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The genetics of common disorders e Congenital diaphragmatic hernia Q7
Anne M. Slavotinek* Department of Pediatrics, Division of Genetics, University of California, MSC 2711, Rock Hall Room RH284D, 1550 4th St, San Francisco, CA 94143-2711, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 January 2014 Accepted 20 April 2014 Available online xxx
Congenital diaphragmatic hernia (CDH) is a common birth defect with a high mortality and morbidity. Although numerous chromosomal aberrations and gene mutations have been associated with CDH, the etiology of the diaphragmatic defect is identified in less than 50% of patients. This review discusses the some of the more frequent, recurrent karyotypic abnormalities in which CDH is a feature, including 15q26, 8p23.1 and 4p16.3 deletions and tetrasomy 12p (PallistereKillian syndrome), together with some of the syndromes in which CDH is a relatively common feature, including Fryns syndrome, MatthewWood syndrome, overgrowth syndromes and DonnaieBarrow syndrome. In the era of genomic technologies, our knowledge of the genes and chromosome regions involved in pathogenesis of CDH is likely to advance significantly. Ó 2014 Published by Elsevier Masson SAS.
Keywords: Congenital diaphragmatic hernia Fryns syndrome 15q26 deletion syndrome
1. Introduction
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Congenital diaphragmatic hernia (CDH) is a structural birth defect characterized by defective formation of the diaphragm [Brady et al., 2011; Enns et al., 1998; Greer, 2013; Pober et al., 2010; Slavotinek, 2005]. Diaphragmatic eventration, or significant thinning of the diaphragm, is considered to be a related birth defect that may share a similar etiology. Diaphragmatic hernias are present in 1 in 2000e3000 live births and it has been estimated that 1600 neonates with CDH are born in the United States each year [Torfs et al., 1992]. CDH is a significant malformation because the diaphragmatic defect permits herniation of the abdominal contents into the thorax, causing pulmonary hypoplasia, pulmonary hypertension, feeding difficulties and gastroesophageal reflux that result in long-term morbidity with hearing impariment, growth retardation and developmental delays [Cass, 2005; Colvin et al., 2005; West and Wilson, 2005] (Fig. 1). There are several different types of diaphragmatic hernia. The commonest defect is located in the posterolateral diaphragm (Bochdalek hernia) and hernias involving the anterior portion of the diaphragm (Morgagni hernia) are less frequent [Ackerman et al., 2012]. CDH occurs as an isolated malformation (simplex CDH) in an estimated 40e50% of patients and is present with extra-diaphragmatic malformations (complex CDH) in the remainder [Brady et al., 2011; Enns et al., 1998; Skari et al., 2000]. Additional malformations that can occur with CDH and that are considered to be complications of the hernia per se include * Tel.: þ1 (415) 514 1783; fax: þ1 (415) 476 9305. E-mail address: [email protected].
pulmonary hypoplasia, patent ductus arteriosus, patent foramen ovale and intestinal malrotation [“CDH syndrome”; Skarsgard and Harrison, 1999]. Other organs that can be malformed in patients with CDH include the central nervous system (5e75% patients), cardiovascular system (4e63% patients), genitourinary system (5e27% patients) and gastrointestinal system [1e20% patients; Enns et al., 1998]. In mouse, the diaphragm develops between embryonic day (E) 10.5 and E15.5, with closure at E12.5-E13.5, corresponding to the 4th to 6th weeks of human gestation [Babiuk et al., 2003; Greer, 2013]. The primordial diaphragm arises from closure of the pleuroperitoneal folds (PPFs) that form the anlagen for the lateral, muscular component of the diaphragm [Greer, 2013]. The PPFs extend from the lateral cervical body wall and fuse ventrally with the septum transversum and the posthepatic mesodermal plate. Myogenic precursor cells then delaminate from the ventrolateral lips of the hypaxial dermomyotome, migrate and reach the primary diaphragm at E12.5, after which they proliferate to form the diaphragm muscle [Brady et al., 2011; Pober et al., 2010; Russell et al., 2012]. Defects at all of these stages of development, including failed closure of the PPFs, disordered cell migration and abnormal myogenesis or extracellular matrix formation [Russell et al., 2012], can cause CDH.
2. Genetic causes of CDH in humans A brief summary of etiological factors for CDH is provided in Table 1. In more than 70% of individuals with CDH, the etiology remains unknown [Pober et al., 2010].
http://dx.doi.org/10.1016/j.ejmg.2014.04.012 1769-7212/Ó 2014 Published by Elsevier Masson SAS.
Please cite this article in press as: Slavotinek AM, The genetics of common disorders e Congenital diaphragmatic hernia, European Journal of Medical Genetics (2014), http://dx.doi.org/10.1016/j.ejmg.2014.04.012
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diaphragmatic defects in human patients. One small study demonstrated a statistically significant reduction in plasma retinol and retinol-binding protein in newborns with CDH compared to controls [Major et al., 1998]. An intake of dietary vitamin A below the recommended daily intake was also associated with an increased risk of a baby with CDH in mothers of normal weight [Beurskens et al., 2013]. However, no hernia has as yet been attributed to vitamin deficiency [Pober et al., 2010]. 4. Chromosome aberrations and CDH In an estimated 2%e33% of patients with CDH, a causative cytogenetic aberration is detected [Enns et al., 1998; Holder et al., 2007; Howe et al., 1996; Lurie, 2003; Pober et al., 2010; Yu et al., 2012]. Many of the commonest chromosome aberrations are diagnosable with a karyotype, but array comparative genomic hybridization (array CGH) is almost always performed. To date, the largest array CGH study on 256 probands with CDH found chromosome abnormalities in 6.3% of affected individuals [Yu et al., 2012]. CDH has been connected with cytogenetic abnormalities on almost every chromosome arm and recurrent aberrations have provided information about the postulated locations of CDH-causing genes [Holder et al., 2007; Lurie, 2003; Q2 Yu et al., 2012]. Table 2 summarizes a selection of the more frequent, recurrent chromosome aberrations that have been linked to CDH and a brief discussion is provided below. 5. Chromosome aberrations and CDH e aneuploidy
Fig. 1. Photograph of a term neonate with left congenital diaphragmatic hernia, showing herniation of the abdominal contents into the left thoracic cavity. Courtesy of Dr Philip Ursell, Department of Pathology and Laboratory Medicine, University of California, San Francisco.
3. Environmental and nutritional factors There are few teratogenic agents or environmental factors that are known to cause CDH in humans. The immunosuppressive drug, mycophenylate mofetil, and allopurinol, a drug used in the treatment of hyperuricemia, have both been associated with CDH and overlapping patterns of birth defects [Kozenko et al., 2011; Parisi et al., 2009; Perez-Aytes et al., 2008]. Disruption to purine biosynthesis has been hypothesized to be the cause of the malformations for both drugs [Kozenko et al., 2011]. One case of diaphragmatic hernia was observed following lithium treatment in the first trimester of pregnancy [Hosseini et al., 2010]. Vitamin A deficiency and disturbances to retinoic metabolism have been implicated in the pathogenesis of CDH in animal models [Clugston et al., 2006; Kling and Schnitzer, 2007] and this mechanism has been investigated as a putative cause of
Several different chromosome aneuploidies have been associated with CDH. Tetrasomy 12p (PallistereKillian syndrome (PKS; MIM 601803)) has a phenotype similar to Fryns syndrome with dysmorphic features that include a high forehead and high anterior hairline, nail hypoplasia, streaky skin pigmentation, cardiac defects and CDH [Bergoffen et al., 1993; McPherson et al., 1993; Wilkens et al., 2012]. PKS has classically been diagnosed by performing a karyotype on skin fibroblasts or a tissue other than blood and such testing has been considered mandatory prior to establishing a diagnosis of Fryns syndrome [Pober et al., 2010], as array CGH testing on peripheral blood will detect PKS in less than 50% of cases [Conlin et al., 2012]. Patients with trisomy 21 have had Morgagni hernias that were detected after the neonatal period or identified serendipitously [Beg et al., 2010; Casaccia et al., 2009; Jetley et al., 2011]. It has been estimated that approximately one to two percent of babies with trisomy 18 have had CDH [Pober et al., 2010]. The recurrent translocation der (22) t(11; 22)(q23; q11), resulting in trisomy 22 and monosomy 11, has also been associated with CDH in 5e10% of cases [Borys and Taxy, 2004; Pober et al., 2010]. Mosaicism for trisomy 9 and trisomy 16 [Chen et al., 2004] are other examples of recurrent aneuploidies found in patients with CDH [Chen et al., 2004; Kosaki et al., 2006; Takahashi et al., 2010]. 6. Chromosome aberrations and CDH e autosomal deletions
Table 1 Known causes of simplex and complex congenital diaphragmatic hernia in humans. Cause
Examples
Frequency
References
Environmental factors Chromosome aberrations Single gene mutations Unknown
Vitamin A deficiency 15q26, 8p23.1 deletions e.g. STRA6, GPC3, FOG2 e
Rare
[Clugston et al., 2006; Pober et al., 2011] [Yu et al., 2013]
6.3% (2e31%) 70%
[Slavotinek, 2007; Pober et al., 2011] [Pober et al., 2011]
Monosomy for chromosome 15q24 to 15qter was one of the earliest autosomal deletions associated with left-sided CDH [Klaassens et al., 2005; Slavotinek et al., 2005] and has been reportded to be the commonest structural chromosome aberration in complex CDH [Klaassens et al., 2007]. Clinical features besides CDH comprise congenital heart disease with hypoplastic left heart syndrome and coarctation of the aorta, reduced growth, pulmonary hypoplasia, mild facial dysmorphism, fifth finger clinodactyly and brachydactyly, talipes and a single umbilical artery. The critical region has been localized to a 1.8 Mb
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Table 2 Selected chromosome rearrangements in complex congenital diaphragmatic hernia. Locus
% Of aberrations with CDH
Candidate Gene(s)
Clinical features
Reference
1q41-1q42
e
HLX; DISP1
[Slavotinek et al., 2009]
8p23.1 Iso12p
e CDH in 5/45 and 11/38
GATA4, SOX7 ING4, CHD4, MAGP2
15q26.2
CDH in 19/21
NR2F2, ARRDC4, IGF21R
Pulmonary hypoplasia; IUGR, neck webbing, genital hypoplasia, talipes, digital contractures ASD, VSD, AVSD, other CHD Developmental delay; hypotonia; pigmentary streaks; facial dysmorphism; CHD; seizures IUGR; VSD; pulmonary hypoplasia; facial dysmorphism; cleft palate; renal hypoplasia; single umbilical artery
[Shimokawa et al., 2005; Wat et al., 2009] [Izumi et al., 2012; Wilkens et al., 2012] [Slavotinek et al., 2006]
CDH ¼ congenital diaphragmatic hernia; IUGR ¼ intrauterine growth retardation; VSD ¼ ventricular septal defect; ASD ¼ atrial septal defect; AVSD ¼ atrioventricular septal defect; CHD ¼ congenital heart disease.
region containing seven genes, but of those genes, only IGF1R and ARRDC4 are expressed in the diaphragm [Mosca et al., 2011]. Others have suggested that NR2F2 is the best candidate based on the finding of diaphragmatic hernia in a conditional mouse model of loss of function for this gene [You et al., 2005]. No mutations in these gene have been identified in human patients. Deletions of chromosome 8p23.1 also cause CDH, most commonly in assiocation with cardiac septal defects [Faivre et al., 2004; Keitges et al., 2013; Shimokawa et al., 2005; Slavotinek, 2005; Wat et al., 2009]. Mouse models of loss of function have implicated Gata4 and Sox7 that are found within the critical X interval, in the pathogenesis of anterior diaphragmatic hernias in mice [Wat et al., 2012], but only mutations (rather than deletions) in GATA4 have so far been described in humans [Yu et al., 2013]. CDH can complicate 4p monosomy [Wolf Hirschhorn syndrome; MIM 194190; Basgul et al., 2006; Casaccia et al., 2006; van Dooren et al., 2004; Sergi et al., 1998], for which FGFRL1 has been suggested as a candidate gene because of fully penetrant diaphragmatic hypoplasia in mice with loss of Fgfrl1 function [Baertschi et al., 2007; Catela et al., 2009]. However, no mutations in this gene were identified in patients with CDH [LopezJimenez et al., 2010]. Other cytogenetic aberrations with CDH include chromosome 1q41-1q42 deletions [Kantarci et al., 2006; Slavotinek et al., 2006] and Xpter-Xp22 deletions [Plaja et al., 2004; Qidwai et al., 2010], in which disruption to the Holocytochrome C synthase gene (HCCS; MIM 300065) was considered likely to be responsible for the hernias because loss of function for this gene causes Microphthalmia linear skin defects syndrome (MLS; MIM 309801) in which CDH is a recognized finding [Qidwai et al., 2010]. More recently, CDH has been designated as a feature of
several microdeletion syndromes, among them 16p11.2 deletions [Fernandez et al., 2010; Wat et al., 2011] and 15q24 deletions [Magoulas and El-Hattab, 2012]. 7. Mendelian inheritance e simplex CDH Simplex or isolated CDH is usually a sporadic condition, although pedigrees consistent with Mendelian inheritance patterns have been described [Carmi et al., 1990; Farag et al., 1994; Hitch et al., 1989; Mitchell et al., 1997]. The sibling recurrence risk, an indirect measure of heritability, is low at 1e2% [Pober et al., 2010] and the etiology for most cases of simplex CDH has been difficult to elucidate. Mutations have been described in only a few genes, including FOG2 [Ackerman et al., 2005], GATA4 [Yu et al., 2013] and FREM1 [Yu et al., 2013] and in two of these genes (FOG2 and FREM1), only one mutation in each gene has been described. Corresponding mouse models for loss of function or targeted loss of function in selected tissues have been associated with diaphragmatic defects for all of these genes, supporting the imputation of pathogenesis for these mutations [Ackerman et al., 2005; Beck et al., 2013; Jay et al., 2007]. 8. Complex CDH and CDH and syndromes e known genes CDH is a clinical finding in more than 70 Mendelian disorders [Pober et al., 2010] and it has been estimated that at least 10% of patients with CDH have an underlying syndrome diagnosis [Enns et al., 1998]. However, the frequency of CDH in many of the syndromes is low [Slavotinek, 2007] and extreme genetic heterogeneity is likely for complex CDH and simplex CDH. Some
Table 3 Selected syndromes associated with congenital diaphragmatic hernia. Syndrome
Gene/locus
Clinical features
References
Overgrowth syndromes SimpsoneGolabieBehmel syndrome (SGBS; MIM 312870)
GPC3; Xq26
CDH (rare), pre and postnatal macrosomia, “coarse” facies, postaxial polydactyly, hypoplastic nails, developmental delay CDH (rare), macrosomia, omphalocele, macroglossia, neonatal hypoglycemia
[Chen et al., 1993; Gurrieri et al., 1992]
BeckwitheWiedemann syndrome (BWS; MIM 130650) Xp-linked syndromes Microphthalmia with linear skin defects (MLS; MIM 309801) Goltz syndrome (MIM 30560)
IGF2/H19/p57KIP2 and other genes; 11p15.5 HCCS; PORCN; Xp22
Craniofrontonasal syndrome (CFNS; MIM 304110) Syndromes with sex reversal PAGOD syndrome
EFNB1; Xp22
Unknown
Denys-Drash syndrome
WT1; 11p13
CDH, cardiomyopathy, microphthalmia, dermal aplasia CDH (rare), focal dermal hypoplasia, dental hypoplasia, syndactyly CDH (rare), coronal synostosis, hypertelorism; digital anomalies CDH, sex reversal, omphalocele, pulmonary artery hypoplasia, dextrocardia CDH, nephromegaly, glomerulopathy, growth 90th centile, male pseudohermaphroditism
[Enns et al., 1998]
[Qidwai et al., 2010] [Han et al., 2000; Patel et al., 1997] [Brooks et al., 2002; McGaughran et al., 2002] [Macayran et al., 2002] [Denamur et al., 2000; Devriendt et al., 1995]
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of the commoner syndromes in which CDH is a feature have been listed in Table 3. 9. CDH and overgrowth syndromes CDH has been reported in overgrowth syndromes (height and weight >90th centile), including SimpsoneGolabieBehmel syndrome (SGBS; MIM 312870) and infrequently, BeckwitheWiedemann syndrome [Witters et al., 2004] and Perlman syndrome [Greenberg et al., 1988]. Although CDH is relatively rare in SGBS, the syndrome shows clinical overlap with Fryns syndrome and patients with both syndromes can have pre- and postnatal macrosomia, coarse facies, heart disease and nail hypoplasia [Golabi et al., 2011]. The causative gene is glypican-3 gene (GPC3) on chromosome Xq26 [Pilia et al., 1996] and the mutational spectrum primarily includes deletions and missense mutations [Li et al., 2001]. GPC3-deficient mice have overgrowth, renal dysplasia and abnormal lung development but do not display CDH [Cano-Gauci et al., 1999]. CDH can occur with microphthalmia, defects in the formation of the pulmonary arteries and cardiac lesions in Matthew-Wood syndrome [MIM 601186; Berkenstadt et al., 1999; Seller et al., 1996]. Mutations in STRA6 have been detected in these patients [Golzio et al., 2007; Pasutto et al., 2007] and this syndrome is worth considering if the diaphragmatic defect is associated with the features above. DonnaieBarrow syndrome (MIM 222448) comprises CDH in 50% affected patients, omphalocele, absent corpus callosum, hypertelorism, myopia and sensorineural deafness [Donnai and Barrow, 1993]. Inheritance is autosomal recessive. The facial features are characteristic and include a large anterior fontanelle, hypertelorism, downslanting palpebral fissures, a short nose with a broad tip and low-set and posteriorly rotated ears. Rarer features were proteinuria despite structurally normal kidneys and iris coloboma [Chassaing et al., 2003]. Loss of function mutations in LRP2 gene are causative [Kantarci et al., 2007]. The mechanism for CDH in DonnaieBarrow syndrome has not yet been elucidated. Megalin, the LRP2-encoded protein, is present on the apical surfaces of absorptive epithelial cells and facilitates uptake of lipoproteins, sterols, vitamin-binding proteins and hormones [Storm et al., 2013]. Craniofrontonasal syndrome includes coronal synostosis with hypertelorism, facial asymmetry, a broad and bifid nasal tip and skeletal anomalies [CFNS; MIM 304110; Saavedra et al., 1996]. CDH has been described in both sexes with CFNS [Brooks et al., 2002; McGaughran et al., 2002]. Diaphragmatic hernia has been noted in two patients with severe presentations of Goltz syndrome caused by PORCN mutations at Xp22 [Wang et al., 2007], one with CDH, anophthalmia total anomalous pulmonary venous return but with minimal skin defects [Patel et al., 1997] and one with CDH, truncus arteriosus a ventricular septal defect and right renal agenesis [Han et al., 2000]. Less common syndrome associations with CDH caused by mutations in known genes have been reviewed in Pober et al. [2010] and have included Cornelia de Lange syndrome [Hosokawa et al., 2010; Wilmink et al., 2009], Denys-Drash syndrome [Denamur et al., 2000; Devriendt et al., 1995], Kabuki syndrome [Donadio et al., 2000], Poland syndrome [Sunitha et al., 2013], hydrolethalus syndrome [Salonen and Herva, 1990], spondylocostal dystosis [Cetinkaya et al., 2008; Onay et al., 2008] and neonatal cutis-laxa with marfanoid phenotype [Bonneau et al., 1991]. Many of these conditions can recognized by facial gestalt and thus the opinion of a dysmorphologist is vital in the neonatal evaluation of an infant with CDH.
10. Syndromes with CDH e unknown genes Fryns syndrome [FS; MIM 229850; Fitch, 1988; Fryns et al., 1979] is probably the commonest syndrome diagnosis advanced for patients with CDH, but the gene remains unknown, perhaps due to the considerable pleiotropy of the condition and the genetic heterogeneity of CDH. Characteristic features include left-sided diaphragmatic hernias, pulmonary hypoplasia, brachytelephalangy or hypoplasia of the distal phalanges and nails, dysmorphic features with hypertelorism, a flat nasal bridge, anterverted nose, dysplastic ears and micrognathia, orofacial clefting, hydrocephalus and neuronal heterotopias, cardiac defects, renal dysplasia and genitourinary malformations [Slavotinek, 2004]. It is important to diagnose FS due to the autosomal recessive inheritance pattern with this syndrome. The prognosis for FS remains poor and early demise from pulmonary hypoplasia in the neonatal period is frequent [Pober et al., 2010; Slavotinek, 2004]. Many cases initially diagnosed as having FS have later been found to have chromosome aberrations and thus normal array comparative genomic hybridization (array CGH) and skin fibroblast karyotype analysis have been recommended prior to making the diagnosis. Finally, CDH can be associated with unilateral or bilateral radial ray defects and the combination of CDH, omphalocele and radial ray malformations has been termed Gershoni-Baruch syndrome [Gershoni-Baruch et al., 1990; Wallerstein et al., 1997]. One fetus with CDH, radial ray hypoplasia and coronal craniosynostosis was shown to have a mutation in TWIST1 [Piard et al., 2012], but the gene for Gershoni-Baruch syndrome is unknown. 11. Summary CDH is a common birth defect with a high mortality and morbidity. Environmental causes are rarely implicated in human disease, but a multitude of chromosome aberrations and single gene syndromes have been associated with diaphragmatic defects. There is no one underlying causative mechanism. Much remains to be discovered about the etiology of this malformation and it is likely that genomic technologies will advance our understanding of the genes and chromosome regions involved in pathogenesis. Uncited references Allanson and Richter, 1991, Brady et al., 2013, Cano-Gauci et al., 2001, Chen et al., 1998, Chung et al., 2013, Faivre et al., 1998, Hogue et al., 2010, Kayserili et al., 2001, Kunze et al., 1979, Lin et al., 2005, Moore et al., 1998, Plaja et al., 1994, Sugimoto et al., 2000, Van Hove et al., 1995, Vasudevan et al., 2006, Veldman et al., 2002, References Ackerman KG, Herron BJ, Vargas SO, Huang H, Tevosian SG, Kochilas L, et al. Fog2 is required for normal diaphragm and lung development in mice and humans. PLoS Genet 2005;1:58e65. Ackerman KG, Vargas SO, Wilson JA, Jennings RW, Kozakewich HP, Pober BR. Congenital diaphragmatic defects: proposal for a new classification based on observations in 234 patients. Pediatr Dev Pathol 2012;15:265e74. Allanson J, Richter S. Linear skin defects and congenital microphthalmia: a new syndrome at Xp22.2. J Med Genet 1991;28:143e4. Babiuk RP, Zhang W, Clugston R, Allan DW, Greer JJ. Embryological origins and development of the rat diaphragm. J Comp Neurol 2003;455:477e87. Baertschi S, Zhuang L, Trueb B. Mice with a targeted disruption of the Fgfrl1 gene die at birth due to alterations in the diaphragm. FEBS J. 2007;274:6241e53. Basgul A, Kavak ZN, Akman I, Basgul A, Gokaslan H, Elcioglu N. Prenatal diagnosis of WolfeHirschhorn syndrome (4p-) in association with congenital diaphragmatic hernia, cystic hygroma and IUGR. Clin Exp Obstet Gynecol 2006;33:105e6. Beck TF, Shchelochkov OA, Yu Z, Kim BJ, Hernández-García A, Zaveri HP, et al. Novel frem1-related mouse phenotypes and evidence of genetic interactions with gata4 and slit3. PLoS ONE 2013;8:e58830.
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The genetics of common disorders e Congenital diaphragmatic hernia Q7
Anne M. Slavotinek* Department of Pediatrics, Division of Genetics, University of California, MSC 2711, Rock Hall Room RH284D, 1550 4th St, San Francisco, CA 94143-2711, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 20 January 2014 Accepted 20 April 2014 Available online xxx
Congenital diaphragmatic hernia (CDH) is a common birth defect with a high mortality and morbidity. Although numerous chromosomal aberrations and gene mutations have been associated with CDH, the etiology of the diaphragmatic defect is identified in less than 50% of patients. This review discusses the some of the more frequent, recurrent karyotypic abnormalities in which CDH is a feature, including 15q26, 8p23.1 and 4p16.3 deletions and tetrasomy 12p (PallistereKillian syndrome), together with some of the syndromes in which CDH is a relatively common feature, including Fryns syndrome, MatthewWood syndrome, overgrowth syndromes and DonnaieBarrow syndrome. In the era of genomic technologies, our knowledge of the genes and chromosome regions involved in pathogenesis of CDH is likely to advance significantly. Ó 2014 Published by Elsevier Masson SAS.
Keywords: Congenital diaphragmatic hernia Fryns syndrome 15q26 deletion syndrome
1. Introduction
Q1
Congenital diaphragmatic hernia (CDH) is a structural birth defect characterized by defective formation of the diaphragm [Brady et al., 2011; Enns et al., 1998; Greer, 2013; Pober et al., 2010; Slavotinek, 2005]. Diaphragmatic eventration, or significant thinning of the diaphragm, is considered to be a related birth defect that may share a similar etiology. Diaphragmatic hernias are present in 1 in 2000e3000 live births and it has been estimated that 1600 neonates with CDH are born in the United States each year [Torfs et al., 1992]. CDH is a significant malformation because the diaphragmatic defect permits herniation of the abdominal contents into the thorax, causing pulmonary hypoplasia, pulmonary hypertension, feeding difficulties and gastroesophageal reflux that result in long-term morbidity with hearing impariment, growth retardation and developmental delays [Cass, 2005; Colvin et al., 2005; West and Wilson, 2005] (Fig. 1). There are several different types of diaphragmatic hernia. The commonest defect is located in the posterolateral diaphragm (Bochdalek hernia) and hernias involving the anterior portion of the diaphragm (Morgagni hernia) are less frequent [Ackerman et al., 2012]. CDH occurs as an isolated malformation (simplex CDH) in an estimated 40e50% of patients and is present with extra-diaphragmatic malformations (complex CDH) in the remainder [Brady et al., 2011; Enns et al., 1998; Skari et al., 2000]. Additional malformations that can occur with CDH and that are considered to be complications of the hernia per se include * Tel.: þ1 (415) 514 1783; fax: þ1 (415) 476 9305. E-mail address: [email protected].
pulmonary hypoplasia, patent ductus arteriosus, patent foramen ovale and intestinal malrotation [“CDH syndrome”; Skarsgard and Harrison, 1999]. Other organs that can be malformed in patients with CDH include the central nervous system (5e75% patients), cardiovascular system (4e63% patients), genitourinary system (5e27% patients) and gastrointestinal system [1e20% patients; Enns et al., 1998]. In mouse, the diaphragm develops between embryonic day (E) 10.5 and E15.5, with closure at E12.5-E13.5, corresponding to the 4th to 6th weeks of human gestation [Babiuk et al., 2003; Greer, 2013]. The primordial diaphragm arises from closure of the pleuroperitoneal folds (PPFs) that form the anlagen for the lateral, muscular component of the diaphragm [Greer, 2013]. The PPFs extend from the lateral cervical body wall and fuse ventrally with the septum transversum and the posthepatic mesodermal plate. Myogenic precursor cells then delaminate from the ventrolateral lips of the hypaxial dermomyotome, migrate and reach the primary diaphragm at E12.5, after which they proliferate to form the diaphragm muscle [Brady et al., 2011; Pober et al., 2010; Russell et al., 2012]. Defects at all of these stages of development, including failed closure of the PPFs, disordered cell migration and abnormal myogenesis or extracellular matrix formation [Russell et al., 2012], can cause CDH.
2. Genetic causes of CDH in humans A brief summary of etiological factors for CDH is provided in Table 1. In more than 70% of individuals with CDH, the etiology remains unknown [Pober et al., 2010].
http://dx.doi.org/10.1016/j.ejmg.2014.04.012 1769-7212/Ó 2014 Published by Elsevier Masson SAS.
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diaphragmatic defects in human patients. One small study demonstrated a statistically significant reduction in plasma retinol and retinol-binding protein in newborns with CDH compared to controls [Major et al., 1998]. An intake of dietary vitamin A below the recommended daily intake was also associated with an increased risk of a baby with CDH in mothers of normal weight [Beurskens et al., 2013]. However, no hernia has as yet been attributed to vitamin deficiency [Pober et al., 2010]. 4. Chromosome aberrations and CDH In an estimated 2%e33% of patients with CDH, a causative cytogenetic aberration is detected [Enns et al., 1998; Holder et al., 2007; Howe et al., 1996; Lurie, 2003; Pober et al., 2010; Yu et al., 2012]. Many of the commonest chromosome aberrations are diagnosable with a karyotype, but array comparative genomic hybridization (array CGH) is almost always performed. To date, the largest array CGH study on 256 probands with CDH found chromosome abnormalities in 6.3% of affected individuals [Yu et al., 2012]. CDH has been connected with cytogenetic abnormalities on almost every chromosome arm and recurrent aberrations have provided information about the postulated locations of CDH-causing genes [Holder et al., 2007; Lurie, 2003; Q2 Yu et al., 2012]. Table 2 summarizes a selection of the more frequent, recurrent chromosome aberrations that have been linked to CDH and a brief discussion is provided below. 5. Chromosome aberrations and CDH e aneuploidy
Fig. 1. Photograph of a term neonate with left congenital diaphragmatic hernia, showing herniation of the abdominal contents into the left thoracic cavity. Courtesy of Dr Philip Ursell, Department of Pathology and Laboratory Medicine, University of California, San Francisco.
3. Environmental and nutritional factors There are few teratogenic agents or environmental factors that are known to cause CDH in humans. The immunosuppressive drug, mycophenylate mofetil, and allopurinol, a drug used in the treatment of hyperuricemia, have both been associated with CDH and overlapping patterns of birth defects [Kozenko et al., 2011; Parisi et al., 2009; Perez-Aytes et al., 2008]. Disruption to purine biosynthesis has been hypothesized to be the cause of the malformations for both drugs [Kozenko et al., 2011]. One case of diaphragmatic hernia was observed following lithium treatment in the first trimester of pregnancy [Hosseini et al., 2010]. Vitamin A deficiency and disturbances to retinoic metabolism have been implicated in the pathogenesis of CDH in animal models [Clugston et al., 2006; Kling and Schnitzer, 2007] and this mechanism has been investigated as a putative cause of
Several different chromosome aneuploidies have been associated with CDH. Tetrasomy 12p (PallistereKillian syndrome (PKS; MIM 601803)) has a phenotype similar to Fryns syndrome with dysmorphic features that include a high forehead and high anterior hairline, nail hypoplasia, streaky skin pigmentation, cardiac defects and CDH [Bergoffen et al., 1993; McPherson et al., 1993; Wilkens et al., 2012]. PKS has classically been diagnosed by performing a karyotype on skin fibroblasts or a tissue other than blood and such testing has been considered mandatory prior to establishing a diagnosis of Fryns syndrome [Pober et al., 2010], as array CGH testing on peripheral blood will detect PKS in less than 50% of cases [Conlin et al., 2012]. Patients with trisomy 21 have had Morgagni hernias that were detected after the neonatal period or identified serendipitously [Beg et al., 2010; Casaccia et al., 2009; Jetley et al., 2011]. It has been estimated that approximately one to two percent of babies with trisomy 18 have had CDH [Pober et al., 2010]. The recurrent translocation der (22) t(11; 22)(q23; q11), resulting in trisomy 22 and monosomy 11, has also been associated with CDH in 5e10% of cases [Borys and Taxy, 2004; Pober et al., 2010]. Mosaicism for trisomy 9 and trisomy 16 [Chen et al., 2004] are other examples of recurrent aneuploidies found in patients with CDH [Chen et al., 2004; Kosaki et al., 2006; Takahashi et al., 2010]. 6. Chromosome aberrations and CDH e autosomal deletions
Table 1 Known causes of simplex and complex congenital diaphragmatic hernia in humans. Cause
Examples
Frequency
References
Environmental factors Chromosome aberrations Single gene mutations Unknown
Vitamin A deficiency 15q26, 8p23.1 deletions e.g. STRA6, GPC3, FOG2 e
Rare
[Clugston et al., 2006; Pober et al., 2011] [Yu et al., 2013]
6.3% (2e31%) 70%
[Slavotinek, 2007; Pober et al., 2011] [Pober et al., 2011]
Monosomy for chromosome 15q24 to 15qter was one of the earliest autosomal deletions associated with left-sided CDH [Klaassens et al., 2005; Slavotinek et al., 2005] and has been reportded to be the commonest structural chromosome aberration in complex CDH [Klaassens et al., 2007]. Clinical features besides CDH comprise congenital heart disease with hypoplastic left heart syndrome and coarctation of the aorta, reduced growth, pulmonary hypoplasia, mild facial dysmorphism, fifth finger clinodactyly and brachydactyly, talipes and a single umbilical artery. The critical region has been localized to a 1.8 Mb
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Table 2 Selected chromosome rearrangements in complex congenital diaphragmatic hernia. Locus
% Of aberrations with CDH
Candidate Gene(s)
Clinical features
Reference
1q41-1q42
e
HLX; DISP1
[Slavotinek et al., 2009]
8p23.1 Iso12p
e CDH in 5/45 and 11/38
GATA4, SOX7 ING4, CHD4, MAGP2
15q26.2
CDH in 19/21
NR2F2, ARRDC4, IGF21R
Pulmonary hypoplasia; IUGR, neck webbing, genital hypoplasia, talipes, digital contractures ASD, VSD, AVSD, other CHD Developmental delay; hypotonia; pigmentary streaks; facial dysmorphism; CHD; seizures IUGR; VSD; pulmonary hypoplasia; facial dysmorphism; cleft palate; renal hypoplasia; single umbilical artery
[Shimokawa et al., 2005; Wat et al., 2009] [Izumi et al., 2012; Wilkens et al., 2012] [Slavotinek et al., 2006]
CDH ¼ congenital diaphragmatic hernia; IUGR ¼ intrauterine growth retardation; VSD ¼ ventricular septal defect; ASD ¼ atrial septal defect; AVSD ¼ atrioventricular septal defect; CHD ¼ congenital heart disease.
region containing seven genes, but of those genes, only IGF1R and ARRDC4 are expressed in the diaphragm [Mosca et al., 2011]. Others have suggested that NR2F2 is the best candidate based on the finding of diaphragmatic hernia in a conditional mouse model of loss of function for this gene [You et al., 2005]. No mutations in these gene have been identified in human patients. Deletions of chromosome 8p23.1 also cause CDH, most commonly in assiocation with cardiac septal defects [Faivre et al., 2004; Keitges et al., 2013; Shimokawa et al., 2005; Slavotinek, 2005; Wat et al., 2009]. Mouse models of loss of function have implicated Gata4 and Sox7 that are found within the critical X interval, in the pathogenesis of anterior diaphragmatic hernias in mice [Wat et al., 2012], but only mutations (rather than deletions) in GATA4 have so far been described in humans [Yu et al., 2013]. CDH can complicate 4p monosomy [Wolf Hirschhorn syndrome; MIM 194190; Basgul et al., 2006; Casaccia et al., 2006; van Dooren et al., 2004; Sergi et al., 1998], for which FGFRL1 has been suggested as a candidate gene because of fully penetrant diaphragmatic hypoplasia in mice with loss of Fgfrl1 function [Baertschi et al., 2007; Catela et al., 2009]. However, no mutations in this gene were identified in patients with CDH [LopezJimenez et al., 2010]. Other cytogenetic aberrations with CDH include chromosome 1q41-1q42 deletions [Kantarci et al., 2006; Slavotinek et al., 2006] and Xpter-Xp22 deletions [Plaja et al., 2004; Qidwai et al., 2010], in which disruption to the Holocytochrome C synthase gene (HCCS; MIM 300065) was considered likely to be responsible for the hernias because loss of function for this gene causes Microphthalmia linear skin defects syndrome (MLS; MIM 309801) in which CDH is a recognized finding [Qidwai et al., 2010]. More recently, CDH has been designated as a feature of
several microdeletion syndromes, among them 16p11.2 deletions [Fernandez et al., 2010; Wat et al., 2011] and 15q24 deletions [Magoulas and El-Hattab, 2012]. 7. Mendelian inheritance e simplex CDH Simplex or isolated CDH is usually a sporadic condition, although pedigrees consistent with Mendelian inheritance patterns have been described [Carmi et al., 1990; Farag et al., 1994; Hitch et al., 1989; Mitchell et al., 1997]. The sibling recurrence risk, an indirect measure of heritability, is low at 1e2% [Pober et al., 2010] and the etiology for most cases of simplex CDH has been difficult to elucidate. Mutations have been described in only a few genes, including FOG2 [Ackerman et al., 2005], GATA4 [Yu et al., 2013] and FREM1 [Yu et al., 2013] and in two of these genes (FOG2 and FREM1), only one mutation in each gene has been described. Corresponding mouse models for loss of function or targeted loss of function in selected tissues have been associated with diaphragmatic defects for all of these genes, supporting the imputation of pathogenesis for these mutations [Ackerman et al., 2005; Beck et al., 2013; Jay et al., 2007]. 8. Complex CDH and CDH and syndromes e known genes CDH is a clinical finding in more than 70 Mendelian disorders [Pober et al., 2010] and it has been estimated that at least 10% of patients with CDH have an underlying syndrome diagnosis [Enns et al., 1998]. However, the frequency of CDH in many of the syndromes is low [Slavotinek, 2007] and extreme genetic heterogeneity is likely for complex CDH and simplex CDH. Some
Table 3 Selected syndromes associated with congenital diaphragmatic hernia. Syndrome
Gene/locus
Clinical features
References
Overgrowth syndromes SimpsoneGolabieBehmel syndrome (SGBS; MIM 312870)
GPC3; Xq26
CDH (rare), pre and postnatal macrosomia, “coarse” facies, postaxial polydactyly, hypoplastic nails, developmental delay CDH (rare), macrosomia, omphalocele, macroglossia, neonatal hypoglycemia
[Chen et al., 1993; Gurrieri et al., 1992]
BeckwitheWiedemann syndrome (BWS; MIM 130650) Xp-linked syndromes Microphthalmia with linear skin defects (MLS; MIM 309801) Goltz syndrome (MIM 30560)
IGF2/H19/p57KIP2 and other genes; 11p15.5 HCCS; PORCN; Xp22
Craniofrontonasal syndrome (CFNS; MIM 304110) Syndromes with sex reversal PAGOD syndrome
EFNB1; Xp22
Unknown
Denys-Drash syndrome
WT1; 11p13
CDH, cardiomyopathy, microphthalmia, dermal aplasia CDH (rare), focal dermal hypoplasia, dental hypoplasia, syndactyly CDH (rare), coronal synostosis, hypertelorism; digital anomalies CDH, sex reversal, omphalocele, pulmonary artery hypoplasia, dextrocardia CDH, nephromegaly, glomerulopathy, growth 90th centile, male pseudohermaphroditism
[Enns et al., 1998]
[Qidwai et al., 2010] [Han et al., 2000; Patel et al., 1997] [Brooks et al., 2002; McGaughran et al., 2002] [Macayran et al., 2002] [Denamur et al., 2000; Devriendt et al., 1995]
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of the commoner syndromes in which CDH is a feature have been listed in Table 3. 9. CDH and overgrowth syndromes CDH has been reported in overgrowth syndromes (height and weight >90th centile), including SimpsoneGolabieBehmel syndrome (SGBS; MIM 312870) and infrequently, BeckwitheWiedemann syndrome [Witters et al., 2004] and Perlman syndrome [Greenberg et al., 1988]. Although CDH is relatively rare in SGBS, the syndrome shows clinical overlap with Fryns syndrome and patients with both syndromes can have pre- and postnatal macrosomia, coarse facies, heart disease and nail hypoplasia [Golabi et al., 2011]. The causative gene is glypican-3 gene (GPC3) on chromosome Xq26 [Pilia et al., 1996] and the mutational spectrum primarily includes deletions and missense mutations [Li et al., 2001]. GPC3-deficient mice have overgrowth, renal dysplasia and abnormal lung development but do not display CDH [Cano-Gauci et al., 1999]. CDH can occur with microphthalmia, defects in the formation of the pulmonary arteries and cardiac lesions in Matthew-Wood syndrome [MIM 601186; Berkenstadt et al., 1999; Seller et al., 1996]. Mutations in STRA6 have been detected in these patients [Golzio et al., 2007; Pasutto et al., 2007] and this syndrome is worth considering if the diaphragmatic defect is associated with the features above. DonnaieBarrow syndrome (MIM 222448) comprises CDH in 50% affected patients, omphalocele, absent corpus callosum, hypertelorism, myopia and sensorineural deafness [Donnai and Barrow, 1993]. Inheritance is autosomal recessive. The facial features are characteristic and include a large anterior fontanelle, hypertelorism, downslanting palpebral fissures, a short nose with a broad tip and low-set and posteriorly rotated ears. Rarer features were proteinuria despite structurally normal kidneys and iris coloboma [Chassaing et al., 2003]. Loss of function mutations in LRP2 gene are causative [Kantarci et al., 2007]. The mechanism for CDH in DonnaieBarrow syndrome has not yet been elucidated. Megalin, the LRP2-encoded protein, is present on the apical surfaces of absorptive epithelial cells and facilitates uptake of lipoproteins, sterols, vitamin-binding proteins and hormones [Storm et al., 2013]. Craniofrontonasal syndrome includes coronal synostosis with hypertelorism, facial asymmetry, a broad and bifid nasal tip and skeletal anomalies [CFNS; MIM 304110; Saavedra et al., 1996]. CDH has been described in both sexes with CFNS [Brooks et al., 2002; McGaughran et al., 2002]. Diaphragmatic hernia has been noted in two patients with severe presentations of Goltz syndrome caused by PORCN mutations at Xp22 [Wang et al., 2007], one with CDH, anophthalmia total anomalous pulmonary venous return but with minimal skin defects [Patel et al., 1997] and one with CDH, truncus arteriosus a ventricular septal defect and right renal agenesis [Han et al., 2000]. Less common syndrome associations with CDH caused by mutations in known genes have been reviewed in Pober et al. [2010] and have included Cornelia de Lange syndrome [Hosokawa et al., 2010; Wilmink et al., 2009], Denys-Drash syndrome [Denamur et al., 2000; Devriendt et al., 1995], Kabuki syndrome [Donadio et al., 2000], Poland syndrome [Sunitha et al., 2013], hydrolethalus syndrome [Salonen and Herva, 1990], spondylocostal dystosis [Cetinkaya et al., 2008; Onay et al., 2008] and neonatal cutis-laxa with marfanoid phenotype [Bonneau et al., 1991]. Many of these conditions can recognized by facial gestalt and thus the opinion of a dysmorphologist is vital in the neonatal evaluation of an infant with CDH.
10. Syndromes with CDH e unknown genes Fryns syndrome [FS; MIM 229850; Fitch, 1988; Fryns et al., 1979] is probably the commonest syndrome diagnosis advanced for patients with CDH, but the gene remains unknown, perhaps due to the considerable pleiotropy of the condition and the genetic heterogeneity of CDH. Characteristic features include left-sided diaphragmatic hernias, pulmonary hypoplasia, brachytelephalangy or hypoplasia of the distal phalanges and nails, dysmorphic features with hypertelorism, a flat nasal bridge, anterverted nose, dysplastic ears and micrognathia, orofacial clefting, hydrocephalus and neuronal heterotopias, cardiac defects, renal dysplasia and genitourinary malformations [Slavotinek, 2004]. It is important to diagnose FS due to the autosomal recessive inheritance pattern with this syndrome. The prognosis for FS remains poor and early demise from pulmonary hypoplasia in the neonatal period is frequent [Pober et al., 2010; Slavotinek, 2004]. Many cases initially diagnosed as having FS have later been found to have chromosome aberrations and thus normal array comparative genomic hybridization (array CGH) and skin fibroblast karyotype analysis have been recommended prior to making the diagnosis. Finally, CDH can be associated with unilateral or bilateral radial ray defects and the combination of CDH, omphalocele and radial ray malformations has been termed Gershoni-Baruch syndrome [Gershoni-Baruch et al., 1990; Wallerstein et al., 1997]. One fetus with CDH, radial ray hypoplasia and coronal craniosynostosis was shown to have a mutation in TWIST1 [Piard et al., 2012], but the gene for Gershoni-Baruch syndrome is unknown. 11. Summary CDH is a common birth defect with a high mortality and morbidity. Environmental causes are rarely implicated in human disease, but a multitude of chromosome aberrations and single gene syndromes have been associated with diaphragmatic defects. There is no one underlying causative mechanism. Much remains to be discovered about the etiology of this malformation and it is likely that genomic technologies will advance our understanding of the genes and chromosome regions involved in pathogenesis. Uncited references Allanson and Richter, 1991, Brady et al., 2013, Cano-Gauci et al., 2001, Chen et al., 1998, Chung et al., 2013, Faivre et al., 1998, Hogue et al., 2010, Kayserili et al., 2001, Kunze et al., 1979, Lin et al., 2005, Moore et al., 1998, Plaja et al., 1994, Sugimoto et al., 2000, Van Hove et al., 1995, Vasudevan et al., 2006, Veldman et al., 2002, References Ackerman KG, Herron BJ, Vargas SO, Huang H, Tevosian SG, Kochilas L, et al. Fog2 is required for normal diaphragm and lung development in mice and humans. PLoS Genet 2005;1:58e65. Ackerman KG, Vargas SO, Wilson JA, Jennings RW, Kozakewich HP, Pober BR. Congenital diaphragmatic defects: proposal for a new classification based on observations in 234 patients. Pediatr Dev Pathol 2012;15:265e74. Allanson J, Richter S. Linear skin defects and congenital microphthalmia: a new syndrome at Xp22.2. J Med Genet 1991;28:143e4. Babiuk RP, Zhang W, Clugston R, Allan DW, Greer JJ. Embryological origins and development of the rat diaphragm. J Comp Neurol 2003;455:477e87. Baertschi S, Zhuang L, Trueb B. Mice with a targeted disruption of the Fgfrl1 gene die at birth due to alterations in the diaphragm. FEBS J. 2007;274:6241e53. Basgul A, Kavak ZN, Akman I, Basgul A, Gokaslan H, Elcioglu N. Prenatal diagnosis of WolfeHirschhorn syndrome (4p-) in association with congenital diaphragmatic hernia, cystic hygroma and IUGR. Clin Exp Obstet Gynecol 2006;33:105e6. Beck TF, Shchelochkov OA, Yu Z, Kim BJ, Hernández-García A, Zaveri HP, et al. Novel frem1-related mouse phenotypes and evidence of genetic interactions with gata4 and slit3. PLoS ONE 2013;8:e58830.
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Faivre L, Morichon-Delvallez N, Viot G, Narcy F, Loison S, Mandelbrot L, et al. Prenatal diagnosis of an 8p23.1 deletion in a fetus with a diaphragmatic hernia and review of the literature. Prenat Diagn 1998;18:1055e60. Farag TI, Bastaki L, Marafie M, al-Awadi SA, Krsz J. Autosomal recessive congenital diaphragmatic defects in the Arabs. Am J Med Genet 1994;50:300e1. Fernandez BA, Roberts W, Chung B, Weksberg R, Meyn S, Szatmari P, et al. Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder. J Med Genet 2010;47:195e203. Fitch N. Fryns syndrome. J Med Genet 1988;25:135. Fryns JP, Moerman F, Goddeeris P, Bossuyt C, Van den Berghe H. A new lethal syndrome with cloudy corneae, diaphragmatic defects and distal limb deformities. Hum Genet 1979;50:65e70. Gershoni-Baruch R, Machoul I, Weiss Y, Blazer S. 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