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Edited by: Iulian P. VELEA, Corina PAUL, Stuart J. BRINK

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Descrierea CIP a Bibliotecii Naţionale a României Theoretical and practical update in pediatric endocrinology and diabetes / ed.: Iulian Velea, Corina Paul, Stuart J. Brink. - Timişoara : Mirton, 2014 Bibliogr. ISBN 978-973-52-1441-8 I. Velea, Iulian (ed.) II. Paul, Corina (ed.) III. Brink, Stuart J. (ed.) 616.43-053.2


Edited by: Iulian P. VELEA, Corina PAUL, Stuart J. BRINK

EDITURA MIRTON Timişoara 2014

Contributors: Jeremy Allgrove, MA, MD, FRCP, FRCPCh Consultant Paediatric Endocrinologist, Department of Paediatric Endocrinology and Diabetes, Royal London and Great Ormond Street Hospitals, United Kingdom

Adriana Luminita Balasa, MD Pediatrician, Clinic of Pediatrics, Clinical County Hospital Constanţa, Romania

Stuart J. Brink, MD Senior Endocrinologist, New England Diabetes and Endocrinology Center (NEDEC), Waltham MA, USA Associate Clinical Professor of Pediatrics, Tufts University School of Medicine, Boston MA, USA

Manuel Rui G. Carrapato, MD, PhD, FRCP, DCH Professor of Pediatric Sciencies, Faculty of Health Sciencies, Fernando Pessoa University, Rua Carlos Maia, Oporto, Portugal Head of Pediatric and Neonatal Department, São Sebastião Hospital, Rua Dr Cândido Pinho, Santa Maria da Feira- Portugal

Ioana Ciucă MD, PhD, Assistant Professor, Department of Pediatrics, UMPh “Victor Babeş” Timişoara Senior Pediatrician Clinic II Pediatrics, Clinical County Hospital, Timisoara, Romania

Adela Chiriţă – Emandi MD, PhD, Assistant Professor, Department of Medical Genetics., UMPh “Victor Babeş” Timişoara, Romania

Rodica Elena Cornean MD, PhD Assistant Professor of Medical Genetics, Department of Molecular Sciences-Medical Genetics Senior Pediatrician, 2nd Paediatric Clinic, Clinical Emergency Hospital for Children UMPh “Iuliu Hatieganu”, Cluj-Napoca.

Dana Liana David, MD, PhD Associate Professor in Biochemistry Department, UMPh “Victor Babes” Timişoara, Romania Senior Endocrinologist, Clinical Municipal Hospital Timişoara, Romania

Vlad David, MD, PhD Assistant Professor Department of Pediatric Surgery, UMPh “V. Babeş” Timisoara, Romania Department of Pediatric Surgery “Luis Ţurcanu” Emergency Hospital for Children, Timisoara, Romania

Gabriela Doroş MD, PhD Associate Clinical Professor of Pediatrics at the UMPh “V. Babeş” Timisoara, Romania Senior Pediatrician at Clinic III Pediatrics, “Luis Ţurcanu” Emergency Hospital for Children, Timisoara, Romania

Stephen Greene MD Professor of child and adolescent health, Child Health, Scool of Medicine, University of Dundee, Scotland, UK

Marilena Lăzărescu, MD Junior Doctor, Clinic II Pediatrics, Clinical County Hospital Timisoara, Romania

Florin Mangu, MD Pediatrician, Clinic of Pediatrics, Clinical County Hospital Constanţa, Romania

Cristina Maria Mihai, MD, PhD, Associate Clinical Professor of Pediatrics at the Faculty of Medicine Constanţa, Romania Senior Pediatrician, Clinic of Pediatrics, Clinical County Hospital Constanţa, Romania

Mirela Mogoi MD, PhD student Junior Doctor, Clinic II Pediatrics, Clinical County Hospital Timisoara, Romania

Aritinia Moroşanu MD, Pediatrician at Clinical County Hospital Craiova, Clinic I Pediatrics

Carmen Niculescu MD, Pediatrician at Clinical County Hospital Craiova, Clinic I Pediatrics

Corina Paul MD, PhD Lecturer, Department of Pediatrics, UMPh “Victor Babeş” Timişoara. Senior Pediatrician Clinic II Pediatrics, Clinical County Hospital, Timisoara, Romania

Anca Daniela Pinzaru, MD Junior Doctor, Clinic of Pediatrics, Clinical County Hospital Constanţa, Romania

Alex Pirvan MD, PhD, Lecturer Department of Pediatrics, UMPh “Iuliu Haţieganu” Cluj Napoca Senior Pediatrician Clinic II Pediatrics UMPh “Iuliu Haţieganu”, Cluj-Napoca, Romania

Liviu Pop, MD, PhD, Professor of Pediatrics at the UMPh “V. Babeş” Timisoara, Senior Pediatrician at Clinic II Pediatrics, Clinical County Hospital Timisoara, Romania

Lenuţa Popa, MD, PhD Associate Clinical Professor of Pediatrics, Endocrinology Compartment, Pediatrics Clinic 1, UMPh “Iuliu Haţieganu”, Cluj-Napoca, Romania

Ileana Puiu MD, PhD Associate Clinical Professor at University of Medicine and Pharmacy Craiova Senior Pediatrician at Clinical County Hospital Craiova, Clinic I Pediatrics

Maria Puiu MD, PhD Professor, Department of Medical Genetics, UMPh “Victor Babeş” Timişoara, Romania Geneticist at “Luis Ţurcanu” Emergency Hospital for Children, Timisoara, Romania

Radu Sorin Şerban MD, PhD Lecturer, Department of Pediatrics, UMPh “Iuliu Haţieganu”, Cluj-Napoca, Romania Senior Pediatrician Pediatrics Clinic 1, UMPh “Iuliu Haţieganu”, Cluj-Napoca, Romania

Ionelea Tămăşan MD, PhD Assistant Professor, Department of Pediatrics, UMPh “Victor Babeş” Timişoara, Romania Pediatrician Clinic II Pediatrics, Clinical County Hospital, Timisoara, Romania

Iulian P. VELEA, MD, PhD Associate Clinical Professor of Pediatrics at the UMPh “V. Babeş” Timisoara, Romania Senior Pediatrician at Clinic II Pediatrics, Clinical County Hospital Timisoara, Romania

Oana Alexandra Velea MD, PhD Student Assistant Professor, Clinic of Odontotherapy and Endodontics, Faculty of Dental Medicine, UMPh “Victor Babes”, Timisoara, Romania

Preface Training in pediatric endocrinology and diabetes becomes an important priority for our medical society, because, at the moment, diabetes mellitus and the endocrinological disorders of the children and adolescents are shared between adult endocrinologists, diabetologists and pediatricians with interest in the field. Along with joining the European Community, in 2012, the medical board decided to align the subspecialties in Pediatrics (i.e cardiology, nephrology, endocrinology and diabetes) to the European standards, on the decision of the Health Ministry. We started to organize the National Symposiums of Pediatric Endocrinology (ENDOPED) since 2010 sustained, also, by medical personalities in the field - Stuart J. Brink, William L. Clarke, Carine de Beaufort, Jeremy Allgrove, Linda Fisher, Larry Deeb, Manuel Rui Carrapato. Our intention was to get together all pediatricians with interest in pediatric endocrinology and diabetes, aiming to improve our knowledges and share experience. Also, this year, we are going to edit a volume “Theoretical and practical update in pediatric endocrinology and diabetes”, with the most important themes debated during the symposium which, we hope should be useful for all our colleagues. This way, I would like to thank our foreign lecturers, especially to Prof. Stuart J. Brink from Boston (USA), for his involvement and dedication, but also, to our Romanian colleagues for their annual participation at these symposiums.

Timisoara, April 2014

Iulian P. Velea

Contents 1.

Pituitary stalk interruption syndrome Lenuţa Popa


Endocrine control of calcium metabolism Jeremy Allgrove



Hyper- and hypocalcaemic disorders of children Jeremy Allgrove



Hormonal aspects of catamenial epilepsy in adolescent girls Dana L. David, Iulian P. Velea, Corina Paul



Management of the new case of diabetes Stephen Green



Diabets and thyroid disorders Stephen Green



Celiac diseases and type 1 diabetes mellitus Alexandru Pirvan



Comparative study of clinical manifestations in patients with celiac disease and diabetes related to celiac disease Cristina Mihai, Adriana Luminita Balasa, Florin Mangu, Anca Daniela Pinzaru



Diabetes in mucoviscidosis (cystic fibrosis) Liviu Pop, Iulian P.Velea, Ioana Ciucă, Ionela Tămăşan


10. How should children and youth with type 2 diebetes be treated ? Stuart J. Brink



11. Insulin resistance in child and teenager Ileana Puiu, Carmen Niculescu, Aritina Moroşanu


12. Vitamin D – Diabetes Mellitus relationship Iulian P.Velea, Marilena Lăzărescu, Oana Alexandra Velea


13. Vitamin D status in overweight and obese children Monteiro,J.; Aguiar,B.; Leite,A.L.; Monteiro M.I.; Nunes,I; Marques, E; Faria, S; Costa, M.; Gomes,L.; Carrapato MRG.


14. How much is too much vitamin D for children? Adela Chiriţă Emandi; Gabriela Doroş, Vlad David, Maria Puiu


15. Using simple screening tools for assessing obesity related cardiometabolic risk factors in children Mirela Mogoi, Iulian P. Velea, Corina Paul


16. ROHHADNET Syndrome Rodica Elena Cornean


17. Apolipoprotein B100 and risk for cardiovascular disease in children and adolescents Lenuţa Popa, Şerban Radu-Sorin


18. Growth and puberty in children born small for gestational age. Corina Paul, Iulian P. Velea



Lenuţa Popa

Introduction and Definition At the beginning of the 20th century endocrine functions became recognized and thereafter the various hormones produced by the pituitary gland were isolated and characterized. In the mid-twentieth century once that the major role of the hypothalamus in the control of pituitary function was recognized by Harris, the new discipline of neuroendocrinology developed. Pituitary stalk interruption syndrome (PSIS) also named pituitary stalk dysgenesis is a rare congenital, structural disorder of pitutary stalk and nerohypophysis associated with secondary abnormalities of adenohypophysis and various degrees of anterior pituitary hormone deficiency. 1 In agreement with Orphanet classification of rare diseases it is a rare endocrine disease, and an important cause of non-acquierd pituitary hormone deficiency. First described by Fujisawa in 1987, it is more frequent in males compared to females with a sex ratio of 2.3- 6.8/1 and an estimated incidence of 0,5 / 1.000.000 newborns.2,3,4,5,8 As the marker of congenital anterior-pituitary insufficiency, PSIS is frequent manifested as a permanent growth hormon deficit (GHD) or as a multiple pituitary hormone deficiency (MPHD) defined as a deficiency in two or more pituitary hormones. Posterior pituitary function is normal in these patients. 1,4,6,7,8 Beeing a relatively newly recognized disorder pituitary stalk dysgenesis has an uncertain prevalence that was estimated in different


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retrospective studies to range beteewn 11.2% in adult patients and 21.9% in children. PSIS was identified by magnetic resonance imaging (MRI), which provides precise visualization of structural abnormalities in the hypothalamic and pituitary area and surrounding regions. 3,9 The classic triad characteristic of PSIS consists of: - 1.thin, interrupted or absent pituitary stalk; - 2. ectopic or absent posterior pituitary, and - 3. anterior pituitary hypoplasia or aplasia. 3,5,6,7,9,10,11,12 The variants of this classic triad are characterized between others by the presence of normal anterior pituitary lobe or only by ectopic PSIS, are posterior pituitary.4,6 Both, classic triad and variants of commonly seen in patients with MPHD.3,10 Isolated hypoplasia of anterior pituitary lobe cannot be considered as a variant of PSIS.

Ethiology of PSIS PSIS is a developmental hypotalamo-pituitary axis abnormality with a largely unknown ethiology and pathogenesis as well.9,11,13, 14 Although, during the last decade, progress in molecular biology as well as the advent of magnetic resonance imaging has reduced the number of idiopathic pituitary diseases, to date, majority of PSIS, similar to congenital hypopituitarism, are idiopathic and only rare cases have been assigned to a known genetic cause. Because of complexity of pituitary embryogenesis and phenotypic variability among PSIS patients, a multigenic pattern of pituitary stalk disgenesis have been sugessted. 12,14 Mutations within HESX1, LHX3, LHX4, GLI2, SOX2, and SOX3 genes are rare causes of congenital hypopituitarism.(16) Rare mutations of the of transcription factors genes as HESX1, GLI2, LHX4 and SOX3 genes, involved in early pituitary development, that are also the most frequently mutations found in syndromic MPHD, have been reported in a few number of cases with PSIS.1,3,9,10,11,15,16,17,18 Mutations in early developmental genes such as HESX1, SOX2 and LHX3 are associated with complex pituitary phenotypes as they are expressed in both the hypothalamo-pituitary region as well other regions. 19,20 Less than 5 % of cases of pituitary stalk dysgenesis is the result of mutations in genes required for pituitary development and function more exactly pituitary transcription factors genes. 1,14,18 Mutations in early-expressed during embrionic development genes, or homeobox genes are not pituitary specific, and their mutations may cause complex cranio-facial congenital defects and of many other organ or tissular abnormalities. 16,20,21 PSIS has been considered as a hypomorphic form of midline abnormalities.14 Animal models from basic research studies provided the framework for understanding genotype-phenotype relationship of hypotalamo-pituitary axis anomalies. (Table 1.1) For example, HESX1

Pituitary stalk interruption syndrome in children


mutations can cause MPHD or occasionally, isolated GH deficiency that are associated with pituitary stalk dysgenesis, while mutations within PROP1 gene are the common cause of familial congenital hypopituitarism without structural abnormalities. Furthemore, mutations within GLI3 gene have been showed to result in disruption of epithelial-mesenchymal interaction involving different organs and tissues that cause Pallister-Hall syndrome in wich pituitary insufficiency is associated with multiple congenital anomalies.15 Transcription factor SOX3 is involved in X-linked mental retardation associated with GHD.(18) The male preponderance between PSIS patients observed in some studies suggested an X-linked inheritance. Recently, X-linked inherited SOX3 mutations were reported to be responsible for hypopituitarism in patients with PSIS.9 Table 1.1. Structural abnormalities and hormone deficiencies associated with dysgenetic pituitary stalk of different ethiology TF gene









PSD asociated abdnormalities PP: Ectopic / Eutopic AP:Hypoplastic/normal PP: Ectopic / Eutopic AP:Hypo-/Hyperplastic / normal PP: Ectopic / Eutopic AP: Hypoplastic AP PP: Ectopic / Eutopic AP: Hypoplastic


Other syndromic features Septo-optic dysplazia Eye abnormalities Polydactily Chiari malformation type 1 Corpus callosum hypoplasia Sella turcica hypoplasia Mental retardation

Corpus callosum disgenesis Eye abnormalities Clinodactiliy GLI2 AD PP: Ectopic GH, TSH, LH, Holoprosenchephaly AP: Hypoplastic FSH, PRL ± Cleft lip ACTH Solitary central incisor Polydactily Pituitary stalk dysgenesis (PSD), Transcription factor (TF), Posterior pituitary (PP), Anterior pituitary (AP)

Short stature, bilateral cryptorchidism, micropenis, and heart defect were described in children with 17q21.31 microdeletion syndrome and PSIS.(8) This syndrome is one of the first genomic disorders identified by array comparative genomic hybridization (array-CGH) analysis, and have an incidence of 1 in 16,000 births. The most ferquent clinical caracteristics are mental retardation, facial dysmorphism, childhood feeding difficulties, seizures and a typical behavioral phenotype (friendly


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and cooperative but also hyperactivite, bad humor, temper tantrums and poor interaction patients). Central nervous system involvement consists of dysgenesis or absence of corpus callosus, enlargement of lateral ventricles, Chiari malformation type 1 and abnormalities of cyngulate gyrus. Short stature, bilateral cryptorchidism, micropenis, and heart defect were described in children with 17q21.31 microdeletion syndrome and PSIS.8,22 The critical 17q21.31 region includes the gene encoding for corticotropin-releasing hormone receptor 1, a protein implicated in hyperexcitability, and potentially in infantile spasms favorably influenced by ACTH therapy. 22 Autosomal dominant mutations in LHX4 are involced in abnormal embryonic development of the anterior pituitary glanda. Microdeletion 1q25 syndrom characterized by the entire deletion of LHX4 gene, is recognized to cause the pituitary dysgenesis associated with and variable MPHD 23.

Normal and Pathologic Pituitary Gland Development Pituitary Gland Development The pituitary gland is a master regulator of basic physiological functions, including growth, pubertal development, fertility, lactation, the stress response and metabolic homeostasis. 24,25 The anterior pituitary comprises five different cell types secreting six well-known hormones: growth hormone (GH) thyrotrop hormone (TSH), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), adrenocorticotrop hormone (ACTH), prolactin (PRL). The intermediate lobe secretes pro-opiomelanocortin (POMC), which is a precursor to melanocyte-stimulating hormone (MSH) and endorphins, and is involuted in the adult. The posterior pituitary, or neurohypophysis is responsible for storing and secreting antidiuretic hormone and oxytocin, which are produced by neurons in the paraventricular and supraoptic nuclei of the hypothalamus. 16, 17, 19 Genetic or environmental factors may contribute to disturbed hypothalamic-pituitary axis development but the underlying mechanisms involved in most cases of PSIS remain to be identified. 9,13 Embriology of pituitary gland is a complex process very well orchestrated by temporal and spatial interaction beteewn extrinsic signals from the ventral diencephalon and surrounding structures involving WNT, BMP, FGF, Notch, and Hedgehog pathways and activation of transcription factors. 16,27 Alterations in signaling WNT, BMP, FGF, Notch, and Hedgehog pathways affect the induction, morphology, growth and size of pituitary gland.16 Normal pituitary development depends on the sequential expression of transcription factors. 9,16,19,24,25,26 Transcription factors GLI2, SOX2, SOX3, and TCF7L2 genes are primarily expressed in the neural ectoderm.16

Pituitary stalk interruption syndrome in children


The two pituitary components, adenohypophysis, comprising anterior and intermediate lobes of pituitary gland, and neurohypophysis respectively develop from different embryological tissues.26,27 The adenohypophysis derives from an invagination of the oral ectoderm named Rathke’s pouch. Intermediate lobe of the fetus pituitary gland undergoes involution during the third trimester of pregnancy.The posterior pituitary gland derives from neural tissue from the floor of the third ventricle and originates from the infundibulum, a ventral evagination of the diencephalon. It consists of the distal axons of the hypothalamic magnocellular neurones that shape the neurohypophysis. After its downward migration, it is encapsulated together with the ascending ectodermal cells of Rathke’s pouch. 9,17, 26,27 PSIS Patogenesis In the early stages of pituitary organogenesis, the close interaction between the primordium of anterior gland pitutary primordium, which is the Rathke’s pouch and the evagination of the ventral diencephalon neuroectoderm is critical for pituitary gland formation. A normal pituitary stalk allows a normal connection between hypothalamus and pituitary gland. Dysgenesis of pituiray stalk by defective angiogenesis and disruption of the vascular portal system impaires both pituitary blood supply and hypophysiotropic hypothalamic hormones signalling to reach their pituitary cell targets and thus resulting in pituitary hypoplasia and pituitary insuficiency. 28,29 Ectopic posterior pituitary can be the consequence of an additionally defective neuronal migration and axon projections along the pituitary stalk. A high correlation have been established between the structural abnormalities of PSIS and anterior pituitary function. Different level of vascular blood flow preservation in the pituitary stalk may account for the differences in evolving pituitary hormone deficits.14,30,31 In normal subjects, the posterior lobe is supplied directly by the inferior pituitary arteries and the anterior pituitary lobe through the pituitary portal system. 9 Structural abnormalities of hipotalamic-pituitary axis including anterior pituitary hypoplasia, pituitary stalk interruption, ectopic posterior pituitary, and empty sella are recognized causes of congenital hypopituitarism in childhood. Empty sella syndrome consists of the filled superior portion of the sella turcica with cerebrospinal fluid caused by a thin or absent sellar diaphragm, which leads to sella enlargement secondary to chronic cerebrospinal fluid pulsation. Pituitary gland is flattened in appearance. Although it is generally asymptomatic, in a child empty sella can be associated with pituitary hormone abnormalities, cerebrospinal fluid rhinorrhea or visual field abnormalities.10, 28, 32 Classic PSIS or its variant is a particular entity in the population of patients with hypopituitarism being associated with complete or permanent GHD in almost all affected children (> 95 % of cases).7,9


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Hormone deficiencies may evolve progressively through childhood, overlaping GH therapeutic replacement and leading to panhypopituitarism and may be associated with significant morbidity and mortality. 31 The severity of structural abnormalities are highly correlated with hormonal deficits. 9) Heterogeneous pituitary stalk lesions result in different degree of dopaminergic pathway disconnection and both hyperprolactinemia and prolactin deficiency may be rarely found in patients wuth PSIS.9,11 Lossing of dopaminergic inhibition of the prolactin secretion result in hyperprolactinemia.11,30 Furthermore, the capacity of the pituitary cells to secrete GH, TSH, ACTH, and gonadotropins may be dissociated in these subjects and response to stimulation tests using hypothalamic factors may depends on the cause of PSIS, the volume of the anterior pituitary, and the age at clinical evaluation.21

Magnetic Resonance Imaging Assessment Normal Aspects and Pathologic Findings During the last three decades, neuroimaging techniques progressively expanded and improved becoming an essential part of the diagnostic process in children with GHD.Thus, the so-called pituitary stalk interruption syndrome, first described 27 years ago, is now routinely diagnosed by MRI criteria. MRI is the radiological examination of choice for visualising the hypothalamo-pituitary and parasellar regions and for identifing its structural abnormalities in children starting from neonatal period. MRI is a particularly advantageous imaging method as it provides high contrast resolution, fine sections, the possibility of multiplanar imaging, omits artefacts from bone structures and avoids X-ray exposure. 3,10,11,33,34 MRI contraindications include pacemakers, vascular clips or other metallic devices, foreign bodies or cochlear implants.3 Incomplete cooperation and/or the need for sedation or anaesthesia in children may negatively impact both imaging quality and scanning time.7 As a standard investigation in pediatric endocrinology, MRI allows detailed and precise anatomical informations about the pituitary gland location, shape and size, less or more homogeneous parenchymal enhancement and allows differention between the anterior and posterior pituitary lobes do to of hyprintense characteristic signal of the last. 3,7,9,10,11, 33, 35

A high-quality MRI scans, should routinely entail 3 mm sagittal and coronal sections on high-resolution T1-weighted images, with a maximum of 10% interslice gaps. 7,32 Coronal scans allow for the visualization of the pituitary gland, stalk, chiasm and parasellar regions. Sagittal images are best suited for the evaluation of the midline plane. Ideally, T1-weighted images should be obtained both before and after intravenous contrast agent administration.3

Pituitary stalk interruption syndrome in children


The MRI characteristics of the normal pituitary gland are well established for children.(36) In fetuses, newborns, and infants under the age of 2 months, the pituitary gland is bulbous in shape, round, ovoid or irregular triangular with a typically convex upper margin. It is an entire bright and hypointense structure with a very high signal intensity on T1weighted images without differentiation between anterior and posterior lobe. 3,36 The brightness of the adenohypophysis may be accounted for by intense cellular activity and high levels of protein synthesis at this age. 36 The pituitary stalk, represented by a linear isointense structure connecting the hypothalamic region to the floor of the sella turcica, has been detected on coronal or sagittal section in 100% of foetuses from the 26th week of gestational age.3 After the second month of life the gland progresses towards adult appearance, with a flat superior surface and isointensity of the anterior lobe on T1- and T2- weighted images and marked hyperintensity of the posterior lobe on T1-weighted images that becomes progressively recognizable as a bright spot. 3,11, 32 The normal size of the pituitary gland varies by age. Pituitary gland height decreases during the first year of life and gradually increases from the second year until puberty. 36 During puberty, the anterior pituitary gland undergoes profound in size and shape in girls in whom physiological symmetrical hypertrophy directly related to GH-secreting cells number and GH levels, result in a nearly spherical gland with convex upper margin and changes only in size in boys. Its height ranges between 3 and 6 mm in prepubertal children, and 10 - 12 mm in pubertal girls and may reach 7 - 8 mm in pubertal boys.3 Pituitary gland decreases in size after puberty. 27 The posterior pituitary does not undergo physiological variations in either size or signal hyperintensity during childhood.3 The T1 hypersignal of the neurohypophysis has been attributed to storage of the neurophysinvasopressin complex and is considered a marker of neurohypophyseal functional integrity.3 A normal pituitary stalk usually tapers smoothly along pituiary posterior lobe and should not exceed basilar artery diameter being of approximately 3 mm in diameter near the optic chiasm and 2 mm at distal glandular end.3 In general, a thin stalk is less than 1 mm at any point. 10 A contrast agent MRI is necessary for pituitary stalk visualization, in children with hypopituitarism and in those with central diabetes insipidus. (Figure no.1.1.) MRI with Gadolinium-Diethylene Triamine Pentaacetic Acid (GdDTPA), a contrast agent wich should be administered intravenously in the dosage of 0.1 ml/kg body weight, improves the examination of the pituitary stalk, by increased sensitivity in identifying the vascular component of pituitary stalk. The thin pituitary stalk cannot be definitely excluded without enhancement and dynamic scans.5,10,11


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Figure no.1.1. T1-weighted sagital image of: a) physiologically bright posterior pituitary lobe and normal pituitary stalk (arrowhead) ; b) ectopic posterior pituitary lobe, hypoplastic anterior pituitary lobe (arrowhead) and invisible pituitary stalk. (personal collection)

Dynamic contrast-enhanced studies allow detection of blood flow within pituitary stalk, and overall contribute to improved our knowledge and understanding on function of the hypothalamic - pituitary axis and pathogenesis of hypotalmic- pituitary diseases. A delayed maximum enhancement may be a result of attenuated pituitary perfusion and consequent ischemia as the causes of pituitary dysfunction in PSIS. Recently, high-resolution, heavily T2-weighted sagittal images/T2DRIVE or fast imaging employing steady state acquisition sequence obtained at sub-millimetre thickness, provide an excellent visualization of the suprasellar region and are especially suited to the assessment of the pituitary stalk without using contrast medium.32 Ectopic posterior pituitary may be located anywhere from the median eminence to the distal stalk.2,32 Ectopic neurohypophysis may be located at the level of median eminence in cases with normal pituitary stalk, at any level along of a vizibile thin stalk, and exceptionally near the optic chiasm and hypothalamus base. In the second condition GH secretory capacity may increase with age.9 Ectopic posterior pituitary gland is a marker of PSIS and pituitary dysfunction. 5,31

Pituitary stalk interruption syndrome in children


Absence of the posterior lobe bright signal, with or without a thick pituitary stalk or a mass at any site from the median eminence to the posterior pituitary lobe, may be found in diabetes insipidus.36 MRI phenotype of PSIS is a predictor of the occurrence of pituitary hormone deficiencies and it is correlated with the severity of endocrine dysfunction.11 Structural abnormalities of hypothalamo-pituitary axis associate severe GHD and MPHD.32 MRI is not invasive.Cerebral MRI with pituitary protocol is advisable in all children with GHD, even in though with isolated GHD, in children with MPHD, central diabetes insipidus, and syndromic hypopituitarism. Axial T2-weighted fluid attenuation inversion recovery images covering the entire brain are recommended in order to screen for additional abnormalities.32 Relevance of MRI for Pituitary Functional Prognostic MRI findings have diagnostic and long-term prognostic significances regarding the endocrine dysfunction. The identification of posterior pituitary hyperintensity, is considered a marker of neurohypophyseal functional integrity, Visibility of the pituitary stalk was associated with a particularly good anterior pituitary functional prognostic. Posterior pituitary ectopia with normal, thin or absent pituitary stalk is a sensitive and specific indicator of hypopituitarism.15,34,37 Ectopic posterior pituitary at the level of median eminence have been associated with MPHD, and its location along pituitary stalk with a good prognostic for hormonal profile.(Figure no.1.2.)

Figure no. 1.2 - Anatomical characteristics and functional significance of ectopia of posterior pituitary lobe assessed by MRI Anterior pituitary (AP); Central diabetes insipidus (CDI); Multiple pituitary hormone deficiency (MPHD) Isolated growth hormone deficiency (IGHD)


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Early detection of ectopic neurohypophisis is predictive of GHD than can be asymptomatic during first years of life. Children with invizible pituitary stalk have a 27 times greater risk of developing MPHD than those with a vascular residue of a thin stalk. 3 PSIS is highly predictive of permanent severe GHD. 37,38 MRI findings may help planning the strategy for genetic analysis, and by a better selection of patients may serve for reducing the cost of genetic screening.9. A positive family history of hypopituitarism or consanguinity recommendes the screening for HESX1 and LHX4 mutations in cases with PSIS. In sporadic PSIS cases these defects may can be ruled out as common ethiology of the syndrome. Genetic screening for OTX2 mutations should be performed in cases with associated ocular malformation and with or without signs of hypopituitarism.9,18 The sceerning of PROP1, POU1F1 or LHX3 gene mutations, the common cause of congenital MPHD is not recommended in cases with PSIS because pituitary stalk interruption and ectopic posterior pituitary lobe practically exclude mutations of these genes that control anterior pituitary development, pituitary cell terminal differentiation and pituitary cell proliferation. 15,18

Clinical Manifestations and Mangement of PSIS Clinical Manifestations of PSIS Clinical data concerning this syndrome are limited. PSIS represent a distinct anatomical and endocrinological syndrome that has been shown to be associated with either isolated GHD or MPHD and frequent with extrapituitary malformations or dysmorfic features. Clinical phenotype is highly variable depending on the type and severity of endocrine disfuction, associated abnormalities and the age of hypopituitarism onset.1,2,4,6,11,19,29, 33 One of the primary sources of diagnostic information relevant to hypotalamo-pituitary abnormalities is family history of microphallus, strabismus, bilateral coloboma, microcephaly familial PSIS, MPHD or isolated GHD. 5,21 Clinical manifestations of PSIS may occur early, in perinatal period, with non-specific symptoms as respiratory distress, hypoglycemia and recurrent hypoglycemic seizures, prolonged jaundice or during the first two to three years of age with the signs of isolated GHD, the first manifest pituitary hormone deficit. It is rarelly diagnosed at birth, during neonatale period or during first months of life in symptomatic cases of MPHD, but may identified at any age until puberty when manifests delayed appearance or absence of secondary sexual characteristics and even postpuberty. In the Fernandez-Rodriguez E. et all. retrospective and prospective study involving 231 hypopituitary adult patients, including 26 diagnosed with pytuitary stalk disgenesis was diagnosed before 14 years of age in 46.2% of cases, between 14 and 18 years of age in 23%, and in

Pituitary stalk interruption syndrome in children


adulthood in 30.8%.1 A mean age at diagnosis of 3.6 years was reported in weastern PSIS children studies.4 Affected newborns may be initially asymptomatic but at risk of developing hypopituitarism over time or may present with non-specific symptoms, with or without associated ocular, midline and/or genital abnormalities. The discovery of a such developmental defect in a newborn should lead to cerebral MRI assessment of the hypothalamo-hypopituitary axis. (Table I. 2) Table I. 2. Clinical findings suggestive for PSIS diagnosis -




Positive family history Intrauterine growth retardation Advers perinatal retardation • breech / forceps delivery • cesarean section • neonatal distress /.hypoxemia • prolonged unconjugated jaundice • hypoglycemia • recurrent seizures • hyponatremia • feeding difficulties • hypotonia Congenital genitalia anomalies in males • Micropenis • Microrchidism • cryptorhidism Hypopituitarism evolving manifestations • Strabismus • Solitary maxillary central incisor • Cleft upper lip Other organ malformations

Neonatal signs may be observed in patients with severe anterior pituitary hypoplasia. Symptomatic newborns have a high risk of cardiomyophaty and cardiac insufficiency with reduced myocardial contractility and hemodynamic instability, irreversible central nervous system damage or premature death by a combination of hypoglycemia, hyponatremia, heart faillure and seizures.4,6,8,23 MPHD is a life-threatening condition and a clinical picture of MPHD present perinatally or during first months of life may suggest the presence of PSIS.8, 23 A high incidence of adverse perinatal events, such as breech or forceps delivery, cesarean section neonatal distress and/or neonatal hypoxemia with low Apgar score and/or requiring neonatal resuscitation, hypoglycemia and recurrent hypoglycemic seizures because of GH and ACTH deficiencies, prematurity, prolonged non-conjugated jaundice and


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frequent vomiting, has been described among children with hipotalamicpituitary deficiency.4,7,8,15,14,30,37,39,40 Severe neonatal distress affects about ¼ of patients with PSIS.7 Breech delivery and cesarean section for dystocia were reported in 88.9% and 34.5% of cases respectively. 2 The cause - effect relationship between abnormalities of pituitary gland and of birth presentation is a topic of interest. It was postulated that the hypopituitarism leads to the abnormal birth through not yet understood mechanisms. 30 During the time two hypothesis regarding to PSIS associated perinatal events have been developed, traumatic hypothesis and malformative hypothesis respectively. The first hypothesis proposed at birth hypotalamic or pituitary trauma as pathophysiological mechanism leading to perinatal events of PSIS do to the high frequency of obstetric complications and perinatal anoxia observed in these children. According to malformative hypothesis, perinatal pathology seems to be a direct or indirect consequence rather than the cause of the PSIS. 2,21 Endocrine dysfunctional state resulting from dysgenesis of hypothalamopituitary axis could be the cause of hypotonia and abnormal, slow fetal movements leading to intrauterine malposition, malpresentation, and dystocia similar to those described in other hypotalamic dysfunctinal genetic syndromes as Prader Willi syndrome. Thus perinatal advers events may be related with pituitary dysfunction. Recurrent or persistent hypoglycemia unexplained by other neonatal conditions suggests cortisol deficiency and may be associated with prolonged jaundice and/or low blood pressure and recurrent sezures. GH and ACTH plasma concentrations should be measured during spontaneous hypoglycemia knowing that hypoglycemia is the most important stimulus for GH and ACTH secretion.5,9 Association of hypoglycemia and micropenis in neonates and infants is highly suggestive of an MPHD. 6,12 Clinicians should be aware of newborn breech delivery or cesarean section in planning a diagnostic workup for GHD and adrenal insufficiency in a newborn with hypoglycemia.4 Breech presentation, neonatal hypoglycemia, and micropenis are considered the factors that best discriminate patients with MPHD from those with an isolated GHD.9,30 Genitalia congenital anomalies such as microphallus in boys reported in 23.4%.of children and defined as a penis length of ≤ 2.5 cm or less than -2 SD for age, microrchidism and cryptorchidism accounting for 6.3% of the male patients have to be correlated with complete gonadotropin deficiency. 9,12,40 Severe GHD leads to poor growth in the first year of life. The presenting sign of GHD is low growth velocity. Based on severe growth impairment an early diagnosis is possible around the age of 2 years. In a small French study of forteen PSIS children almost one third of PSIS patients have been diagnosed during the first 2 months of life.8 In an infant GHD may be confirmed on the basis of low concentrations of insulin-like growth factor 1 (IGF1) and IGF-binding protein 3 in

Pituitary stalk interruption syndrome in children


combination with a poor growth rate and other hormonal deficiencies. GH provocation tests except glucagon test are contraindicated in children less than 1 year of age. 19 In older children, the diagnosis is based on low growth velocity, short stature delayed bone age and. 41,43 Patients with PSIS have greatest deviation from the mid-parental height and shorter stature compared with patients with other ethiology of growth failure. Insidious onset of pituitary insuficiency as isolated GHD, the first pituitary hormone deficit found at first assessment in 92- 100% of patients, is followed by progressive MPHD. The most common presenting clinical feature is low growth velocity identifiable in all children during the first or the second year of age.1, 2 MPHD is seldom present at birth or at the diagnosis of PSIS when it is manifested with afore-mentionated symptoms and/or as early severe growth failure secondary to GH and TSH deficiencies.23 Additionale pituitary endocrine dysfunctions may occur during the next two decade needing close and long-term follow-up and appropriate hormone replacement therapy. The frequency of MPHD in PSIS varied in different series beetwen 87.5% and 92.7% of cases. Thyrotropin deficiency and secondary hypothyroidism is the second most frequent expression of hypopituitarism present in 76.3% to 91% of PSIS patients.1,2 Gonadotrophin deficiency is a common finding in patients with PSIS with a variable severity ranging from complete gonadotrophin deficiency to normogonadotropic amenorrhoea. at puberty prevalence of gonadotrophin deficiency may reache to 95.8% 2. Incomplet puberty development including absent pubic or axillary hair, hypoplasia of mammary glands, ovarian dysgenesis, infantile uterus and genitalia or primary amenorrhea. FSH and LH deficiency resultes in delayed or absent puberty. Posterior pituitary function is usually maintained.9,11,18,31 An incomplete pubertay in girls with hypogonadotropic hypogonadism may manifest with the presence of thelarche at the age of 13 years hypoplasia of mammary glands, absent pubic or axillary hair, ovarian dysgenesis, infantile uterus and genitalia but with primary or with secondary amenorrhea at the age of 16 years. Micropenis in a boy patient present at PSIS diagnosis time is the sign of hypogonadism. Moreover, the absence of pubertal development have to be considered in the absence of breast development at 13 years in female or if testicular volume is below 4 ml at 14, 5 years in male patients. Hypodynamia, fatigue and increased susceptible to upper respiratory infections are present in some children with pituitary stalk dysgenesis.2 Defects in organogenesis of pituitary gland are sometimes associated with congenital anomalies that affect head development.16,32


Lenuta Popa

Associated malformations are more likely to be found in children with MPHD.6 The frequency of neuroanatomical abnormalities consisting in a great variety of structural defects both within and outside the hypothalamic-pituitary region, in 15, 043 of 43, 725 children with nonacquired GHD of idiopathic or known congenital ethiology who were enrolled in KIGS (Pfizer International Growth Database) between 1987 and 2011 a was of 26.80%.32 Extrapituitary abnormalities which can be detected with current sensitive cerebral MRI techniques in children with PSIS have been reported in 20-58% of cases.2,6,15,16 Abnormalities of the central nervous system cerebral associated with PSIS consist of cerebellar atrophy or dysplasia, microcephaly, bilateral optic nerve hypoplasia, holoprosencephaly, type I Arnold Chiari malformation, cerebellar and corpus callosum atrophy, internal carotid arteries agenesis.3 The most useful for PSIS diagnosis and prioritizing genes for molecular studies in human patients are besides pituitary stalk dysgenetic findings (figure no.1.3), a number of midline abnormalities such as palatine cleft, anus anteposition, interatrial septal defect, persistent common atriventricular ostrium and single ventricle, nasal pyriform aperture stenosis, and a single central incisor that is a feature of holoprosencephaly.9,16,15

Figure no.1.3. Diagnosis algorithm in children with PSIS

Pituitary stalk interruption syndrome in children


Congenital hypopituitarism associated to dysmorphic features are generally linked to early-expressed genes during pituitary development as GLI2, SOX2, SOX3, HESX1, LHX3, LHX4, whereas non-syndromic hypopituitarism is generally due to defects in later-expressed, pituitaryspecific genes such as PROP1 and POU1F1.16 Non-pituitary related syndromic features such as Chiari malformation, craniofacial abnormalities, limited neck rotation, eye abnormalities, and hearing deficits can suggest a causative gene that could account for hypopituitarism and the syndromic features. 16 Malformations involving the heart, limbs and skeleton, sella turcica, the kidneys, the gastrointestinal tract and the skin were also reported.10,15,21. Some PSIS patients may have more than one abnormality.5,9 Extrapituitary malformations and suggestive perinatally adverse events may prompt PSIS diagnosing but they may be also associated with more severe form of pituitary hypoplasia and a greater severity of endocrine dysfunction.

Management of PSIS The routine long-term follow-up of patients with PSIS should be performed by a pediatric endocrinologist.41,42,43,44 Pituitary function should be periodically assessed in subjects with isolated GHD or MPHD, as they may develop additional pituitary hormone deficiencies and severe adrenal insufficiency and hypogonadotropic hypogonadism.28 As MPHD is not demonstrated at the first evaluation, progression to complete anterior pituitary deficiency may occur progressively, during the second or even the third decade of their life.5 Investigations include a combination of auxological measurements, basic and provocative tests of the hypothalamo-pituitary axis function and neuroradiology. Gonadotropic axis should be investigated at puberty age. FSH and LH deficiency is suggested by delayed, incomplet or absent pubertal development and confirmed by low serum testosterone in boys and or estradiol levels girls patients and by blunted FSH and LH response to a gonadotropin-releasing hormone stimulation test. The level of vascular blood flow preservation in the dysgenetic pituitary stalk may account for the differences in hormone deficiencies in PSIP children. A MRI of the brain with particular attention to the hypothalamicpituitary region should be carried out in any child diagnosed as having GHD.3,4,41,42,43 A normal MRI or isolated anterior pituitary hypoplasia generally indicates isolated growth hormone deficiency that is mostly transient and resolves upon adult height achievement and a the classic


Lenuta Popa

triad of pituitary stalk dysgenesis is more frequently reported in MPHD patients and is generally associated with permanent GHD.3 Ectopic posterior pituitary itself has a 100% predictive value and a 100% specificity for GH deficiency in children with growth failure.12 Central diabetes insipidus by antidiuretic hormone deficiency have to be rould out in a child with clinical features of MPHD by 12 hours the water deprivation test. Conventional hormone replacement therapy consists of recombinant human growth hormone (rhGH), hydrocortisone, levothyroxine sodium, estradiol or testosteron necessary to improve growth velocity and avoid adverse clinical symptoms.6, 8, 40,44 Diagnosis of ACTH deficiency is essential to the initiation of hydrocortisone treatment. Early diagnosis and treatment of GHD are necessary to allow catchup growth to optimal height before puberty. Height gain was significantly higher in patients who started GH treatment before 4 years. Increase in height and change in height velocity are useful in clinical practice to assess the response to GH. 40,41,43 Growth deficit in these children responds very well to rhGH therapy, in particular during the first year.8 The objective of treatment of GH deficiency in childhood is to achieve normal final height with the best metabolic and body composition benefits.34,44 Treatment with testosterone injections was reported to be efficient on penile growth in neonates and small infants but treatment with recombinant human FSH at age of 5-8 years seems to be less effectiv regarding increasing of the testicular volume and plasmatic levels of antimullerian hormon and Inhibin B. 29 Reassessment of the GH–IGF axis at the end of growth has been recommended for all young people with childhood onset GHD except those with severe panhypopituitarism defined as four or five hormone deficiencies. At transition to adulthood retesting GH levels is unnecessary in children with a proven structural hypotalamo- pituitary axis abnormality such as PSIS.31 We may conclude that MRI is an essential tool in the assessment of patients with suspected hypothalamo-pituitary pathology. Establishing endocrine and MRI phenotypes is extremely useful for the selection and management of patients with hypopituitarism, both in terms of possible genetic counselling and in the early diagnosis of evolving anterior pituitary hormone deficiencies. Importance of periodic follow-up of pituitary hormone status as well as sexual development in these children is indisputable. Clinician have to recognized early signs of a hormonal deficiency and avoid diagnostic delay of a growth hormon deficit or a multiple pituitary hormone deficiency.

Pituitary stalk interruption syndrome in children


References 1.

2. 3. 4.



7. 8. 9.

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Fernandez-Rodriguez E., Quinteiro C., Barreiro J., Marazuela M., Pereiro I., Peinó R., Pituitary stalk dysgenesis-induced hypopituitarism in adult patients: Prevalence of evolution of hormone dysfunction and genetic analysis, Neuroendocrinology, 2011, 93(3): 181 - 188; Guo Q, Yang Y, Mu Y, Lu J, Pan C, et al., Pituitary Stalk Interruption Syndrome in Chinese People: Clinical Characteristic Analysis of 55 Cases, PLoS ONE, 2013, 8(1): e53579. Iorgi N., Allegri A.E., Napoli F., Bertelli E., Olivieri I., Rossi A., Maghnie M., The use of neuroimaging for assessing disorders of pituitary development, Clin Endocrinol, 2012, 76(2):161 - 176; Gascoin-Lachambre G., Brauner R., Duche L., Chalumeau M., Pituitary Stalk Interruption Syndrome: Diagnostic Delay and Sensitivity of the Auxological Criteria of the Growth Hormone Research Society. PLoS ONE, 2011, 6(1): e16367; Chen S., Léger J., Garel C., Hassan M., Czernichow P., Growth hormone deficiency with ectopic neurohypophysis: anatomical variations and relationship between the visibility of the pituitary stalk asserted by magnetic resonance imaging and anterior pituitary function, J Clin Endocrinol Metabol, 1999, 84: 2408 - 2413; Pham L.L., Lemaire P., Harroche A., Souberbielle J.C., Brauner R., Pituitary Stalk Interruption Syndrome in 53 Postpubertal Patients: Factors Influencing the Heterogenity of Its Presentation, PloS ONE, 2013, 8(1),e:53189; Nagel B.H.P., Palmbach M., Petersen D., Ranke M.B., Magnetic resonance images of 91 children with different causes of short stature: pituitary size reflects growth hormone secretion, Eur J Pediatr, 1997,156:758 - 763; Chehadeh S., Bensignor C., Monléon J.V., Méjean N., Huet F., The pituitary stalk interruption syndrome: endocrine features and benefits of growth hormone therapy, Ann Endocrinol, 2010, 71(2):102- 110; Reynaud R., Albarel F., Saveanu A., Kaffel N., Castinetti F., Lecomte P. et al., Pituitary stalk interruption syndrome in 83 patients: novel HESX1 mutation and severe hormonal prognosis in malformative forms, Eur J Endocrinol, 2011, 164(4): 457- 465; Tsai S.L., Laffan E., Lawrence S., A retrospective review of pituitary MRI findings in children on growth hormone therapy, Pediatr Radiol, 2012, 42(7):799- 804; Wang Q., Yanyan Hu Y., Li G., Sun X., Pituitary stalk interruption syndrome in 59 children: the value of MRI in assessment of pituitary functions, European Journal of Pediatrics, 2014, 173 (5): 589 - 595; Rottembourg D., Linglart A., Adamsbaum C., Lahlou N., Teinturier C., Bougnères P., Carel J. C., Gonadotrophic status in adolescents with pituitary stalk interruption syndrome, Clin Endocrinol, 2008, 69:105 111; Romero C.J., Nesi-Franca S., Radovick S., The molecular basis of hypopituitarism, Trends Endocrinol Metabol, 2009, 20: 506 - 516; Reynaud R., Jayakody S.A., Monnier C., Saveanu A., Bouligand J., Guedj, al., PROKR2 Variants in Multiple Hypopituitarism with Pituitary Stalk Interruption, J Clin endocrinol Metabol, 2012, 97(6): e1063 - e1074;


Lenuta Popa 15. Simon D., Hadjiathanasiou C., Garel C., Czernichow P., Leger J., Phenotypic variability in children with growth hormone deficiency associated with posterior pituitary ectopia, Clin Endocrinol, 2006, 64 (4): 416 - 422; 16. Davis S.W., Castinetti F., Carvalho L.R., Ellsworth B.S., Potok M.A., Lyons R.H. et al., Molecular mechanisms of pituitary organogenesis: in search of novel regulatory genes, Mol Cell Endocrinol, 2009, 323: 4 - 19; 17. Mehta A., Dattani M.T., Developmental disorders of the hypothalamus and pituitary gland associated with congenital hypopituitarism, Res Clin Endocrinol Metab, 2008, 22 (1):191 - 206; 18. Lamine F., Kanoun F., Chihaoui M., Slimane H., Saveanu A., Barlier A. et al., Unilateral agenesis of internal carotid artery associated with congenital combined pituitary hormone deficiency and pituitary stalk interruption without HESX1, LHX4 or OTX2 mutation: a case report, Pituitary, 2012, 15: S81 - S86; 19. Mehta A., Hindmarsh P.C., Mehta H., Turton J.P.G., Russel-Eggitt I., Taylor D., et al., Congenital hypopituitarism: clinical, molecular and neuroradiological correlates, Clin Endocrinol, 2009, 71:376 - 382; 20. Sertedaki A., Voutetakis A., Valavani E., Magiakou M.A., KanakaGantenbein C., Chrousos G.P. et al., Pituitary Stalk Interruption Syndrome and Isolated Pituitary Hypoplasia May Be Caused by Mutations in Holoprosencephaly-Related Genes, The Journal of Clinical Endocrinology & Metabolism, 2013, 98 (4): E779-784; 21. Pinto G., Netchine I., Sobrier M.L., Brunelle F., Souberbielle J.C., Brauner R., Pituitary stalk interruption syndrome: a clinical-biological-genetic assessment of ist pathogenesis, J Clin Endocrinol Metab, 1997;82:3450 3454; 22. Terrone G. et all., A further contribution to the delineation of the 17q21.31 microdeletion syndrome: Central nervous involvement in two Italian patients, European Journal of Medical Genetics, 2012, 55 (8-9): 466 - 471 23. Filges A., Bischof-Renner A.,Röthlisberger B., Potthoff C.,Glanzmann R., Günthard J., Pan-hypopituitarism Presenting as Life-Threatening Heart Failure Caused by an Inherited Microdeletion in 1q25 Including LHX4, Pediatrics, 2012,129: e529 24. Gaston-Massuet C., Andoniadou C.L., Signore M. et al., Genetic interaction between the homeobox transcription factors HESX1 and SIX3 is required for normal pituitary development, Dev Biol, 2008; 324:322 - 333; 25. Kelberman D., Rizzoti K., Lovell-Badge R., Robinson I., Dattani M.T., Genetic regulation of pituitary gland development in human and mouse, Endocr Rev, 2009, 30:790 - 829; 26. Moraes D.C., Vaisman M., Conceicao F.L., Ortiga-Carvalho T. M., Pituitary development: a complex, temporal regulated process dependent on specific transcriptional factors, J Endocrinol, 2012, 215 (2) 239; 27. Zhu X., Lin C.R., Prefontaine G.G., Tollkuhn J., Rosenfeld M.G., Genetic control of pituitary development and hypopituitarism, Curr Opinion Genet Develop, 2005, 15:332 - 340; 28. Iorgi N., Secco A., Napoli F., Tinelli C., Calcagno A., Fratangeli N. et al., Deterioration of Growth Hormone (GH) Response and Anterior Pituitary Function in Young Adults with Childhood-Onset GH Deficiency and Ectopic Posterior Pituitary: A Two-Year Prospective Follow-Up Study, J Clin Endocrinol Metabol, 2007, 92 (10): 3875 - 3884;

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29. Lucci-Cordisco E., Scommegna S., Orteschi D., Galeazzi D., Neri G., Boscherini B., Three unrelated patients with congenital anterior pituitary aplasia and a characteristic physical and neuropsychological phenotype: A new syndrome?, Am J Med Genet, 2012, 158A:2750 – 2755; 30. Jagtap V.S., Acharya S.V., Sarathi V., Anurag R. Lila A.R., Budyal S.R. et al., Ectopic posterior pituitary and stalk abnormality predicts severity and coexisting hormone deficiencies in patients with congenital growth hormone deficiency, Pituitary, 2012, 15 (2): 243; 31. Murray P.G., Hague C., Fafoula O., Gleeson H., Patel L., Banerjee I., Raabe A.L., et al., Likelihood of persistent GH deficiency into late adolescence: relationship to the presence of an ectopic or normally sited posterior pituitary gland, Clin Endocrinol, 2009, 71 (2): 215 - 219; 32. Maghnie M., Lindberg A., Koltowska-Haggstrom M., Ranke M.B., Magnetic resonance imaging of CNS in 15 043 children with GH deficiency in KIGS (Pfizer International Growth Database), Europ J Endocrinol, 2013, 168 (2) 211; 33. Kalina M., Kalina-Faska B., Gruszczyńska K., Baron J., Małecka-Tendera E., Usefulness of magnetic resonance findings of the hypothalamicpituitary region in the management of short children with growth hormone deficiency: evidence from a longitudinal study, Childs Nerv Syst, 2012, 28(1): 121 - 127; 34. Zenaty D., Garel C., Limoni C., Czernichow P., Léger J., Presence of magnetic resonance imaging abnormalities of the hypothalamic-pituitary axis is a significant determinant of the first 3 years growth response to human growth hormone treatment in prepubertal children with nonacquired growth hormone deficiency, Clin Endocrinol, 2003, 58:647 – 652; 35. Di Iorgi N., Morana G. Gallizia A.L., Maghnie M., Pituitary gland imaging and outcome, Endocr Dev., 2012;23:16 - 29; 36. Delman B.N., Fatterpekar G.M., Law M., Naidich T.P., Neuroimaging for the pediatric endocrinologist, Pediatric Endocrinol Rev, 2008, 5, S2: 708 -719; 37. Maghnie M., Ambrosini L., Cappa M., Pozzobon G., Ghizzoni L., Ubertini M.G. et al., Adult height in patients with permanent growth hormone deficiency with and without multiple pituitary hormone deficiencies, J Clin Endocrinol Metab, 2006, 91:2900 - 2950; 38. Kelberman D., Rizzoti K., Lovell-Badge R., Robinson I., Dattani M.T., Genetic regulation of pituitary gland development in human and mouse, Endocr Rev, 2009, 30:790 - 829; 39. Osorio M.G.F., Marui S., Jorge A.A.L., Latronico A.C., Lo L.S.S., Leite C.C., et al., Pituitary Magnetic Resonance Imaging and Function in Patients with Growth Hormone Deficiency with and without Mutations in GHRH-R, GH-1, or PROP-1 Genes, J Clin Endocrinol Metab, 2002, 87: 5076 - 5084; 40. Louvel M., Mariana Marcu, Christine Trivin, Jean-Claude Souberbielle, Raja Brauner, Diagnosis of growth hormone (GH) deficiency: comparison of pituitary stalk interruption syndrome and transient GH deficiency, BMC Pediatrics 2009, 9:29; 41. Allen D.B., Cuttler L., Short Stature in Childhood – Challenges and Choices, N Engl J Med, 2013, 368:1220 - 1228; 42. Arrigo T, De Luca F, Maghnie M, Blandino A, Lombardo F, et al., Relationships between neuroradiological and clinical features in apparently idiopathic hypopituitarism, Eur J Endocrinol, 1998,139: 84 - 88;


Lenuta Popa 43. Growth Hormone Research Society, Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society, J Clin Endocrinol Metab, 2000, 85:3990 – 3993; 44. Rosenfeld R.G., Cohen P., Robison L.L. et al., Long-term surveillance of growth hormone therapy, J Clin Endocrinol Metab, 2012; 97:68 - 72.

Lenuţa Popa, MD, PhD, Associate Clinical Professor of Pediatrics Endocrinology Compartment, Pediatrics Clinic I, University of Medicine and Pharmacy “Iuliu Haţieganu”, Cluj-Napoca, Romania E-mail : [email protected] April, 2014


Jeremy Allgrove

Introduction Approximately 99% of total body calcium is contained in bone with the remainder in plasma where the concentration is very tightly regulated in order to maintain optimum function of nerve and muscle. Two principal factors, parathyroid hormone (PTH) and activated vitamin D, 1,25-dihydroxyvitmin D (1,25(OH)2D), are responsible for this whilst two other factors, parathyroid hormone-related peptide (PTHrP) and calcitonin (CT) play more minor roles. The relationship between calcium and PTH can be viewed as a cascade which begins with calcium and progresses via the calcium-sensing receptor (CaSR) via the parathyroid glands (PTGs) and PTH receptor to the target organs. The role of vitamin D is principally to facilitate gastrointestinal absorption of calcium in order to be able to provide sufficient calcium for bone mineralisation which then acts as a reservoir for the supply of calcium for other physiological purposes. CT has an effect that is directly opposite to that of PTH but has little part to play in postnatal life but may have an important role in bone development in the fetus. It is also a useful tumour marker in some forms of multiple Endocrine Neoplasms. PTHrP has an important paracrine effect in collagen development but has little endocrine effect in postnatal life although it is probably important in maintaining the positive gradient of calcium across the placenta. It is also an important cause of hypercalcaemia of malignancy in some tumours.


Jeremy Allgrove

The calcium cascade

Figure no. 2.1 summarises the principal steps in the calcium cascade. Ca CaSR Parathyroid Glands


The Calcium Cascade


Target Organs: Kidney, Bone

Figure 2.1 - The Calcium Cascade

Calcium-sensing receptor Circulating concentrations of calcium are normally kept within very narrow limits (2.2 – 2.6 mmol/L postnatally). The concentration is continuously sensed by a G-protein-coupled receptor, the CaSR, which is present both in the PTGs and renal tubules. In the glands, PTH secretion is regulated in response to the calcium concentration. The relationship between calcium and PTH secretion is sigmoid in nature – high concentrations of calcium inhibit PTH secretion and vice versa (Figure no. 2.2). When calcium concentrations fall, PTH is secreted in order to stimulate calcium reabsorption from bone in order to restore normality. If calcium concentrations rise for any reason, PTH secretion is switched off to allow them to return to normal. The CaSR is a large protein consisting of 1078 amino acids which has an extracellular calcium-sensing component, a seven transmembrane domain and a smaller intracellular section. Another gene, GNA11, codes for a second messenger that transmits the message to the cell. In addition, another gene, AP2S1, codes for a third protein that acts to internalise the CaSR/GNA11 complex. Inactivating mutations in any of these genes lead to persistent hypercalcaemia, which is usually benign, associated with low


Endocrine Control of Calcium Metabolism


urinary calcium excretion and a group of conditions known as Familial Benign Hypercalcaemia (FBH). Activating mutations of either CaSR or GNA11 cause a form of primary hypoparathyroidism which is associated with hypercalciuria. 80


Inactivating mutations 60



Intact PTH



Activating mutations


Ca++ 0 0,95












Figure 2.2 - Relationship between plasma ionised calcium and parathyroid hormone secretion. The relationship is sigmoid in nature. Activating mutations of the CaSR shift the curve to the left whilst inactivating mutations shift it to the right.

The parathyroid glands There are usually four glands, but may be as many as seven, situated within the substance of the thyroid gland. They are derived from the third (lower) and fourth (upper) branchial arches. Their development is modulated by a number of genes, some of which (e.g. GCMB) have no other function, whilst others, e.g. GATA3, have a role in the development of other organs such as kidney and hearing. Mutations in these genes may give rise to primary hypoparathyroidism which may be isolated or associated with other features. Another gene, TBX1, is contained within a section of the long arm of chromosome 22 and is frequently deleted as part of the 22q11.2 deletion syndrome. The parathyroid glands are responsible for secreting parathyroid hormone (PTH). At physiological doses, this has an anabolic effect on bone and helps to promote bone formation but, at supraphysiological doses, it contributes to bone resorption which helps to maintain plasma calcium concentrations.



Jeremy Allgrove

It also has an effect to increase phosphate excretion in renal tubules and to stimulate 1α-hydroxylase of 25-hydroxy vitamin D (25OHD). Parathyroid hormone This is an 84 amino acid single chain polypeptide hormone secreted by the PTGs principally in response to hypocalcaemia. It stimulates calcium reabsorption from bone by an action on osteocytes which is mediated via osteoblasts. PTH is secreted in response to hypocalcaemia and suppressed by hypercalcaemia and there is a sigmoid relationship between the two. Rare mutations of the PTH gene may lead to congenital hypoparathyroidism. The PTH receptors There are two PTH receptors, PTHR1 and PTHR2. The first of these is the most important for calcium metabolism. It is present in a wide variety of tissues but particularly osteoblasts and renal tubules. Inactivating mutations of the PTH1R result in Blomstrand’s Chondrodysplasia which is usually lethal whilst activating mutations lead to Jansen’s Metaphyseal Chondrodysplaia which may cause transient hypercalcaemia during infancy as well as short stature. The second messenger The action of PTH, once it has combined with its receptor, is mediated via a G-protein coupled second messenger which has alpha and beta/gamma components. When PTH binds with the receptor, it uncouples the alpha from the beta/gamma components. The alpha component then stimulates adenylate cyclase to form cAMP from ATP. This then results in downstream expression of the effects of PTH such as bone resorption and increase in 1-alpha hydroxylase conversion of 25-hydroxyvitamin D (25OHD) to its active product, 1,25dihydroxyvitamin D (1,25(OH)2D). At the same time as the alpha and beta/gamma subunits are being uncoupled, the GPD which is associated with the Gsα subunit is converted to GTP. Following the action, this then is degraded back to GDp by the naturally occurring GTPase present in association with the Gsα subunit so the alpha and beta/gamma subunits reunite and the cell returns to its resting state (Figure 3 a,b and c).


Endocrine Control of Calcium Metabolism


PTH1R  α Gs


β χ C




Adenylate cyclase



PKA Phosphodiesteras

Figure 2.3 - Diagrammatic representation of the Gsα messenger. 2.3.a – resting state. Stimulation of the receptor results in dissociation of the from the β/γ subunit.



α GTPase


β χ


Adenylate cyclase


cAMP  Phosphodiesterase




Figure 2.3b. – activated. Adenylate cyclase converts ATP to cAMP which then has downstream effects.



Jeremy Allgrove

PTH1R  α GTPase

β χ


ATP  Adenylate cyclase


PKA  Phosphodiesterase 




Figure no. 2.3c. – Return to resting state. GTPase converts GTP to GDP which results in reassociation of the α and β/γ subunits.

The gene is a complex one that results in several gene products, most of which are biallelic in expression. In addition, there are several upstream controlling sequences whose function can influence the activity of the gene itself. In some tissues, however, such as renal tubules expression is monoallelic being expressed only in either paternal or maternal tissues whilst the other allele is methylated and therefore not expressed (Figure no. 2.4.). Inactivating mutations occurring in the gene itself result in the features of Albright’s Hereditary Osteodystrophy (AHO - short stature, round facies, shortened metcarpals and metatarsals, obesity, impaired intelligence etc.). In addition, if the mutation is on the maternal allele, resistance to PTH also occurs which results in hypocalcaemia with raised PTH, a condition known as pseudohypoparathyroidism Type 1a. In contrast, mutations on the paternal allele, whilst causing AHO, are not associated with hypocalcaemia, a condition known as pseudopseudohypoparathyroidism. Where the condition is inherited, the development of hypocalcaemia is dependent on the parent of origin. Thus both conditions can occur within the same family. Since the Gsα second messenger is common to several polypeptide hormones, these patients may also suffer from hypothyroidism and delayed or altered puberty.


Endocrine Control of Calcium Metabolism

STX16 M +

Nesp55 -

Nespas +







3N 4 5

+ allele-specific methylation


exons 2 - 13 exon 1

Gsα exons 2 - 13

A/B paternal

exons 2 - 13 XL exons 2 -13


exons 2 - 13

Figure no. 2.4. - Diagrammatic representation of the GNAS gene.

If there is no mutation in the Gsα gene itself but there are methylation defects present, particularly on the maternal allele, AHO is not present but hypocalcaemia may develop because of PTH resistance. This is known as pseudohypoparathyroidism Type 1b. In these cases intelligence is usually normal. Occasionally, activating mutations of the Gsα may occur. These are usually somatic mutations which result in McCune-Albright syndrome, a combination of fibrous dysplastic bone cysts, characteristic pigmented skin lesions and sometimes inappropriate stimulation of Gsα-mediated endocrine organs, particularly the thyroid and adrenal which can be troublesome and difficult to treat.

The target organs

Bone and kidney are the principal target organs of PTH. In bone, receptors are present particularly on osteoblasts which then communicate with osteoclasts mainly via their products, RANK-ligand (RANKL) and osteoprotegerin (OPG). The former acts to stimulate RANK receptors on the surface of osteoclasts whilst the latter acts as a natural inhibitor of RANKL. Inactivating mutations in either RANK or RANKL result in rare



Jeremy Allgrove

forms of osteoclast-poor osteopetrosis whilst inactivating mutations in OPG cause Juvenile Paget’s Disease. Receptors in renal tubules serve to increase calcium reabsorption, stimulate phosphate excretion and promote the formation of 1,25()H)2D. Receptors are present in many other target organs such as muscle and have an influence on calcium metabolism.

Vitamin D metabolism The second important mediator of calcium metabolism is vit. D. Vitamin D synthesis Metabolism ov vitamin D is summarised in Figure no.2.5.


sunlight Diet Previtamin D

body heat


1α-hydroxycholecalciferol (alfacalcidol)

Vitamin D 25-

25-OH vitamin D

25-hydroxyvitamin D 1α-hydroxylase

1,25(OH)2 vitamin D Vitamin D 25-hydroxylase

Vitamin D receptor

Peripheral action

Vitamin D 24-

24,25-dihydroxyvitamin D

Figure no. 2.5. - Diagrammatic representation of vitamin D metabolism.


Endocrine Control of Calcium Metabolism


Vitamin D is mainly obtained by the action of ultraviolet light on 7dehydrocholesterol which it converts to pre-vitamin D by breaking the B ring of the steroid molecule. This then undergoes stoichiometric transformation to cholecalciferol (vitamin D3) by the action of body heat. Vitamin D, in the form of either cholecalciferol or ergocalciferol (vitamin D2) can also be obtained from dietary sources although this usually amounts to no more than twenty percent of total under normal physiological conditions. Both are metabolised similarly and have a similar action although D2 probably has a shorter half-life. Vitamin D is mainly stored in fat. Vitamin D metabolism - 1 Vitamin D then undergoes two hydroxylation steps to convert it to its active form, 1,25(OH)2D. The first of these, hydroxylation at the 25position, occurs in the liver to form 25OHD. This is the main circulating form of vitamin D and is what is measured when a vitamin D measurement is requested. Its concentration gives a good measure of vitamin D status of the individual. It circulates in nanomolar concentrations. It has little physiological activity. Rare forms of deficiency of the enzyme, vitamin D 25-hydroxylase, may result in rickets and liver disease can have a similar effect. The enzyme also converts the synthetic compound 1α-hydroxycholecalciferol (alfacalcidol) to 1,25(OH)2D. Vitamin D metabolism – 2 The second, more important, hydroxylation step occurs mainly in the kidney where a second enzyme, 25 hydroxyvitamin D-1α-hydroxylase, converts 25OHD to 1,25()H)2D, the active hormonal form of vitamin D. This is highly active and circulates in picomolar concentrations. Its activity is controlled mainly by PTH and phosphate as well as the phosphatecontrolling hormone Fibroblast Growth Factor 23 (FGF23). Genetic mutations in the gene for this enzyme result in Vitamin D Dependent Rickets Type 1 (VDRR1). Diminished function also occurs in chronic kidney disease and contributes to the development of renal bone disease. Vitamin D metabolism – 3 A second enzyme, Vitamin D-24-hydroxylase is also active in controlling 1,25(OH)2D concentrations. It converts 25OHD to the inactive 24,25(OH)2D and 1,25(OH)2D to the relatively inactive 1,24,25(OH)3D thus acting as a safety valve to prevent excess vitamin D activity. Deficiency of this enzyme has recently been described as causing a form of Infantile Hypercalcaemia and as a cause of renal stones in adults.



Jeremy Allgrove

Vitamin D receptor The vitamin D receptor is a member of the thyroid-steroid-retinoid receptor superfamily. It contains vitamin D (C-terminal) and DNA (Nterminal) binding sites. Ligand binding with the receptor results in pseudodimerisation with the retinoid-X-receptor. This causes dissociation of co-repressors and recruitment of co-transactivators, binding to DNA and protein synthesis. Mutations in the receptor result in Vitamin D Dependent Rickets Type 2 (VDDR), more properly known as true vitamin D resistance. Vitamin D actions The vitamin D receptor is present in most tissues. The most important of these for calcium metabolism are those in gut and kidney. In the gut vitamin D promotes calcium absorption via the active transport mechanism. In the kidney, it affects calcium transport across renal tubules. There are also receptors in bone which promote bone mineralisation but there is no absolute necessity for these since the principal purpose of vitamin D is to provide a ready source of calcium for bone mineralisation.

Other hormonal influences Apart from PTH and vitamin D, there are other hormonal influences which have relatively minor effects during postnatal life. These include PTH-related Protein (PTHrP), which has an effect in fetal life in maintaining the gradient of calcium across the placenta and also has an important paracrine effect in cartilage development postnatally, and calcitonin, which is probably important in fetal bone development but which has little part to play in postnatal calcium metabolism. However, PTHrP is important as a mediator of hypercalcaemia in some forms of malignancy and calcitonin is a useful marker of tumour growth in Multiple Endocrine Neoplasia Type 2. FGF23 is a hormone closely involved in phosphate metabolism which also has some influence on calcium but is outwith the scope of this article.

Interactions between calcium, PTH and vitamin D

The relationship between calcium, PTH and vitamin D is shown in Fig X. When the plasma calcium concentration falls, this fact is sensed by the CaSR which induces PTH secretion. This stimulates 1,25(OH)2D formation which, in turn, increases calcium absorption in the gut, mediates bone resorption and enables excess phosphate from the latter to be excreted in the kidney. All of these


Endocrine Control of Calcium Metabolism


combine to restore calcium concentrations to normal. These relationships are summarised in Figure no.2..6. Hypocalcaemia


↑ Renal PO4 excretion 

↑ Plasma calcium 

↓Plasma PO4  ↑Gut Ca absorption 

↑PTH  ↑1α‐hydroxylase  ↑Bone resorption 

↑1,25(OH)2D  ↓Ca fractional excretion 

Figure no. 2.6.- Effects of the various processes of calcium metabolism in restoring plasma calcium to normal after a hypocalcaemic stress.


The metabolism of calcium is complex but important to maintain normal neuromuscular function. If any of the processes goes awry, the resulting hypo- or hypercalcaemia can have serious consequences.

Jeremy Allgrove, MA, MD, FRCP, FRCPCh Consultant Paediatric Endocrinologist, Department of Paediatric Endocrinology and Diabetes, Royal London and Great Ormond Street Hospitals, United Kingdom E-mail: [email protected] 

April, 2014 



Jeremy Allgrove

Introduction In contrast to adults, hypocalcaemia is more common than hypercalcaemia in children. In order to arrive at a satisfactory diagnosis, it is necessary to have a thorough understanding of the physiology of calcium metabolism so that a logical approach can be undertaken. Investigation of disorders of calcium metabolism consists initially of measurement of bone profile (calcium, albumin, phosphate, alkaline phosphatase and magnesium), creatinine, 25OHD and PTH. In addition, it is important to measure urinary calcium excretion (most conveniently done by measuring the calcium/creatinine ratio). Further investigations will depend on the initial results and may include X-rays to look for the presence of rickets or skeletal abnormalities, bone density scans, nuclear medicine examinations such as SestaMIBI scans to try to identify parathyroid gland tumours, ultrasound scanning of kidneys to look for nephrocalcinosis, CT scans of the brain to identify intracerebral calcification and blood pH to exclude renal tubular problems. Finally, since many of the conditions occurring in childhood are genetic in origin, extraction and storage of DNA for further analysis may be necessary.

Hypocalcaemia Hypocalcaemia may present in a number of ways. Symptoms of hypocalcaemia are related to the increased excitability of nerve and


Jeremy Allgrove

muscle. In general, the lower the plasma calcium concentration, the more severe the symptoms. However, if hypocalcaemia develops gradually, symptoms may not occur until very low concentrations are reached whereas, if the calcium concentration falls quickly, symptoms may occur at a higher level. Tingling of the hands and feet may be followed by muscular jerking movements which, in more extreme cases, can lead to overt convulsions. If present for any length of time, chronic muscle pain can be debilitating. Infants may present with stridor. Clinically, muscle spasms of the hand may present as carpo-pedal spasm (‘main de coucheur’). Hypocalcaemia may be suspected if the Chvostek sign (tapping on the facial nerve as it passes over the zygoma resulting in twitching of the facial muscles) is positive. The causes of hypocalcaemia in childhood can be classified in several ways but one of the most useful is to consider whether it is associated with low, normal or raised concentrations of PTH.

Hypocalcaemia associated with low PTH Hypoparathyroidism The combination of hypocalcaemia with inappropriately low or undetectable PTH suggests the possibility of hypoparathyroidism. Vitamin D deficiency should always be excluded as, although this is usually associated with raised PTH, this is not always the case and correction of vitamin D deficiency may resolve the problem. It may be an isolated problem or be associated with other features such as deafness, renal cysts, cardiac anomalies, immune deficiency or mental retardation. Hypoparathyroidism is associated with a low urinary calcium/creatinine (Ca/Creat) ratio and a raised Ca/Creat should raise a suspicion of a CaSR mutation.

Genetic syndromes associated with hypoparathyroidism a. 22q Deletion syndrome The commonest genetic cause of hypoparathyroidism occurs in association with a microdeletion of the long arm of chromosome 22 (22q11.2 DS). This should be excluded by FISH analysis or microarray. The syndrome is variable in severity and may be associated with cardiac anomalies (mainly of the aortic arch outflow tract), immune deficiency and swallowing and speech difficulties. b. Glial Cell Missing B (GCMB) GCMB is an ancient gene found in the fruit fly, drosophila. Its only function in man is to act as one of the genes controlling PTG development.

Hyper- and Hypocalcaemic Disorders of Children


  Thus its abnormalities result in isolated hypoparathyroidism. It may be autosomal recessive or dominant. a. PTH gene mutation This also results in isolated congenital hypoparathyroidism resulting from abnormal PTH structure. b. Autoimmune Polyglandular (APECED) Syndrome This is an autosomal recessive condition which results from mutations in the Autoimmune Regulator (AIRE 1) gene. Patients frequently have candidiasis of the finger and toe nails and may develop other autoimmune conditions such as Addison’s Disease or hypothyroidism. c. Hypoparathyroid, Deafness, Renal anomalies (HDR) This is also autosomal recessive and results from mutations in the GATA3 gene. As the name implies, hypoparathyroidism is associated with deafness and renal cyst formation which may eventually result in renal failure. d. Sundry other genetic abnormalities These include several autosomal recessive conditions such as Sanjad-Sakati and Kenny-Caffey syndromes as well as a number of mitochondrial disorders.

Acquired syndromes associated with hypoparathyroidism In addition to the genetic disorders, several acquired conditions can occur. These include autoimmune hypoparathyroidism (often part of the APECED syndrome – see above) or infiltration of the parathyroid glands with iron in β-thalassaemia. 1. Hypocalcaemia associated with normal PTH Inactivating mutations of the CaSR result in a shift of the PTH secretion curve to the left causing PTH secretion to be switched off at a lower concentration of calcium than normal. This results in a situation where effective hypoparathyroidism is present but usually in the context of a normal level of PTH. These patients may present with hypocalcaemic symptoms but differ from other forms of hypoparathyroidism in that urinary calcium excretion is usually elevated. This makes treatment very difficult since raising the plasma calcium to a degree that prevents symptoms may make nephrocalcinosis worse and increase the risk of kidney failure in later life. Some patient scan be managed with no treatment whilst others may require small doses of active vitamin D metabolites.


Jeremy Allgrove

Recent studies have suggested that subcutaneous PTH, given by continuous infusion, may be of benefit. 2. Hypocalcaemia associated with raised PTH Genetic disorders of vitamin D metabolism a. 25-hydroxylase deficiency This very rare condition may result in rickets which can be treated with high dose vitamin D. b. 1α-hydroxylase deficiency (Vitamin D Dependent Rickets Type 1, VDDR1) These patients usually present during the toddler age group with clinical rickets, bowed legs and hypocalcaemia. They do not respond to treatment with vitamin D but do respond well to activated vitamin D analogues which is required life-long. c. Vitamin D receptor deficiency (Vitamin D Dependent Rickets Type 2, VDDR2) This more properly called vitamin D receptor defect and is caused by mutations in the vitamin D receptor. In its most severe form, it is associated with complete hair loss. These patients do not respond to high dose vitamin D or active vitamin D analogues but require intravenous infusion of calcium, phosphate and magnesium. Once the rickets have healed, they can usually be maintained on high dose oral calcium supplements.

Acquired disorders of vitamin D Deficiency of vitamin D may result in several syndromes associated with hypocalcaemia. a. Congenital rickets This is very rare and usually associated with mothers who themselves are severely deficient (25OHD undetectable). Infants present with respiratory difficulty, severe radiological changes of rickets and may have fractures. They respond to vitamin D and calcium supplementation but may take weeks or months to recover completely. b. Dilated cardiomyopathy This occurs in a small proportion of infants with severe vitamin D deficiency. These patients present with a combination of heart failure, respiratory difficulty and hypocalcaemia. Cardiorespiratory support may be required but eventually they respond to treatment with vitamin D. As with congenital rickets, they may take several months to recover fully. It is a potentially lethal condition.

Hyper- and Hypocalcaemic Disorders of Children


  c. Classical rickets Most children with rickets caused by vitamin D deficiency present in the toddler age group with bowed legs, difficulty in walking and often have a degree of developmental delay. Radiological appearances of rickets consist of widened, frayed and cupped epiphyses with some degree of undermineralisation of bones. Occasionally fractures may be present if the rickets are severe. They respond to treatment with vitamin D and should not be treated with activated metabolites. d. Hypocalcaemia without rickets This particularly affects teenagers who may present with hypocalcaemic convulsions without evidence of rickets. They may have a history of muscle spasms over a period of weeks or months prior to presentation. Treatment with intravenous calcium can afford almost instant relief from the pain of the muscle spasm. Biochemically they have a low calcium, raised phosphate, low 25OHD and raised PTH. They may be confused with patients with pseudohypoparathyroidism (see below) but respond satisfactorily to treatment with vitamin D.

Resistance to PTH Pseudohypoparathyroidism (PsHP) is the name given to the condition in which, despite adequate vitamin D concentrations, patients have hypocalcaemia with raised phosphate. There are several variants of this condition. 1. PsHP Type 1a This is caused by mutations in the Gsα gene. The resulting defect in the second messenger causes resistance to several hormones whose message is relayed via this mechanism. Apart from PTH these include TSH, gonadotrophins and growth hormone releasing hormone. Effects in bone also cause several abnormalities which together are termed Albright’s Hereditary Osteodystrophy (AHO) and include short stature, round facies and, typically, shortening of the fourth and fifth metacarpals and metatarsals. Biochemically these patients have low calcium, raised phosphate, raised PTH and normal vitamin D. 2. PsHP Type 1b In this condition there is no mutation in the Gsα gene. However, methylation defects occur within some or all of the associated parts of the gene complex. If inappropriate methylation of the maternally imprinted genes occurs, the biochemical features of PsHP occur but without AHO or the developmental problems that occur in PsHP Type 1a.


Jeremy Allgrove

3. Pseudo-pseudophypoparathyroidism (PsPsHP) In this condition, hypocalcaemia does not occur whilst the other features such as AHO are present. This situation arises when the condition is inherited from the father or when the paternal rather than maternal alleles are affected.

Hypercalcaemia Symptoms of hypercalcaemia are, in many respects, opposite to those of hypocalcaemia. Abdominal pain, lethargy and constipation may be accompanied by thirst, polyuria and polydipsia if hypercalciuria is also present. Long standing hypercalciuria may lead to renal stones and, ultimately, to renal failure. As with hypocalcaemia, it is convenient to divide the causes of hypercalcaemia according to whether or not PTH is low, normal or raised. Hypercalcaemia associated with low PTH This situation arises when hypercalcaemia results from some mechanism that is not driven by PTH. In many instances this is because of vitamin D toxicity of one sort or another. 1. Subcutaneous fat necrosis of the newborn This usually arises in otherwise healthy term neonates who suffer a mild degree of birth asphyxia. Shortly after birth they develop hard patches of skin which are usually redden in colour. Hypercalcaemia results from increased formation of 1,25(OH)2D as a result of increased 1αhydroxylase activity by macrophages that invade the skin lesions as part of the healing process. Symptoms of hypercalcaemia are accompanied by polyuria and polydipsia. Treatment is initially with hyperhydration. Thereafter, if hypercalcaemia persists, steroids or bisphosphonates may be useful in controlling the hypercalcaemia. The choice of treatment is controversial. The condition settles with time as the skin lesions resolve. 2. Idiopathic hypercalcaemia of infancy Some neonates develop hypercalcaemia, the cause of which remains unclear. In some instances, these infants have been shown to have a defect in 24-hydroxylase activity so cannot detoxicate vitamin D metabolites effectively thus resulting in inappropriately elevated 1,25(OH)2D. In others the cause is not clear although usually the condition settles. 3. Hypercalcaemia of malignancy Some patient with malignancy develop hypercalcaemia. This can either be because the tumour (e.g. leukaemia) is itself eroding bone or because the tumour is secreting inappropriate quantities of PTHrP which

Hyper- and Hypocalcaemic Disorders of Children


  has a similar effect to PTH in causing bone resorption. In general the most effective treatment is to remove or treat the tumour. 4. Vitamin D toxicity If excess quantities of vitamin D are administered it is possible to cause toxicity although very high amounts are usually required to achieve this effect. However, if activated vitamin D metabolites are administered in error, hypercalcaemia can occur quite quickly. Hypercalcaemia associated with normal PTH In this situation, hypercalcaemia occurs which does not suppress PTH secretion. Familial Benign Hypercalcaemia In this condition there is an inactivating mutation of the CaSR or one of its components. The curve of relationship between PTH secretion and Plasma calcium is shifted to the right such that PTH is not switched off until plasma calcium reaches a supranormal concentration. As the name implies, the condition is benign and is not usually associated with hypercalciuria so they are not at risk of nephrocalcinosis. Usually, no treatment is required. Hypercalcaemia associated with raised PTH This situation arises when there is inappropriate hypersecretion of PTH. 1. Primary hyperparathyroidism Parathyoid tumours are rare in children and most of them are genetic in origin, often associated with multiple tumours. a. Multiple Endocrine Neoplasia Type 1 (MEN1) This is caused by mutations in the MEN1 gene. Parathyroid gland tumours are the most common, occurring in about 90% of cases, followed by pancreatic (60%) and anterior pituitary (30%) tumours. Less commonly adrenal cortical or carcinoid tumours may occur. Screening of subjects at risk of developing such tumours is essential so that they can be treated before they become clinically relevant. b. Multiple Endocrine Neoplasia Type 2 (MEN2) This is caused by mutations in the c-ret proto-oncogene. Three different types of this condition are described. In MEN2A parathyroid, medullary carcinoma of the thyroid (MCT) and phaeochromocytomas all occur. In MEN2B parathyroid tumours do not occur but MCT, phaeochromocytomas and intestinal endocrine tumours are associated with mucosal neurofibromas. In MEN2C, only MCT occurs. c. Multiple Endocrine Neoplasia Type 4 (MEN4)


Jeremy Allgrove

This is caused by mutations in a gene known as CDKN1B. Pituitary, parathyroid and other tumours occur, usually in adulthood. d. Hyperparathyroid-Jaw-Tumour Syndrome (HYP-JT) Inactivating mutations of HRPT2 (parafibromin) result in disruption of the parafibromin complex that is created with a number of other proteins. Parathyroid tumours as well as fibro-osseous tumours of the mandible and renal tumours may occur. Parathyroid carcinomas usually have mutations in the same gene. e. Isolated parathyroid tumours These can all be caused by mutations in any of the above genes. In addition, several other genes, including the PTH gene itself and PRAD1 (cyclin) may also be associated with isolated parathyroid tumours. Treatment of parathyroid tumours is parathyroidectomy. If the cause is an isolated parathyroid adenoma, it is usually sufficient to remove that gland alone. If more generalised hyperplasia is present it may be necessary to remove most of the glands. This should be undertaken by an experienced endocrine surgeon.

Neonatal severe hyperparathyroidism (NSHPTH) Another cause of parathyroid tumours is NSHPTH. This usually is caused by a homozygous (or compound heterozygous) mutation in the CaSR gene. Occasionally, heterozygous mutations can also result in a similar clinical picture especially if the mutation has been inherited from the father or is a new mutation. Vitamin D deficiency may worsen the effect. Infants present in the early neonatal period with respiratory difficulty, radiological features of severe hyperparathyroidism and may also have fractures. Supportive therapy (IV fluids, respiratory support etc.) may be required pending surgery. Parathyoidectomy must be total otherwise it is not curative. It does render the individual hypoparathyroid and they will therefore need treatment for hypoparathyroidism as a result. Those individuals with heterozygous mutations may settle with supportive therapy alone and eventually end up with a clinical picture of Familail Benign Hypercalcaemia (see above).

Tertiary Hyperparathroidism If hypocalcaemic stresses are present for long periods, the parathyroid glands may change from being secondarily active to becoming autonomous. The patients become hypercalcaemic as a result of them

Hyper- and Hypocalcaemic Disorders of Children


  developing parathyroid hyperplasia and may require parathyroidectomy. The most likely situations in which this arises are chronic vitamin D deficiency and chronic kidney failure. Summary Conditions associated with hypo- or hypercalcaemia are relatively rare in childhood but can have devastating effects on the individual affected. A thorough understanding of the various mechanisms is necessary to make a correct diagnose. Having done this, most of the conditions can be successfully treated.

Jeremy Allgrove, MA, MD, FRCP, FRCPCh Consultant Paediatric Endocrinologist, Department of Paediatric Endocrinology and Diabetes, Royal London and Great Ormond Street Hospitals, United Kingdom E-mail: [email protected]

April, 2014


Dana Liana David, Iulian P. Velea, Corina Paul

Introduction Epilepsy is one of the most common neurological disorders characterised by the unpredictable occurrence of seizures. Catamenial epilepsy is a form of epilepsy. In ancient times, the cyclical nature of epileptic attacks was attributed to the cycles of the moon1. In 1857, Sir Charles Locock first described the relationship between epileptic seizures and the menstrual cycle 2.

Definition There are simple definitions for a rapid clinical assessment of subjects with catamenial epilepsy, but they are arbitrary, quite variable, and there is little consensus in the clinical scientific literature for unified definition According to Duncan et al., catamenial epilepsy is defined as the cyclical increase in seizures around the time of menses or at other phases of the menstrual cycle. Catamenial epilepsy is defined based upon the criteria of having at least 75% of the seizures during a 10-day period of the menstrual cycle beginning 4 days before menstruation.3 Herzog et al. defined catamenial epilepsy as a greater than average seizure frequency during perimenstrual or periovulatory periods in normal ovulatory cycles and during the luteal phase in anovulatory cycles.4


Dana Liana David, Iulian P. Velea, Corina Paul

Tuveri et al. utilised a fractional change method to calculate the catamenial change in seizure frequency. 5 In general, a twofold or greater increase in seizure frequency during a particular phase of the menstrual cycle could be considered as catamenial epilepsy6. Herzog et al. defined three forms of catamenial epilepsy: • perimenstrual (C1: days –3 to 3) • periovulatory (C2: days 10 to –13) in normal cycles, • luteal (C3: days 10–3) in inadequate luteal phase cycles, where day 1 is the first day of menstrual flow and ovulation is presumed to occur 14 days before the subsequent onset of menses (day –14)). These three patterns can be demonstrated simply by: - charting menses and seizures - obtaining a mid-luteal phase serum progesterone level to distinguish between normal and inadequate luteal phase cycles ( 125 nmol/l are related to an increased morbidity and mortality risk. For adults, the adequate circulating 25OHD level is considered to be between 75 to 125 nmol/l. It is also noteworthy that under sun-rich living conditions mean circulating 25OHD levels of 135163 nmol/l (54-65 ng/ml) have been reported. Since skin synthesis of vitamin D does not lead to intoxication, this upper limit of the adequate range of circulating 25OHD seems to be conservative. On the other hand, prolonged routine consumption of high doses of vitamin D may interfere with Klotho and FGF23 regulation of phosphate homeostasis with detrimental health consequences.

Conclusions: There is a need for additional high quality studies in infants and children inquiring about adequate range of circulating of vitamin D and safety of high supplementation doses. In clinical practice, oral vitamin D dosing has to consider that the increment in circulating 25OHD depends on baseline 25OHD levels and the person's body weight. Key words: vitamin D level, safety, upper limit

Introduction and aim Vitamin D is possibly the most intensely studied, yet most confusing, focus in the past decade in the medical world. This confusion is in part related to the fact that there is no clear definition of what vitamin D is. Some descriptions treat it as a vital nutrient, some as a hormone. Further, there is no consensus on the definitions of the deficient and insufficient thresholds. Additionally, when it comes to children studies are even more sporadic. However, vitamin D deficiency seems to be a global public health problem in all age groups. Adequate vitamin D status is very important for normal bone metabolism, but also for optimal function of many organs and tissues, especially in growing children. Oral vitamin D supplementation is widespread, sometimes using high doses (intended and accidental) that lend potential for an increased incidence of vitamin D toxicity. However, studies regarding vitamin D safety in children are scarce. Vitamin D toxicity is relatively rarely reported in children. Vitamin D intoxication can present with the following symptoms: hypercalcemia, normal or high serum phosphorus levels, normal or low levels of alkaline phosphatase, high levels of serum 25OHD, low serum parathyroid hormone, and high urine calcium/creatinine. Serum 25OHD levels above 375 nmol/l (150 ng/ml) are considered as Vitamin D intoxication 1. However, some observational studies indicate that circulating 25OHD levels > 125 nmol/l are related to an increased morbidity and mortality risk 2.

How much is too much vitamin D for children?


For adults, the adequate circulating 25OHD level is considered to be between 75 to 125 nmol/l. It is also noteworthy that under sun-rich living conditions mean circulating 25OHD levels of 135-163 nmol/l (54-65 ng/ml) have been reported. Since skin synthesis of vitamin D does not lead to intoxication, this upper limit of the adequate range of circulating 25OHD seems to be very conservative 3. On the other hand, it would be more appropriate to define adequate circulating 25OHD levels, based on the individual's body weight and age, instead of a fixed value adopted from adult studies. This material aims to find evidence regarding factors that influence vitamin D metabolism, adequate range and upper limit of circulating vitamin D and supplementation regimens, in infants and children.

METHOD This nonsystematic review chapter has been constructed using an evidence-based approach. Data from clinical and observational studies and review articles were all considered when shaping this review. Literature searches for topics relating to vitamin D were carried out in PubMed and EMBASE between 1st to 30th march 2014, using Medical Subject Heading Terms and relevant keywords in adults and pediatrics (“vitamin D excess”, “vitamin D intoxication”, “vitamin D safety”, “hypervitaminosis”, “vitamin D and hypercalcemia”, “vitamin D and hypercalciuria”, “calcitriol and intoxication”, “calcitriol and hypercalcemia”; “children”). To ensure relevance to the modern day clinical setting, literature searches were limited to articles published since 1 January 2000. Older, historically significant, articles identified by the authors were also included. Only articles from the peer-reviewed literature were included in the literature search. Articles in a non-English language were not included. Abstracts from industry-sponsored meetings were not included. Vitamin D (25-Hydroxyvitamin D) ng/ml nmol/l Conversion 1 ng/ml = 2.496 nmol/l 1 nmol/l = 0.4006 ng/ml

Vitamin D metabolism Vitamin D3 is generated from endogenous 7-dehydrocholesterol via sun exposure. Additionally, vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol) can be absorbed from certain foods and supplementation regimens. The most important steps in vitamin D metabolism are shown in figure no.14.1.


Adela Chirita, Gabriela Doroş, Vlad David, Maria Puiu

Figure 14. 1. Steps of vitamin D synthesis and metabolism. Cholecalciferol or vitamin D3 is produced from 7- dehydrocholesterol in the skin by exposure to sunlight (UVA, UVB). Vitamin D3 formed in the skin, as well as vitamin D3 and D2 obtained from dietary sources or commercially available supplements, circulate in the bloodstream bound to the vitamin D binding protein (DBP). Vitamin D3 is converted to 25-hydroxyvitamin D (25OHD) in the liver in a constitutive process, by the enzyme vitamin D-25-hydroxylase. Vitamin D-25-hydroxylase activity is inhibited by 25OHD (negative feedback). 25OHD is further hydroxylated in the kidney to the active form 1,25 dihydroxyvitamin D (1,25OH2D). The primary regulatory pathways that control the production of 1,25OH2D and activity of CYP27B1, which catalyzes the conversion of 25OHD to 1,25(OH)2D. Hypercalcemia inhibits 1,25OH2D synthesis, while hypocalcemia stimulates its production primarily due to an increase in parathyroid hormone (PTH) secretion. Hyposphatemia and PTH up-regulate CYP27B1 and increase renal production of 1,25OH2D, whereas fibroblast growth factor 23 (FGF-23) does the opposite. 1,25OH2D regulates its own synthesis by down-regulating CYP27B1 activity and suppressing PTH secretion. 1,25OH2D, the active vitamin D form, binds to the vitamin D receptor (VDR) to increase intestinal calcium absorption and exert the other vitamin D related actions. Finally, 1,25OH2D increases CYP24A1 activity to catabolize 25OHD and 1,25OH2D to water soluble products that are excreted in the bile. The enzymes involved in each step, all cytochrome P450s (CYP) are shown.

How much is too much vitamin D for children?


Factors that Influence Vitamin D Synthesis

Factors that impact on vitamin D synthesis in the skin but also factors that influence vitamin D metabolism in the liver and kidneys are presented below and summarized in figure no. 14.2.

Figure no. 14. 2. Factors influencing vitamin D synthesis The solar zenith angle is the angle measured from directly overhead to the geometric center of the sun's disc. The solar elevation angle is the altitude of the sun, the angle between the horizon and the center of the sun's disc. This angle is increased at higher latitudes, early morning and late afternoon when the sun is not directly overhead, and during the winter months. As the solar zenith angle increases, the amount of UVB radiation reaching the earth’s surface is reduced. Therefore, at higher latitudes, greater distance from the equator, more of the UVB radiation is absorbed by the ozone layer thereby reducing or eliminating the cutaneous production of vitamin D3. 6 Thus, persons living above and below approximately 33° latitude have very little if any vitamin D3 produced in the skin from sun exposure in the winter. People who live farther North and South often cannot make any vitamin D3 in their skin for up to 6 months of the year 7. In the early morning and late afternoon the zenith angle of the sun is also more oblique similar to winter sunlight and as a result very little if any vitamin D3 can be produced in the skin before 10 a.m. and after 3 p.m. even in the summer time 8.


Adela Chirita, Gabriela Doroş, Vlad David, Maria Puiu

Air pollution (atmospheric components) including nitrous oxide and ozone are common in many large cities and will absorb solar UVB radiation and therefore reduce the effectiveness of sun exposure in producing vitamin D3 in the skin 9. Altitude can also have a dramatic influence on the amount of solar UVB that reaches the earth’s surface because the higher the altitude the shorter the path length that UVB has to travel through and thus the skin can produce more vitamin D3 9. Sunscreens were specifically designed to absorb solar UVB radiation 10. Sunscreens with a sun protection factor (SPF) of 30 or above absorbs approximately 95–98% of solar UVB radiation 11. Therefore the topical application of a sunscreen with SPF above 30 reduces the capacity of the skin to produce vitamin D3 almost completely. Skin Pigment in Africans is extremely dark and intense, nevertheless a small amount of UVB radiation is able to penetrate into the epidermis to produce vitamin D3 12. The response of 25OHD levels to UVB light is dependent on skin pigmentation and the amount of UVB given 13. Aging is a factor for decreased production of vitamin D 14. It was observed that 7-dehydrocholesterol concentrations in human epidermis were inversely related to age 15. Exposure of a young adult in a bathing suit to one minimal erythemal dose of UV radiation in a tanning bed was comparable to ingesting approximately 20,000 IUs of vitamin D2. When a healthy 75 y old male in a bathing suit was exposed to UVB radiation in a tanning bed three times a week for 7 weeks he was able to raise and maintain his blood levels of 25OHD into the healthy normal range of ~50 ng/ml. Obesity influences vitamin D metabolism. Large studies 16,17 found that obesity is associated with lower 25OHD concentrations, high PTH concentrations and low 1,25OHD concentrations. Possible mechanisms for lower 25OHD concentrations in obese individuals according to Vanlint are as follows: lower dietary intake of calcium and vitamin D, reduced cutaneous synthesis (due to altered behaviour – exposure of less skin and reduced synthetic capacity), reduced intestinal absorption, altered metabolism (due to reduced activation and increased catabolism), sequestration of 25OHD in the adipose tissue, or perhaps lower 25OHD in obese versus non obese is essentially due just to a volumetric dilutional model, as shown by Dorinic et all.18 A study in 127 obese children with median age 13.0 +/- 3.0 years (49 Caucasian, 39 Hispanic, and 39 African American; 61.2% female; evaluated considering season, found that hypovitaminosis D was present in 74% of the cohort (serum 25OHD concentration 50 nmol/L to indicate sufficiency and a serum concentration 0.60 is associated with a statistically significant increased risk of metabolic syndrome, prediabetes, hypertension, and dyslipidemia.

Results / Conclusions

*Overweight > 90th percentiles ageand sex-specific for different anthropometric variables. *Tanner: self – assessed by pubic hair

*patients were from the German/Austrian/Swiss Adiposity Patients Registry * Tanner stage was assessed

*BF% was assessed using (2)H2O and (2)H2(18)O isotope dilution in general population and bioelectrical impedance for overweight / obese children

*Obesity def: > 95th percentile, Italian charts *Tanner stage was assessed * the cut-off: 0.60 had sensitivity = 61%, specificity = 54% in detecting children with MS


186 Mogoi Mirela, Velea P. Iulian, Paul Corina

Using simple screening tools for assessing obesity…


Another important limitation is the lack of age specific cut-offs and the reference values for each country. So to overcome these limitations, the use of WtHR has been proposed.

Waist to height ratio Measuring WtHR may represent a powerful tool in the hands of pediatricians to identify obese children with high cardiovascular and metabolic risk21. It is easier to obtain, and it does not involve tables as BMI or WC does. It is less influenced by sexual maturity and it can be used in normal weight individuals as well. 12,22,23 All these characteristics are essential for any screening tool. In current practice, it is used the cut-off value of 0.5 which allows the characterization of visceral fat in normal weight or obese children and adults. 8,24 In a systematic review 78 studies comparing WTHR, WC and BMI as predictors of diabetes and cardiovascular diseases were analyzed. From those 22 prospective studies demonstrated that WtHR and WC were significant predictors more often than BMI with similar odds ratio (OR). 25 So the simple message “keep your waist circumference to less than half your weight” 26 it is applicable.

Neck circumference Neck circumference (NC) is measure with a flexible, non elastic ruler tape, at the level of the thyroid cartilage, on the mid-point of the neck. The patient is asked to stay with the eyes facing forward, and to have normal breathing. Neck circumference was used as a screening tool mainly in adults because of his positive correlation with BMI.27 In adult population it has been positively associated with obstructive sleep apnea, diabetes, and hypertension, too.28 There are only a few studies that are trying to find out if whether there is a correlation between NC and BMI 29,30,31 or NC and WC26 and are also trying to establish the best cut-offs that can be used in the pediatric population. In one study published in 2010 by Hatipoglu et all.31, 967 children aged 6–18 years were analyzed, 412 were overweight and obese patients (208 girls and 204 boys) and 555 were considered to be healthy children (284 girls and 271 boys). They found significant and positive correlations between BMI-WC, BMI-NC, and WC-NC (p