eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Meckel-Gruber Syndrome

Suzanne M Carter, MS, Senior Genetic Counselor, Associate, Department of Obstetrics and Gynecology, Division of Reproductive Genetics, Montefiore Medical Center, Albert Einstein College of Medicine
Susan J Gross, MD, FRCS(C), FACOG, FACMG, Codirector, Division of Reproduction Genetics, Associate Professor, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine

Updated: May 15, 2007

Introduction

Background

Meckel-Gruber syndrome (MKS) (OMIM 24900) is a lethal, rare, autosomal recessive condition mapped to chromosomes 17q21-24, 11q13, and 8q24. This mapping suggests genetic heterogeneity in MKS. The triad of occipital encephalocele, large polycystic kidneys, and postaxial polydactyly characterizes MKS. Associated abnormalities include oral clefting, genital anomalies, CNS malformations, 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 MKS. The induction cascades of early morphogenesis involve numerous growth factors, homeo box genes, and paired domain genes.

Frequency

International

Worldwide, the incidence of MKS is 1 per 13,250-140,000 live births. Individuals of Finnish descent have a higher incidence (1 per 9000 live births).  

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%.

Race

Although individuals of Finnish descent have the highest birth incidence, MKS 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 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

• Occipital encephalocele
  
  
  • 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.
• Polycystic kidneys
  
  
  • Cystic dysplasia of the kidneys is the most constant and characteristic feature of Meckel-Gruber syndrome (MKS).
  • Kidneys may be enlarged 10-20 times their normal size. Abnormal kidneys function poorly and cause oligohydramnios.
• Postaxial polydactyly: Although all 4 extremities are usually affected, polydactyly is the most variable feature of the classic triad of major abnormalities. In some cases, however, polydactyly is not exhibited.
• Hepatic dysgenesis
  
  
  • A hepatic lesion is a consistent feature.
  • 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. 
• Oral clefts: Cleft lip and cleft palate may also be present.
• Genital anomalies: Without chromosome analysis or gonadal histology, genital ambiguity secondary to external genital anomalies can cause confusion in sex assignment of the fetus or infant.
• Dandy-Walker malformation

• 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.

Causes

• MKS is an autosomal recessive disorder.
• Because the phenotypic overlap with trisomy 13 is considerable, the gene for MKS was postulated to be on chromosome 13. Analysis of polymorphic DNA markers from 5 Finnish families, however, revealed the MKS locus to be chromosome bands 17q21-24, telomeric to the homeo box B (HOXB) region. Disruption of the same HOXB genes in mice leads to malformations that resemble MKS; however, this locus has been excluded as a causative locus for MKS.
• A subset of Middle Eastern and Northern African families with MKS 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 MKS.
• A recent study investigated the genetic basis of MKS in 8 consanguineous kindreds originating from the Indian subcontinent. The results do not show linkage to either MKS1 or MKS2 (Morgan, 2002). A third MKS locus (MKS3) has been localized to chromosome 8q24 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 - and MKS2 -linked kindreds suggests that polydactyly (and possibly encephalocele) appear less common in MKS3 -linked families.

Differential Diagnoses

Smith-Lemli-Opitz Syndrome

Other Problems to Be Considered

Hydrocephalus
Meckel syndrome type 2
Trisomy 13

Workup

Laboratory Studies

• Chromosome analysis
  
  
  • Chromosome analysis is essential to exclude trisomy 13, which Meckel-Gruber syndrome (MKS) mimics. Trisomy 13 carries a 1% recurrence risk, as opposed to the 25% recurrence rate for MKS. 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.

Imaging Studies

• Prenatal ultrasonography  
  
  
  • Prenatal ultrasonography is currently the best method available to diagnose MKS.
  • 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.
  • 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.
  • 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 MKS because they are visible only during postmortem examination. Development arrests at the stage of bilaminar plates, which atrophy during normal development. In MKS, 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.

Treatment

Surgical Care

Cardiac repair or neurosurgical intervention for encephalocele may be warranted.

Consultations

Pathologist

Medication

Specific drug therapy is not currently a component of the standard of care for this syndrome because no treatment has been found for this lethal condition.

Follow-up

Complications

• Pulmonary hypoplasia
• Renal failure

Prognosis

• The mortality rate is 100%.

Patient Education

• Provide genetic counseling for future pregnancies.

Miscellaneous

Medicolegal Pitfalls

• Failure to offer or provide genetic counseling for future pregnancies
• Failure to offer first trimester ultrasonography if the patient at risk presents early in pregnancy

References

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2. 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].

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

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6. 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].

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8. 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].

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10. 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].

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

12. 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].

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14. 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].

15. 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].

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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, Gruber syndrome, Gruber's syndrome, trisomy 13, Meckel syndrome type 1, MKS1, MES

Contributor Information and Disclosures

Author

Suzanne M Carter, MS, Senior Genetic Counselor, Associate, Department of Obstetrics and Gynecology, Division of Reproductive Genetics, Montefiore Medical Center, Albert Einstein College of Medicine
Suzanne M Carter, MS is a member of the following medical societies: American Bar Association
Disclosure: Nothing to disclose.

Coauthor(s)

Susan J Gross, MD, FRCS(C), FACOG, FACMG, Codirector, Division of Reproduction Genetics, Associate Professor, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine
Susan J Gross, MD, FRCS(C), FACOG, FACMG is a member of the following medical societies: American College of Medical Genetics, American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, American Medical Association, American Society of Human Genetics, and Royal College of Physicians and Surgeons of Canada
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.com, Inc
Disclosure: Nothing to disclose.

Managing Editor

Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine
Margaret McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and American Society of Human Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru 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 A Buehler, MD, Professor, Department of Pathology and Microbiology, Director, Hattie B Munroe Center for Human Genetics, Chairman, Department of Pediatrics, University of Nebraska Medical Center
Bruce A 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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