Meckel Gruber syndrome associated with anencephaly—an unusual reported case

Meckel Gruber syndrome associated with anencephaly—an unusual reported case Meckel–Gruber syndrome (MGS) is a rare and lethal ciliopathic disorder, with the incidence ranging between 1 in 13 000–400 000 live births. MGS is characterized by multisystem developmental malformations with the classical features of renal cystic dysplasia, occipital encephalocele and post-axial polydactyly. Except for occipital encephalocele, the CNS abnormalities associated with MGS that are less frequently reported include hydrocephaly, anencephaly or malformation of cerebellum. Our presented case of MGS is associated with anencephaly and other facial abnormalities. This kind of ailment is infrequently reported in literature. INTRODUCTION CASE REPORT Meckel–Gruber syndrome (MGS) is a rare and lethal ciliopathic A 40-year-old grand multiparous woman gravida 9 para 8 was disorder, with the incidence ranging between 1 in 13 000–400 000 referred to our hospital at 24 weeks of gestation for a detailed live births. It is a congenital autosomal recessive condition and anatomy scan because of a foetus with bilateral enlarged cystic carries a 25% risk of recurrence in each pregnancy [1,2]. kidneys, oligohydramnios, and microcephaly. Her obstetric his- MGS is characterized by multisystem developmental malfor- tory revealed that she had given birth to seven healthy babies mations with the classical features of renal cystic dysplasia, in her previous pregnancies, but the last pregnancy had history occipital encephalocele and post-axial polydactyly. The criteria of early neonatal death due to suspected MGS (bilateral dys- for the diagnosis of MGS is the presence of at least two of the plastic kidney, anencephaly, cleft lip and palate, occipital ence- three classic features such as dysplastic cystic kidney, occipital phalocele). She has history of a first degree consanguineous encephalocele and polydactyly, which are commonly observed marriage. Our antenatal ultrasonographic scan revealed multi- with the frequency of 100, 90 and 83.5% respectively [3,4]. cystic dysplastic kidneys (Fig. 1), absence of bladder, marked Except for occipital encephalocele, the CNS abnormalities oligohydramnios, anencephaly and occipital encephalocele. associated with MGS that are less frequently reported include The patient was counselled in detail regarding the poor foetal hydrocephaly, anencephaly or malformation of cerebellum. prognosis. A termination of the pregnancy was not offered as Our presented case of MGS is associated with anencephaly and an option because of cultural and religious constraints. other facial abnormalities. This kind of ailment is infrequently At 30.2 weeks of gestation, she experienced labour pains. reported in literature [5]. Five hours after admission, she had a spontaneous vaginal Received: September 17, 2017. Revised: November 8, 2017. Accepted: November 16, 2017 © The Author 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx092/4846368 by Ed 'DeepDyve' Gillespie user on 16 March 2018 46 H.N.A. Yaqoubi and N. Fatema Figure 3: Occipital encephalocele. Figure 1: Ultrasound image shows bilateral dysplastic cystic kidneys. Figure 4: Distended abdomen due to bilateral renal mass. Figure 2: New-born with anencephaly, cleft lip, upper slanting of eyes. Previous studies state that 57% of MGS cases had the three cardinal features, 16% had only polycystic kidney and polydac- tyly, and the rest exhibited other variations [7]. delivery of a male foetus with an Apgar score of 1 in 1 min and The phenotypic variability of MGS might be due to several 1 in 5 min and a weight of 2.4 kg. The new-born was examined gene mutations. Genetic mapping of the syndrome is still by our neonatologist, and the external examination revealed incomplete, and the most frequently responsible genes are anencephaly (Fig. 2) with head circumference 25.5 cm, occipital MKS1 on chromosome 17, MKS2 on 11 and MKS3 on 8 [1,6,8]. encephalocele (Fig. 3), cleft lip and cleft palate (Fig. 2), upper Commonly encountered CNS abnormalities associated slanting of eyes (Fig. 2), low set ears, huge distended abdomen with MGS previously reported in the literature include due to bilateral renal mass (Fig. 4), flexion of both wrist joint occipital encephalocele, microcephaly, Dandy–Walker mal- and post-axial hexadactyly on both feet. We kept the new-born formation and holoprosencephaly [6]. The less frequently under human care after counselling the parents. Approxi- reported CNS anomalies of MGS include anencephaly and mately 1 h after delivery, the baby expired. hydrocephaly [5]. A diagnosis of MGS was suggested, based on the presence of In a recent population-based study of MGS, it was found the classical features. The patient denied consent for a genetic that among 173 cases of MGS, only 3.5% cases were associated analysis and autopsy of the infant. with anencephaly. In another study of 67 cases of MGS, only one case was found with anencephaly [3,5]. DISCUSSION In our case, we found the foetus with anencephaly along MGS is a lethal syndrome, causing anomalies of the central ner- with other cardinal features of MGS. vous system (CNS), cystic dysplasia of the kidneys, and malfor- The differential diagnosis of MGS includes trisomy 13, trisomy 18, Joubert syndrome, Bardet–Biedl syndrome and Smith–Lemli– mations of the extremities. Other anomalies associated with MGS areintrauterinegrowthretardation (IUGR),singleumbilicalartery, Opitz syndrome [4]. Trisomy 13 is the most likely syndrome to be cardiovascular defects, cleft palate, several genital abnormalities, confused with MGS. Enlarged kidneys, severe oligohydramnios and oligohydramnios and hepatic periportal fibrosis [6]. and the presence of an occipital cephalocele favours the diagnosis Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx092/4846368 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Meckel Gruber syndrome 47 of MGS, whereas holoprosencephaly or other midline CNS anom- REFERENCES alies favors trisomy 13 [9]. 1. Yuksel MA, Mammadov Z, Sofiyeva N, Alici Davutoglu E, MGS is best diagnosed prenatally by ultrasonography early Temel Yuksel I, Madazli R. An unusual case of Meckel– in the second trimester. No specific biochemical and chromo- Gruber syndrome (MKS) associated with visceroatrial het- somal studies indicate the presence of the MGS. Therefore, the erotaxy and facial anomalies. J Obstet Gynaecol (Lahore) prenatal ultrasonography detection of MGS is important for the [Internet] 2016;36:524–5. http://www.tandfonline.com/doi/ diagnosis, which can be confirmed later by genetic analysis and full/10.3109/01443615.2015.1110123. careful post-mortem examination to establish the diagnosis. 2. Vernekar JA, Mishra G, Pinto R, Bhandari M, Mishra M. Clinical diagnosis is suggested on the basis of the presence of Antenatal ultrasonic diagnosis of Meckel Gruber syndrome classical clinical features and when the syndrome recurs in (a case report with review of literature). Australas Radiol subsequent pregnancies [2,9]. [Internet] 1991;35:186–8. http://doi.wiley.com/10.1111/j.1440- Although in our case, genetic analysis and post-mortem 1673.1991.tb02864.x. examination were not performed, prenatal USG findings, the 3. Barisic I, Boban L, Loane M, Garne E, Wellesley D, Calzolari presence of cardinal features and history of recurrence of simi- E, et al. Meckel–Gruber syndrome: a population-based study lar anomalies that were clinically felt to represent MGS were on prevalence, prenatal diagnosis, clinical features, and used to establish the diagnosis. survival in Europe. Eur J Hum Genet [Internet] 2015;23:746–52. MGS is inherited in an autosomal recessive manner so, the http://www.ncbi.nlm.nih.gov/pubmed/25182137. chance of giving birth to another child with MGS is 1 in 4 (25%) 4. Jeevika M, Reddy TA, Kumar KA, Konareddy R. Meckel for each pregnancy [1,10]. Gruber syndrome—a case report. IOSR J Dent Med Sci Ver III MGS is a fatal disorder resulting in intrauterine or early neo- [Internet] 2016;15:2279–861. www.iosrjournals.org. natal death, thus prenatal diagnosis is important for the counsel- 5. Salonen R, Opitz JM, Reynolds JF. The Meckel syndrome: ling of the parents regarding the poor foetal prognosis and to clinicopathological findings in 67 patients. Am J Med Genet explain the chances of recurrence in subsequent pregnancies [2]. [Internet] 1984;18:671–89. http://doi.wiley.com/10.1002/ajmg. ACKNOWLEDGEMENTS 6. Nergiz S, Sezer SD, Altınkaya SÖ, Küçük M, Yüksel H. Meckel Gruber syndrome—a case report and review of lit- None. erature. Gynecol Obstet Reprod Med [Internet] 2016;20. http:// gorm.com.tr/index.php/GORM/article/view/169/106. CONFLICT OF INTEREST STATEMENT 7. Gupta M, Mehta A, Gupta R, Gupta R, Singh S. Prenatal diag- None declared. nosis of Meckel-Gruber syndrome with Dandy Walker mal- formation. JK Sci J Med Educ Res 2005;7:164–6. https://www. jkscience.org/archive/Volume73/prenatal.pdf. ETHICAL APPROVAL 8. Itchimouh S, Khabtou K, Mahdaoui S, Boufettal H, Samouh Not applicable. N. Syndrome de Meckel Gruber: à propos d’un cas rare. Pan Afr Med J [Internet] 2016;25:43. http://www.panafrican-med- CONSENT journal.com/content/article/25/43/full/. 9. Nyberg DA, Hallesy D, Mahony BS, Hirsch JH, Luthy DA, Informed written consent was taken from the patient. Hickok D. Meckel-Gruber syndrome. Importance of prenatal diagnosis. J Ultrasound Med [Internet] 1990;9:691–6. http:// GUARANTOR www.ncbi.nlm.nih.gov/pubmed/2277397. Principal investigator. 10. https://ghr.nlm.nih.gov/condition/meckel-syndrome#inheritance. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx092/4846368 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Oxford Medical Case Reports Oxford University Press

Meckel Gruber syndrome associated with anencephaly—an unusual reported case

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Abstract

Meckel–Gruber syndrome (MGS) is a rare and lethal ciliopathic disorder, with the incidence ranging between 1 in 13 000–400 000 live births. MGS is characterized by multisystem developmental malformations with the classical features of renal cystic dysplasia, occipital encephalocele and post-axial polydactyly. Except for occipital encephalocele, the CNS abnormalities associated with MGS that are less frequently reported include hydrocephaly, anencephaly or malformation of cerebellum. Our presented case of MGS is associated with anencephaly and other facial abnormalities. This kind of ailment is infrequently reported in literature. INTRODUCTION CASE REPORT Meckel–Gruber syndrome (MGS) is a rare and lethal ciliopathic A 40-year-old grand multiparous woman gravida 9 para 8 was disorder, with the incidence ranging between 1 in 13 000–400 000 referred to our hospital at 24 weeks of gestation for a detailed live births. It is a congenital autosomal recessive condition and anatomy scan because of a foetus with bilateral enlarged cystic carries a 25% risk of recurrence in each pregnancy [1,2]. kidneys, oligohydramnios, and microcephaly. Her obstetric his- MGS is characterized by multisystem developmental malfor- tory revealed that she had given birth to seven healthy babies mations with the classical features of renal cystic dysplasia, in her previous pregnancies, but the last pregnancy had history occipital encephalocele and post-axial polydactyly. The criteria of early neonatal death due to suspected MGS (bilateral dys- for the diagnosis of MGS is the presence of at least two of the plastic kidney, anencephaly, cleft lip and palate, occipital ence- three classic features such as dysplastic cystic kidney, occipital phalocele). She has history of a first degree consanguineous encephalocele and polydactyly, which are commonly observed marriage. Our antenatal ultrasonographic scan revealed multi- with the frequency of 100, 90 and 83.5% respectively [3,4]. cystic dysplastic kidneys (Fig. 1), absence of bladder, marked Except for occipital encephalocele, the CNS abnormalities oligohydramnios, anencephaly and occipital encephalocele. associated with MGS that are less frequently reported include The patient was counselled in detail regarding the poor foetal hydrocephaly, anencephaly or malformation of cerebellum. prognosis. A termination of the pregnancy was not offered as Our presented case of MGS is associated with anencephaly and an option because of cultural and religious constraints. other facial abnormalities. This kind of ailment is infrequently At 30.2 weeks of gestation, she experienced labour pains. reported in literature [5]. Five hours after admission, she had a spontaneous vaginal Received: September 17, 2017. Revised: November 8, 2017. Accepted: November 16, 2017 © The Author 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx092/4846368 by Ed 'DeepDyve' Gillespie user on 16 March 2018 46 H.N.A. Yaqoubi and N. Fatema Figure 3: Occipital encephalocele. Figure 1: Ultrasound image shows bilateral dysplastic cystic kidneys. Figure 4: Distended abdomen due to bilateral renal mass. Figure 2: New-born with anencephaly, cleft lip, upper slanting of eyes. Previous studies state that 57% of MGS cases had the three cardinal features, 16% had only polycystic kidney and polydac- tyly, and the rest exhibited other variations [7]. delivery of a male foetus with an Apgar score of 1 in 1 min and The phenotypic variability of MGS might be due to several 1 in 5 min and a weight of 2.4 kg. The new-born was examined gene mutations. Genetic mapping of the syndrome is still by our neonatologist, and the external examination revealed incomplete, and the most frequently responsible genes are anencephaly (Fig. 2) with head circumference 25.5 cm, occipital MKS1 on chromosome 17, MKS2 on 11 and MKS3 on 8 [1,6,8]. encephalocele (Fig. 3), cleft lip and cleft palate (Fig. 2), upper Commonly encountered CNS abnormalities associated slanting of eyes (Fig. 2), low set ears, huge distended abdomen with MGS previously reported in the literature include due to bilateral renal mass (Fig. 4), flexion of both wrist joint occipital encephalocele, microcephaly, Dandy–Walker mal- and post-axial hexadactyly on both feet. We kept the new-born formation and holoprosencephaly [6]. The less frequently under human care after counselling the parents. Approxi- reported CNS anomalies of MGS include anencephaly and mately 1 h after delivery, the baby expired. hydrocephaly [5]. A diagnosis of MGS was suggested, based on the presence of In a recent population-based study of MGS, it was found the classical features. The patient denied consent for a genetic that among 173 cases of MGS, only 3.5% cases were associated analysis and autopsy of the infant. with anencephaly. In another study of 67 cases of MGS, only one case was found with anencephaly [3,5]. DISCUSSION In our case, we found the foetus with anencephaly along MGS is a lethal syndrome, causing anomalies of the central ner- with other cardinal features of MGS. vous system (CNS), cystic dysplasia of the kidneys, and malfor- The differential diagnosis of MGS includes trisomy 13, trisomy 18, Joubert syndrome, Bardet–Biedl syndrome and Smith–Lemli– mations of the extremities. Other anomalies associated with MGS areintrauterinegrowthretardation (IUGR),singleumbilicalartery, Opitz syndrome [4]. Trisomy 13 is the most likely syndrome to be cardiovascular defects, cleft palate, several genital abnormalities, confused with MGS. Enlarged kidneys, severe oligohydramnios and oligohydramnios and hepatic periportal fibrosis [6]. and the presence of an occipital cephalocele favours the diagnosis Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx092/4846368 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Meckel Gruber syndrome 47 of MGS, whereas holoprosencephaly or other midline CNS anom- REFERENCES alies favors trisomy 13 [9]. 1. Yuksel MA, Mammadov Z, Sofiyeva N, Alici Davutoglu E, MGS is best diagnosed prenatally by ultrasonography early Temel Yuksel I, Madazli R. An unusual case of Meckel– in the second trimester. No specific biochemical and chromo- Gruber syndrome (MKS) associated with visceroatrial het- somal studies indicate the presence of the MGS. Therefore, the erotaxy and facial anomalies. J Obstet Gynaecol (Lahore) prenatal ultrasonography detection of MGS is important for the [Internet] 2016;36:524–5. http://www.tandfonline.com/doi/ diagnosis, which can be confirmed later by genetic analysis and full/10.3109/01443615.2015.1110123. careful post-mortem examination to establish the diagnosis. 2. Vernekar JA, Mishra G, Pinto R, Bhandari M, Mishra M. Clinical diagnosis is suggested on the basis of the presence of Antenatal ultrasonic diagnosis of Meckel Gruber syndrome classical clinical features and when the syndrome recurs in (a case report with review of literature). Australas Radiol subsequent pregnancies [2,9]. [Internet] 1991;35:186–8. http://doi.wiley.com/10.1111/j.1440- Although in our case, genetic analysis and post-mortem 1673.1991.tb02864.x. examination were not performed, prenatal USG findings, the 3. Barisic I, Boban L, Loane M, Garne E, Wellesley D, Calzolari presence of cardinal features and history of recurrence of simi- E, et al. Meckel–Gruber syndrome: a population-based study lar anomalies that were clinically felt to represent MGS were on prevalence, prenatal diagnosis, clinical features, and used to establish the diagnosis. survival in Europe. Eur J Hum Genet [Internet] 2015;23:746–52. MGS is inherited in an autosomal recessive manner so, the http://www.ncbi.nlm.nih.gov/pubmed/25182137. chance of giving birth to another child with MGS is 1 in 4 (25%) 4. Jeevika M, Reddy TA, Kumar KA, Konareddy R. Meckel for each pregnancy [1,10]. Gruber syndrome—a case report. IOSR J Dent Med Sci Ver III MGS is a fatal disorder resulting in intrauterine or early neo- [Internet] 2016;15:2279–861. www.iosrjournals.org. natal death, thus prenatal diagnosis is important for the counsel- 5. Salonen R, Opitz JM, Reynolds JF. The Meckel syndrome: ling of the parents regarding the poor foetal prognosis and to clinicopathological findings in 67 patients. Am J Med Genet explain the chances of recurrence in subsequent pregnancies [2]. [Internet] 1984;18:671–89. http://doi.wiley.com/10.1002/ajmg. ACKNOWLEDGEMENTS 6. Nergiz S, Sezer SD, Altınkaya SÖ, Küçük M, Yüksel H. Meckel Gruber syndrome—a case report and review of lit- None. erature. Gynecol Obstet Reprod Med [Internet] 2016;20. http:// gorm.com.tr/index.php/GORM/article/view/169/106. CONFLICT OF INTEREST STATEMENT 7. Gupta M, Mehta A, Gupta R, Gupta R, Singh S. Prenatal diag- None declared. nosis of Meckel-Gruber syndrome with Dandy Walker mal- formation. JK Sci J Med Educ Res 2005;7:164–6. https://www. jkscience.org/archive/Volume73/prenatal.pdf. ETHICAL APPROVAL 8. Itchimouh S, Khabtou K, Mahdaoui S, Boufettal H, Samouh Not applicable. N. Syndrome de Meckel Gruber: à propos d’un cas rare. Pan Afr Med J [Internet] 2016;25:43. http://www.panafrican-med- CONSENT journal.com/content/article/25/43/full/. 9. Nyberg DA, Hallesy D, Mahony BS, Hirsch JH, Luthy DA, Informed written consent was taken from the patient. Hickok D. Meckel-Gruber syndrome. Importance of prenatal diagnosis. J Ultrasound Med [Internet] 1990;9:691–6. http:// GUARANTOR www.ncbi.nlm.nih.gov/pubmed/2277397. Principal investigator. 10. https://ghr.nlm.nih.gov/condition/meckel-syndrome#inheritance. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/2/omx092/4846368 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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Published: Feb 1, 2018

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