Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 17190001; ICD10CM: Q79.0; ORPHA: 2140; DO: 3827;
Cytogenetic location: 15q26.1 Genomic coordinates (GRCh38): 15:88,500,001-93,800,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q26.1 | Diaphragmatic hernia 1 | 142340 | Multifactorial | 2 |
Congenital diaphragmatic hernia (CDH) refers to a group of congenital defects in the structural integrity of the diaphragm which are often associated with lethal pulmonary hypoplasia and pulmonary hypertension. Prevalence in newborns ranges from 1 in 2,500 to 1 in 4,000, and there is a 30 to 60% mortality rate (Langham et al., 1996; Harrison et al., 1994; Nobuhara et al., 1996). Most cases of congenital diaphragmatic hernia are sporadic.
Genetic Heterogeneity of Diaphragmatic Hernia
Congenital diaphragmatic hernia-1 (DIH1) maps to chromosome 15q26. Also see DIH2 (222400), which maps to chromosome 8p23; DIH3 (610187), caused by mutation in the ZFPM2 gene (603693) on chromosome 8q23; DIH4 (620025), caused by mutation in the ALDH1A2 gene (603687) on chromosome 15q21; and DIH5 (306950), caused by mutation in the PLS3 gene (300131) on chromosome Xq23.
Congenital diaphragmatic hernia can also present with other congenital anomalies. Fryns syndrome (229850) may be the most common autosomal recessive syndrome with DIH as a cardinal feature (Slavotinek et al., 2005). See also thoracoabdominal syndrome (THAS; 313850), which maps to chromosome Xq25-q26.
Holder et al. (2007) reviewed the genetic factors in congenital diaphragmatic hernia. Pober (2008) reviewed genetic aspects of congenital diaphragmatic hernia, with emphasis on various syndromes in which CDH occurs along with other manifestations.
There are several different types of CDH, including Bochdalek, Morgagni, and central (septum transversum) diaphragmatic hernia (Stokes, 1991). Approximately 70 to 90% of CDH cases are 'Bochdalek-type,' or posterolateral hernias, most often occurring on the left side. Morgagni CDH is less common and forms in the anterior retrosternal diaphragm. Central CDH occurs in the midline of the septum transversum and accounts for 1 to 2% of cases of CDH. The pathologic consequences of CDH result from the abdominal contents entering the thoracic cavity. Hypoplasia of the lung due to decreased thoracic volume results in compromised pulmonary capacity often resulting in neonatal death.
Unilateral agenesis of the diaphragm is considered to be an extreme form of congenital diaphragmatic hernia (Baglaj et al., 1999).
Enns et al. (1998) reviewed 60 patients with congenital diaphragmatic defects detected prenatally. In 29 of these, therapeutic or spontaneous abortion was the outcome of the pregnancy; anomalies in addition to diaphragmatic defects were present in 16 of 31 patients evaluated postnatally. Syndromes diagnosed postnatally in 7 of 16 patients included Fryns syndrome (229850) in 2, Simpson-Golabi-Behmel syndrome (312870) in 2, tetrasomy 12p (601803) in 1, Brachmann-de Lange syndrome (122470) in 1, and lethal multiple pterygium syndrome (253250) in 1. They were unable to make a specific diagnosis in 9 of 16 patients with multiple malformations.
Using population-based data from ongoing studies in the California Birth Defects Monitoring Program, Slavotinek et al. (2007) compared additional clinical features of 38 (26%) patients with right-sided CDH and 108 (74%) with left-sided CDH. There were statistically significant differences in frequencies of atrial septal defect (1/38 right-CDH and 20/108 left-CDH cases; p = 0.015), bilateral pulmonary hypoplasia (22/108 left-CDH cases and 15/38 right-CDH cases; p = 0.029), abnormal skull or facial shape (17/108 left-CDH patients and 1/38 right-CDH cases; p = 0.043), assorted digital anomalies excluding syndactyly, polydactyly or absence of a digit (13/108 left-CDH patients and 0/38 right-CDH patients; p = 0.021), and assorted limb anomalies excluding limb reduction defects (18/108 left-CDH patients and 0/38 right-CDH patients; p = 0.004).
Passarge et al. (1968) reported unilateral agenesis of the diaphragm in a brother and sister and found 4 other reports of multiple affected sibs. A sibship with at least 3 affected was reported by Ten Kate and Anders (1970). Daentl and Passarge (1972) found that 2 or more sibs had been affected in 9 unrelated families and found probable consanguinity in 1, suggesting autosomal recessive inheritance.
Wolff (1980) comprehensively reviewed 17 reports dealing with familial congenital diaphragmatic hernia and concluded that multifactorial inheritance is most likely.
Arad et al. (1980) described congenital defects of the diaphragm in 2 female offspring of healthy Arab parents related as first cousins once removed, twice second cousins and second cousins once removed (F = 9/128). In 1 infant, the diaphragmatic defect took the form of a Bochdalek-type, posterolateral hernia. In the second, both diaphragms were almost completely lacking.
Norio et al. (1984) reported 14 cases from 5 Finnish families affected with a life-threatening congenital diaphragmatic defect. Diaphragmatic defects occurred in 3 sibs and in the son of their half brother. Diaphragmatic defects probably occurred in all 4 offspring of a couple related as first cousins and second cousins. In the other Finnish families and most reported familial cases, only 2 sibs were affected. Norio et al. (1984) reviewed data on 53 previously reported familial cases, and presented a number of factors favoring multifactorial rather than recessive inheritance. The recurrence risk for sibs after the birth of one affected sib was judged to be about 2%.
Schubert-Staudacher and Jauch (1984) reported bilateral eventration of the diaphragm in 2 offspring of nonconsanguineous parents. The authors quoted others who had pointed out that familial cases are more often bilateral than are sporadic cases.
Czeizel and Kovacs (1985) described sibs with isolated congenital diaphragmatic defect of the Bochdalek type. Toriello et al. (1985) reported a male infant with unilateral pulmonary and diaphragmatic agenesis and his sister with bilateral pulmonary and diaphragmatic agenesis. Toriello et al. (1986) described 3 sisters with isolated unilateral agenesis of the diaphragm.
Bocian et al. (1986) reported 2 families with multiple occurrence of congenital diaphragmatic defects. In one of the families, the lesion was detected in the fetus by ultrasound at 14 weeks. Segregation analysis of these families and of 17 other multiplex families from the literature led Bocian et al. (1986) to the conclusion that the autosomal recessive hypothesis 'cannot be rejected.' On the other hand, multifactorial determination was rejected by the data.
Hubert and Toyama (1987) described a 'right thoracic stomach' in a 2-month-old boy whose mother had been operated on for the same abnormality at about the same age.
Among the children of an Arab couple related as second cousins, Farag et al. (1989) observed 2 brothers, one with an extensive left-sided Bochdalek-type hernia, and the second with hemidiaphragmatic agenesis. Farag et al. (1994) described a Kuwaiti family and an Egyptian family in each of which 3 children of consanguineous parents had congenital diaphragmatic defects.
Narayan et al. (1993) described congenital diaphragmatic hernia in a brother and sister and in a male first cousin.
Mitchell et al. (1997) reported 4 cases of left-sided congenital diaphragmatic hernia in 2 generations of a consanguineous Pakistani family. Two children had associated cardiac abnormalities, but there were no other dysmorphic features.
Pober et al. (2005) reviewed and classified 203 unrelated cases of Bochdalek-type hernia identified over a 28-year period through a hospital-based surveillance program. Phenotypically, 112 (55%) cases had an isolated defect, and 91 (45%) had a defect in association with additional malformations as part of a syndrome. Family histories showed that only 1 affected infant, who had an isolated defect, had a previous sib who also had an isolated defect, for a recurrence rate of 0.9%. However, 4% of all sibs had a major malformation other than CDH, including cleft lip and palate, hydronephrosis, renal agenesis/dysgenesis, anencephaly, and congenital heart defects. There were 8 twin pairs, including 5 monozygotic pairs, all of whom were discordant for CDH; in 2 cases the cotwin had other malformations. Pober et al. (2005) presented a detailed review of the literature, and suggested that previous studies may have overestimated the concordance for CDH among twins. Pober et al. (2005) hypothesized that de novo dominant mutations or epigenetic factors likely contribute to the development of CDH.
Chromosome 15q
Although most cases of congenital diaphragmatic hernia are idiopathic, chromosomal abnormalities have been implicated in approximately 15% of cases. Biggio et al. (2004) cited numerous reports of either de novo deletion or unbalanced translocations involving the 15q24-q26 region, suggesting that this region is critical to normal development of the diaphragm. They described a patient with deletion of 15q26.1, the smallest isolated chromosomal aberration on distal 15q that had been reported to that time. In addition to diaphragmatic hernia, coarctation of the aorta and dysmorphic features were present. Biggio et al. (2004) noted that the myocyte-specific enhancer factor-2 (MEF2) proteins play a critical role in the control of muscle differentiation and development. They proposed MEF2A (600660), a member of the MEF2 gene family mapping to 15q26, as a candidate gene.
By array CGH, Slavotinek et al. (2005) screened patients with DIH and additional phenotypic anomalies consistent with Fryns syndrome for cryptic chromosomal aberrations. They identified submicroscopic chromosome deletions in 3 probands who had previously been diagnosed with Fryns syndrome and had normal karyotyping with G-banded chromosome analysis. Two female infants were found to have microdeletions involving 15q26.2, and 1 male infant had a deletion in band 8p23.1.
Chromosome 1q41-q42
Youssoufian et al. (1988) reported an infant with a diaphragmatic hernia and a de novo interstitial deletion of chromosome 1q32.3-q42.3. The patient died at age 8 hours. The patient had other abnormal clinical features, including low-set ears, mild webbing of the neck, undescended testes, hypospadias, equinovarus, and flexion contractures of the fingers. Smith et al. (1994) reported a 9-year-old boy with multiple congenital anomalies, including diaphragmatic hernia, bilateral clinical anophthalmia, and tetralogy of Fallot who had an apparently balanced reciprocal translocation t(1;15)(q41;q21.2). These patients had a phenotype that may be consistent with a contiguous gene deletion syndrome involving 1q41-q42 (612530), of which CDH is a feature.
Kantarci et al. (2006) reported a newborn female with Fryns syndrome (229850) associated with a de novo approximately 5-Mb deletion of chromosome 1q41-q42.12. She died at 1 hour of age of respiratory insufficiency and congenital diaphragmatic hernia. Kantarci et al. (2006) concluded that there may be a possible locus for Fryns syndrome at 1q41-q42, and more specifically that this region may harbor one or more genes required for normal diaphragmatic development. In further analysis of the patient reported by Kantarci et al. (2006), Kantarci et al. (2010) used multiplex ligation-dependent probe amplification (MLPA) to extend the minimally deleted region to approximately to 6.1 to 6.2 Mb spanning from the EPRS gene (138295) to the ACBD3 gene (606809).
Slavotinek et al. (2006) identified a de novo interstitial deletion of 1q32.3-q42.2 in a male with CDH and pulmonary hypoplasia with multiple other congenital anomalies suggestive of Fryns syndrome. The authors referred to the reports of Youssoufian et al. (1988) and Kantarci et al. (2006).
Using MLPA analysis, Kantarci et al. (2010) found that 2 of 179 patients with CDH had deletions at chromosome 1q41-q42. One patient had previously been reported by Kantarci et al. (2006), and the other was reported for the first time. The second patient had multiple congenital anomalies, including pulmonary hypoplasia, talipes equinovarus, undescended testes and dysmorphic facial features; he died at age 1 month. The deletion extended from the BPNT1 gene (604053) on chromosome 1q41 to the PSEN2 gene (600759) on chromosome 1q41.13.
Wat et al. (2011) identified a de novo deletion at chromosome 1q41-q42 in 1 of 45 unrelated patients with CDH. This patient had multiple congenital anomalies and developmental delay. The deletion breakpoints in the patient reported by Wat et al. (2011) allowed definition of a new 2.2-Mb minimal deleted region for congenital diaphragmatic hernia on 1q41-q42 (223,073,839 to 225,318,623, GRCh37), which contains 15 genes including DISP1 (607502), but not including HLX (142995).
Chromosome 11q
Klaassens et al. (2006) reported 2 brothers with partial trisomy 11q, 1 of whom had left-sided posterolateral CDH. Array-based comparative genomic hybridization and FISH enabled mapping of the duplication to a 19-Mb region on 11q23.3-qter, suggesting that duplication of a gene within this region may predispose to the development of CDH.
Wat et al. (2011) reported a patient with multiple congenital anomalies, including CDH, who had an unbalanced maternal translocation between chromosome 13q and 11q, resulting in a 47,XX,+der(13)t(11;13)(q23;q12.3). She was trisomic for a part of chromosome 13q12.3 and a part of chromosome 11q23-qter.
DIH1 Locus on Chromosome 15q
To define candidate regions for CDH, Klaassens et al. (2005) analyzed cytogenetic data collected on 200 CDH cases, of which 7% and 5% showed numerical and structural abnormalities, respectively. The authors focused on the most frequent structural anomaly found: a deletion on 15q. They analyzed material from 3 of their patients and from 4 previously reported patients with CDH and a 15q deletion. Using array-based comparative genomic hybridization and FISH to determine the boundaries of the deletions and by including data from 2 individuals with terminal 15q deletions but without CDH, they were able to exclude a substantial portion of the telomeric region from the genetic etiology of this disorder. Moreover, 1 patient with CDH harbored a small interstitial deletion. Together these findings allowed them to define a minimal deletion region of approximately 5 Mb at chromosome 15q26.1-q26.2. This region contained 4 known genes, of which 2--NR2F2 (107773) and CDH2 (114020)--were considered particularly intriguing gene candidates for CDH.
Castiglia et al. (2005) also examined the probable location of a gene involved in CDH by the study of a patient with a de novo deletion at 15q26.1-q26.2 without CDH. Klaassens et al. (2005) pointed out that 15q26.1-q26.2 is a gene-poor region and that haploinsufficiency of this region might not be completely penetrant. They still proposed NR2F2 as the most likely candidate gene for CDH.
In a patient with CDH and multiple congenital anomalies, Bleyl et al. (2007) identified heterozygosity for a 2889C-G transversion in the PDGFRA gene (173490) predicting a leu967-to-val substitution. The change was not seen in 768 chromosomes. However, the patient's skin karyotype revealed 46,XX with 1 in 50 cells showing mosaicism for trisomy 15. The patient had left-sided CDH and multiple anomalies including pulmonary hypoplasia, congenital heart disease with a ventricular septal defect, secundum type atrial septal defect and tricuspid regurgitation, malrotation of the intestines, multicystic liver, neck webbing, dysmorphic facial features, and streaky skin hyperpigmentation. Bleyl et al. (2007) concluded that the physical anomalies could be related to trisomy 15 mosaicism, the PDGFRA alteration, or a combination of both. Although the patient had many phenotypic features typical of trisomy 15 and streaky skin hyperpigmentation supported mosaicism, the authors noted that diaphragmatic defects had not previously been described in patients with trisomy 15.
Associations Pending Confirmation
In a 6-year-old boy with multiple congenital anomalies, including congenital left-sided Bochdalek diaphragmatic hernia, ventricular septal defect and abnormal aorta, and left-sided cleft lip with bilateral cleft palate, Kantarci et al. (2010) identified mosaicism for a de novo heterozygous 4412C-G transversion in the DISP1 (607502) gene on chromosome 1q42, resulting in an ala1471-to-gly (A1471G) substitution. Studies of patient tissues showed that the mutant allele was present in 43% of lymphoblastoid cells, 12% of peripheral blood lymphocytes, and 4.5% in saliva. The patient had hypotonia but otherwise had normal development. No DISP1 mutations were found in 178 additional patients with congenital diaphragmatic hernia.
In a 6-month-old boy of European descent with isolated congenital diaphragmatic hernia (CDH), and a 3-year-old girl with multiple congenital anomalies including CDH, Jordan et al. (2018) identified biallelic variants in the FREM2 gene (608945).
Yuan et al. (2003) described central diaphragmatic hernia in mice in whom a knockout of the Slit3 gene (603745) had been introduced. The central tendon region of the diaphragm failed to separate from liver tissue. The liver showed continuous growth into the thoracic cavity.
You et al. (2005) generated tissue-specific Nr2f2 -/- mice and observed the development of dorsolateral Bochdalek-type congenital diaphragmatic hernias. The authors noted that in patients with a 5-Mb deletion on chromosome 15q26.1-q26.2, Klaassens et al. (2005) found left-sided Bochdalek-type hernias similar to those seen in the conditional knockout mice. You et al. (2005) suggested that NR2F2 is a likely contributor to the formation of CDH in patients with 15q deletions.
Bleyl et al. (2007) observed that the homozygous Pgfra (173490)-null mouse had posterolateral diaphragmatic defects and concluded that the mouse is a model for human congenital diaphragmatic hernia.
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