic, MD, PhD, Zoran Gucev, MD, PhD



Diagnosis and management of pediatric nephrolithiasis/ nephrocalcinosis is a very complex and challenging task for every pediatrician. It is based on correct disease history taking, which may guide to the mode of inheritance (dominant, recessive, x-linked). Ethnicity and consanguinity should also be investigated since they predispose to high prevalence of certain disorders. One should always begin with cheap and available screening tests. Herein we will review clinical, biochemical, metabolic and genetic characteristics of the inherited diseases which lead to nephrolithiasis/nephrocalcinosis, such as: idiopathic hypercalciuria, renal hypophosphatemia, renal tubular acidosis, idiopathic infantile hypercalcemia, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, hypocitraturia, cystinuria, primary hyperoxaluria and renal hypouricemia. Modern genetic techniques such as next generation sequencing enable nowadays diagnosis of rare disease using only a blood

sample, trough massive parallel resequencing of many genes. This is very helpful for anuric patients or on dialysis

where blood and urine biochemistry are not informative. Genetic testing also replaces invasive liver biopsy or unpleasant acidification tests and enables prenatal or early postnatal diagnosis.


Ref: Ped. Endocrinol. Rev. 2015;13(1):468-476

Key words: Nephrolithiasis, Nephrocalcinosis, Hypercalciuria,

Hyperoxaluria, Hypouricemia, Cystinuria, Genetics



2015 Annual Meeting of the Pediatric Endocrine Society San Diego, CA (April 25-27,2015) Selected Highlights

Monica Serrano-Gonzalez, MD, Patrick Shepherd, MD, Griselda Alvarez, MD, Anna Ryabets-Lienhard, DO


Ref: Ped. Endocrinol. Rev. 2015;13(1):480-489


Key words: Gender dysphoria, Gonadotropin-Releasing

Hormone Analogs (GnRHa), Cross-sex hormones, Maturity Onset Diabetes of the Young (MODY), Monogenic diabetes, Cystic Fibrosis-Related Diabetes (CFRD), Medication-induced diabetes, Fertility preservation, Osteoimmunology, Osteoclastic differentiation


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