eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Meckel-Gruber Syndrome

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
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
Contributor Information and Disclosures

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.

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
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References

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Further Reading

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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

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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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