Meckel-Gruber Syndrome 

Updated: Jun 12, 2019
Author: Parul Bhagwati Jayakar, MD, MS, FACMG; Chief Editor: Luis O Rohena, MD, FAAP, FACMG 

Overview

Practice Essentials

Meckel-Gruber syndrome (MKS) is a lethal, rare, autosomal recessive condition characterized by the triad of occipital encephalocele, large polycystic kidneys, and postaxial polydactyly. Associated abnormalities include oral clefting; genital anomalies; central nervous system (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.[1]

The first reports of Meckel-Gruber syndrome 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 either Meckel syndrome or Gruber syndrome.

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

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[13] :

  • 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%)

Workup

Prenatal ultrasonography is currently the best method available to diagnose Meckel-Gruber syndrome and is available in 2-dimensional (2D), 3-dimensional (3D), and 4-dimensional (4D) modalities.

Magnetic resonance imaging (MRI) is a valuable complement to ultrasonography in assessing fetal anomalies in the presence of severe oligohydramnios. It is mainly used when ultrasonography findings are inconclusive or are insufficient to guide treatment choices.

Chromosome analysis is essential to exclude trisomy 13, which Meckel-Gruber syndrome mimics.

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’ gestation if an adequate fluid pocket is present.

Management

Cardiac repair or neurosurgical intervention for encephalocele may be warranted in patients with Meckel-Gruber syndrome.

Pathophysiology

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.[14] B9d1 and B9d2 are essential components of a B9 protein complex and, when this is disrupted, Meckel syndrome results.[15]

With tectonic family member 2 (Tctn2) protein mutation also being linked to Meckel-Gruber syndrome, a study by Weng et al using a knockout human retinal pigment epithelial cell line reported an association between Tctn2 depletion and the following[16] :

  • Partial damage to the ciliary transition zone, a diffusion barrier involved in the regulation of both ciliogenesis and receptor localization for key signaling events
  • Ciliary membrane protein loss
  • Leakage of intraflagellar transport 88 (Ift88) protein toward the lumen of the ciliary basal body
  • Shortening and curving of the cilium

Epidemiology

Frequency

International

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 1300 (carrier rate, 1 in 18).[17, 18] 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.

Mortality/Morbidity

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.[19]

Race

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

Sex

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

 

Presentation

History

See the list below:

  • Fetal ultrasonography can be used to detect an occipital encephalocele and dysplastic kidneys in fetuses with Meckel-Gruber syndrome (MGS) 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

See the list below:

  • CNS

    • Occipital encephalocele is characterized by 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 CNS structures.

    • Dandy-Walker malformation occurs as a disturbance in rhombencephalon development. Although rare, 7 cases of Dandy-Walker malformation have been reported. This complex dysembryogenesis includes a central cyst that communicates with the fourth ventricle, agenesis of vermis, and splaying of the cerebellar hemispheres.

    • Hydrocephalus is usually present.

    • Arnold-Chiari malformation may be noted.

    • Microcephaly, anencephaly, and the absence of olfactory lobes and tract may also be also observed.

  • Cardiac: Atrial septal defect, coarctation of aorta, and pulmonary stenosis may be present.

  • Lung: Hypoplasia is secondary to oligohydramnios.

  • Renal

    • Polycystic kidneys may be observed.

    • Cystic dysplasia of the kidneys is the most constant and characteristic feature of Meckel-Gruber syndrome.

    • Kidneys may be enlarged 10-20 times their normal size.

    • Abnormal kidneys function poorly and cause oligohydramnios.

  • Extremities: Polydactyly is also reported. Although all 4 extremities are usually affected, postaxial polydactyly is the most variable feature of the classic triad of major abnormalities. However, in some cases, preaxial polydactyly is present or not exhibited at all.[20]

  • Liver: Hepatic dysgenesis is also noted. A hepatic lesion is a consistent feature, as reported in a series of 677 patients from Finland.[21] The development of the intrahepatic biliary system is arrested, with varying degrees of reactive bile duct proliferation, bile duct dilatation, portal fibrosis, and portal fibrous vascular obliteration.

  • Facial: Cleft lip and cleft palate may be present. Microphthalmia and micrognathia may be observed.

  • Genital anomalies: Without chromosome analysis or gonadal histology, genital ambiguity secondary to incomplete development of internal/external genitalia can cause confusion in sex assignment of the fetus or infant. Cryptorchidism might be present in males. Urethral atresia has been reported in 4 cases.[22]

Causes

Meckel-Gruber syndrome is an autosomal recessive disorder. It belongs to the ciliopathies, a category of diseases thought to be caused by dysfunction of cilia and flagella.[23, 24] Polycystic liver and kidney disease, Bardet-Biedl syndrome, Alstrom syndrome, and Joubert syndrome also belong to the same group.[25]

Because the phenotypic overlap with trisomy 13 is considerable, the gene for Meckel-Gruber syndrome was postulated to be on chromosome 13. However, analysis of polymorphic DNA markers from 5 Finnish families revealed the Meckel-Gruber syndrome locus to be chromosome bands 17q21-24, telomeric to the homeo-box B (HOXB) region in 17q21-22. Disruption of the same HOXB genes in mice leads to malformations that resemble Meckel-Gruber syndrome; however, this locus has been excluded as a causative locus for Meckel-Gruber syndrome.[26]

A subset of Middle Eastern and Northern African families with Meckel-Gruber syndrome 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 Meckel-Gruber syndrome. Another study investigated the genetic basis of Meckel-Gruber syndrome in 8 consanguineous kindreds originating from the Indian subcontinent. The results do not show linkage to either MKS1 or MKS2.[27]

A third MKS locus (MKS3) has been localized to chromosome 8q21.3-q22.1 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 -linked and MKS2 -linked kindreds suggests that polydactyly (and possibly encephalocele) appear less common in MKS3 -linked families.[28]

A recent report of a Kosovar Albanian family with 2 affected male fetuses with ultrasonographic features of Meckel syndrome found linkage to a 3.2-Mb region on chromosome 12q21.31-q21.33 (MKS4).[29]

Mutations in the RPGRIP1L gene in chromosome 16q12.2 (MKS5) have also been identified in patients with clinical features consistent with Meckel-Gruber syndrome.[5]

Furthermore, a gene on chromosome 4p15 (CC2D2A) was recently considered as the most likely candidate for the clinical features of Meckel syndrome in probands from 11 Finnish families (MKS6).[6] Mutations in the same region have been identified in patients with Joubert syndrome.

 

DDx

Diagnostic Considerations

These include the following:

  • Bardet-Biedl syndrome

  • Carbohydrate-deficient glycoprotein syndrome

  • Hydrolethalus syndrome

  • Joubert syndrome

  • Larsen syndrome

  • Trisomy 13

Differential Diagnoses

 

Workup

Laboratory Studies

Alpha-fetoprotein (AFP) level from either maternal blood or amniotic fluid may help to detect an encephalocele in patients with Meckel-Gruber syndrome (MGS) (although most encephaloceles are closed and do not elevate AFP levels). AFP can be measured in amniotic fluid after about 12 weeks' gestation and in maternal blood after about 15 weeks' gestation.

Chromosome analysis

Chromosome analysis is essential to exclude trisomy 13, which Meckel-Gruber syndrome mimics. Trisomy 13 carries a 1% recurrence risk, as opposed to the 25% recurrence rate for Meckel-Gruber syndrome. 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’ gestation if an adequate fluid pocket is present.

Tests can be done to assess prenatal diagnosis, linkage, as well as carrier testing.

Table. Chromosomal Markers for Meckel Gruber Syndrome (Open Table in a new window)

Protein Name

Locus Name

Gene

Chromosomal Locus

Meckel syndrome type 1 protein

MKS1

MKS1

17q23

...

MKS2

TMEM216

11q13

Meckelin

MKS3

TMEM67

8q21.1-q22.1

...

MKS4

CEP290

12q21.3

Protein fantom

MKS5

RPGRIP1L

16q12.2

Coiled-coil and C2 domain-containing protein 2A

MKS6

CC2D2a

4p15.3

...

MKS7

NPHP3

3q22.1

...

MKS8

TCTN2

12q24.31

...

MKS9

B9D1

17p11.2

...

MKS10

B9D2

19q13.2

...

MKS11

TMEM231

16q23.1

...

MKS12

KIF14

1q32.1

Imaging Studies

Prenatal ultrasonography

Prenatal ultrasonography is currently the best method available to diagnose Meckel-Gruber syndrome and is available in 2-dimensional (2D), 3-dimensional (3D), and 4-dimensional (4D) modalities; 4D is particularly useful in assessing facial features and deformities, musculoskeletal malformations, and limitation of movement.[30, 31]

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.

Color Doppler can be used to assess for lung perfusion in the last trimester, to search for the presence of renal arteries in cases of oligohydramnios, (suspected renal agenesis or hypoplasia), and also to assess flow in the umbilical arteries.

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 protrude through the skull defect.

Large, cystic, echogenic kidneys are a consistent ultrasonographic finding, although oligohydramnios can obscure detection of renal dysplasia. Experienced ultrasonographers may be able to detect polydactyly in the second trimester if oligohydramnios is not present.

MRI

Magnetic resonance imaging (MRI) is a valuable complement to ultrasonography in assessing fetal anomalies in the presence of severe oligohydramnios. It is mainly used when ultrasonography findings are inconclusive or are insufficient to guide treatment choices.

Atlhough MRI is useful in detecting the origin and extent of an abnormality, it must be performed after 18 weeks' gestation. Moreover, while the modality is superior to ultrasonography in detecting CNS abnormalities that are commonly found in Meckel-Gruber syndrome, it is limited in that it cannot be used to assess fetal movement.

MRI can reveal renal size and occipital defects, such as encephaloceles.

Histologic Findings

The primary renal abnormality appears to be failed interaction of the metanephric duct and renal blastema. The kidneys, therefore, show little corticomedullary differentiation, and the nephrons are severely deficient, causing enlargement of the kidneys. Thin-walled cysts appear throughout the parenchyma.

Hepatic lesions can be considered one of the hidden abnormalities of Meckel-Gruber syndrome because they are visible only during postmortem examination. Development arrests at the stage of bilaminar plates, which become atrophic during normal development. In Meckel-Gruber syndrome, the plates do not atrophy and prevent reorganization by the remaining biliary cells to form tubular ducts. The resultant fibrosis can be severe enough to occlude portal veins. Bile canaliculi are smaller and less well developed and have inspissated bile within the abnormal ductules.

 

Treatment

Surgical Care

Cardiac repair or neurosurgical intervention for encephalocele may be warranted in patients with Meckel-Gruber syndrome (MGS).

Airway establishment may be difficult; thus, follow the guidelines provided by the American Society of Anesthesiologists.

Consultations

See the list below:

  • Perinatologist

  • Geneticist

  • Pathologist

 

Medication

Medication Summary

Specific drug therapy is not currently a component of the standard of care for Meckel-Gruber syndrome (MGS) because no treatment has been found for this lethal condition.

 

Follow-up

Complications

See the list below:

  • Pulmonary hypoplasia

  • Renal failure

  • Liver failure

Prognosis

See the list below:

  • The mortality rate is 100%.

  • Most die before or right after delivery, but those who survive longer might have less severe abnormalities.

  • Autopsy provides valuable information that aids in diagnosis and genetic counseling for future pregnancies.

Patient Education

See the list below:

  • Provide genetic counseling for future pregnancies.