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Meckel-Gruber Syndrome

  • Author: Parul Bhagwati Jayakar, MD, MS, FACMG; Chief Editor: Luis O Rohena, MD  more...
Updated: Aug 19, 2015


The first reports of Meckel-Gruber syndrome (MKS) were published in 1822 by Johann Friedrich Meckel. G.B. Gruber also published reports of patients with Meckel-Gruber syndrome in 1934 and gave it the name dysencephalia splanchnocystica. Meckel-Gruber syndrome is also known as Meckel syndrome and Gruber syndrome.

Meckel-Gruber syndrome (OMIM 24900) is a lethal, rare, autosomal recessive condition mapped to 12 different loci in chromosomes 17q21-24 (MKS1), 11q13 (MKS2), 8q21.3-q22.1 (MKS3),[1, 2] 12q21.31-q21.33 (MKS4),[3] 16q12.2 (MKS5),[4] 4p15.3 (MKS6),[5] 3q22.1 (MKS7),[6] 12q24.31 (MKS8),[7] 17p11.2 (MKS9),[8] 19q13.2 (MKS10),[9] 16q23.1 (MKS11),[10] and 1q32.1 (MKS12).[11] This mapping suggests genetic heterogeneity in Meckel-Gruber syndrome.

The triad of occipital encephalocele, large polycystic kidneys, and postaxial polydactyly characterizes Meckel-Gruber syndrome. Associated abnormalities include oral clefting; genital anomalies; CNS malformations, including Dandy-Walker and Arnold-Chiari malformation; and liver fibrosis. Pulmonary hypoplasia is the leading cause of death. Improvements in ultrasonography have enabled prenatal diagnosis as early as 10 weeks' gestation.

A study by Barisic et al, using data from 191 cases of Meckel-Gruber syndrome, as accessed through the European Surveillance of Congenital Anomalies (EUROCAT) network, found the prevalence of various characteristics of the disease to be as follows[12] :

  • Cystic kidneys (97.7%)
  • Polydactyly (87.3%)
  • Encephalocele (83.8%)
  • Fibrotic/cystic changes of the liver (65.5%, as identified via postmortem examination)
  • Other CNS anomalies (51.4%)
  • Orofacial clefts (31.8%)


Failure of mesodermal induction has been suggested to cause Meckel-Gruber syndrome. The induction cascades of early morphogenesis involve numerous growth factors, homeobox genes, and paired domain genes.

One study screened patients with Meckel syndrome for mutations in B9D1 and B9D2 and identified homozygous c.301A>C (p.Ser101Arg) B9D2 mutation. The data showed that the domain-containing proteins Mks1, B9d1, and B9d2 interact physically; the p.Ser101Arg mutation abrogates the ability of B9d2 to interact with Mks1, which suggests that this mutation compromised B9d2 function. The data further show that B9d1 is required for normal Hedgehog (Hh) signaling, ciliogenesis, and ciliary protein localization.[13] B9d1 and B9d2 are essential components of a B9 protein complex and, when this is disrupted, Meckel syndrome results.[14]





Worldwide, the incidence of Meckel-Gruber syndrome is 1 per 13,250-140,000 live births. Individuals of Finnish descent have a higher incidence (1 per 9000 live births, one person in 50 is a carrier). The incidence is also higher among Belgians and Bedouins in Kuwait, with 1 affected birth in 3,500 (carrier rate 1 in 30). The highest incidence is reported in the Gujarati Indians, with 1 affected birth per 1,300 (carrier rate, 1 in 18).[15, 16] The incidence among Jews in Israel is 1 in 50,000 (carrier rate, 1 in 112). Cases of Meckel-Gruber syndrome have been reported in North America, Europe, Israel, Indonesia, India, Kuwait, and Japan.


Oligohydramnios that results from dysplastic kidneys leads to fetal pulmonary hypoplasia. Because the prognosis is grim, with death occurring in utero or shortly after birth, prenatal diagnosis has led to therapeutic abortion of many affected fetuses. The mortality rate is 100% with most fetuses surviving only a few days to weeks.


Although individuals of Finnish descent have the highest birth incidence, Meckel-Gruber syndrome affects all racial and ethnic backgrounds.


The male-to-female ratio is nearly equal, which is consistent with autosomal recessive inheritance.

Contributor Information and Disclosures

Parul Bhagwati Jayakar, MD, MS, FACMG Director of Neurogenetics/Metabolic Program, Director of Cytogenetics Laboratory, Consultant in Clinical Genetics, Division of Genetics and Metabolism, Miami Children's Hospital; Assistant Professor, Genetics Residency Program Director, University of Miami, Leonard M Miller School of Medicine

Parul Bhagwati Jayakar, MD, MS, FACMG is a member of the following medical societies: American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.


Michail Spiliopoulos, MD Clinical Assistant Professor, Department of Obstetrics, Gynecology, and Reproductive Sciences, Temple University Hospital

Michail Spiliopoulos, MD is a member of the following medical societies: American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists

Disclosure: Nothing to disclose.

Anuj Jayakar Georgetown University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University School of Medicine

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD Chief, Medical Genetics, San Antonio Military Medical Center; Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Assistant Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

Christian J Renner, MD Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany

Disclosure: Nothing to disclose.


The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Suzanne M Carter, MS, and Susan J Gross, MD, FRCS(C), FACOG, FACMG, to the original writing and development of this article.

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Table. Chromosomal Markers for Meckel Gruber Syndrome
Protein Name Locus Name Gene Chromosomal Locus
Meckel syndrome type 1 protein MKS1 MKS1 17q23
... MKS2 TMEM216 11q13
Meckelin MKS3 TMEM67 8q21.1-q22.1
... MKS4 CEP290 12q21.3
Protein fantom MKS5 RPGRIP1L 16q12.2
Coiled-coil and C2 domain-containing protein 2A MKS6 CC2D2a 4p15.3
... MKS7 NPHP3 3q22.1
... MKS8 TCTN2 12q24.31
... MKS9 B9D1 17p11.2
... MKS10 B9D2 19q13.2
... MKS11 TMEM231 16q23.1
... MKS12 KIF14 1q32.1
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