Challenges in diagnosing diaphragmatic eventration in a neonate with Fryns syndrome and cleft palate

Abstract

Diaphragmatic eventration is a rare congenital anomaly characterized by the replacement of diaphragmatic muscle with fibroelastic tissue, leading to diaphragm elevation and functional impairment. While it can occur in isolation, it is sometimes associated with congenital syndromes, including septo-optic dysplasia (SOD). This report presents a case of diaphragmatic eventration in a neonate with Fryns syndrome presenting with cleft palate and SOD, highlighting diagnostic challenges. A late preterm female neonate, born via cesarean at 36 weeks gestation, presented with respiratory distress and required intubation and surfactant therapy. Physical examination revealed features suggestive of Fryns syndrome, including coarse facies, microphthalmia, and cleft palate. Imaging studies, including chest X-ray and thoracic ultrasound, raised suspicion of diaphragmatic hernia, but subsequent MRI confirmed diaphragmatic eventration. Additional cranial imaging identified agenesis of the corpus callosum, colpocephaly, and optic nerve hypoplasia, leading to the diagnosis of SOD. Diaphragmatic eventration, though rare, can present in neonates with other congenital anomalies, making diagnosis challenging. In this case, the overlapping symptoms with cleft palate and SOD complicated the clinical picture. Early imaging, including MRI, is crucial for accurate diagnosis and timely management. Multidisciplinary follow-up is essential for optimal patient care.

Introduction

Although respiratory distress is common in newborns, most cases are due to transient tachypnea, while diaphragmatic pathologies are rare [1]. Diaphragmatic eventration is an uncommon congenital anomaly, accounting for 5% of all diaphragmatic malformations. It is characterized by the replacement of diaphragmatic muscle with fibroelastic tissue, leading to an abnormally elevated and functionally impaired diaphragm [[2], [3], [4]]. Newborns with diaphragmatic eventration can present with a wide spectrum of clinical manifestations, ranging from life-threatening respiratory distress requiring advanced respiratory support to asymptomatic cases diagnosed incidentally [1,5]. In the etiology, acquired cases are more common, primarily resulting from trauma, especially birth trauma. Congenital diaphragmatic eventration (CDE), however, is even rarer than acquired cases [2]. It typically presents unilaterally and may occur either in isolation or alongside chromosomal abnormalities and/or congenital syndromes, including Fryns syndrome, Kabuki syndrome, Beckwith-Wiedemann syndrome, Poland syndrome, and Jarcho-Levin syndrome [2,[6], [7], [8], [9]].

Studies on diaphragmatic pathologies have reported that the majority of congenital diaphragmatic hernia (CDH) cases are isolated malformations, but more than 40% of patients have additional major and minor anomalies [7,8]. Although over 70 syndromes, including diaphragmatic pathologies, primarily CDH, have been documented, its co-occurrence with septo-optic dysplasia (SOD) or its components is rare [10]. SOD, also known as de Morsier syndrome, is a rare congenital condition characterized by a classic triad: (a) midline brain defects, such as the absence of the septum pellucidum or agenesis of the corpus callosum, (b) optic nerve hypoplasia, and (c) pituitary hormone abnormalities. A clinical diagnosis is made when at least two of these features are present [11].

Diaphragmatic eventration is even less frequently reported in association with the components of SOD [7,12]. Fryns syndrome, an autosomal recessive genetic disorder, is one of the syndromes that includes diaphragmatic anomalies and shares overlapping features with SOD. It is characterized by diaphragmatic defects (such as diaphragmatic hernia, eventration, hypoplasia, or agenesis), a distinct facial appearance (coarse facies, widely spaced eyes, a broad and depressed nasal bridge with a wide nasal tip, long philtrum, low-set and malformed ears, wide mouth, and small jaw), short distal phalanges of the fingers and toes (with small nails), pulmonary hypoplasia, and associated anomalies (such as polyhydramnios, cloudy corneas and/or microphthalmia, orofacial clefts, renal dysplasia or renal cortical cysts, and malformations affecting the brain, cardiovascular system, gastrointestinal system, and/or genitalia) [7,12,13].

In newborns, due to the similarity in clinical and radiological findings of CDH and the overlapping symptoms with other underlying causes of respiratory distress, the accurate diagnosis of diaphragmatic eventration is often difficult and delayed. This is due to its rarity and the presence of asymptomatic cases, which often make it unlikely to be considered initially [3]. Additionally, the presence of other congenital anomalies in babies further complicates the diagnosis and management of diaphragmatic eventration, as it often leads to a focus on diagnosing CDH instead.

In this Fryns syndrome case report, it is aimed to share the difficulties experienced in diagnosing diaphragmatic eventration in a newborn with cleft palate and SOD who was followed up due to respiratory distress.

Case presentation

A late preterm female neonate weighing 2.75 kg was born at 36 weeks of gestation to a 36-year-old multigravida mother by cesarean delivery. She had an Apgar score of 6 and 7 at one and five minutes, respectively. After birth, she exhibited inadequate respiratory effort and a heart rate of 60-80 beats per minute. Positive pressure ventilation was administered for 15 seconds, after which she was intubated and transferred to the neonatal intensive care unit. Due to increased oxygen demand observed on the ventilator, intratracheal surfactant was administered. The neonate was monitored on invasive mechanical ventilation, and antibiotic therapy was initiated.

During the examination of the neonate, coarse facies, wide-set eyes, microphthalmia, a broad and depressed nasal bridge with a wide nasal tip, and minimally short distal phalanges of the fingers were noted. Additionally, a cleft palate was observed during the physical examination. The family history was significant for a consanguineous marriage.

The chest X-rays of the patient revealed an increased opacity in the left hemithorax, in the paracardiac supradiaphragmatic area, which partially obscured the contour of the left diaphragm (Fig. 1A). The lateral X-ray revealed a supradiaphragmatic radiolucent appearance posteriorly and laterally, consistent with the gastrointestinal lumen (Fig. 1B). On thoracic ultrasound (USG), a clear distinction for diaphragmatic hernia could not be made. Based on the suspicion of a diaphragmatic hernia from the lateral X-ray, a contrast study was performed. The contours of the left hemidiaphragm were observed to be normal, and the stomach lumen, which was level with the contrast, was seen in its normal position beneath the diaphragm (Fig. 1C).

Fig. 1.

Frontal (A) chest X-ray shows focal superior bulging (arrow) of the left hemidiaphragm, (B) lateral chest X-ray shows focal bulging (arrow) of posterior aspects of the left hemidiaphragm and (C) barium passage radiography shows nearly normal contour of diaphragm.

In the neonate, where fluoroscopy could not be performed and the distinction between CDH and CDE could not be made using thoracic ultrasound and barium studies, the onset of gastric bleeding on the 72nd postnatal hour highlighted the need for urgent diagnosis due to the possible risk of gastric volvulus. Thoracic MRI was subsequently performed to rule out herniation of abdominal contents into the thoracic cavity. On the thoracic MRI, coronal T2-weighted images revealed elevation of the spleen and stomach in an area approximately 3 cm wide in the posterior portion of the left hemidiaphragm. However, the diaphragm contours were normal, and continuity of the contour was maintained (Fig. 2). No diaphragmatic defect was observed on any of the images. The findings confirmed the diagnosis of diaphragmatic eventration.

Fig. 2.

Thorax MRI sagittal (A) and coronal (B) T2-weighted images demonstrate slightly hypointense normal diaphragmatic contours (arrow) and normally positioned subdiaphragmatic fatty tissue, which has not herniated into the thoracic cavity. Elevation of the spleen and stomach along with the diaphragm is observed in the posterior part of the left hemidiaphragm.

In the infant's transfontanel ultrasound, colpocephaly and dilatation in the posterior portion of both lateral ventricles were noted. Follow-up cranial MRI revealed agenesis of the corpus callosum and secondary colpocephalic dilation in the posterior horns of both lateral ventricles, along with the appearance of separated lateral ventricles. Agenesis of the septum pellucidum was also identified in the midline (Fig. 3). T1-weighted images showed that the bilateral optic nerves were notably thin, raising suspicion for optic nerve hypoplasia. On eye examination, the optic nerve was assessed as having a suspicious hypoplastic appearance. Based on these findings, the patient was diagnosed with de Morsier syndrome.

Fig. 3.

In the brain MRI axial T2 sequence, there is dilatation of the occipital horns (arrow) of the lateral ventricles, indicative of colpocephaly. The bodies of the lateral ventricles have a parallel orientation and are separated due to the absence of the corpus callosum and septum pellucidum.

The neonate, whose respiratory distress improved, was extubated on postnatal day 13 and was observed on nasal CPAP for 3 more days. An echocardiogram showed no pathology other than a patent foramen ovale, and abdominal ultrasound revealed no additional abnormalities. Laboratory tests conducted to rule out possible hypopituitarism associated with SOD showed only a borderline low growth hormone level of 2.41 µg/L [N: 5-27 µg/L], while other results were within normal limits (cortisol: 8.6 µg/dL [2-11 µg/dL], TSH: 0.371 mIU/L [N: 1-20 mIU/L] and sT4: 1.5 ng/dL [N:0.86-2.49 ng/dL] at the postnatal 6th day, control TSH: 0.934 mIU/L [N:0.5-6.5 mIU/L] and sT4: 1.2 ng/dL [N: 0.89-2.2 ng/dL] at the postnatal 13th day, prolactin: 79.7 µg/L[N: 30-495 µg/L], FSH: 4.8 IU/L [N: 3.89-12.43 IU/L], LH: 0.7 IU/L [N: 0.52-3.08 IU/L], estradiol: 15.7 ng/dL[N:10-32 ng/dL]). By postnatal day 18, the patient was in a stable condition, on full enteral feeding without any respiratory support. On day 21, oral feeding trials were initiated with direct breastfeeding, and the baby was placed under oral rehabilitation due to the cleft palate. The baby was discharged home on day 30, feeding directly from the breast. The patient was discharged with follow-up appointments scheduled with pediatric endocrinology, pulmonology, and genetics clinics. Genetic evaluation could not be performed due to paramedical reasons.

Discussion

In this case report, the challenges in diagnosing CDE in an infant monitored for moderate respiratory distress, with diagnosis of Fryns syndrome and Morsier syndrome, were discussed. Our case involved an infant born with respiratory distress who was intubated within the first hour of life. The infant had inadequate prenatal follow-up and lacked an antenatal diagnosis. The presence of midline defects, such as a coarse facial appearance and cleft palate, suggested the possibility of additional pathologies. While treatments for respiratory distress were ongoing, the initial chest X-ray findings primarily raised suspicion of CDH and CDE. However, the infant’s gastric hemorrhage necessitated a rapid differentiation between gastric volvulus and diaphragmatic hernia.

Diagnosing diaphragmatic eventration in neonates presents several challenges, including the misinterpretation of radiological images and clinical mimicry, especially with CDH, which is more commonly encountered. On a chest X-ray, eventration is typically seen as an elevation of one hemidiaphragm. This appearance can also be similar to other conditions such as CDH, phrenic nerve palsy, or lung pathologies (eg, atelectasis, pneumothorax, lobar pneumonia, or masses) [5,8,14].

In our case, the posterior eventration of the diaphragm created a sharply defined, round, artifact-like image and, due to its focal pathology, did not cause the hemidiaphragmatic elevation commonly seen in CDE, making it indistinguishable from a Bochdalek hernia. This necessitated further investigations. Diaphragmatic motion on fluoroscopy is crucial for diagnosing such pathologies in adults or cooperative pediatric patients, but it was impossible to perform on our newborn patient who required respiratory support. Ultrasound has replaced fluoroscopy for functional diaphragm evaluation in children, allowing confirmation of diaphragm thickness and muscle integrity, thus ruling out complete paralysis [8,14,15]. Ultrasound visualizes the diaphragm as a thick echogenic line due to the reflection of ultrasound waves [8]. However, poor acoustic contrast, which can obscure the image, may limit the investigation, and focal diaphragmatic eventration might be missed depending on the location of the defect. Posterior eventration of the diaphragm is often indistinguishable from a Bochdalek hernia, as seen in our case [6,16].

In our case, the infant being intubated and the focal nature of the eventration made it impossible to differentiate ultrasonographically between focal eventration and diaphragmatic hernia, necessitating further imaging modalities. A clear distinction could not be made on the barium study either. Due to the ionizing radiation and its lower resolution compared to MRI in depicting diaphragm contours, CT was not considered. A definitive diagnosis was made with MRI. In complex cases, MRI is superior in assessing both diaphragmatic structure and function, allowing for the exclusion of herniation of abdominal contents without the risk of ionizing radiation. Additionally, MRI provides excellent soft-tissue resolution, clearly demonstrating the diaphragm as a thin sheet of muscle separating the thoracic and abdominal cavities [8].

MRI is not the standard diagnostic tool for congenital lung abnormalities due to limitations such as high costs, lengthy scan times, and insufficient specialized training in some regions. Furthermore, rapid respiratory rates can degrade image resolution, complicating diagnosis [2]. For instance, Bishara et al. [16] reported a preterm infant with respiratory distress in whom MRI and other imaging techniques failed to distinguish diaphragmatic eventration from CDH, leading to a misdiagnosis that was only corrected via thoracoscopy on day 56. In contrast, our case demonstrates that MRI—when conducted under pediatric radiology supervision—can provide real-time diagnostic clarity even in critically ill, intubated infants despite these challenges.

Diaphragmatic eventration in neonates typically manifests with respiratory distress, tachypnea, and feeding difficulties—clinical features that overlap with more prevalent conditions such as respiratory distress syndrome, pneumonia, CDH, or phrenic nerve palsy [17]. The clinical spectrum varies significantly, from incidental radiographic findings in asymptomatic cases to life-threatening respiratory failure. Like CDH, diaphragmatic eventration may cause pulmonary hypoplasia due to compression of the developing lung by displaced abdominal organs, with severity correlating to defect size [3]. While small, partial defects often remain clinically silent, extensive hemidiaphragmatic involvement can precipitate severe respiratory compromise. In our patient, focal CDE was accompanied by mild neonatal hypoxia necessitating surfactant therapy.

In our patient, the initial presentation of moderately severe respiratory distress requiring intubation—likely due to clinical overlap with other conditions—primarily suggested the more common diagnosis of CDH. The occurrence of gastric bleeding further raised suspicion of gastric volvulus, necessitating urgent diagnostic evaluation. Once CDE was confirmed, the infant's respiratory status improved rapidly after resolution of contributing factors (eg, hypoxic birth events), allowing for relatively early discontinuation of respiratory support by postnatal day 16. This suggested only mild-to-moderate pulmonary hypoplasia.

The absence of persistent respiratory issues following recovery from birth-related hypoxia aligns with the typically asymptomatic course of focal diaphragmatic pathologies [18]. However, the CDE in this case appears to have exacerbated the underlying conditions that required positive pressure ventilation at birth.

Partial diaphragmatic defects predominantly involve the right hemidiaphragm, whereas diffuse defects more commonly affect the left side [5]. In our case, however, the defect was partial (focal) and localized to the left hemidiaphragm—an atypical presentation that further complicated the diagnostic process. Additional factors contributing to the complexity of this case included the coexistence of Morsier syndrome (SOD) and cleft palate, which necessitated a systematic, stepwise diagnostic approach. A review of existing databases revealed that the combination of diaphragmatic abnormalities, cleft palate, and SOD aligns with the clinical features of Fryns syndrome [7,10,13]. The infant’s presentation in this case was consistent with this rare disorder, highlighting the importance of considering syndromic associations in complex neonatal cases.

A clinical diagnosis of Fryns syndrome can be made in a proband meeting six proposed criteria: (a) diaphragmatic anomalies, (b) characteristic facial features, (c) distal digital hypoplasia, (d) pulmonary hypoplasia, (e) at least one associated anomaly (eg, cleft palate, corpus callosum agenesis, or SOD), and (f) a family history suggestive of autosomal recessive inheritance. In our patient, five of these six criteria were met, with the exception of marked distal phalangeal hypoplasia. Although pulmonary hypoplasia was mild and resolved rapidly, the remaining clinical findings aligned closely with the classic diagnostic features of Fryns syndrome.

More than 90% of Fryns syndrome cases present with CDH, while approximately 10% of CDH patients are diagnosed with Fryns syndrome [[19], [20]], Our case represents an atypical presentation due to the presence of CDE rather than CDH [21]. Molecular diagnosis can be confirmed through identification of biallelic pathogenic variants in PIGN via molecular genetic testing in probands with suggestive clinical findings [[22], [23]]. In this case, comprehensive genetic analysis could not be performed due to non-medical constraints, representing a limitation of our study. While no affected siblings were identified in the family history, parental consanguinity was present. It should be noted that the absence of a known family history does not exclude the diagnosis, as Fryns syndrome can occur sporadically or through autosomal recessive inheritance.

The distinction between CDH and CDE carries significant clinical implications due to substantial differences in postnatal management and prognosis. While all neonates with CDH require surgical intervention, most CDE cases are managed conservatively with supportive care, reserving surgical plication only for severe cases [3]. Although diagnostically challenging, accurate identification of CDE is critical for proper clinical decision-making. In our patient, timely MRI diagnosis prevented unnecessary emergency surgery that was initially considered due to suspected gastric volvulus. Such precise differentiation is particularly important as delayed or incorrect diagnosis in severe cases may lead to chronic respiratory complications or inappropriate interventions.

Conclusion

CDE presents significant diagnostic challenges, particularly in critically ill neonates where differentiation from CDH is crucial yet difficult. This case highlights the importance of multimodal imaging for accurate diagnosis and appropriate management, especially when CDE occurs with complex congenital anomalies like Fryns syndrome. Timely recognition prevented unnecessary surgical intervention in our patient while enabling proper respiratory support.

The case underscores that CDE should be considered in all neonates with unexplained respiratory distress and lower lobe opacity on imaging. Such rare presentations provide valuable insights for improving neonatal care, emphasizing the need for thorough evaluation to avoid delayed diagnosis and optimize outcomes. Early differentiation from CDH and other conditions remains essential for guiding treatment decisions in these complex cases.

Data availability statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval statement

This study was conducted in Sancaktepe Prof.Dr.Ilhan Varank Training and Research Hospital and the ethical approval was waived for case reports by the policies of the hospital.

Statement of adherence to preprint policy

The authours declare that this paper has not been published as a preprint or in any other form elsewhere.

Patient consent

Written informed consent was obtained from the participants prior to inclusion in the study.

Publication consent

Written informed consent was obtained from the participant for the publication of identifying information images in this online open-access publication.