AUTHOR INFORMATION

Section 1 of 11

Authored by 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

Coauthored by 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

Suzanne M Carter, MS, is a member of the following medical societies: American Bar Association

Edited by Christian J Renner, MD, Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine; 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; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Suzanne M Carter, MS
Editor's Email:	Christian J Renner, MD

eMedicine Journal, February 24 2007, VOLUME 8, Number 2

INTRODUCTION

Section 2 of 11

Background: Meckel-Gruber syndrome (MKS) (OMIM 24900) is a lethal, rare, autosomal recessive condition mapped to chromosomes 17q21-q24, 11q13, and 8q24, supporting the evidence of genetic heterogeneity of MKS. The triad of occipital encephalocele, large polycystic kidneys, and postaxial polydactyly characterizes MKS. Associated abnormalities include oral clefting, genital anomalies, CNS malformations, and fibrosis of the liver. Pulmonary hypoplasia is the leading cause of death. The improvement of ultrasonography has led to prenatal diagnosis of MKS as early as 10 weeks' gestation.

Pathophysiology: It has been suggested that a failure of mesodermal induction causes MKS. The induction cascades of early morphogenesis involve numerous growth factors, homeo box genes, and paired domain genes.

Frequency:

• Internationally: Worldwide, incidence of MKS varies from 1 in 13,250 to 1 in 140,000 live births. There is a predilection for the Finnish population, in whom the birth incidence is 1 in 9000.

Mortality/Morbidity: Oligohydramnios resulting from dysplastic kidneys leads to fetal pulmonary hypoplasia. Since the prognosis is grim, with death in utero or shortly after birth, prenatal diagnosis has led to therapeutic abortion of many affected fetuses.

Race: Although the Finnish 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

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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


• • This consists of 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 central nervous system (CNS) structures.
  
  
  
• Polycystic kidneys


• • Cystic dysplasia of the kidneys is the most constant and characteristic feature of 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.
  
  
  
  • Arrested development of the intrahepatic biliary system exists 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 an infrequent finding, 7 cases of Dandy-Walker malformation have been reported.
  
  
  
  • This complex dysembryogenesis includes a central cyst communicating 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-q24, 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 eight consanguineous kindreds, originating from the Indian subcontinent, that do not show linkage to either MKS1 or MKS2. 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.
  
  
  

DIFFERENTIALS

Section 4 of 11

Smith-Lemli-Opitz Syndrome

Other Problems to be Considered:

Hydrolethalus
Meckel syndrome type 2
Trisomy 13

WORKUP

Section 5 of 11

Lab Studies:

• Chromosome analysis


• • Chromosome analysis is essential to exclude trisomy 13, which 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 of gestation if an adequate fluid pocket is present.
  
  
  

Imaging Studies:

• Prenatal sonography


• • Prenatal sonography 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 protrudes through the skull defect.
  
  
  
  • Large, cystic echogenic kidneys are a consistent ultrasonographic finding, although oligohydramnios can obscure detection of renal dysplasia. Second trimester detection of polydactyly may be possible with experienced sonographers if oligohydramnios is not present.
  
  
  
• Magnetic resonance imaging (MRI)


• • MRI is a valuable complement to ultrasonography in assessing fetal anomalies in the presence of severe oligohydramnios.
  
  
  
  • MRI can detect renal size and occipital defects such as encephaloceles.
  
  
  

Hepatic lesions can be considered one of the hidden abnormalities of MKS since they are visible only during postmortem examination. An arrest of development occurs 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 so severe as to occlude portal veins.

TREATMENT

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Medical Care: Although most will die shortly before or after delivery, those that survive will be less severely affected

Surgical Care: Cardiac repair or neurosurgical intervention for encephalocele may be warranted

• Airway establishment may be difficult; thus, guidelines from the American Society of Anesthesiologists should be followed

Consultations: A geneticist and pathologist should be consulted.

MEDICATION

Section 7 of 11

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

FOLLOW-UP

Section 8 of 11

Complications:

• Pulmonary hypoplasia



• Renal failure

Prognosis:

• The mortality rate is 100%.

Patient Education:

• Provide genetic counseling for future pregnancies.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Failure to offer or provide genetic counseling for future pregnancies



• Failure to offer first trimester sonography if the patient at risk present early in pregnancy

TEST QUESTIONS

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CME Question 1: What is the recurrence risk for Meckel-Gruber syndrome?

A: 50%
B: 25%
C: 5%
D: 1%
E: None of the above

The correct answer is B: Meckel-Gruber syndrome is an autosomal recessive disorder. For couples who have had an affected pregnancy, the recurrence risk is 25%.

CME Question 2: Which of the following does not fulfill the diagnostic criteria for Meckel-Gruber syndrome?

A: Genital anomalies
B: Occipital encephalocele
C: Polycystic kidneys
D: Postaxial polydactyly
E: Normal karyotype

The correct answer is A: Although genital anomalies are seen in Meckel-Gruber syndrome, they do not constitute part of the minimum diagnostic criteria of occipital encephalocele, polycystic kidneys, and postaxial polydactyly. A normal karyotype is essential since Meckel-Gruber syndrome is not associated with chromosome abnormalities.

Pearl Question 1 (T/F): Trisomy 13 is a phenocopy of Meckel-Gruber syndrome.

The correct answer is True: Trisomy 13 has the 3 common findings of Meckel-Gruber syndrome. Therefore, chromosome analysis is critical for differential diagnosis and to determine recurrence risks for future pregnancies.

Pearl Question 2 (T/F): Meckel-Gruber syndrome has 3 cardinal findings.

The correct answer is True: Occipital encephalocele, polycystic kidneys, and postaxial polydactyly are the 3 cardinal findings of Meckel-Gruber syndrome.

Pearl Question 3 (T/F): Meckel-Gruber syndrome is a benign disorder.

The correct answer is False: Pulmonary hypoplasia is the major cause of mortality in newborns affected with Meckel-Gruber syndrome.

Pearl Question 4 (T/F): Ultrasonography in the first trimester is a good diagnostic tool for detecting Meckel-Gruber syndrome.

The correct answer is True: Ultrasonography may be used to detect oligohydramnios, which is a common finding in the second trimester of affected fetuses. Oligohydramnios can obscure fetal anatomy and prevent identification of polycystic kidneys and an encephalocele.

BIBLIOGRAPHY

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