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Vol. 8.2

December 2010


Growing Pains: Myth or Reality

Liora Harel, MD


Growing pains are common among children aged 2-12 years and are characterized by recurrent, self-limited, bilateral lower extremity pain, mostly in the afternoon and evening, and even at night, in an otherwise healthy child. The etiology is unknown and prognosis is excellent. It is important to distinguish between this benign condition and other serious rheumatic or malignant diseases.

Ref: Ped. Endocrinol. Rev. 2010;8(2):76-78

Keywords: Growing pains, nocturnal pains, children



Short stature Caused by Isolated SHOX Gene Haploinsufficiency: Update on the Diagnosis and Treatment

Mariana F.A. Funari1, MD, Mirian Y. Nishi1, MD, Ivo J. P. Arnhold1, MD, Berenice B. Mendonca1, MD, Alexander A. L. Jorge1,2, MD


Heterozygous SHOX defects are observed in about 50 to 90% of patients with Leri-Weill dyschondrosteosis (LWD), a common dominant inherited skeletal dysplasia; and in 2 to 15% of children with idiopathic short stature (ISS), indicating that SHOX defects are the most important monogenetic cause of short stature. In addition, children selected by disproportionate idiopathic short stature had a higher frequency of SHOX mutations (22%). A careful clinical evaluation of family members with short stature is recommended since it usually revealed LWD patients in families first classified as having ISS or familial short stature. SHOX-molecular analysis is indicated in families with LWD and ISS children with disproportionate short stature. Treatment with recombinant human growth hormone is considered an accepted approach to treat short stature associated with isolated SHOX defect. Here we review clinical, molecular and therapeutic aspects of SHOX haploinsufficiency.

Ref: Ped. Endocrinol. Rev. 2010;8(2):79-85

Key words: Idiopathic Short Stature; Genetic; Growth Hormone Therapy; SHOX Gene; Skeletal Dysplasia; Leri- Weill Dyschondrosteosis; Diagnosis



Genetic and Epigenetic Findings in Silver-Russell Syndrome

Matthias Begemann1, MSc, Sabrina Spengler1, MSc, Carmen Schröder2, MD, Ulrike Kordaß3,MD, Gerhard Binder4, MD, Thomas Eggermann1, PhD, MSc


Silver-Russell syndrome (SRS) is a genetically and clinically heterogeneous disease which is mainly characterized by pre- and postnatal growth restriction. The typical SRS phenotype furthermore includes a relative macrocephaly, a triangular shaped face, body asymmetry, clinodactyly of the fifth finger and other less constant features. In about ~50% of patients (epi)genetic alterations involving chromosomes 7 and 11 can be detected. The major finding (~44%) is a hypomethylation of the imprinting control region 1 (ICR1) in 11p15.5 affecting the expression of H19 and IGF2. 4-10% of the patients carry a maternal UPD of chromosome 7 (UPD(7)mat). In a few cases chromosomal rearrangements have been reported. The diagnostic workup should therefore include 11p15 testing, UPD(7)mat analysis and molecular karyotyping. The recurrence risk is generally low in SRS but it can strongly increase in case of familial epimutations or chromosomal rearrangements. Interestingly, in ~7% of 11p15 hypomethylation carriers, hypomethylation of additional imprinted loci can be detected. Clinically, patients with hypomethylation at multiple loci do not differ from those with isolated ICR1 hypomethylation whereas the UPD(7)mat patients generally show a milder phenotype. Nevertheless, an unambiguous (epi)genotype-phenotype correlation can not be delineated. Furthermore, the pathophysiological mechanisms resulting in the SRS phenotype still remain unknown despite the recent progress in deciphering molecular defects in the disease.

Ref: Ped. Endocrinol. Rev. 2010;8(2):86-93

Keywords: Silver-Russell syndrome; Epimutations; UPD(7) Mat; Chromosome 11p15; Multilocus Hypomethylation; Genetic Counselling; Chromosomal Aberration



Genetic and Epigenetic Influences Associated with Intrauterine Growth Restriction Due to In Utero Tobacco Exposure

Melissa Suter1, PhD, Adi Abramovici1, MD, Kjersti Aagaard-Tillery1, MD, PhD


While many fetuses are exposed to tobacco in utero, not all experience adverse outcomes as a result of this exposure. Mechanisms leading to the attenuation of fetal birth weight and adverse pregnancy outcomes are complex. Therefore many studies have begun to focus, not only on the contribution of maternal and fetal genes to phenotypic outcome, but also on epigenetic changes associated with exposure to maternal tobacco smoke. In this review, we detail the epidemiologic evidence associating an adverse pregnancy outcome to maternal tobacco use. We provide a brief summary of studies demonstrating an association between maternal and fetal gene polymorphisms with low birth weight in response to maternal tobacco exposure. We also review the literature showing epigenetic changes in the offspring associated with in utero tobacco exposure. The complex interplay of genomic and epigenomic factors may contribute to specific phenotypic outcomes and can help begin to elucidate the differential susceptibilities to tobacco smoke in utero.

Ref: Ped. Endocrinol. Rev. 2010;8(2):94-102

Keywords: in utero tobacco exposure, fetal birth

weight, genetics, epigenetics



Non-Classic Unexpected Functions of Vitamin D

Yosef Weisman, MD


Defects in the growth hormone (GH)-insulin-like growth factor (IGF)-I axis may cause GH resistance characterized by IGF-I deficiency and growth failure. The range of defects causing GH resistance is broad as are their biochemical and phenotypical characteristics. We propose that GH-IGF-I axis defects form a continuum of clinical and biochemical effects ranging from GH deficiency to GH resistance. The pathophysiology of GH resistance is described followed by a scheme for investigation of the child with severe short stature and normal GH secretion. We critically discuss GH therapy for such patients and define acceptable growth responsiveness. Finally we discuss therapy with IGF–I within the limits of the USA Food and Drug Administration and European Medicines Agency labels for GH resistance.

Ref: Ped. Endocrinol. Rev. 20010;7(4):

Key words: Growth; Growth Hormone; IGF-I, GH

Resistance; IGF-I T

Ref: Ped. Endocrinol. Rev. 2010;8(2):103-107

Key words: Vitamin D; vitamin D and Cancer; Vitamin D

and Immunity; Vitamin D and Cardiovascular Diseases



Preventive Thyroidectomy in Patients with Hereditary Medullary Thyroid

Carcinoma Found Heterozygote For Mutant RET Proto-Oncogene

Konstantinou Evangelos1, RN, BSN, MSc, PhD, Mariolis Sapsakos Theodoros2, MD, PhD, Fotis Theofanis3, RN, BSN, MSc, PhD, Mitsos Aristotelis4, MD, MSc, PhD(c) Restos Stilianos5, MD, Mamoura Konstantinia6, RN, MSc, Soultati Aspasia7, MD, PhD (c), Elefsiniotis Ioannis8, MD, PhD Kapellakis George9, MD, PhD


The currently available genetic tests for identification of the RET proto-oncogene mutation offer the possibility of prospective successful therapy before the hyperplasia of C-cells evolve to Medullary Thyroid Carcinoma. We present our experience regarding the preventive thyroidectomy of family members with history of Medullary Thyroid Carcinoma, who were found to be heterozygote for mutant RET proto-oncogene. We have retrospectively reviewed 19 members of 6 families with history of Medullary Thyroid Carcinoma, who were heterozygote for mutant RET protooncogene and underwent prophylactic thyroidectomy. All patients included in this series were below twenty years of age. The Medullary Thyroid Carcinoma was asymptomatic and the mutation of RET protooncogene has been also documented pre-operatively in all of them. All patients had undergone total thyroidectomy, while 1 with pheochromocytoma had undergone also left epinephridectomy. Fourteen patients (73.68%) had undergone lymph-nodes resection (in 10 of them the resection was central, in 3 unilateral and in 1 bilateral). Although none of our patients suffered from hyperparathyroidism, 7 parathyroid glands have been also resected from 3 patients, while auto-transfusion has been performed in one. In all patients, preoperative measurement of the calcitonin blood levels before and after stimulation with pentagastrin has been performed.

Ref: Ped. Endocrinol. Rev. 2010;8(2):108-112

Keywords: medullary thyroid carcinoma, RET protooncogene, preventive thyroidectomy, C-cellular hyperplasia, calcitonin, thyroidectomy, lymph-node resection



Meeting Highlights: Endocrine Society, San Diego, California, June 19-22, 2010

Roshanak Monzavi1,4, MD, Mimi Kim1, MD, Juliana Austin, MD2, Amy Vedin1, MD, Sherry Franklin3, MD

Ref: Ped. Endocrynol. Rev. 2010;8(2):113-121

Key Words: growth hormone deficiency, transition period, short stature, recombinant human growth hormone, polycystic ovarian syndrome, CHD7, hypogonadotropic hypogonadism, Kallmann syndrome, CHARGE syndrome, FGFR1, FGF8, prokineticin receptor 2, prokineticin 2, newborn screening, congenital adrenal hyperplasia, congenital hypothyroidism, type 1 diabetes mellitus, and type 2 diabetes mellitus



Highlights from the Second European Workshop on Growth Plate Research 2010

Stephan-Stanislaw Späth1, Lars Sävendahl2, Cecilia Camacho-Hübner2,

Ola Nilsson1,2

Ref: Ped. Endocrinology. Rev 2010;8(1)122-124

Keywords: Gross plate, chondrogenesism,

mineralizations, malnutrition



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