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Volume 12.4

June 2015


Autosomal Dominant Growth Hormone Deficiency (Type II)

Kyriaki S. Alatzoglou MRCPCH, MSc, Dalvir Kular, MMBS, Mehul T. Dattani, MBBS, DCH, FRCPCH, FRCP, MD


Isolated growth hormone deficiency (IGHD) is the commonest pituitary hormone deficiency resulting from congenital or acquired causes, although for most patients its etiology remains unknown. Among the known factors, heterozygous mutations in the growth hormone gene (GH1) lead to the autosomal dominant form of GHD, also known as type II GHD. In many cohorts this is the commonest form of congenital isolated GHD and is mainly caused by mutations that affect the correct splicing of GH-1. These mutations cause skipping of the third exon and lead to the production of a 17.5-kDa GH isoform that exerts a dominant negative effect on the secretion of the wild type GH. The identification of these mutations has clinical implications for the management of patients, as there is a well-documented correlation between the severity of the phenotype and the increased expression of the 17.5-kDa isoform. Patients with type II GHD have a variable height deficit and severity of GHD and may develop additional pituitary hormone defiencies over time, including ACTH, TSH and gonadotropin deficiencies. Therefore, their lifelong follow-up is recommended. Detailed studies on the effect of heterozygous GH1 mutations on the trafficking, secretion and action of growth hormone can elucidate their mechanism on a cellular level and may influence future treatment options for GHD type II.


Ref: Ped. Endocrinol. Rev. 2015;12(4):347-355


Key words: Suggest GHD, Autosomal dominant, Splicing



Why Treat girls with Turner Syndrome with Growth Hormone? Growth and Beyond

Michael B Ranke, MD, PhD, FRCP (Edin) (Prof. Emeritus)


Turner Syndrome (TS) is a rare disorder, characterized by numerous signs and symptoms, which are also highly variable in their expression in individuals. The understanding of the genetic basis of the phenotype has advanced greatly during the past decades. The most consistent features, which negatively affect the quality of life in these individuals, are short stature and impaired gonadal function. After recombinant human growth hormone (rhGH) became available and was shown to improve height, it was then approved and has been used widely. Yet it remains a challenge to decide on the optimal treatment modality for individuals with TS and to evaluate the benefits and risks also in terms of karyotype of GH on growth and on other organ systems. This article reviews some of the major aspects related to these issues.


Ref: Ped. Endocrinol. Rev. 2015;12(4):356-365


Key words: Turner syndrome, Phenotype, Karyotype, Growth Hormone Treatment, Safety



Measurement of Serum 17α-Hydroxyprogesterone in Infants by Radioimmunoassay

Liliana Noemi Muñoz, MD, Mariana Ochetti, MD, Gonzalo Perez, MD, Gabriela Maria Sobrero, MD, Liliana Karina Silvano, PhD, Silvia Edith Martin, MD, Graciela María Testa, MD, Mirta Beatriz Miras, PhD


Determination of 17α-hydroxyprogesterone (17OHP) is used for the diagnosis and monitoring of Congenital Adrenal Hyperplasia (CAH). Problems associated with the specificity of antibodies used in direct immunoassays can yield high false results. Objectives: To analyze serum levels of direct 17OHP (17OHPd) and previous extraction (17OHPe) in the neonatal period, in order to establish reference values. To relate levels of 17OHPd and 17OHPe with other androgens in CAH patients. Subjects and methods: Serum 17OHPd and 17OHPe were measured via RIA-DPC in 400 healthy newborns and infants (aged 2-365 days), and 100 treated CAH patients (aged 1-18 years). The extraction was performed with 3% isopropanol/heptane. The influence of age and gender was assessed by ANOVA. Results: The serum levels of 17OHP were significantly correlated with chronological age, but not with gestational age, sex or birth weight. The difference between 17OHPd and 17OHPe decreased with age. The correlation index between 17OHPd and 17OHPe in CAH patients was 0.93 (p< 0.01). Conclusion: The present results provide 17OHP reference values for infants from birth up to one year of life. The extraction method is necessary in the neonatal period up to 6 months of life. Our data might be useful to make an early CAH diagnosis and follow-up newborns with high 17OHP levels without adrenal pathology.

Ref: Ped. Endocrinol. Rev. 2015;12(4):366-372


Key words: Congenital Adrenal Hyperplasia, 17α- hydroxyprogesterone, Newborns, Reference values



Androgen Insensitivity Syndrome: Management Considerations from Infancy to Adulthood

Min-Jye Chen, MD, Bach-Mai K. Vu, MD, Marni Axelrad, PhD, Jennifer E. Dietrich, MD, MSc, Patricio Gargollo, MD, Sheila Gunn, MD, Charles G. Macias, MD, MPH, Laurence B. McCullough, PhD, David R. Roth, MD, V. Reid Sutton, MD, Lefkothea P. Karaviti, MD, PhD


Androgen insensitivity syndrome (AIS) is an undervirilization syndrome in individuals with 46, XY karyotype. The undervirilization can be complete feminization or incomplete virilization with grades of ambiguity. AIS is caused by mutations in the androgen receptor, resulting in resistance to the physiologic activities of androgens. Differing degrees of resistance lead to three phenotypes: a complete form with female-appearing external genitalia, a partial form with a wide range of virilization, and a mild form with only minor undervirilization.

AIS presents different challenges depending on whether resistance is complete or partial. Challenges include sex assignment, which impacts other medical decisions such as gonadectomy, hormonal replacement, and other surgical interventions. This review describes medical, psychosocial, and ethical concerns for each stage of development in complete and partial AIS, from the neonatal period to adulthood. These aspects of care should be addressed within an ethical framework by a multidisciplinary team, with the patients and families being the stakeholders in the decision-making process.

We use the GRADE system when appropriate to appraise the existing evidence and provide recommendations and guidelines for management of AIS and appropriate transition of patients from pediatric to adult care.


Ref: Ped. Endocrinol. Rev. 2015;12(4):373-387


Key words: Androgen insensitivity syndrome, Transition, Ethics, Gonadectomy, Bone Mineral Density, Management, Sex assignment


Abbreviations used: AIS: androgen insensitivity syndrome; AR: androgen receptor; BMD: bone mineral density; CAIS: complete androgen insensitivity syndrome; CIS: carcinoma in situ; DSD: disorders of sex development; E2: estradiol; FSH: follicle-stimulating hormone; GnRH: gonadotropin releasing hormone; GRADE: Grading of Recommendation, Assessment, Development, and Evaluation; HCG: human chorionic gonadotropin; LH: luteinizing hormone; MAIS: mild androgen insensitivity syndrome; MRI: magnetic resonance imaging; PAIS: partial androgen insensitivity syndrome; PICO, patient, intervention, comparison, outcomes



Achondroplasia: Current Options and Future Perspective

Houda Bouali, MD, Hanane Latrech, MD


Achondroplasia is a human bone genetic disorder of the growth plate and is the most common form of inherited disproportionate short stature. It is inherited as an autosomal dominant disease with essentially complete penetrance. Of these most have the same point mutation in the gene for fibroblast growth factor receptor 3 (FGFR3) which is a negative regulator of bone growth. The clinical and radiological features of achondroplasia can easily be identified; they include disproportionate short stature with rhizomelic shortening, macrocephaly with frontal bossing, midface hypoplasia, lumbar hyperlordosis, and a trident hand configuration. The majority of achondroplasts have a normal intelligence, but many social and medical complications may compromise a full and productive life. Some of them have serious health consequences related to hydrocephalus, craniocervical junction compression, or upper-airway obstruction. In this article, we discuss a number of treatments from the surgical limb lengthening approach and the Recombinant Growth Hormone (rhGH) treatment, to future treatments, which include the Natriuretic Peptide C-type (CNP). The discussion is a comparative study of the complications and drawbacks of various experiments using numerous strategies.


Ref: Ped. Endocrinol. Rev. 2015;12(4):388-395


Key words: Achondroplasia, Fibroblast Growth Factor Receptor 3, Surgical limb lengthening


Abreviations: FGFR3: fibroblast growth factor receptor 3, ACH: Achondroplasia, LLD: Leg-Length Discrepancy, rhGH: Recombinant Growth Hormone, CNP: Natriuretic Peptide C-type



The 2015-USFQ Biennial Meeting on Growth Hormone Research

Jaime Guevara-Aguirre, MD, Enrique Teran, MD, PhD, Ron Rosenfeld, MD


Ref: Ped. Endocrinol. Rev. 2015;12(4):396-407


Key words: Growth hormone, Growth hormone action, Growth hormone receptor, Growth hormone insensitivity, Laron syndrome, Laron mouse, Growth abnormality, Next generation sequences, Galapagos Islands, Darwin Charles, Wallace Alfred



2015 Annual Meeting of the Endocrine Society San Diego, CA (March 5-8, 2015) Selected Highlights

Isabel Hsu, MD, PhD, Elizabeth Burtman, MD, Jessica Ferris, MD, Juliana Austin, MD


Ref: Ped. Endocrinol. Rev. 2015;12(4):408-421


Key words: Polycystic ovary syndrome, Functional ovarian hyperandrogenism, Oral contraceptives, Type 1 diabetes mellitus, Type 2 diabetes mellitus, Transition, Insulin resistance, Lipotoxicity, Thyroid cancer, Thyroid ultrasound, Fine-needle aspiration


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