Meckel-Gruber syndrome (MGS) is a rare, lethal multi-system disorder with a variable phenotype but characterized by multicystic dysplastic kidneys and CNS and hepatic abnormalities.

Epidemiology

The incidence is estimated to be 1:135,000, although much more prevalent (1:9000) in Finland, Belgium and certain populations in India and the Middle East ¹⁰. 

Diagnosis

The diagnosis of Meckel-Gruber syndrome is generally made when renal cystic dysplasia and at least one other typical feature (e.g. occipital encephalocele (or other CNS malformation), hepatic fibrosis, and/or polydactyly) are present ^10,11. On imaging, cystic kidneys and dilated intrahepatic ducts have been proposed to the pathognomic ¹⁰. The definitive diagnosis is made by genetic testing ¹⁰.

Pathology

Meckel-Gruber syndrome shares some features with trisomy 13 and is also called pseudotrisomy 13 ¹. Karyotyping is recommended if the above triad is seen on antenatal scanning.

Markers

• elevated maternal alpha-fetoprotein (MSAFP) ¹⁰

Genetics

Meckel-Gruber syndrome is inherited in an autosomal recessive fashion; the risk of the condition affecting a subsequent child is therefore 25% ¹. There is genetic heterogeneity with at least three genes (MKS1, MKS2 and MKS3) having been identified ^4,7:

• MKS1: on chromosome 17q

• MKS2: on chromosome 11q

• MKS3: on chromosome 8q or 13q

Associations

• central nervous system / craniofacial

  • encephalocele (most common ¹⁰)

  • microcephaly

  • fetal ventriculomegaly

  • agenesis of corpus callosum

  • Dandy-Walker malformation

  • micrognathia

  • cleft lip +/- palate

• cardiovascular

  • cardiac rotational abnormalities

  • ventriculoseptal defect (VSD)

  • aortic hypoplasia

  • aortic coarctation

  • aortic valve stenosis

• musculoskeletal 

  • polydactyly 10

  • webbed neck

  • club foot

  • syndactyly

  • clinodactyly

• hepatobiliary

  • congenital hepatic fibrosis ⁸

Radiographic features

Ultrasound

In addition to the demonstration of the classical features such as an occipital encephalocele, multiple renal cysts and polydactyly, there may be evidence of oligohydramnios (or anhydramnios in severe cases) and microcephaly. 

In utero (and early neonatal life) multicystic renal disease is usually evident as enlarged echogenic kidneys: demonstration of physical cysts within the kidneys only occurs in the minority of cases.

Treatment and prognosis

The condition is almost always fatal at birth either because of pulmonary hypoplasia or neonatal renal failure ^3,5. Parents can be counseled appropriately that the subsequent risk is 25%. 

History and etymology

Meckel-Gruber syndrome is named after ¹⁰

• Johann Friedrich Meckel (the younger) (1781-1833), a German anatomist (also known for Meckel diverticulum) ⁹

• Georg Gruber (1884-1977), a German physician ⁹ who first described the constellation of findings in 1934, terming it dysencephalia splanchnocystica

It was only in 1969 that the moniker "Meckel-Gruber syndrome" was coined by Opitz and Howe ⁹.