Fracture risk and impact in boys with Duchenne muscular dystrophy: A retrospective cohort study

Introduction/Aims: Boys with Duchenne muscular dystrophy (DMD) are at increased risk of fracture. This study investigated the incidence of fractures, factors contributing to risk of first fracture with emphasis on body mass index (BMI), and the impact of fractures on functional capacity in an Australian cohort of boys with DMD. Methods: A retrospective cohort study included boys with DMD who attended a pediatric neuromuscular clinic from 2011 to 2018. Information regarding fractures, anthropometry measurements, body composition and functional assessment was collected. Factors associated with first fracture risk were analyzed with Cox-proportional hazards. Longitudinal analysis of function post-fracture was also conducted. Results: This study included 155 boys with DMD. At least one fracture occurred in 71 (45%) boys; overall incidence of fractures was 399-per-10,000 persons-years. The first fracture was vertebral in 55%; 41% had non-vertebral fractures and 4% had both. Vertebral fractures occurred in significantly older (12.28 vs 9.28 y) boys with longer exposure to glucocorticoids (5.45 vs 2.50 y) compared to non-vertebral fractures. Boys with a history of fracture(s) had a steeper rate of functional decline (measured by Northstar Ambulatory Assessment score) than those with no recorded fractures. Discussion: A high fracture burden was observed in a large Australian cohort of boys with DMD. Further investigation is required to understand preventative strategies and modifiable risk factors to reduce the incidence of fractures in DMD. The impact on fractures on ambulatory capacity should be closely monitored

TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted byclinical, radiographic, and molecular studies in 21 new families

Extent: 8p.Background: The TRPV4 gene encodes a calcium-permeable ion-channel that is widely expressed, responds to many different stimuli and participates in an extraordinarily wide range of physiologic processes. Autosomal dominant brachyolmia, spondylometaphyseal dysplasia Kozlowski type (SMDK) and metatropic dysplasia (MD) are currently considered three distinct skeletal dysplasias with some shared clinical features, including short stature, platyspondyly, and progressive scoliosis. Recently, TRPV4 mutations have been found in patients diagnosed with these skeletal phenotypes. Methods and Results: We critically analysed the clinical and radiographic data on 26 subjects from 21 families, all of whom had a clinical diagnosis of one of the conditions described above: 15 with MD; 9 with SMDK; and 2 with brachyolmia. We sequenced TRPV4 and identified 9 different mutations in 22 patients, 4 previously described, and 5 novel. There were 4 mutation-negative cases: one with MD and one with SMDK, both displaying atypical clinical and radiographic features for these diagnoses; and two with brachyolmia, who had isolated spine changes and no metaphyseal involvement. Conclusions: Our data suggest the TRPV4 skeletal dysplasias represent a continuum of severity with areas of phenotypic overlap, even within the same family. We propose that AD brachyolmia lies at the mildest end of this spectrum and, since all cases described with this diagnosis and TRPV4 mutations display metaphyseal changes, we suggest that it is not a distinct entity but represents the mildest phenotypic expression of SMDK.Elena Andreucci, Salim Aftimos, Melanie Alcausin, Eric Haan, Warwick Hunter, Peter Kannu, Bronwyn Kerr, George McGillivray, RJ McKinlay Gardner, Maria G Patricelli, David Sillence, Elizabeth Thompson, Margaret Zacharin, Andreas Zankl, Shireen R Lamandé and Ravi Savariraya

Case report: hypoglycemia due to a novel activating glucokinase variant in an adult – a molecular approach

We present a case of an obese 22-year-old man with activating GCK variant who had neonatal hypoglycemia, re-emerging with hypoglycemia later in life. We investigated him for asymptomatic hypoglycemia with a family history of hypoglycemia. Genetic testing yielded a novel GCK missense class 3 variant that was subsequently found in his mother, sister and nephew and reclassified as a class 4 likely pathogenic variant. Glucokinase enables phosphorylation of glucose, the rate-limiting step of glycolysis in the liver and pancreatic β cells. It plays a crucial role in the regulation of insulin secretion. Inactivating variants in GCK cause hyperglycemia and activating variants cause hypoglycemia. Spleen-preserving distal pancreatectomy revealed diffuse hyperplastic islets, nuclear pleomorphism and periductular islets. Glucose stimulated insulin secretion revealed increased insulin secretion in response to glucose. Cytoplasmic calcium, which triggers exocytosis of insulin-containing granules, revealed normal basal but increased glucose-stimulated level. Unbiased gene expression analysis using 10X single cell sequencing revealed upregulated INS and CKB genes and downregulated DLK1 and NPY genes in β-cells. Further studies are required to see if alteration in expression of these genes plays a role in the metabolic and histological phenotype associated with glucokinase pathogenic variant. There were more large islets in the patient’s pancreas than in control subjects but there was no difference in the proportion of β cells in the islets. His hypoglycemia was persistent after pancreatectomy, was refractory to diazoxide and improved with pasireotide. This case highlights the variable phenotype of GCK mutations. In-depth molecular analyses in the islets have revealed possible mechanisms for hyperplastic islets and insulin hypersecretion

Multilingual global e-learning pediatric endocrinology and diabetes curriculum for front line health care providers in resource-limited countries: Development study

Background: Electronic learning (e-learning) is a widely accessible, low-cost option for learning remotely in various settings that allows interaction between an instructor and a learner. Objective: We describe the development of a free and globally accessible multilingual e-learning module that provides education material on topics in pediatric endocrinology and diabetes and that is intended for first-line physicians and health workers but also trainees or medical specialists in resource-limited countries. Methods: As complements to concise chapters, interactive vignettes were constructed, exemplifying clinical issues and pitfalls, with specific attention to the 3 levels of medical health care in resource-limited countries. The module is part of a large e-learning portal, ESPE e-learning, which is based on ILIAS (Integriertes Lern-, Informations-und Arbeitskooperations-System), an open-source web-based learning management system. Following a review by global experts, the content was translated by native French, Spanish, Swahili, and Chinese-speaking colleagues into their respective languages using a commercial web-base

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins

Disorders of sex development : insights from targeted gene sequencing of a large international patient cohort

Background: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. Results: We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46, XY DSD and 48 with 46, XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46, XY DSD. In patients with 46, XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. Conclusions: Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes

Clinical management strategies for disorders of gonadal function from infancy to late

© 2013 Dr. Margaret ZacharinPublications included in thesis:Ehtisham, S. , & Zacharin, M. (2009). Primary ovarian failure and small for gestational age: a previously unrecognised association. Journal of Paediatrics and Child Health, 45(5), 313-316. DOI:10.1111/j.1440-1754.2009.01511.xZacharin, M. (2010). Disorders of ovarian function in childhood and adolescence: evolving needs of the growing child: an endocrine perspective. BJOG: An International Journal of Obstetrics and Gynaecology, 117(2), 156-162. DOI: 10.1111/j.1471-0528.2009.02399.xZacharin, M. (2000). Use of androgens and oestrogens in adolescents: a review of hormone replacement treatment. Journal of Pediatric Endocrinology & Metabolism, 13(1), 3-11. DOI: 10.1515/JPEM.2000.13.1.3Greaves, R., Kanumakala, S., Read, A., & Zacharin, M. (2004). Genital abnormalities mimicking congenital adrenal hyperplasia in premature infants. Journal of Paediatric Health, 40(4), 233-236. DOI: 10.1111/j.1440-1754.2004.00345.xGreaves, R., Hunt, R. W., & Zacharin, M. (2008). Transient anomalies in genital appearance in some extremely preterm female infants may be the result of foetal programming causing a surge in LH and the over activation of the pituitary-gonadal axis. Clinical Endocrinology, 69(5), 763-768. DOI: 10.1111/j.1365-2265.2008.03298.xGreaves, R. F., Hunt, R. W., Chiriano, A. S., & Zacharin, M. R. (2008). Luteinizing hormone and follicle-stimulating hormone levels in extreme prematurity: development of reference intervals. Pediatrics, 121(3), e574-e580. DOI: 10.1542/peds.2007-1327Simm, P. J., & Zacharin, M. R. (2006). The psychosocial impact of Klinefelter Syndrome: a 10 year review. Journal of Pediatric Endocrinology & Metabolism, 19(4), 499-505. PMID: 16759035Pedreira, C. C., Hameed, R., Kanumakala, S., & Zacharin, M. (2006). Health-care problems of Turner syndrome in the adult woman: a cross sectional study of a Victorian cohort and a case for transition. Internal Medicine Journal, 36(1), 54-57. DOI: 10.1111/j.1445-5994.2005.00990.xMcDonnell, C. M., Coleman, L., & Zacharin, M. R. (2003). A 3-year prospective study to assess uterine growth in girls with Turner’s syndrome by pelvic ultrasound. Clinical Endocrinology, 58(4), 446-450. DOI: 10.1046/j.1365-2265.2003.01737.xPoomthavorn, P., Stargate, R., & Zacharin, M. (2009). Psychosexual and psychosocial functions of anorchid young adults. Journal of Clinical Endocrinology & Metabolism, 94(7), 2502-2505. DOI: 10.1210/jc.2008-1886Zacharin, M. R., & Warne, G. L. (1997). Treatment of hypogonadal adolescent boys with long acting subcutaneous testosterone pellets. Archives of Disease in Childhood, 76(6), 495-499. DOI: 10.1136/adc.76.6.495Zacharin, M. R., Pua, J., & Kanumakala, S. (2003). Bone mineral density outcomes following long-term treatment with subcutaneous testosterone pellet implants in male hypogonadism. Clinical Endocrinology, 58(6), 691-695. DOI: 10.1046/j.1365-2265.2003.01746.xZacharin, M., Sabin, M. A., Nair, V. V., & Dagabdhao, P. (2012). Addition of recombinant follicle-stimulating hormone to human chorionic gonadotropin treatment in adolescents and young adults with hypogonadism promotes normal testicular growth and may promote early spermatogenesis. Fertility and Sterility, 98(4), 836-842. DOI: 10.1016/j.fertnstert.2012.06.022Zacharin, M. R. (2009). Puberty, contraception and hormonal management for young people with disabilities. Clinical Pediatrics, 48(2), 149-155. DOI: 10.1177/0009922808324492Zacharin, M. R. (2009). Assessing the skeleton in children and adolescents with disabilities: avoiding pitfalls, maximising outcomes: a guide for the general paediatrician. Journal of Paediatrics and Child Health, 45(6), 326-331. DOI: doi:10.1111/j.1440-1754.2009.01506.xJayasinghe, Y., Grover, S. R., & Zacharin, M. (2008). Current concepts in bone and reproductive health in adolescents with anorexia nervosa. BJOG: An International Journal of Obstetrics and Gynaecology, 115(3), 304-315. DOI: 10.1111/j.1471-0528.2007.01601.xZacharin, M., Savasi, I., & Grover, S. (2010). The impact of menstruation in adolescents with disabilities related to cerebral palsy. Archives of Disease in Childhood, 95(7), 526-530. DOI: 10.1136/adc.2009.174680Zacharin, M., Chanoine, J. P., Cassoria, F., Brink, S., Hanas, R., Fideleff, H. L., et al. (2013). Promoting excellence in the care of pediatric endocrine diseases in the developing world. Pediatrics, 131(2), e573-e578. DOI: 10.1542/peds.2012-0848Zacharin, M., Banerjee, I., & Patel, L. (2013). Puberty: normal and abnormal. In M. Zacharin (Ed.), Practical pediatric endocrinology in a limited resource setting (pp. 27-67). Amsterdam; New York: Academic Press.This body of work defines problems of altered sex hormone function from birth to the end of adolescence and demonstrates the ability of interventions to optimize outcomes. The breadth and prevalence of sex hormone alterations in these conditions is outlined and a range of rational and beneficial treatment options to optimize outcomes, reduce risks and increase understanding across the medical and family spectrum is provided. Evidence is given for a clear plan for identification and management, for paediatricians working in resource constrained environments. The document describes normal processes of development, growth and puberty, indicates aberrations due to structural or functional changes, either primary or secondary to acquired health disorders and complications of treatment omission or failure and provides information based on my publications in the area, as to management considerations and strategies at different ages and for different conditions together with implications for health outcomes in the face of adequate treatment or otherwise. New concepts and new treatments are discussed, with particular reference to offering improved outcomes whilst bearing in mind ethical principles underlining management