Meckel-Gruber syndrome together with Dandy–Walker malformation; an atypical case report of a 2nd recurrence in a consanguine marriage

doi:10.21203/rs.3.rs-3143445/v1

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Case Report

Meckel-Gruber syndrome together with Dandy–Walker malformation; an atypical case report of a 2nd recurrence in a consanguine marriage

https://doi.org/10.21203/rs.3.rs-3143445/v1

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published 02 Aug, 2023

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Meckel-Gruber syndrome is a lethal disorder characterized by occipital encephalocele, polycystic kidneys, and polydactyly. In most cases, it is identified and terminated antenatally. In this report, the authors present a case of Meckel-Gruber syndrome together with Dandy-Walker malformation. A pregnant woman referred at the 28th week of gestation with an abnormal ultrasound scan showing posterior encephalocele and bilaterally enlarged kidneys. Further imaging also indicated communication between the 4th ventricle and posterior cerebellar cerebrospinal fluid space, after which the fetus was diagnosed with Meckel Gruber syndrome and Dandy–Walker malformation. Pregnancy termination was refused by the parents and the offspring was prematurely born to be the 2nd recurrence of Meckel Gruber syndrome in this consanguine family. Remarkably, at the 3 different pregnancies, ultrasound was inconclusive before the 7th month of gestation. Though up to date Meckel-Gruber syndrome is ultimately lethal, the lifespan of affected newborns varied greatly. We suggest developing a severity classification to estimate life expectancy in unterminated cases.

Pediatric

Meckel-Gruber

Dandy&ndash

Walker

encephalocele

Congenital neurologic disorders

Meckel-Gruber syndrome (MKS) had been first reported by Johann Meckel in 1822 subsequent to observing two siblings who passed away shortly after their birth with distinctive characteristics including polydactyly, polycystic kidneys, and occipital encephalocele[1]. It is a fatal syndrome with mortality rate of 100%. As a result, most identified cases are terminated antenatally[2].

MKS is characterized by bilateral cystic kidneys, hepatic developmental deformities, and posterior fossa malformations, of which occipital encephalocele is the most frequent[3, 4]. Additionally, postaxial polydactyly is present in around 70–80% of cases and usually affect both feet and hands[5]. Occasional characteristics are present in 25–40% of cases and include malformations of the male genitalia, bowing of the long bones, anencephaly, microcephaly, pulmonary hypoplasia, cleft lip and palate, and congenital heart abnormalities[6, 7].

The degree of cyst formation in renal cystic dysplasia, the most common feature of MKS, varies between individuals. Nevertheless, the kidneys in most cases are grossly enlarged. Abnormal fetal renal function is also a potential cause of oligohydramnios and anhydramnios, which are common in a MKS pregnancy[8]. Diagnosis of MKS is usually done through antenatal ultrasonography (USG) in the late first trimester at which most cases are terminated. The authors hereby report a unique case of 31-year-old female with 2 recurrences of MKS.

A 31-year-old female G6P5A1L2 was referred from another health institute at 28th week of gestation after an abnormal USG result that reported posterior encephalocele, dilated posterior fossa and bilateral echogenic enlarged kidneys with loss of corticomedullary differentiation, as illustrated in Fig. 1a. She has taken 5mg folic acid at the beginning of the pregnancy and began to feel fetal movement by the 5th month. Her repeated ultrasound showed cerebellar vermis hypoplasia with communication between 4th ventricle and posterior cerebellar cerebrospinal fluid (CSF) space shown in Fig. 1b, bilateral enlarged kidney, and Dandy-Walker malformation (DWM) suspicion for post-natal scan. Based on the findings and past history of previous pregnancies, the fetus was diagnosed with MKS.

Syndrome lethality was explained well to the mother, and ethical approval was obtained from the court for termination. However, the mother decided to not terminate the pregnancy. Subsequently, the male baby was delivered at 35 + 6 week by cesarian section (CS) with an APGAR score of 6, 8 and 8 at 1, 5 and 10 minutes, respectively. The anthropometrics were: 2400 gm weight, 50 cm length, 35 cm head circumference, and 31 cm chest circumference. His vitals were: temperature (36°C), heart rate (156bpm), respiratory rate (54bpm), oxygen saturation (94%) and blood pressure (41/28 mmhg); neonatal infant pain scale was 3.

Neonatal examination was remarkable for mild hypotonia, 2cm*2cm occipital encephalocele, which is displayed in Fig. 2, and bilateral palpable kidneys. The newborn was dyspneic and tachypneic with notable chest retractions. Polydactyly, cleft lip, cleft palate, and genitalia malformations were not detected. His suckling was poor since birth, yet improved gradually till the orogastric tube was removed at 17th day of life. Due to pulmonary hypoplasia, the newborn developed respiratory distress syndrome directly after birth in the form of tachypnea and retractions, and he was admitted to the neonatal intensive care unit to be on nasal positive end-expiratory pressure (PEEP) of 5 cmH2O.

Favorably, he changed to nasal canula 7 days later and to room air 2 days before his discharge at 19th day of life, at which he became evidently stable and was subsequently discharged. The neonate came for follow up after a week and then after a month, and he was stable and gaining weight. Nevertheless, the encephalocele measured the same, and the mild hypotonia has not changed. Furthermore, the patient came for follow up at 3 months of age, with evident delayed milestones as he still does not follow moving objects.

Neonatal abdomen USG

Neonatal abdomen USG was also done in the newborn’s 2nd day of life. Normal size (5.3cm), margins, and echo pattern of the liver was noted with no focal lesions. Normal portal vein, common bile duct, gallbladder, pancreas and spleen were also indicated. Furthermore, bilateral adrenal glands show normal parenchymal echogenicity. Both kidneys are grossly enlarged and demonstrate increased parenchymal echogenicity with bilateral multiple regions of cystic changes; largest cyst was noted in the right kidney measuring 0.42cm*0.35cm with no evidence of ascites in the abdomen or the pelvis.

Neonatal head USG

Neonatal head USG in the newborn’s second day of life and found posterior cerebellar CSF cystic space communicating with the 4th ventricle, which is dilated as shown in Fig. 3a. The vermis is not identified and supposed to be hypoplastic, as manifested in Fig. 3b. The anterior and mid-body of corpus callosum are present. A cephalocele was noted at the occipital region with possible skull defect. Findings are consistent and suggestive of DWM along with occipital cephalocele.

Past Pregnancies

The mother stated that her husband was her first-degree cousin. Her 1st pregnancy was diagnosed with MKS by reports of similar findings at the 7th month of gestation. She had given birth by CS, and the baby was admitted directly after delivery to the neonatal intensive care unit to be on endotracheal intubation and nasogastric tube for 9 months, after which he died. The 2nd and 3rd pregnancies ended by CS of a healthy term male and female, respectively. The 4th pregnancy ended by spontaneous miscarriage without an obvious cause, and her 5th pregnancy was also diagnosed with MKS as the first pregnancy at the 7th month of gestation. According to patient, the USG was again unremarkable until the 7th month. Subsequently, a preterm newborn was delivered via CS in his 8th month of gestation, and he survived for only 2 hours before he died.

MKS is a lethal autosomal recessive disorder typically presents with the triad of bilateral cystic kidneys, central nervous system malformation, and polydactyly[1]. The presented case is the 2^nd recurrence of MKS in a family with consanguine marriage and one of the few cases reported in Saudi Arabia.

CNS malformations are considered to be a must in MKS including DWM, defects of corpus callosum, porencephalic dysgenesis, total craniorachischisis, and most commonly occipital encephalocele[4]. Distinctively, the newborn in the presented case was diagnosed with both DWM and occipital encephalocele, indicating a rare occurrence[9].

MKS is inherited by autosomal recessive pattern and have a 25% risk of recurrence if it has occurred in a previous pregnancy[8]. In our case, 3 out of 6 pregnancies were diagnosed with MKS, indicating very high recurrence rate. The estimated incidence of MKS varies widely from a worldwide rate of around (1 in 135,000 births) up to (1 in 3,500 births) in Saudi Arabian population[10]. Even though the incidence is high, very few cases of MKS were reported in Saudi Arabia. The elevated incidence rates in Arab populations have been tracked back to high rates of consanguineous marriages[2]. Thus, the 2 recurrences in the presented case may be explained by the consanguineous marriage of the parents.

As MKS is a lethal syndrome, efforts should be made to diagnose it early in the pregnancy to consider termination. At 10–14 weeks of gestation, USG is usually successful in detecting the triad of polycystic kidneys, polydactyly, and occipital encephalocele[11–13]. Two characteristics of the triad would strongly suggest the diagnosis of MKS[14,15]. Surprisingly, USG was inconclusive before the 7^th month of gestation at 3 different pregnancies in our case. Being operant-dependent, USG might not be the ideal modality to diagnose MKS, especially if other factors that compromise visualization such as obesity and oligohydramnios are present or the case presents with atypical features. Oligohydramnios is known to limit the visualization of MKS features, especially polydactyly, through prenatal ultrasound[16,17]. Thus, if USG is inconclusive in a known high-risk patient, MRI may be recommended as it offer clearer resolution and can better detect CNS malformations, but it is rarely indicated before the 18^th week of gestation[4]. Furthermore, DNA testing of mutations in the distinguished MKS genes often yield a definitive diagnosis[8]. However, it was not indicated in this case as the 2 previous pregnancies that displayed similar characteristics in the same family were diagnosed with MKS.

In a case series of 19 cases in Qatar, none of the live births diagnosed with MKS has survived beyond the 10^th day of life[2]. Several reports from literature have described cases surviving up to 7 and even 18 months[18]. Interestingly, an unusual case reported in 1992 have survived for 28 months[19]. In our reported case, the mother delivered three infants diagnosed by MKS. However, their prognosis varied greatly with the 1^st living for up to 9 months during which he was intubated and put-on feeding tube, the 2^nd surviving for only 2 hours, and the current discharged at his 19^th day of life with relatively favourable diagnosis as he is currently 3-month-10-day-old. Based on these findings, we would suggest developing a grading system of severity for fetuses diagnosed with MKS upon which life expectancy can be estimated in unterminated cases. Although up to date MKS is variably lethal, it would be beneficial for the parents and health care providers to anticipate the lifespan of affected newborns.

An elevated frequency of consanguineous marriages in some countries such as Saudi Arabia has raised the incidence of MKS and other lethal autosomal recessive diseases, calling for public awareness is essential to reduce the rates. In regard to the high recurrence rates of MKS in our case, future pregnancies should be properly followed up by first trimester USG scans, with an early resort to MRI if needed. If possible, preimplantation genetic diagnosis and in-vitro fertilization are also recommended to prevent further recurrences.

MKS is a lethal autosomal recessive disorder typically presents with the triad of bilateral cystic kidneys, central nervous system malformation, and polydactyly[1]. The presented case is the 2nd recurrence of MKS in a family with consanguine marriage and one of the few cases reported in Saudi Arabia.

As MKS is a lethal syndrome, efforts should be made to diagnose it early in the pregnancy to consider termination. At 10–14 weeks of gestation, USG is usually successful in detecting the triad of polycystic kidneys, polydactyly, and occipital encephalocele[11–13]. Two characteristics of the triad would strongly suggest the diagnosis of MKS[14, 15]. Surprisingly, USG was inconclusive before the 7th month of gestation at 3 different pregnancies in our case. Being operant-dependent, USG might not be the ideal modality to diagnose MKS, especially if other factors that compromise visualization such as obesity and oligohydramnios are present or the case presents with atypical features. Oligohydramnios is known to limit the visualization of MKS features, especially polydactyly, through prenatal ultrasound[16, 17]. Thus, if USG is inconclusive in a known high-risk patient, MRI may be recommended as it offer clearer resolution and can better detect CNS malformations, but it is rarely indicated before the 18th week of gestation[4]. Furthermore, DNA testing of mutations in the distinguished MKS genes often yield a definitive diagnosis[8]. However, it was not indicated in this case as the 2 previous pregnancies that displayed similar characteristics in the same family were diagnosed with MKS.

In a case series of 19 cases in Qatar, none of the live births diagnosed with MKS has survived beyond the 10th day of life[2]. Several reports from literature have described cases surviving up to 7 and even 18 months[18]. Interestingly, an unusual case reported in 1992 have survived for 28 months[19]. In our reported case, the mother delivered three infants diagnosed by MKS. However, their prognosis varied greatly with the 1st living for up to 9 months during which he was intubated and put-on feeding tube, the 2nd surviving for only 2 hours, and the current discharged at his 19th day of life with relatively favourable diagnosis as he is currently 3-month-10-day-old. Based on these findings, we would suggest developing a grading system of severity for fetuses diagnosed with MKS upon which life expectancy can be estimated in unterminated cases. Although up to date MKS is variably lethal, it would be beneficial for the parents and health care providers to anticipate the lifespan of affected newborns.

MKS

Meckel-Gruber syndrome

USG

ultrasonography

DWM

Dandy-Walker malformation

cesarian section

CSF

cerebrospinal fluid

CNS

central nervous system

PEEP

positive end-expiratory pressure

Acknowledgement: N/A

Research ethics and patient consent: Written informed consent for patient information and images to be published has been obtained from the patient’s guardian.

Consent for publication: Not applicable.

Declaration of Conflicting Interests: The authors declare no competing interests.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author Contributions: Ebtsam Abdulaziz Abdulghani conceived the original idea of this paper, collected the data, and edited and reviewed the manuscript draft. Mohamad S. Alsamal and Osama A. Zitoun reported the data, did literature review, and drafted and edited the manuscript draft. Idris Sula helpend in the final review and submission process. All authors approved the final version of the manuscript.

Data availability:

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

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No competing interests reported.

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Journal Publication

published 02 Aug, 2023

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Editorial decision: Accepted
23 Jul, 2023
Reviews received at journal
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Reviewers agreed at journal
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You are reading this latest preprint version

Meckel-Gruber syndrome together with Dandy–Walker malformation; an atypical case report of a 2nd recurrence in a consanguine marriage

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