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Bilateral Congenital Diaphragm Agenesis in a Neonate with Hydrocephalus: Case Report

Congenital diaphragmatic hernia (CDH) is one of the most common anomalies in neonates. Diaphragmatic agenesis (DA) is rare and is considered at the extreme spectrum of CDH, it is associated with a higher rate of multiple anomalies. A male neonate with antenatal diagnosis of CDH and hydrocephalus was born at estimated gestational age of 36 + 4 weeks by emergency Caesarean section due to fetal distress. Chest x-ray showed a common pleuroperitoneal cavity with the liver, spleen, and stomach seen in the thoracic cavity suggesting the diagnosis of bilateral absence of the diaphragm, the neonate died after an hour and a half. DA associated with hydrocephalus has never been previously reported in the literature.


Introduction
Congenital diaphragmatic hernia (CDH) describes a broad spectrum of congenital anomalies of the diaphragm ranging from small defects to complete absence. The most extreme variant is agenesis of the diaphragm (DA) and may be unilateral or bilateral. CDH carries a poor prognosis mostly due to pulmonary hypoplasia, although survival rates also depend on the presence or absence of associated major congenital anomalies and chromosomal defects [1,2].
CDH is considered one of the most common congenital anomalies in neonates accounting for 2.4 to 4.1 per 10000 births in Europe [3]. The type of CDH depends on the location of the defect: 1) posterolateral through the foramen of Bochdalek, 2) parasternal in the anterior portion of the diaphragm (Morgagni hernia), 3) septum transversum defects in the central tendon, 4) and hiatal hernia [4]. The posterolateral defect/Bochdalek hernia is the most common type seen in 85-90% of cases [3].
Diaphragmatic defects were described in association with trisomies 18 and 21, vitamin A deficiency, and maternal drug use [5].
Although most of the cases are sporadic, few authors have suggested an autosomal mode of inheritance in cases were siblings were affected with unilateral agenesis of the diaphragm [4].
The most common associated congenital anomaly with CDH is cardiovascular anomalies ranging from septal defects to hypoplastic heart [6].
We present a rare case of bilateral diaphragmatic agenesis with a common pleuroperitoneal cavity associated with hydrocephalus in a male neonate with a sibling with hydrocephalus suggesting a rare syndrome, and we review cases previously presented in the literature.

Clinical observation and imaging findings
A male neonate was born at 36 + 4 weeks estimated gestation age with antenatal diagnosis of CDH and hydrocephalus by Caesarean section due to fetal distress. His Apgar scores were 4, 5, 7 at 1, 5 and 10 minutes respectively. The baby was intubated immediately and put on synchronized intermittent mandatory ventilation, and was transferred to the neonatal intensive care unit.
On physical examination, the baby was flaccid, cyanosed, and with large head, head circumference was 37 cm which is above the 97 th percentile (normal 32 ± 3 cm). Antenatally, at the age of 18 weeks estimated gestation age, the atrial width for the lateral ventricles was 10 mm and 11 mm on the right and on the left respectively and remained so until the time of delivery. According to reference ranges of fetal ventricle size by ultrasound provided by Ishola et al, our patient's measurements were above the 95 th percentile [7]. Unfortunately images of hydrocephalus were not provided in the records.
No dysmorphic features were noted. Physical chest examination by auscultation revealed decreased air entry; oxygen saturation was less than 70. A chest x-ray was done and showed bilateral pneumothoraces and pneumoperitoneum. Soft tissue densities within both hemithoraces were noted mostly representing the right and left liver lobes and the spleen, the nasogastric tube (NGT) was seen coiled in the intrathoracic stomach with few bowel loops in the left hemithorax as well. Collapsed lungs were noted in the apices bilaterally. The chest x-ray findings were suggestive of a single pleuroperitoneal cavity with absence of both hemidiaphragms (Fig. 1).
The baby became distressed with severe oxygen desaturation and asystole. 10 cycles of cardiopulmonary resuscitation were performed with no success. The baby died at the age of one hour and a half. An autopsy was not performed.
At 18 weeks estimated gestation age amniocentesis was performed, the fetus was normal male karyotype.
The parents were counselled regarding poor prognosis of the fetus, and agreed to no surgical intervention after birth.
The parents were unrelated healthy individuals. An older sibling of our patient suffered from hydrocephalus and was treated by ventriculoperitoneal shunting.
Counselling regarding future pregnancies was performed, the parents wished to conceive again and undergo routine detailed antenatal examinations and amniocentesis. The mother is currently pregnant with her third child at 34 estimated gestational age with a healthy fetus.

Discussion
The diaphragm is formed between the 3 rd and 8 th weeks of gestation by fusion of the: 1) septum transversum which forms the central tendon, 2) the dorsal oesophageal mesentery which gives rise to the median portion of the diaphragm, 3) the pleuroperitoneal membrane which separates the pleural and peritoneal cavities, 4) the muscular portion of the body wall which forms a narrow segment inserting the diaphragm to the ribs and the sternum [4].
CDH is considered one of the most common congenital anomalies in neonates. Unilateral diaphragmatic defects are more common than bilateral defects and are associated with other anomalies in 30-40% in comparison to 70% in bilateral defects. Agenesis of the diaphragm is a rare condition with only 10 cases reported in the literature up to 2017 [3]. It was found that 73% of cases with DA have associated malformations where cardiovascular anomalies remaining the commonest as seen in patients with CDH. The survival rate of the affected patients depends largely on the cardiopulmonary function and associated anomalies rather than the size of the defect [2].
The diaphragm muscle precursors originate from the cervical somites, as they migrate to the pleuroperitoneal folds they start to proliferate and differentiate. There are genes that are required for migration of the diaphragm muscle precursors. These genes interact with one another in the embryonal pathway for the development of the brain, heart, lungs, diaphragm, kidneys, and pancreas [3]. Therefore, multiple anomalies are present in patients with CDH and DA.
In a large study conducted by Neville et al reviewing 1833 patients with CDH, 17 had bilateral CDH, 12 had associated anomalies the most common being cardiovascular, one case had Fryns syndrome, and one case had Simpson Golabi Behmel syndrome. None of the patients was reported to have hydrocephalus [6]. In a case study by Fauz et al, 166 cases with CDH were reviewed, 4 of them had hydrocephalus [7]. Nineteen cases reviewed by Baglaj et al showed 2 of the patients who had CDH had associated hydrocephalus and none of the cases with DA had hydrocephalus [1]. In a literature review by Al Adnani el al none of the 10 cases with DA had hydrocephalus [3]. In a study conducted by Radhakrishnan et al on brain magnetic resonance imaging in fetuses with CDH none had hydrocephalus. However, they observed enlargement of the extraaxial spaces [8].
DA is believed to be an extreme form of CDH and not a separate entity according to a study conducted by Baglaj et al [1]. In all the previously reported patients in the literature with unilateral or bilateral DA; none of them had hydrocephalus, although it was observed uncommonly in patients with CDH. Therefore, we believe our case is a rare case, and since our patient had hydrocephalus and so did his sibling; we postulate the possibility of our patient being part of an undiagnosed syndrome such as Fryns syndrome or Bieber syndrome [9].
DA is basically an intraoperative diagnosis and no diagnostic studies or clinical parameters identify the babies during the preoperative period [1]. Therefore, since an autopsy was not performed in our patient, an undiagnosed syndrome remains a suggestion.
Genetic counselling is an important point in cases of congenital malformations to assess in future pregnancies and treatment options.

Conclusion
DA is a very rare entity with only few cases reported in the literature. The affected neonates are of a higher risk of associated life threatening anomalies. Therefore, it is essential to do a detailed antenatal scans in fetuses found to have congenital diaphragmatic defects to determine the need for early intervention and for genetic counselling for possible hereditary syndromes and future pregnancy planning for the parents. Fig. 1. Chest and abdomen x-ray showing bilateral pneumothraces and pneumoperitoneum, with soft tissue densities in both hemithoraces mostly the right and liver lobes. Small collapsed lungs are seen at the apices. Bilateral inguinal hernia containing bowel loops are also noted. Findings are consistent with common pleuroperitoneal cavity as a result of bilateral diaphragmatic agenesis.