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Congenital diaphragmatic hernia and interstitial deletion of chromosome 3

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Editor—Congenital diaphragmatic hernia (CDH) is seen in 1/2000 to 1/5000 fetuses and liveborn infants.1 2Around 60% of fetuses diagnosed by antenatal ultrasound scanning at 20 weeks' gestation die in utero and the mortality rate in those surviving to term remains 30-50%. Coexistent major structural malformations are seen in a large proportion of cases, the commonest in liveborn infants being cardiac anomalies and neural tube defects.3

The genetic contribution to the aetiology of CDH is poorly understood. Although no large scale, population based, offspring recurrence study exists, familial clustering of CDH has been attributed to polygenic inheritance, which predicts an offspring recurrence risk of 1-2%. Familial congenital diaphragmatic hernia is, however, well described with autosomal dominant inheritance in most reported families, although no linkage studies have been performed. Candidate genes may therefore be localised by studying the large proportion of patients with CDH and an underlying chromosome abnormality. Autosomal trisomies, typically of chromosomes 13, 18, and 21, account for many of these cases. More complex structural rearrangements have also been reported in some series, although many of these cases have additional organ malformations.4-6 However, a number of de novo structural anomalies associated with CDH have been documented, defining candidate loci for future study; these are summarised in table1.

Table 1

Candidate loci for congenital diaphragmatic hernia

Case report

We report a male infant with CDH associated with a proximal deletion of the long arm of chromosome 3 in mosaic form. Clinical genetic evaluation was sought during the third pregnancy of a 29 year old female and a 32 year old male. She had previously had two healthy children and there was no history of pregnancy loss. Fetal ultrasound examination at 22 weeks' gestation showed a large, left sided diaphragmatic hernia with mediastinal shift but no hydrops. No other structural abnormality was seen. A placental biopsy was taken for cytogenetic analysis. Both direct and long term preparations showed an abnormal mosaic male karyotype with an additional, unidentified small chromosome in approximately 50% of cells examined. Analysis of cultured amniocytes confirmed the marker chromosome in 50% of cells. Fluorescence in situ hybridisation (FISH) studies indicated that the marker was derived from the centromeric region of chromosome 3 (fig 1A) and contained euchromatic material. The karyotype was assigned as 47,XY,+mar.ish der(3)(D3Z1+)/46,XY and was interpreted as mosaic partial trisomy 3.

Figure 1

(A) Image of FISH studies performed on cultured amniocytes showing hybridisation of the probe D3Z1 to the centromeric regions of both chromosomes 3 and the marker chromosome (arrows). (B) Partial karyotype from a chromosomally “balanced” postnatal peripheral lymphocyte showing both an intact and deleted chromosome 3 and a ring chromosome derived from the deleted segment.

Polyhydramnios developed from 30 weeks' gestation but remained stable with no hydrops. A male infant was delivered at term by elective caesarian section for breech presentation. He required ventilation from birth. A chest x ray confirmed a large, left sided congenital diaphragmatic hernia with extreme pulmonary hypoplasia. Echocardiography showed a grossly dilated right ventricle with high right sided pressures creating a right-left shunt through a patent ductus arteriosus. Surgical repair of the diaphragmatic hernia could not be contemplated at any stage owing to the child's unstable clinical state. Despite full supportive treatment, his condition deteriorated and he died on his second day of life following withdrawal of intensive care. Necropsy showed a non-dysmorphic male infant with the following growth parameters: head circumference 36.5 cm (75th-91st centile), height 53 cm (75th centile), and weight 4200 g (91st centile). The right hemidiaphragm was present and the right lung was trilobed, hypoplastic, and compressed. The left hemidiaphragm was absent and the chest contained a diaphragmatic hernia consisting of stomach, pancreas, duodenum, small bowel, a large segment of colon, the left lobe of the liver, and the spleen. The left lung was twisted on its pedicle and was extremely hypoplastic. Cardiac situs was normal but the mediastinal contents were displaced to the right. Cardiac anatomy was normal and there was a wide patent ductus arteriosus. Gross brain anatomy was normal; histological examination showed evidence of early global hypoxic/ischaemic damage and mild brain stem atrophy around an enlarged cerebral aqueduct. There were no other significant histological findings.

Postnatal cytogenetic analysis of peripheral lymphocytes enabled further characterisation of the abnormal mosaic karyotype detected antenatally. Two cell populations were present in approximately equal proportions. The first contained 46 chromosomes with an interstitial deletion of a proximal segment of the long arm of chromosome 3 extending into the subcentromeric region and resulting in monosomy of 3q11.1 to 3q13.2. The second cell population contained 47 chromosomes with the same deleted chromosome 3 and a small additional ring chromosome identical to the marker chromosome detected antenatally and composed of pericentromeric chromosome 3 material (fig1B). The karyotype was reassigned as 46,XY,del(3)(q11.1q13.2)/47,XY, del (3)(q11.2q13.2),+r(3). Parental karyotypes were normal.


The proximal breakpoint for the deletion reported here was located within the centromeric region of chromosome 3, to which the FISH probe D3Z1 hybridises, and the deleted segment contained both euchromatin and heterochromatin. It is likely, therefore, that the ring chromosome present in 50% of this infant's lymphocytes was composed of deleted material from proximal 3q and the cell population containing this ring was therefore effectively “balanced”. The second cell population was haploinsufficient for the chromosomal region 3q11.1-3q13.2. In both cell populations, disruption of a gene at the distal breakpoint cannot be excluded.

Reports of interstitial deletion of the long arm of chromosome 3 are rare, with deletions involving band 2 being more commonly reported. The small number of case reports detail variable multiple congenital abnormalities and neurodevelopmental delay. Deletions involving band 3q23 are, however, associated with features of the blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), an autosomal dominant disorder which maps to this region.8 9Few subjects with proximal 3q deletions involving band 1 have been described; of those published, none had CDH and, although no clear phenotype has emerged, a small number share features such as absent corpus callosum, hypotonia, and severe neurodevelopmental delay.10-15

The deletion in our patient is just proximal to that found in a fetus reported by Wolstenholme et al.16 The fetus was ascertained antenatally following detection of a large diaphragmatic hernia on ultrasound scanning. Fetal necropsy confirmed a left sided diaphragmatic hernia and showed facial features consistent with BPES. The fetal karyotype showed an interstitial deletion of the long arm of chromosome 3: 46,XY,del(3)(q21q23). This mapped the BPES locus more accurately to 3q23 but the significance of the diaphragmatic hernia was unclear. The finding of diaphragmatic hernias in both cases is therefore of interest, although difficult to explain since the deletion intervals do not appear to overlap. A gene involved in the development of the diaphragm may map to proximal 3q and may, for example, be susceptible to position effect. We propose that the congenital diaphragmatic hernia in our case is a direct consequence of mosaic proximal 3q deletion.

A further locus on distal 3q is suggested by the occurrence of CDH in severe de Lange syndrome, whose critical region appears to lie at 3q26.3, and the similarity between mild de Lange syndrome and the dup(3q) syndrome.24-26 However, CDH has not been reported in dup(3q) syndrome and the relationship between these syndromes has yet to be determined.

Proximal 3q and the loci detailed in table 1 therefore provide a focus for future molecular genetic studies of familial CDH. This case also clearly underlines the importance of postnatal confirmation of all karyotypic abnormalities detected antenatally.


The authors wish to thank Dr S Vadeyar in the Department of Fetomaternal Medicine, Queen's Medical Centre, Nottingham for referring this case. Dr J Grant, Department of Neonatal Intensive Care, was responsible for postnatal supportive care. Necropsy was performed by Dr C J H Padfield in the Department of Pathology, Queen's Medical Centre, Nottingham. We thank Dr K Ocraft, Mr A Wilkinson, and Mrs C Cooper from the Prenatal Division, Cytogenetics Service, Nottingham City Hospital for their prenatal diagnostic work and for providing illustrations for this report.