MECKEL – GRUBER SYNDROME

Meckel – Gruber syndrome is a severe autosomal – recessive condition, affecting multiple organs and most often lethal within the first days of life. Its incidence ranges between 1:13.500 and 1:40.000 live births. Typical clinical signs are an occipital encephalocele, microphthalmia, bilateral dysplastic cystic kidneys and other malformations of the CNS. Further MKS can be associated with polydactyly, situs inversus, biliary duct proliferation and pulmonary hypoplasia. Most of these changes can be detected before the 14th week of gestation leading to termination of pregnancy.

Different ciliary genes could be identified as responsible for MKS. There is a significant genetic and clinical overlap with other ciliopathies as the Joubert syndrome or Nephronophthisis. A correlation between type of underlying mutation and severity of disease could be found for some genes. Due to high phenotypic variability even within families, effects of additional genetic modifiers are highly discussed.

Meckel – Gruber syndrome – summary
synonyms
  • Meckel syndrome
  • Dysencephalia splanchno-cystica
  • Gruber syndrome
main symptoms
  • cystic renal displasia
  • occipital encephalocele (>80%)
  • other malformations of CNS
  • microphthalmia, Anophthalmia
  • postaxial polydaktyly
  • congenital hepatic fibrosis
  • bile duct Proliferation
  • oligohydramnion
  • pulmonary hypoplasia
additional findings
  • situs inversus
  • facial dysmorphies
  • shortened bones
  • congenital heart defect
  • pancreatic cysts
  • accessory Spleen
  • genital malformation
  • coloboma of iris or Retina
  • elevated alpha fetoprotein
manifestation antenatal. A typical trias of malformation of kidneys, CNS and extremities allows a diagnosis before 14th week of gestation.
frequency highly variable: 1:13.500 (Massachusetts), 1 : 140.000 (Great Britain), Finland 1 : 8.500
inheritance autosomal – recessive
pathogenesis All genes encode for proteins of the primary cilium. The exact pathomechanism remains to be elucidated.
progress and prognosis High rates of intrauterine death. Live births die within the first hours or days of life.
treatment not available

Meckel - Gruber Syndrom genes known to date
Disease OMIM Phenotype Nr Gene OMIM – Gene number alternative Phenotype + OMIM Phenotype Nr
1 MKS1 249000 MKS 1 609883 BBS13 615990
JBTS28 617121
2 MKS2 603194 TMEM216 613277 JBTS2 608091
3 MKS3 607361 TMEM67 609884 COACH syndrome 216360
JBTS6 610688
NPHP11 613550
4 MKS4 611134 CEP290 610142 BBS14 615991
JBTS5 610188
LCA10 611755
SLSN6 610189
5 MKS5 611561 RPGRIP1L 610937 COACH syndrome 216360
JBTS7 611560
6 MKS6 612284 CC2D2A 612013 COACH syndrome 216360
JBTS9 612285
7 MKS7 267010 NPHP3 608002 NPHP3 604387
8 MKS8 613885 TCTN2 613846 JBTS24 616654
9 MKS9 614209 B9D1 614144 JBTS27 617120
10 MKS10 614175 B9D2 611951 JBTS34 614175
11 MKS11 615397 TMEM 231 614949 JBTS20 614970
12 MKS12 616258 KIF14 611279
13 Meckel/Joubert Phänotyp 617562 TMEM 237 614423 JBTS29 617562
MKS13 617562

 

(01/2018)

sources
  • Barker AR, Thomas R, Dawe HR. Meckel-Gruber syndrome and the role of primary cilia in kidney, skeleton, and central nervous system development. Organogenesis. 2014;10:96–107.
  • Huber C, Cormier-Daire V. Ciliary disorder of the skeleton. Am J Med Genet C Semin Med Genet. 2012;160C:165–74.