Congenital diaphragmatic hernia, development, fetal anomalies, polycystic kidney: A rare fetal autopsy case with literature review

INTRODUCTION

The mature diaphragm develops from several embryonic origins, including the septum transversum, pleuroperitoneal folds (PPFs), muscular ingrowths from the body wall, and the dorsal mesentery of the esophagus. Studies on transgenic mouse models have advanced our understanding of normal diaphragm development. Congenital diaphragmatic hernia (CDH) is a relatively uncommon condition in which the diaphragm fails to fully form or fuse during embryologic development, allowing the thoracic and abdominal compartments to communicate. This deformity, with a frequency of 1 in 2000-4000 births and between 1/2000 and 1/7000 cases in autopsy series, accounts for 8% of all significant congenital malformations.^[1] Based on the location of the defect, CDH is categorized into different types. Bochdalek hernias, the most common (70-75%), are caused by a defect in the posterolateral region of the diaphragm; they are more prevalent on the left side and less common on the right. Central hernias account for 2-5% of cases, while anteromedial diaphragm defects cause Morgagni hernias, which comprise 20-25% of cases. Bilateral abnormalities are extremely uncommon and are always fatal. Diaphragm eventration resulting from incomplete muscularization of the diaphragm is also included within the spectrum of CDH.^[2] Approximately 50-80% of CDHs are identified prenatally when the intestines and liver are visible in the chest along with an abnormally positioned heart. Despite improvements in the management of CDH, the disease’s mortality and morbidity rates remain high. In addition, newborns with CDH have longer hospital stays, necessitating a multidisciplinary approach to care and post-discharge monitoring.^[3]

CASE REPORT

A 21-year-old primigravida was referred to the department of obstetrics and gynecology of a tertiary care center for an antenatal ultrasound at 16 weeks of gestation, with a history of vaginal bleeding. The present pregnancy was conceived spontaneously, with no history of ovulation induction. There was no history of consanguinity in the parents, and no history of smoking, alcohol intake, or teratogenic drug exposure during pregnancy. The patient had no risk factors for gestational diabetes, with a body mass index of 22.6, and no significant family history. The blood sugar profile was normal after admission, and hemoglobin A1C was 5.8. Ultrasound examination showed a single live fetus corresponding to 16 weeks of gestation. Marginal subchorionic bleed was present. The heart was pushed to the right side, with echogenic bowels and the stomach in the left half of the thorax. The stomach was visualized posterior to the heart. Both kidneys showed increased echogenicity [Figure 1a and b]. A diagnosis of left-sided diaphragmatic hernia with autosomal recessive polycystic kidney disease (ARPKD) was given by the radiologist. The patient was counseled about the diagnosis. A targeted imaging for fetal anomalies scan at 20 weeks confirmed the findings of a left-sided diaphragmatic hernia with likely ARPKD [Figure 1a]. No other anomalies were identified. After discussing the prognosis with the parents, termination of pregnancy was decided on. Genetic testing was not performed due to financial constraints, despite counseling. The family declined chromosomal microarray (CMA) or exome sequencing, which could have aided in identifying potential syndromic or chromosomal associations. Informed consent was obtained from the family for a fetal autopsy, ensuring their understanding of the purpose and procedures.

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Figure 1:

(A) Targeted imaging for fetal anomalies scan at 20 weeks, transverse section of the chest showing heart (short arrow) displaced to the right with echogenic bowels occupying the left side of the chest, stomach (*asterisk) lies posterior to heart. Dashed white arrow- right lung. (B) Coronal image of fetal abdomen at 16 weeks of gestation (yellow arrows) marks shows increased echogenicity of both kidneys.

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Autopsy report

The fetus was sent to the department of anatomy for autopsy, where a detailed examination was conducted as per standard protocols to investigate the developmental anomalies and correlate them with the radiological findings. The fetus was male, corresponding to a gestational age (GA) of 22 weeks, and weighed 1027 g. The crown-to-rump length was 23.5 cm, and the chest and abdominal circumferences were 21 cm and 19 cm, respectively. The biparietal diameter was 6.2 cm. The development of the skin, fontanelles, eyes, ears, nose, and oral cavity was normal for the GA. The thorax was barrel-shaped with a flat abdomen. The scrotum was empty, and the urethra was patent with a normal position of the external urethral meatus. The anal orifice was normally positioned and patent. No midline defects were noted on external examination. Both upper and lower limbs were normal and symmetrical.

Internal examination revealed a normal trachea, esophagus, thymus, and thyroid. Upon opening the thoracic cage, left lung hypoplasia and the absence of the left dome of the diaphragm were noted. The left lobe of the liver and some loops of the intestine occupied the left thoracic cavity, lateral to the left lung. The rest of the intestines were in the left abdominal cavity. The stomach was normally positioned, with the spleen and pancreas located posterior to it. The right lobe of the liver was under the right dome of the diaphragm [Figures 2b and 3]. The pericardial cavity, heart, aorta, and its branches were normal. Both kidneys were lobulated. The right kidney weighed 10 g, measuring 3.3 × 1.7 cm, and the left kidney weighed 7 g, measuring 3.4 × 2 cm. Each kidney presented a cyst measuring about 2 × 2 cm. The testis was bilaterally seen as pea-sized masses in the inguinal region, attached to the gubernaculum. The head and brain were normal for the GA. The placenta and umbilical cord were also normal. Based on these findings, a diagnosis of CDH with PKD was made.

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Figure 2:

(A and B) Dissection of the thoracoabdominal cavity in a fetus showing congenital diaphragmatic hernia with herniation of intestinal loops into the left thoracic cavity. (A) Initial exposure demonstrated herniated bowel loops in the thoracic cavity, compressing the left lung. (B) Further retraction highlighting the relation of the herniated intestines with the heart and liver lobes. The displaced thoracic and abdominal viscera are labelled: H: Heart, LLL: Left liver lobe, RLL: Right lobe of liver, RL: Right lung, UC: Umbilical cord.

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Figure 3:

Diagrammatic representation of the various sources for the development of the diaphragm. ST: Septum transversum, PPM: Pleuroperitoneal membrane, M: Muscular ingrowth from the body wall, IVC: Inferior vena cava, AA: Abdominal aorta, E: Esophagus (Image created by one of the authors, Rohini Motwani).

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DISCUSSION

Based on the maternal history, family history, prenatal ultrasound findings, and fetal autopsy, this case represents CDH associated with PKD. The etiology of CDH is currently thought to be multifaceted, although it remains mostly unknown. Approximately 30–40% of CDH cases have a known genetic cause. Of these, about 10% of cases are caused by chromosomal abnormalities^[4] while 10–22% result from de novo mutations.^[5,6] Defective development or fusion of the septum transversum, PPFs, dorsal mesentery of the esophagus, and muscular ingrowth from the lateral body wall can all account for the embryological basis of CDH [Figure 2]. Development of these structures takes place between the 4^th and 10^th weeks of gestation, a crucial period that overlaps with early renal morphogenesis. Therefore, the simultaneous emergence of diaphragmatic and renal abnormalities, as seen in this case, may be explained by disruption during this window. In our case, the diaphragmatic defect was left-sided, consistent with a Bochdalek hernia, which represents the most common form of CDH [Figure 4]. Left-sided defects are more frequent due to delayed closure of the pleuroperitoneal canal and absence of hepatic support, permitting herniation of abdominal viscera into the thoracic cavity and leading to significant pulmonary hypoplasia.”

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Figure 4:

Diagrammatic representation of the location of the congenital defects of the diaphragm (view from below) showing types of the congenital diaphragmatic hernia (CDH). A: Anterior, PL(R): Right posterolateral defect, PL (L): Left posterolateral, IVC: Inferior Vena Cava, E: Esophagus (Image created by one of the authors, Rohini Motwani).

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In most cases, the defect is isolated, with pulmonary hypoplasia being common. Some non-isolated CDH cases present with patterns of anomalies suggestive of a specific genetic syndrome. Fryns syndrome is the most frequently diagnosed condition in patients with CDH when a syndromic diagnosis is made.^[7] However, reports of Fryns-like phenotypes associated with chromosomal abnormalities, such as partial trisomy 22, deletion of the terminal region of 6q, 8p23.1, and 15q26, as well as duplication of 1q24-q31.2, suggest that some CDH cases linked to this autosomal recessive syndrome are likely genocopies.^[7,8]

In this case, CDH is associated with PKD. Shantikumar et al. reported two cases of CDH with PKD associated with a 17q12 deletion.^[9] 17q12 deletions involving the hepatocyte nuclear factor 1 beta gene cause a variable phenotype that includes PKD, congenital anomalies of the kidneys, maturity-onset diabetes of the young, and other abnormalities. Goumy et al. reported a 5-year-old male with CDH and multicystic renal dysplasia, minor facial dysmorphic features, and skeletal anomalies due to a de novo 17q12 microdeletion, reinforcing the hypothesis that 17q12 deletions are linked to CDH.^[10] Chromosome 17q12 deletion syndrome is a rare genetic disorder associated with a 1.4-1.5 Mb deletion at chromosome 17q12. It leads to a spectrum of manifestations, including diaphragmatic hernia, kidney abnormalities, and neurodevelopmental delay. This deletion is usually sporadic but can also be inherited.^[11] Ford^[12] reported two cases of stillborn male babies: one with a massive diaphragmatic hernia with PKD, and the other with a massive CDH and renal agenesis. Although genetic testing could not be pursued in this case due to financial constraints, its role remains critical in cases where CDH coexists with renal anomalies. Testing such as CMA or whole-exome sequencing could potentially reveal underlying genetic syndromes, including 17q12 deletion syndrome, Fryns syndrome, or other microdeletion/ microduplication syndromes. The absence of genetic confirmation in this case underscores a common challenge in resource-limited settings.

Considering other environmental factors, maternal obesity and pre-gestational hypertension have been linked to a higher risk of CDH.^[13] In addition, exposure to methotrexate, cadmium, fungicides, insecticides, immunosuppressants, antidepressants, alcohol, and smoking has been associated with CDH.^[14-16] However, in this case, there was no such exposure.

CONCLUSIONS

CDH associated with PKD is a rare and severe fetal condition, typically diagnosed in the second trimester, with a poor prognosis due to combined pulmonary and renal compromise. Outcomes depend on the severity of lung hypoplasia, renal involvement, and associated anomalies. Management requires a multidisciplinary approach and thorough parental counseling regarding high perinatal risks. Genetic evaluation should be considered where feasible; however, in the absence of molecular confirmation, phenotypic diagnosis remains important, emphasizing the need for affordable and accessible genetic services, especially in low-resource settings.