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Pediatric Endocrinology Reviews (PER) is the most respected international peer reviewed journal in Pediatric Diabetes, Nutrition Metabolism and Genetics. Hypothyriodism, Hyperthyriodism, Glycemic Management for Children with Diabetes Glucose Monitoring Adrenal Insufficiency Turner Syndrome Late Adolescence Klinefelter Syndrome Children with Short Stature and Growth Failure: Heightism Type 1 Diabetes in Children Growth Hormone Treatment for GHD Insulin-like Growth Factor-I Growth Hormone Deficiency SGA Children with Short Stature Receiving GH Treatment Hypothalamic Obesity Adolescent Gynecomastia Hematospermia in Adolescents Gain-of-Function CDKN1C Mutations Craniopharyngioma Succinate-Dehydrogenase Deficient Paragangliomas/Pheochromocytomas Adrenal Steroidogenesis: Impact on Gonadal Function Focal Congenital Hyperinsulinism (CHI)  Longevity Hormone Klotho Pediatric Congenital Hypothyroid Lysosomal Storage Diseases Juvenile NCL (CLN3 Disease) GM1 and GM2 Gangliosidoses Types A and B Niemann-Pick Disease CLN2 Disease (Classic Late Infantile Neuronal Ceroid Lipofuscinosis) Krabbe Disease Fucosidosis Nuclear Factor Kappa B (NF-κB) in Growth Plate Chondrogenesis Persistent Müllerian Duct Syndrome LHX4 Gene Alterations Stunted Growth 45,X/46,XY Gonadal Dysgenesis Thyroid Hemiagenesis Nutrimetabolomics and Adipocitokines Chromosomal Microarray Analysis (CMA) Chromosomal microarray, Copy Number Variant (CNV), Prenatal, Amniocentesis, Comparative genomic hybridization, SNP array, Diagnosis, Clinical Abreviations: aCGH – array-based comparative genomic hybridization, ASD – autism spectrum disorder, BAC – bacterial artificial chromosome, CHD – congenital heart disease, CMA – chromosomal microarray analysis, CNV – copy number variant, CVS – chorionic villus sampling, DD – developmental delay, DNA – deoxyribonucleic acid, FISH – fluorescent in situ hybridization, GABA - gammaaminobutyric acid, ID – intellectual disability, LOH – loss of heterozygosity, NGS – next generation sequencing, NIPT – noninvasive prenatal testing, NOS – not otherwise specified, PGD - preimplantation genetic diagnosis, SNP – single nucleotide polymorphism, VUS – variant of unclear clinical significance Central precocious puberty, Traumatic brain injury, Pathophysiology Nephrolithiasis, Nephrocalcinosis, Hypercalciuria, Hyperoxaluria, Hypouricemia, Cystinuria, Genetics 

Vol. 10 Supplement 2

June 2013

 

Nutritional Rickets: Pathogenesis and Prevention

John M Pettifor MBBCh, PhD

Abstract

Nutritional rickets remains a public health c o n c e r n i n m a n y a r e a s o f t h e w o r l d despite cheap and effective means of preventing the disease. The roles of vitamin D deficiency, low dietary calcium intakes and the interrelationships between the two in the pathogenesis of the disease are discussed. It is now recognized that vitamin D deficiency in the pregnant and lactating mother predisposes to the development of rickets in the breastfed infant, and that cultural and social factors are important in the pathogenesis of the disease during the adolescent growth spurt. Prevention of rickets is dependent on the awareness of the medical profession and the general public of the need to ensure adequate intakes of vitamin D in at-risk populations, and of the importance of increasing dietary intakes of calcium using locally available and inexpensive foods in communities in which dietary calcium deficiency rickets is prevalent.

Ref: Ped. Endocrinol. Rev. 2013;10(Suppl2): 7-13

Keywords: Vitamin D deficiency, The Role of Vitamin D, Nutritional Rickets

Pediatric Endocrinology Reviews (PER) ● Volume 10 ● Supplement 2 ● June 2013 7

 

Vitamin D Action: Lessons from VDR and Cyp27b1 Null Mice

Roger Bouillon, MD, PhD, FRPC, Liesbet Lieben, PhD, Chantal Mathieu, PhD, MD, Annemieke Verstuyf, MD, Geert Carmeliet, PhD, MD

Abstract

Even one century after its discovery, there are still many gaps in the understanding o f t h e v i t a m i n D e n d o c r i n e s y s t e m . Inactivation of the vitamin D receptor (VDR) or the enzymes metabolizing its ligand (especially Cyp27b1) in mice has clearly demonstrated that the active form of vitamin D [1,25(OH)2D] is essential to stimulate calcium absorption in the gut during normal/low calcium intake, and as a consequence, that 1,25(OH)2D is required to maintain normal serum calcium, bone and growth plate homeostasis. These findings have resulted in clear clinical guidelines for the treatment of vitamin D-related bone diseases of infants, chi ldren and adul t s . Tissue-spe c i f i c VDR or Cyp27b1 deletion in mice has also proven to be useful to define the precise role of 1,25(OH)2D action in cells belonging to the intestine, bone, growth plate and also to many non-classical target tissues. Indeed, experimental findings show t h a t 1,25(OH)2D has numerous extra - skeletal effects, and observational studies in man demonstrate that disturbances in the vitamin D pathway are associated with major human diseases such as cancer, infections, autoimmune diseases, cardiovascular and metabolic diseases, muscle function, reproduction and neurocognitive disorders. We will compare the findings in VDRand Cyp27b1-null mice with findings in man to elucidate what is presently understood of the vitamin D endocrine system and to identify the still outstanding questions.

Ref: Ped. Endocrinol. Rev. 2013;10(Suppl 2): 14-26

Keywords: Vitamin D, vitamin D receptor, rickets, osteomalacia, knock-out mice, 25OHD-vitamin D-1- alpha-hydroxylase, extra-skeletal effects of vitamin D

 

The Changing Face of Hypophosphatemic Disorders in the FGF-23 Era

Janet Y. Lee1, MD, M.P.H, Erik A. Imel2, MD.

Abstract

In the past decade, research in genetic disorders o f h y p o p h o s p h a t e m i a h a s s i g n i f i c a n t l y expanded our understanding of phosphate metabolism. X-linked hypophosphatemia (XLH) is the most common inherited form of rickets d u e t o r e n a l p h o s p h a t e w a s t i n g . R e c e n t understanding of the mechanisms of disease and role of fibroblast growth factor 23 (FGF-23) in XLH and other hypophosphatemic disorders have opened new potential therapeutic avenues. We will discuss the current standard of treatment for XLH as well as promising future directions under study.

Ref: Ped. Endocrinol. Rev. 2013;10(Suppl2): 27-39

Key Words: X-linked hypophosphatemia, phosphate, FGF-23, 1,25(OH)2D

 

Hypophosphatasia

Cheryl Rockman-Greenberg, MD, CM, FRCPC, FCCMG

Abstract

Hypophosphatasia (HPP) is a rare, inherited, potenti a l l y l ife-threatening metabol ic disorder that arises from loss-of-function mutations in the gene that encodes the tissuenonspecific isoenzyme of alkaline phosphatase (TNSALP). As a result of these mutations (as many as 260 genetic mutations have been associated with HPP) , pat i ent s have d i s o r d e r e d bone mineralization leading to rickets, osteomalacia, fractures and other skeletal abnormalities as w e l l a s o t h e r s y s t e m i c complic a t ion s s uch as seizures, respiratory compromise, dental anomalies, nephrocalcinosis and/or weakness and chronic pain. HPP may appear across the age spectrum, from in utero, to infancy, childhood, adolescence and/or adulthood. More severe cases tend to be seen in utero and infancy, and in these instances, mortality may be as high as 50%. In surviving or older patients, disability and poor quality of l ife may be seen. Based on cl inical presentation, HPP can be mistakenly diagnosed as other skeletal diseases, but a low alkaline phosphatase is an important, distinguishing sign of this condition. While patients with HPP may benefit from supportive measures, at the present time, there is no approved specific therapy for

HPP.

Ref: Ped. Endocrinol. Rev. 2013;10(Suppl2): 40-48

Key words: hypophosphatasia, alkaline phosphatase, tissue non-specific alkaline phosphatase, metabolic bone disorder, rickets, osteomalacia

 

Title: Fibrous Dysplasia

Steven Lietman1, MD, Michael A. Levine2, MD

Abstract

Fi b r o u s d y s p l a s i a i s a d e v e l o p m e n t a l abnormality of bone that is characterized by a highly disorganized mixture of immature f i b r o u s t i s s u e and f r agment s o f immat u r e trabecular bone. Fibrous dysplasia may arise as a single, discrete (monostotic) lesion or can occur with a more widespread distribution with multiple lesions that affect many bones (oligoor polyostotic). Fibrous dysplasia is usually an isolated skeletal finding but can sometimes occur as a component of a multisystem developmental disorder known as McCune-Albright syndrome (MAS) that i s also assoc iated with endocrine hyperfunction (e.g. precocious puberty) and café au lait cutaneous macules. The identification of activating mutations in GNAS in a subset of human GH-secreting pituitary tumors and autonomously functioning human thyroid tumors provided the initial basis for understanding the molecular pathophysiology of McCune-Albright syndrome and fibrous dysplasia. These observations led to the concept that activating mutations of the GNAS gene convert it into a putative oncogene r e f e r r e d t o a s g s p ( G s α o r G α s ) . T h e c l a s s i c radiographi c feature of fibrous dysplasia is a hazy, r a d i o lucent, or ground-g lass, pattern resulting from the defective mineralization of immature dysplastic bone; it is usually strikingly different from the radiographic appearance of normal bone, calcified cartilage, or soft tissue. The surgical approach to fibrous dysplasia should in general be conservative. Recent research s u g g e s t s t h a t t h e W n t / β - c a t e n i n p a t h w a y m a y play a rol e i n f ibrous d y s p l a s ia as patients with act ivating GNAS mutations speci f ically s h o w e d t h a t G α s m u t a t i o n s a c t i v a t e d W n t / β - catenin signaling. Thus inhibition of β-catenin signaling or silencing GNAS alleles that encode c o n s t i t u t i v e l y a c t i v e G s α m o l e c u l e s i n f i b r o u s dysplasia and McCune-Albright syndrome offer pot e n t i a l t h e rapeut i c p romise and deserve further study. In summary fibrous dysplasia is a developmental abnormality of bone with a known molecular etiology; Further knowledge about the molecular pathology of fibrous dysplasia may lead to improved conservative therapies in the near future.

Ref: Ped. Endocrinol. Rev. 2013;10(Suppl2): 49-56

Key Words: McCune-Albright syndrome, GNAS, bisphosphonates, denosumab, Wnt/β-catenin pathway, gsp mutation

 

Osteogenesis Imperfecta

Mouna Ben Amor1, MD, Frank Rauch1, MD, Elena Monti2, MD, Franco Antoniazzi3 MD

Abstract

Osteogenesis imperfecta (OI), an inherited skeletal disorder characterized by low bone mass, bone fragility, and often short stature. Th e c l in ic a l severity varies widely from being near ly asymptomatic with a mild predisposition to fractures, normal stature and normal lifespan being to profoundly disabling and even lethal. Extra skeletal manifestations may include blue-grey sclera and dental abnormalities. I n i t i a l l y, t h e c l a s s i f i c a t i o n o f O I i n t o f o u r types was based on clinical findings, but more recently additional types OI (types V-XI) have been ascertained, based on the identification of different mutations. While this classification is somewhat controversial, it is described in this article. The treatment of patients with OI is based on the nature and severity of symptoms. The goal of therapy is to prevent fractures and disability, improve function and quality of life. A mul t idisci p l inary approach is needed, and treatment options include medication such as bisphosphonates, surgery, and rehabilitation. Investigations continue to explore gene and cell therapies that may be developed in the future.

Ref: Ped. Endocrinol. Rev. 2013;10(suppl 2): 57-65

Keywords: Osteogenesis imperfecta (OI), OI type III, OI type IV

 

Skeletal Abnormalities in Lysosomal Storage Diseases

David A. Stevenson1, MD, Robert D. Steiner2, MD

Abstract

Many of the lysosomal storage diseases (LSDs) have skeletal abnormalities causing significant morbidity. Dysostosis multiplex describes a constellation of radiographic skeletal findings that are helpful in diagnosing many of the LSDs, particularly the mucopolysaccharidoses (MPS). This review discusses the cl inical and radiographic skeletal manifestations of various LSDs with an emphasis on disorders that have s i g n i f i c a n t s k e l e t a l i n v o l v e m e n t ( e g , M P S disorders, mucolipidosis type II and III, Gaucher). Enzyme replacement therapy (ERT) for several of the LSDs has been beneficial for many of the clinical manifestations, but efficacy with regard to the skeletal abnormalities is not as obvious. As the pathophysiology of the skeletal abnormalities associated with LSDs becomes better elucidated, investigators wil l l ikely to develop improved therapies to specifically target bone and wil l alleviate the skeletal problems.

Ref: Ped. Endocrinol. Rev. 2013;10(Suppl2): 66-76

Keywords: bone, lysosomal storage diseases, mucopolysaccharidosis, skeletal

 

Bone Lessons from Marfan Syndrome and Related Disorders: Fibrillin, TGF-Β and BMP at the Balance of Too Long and Too Short

Bart L. Loeys1, MD, Geert Mortier1, MD, Harry C. Dietz2, MD

Abstract

The extracellular matrix (ECM) is a complex e n t i t y w i t h s t ruc t u r a l p rot e i n s ( s u c h a s f ibri l l i n s , c ollagen, elastin), ground substance (proteoglycans), modifying enzymes ( ADAMTS , P L O D , l y s y l o x i d a s e s ( L OX) ) a n d cytokines that regulate morphogenesis, growth, homeostasis and repair (transforming growth factor-beta [TGF-β], bone morphogenic protein [BMP]). Over the last decade, the intimate relationship between structural proteins and these growth factors has emerged. The study of the extracellular matrix in human conditions and relevant mouse models is gradually unmasking the key role of these structural molecules in the regulation of the bio-availability of these growth factors. Major progress has been made in the study of the cardiovascular system (1) and the first clues in the skeletal system have emerged. (2) In this review, we will discuss the clinical, molecular, and pathogenic aspects of Marfan syndrome, Loeys-Dietz syndrome and related disorders with emphasis on the role of fibrillins and TGF-β.

Ref: Ped. Endocrinol. Rev. 2013;10(Suppl2): 77-83

Key words: Marfan syndrome, fibrillins and TGF-β.

 

Causes of Secondary Pediatric Osteoporosis

Maria Luisa Bianchi, MD

Abstract

Se c o nda r y o s t e o p o r o s i s i s i n c r e a s i n g l y o b s e r v e d i n b o t h a d u l t a n d p e d i a t r i c patients affected by many heterogeneous diseases. Most forms of secondary osteoporosis derive from one or more of the following causes: malnutrition, malabsorption, immobilization and/or reduced mechanical loa d , v itamin D deficiency, chronic inflammation, hormonal derangements, and chronic use of glucocorticoids a n d o t h e r d r u g s . C o n s i d e r i n g t h e l a c k o f symptoms in the early phases, both the risk and the presence of secondary osteoporosis tend to be underestimated, and as a consequence, appropriate prevention/treatment measures are often delayed or not taken at all. Failure to accumulate an appropriate bone mass for gender and age or to build an architectural ly “strong” bone must always be suspected when a child or adolescent presents with frequent and/ or low-trauma fractures, chronic bone pain, or an incidental finding of “osteopenia” on plain X - r ays . Known r i s k fac t o r s must always be considered.

Ref: Ped. Endocrinol. Rev. 2013;10(suppl 2): 84-96

Key words: children, bone mineral density, osteoporosis, fractures, calcium, vitamin D, malabsorption, inflammation, physical activity, glucocorticoids

 

Fibrodysplasia Ossificans Progressiva: Diagnosis, Management, and Therapeutic Horizons

Robert J. Pignolo1,2,4, MD, PhD, Eileen M. Shore1,3,4, PhD., Frederick S. Kaplan1,2,4, MD

Abstract

Fibrodysplasia ossificans progressiva (FOP), a r a r e a n d d i s a b l i n g g e n e t i c condition characterized by congenital malformations of the great toes and progressive heterotopic endochondral ossi f ication (HEO) which is the most catastrophic of HEO disorders in humans. Flare-ups of FOP are episodic; immobil ity is cumulative. Heterozygous activating mutations in activin receptor IA/activin-like kinase-2 (ACVR1/ ALK2), a bone morphogenetic protein (BMP) type I receptor, exist in all sporadic and familial cases of FOP. The discovery of the FOP gene established a critical milestone in our understanding of FOP, and revealed a highly conserved therapeut ic t a r g e t i n t h e BMP s i g n a l i n g pathway. T h i s discovery has advanced efforts to develop novel therapies for this disabling disorder of tissue metamorphosis. While effective treatment of FOP wil l l ikely be based on interventions that modulate overactive ACVR1/ALK2 signaling, or that specifically block postnatal HEO, current management is f ocused on earl y d iagnos i s , assiduous avoidance of injury or iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function.

Ref: Ped. Endocrinol. Rev. 2013;10(Suppl 2): 97-108

Key words: fibrodysplasia ossificans progressiva, heterotopic ossification, activin receptor IA/activin-like kinase-2 (ACVR1/ALK2), BMP signaling