Meckel-Gruber Syndrome

Meckel-Gruber Syndrome

Meckel-Gruber Syndrome (MKS) is a rare, lethal, autosomal recessive genetic disorder characterized by a triad of central nervous system malformations, polycystic kidneys, and polydactyly. It is the most common syndromic cause of neural tube defects.

Key Points:

  • Incidence: 1 in 13,250 to 1 in 140,000 live births
  • Inheritance: Autosomal recessive
  • Genes involved: Multiple, including MKS1, TMEM67, CEP290, RPGRIP1L
  • Classic triad: Occipital encephalocele, polycystic kidneys, and polydactyly

Clinical Features

The clinical presentation of Meckel-Gruber Syndrome is characterized by a spectrum of congenital anomalies:

  1. Central Nervous System:
    • Occipital encephalocele (90% of cases)
    • Other neural tube defects (e.g., anencephaly, holoprosencephaly)
    • Hydrocephalus
    • Cerebellar hypoplasia
  2. Renal System:
    • Bilateral enlarged cystic kidneys (95-100% of cases)
    • Oligohydramnios due to decreased fetal urine production
  3. Skeletal System:
    • Postaxial polydactyly (75% of cases)
    • Syndactyly
    • Club foot
  4. Other Features:
    • Cleft lip/palate
    • Congenital heart defects
    • Hepatic fibrosis and bile duct proliferation
    • Genital anomalies
    • Microphthalmia

Diagnosis

Diagnosis of Meckel-Gruber Syndrome can be made prenatally or postnatally:

Prenatal Diagnosis:

  • Ultrasonography: Can detect characteristic features as early as 11-14 weeks of gestation
  • Fetal MRI: For better delineation of CNS anomalies
  • Amniocentesis or chorionic villus sampling: For genetic testing

Postnatal Diagnosis:

  • Clinical examination: Identification of characteristic triad
  • Imaging studies: CT, MRI for CNS anomalies; renal ultrasound
  • Genetic testing: Molecular analysis of known MKS genes

Diagnostic Criteria:

At least two of the following three anomalies:

  1. Cystic renal dysplasia
  2. Occipital encephalocele or other CNS malformations
  3. Polydactyly

Plus, at least one of the following:

  • Facial clefting
  • Congenital heart defects
  • Liver fibrosis
  • Genital anomalies

Management

Management of Meckel-Gruber Syndrome is primarily supportive and palliative due to its lethal nature. Key aspects include:

Prenatal Management:

  • Genetic counseling for parents
  • Discussion of pregnancy termination options
  • Monitoring for oligohydramnios and other complications

Postnatal Management:

  • Multidisciplinary approach involving neonatologists, geneticists, neurologists, and palliative care specialists
  • Symptomatic treatment of associated anomalies
  • Comfort care and family support

Long-term Considerations:

  • Genetic counseling for future pregnancies
  • Preimplantation genetic diagnosis for subsequent pregnancies
  • Psychological support for affected families

Prognosis

The prognosis for Meckel-Gruber Syndrome is poor:

  • Majority of affected fetuses result in stillbirth or termination of pregnancy
  • Live-born infants usually do not survive beyond a few hours or days after birth
  • Death typically results from pulmonary hypoplasia secondary to oligohydramnios or from CNS complications

Recurrence Risk:

For parents of an affected child, the recurrence risk in subsequent pregnancies is 25% due to the autosomal recessive inheritance pattern.



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