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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 

Vol. 9 supplement 2

May 2012

 

Turner Syndrome: Strategies to Improve Care Outcomes

Corresponding Author: Paul Saenger, MD

Ref: Ped. Endocrinol. Rev. 2012;696-697

Keywords: Turner Syndrome, Strategies of Treatment

 

Ending the Late Diagnosis of Turner Syndrome Through a Novel High- Throughput Assay

Scott A. Rivkees, MD

Abstract

Turner syndrome (TS) occurs when an X-chromosome is completely or partially deleted, or when X-chromosomal mosaicism is present. Girls with TS benefit from early diagnosis and treatment with growth hormone; however, many girls with TS are not detected until after 10 years of age resulting in delayed evaluation and treatment. To facilitate the detection of TS, we developed a high-throughput test for TS, based on a quantitative method of genotyping to detect X-chromosome abnormalities. This test utilizes pyrosequencing to quantitate relative allele strength (RAS) from single nucleotide polymorphisms (SNPs) using 18 informative SNP markers that span the X-chromosome and one marker for the detection of Y-chromosome material. To determine the validity of this rapid test for TS detection, we undertook a large-scale study using DNA from 132 females without TS and 74 females with TS for whom karyotypes were available. TS was identified with 96.0% sensitivity and 97.0% specificity in this cohort. We also tested buccal swab DNA from a group of 72 females without TS and 69 females with TS. In this group, TS was identified with 97.1 sensitivity and 90.3% specificity. These results demonstrate the validity of a high-throughput, pyrosequencing based test for the accurate detection of TS, providing a potential alternative to karyotype testing.

Ref: Ped. Endocrinol. Rev. 2012;9(Suppl.2):698-700

Key words: Turner syndrome, chromosome, pyrosequencing, karyotype, single nucleotide polymorphism

 

Turner Syndrome Strategies to Improve Care Outcomes - Cardiac Evaluation Using New Imaging Techniques

Laura Mazzanti1, PhD, Luigi Lovato2, MD, Daniela Prandstraller3, MD, Emanuela Scarano1 , MD, Federica Tamburrino1, MD, Francesca Montanari1, MD, Gian Gaspero Mineo2, MD, Annamaria Perri1, MD, Benedetta Vestrucci1, MD, Andrea Giardini4, MD

Abstract

Turner syndrome (TS) is at high risk for congenital heart diseases (CHD), aortic dilatation (AoDil) and dissection. New imaging techniques such as MRI have revealed the presence of vascular anomalies (VA) undetected at echo. MR angiography has shown a high prevalence of aortic and venous anomalies. The VA often coexist and interact to increase the risk of premature death in adulthood. AoDil and VA have been found also in asymptomatic individuals with no predisposing factors, but the prevalence is still unknown. We evaluated 100 TS subjects (15-35 yrs) with no aortic CHD at echocardiography with transthoracic MRA; 42 of them showed VA and 58 did not. Aortic diameters were indexed on BSA. At the sinuses of Valsalva a higher prevalence of AoDil was found in subjects with VA than without; 57% of them showed AoDil. The presence of VA (elongation of the transverse arch, bovine arch, left superior vena cava, PAPVD etc.) increased their relative risk of AoDil by more than 2 times. Excluding BSA influence, a severe phenotype influenced positively ascending AoDil. New imaging techniques enhance our ability to provide a prognosis for their adult age and in particular before they seek to become pregnant. Ref: Ped. Endocrinol. Rev. 2012;9(Suppl.2):701-709 Key words: Turner syndrome; congenital heart disease; echocardiography; thoracic MRI; aortic dimensions; aortic dilatation; aortic dissection; pregnancy;

Abbreviations: CHD, congenital heart disease; COA, Coarctation of aorta; BAV, Bicuspid aortic valve; PAPVD, partial anomalous pulmonary venous drainage; AoVD, aortic valve disease; AoDil, Aortic dilatation; STJ, sino-tubular junction; BSA, Body surface area; ASI, Ascending aortic diameter indexed for BSA; AD/ DD, ascending and descending aortic diameter ratio, VA vascular anomalies.

 

Cognition and Behavior in Turner Syndrome: a Brief Review

Hong DS, MD, Reiss AL, MD

Abstract

There is increasing evidence that Turner syndrome is associated with a distinct pattern of cognitive and neurophysiological characteristics. Typically this has been characterized by relative strengths in verbal skills, contrasting with relative weaknesses in arithmetic, visuospatial and executive function domains. Potential differences in social cognitive processing have also been identified. More recently, applications of neuroimaging techniques have further elucidated underlying differences in brain structure, function and connectivity in individuals with Turner syndrome. Ongoing research in this area is focused on establishing a unified mechanistic model incorporating genetic influences from the X chromosome, sex hormone contributions, neuroanatomical variation and differences in cognitive processes. This review broadly covers current understanding of how X-monosomy impacts neurocognitive phenotype both from the perspective of cognitive-behavioral and neuroimaging studies. Furthermore, relevant clinical aspects of identifying potential learning difficulties and providing anticipatory guidance for affected individuals with TS, are briefly discussed.

Ref: Ped. Endocrinol. Rev. 2012;9(Suppl.2):710-712

Keywords: Turner syndrome (TS), X-monosomy, pseduoautosomal region (PAR)

 

Ovarian Function and In Vitro Fertilization (IVF) In Turner Syndrome

Outi Hovatta, MD, PhD

Abstract

Normal numbers of oocytes and ovarian follicles develop to the ovaries during the first half of the fetal life. The oocytes then start gradually disappearing. Abnormal meiotic division due to the lack of a paring X-chromosome has been suggested as the causative factor. A large proportion, 40-50% of Turner girls have at least some pubertal development, and about 10 % may undergo menarche. Ovarian follicles have been found in some 40% of teenagers with Turner syndrome. Serum concentrations of antimullerian hormone (AMH) and follicle stimulation hormone (FSH), karyotype with mosaicism or structural chromosomal abnormalities, and spontaneous onset of pubertal development are positive prognostic signs for the presence of oocytes and ovarian function. Spontaneous pregnancies occur in some 2-10% of Turner women, a higher number than estimated earlier. This is probably due to failed identification of the syndrome among Turner women with ovarian function. Premature ovarian failure (POF) at some age can be expected in most of Turner women. FSH-stimulated oocyte retrieval and IVF can be carried out before predicted POF. Counseling not to postpone childbearing unnecessarily is advisable. Collected oocytes can be cryopreserved using vitrification, and stored until a pregnancy is desired. Large number of primordial oocytes within ovarian follicles can be stored in within superficial biopsied pieces of ovarian cortical tissue, for transplantation back to the ovary later on. Oocyte donation is an effective infertility treatment for Turner women who have undergone POF. Adequate hormonal replacement therapy (HRT) before IVF is necessary. Only one embryo at a time should be transferred particularly to these women in order to avoid pregnancy complications. Pregnancies in Turner syndrome women have high risks. Comprehensive health control including MRI of the aorta is recommended already before a planned pregnancy, and aorta has to be followed up by echography at least twice during the pregnancy to evaluate the risk of aortic dissection. Some 30% of Turner women develop hypertension during pregnancy, but this is also common among all oocyte donation pregnancies.

Ref: Ped. Endocrinol. Rev. 2012;9(Suppl.2):713-717

Keywords: Ovarian Function, In Vitro Fertilization (IVF), Oocytes

 

Estrogen Therapy in Turner Syndrome: Does The Type, Dose and Mode of Delivery Matter?

Nelly Mauras1, MD, Lournaris Torres-Santiago1,3, MD, Martha Taboada1,2, MD, Richard Santen4, MD

Abstract

The best type, dose and route of estrogen replacement in hypogonadal females has not been fully elucidated and is the subject of this brief review. When feminizing girls with different forms of hypogonadism micronized 17βE2 should be considered the first choice as it is the most physiological and can be accurately measured in plasma. Most studies of the metabolic effects of the different routes have also used different types of estrogen making comparisons difficult. However, when using the same estradiol compound, 17βE2 transdermal results in E2, E1 and bioestrogen concentrations closer to normal as compared to oral and achieves greater suppression of LH/FSH but similar IGF-I and lipid concentrations. Whether this translates into better body composition and metabolic outcomes in girls with hypogonadism is being actively investigated and data will soon be available.

Ref: Ped. Endocrinol. Rev. 2012;9(Suppl.2):718-722

Key words: (8): estradiol, estrone, IGF-I, puberty, hypogonadism, Turner Syndrome, pharmacokinetics, transdermal

 

Growth Hormone Therapy in Turner Syndrome

Marsha L. Davenport, MD

Abstract

Short stature is the single most common physical abnormality in Turner syndrome (TS) with adult stature averaging 20 cm shorter than that of the general population. Randomized, placebo-controlled studies to final adult height have proven that GH therapy is effective in increasing stature in TS. Recently, randomized, controlled studies have demonstrated that adjunctive therapies with low-dose estrogen or low-dose oxandrolone enhance stature further. These therapies may provide benefits beyond height augmentation.

Ref: Ped. Endocrinol. Rev. 2012;9(Suppl.2):723-724

Key words: growth hormone, Turner syndrome, growth, estrogen, oxandrolone, short stature, puberty

 

Trends in GH Use in a Turner Syndrome Natural History Study

Liat Gutin, BS, Suzanne Collier, BA, Vladimir K. Bakalov, MD, Carolyn Bondy, MD

Abstract

The present observations are derived from 273 girls and women aged 7-40 years participating in the National Institutes of Health natural history study of Turner syndrome (TS) in the interval 2001-2011. There was a higher percentage of GH use among individuals in the pediatric age group (7-17, n=118, 83%) compared to young adult women with prior GH use (18-40, n=155, 61%). The major factor in this divergence seems to be a trend toward earlier diagnosis of TS in the younger age group. We find a striking association between history of GH use and lower total body and abdominal fat mass in young adults with TS approximately one decade after discontinuation of GH treatment. The interpretation of this observation is limited by the fact that our study subjects were not randomly assigned to GH treatment. There may be a bias involving poor health care, childhood obesity, delayed diagnosis, absent GH treatment and persistent adult obesity. Further studies on the socioeconomic factors implicated in patterns of GH use and non-use for girls with TS are needed to illuminate this important issue.

Ref: Ped. Endocrinol. Rev. 2012;9(Suppl 2):725-727

Keywords: GH Treatment, Turner Syndrome TS, NICHD, GH Use Trends

 

Genomic Imprinting and Turner Syndrome

Carolyn A Bondy, MD, Helen Y. Hougen, BA, Jian Zhou, MD, PhD and Clara M Cheng, PhD

Abstract

The term ‘genomic imprinting’ refers to selective repression of transcription from distinct chromosomal regions determined by their maternal or paternal inheritance. There are two potentially important aspects of imprinting that may manifest in individuals with X monosomy, or Turner syndrome (TS). Given that men are monosomic for Xm while women are mosaic for Xm:Xp, genomic imprinting of important X-linked genes should be associated with sexually dimorphic traits, e.g., social skills, regional fat deposition and adult height. Such X-imprinted traits are predicted to differ in Turner groups monosomic for Xm vs. Xp. We review relevant studies of psychosocial attributes, regional fat distribution and height in TS related to parent of origin for the single normal X chromosome. In addition, we review recent evidence that monosomy for the X chromosome per se, regardless of the parental origin, may disrupt the normal distribution of autosomal imprint patterns. This may contribute to a high rate of fetal loss in human monosomy via impaired placentation in the most severe cases, and to loss of paternal contribution to growth in the mildest manifestation.

Ref: Ped. Endocrinol. Rev. 2012;9(Suppl.2):728-732

Key words: X chromosome, Growth, Insulin like growth

factor 2, Fetal development

 

New Roles of SHOX as Regulator of TargetGenes

1Rappold, G.A., PhD, 1Durand, C., PhD, 1Decker, E., PhD, 1,2Marchini, A., PhD, 1Schneider, K.U., PhD

Abstract

The homeobox gene SHOX encodes a transcription factor which is important for normal limb development. Approximately 5 to 10% of short patients exhibit a mutation or deletion in either the SHOX gene or its downstream enhancer regions. In humans, SHOX deficiency has been associated with various short stature syndromes as well as non-syndromic idiopathic short stature. A common feature of these syndromes is disproportionate short stature with a particular shortening of the forearms and lower legs. Madelung deformity, cubitus valgus, high-arched palate and muscular hypertrophy also differed markedly between patients with or without SHOX gene defects. A clinical trial in patients with SHOX deficiency and Turner syndrome demonstrated highly significant growth hormone-stimulated increases in height velocity and height SDS in both groups. Employing microarray analyses and cell culture experiments, a strong effect of SHOX on the expression of the natriuretic peptide BNP and the fibroblast growth factor receptor gene FGFR3 could be demonstrated. We found that BNP was positively regulated, while Fgfr3 was negatively regulated by SHOX. A regulation that occurs mainly in the mesomelic segments, a region where SHOX is known to be strongly expressed, offers a possible explanation for the phenotypes seen in patients with FGFR3 (e.g. achondroplasia) and SHOX defects (e.g. Léri-Weill dyschondrosteosis).

Ref: Ped. Endocrinol. Rev. 2012;9(Suppl.2):733-738

Keywords: SHOX, target genes, Turner syndrome, BNP, FGFR3

 

The SHOX gene (short stature Clinical Care of Adult Turner Syndrome – New Aspects

Christian Trolle1, MD, Kristian Havmand Mortensen 1, MD, Britta E. Hjerrild1, MD, Line Cleemann2, MD, Claus H. Gravholt1,3, MD, PhD

Abstract

Turner syndrome (TS) is characterized by numerous medical challenges during adolescence and adulthood. Puberty has to be induced in most cases, and female sex hormone replacement therapy (HRT) should continue during adult years. These issues are normally dealt with by the paediatrician, but once a TS female enters adulthood it is less clear who should be the primary care giver. Morbidity and mortality is increased, especially due to the risk of dissection of the aorta and other cardiovascular diseases, as well as the risk of type 2 diabetes, hypertension, osteoporosis, thyroid disease and other diseases. The proper dose of HRT with female sex steroids has not been established, and, likewise, benefits and/or drawbacks from HRT have not been thoroughly evaluated. The transition period from paediatric to adult care seems to be especially vulnerable and the proper framework for transition has not yet been established. Likewise, no framework is in place for continuous follow-up during adult years in many countries. Today, most treatment recommendations are based on expert opinion and are unfortunately not evidence based, although more areas, such as growth hormone and oxandrolone treatment for increasing height, are becoming well founded. Osteoporosis, diabetes, both type 1 and 2, hypothyroidism, obesity and a host of other endocrine diseases and conditions are seen more frequently in TS. Prevention, intervention and proper treatment is only just being recognized. Hypertension is frequent and can be a forerunner of cardiovascular disease. The description of adult life with TS has been broadened and medical, social and psychological aspects are being added at a compelling pace. Proper care during adulthood should be studied and a framework for care should be in place, since most morbidity potentially is amenable to intervention. In summary, TS is a condition associated with a number of diseases and conditions which need the attention of a multi-disciplinary team during adulthood.

Ref: Ped. Endocrinol. Rev. 2012;9(Suppl 2):739-749

Keywords: Turner syndrome, adult height, genes, growth, growth hormone, androgens, estrogens, glucose metabolism, cardiovascular diseases, ischemic heart disease, hypertension, insulin resistance, morbidity, mortality, puberty, thyroid function, liver function, epidemiology