eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Meckel-Gruber Syndrome

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
Coauthor(s): Michail Spiliopoulos, MD, Fellow, Department of Medical Genetics, Jackson Memorial Hospital, University of Miami, Leonard M Miller School of Medicine; Anuj Jayakar, Georgetown University School of Medicine
Contributor Information and Disclosures

Updated: Jan 11, 2010

Introduction

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.

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.

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.

Clinical

History

  • Fetal ultrasonography can be used to detect an occipital encephalocele and dysplastic kidneys in fetuses with Meckel-Gruber syndrome (MGS) if oligohydramnios is not present.
  • Newborns die shortly after birth from pulmonary hypoplasia. The most striking feature is an occipital encephalocele. Also, polydactyly is easily seen. Postmortem examination of the kidneys reveals marked cystic dysplasia.
  • Pregnancy history should be reviewed for stillbirths or early neonatal deaths with findings of polycystic kidneys, occipital encephalocele, and polydactyly. Also, the possibility of consanguinity should be addressed.

Physical

  • CNS
    • Occipital encephalocele is characterized by extrusion or herniation of rhombic roof elements, cerebellar vermis, and caudal third ventricle and distended fourth ventricle through a widened posterior fontanelle.
    • Occasionally, the medial occipital cortex is included in the sac formed by the dilated caudal third ventricle.
    • A dural sac covers the protruding CNS structures.
    • Dandy-Walker malformation occurs as a disturbance in rhombencephalon development. Although rare, 7 cases of Dandy-Walker malformation have been reported. This complex dysembryogenesis includes a central cyst that communicates with the fourth ventricle, agenesis of vermis, and splaying of the cerebellar hemispheres.
    • Hydrocephalus is usually present.
    • Arnold-Chiari malformation may be noted.
    • Microcephaly, anencephaly, and the absence of olfactory lobes and tract may also be also observed.
  • Cardiac: Atrial septal defect, coarctation of aorta, and pulmonary stenosis may be present.
  • Lung: Hypoplasia is secondary to oligohydramnios.
  • Renal
    • Polycystic kidneys may be observed.
    • Cystic dysplasia of the kidneys is the most constant and characteristic feature of Meckel-Gruber syndrome.
    • Kidneys may be enlarged 10-20 times their normal size.
    • Abnormal kidneys function poorly and cause oligohydramnios.
  • Extremities: Polydactyly is also reported. Although all 4 extremities are usually affected, postaxial polydactyly is the most variable feature of the classic triad of major abnormalities. However, in some cases, preaxial polydactyly is present or not exhibited at all.5
  • Liver: Hepatic dysgenesis is also noted. A hepatic lesion is a consistent feature, as reported in a series of 677 patients from Finland.6 The development of the intrahepatic biliary system is arrested, with varying degrees of reactive bile duct proliferation, bile duct dilatation, portal fibrosis, and portal fibrous vascular obliteration.
  • Facial: Cleft lip and cleft palate may be present. Microphthalmia and micrognathia may be observed.
  • Genital anomalies: Without chromosome analysis or gonadal histology, genital ambiguity secondary to incomplete development of internal/external genitalia can cause confusion in sex assignment of the fetus or infant. Cryptorchidism might be present in males. Urethral atresia has been reported in 4 cases.7

Causes

  • Meckel-Gruber syndrome is an autosomal recessive disorder. It belongs to the ciliopathies, a category of diseases thought to be caused by dysfunction of cilia and flagella. Polycystic liver and kidney disease, Bardet-Biedl syndrome, Alstrom syndrome, and Joubert syndrome also belong to the same group.8
  • Because the phenotypic overlap with trisomy 13 is considerable, the gene for Meckel-Gruber syndrome was postulated to be on chromosome 13. However, analysis of polymorphic DNA markers from 5 Finnish families revealed the Meckel-Gruber syndrome locus to be chromosome bands 17q21-24, telomeric to the homeo-box B (HOXB) region in 17q21-22. Disruption of the same HOXB genes in mice leads to malformations that resemble Meckel-Gruber syndrome; however, this locus has been excluded as a causative locus for Meckel-Gruber syndrome.9
  • A subset of Middle Eastern and Northern African families with Meckel-Gruber syndrome did not show linkage to chromosome arm 17q. A second locus (MKS2) has been mapped to band 11q13, demonstrating the clinical and genetic heterogeneity of Meckel-Gruber syndrome. Another study investigated the genetic basis of Meckel-Gruber syndrome in 8 consanguineous kindreds originating from the Indian subcontinent. The results do not show linkage to either MKS1 or MKS2.10
  • A third MKS locus (MKS3) has been localized to chromosome 8q21.3-q22.1 in this cohort by a genome-wide linkage search using autozygosity mapping. Comparison of the clinical features of MKS3 -linked cases with reports of MKS1 -linked and MKS2 -linked kindreds suggests that polydactyly (and possibly encephalocele) appear less common in MKS3 -linked families.11
  • A recent report of a Kosovar Albanian family with 2 affected male fetuses with ultrasonographic features of Meckel syndrome found linkage to a 3.2-Mb region on chromosome 12q21.31-q21.33 (MKS4).12
  • Mutations in the RPGRIP1L gene in chromosome 16q12.2 (MKS5) have also been identified in patients with clinical features consistent with Meckel-Gruber syndrome.3
  • Furthermore, a gene on chromosome 4p15 (CC2D2A) was recently considered as the most likely candidate for the clinical features of Meckel syndrome in probands from 11 Finnish families (MKS6).4 Mutations in the same region have been identified in patients with Joubert syndrome.

More on Meckel-Gruber Syndrome

Overview: Meckel-Gruber Syndrome
Differential Diagnoses & Workup: Meckel-Gruber Syndrome
Treatment & Medication: Meckel-Gruber Syndrome
Follow-up: Meckel-Gruber Syndrome
References
Further Reading
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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. 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].

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

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

  8. 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].

  9. 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].

  10. 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].

  11. 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].

  12. 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].

  13. 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].

  14. 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].

  15. 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].

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

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

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

  19. 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].

  20. 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].

  21. 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].

  22. 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].

  23. 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].

  24. 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].

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

  26. 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].

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

  28. 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].

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

  30. 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].

  31. 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].

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Keywords

Meckel-Gruber syndrome, MKS, occipital encephalocele, large polycystic kidneys, postaxial polydactyly, oral clefting, genital anomalies, CNS malformations, liver fibrosis, pulmonary hypoplasia, oligohydramnios, dysencephalia splanchnocystica, treatment, symptoms

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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.

Medical Editor

Christian J Renner, MD, Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

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

CME Editor

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.

 
 
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