Meckel-Gruber Syndrome Clinical Presentation

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



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  • 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]



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.