Meckel-Gruber Syndrome

Introduction

Meckel-Gruber syndrome, also known as Meckel syndrome or Gruber syndrome, is a severe ciliopathy. This developmental disorder was first described by Meckel in 1822 and later by Gruber in 1934. The minimum diagnostic criteria are controversial because the clinical manifestations of the syndrome are highly variable. The classic triad consists of a central nervous system malformation, typically occipital encephalocele; cystic kidneys; and polydactyly, most commonly postaxial. Fraser et al. reviewed affected siblings of probands, and proposed broadening the diagnostic criteria to include cystic kidney disease plus two or more frequently seen anomalies. Salonen et al. suggested including hepatic abnormalities in the triad instead of polydactyly.

Most affected individuals die in utero , or mothers elect for termination of pregnancy. The postnatal mortality is 100% for individuals who survive to birth, with the longest survivor dying at 28 months. The major causes of death are pulmonary hypoplasia from oligohydramnios and liver disease.

Twelve genetic mutations are associated with Meckel-Gruber syndrome (designated MKS1 through MKS12). There is variable expressivity of the condition within families. Genotype-phenotype interactions have been noted; for example, polydactyly and encephalocele are commonly identified in individuals with MKS1 mutations but are rarer in individuals with MKS3 mutations. In all cases, this disorder has shown autosomal recessive inheritance.

Disorder

Definition

Meckel-Gruber syndrome is considered in an individual with a normal karyotype who has at least two of the three classic features: occipital encephalocele ( Figs. 133.1 and 133.2 ); large, polycystic kidneys ( Fig. 133.3 ); and postaxial polydactyly ( Fig. 133.4 ).