Growth in CHARGE syndrome: optimizing care with a multidisciplinary approach

Journal of Multidisciplinary Healthcare Dovepress open access to scientific and medical research Journal of Multidisciplinary Healthcare downloaded from https://www.dovepress.com/ by 88.198.20.149 on 13-Nov-2019 For personal use only. Open Access Full Text Article Growth in CHARGE syndrome: optimizing care with a multidisciplinary approach This article was published in the following Dove Press journal: Journal of Multidisciplinary Healthcare Dieuwerke R Dijk 1 Gianni Bocca 2 Conny M van RavenswaaijArts 1 1 Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; 2 Department of Pediatrics, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Abstract: CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital hypoplasia, Ear anomalies including hearing loss) syndrome is a rare syndrome with an incidence of approximately 1:15,000 newborns. It is caused by pathogenic variants in the CHD7 gene and clinically characterized by a wide range of anomalies with variable expression. Growth retardation affects 60–72% of children with CHARGE syndrome, making it one of the most prominent medical issues in the syndrome. Growth retardation in CHARGE syndrome is thought to be multifactorial and can be influenced by almost all co-morbidities, requiring a multidisciplinary approach to the different medical problems. In this systematic review, we describe what is currently known about growth in CHARGE syndrome and how it is influenced by commonly seen clinical problems including feeding difficulties, hypogonadotropic hypogonadism and growth hormone deficiency. Furthermore, we provide recommendations for a multidisciplinary approach. Keywords: CHARGE syndrome, growth, short stature, multidisciplinary, hypogonadotropic hypogonadism Introduction Correspondence: Dieuwerke R Dijk Department of Genetics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, PO Box 30 001, Groningen 9700 RB, The Netherlands Tel +31 50 361 7100 Fax +31 50 361 7231 Email CHARGE syndrome (OMIM 214800) is a rare disorder with an estimated incidence of 1 in 15,000 to 1 in 17,000 live births.1 It is characterized by a wide spectrum of anomalies that vary among patients. In 1981, Pagon introduced the acronym CHARGE based on some of the most prevalent anomalies in the syndrome: Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital hypoplasia and Ear and hearing abnormalities.2 CHARGE syndrome can be clinically diagnosed by using the Blake or Verloes criteria.3,4 In 2004, variants in the CHD7 gene (OMIM 608892) were identified to be responsible for the CHARGE phenotype.5 Since then, more than 1000 variants in CHD7 have been identified, and a CHD7 variant is found in 83–95% of patients fulfilling Blake or Verloes’ diagnostic criteria.6,7 Next-generation sequencing techniques have led to the identification of an increased number of CHD7 gene variants and to increased detection of these variants in patients with a mild phenotype. The majority of CHD7 gene variants are nonsense or frameshift mutations, while missense and splice site mutations have been detected in a minority of cases, and deletions, duplications and chromosomal rearrangements are rare.1 CHARGE syndrome is a clinically variable syndrome, and there is no clear correlation between genotype and phenotype when focusing on individual cases. However, patients with a missense mutation generally have a milder phenotype, and missense mutations are more frequently found in patients with Kallmann syndrome.8–10 607 submit your manuscript | www.dovepress.com Journal of Multidisciplinary Healthcare 2019:12 607–620 DovePress © 2019 Dijk et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://doi.org/10.2147/JMDH.S175713 Powered by TCPDF (www.tcpdf.org) REVIEW Dovepress Journal of Multidisciplinary Healthcare downloaded from https://www.dovepress.com/ by 88.198.20.149 on 13-Nov-2019 For personal use only. Dijk et al CHARGE syndrome is thought to be caused by a loss of function of CHD7 and has an autosomal dominant inheritance pattern. Most cases are caused by de novo mutations, although some familiar cases have been reported.1,11,12 In 2016, new clinical criteria were proposed that consist of the revised Blake criteria with the addition of a pathogenic variant in the CHD7 gene as a major criterion.13 Growth retardation and hypogonadotropic hypogonadism (HH) are important aspects of CHARGE syndrome in both boys and girls. Short stature is reported in 60–72% of patients with CHARGE syndrome, although the underlying cause is often not well-documented.14–16 HH is also highly prevalent, and 60–88% of patients with CHARGE syndrome do not achieve puberty spontaneously. Nonetheless, there are no syndrome-specific guidelines on how to induce puberty in this group of patients who frequently exhibit challenging behavior and therefore may respond differently to hormone replacement therapy.7,16–19 A number of studies have now been published that describe aspects of growth and puberty in CHARGE syndrome. The aim of this review is to summarize what is currently known about growth in CHARGE syndrome in order to make recommendations for the multidisciplinary approach and identify what future studies are needed to develop evidence-based guidelines for growth and puberty surveillance in CHARGE syndrome. Methods For this systematic review, we conducted a literature search on growth and puberty in CHARGE syndrome in PubMED using MeSH terms and in Embase using Emtree terms. We also searched on title and abstract based on keywords related to growth and puberty and included publications regarding CHD7 and Kallmann syndrome because HH is also a feature of Kallmann syndrome and mutations in the CHD7 gene may be found in these patients.20 Our search terms and selection process are described in Figure 1. We excluded all duplicate records and those that were not in English and selected possibly relevant records on title and abstract. The final selection was made after reading the complete publication (DD, GB). The references of the selected articles were checked for any relevant articles that might have been missed. Fetal growth In a cohort of 119 children with (...truncated)