Meckel-Gruber Syndrome 

  • Author: Parul Bhagwati Jayakar, MD, FACMG; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Sep 22, 2011
 

Background

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 6 different loci in chromosomes 17q21-24 (MKS1), 11q13 (MKS2), 8q21.3-q22.1 (MKS3),[1] 12q21.31-q21.33 (MKS4),[2] 16q12.2 (MKS5),[3] and 4p15.3 (MKS6).[4] . This mapping suggests genetic heterogeneity in Meckel-Gruber syndrome. More than 200 cases have been reported.

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.

Next

Pathophysiology

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. B9d1 and B9d2 are essential components of a B9 protein complex and, when this is disrupted, Meckel syndrome results.[5]

Previous
Next

Epidemiology

Frequency

International

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). 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.

Mortality/Morbidity

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.

Race

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

Sex

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

Previous
Proceed to Clinical Presentation
 
 
Contributor Information and Disclosures
Author

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

Disclosure: Nothing to disclose.

Coauthor(s)

Michail Spiliopoulos, MD  Fellow, Department of Medical Genetics, Jackson Memorial Hospital, University of Miami, Leonard M Miller School of Medicine

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

Disclosure: Nothing to disclose.

Anuj Jayakar  Georgetown University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Disclosure: Nothing to disclose.

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, New York

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

Disclosure: Genzyme Grant/research funds PI

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

Additional Contributors

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.

References

  1. Smith UM, Consugar M, Tee LJ, McKee BM, Maina EN, Whelan S. The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat Genet. Feb 2006;38(2):191-6. [Medline].

  2. Baala L, Audollent S, Martinovic J, Ozilou C, Babron MC, Sivanandamoorthy S. Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome. Am J Hum Genet. Jul 2007;81(1):170-9. [Medline].

  3. Delous M, Baala L, Salomon R, Laclef C, Vierkotten J, Tory K. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet. Jul 2007;39(7):875-81. [Medline].

  4. Tallila J, Jakkula E, Peltonen L, Salonen R, Kestila M. Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle. Am J Hum Genet. Jun 2008;82(6):1361-7. [Medline].

  5. Dowdle WE, Robinson JF, Kneist A, et al. Disruption of a ciliary B9 protein complex causes Meckel syndrome. Am J Hum Genet. Jul 15 2011;89(1):94-110. [Medline]. [Full Text].

  6. Wright C, Healicon R, English C, Burn J. Meckel syndrome: what are the minimum diagnostic criteria?. J Med Genet. Jun 1994;31(6):482-5. [Medline].

  7. Salonen R, Norio R. The Meckel syndrome in Finland: epidemiologic and genetic aspects. Am J Med Genet. Aug 1984;18(4):691-8. [Medline].

  8. Salonen R. The Meckel syndrome: clinicopathological findings in 67 patients. Am J Med Genet. Aug 1984;18(4):671-89. [Medline].

  9. Badano JL, Mitsuma N, Beales PL, Katsanis N. The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet. 2006;7:125-48. [Medline].

  10. Paavola P, Salonen R, Weissenbach J. The locus for Meckel syndrome with multiple congenital anomalies maps to chromosome 17q21-q24. Nat Genet. Oct 1995;11(2):213-5. [Medline].

  11. Morgan NV, Gissen P, Sharif SM, Baumber L, Sutherland J, Kelly DA. A novel locus for Meckel-Gruber syndrome, MKS3, maps to chromosome 8q24. Hum Genet. Oct 2002;111(4-5):456-61. [Medline].

  12. Consugar MB, Kubly VJ, Lager DJ, Hommerding CJ, Wong WC, Bakker E. Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3. Hum Genet. Jun 2007;121(5):591-9. [Medline].

  13. Frank V, den Hollander AI, Bruchle NO, Zonneveld MN, Nurnberg G, Becker C. Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome. Hum Mutat. Jan 2008;29(1):45-52. [Medline].

  14. Behairy NH, Talaat S, Saleem SN, El-Raouf MA. Magnetic resonance imaging in fetal anomalies: What does it add to 3D and 4D US?. Eur J Radiol. Mar 24 2009;[Medline].

  15. Ahdab-Barmada M, Claassen D. A distinctive triad of malformations of the central nervous system in the Meckel-Gruber syndrome. J Neuropathol Exp Neurol. Nov 1990;49(6):610-20. [Medline].

  16. Alexiev BA, Lin X, Sun CC. Meckel-Gruber syndrome: pathologic manifestations, minimal diagnostic criteria, and differential diagnosis. Arch Pathol Lab Med. Aug 2006;130(8):1236-8. [Medline].

  17. Blankenberg TA, Ruebner BH, Ellis WG. Pathology of renal and hepatic anomalies in Meckel syndrome. Am J Med Gen. 1987;3:395-410. [Medline].

  18. Farag TI, Usha R, Uma R. - Usha R. Clin Genet. Sep 1990;38(3):176-9. [Medline].

  19. Herman TE, Siegel MJ. Special imaging casebook. Meckel-Gruber syndrome. J Perinatol. Mar-Apr 1996;16(2 Pt 1):144-6. [Medline].

  20. Johnson CA, Gissen P, Sergi C. Molecular pathology and genetics of congenital hepatorenal fibrocystic syndromes. J Med Genet. May 2003;40(5):311-9. [Medline].

  21. Liu SS, Cheong ML, She BQ, Tsai MS. First-trimester ultrasound diagnosis of Meckel-Gruber syndrome. Acta Obstet Gynecol Scand. 2006;85(6):757-9. [Medline].

  22. Loo CK, Freeman B, Killingsworth M, Wu XJ. An immunohistochemical study of human fetal liver in the Meckel-Gruber syndrome. Pathology. Apr 2005;37(2):137-43. [Medline].

  23. Mittermayer C, Lee A, Brugger PC. Prenatal diagnosis of the Meckel-Gruber syndrome from 11th to 20th gestational week. Ultraschall Med. Aug 2004;25(4):275-9. [Medline].

  24. Miyazu M, Sobue K, Ito H. Anesthetic and airway management of general anesthesia in a patient with Meckel-Gruber syndrome. J Anesth. 2005;19(4):309-10. [Medline].

  25. Morgan NV, Gissen P, Sharif SM. A novel locus for Meckel-Gruber syndrome, MKS3, maps to chromosome 8q24. Hum Genet. Oct 2002;111(4-5):456-61. [Medline].

  26. Nyberg DA, Hallesy D, Mahony BS. Meckel-Gruber syndrome. Importance of prenatal diagnosis. J Ultrasound Med. Dec 1990;9(12):691-6. [Medline].

  27. Paavola P, Avela K, Horelli-Kuitunen N. High-resolution physical and genetic mapping of the critical region for Meckel syndrome and Mulibrey Nanism on chromosome 17q22-q23. Genome Res. Mar 1999;9(3):267-76. [Medline].

  28. Paavola P, Salonen R, Baumer A. Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet. Nov 1997;101(1):88-92. [Medline].

  29. Roume J, Genin E, Cormier-Daire V. A gene for Meckel syndrome maps to chromosome 11q13. Am J Hum Genet. Oct 1998;63(4):1095-101. [Medline].

  30. Salonen R. The Meckel syndrome: clinicopathological findings in 67 patients. Am J Med Genet. Aug 1984;18(4):671-89. [Medline].

  31. Sepulveda W, Sebire NJ, Souka A, Snijders RJ, Nicolaides KH. Diagnosis of the Meckel-Gruber syndrome at eleven to fourteen weeks' gestation. Am J Obstet Gynecol. Feb 1997;176(2):316-9. [Medline].

  32. Yapar EG, Ekici E, Dogan M. Meckel-Gruber syndrome concomitant with Dandy-Walker malformation: prenatal sonographic diagnosis in two cases. Clin Dysmorphol. Oct 1996;5(4):357-62. [Medline].

 
Previous
Next
 
Table. Chromosomal Markers for Meckel Gruber Syndrome
Protein NameLocus NameGeneChromosomal Locus
Meckel syndrome type 1 proteinMKS1MKS117q23
...MKS2...11q13
MeckelinMKS3TMEM678q21.1-q22.1
...MKS4CEP29012q21.3
Protein fantomMKS5RPGRIP1L16q12.2
Coiled-coil and C2 domain-containing protein 2AMKS6CC2D2a4p15.3
Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.