eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Meckel-Gruber Syndrome: Differential Diagnoses & Workup

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

Differential Diagnoses

Bardet-Biedl syndrome
Smith-Lemli-Opitz Syndrome
Carbohydrate-deficient Glycoprotein syndrome
Trisomy 13
Hydrolethalus syndrome
Joubert syndrome
Larsen syndrome

Other Problems to Be Considered

Hydrocephalus

Workup

Laboratory Studies

Alpha-fetoprotein (AFP) level from either maternal blood or amniotic fluid may help to detect an encephalocele in patients with Meckel-Gruber syndrome (MGS) (although most encephaloceles are closed and do not elevate AFP levels). AFP can be measured in amniotic fluid after about 12 weeks' gestation and in maternal blood after about 15 weeks' gestation.

Chromosome analysis

  • Chromosome analysis is essential to exclude trisomy 13, which Meckel-Gruber syndrome mimics. Trisomy 13 carries a 1% recurrence risk, as opposed to the 25% recurrence rate for Meckel-Gruber syndrome. Linkage or mutation analysis is not yet available.
  • If anomalies are detected early in the first trimester, chorionic villus sampling (CVS) can be performed at 10-12 weeks' gestation or later in pregnancy if oligohydramnios does not permit amniocentesis.
  • Amniocentesis is performed after 14 weeks' gestation if an adequate fluid pocket is present.
  • Tests can be done to assess prenatal diagnosis, linkage, as well as carrier testing.
  • Chromosomal Markers for Meckel Gruber Syndrome

    Open table in new window

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    Table
    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
    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

Imaging Studies

Prenatal ultrasonography

  • Prenatal ultrasound is currently the best method available to diagnose Meckel-Gruber syndrome and is available in 2-dimensional (2D), 3-dimensional (3D), and 4-dimensional (4D) modalities; 4D is particularly useful in assessing facial features and deformities, musculoskeletal malformations, and limitation of movement.13
  • The second trimester is the usual time of diagnosis; however, with a skilled operator, first-trimester diagnosis may be possible for both high-risk and low-risk families.
  • Color Doppler can be used to assess for lung perfusion in the last trimester, to search for the presence of renal arteries in cases of oligohydramnios, (suspected renal agenesis or hypoplasia), and also to assess flow in the umbilical arteries.
  • Diagnosis in the second trimester becomes more difficult when oligohydramnios secondary to poor renal output impairs visualization.
  • Occipital encephalocele is easily visualized beginning in late first trimester. Part of the brain and meninges protrude through the skull defect.
  • Large, cystic, echogenic kidneys are a consistent ultrasonographic finding, although oligohydramnios can obscure detection of renal dysplasia. Experienced ultrasonographers may be able to detect polydactyly in the second trimester if oligohydramnios is not present.

MRI

  • MRI is a valuable complement to ultrasonography in assessing fetal anomalies in the presence of severe oligohydramnios.
  • It is mainly used when ultrasonography findings are inconclusive or are insufficient to guide treatment choices.
  • It is useful in detecting origin and extent of an abnormality but must be performed after 18 weeks' gestation.
  • It is superior to ultrasonography in detecting CNS abnormalities that are commonly found in Meckel-Gruber syndrome but is limited in that it cannot be used to assess fetal movement.
  • MRI can reveal renal size and occipital defects, such as encephaloceles.

Histologic Findings

  • The primary renal abnormality appears to be failed interaction of the metanephric duct and renal blastema. The kidneys, therefore, show little corticomedullary differentiation, and the nephrons are severely deficient, causing enlargement of the kidneys. Thin-walled cysts appear throughout the parenchyma.
  • Hepatic lesions can be considered one of the hidden abnormalities of Meckel-Gruber syndrome because they are visible only during postmortem examination. Development arrests at the stage of bilaminar plates, which become atrophic during normal development. In Meckel-Gruber syndrome, the plates do not atrophy and prevent reorganization by the remaining biliary cells to form tubular ducts. The resultant fibrosis can be severe enough to occlude portal veins. Bile canaliculi are smaller and less well developed and have inspissated bile within the abnormal ductules.

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

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  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].

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  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].

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  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].

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  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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