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REVIEW ARTICLE Genetic Factors in Congenital Diaphragmatic Hernia

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REVIEW ARTICLE Genetic Factors in Congenital Diaphragmatic Hernia View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector REVIEW ARTICLE Genetic Factors in Congenital Diaphragmatic Hernia A. M. Holder,* M. Klaassens,* D. Tibboel, A. de Klein, B. Lee, and D. A. Scott Congenital diaphragmatic hernia (CDH) is a relatively common birth defect associated with high mortality and morbidity. Although the exact etiology of most cases of CDH remains unknown, there is a growing body of evidence that genetic factors play an important role in the development of CDH. In this review, we examine key findings that are likely to form the basis for future research in this field. Specific topics include a short overview of normal and abnormal diaphragm development, a discussion of syndromic forms of CDH, a detailed review of chromosomal regions recurrently altered in CDH, a description of the retinoid hypothesis of CDH, and evidence of the roles of specific genes in the development of CDH. Congenital diaphragmatic hernia (CDH [MIM 142340, Overview of Normal and Abnormal Diaphragm 222400, 610187, and 306950]) is defined as a protrusion Development of abdominal viscera into the thorax through an abnormal opening or defect that is present at birth. In some cases, this protrusion is covered by a membranous sac. In con- The development of the human diaphragm occurs be- trast, diaphragmatic eventrations are extreme elevations, tween the 4th and 12th wk of gestation. Traditional views rather than protrusions, of part of the diaphragm that is of diaphragm development suggest that the diaphragm 9 often atrophic and abnormally thin. CDH is a relatively arises from four different structures. The septum trans- common birth defect, with an incidence of ∼1 in every versum gives rise to the central portion of the diaphragm, 3,000 live births.1,2 CDH is often associated with poten- the pleuroperitoneal folds (PPFs) give rise to the poster- tially lethal lung hypoplasia and pulmonary hyperten- olateral section of the diaphragm, the dorsal (esophageal) sion. Despite advances in therapy, mortality remains high, mesentery gives rise to a portion of the diaphragm pos- terior to the esophagus, and elements from the thoracic especially among severely affected infants, and long-term body wall contribute to a rim of musculature around the morbidity among survivors is common.3 diaphragm’s periphery. In contrast to this traditional view, The most common type of CDH is the posterolateral, systematic examinations of diaphragm development in or Bochdalek-type, hernia, which accounts for 90%–95% rodents have failed to identify contributions to the dia- of CDH cases.1 Other types of CDH include anterior re- phragm musculature from the lateral body wall, the sep- trosternal or peristernal Morgagni hernias, central (septum tum transversum, or the esophageal mesenchyme.10 transversum) hernias, and pars sternalis hernias, which are Rather, myogenic cells and axons were shown to coalesce found in the pentalogy of Cantrell—a rare association in- within the PPF and then to expand to form the neuro- volving abnormalities of the anterior diaphragm, sternum, muscular component of the diaphragm.10 If further in- heart, and abdominal wall. vestigation shows that this model provides an accurate Although there are multiple examples of familial cases depiction of diaphragm development in humans, the clas- of CDH in the literature, the recurrence risk for isolated sic view of diaphragm development will need to be ! cases of CDH is often reported to be 2% on the basis of revised.11 a mathematical model of multifactorial inheritance Several theories have been proposed concerning the pri- 1,4,5 risk. Empiric data also suggest a relatively low recur- mary embryologic events that lead to the development of 6–8 rence risk for CDH. Although multifactorial inheritance CDH. Events implicated in these theories have included may best explain most cases of CDH in humans, much (1) abnormalities in (ipsilateral) lung development, (2) has been learned about the genetic factors that play a role failure of closure of the pleuroperitoneal canals, (3) de- in the development of CDH by studies of patients with fective myoblast formation, and (4) abnormal phrenic CDH caused by specific genetic syndromes and chromo- nerve innervation.12–14 some anomalies. Our understanding of CDH has also been Although it is possible that each of these abnormalities aided by basic research with the use of dietary, teratogen- may play a role in the development of some cases of CDH, induced, and knockout models of CDH. there is growing evidence from animal models that CDH From the Department of Molecular and Human Genetics, Baylor College of Medicine (A.M.H.; B.L.; D.A.S.), and Howard Hughes Medical Institute (A.M.H.; B.L.), Houston; and Departments of Pediatric Surgery (M.K.; D.T.) and Clinical Genetics (M.K.; A.d.K.), Erasmus Medical Centre, Rotterdam, The Netherlands Received November 30, 2006; accepted for publication February 1, 2007; electronically published April 4, 2007. Address for correspondence and reprints: Dr. Brendan Lee, 635E, One Baylor Plaza, Houston, TX 77030. E-mail: [email protected] * These two authors contributed equally to this work. Am. J. Hum. Genet. 2007;80:825–845. ᭧ 2007 by The American Society of Human Genetics. All rights reserved. 0002-9297/2007/8005-0003$15.00 DOI: 10.1086/513442 www.ajhg.org The American Journal of Human Genetics Volume 80 May 2007 825 Table 1. Examples of Genetic Syndromes Associated with CDH Syndrome Name Chromosome(s) Gene(s) Brief Description Beckwith-Wiedemann (MIM 11p15, 5q35 CDKN1C (MIM 600856), NSD1 (MIM Autosomal dominant inheritance, macroglossia, hypoglycemia, viscero- 130650) 606681) megaly, abdominal-wall defects, and overgrowth CHARGE (MIM 214800) 8q12.1 CHD7 (MIM 608892) Autosomal dominant inheritance, coloboma, cardiac abnormalities, choanal atresia, growth retardation, genital abnormalities, ear ab- normalities, and hearing loss Cornelia de Lange (MIM 122470 5p13.1, Xp11.22-p11.21 NIPBL (MIM 608667), SMC1A (MIM Autosomal dominant inheritance, distinctive facial features, micro- and 300590) 300040) cephaly, hirsutism, malformations of the upper limbs, and growth retardation Craniofrontonasal (MIM 304110) Xq12 EFNB1 (MIM 300035) X-linked dominant inheritance, females more severely affected, cranio- synostosis, hypertelorism, broad nasal tip, grooved nails of the hal- lux and thumb, syndactyly, and skeletal abnormalities Denys-Drash (MIM 194080) 11p13 WT1 (MIM 607102) Autosomal dominant inheritance, male pseudohermaphroditism, geni- tal abnormalities, and increased risk of Wilms tumor Donnai-Barrow (MIM 222448) 2q23-q3130 … Autosomal recessive inheritance, CDH, omphalocele, agenesis of the corpus callosum, hypertelorism, and hearing loss Fryns (MIM 229850) Fryns-like phenotype has been seen with … Autosomal recessive inheritance, CDH, coarse facial features, cleft lip/ duplication of 1q24-q31.2; deletion of palate, cardiac malformations, cerebral abnormalities, and hypoplas- the terminal portion of 6q, 8p23.1, and tic finger/toenails 15q26; and partial trisomy 2224,26–29 Pallister-Killian (MIM 601803) Mosaic tetrasomy 12p … Coarse facial features with broad forehead and hypertelorism, sparse temporal hair, hypopigmentations, and mental retardation Simpson-Golabi-Behmel (MIM Xq26, Xp22.3-p22.2 GPC3 (MIM 300037), CXORF5 (MIM X-linked recessive inheritance, macrosomia, coarse facial features, hy- 312870 and 300209) 300170) pertelorism, macroglossia, skeletal abnormalities, abdominal-wall defects, and renal abnormalities Thoracoabdominal (MIM 313850) Xq25-q26.1 … X-linked dominant inheritance, diaphragmatic and ventral hernias, hy- poplastic lungs, and cardiac anomalies Wolf-Hirschhorn (MIM 194190) 4p16 … “Greek helmet” facial appearance, mental and growth retardation, cleft lip/palate, cardiac defects, and epilepsy arises from malformation of the amuscular mesenchymal diagnosed syndrome is Fryns syndrome (MIM 229850).23–25 substratum of the PPF before pleuroperitoneal canal However, reports of individuals with Fryns-like pheno- closure.10,15,16 Critical findings that support this model in- types associated with chromosomal anomalies—including clude the normal formation of the primordial diaphragm duplication of 1q24-q31.2; deletion of the terminal por- in Fgf10Ϫ/Ϫ mouse embryos that have complete lung agen- tion of 6q, 8p23.1, and 15q26; and partial trisomy 22— esis and the ability to induce defects characteristic of CDH suggests that some cases of CDH attributed to this auto- in c-metϪ/Ϫ mouse embryos that do not form diaphragm somal recessive syndrome are likely to represent geno- muscle fibers because of a defect in muscle precursor copies of this disorder.24,26–29 migration.16 Many of the syndromes associated with CDH have spe- Pulmonary hypoplasia is one of the most serious clinical cific Mendelian inheritance patterns and, in some cases, complications accompanying CDH. The role of physical the location and/or the identity of the causative gene(s) compression on the development of pulmonary hypopla- is known. Examples of CDH syndromes associated with a sia in CDH was effectively demonstrated in studies of sur- particular chromosomal locus or causative gene(s) are gically produced CDH in fetal lambs and is consistent with shown in table 1. CDH is a cardinal feature of some of the observation that pulmonary hypoplasia is usually these syndromes, whereas, for others, the rates of CDH more severe on the side of the diaphragmatic defect.17,18 are lower but probably exceed the
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