Meckel-Gruber Syndrome

Updated: Jul 28, 2017
  • Author: Parul Bhagwati Jayakar, MD, MS, FACMG; Chief Editor: Luis O Rohena, MD, FAAP, FACMG  more...
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The first reports of Meckel-Gruber syndrome (MKS) were published in 1822 by Johann Friedrich Meckel. G.B. Gruber also published reports of patients with Meckel-Gruber syndrome in 1934 and gave it the name dysencephalia splanchnocystica. Meckel-Gruber syndrome is also known as Meckel syndrome and Gruber syndrome.

Meckel-Gruber syndrome (OMIM 24900) is a lethal, rare, autosomal recessive condition mapped to 12 different loci in chromosomes 17q21-24 (MKS1), 11q13 (MKS2), 8q21.3-q22.1 (MKS3), [1, 2] 12q21.31-q21.33 (MKS4), [3] 16q12.2 (MKS5), [4] 4p15.3 (MKS6), [5] 3q22.1 (MKS7), [6] 12q24.31 (MKS8), [7] 17p11.2 (MKS9), [8] 19q13.2 (MKS10), [9] 16q23.1 (MKS11), [10] and 1q32.1 (MKS12). [11] This mapping suggests genetic heterogeneity in Meckel-Gruber syndrome.

The triad of occipital encephalocele, large polycystic kidneys, and postaxial polydactyly characterizes Meckel-Gruber syndrome. Associated abnormalities include oral clefting; genital anomalies; CNS malformations, including Dandy-Walker and Arnold-Chiari malformation; and liver fibrosis. Pulmonary hypoplasia is the leading cause of death. Improvements in ultrasonography have enabled prenatal diagnosis as early as 10 weeks' gestation.

A study by Barisic et al, using data from 191 cases of Meckel-Gruber syndrome, as accessed through the European Surveillance of Congenital Anomalies (EUROCAT) network, found the prevalence of various characteristics of the disease to be as follows [12] :

  • Cystic kidneys (97.7%)

  • Polydactyly (87.3%)

  • Encephalocele (83.8%)

  • Fibrotic/cystic changes of the liver (65.5%, as identified via postmortem examination)

  • Other CNS anomalies (51.4%)

  • Orofacial clefts (31.8%)



Failure of mesodermal induction has been suggested to cause Meckel-Gruber syndrome. The induction cascades of early morphogenesis involve numerous growth factors, homeobox genes, and paired domain genes.

One study screened patients with Meckel syndrome for mutations in B9D1 and B9D2 and identified homozygous c.301A>C (p.Ser101Arg) B9D2 mutation. The data showed that the domain-containing proteins Mks1, B9d1, and B9d2 interact physically; the p.Ser101Arg mutation abrogates the ability of B9d2 to interact with Mks1, which suggests that this mutation compromised B9d2 function. The data further show that B9d1 is required for normal Hedgehog (Hh) signaling, ciliogenesis, and ciliary protein localization. [13] B9d1 and B9d2 are essential components of a B9 protein complex and, when this is disrupted, Meckel syndrome results. [14]





Worldwide, the incidence of Meckel-Gruber syndrome is 1 per 13,250-140,000 live births. Individuals of Finnish descent have a higher incidence (1 per 9000 live births, one person in 50 is a carrier). The incidence is also higher among Belgians and Bedouins in Kuwait, with 1 affected birth in 3,500 (carrier rate 1 in 30). The highest incidence is reported in the Gujarati Indians, with 1 affected birth per 1,300 (carrier rate, 1 in 18). [15, 16] The incidence among Jews in Israel is 1 in 50,000 (carrier rate, 1 in 112). Cases of Meckel-Gruber syndrome have been reported in North America, Europe, Israel, Indonesia, India, Kuwait, and Japan.


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%, with most fetuses surviving only a few days to weeks.

A study by Al-Belushi et al determined that among the report’s cases of prenatally discovered Meckel-Gruber syndrome, diagnostic results revealing no obvious polycystic kidney disease or severe oligohydramnios were consistent with live birth. However, 100% mortality occurred in the live-born infants within a few weeks postdelivery. [17]


Although individuals of Finnish descent have the highest birth incidence, Meckel-Gruber syndrome affects all racial and ethnic backgrounds.


The male-to-female ratio is nearly equal, which is consistent with autosomal recessive inheritance.