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2013-02-14-16 Meckel Gruber syndrome: review of three cases at different gestational age © Khodjaeva www.TheFetus.net.


Meckel Gruber syndrome: review of three cases at different gestational age


Guzal KhodjaevaMD, PhD, RDMS; Ergash Tadjiddinov, MD.

Scientific Medical Center of Obstetrics and Gynecology, Republic of Uzbekistan



Definition

Meckel syndrome, also known as Meckel-Gruber syndrome, is a severe pleiotropic autosomal recessive developmental disorder caused by dysfunction of primary cilia during early embryogenesis. The classic triad of Meckel syndrome comprises:

  1. cystic renal disease;
  2. central nervous system malformation, most commonly occipital encephalocele;
  3. polydactyly, most often postaxial.

Synonyms

Dysencephalia splanchnocystica.

Diagnostic criteria

There is extensive clinical variability and controversy as to the minimum diagnostic criteria.

Early reports, including that of Opitz and Howe, [4] and Wright et al. [7], stated that the classic triad of Meckel syndrome comprises:
  1. cystic renal disease;
  2. central nervous system malformation, most commonly occipital encephalocele;
  3. polydactyly, most often postaxial.
However, based on a study of 67 patients, Salonen [5] concluded that the minimum diagnostic criteria are:
  1. cystic renal disease;
  2. central nervous system malformation,
  3. hepatic abnormalities, including portal fibrosis or ductal proliferation. 
In a review of Meckel syndrome, Logan et al. [4] stated that the classic triad first described by Meckel [1] included
  1. occipital encephalocele;
  2. cystic kidneys;
  3. fibrotic changes of the liver.

History

The first reports of Meckel-Gruber syndrome were published in 1822 by Johann Friedrich Meckel [1]. 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 [2].

The triad of occipital encephalocele, large polycystic kidneys, and postaxial polydactyly characterizes Meckel-Gruber syndrome. Majewski et al. [3] concluded that sometimes the polydactyly in Meckel syndrome is preaxial and that bowing of the long bones of the limbs occurs in about one-sixth of cases.

Associated abnormalities

Oral clefting, genital anomalies, central nervous system malformations, including Dandy-Walker and Arnold-Chiari malformation, hepatic fibrosis, m
icrognathia, hypopituitarism, cardiac and genital anomalies, short-webbed neck, accessory spleens, syndactyly, clinodactyly, clubbed feet.

Prevalence

The incidence of
Meckel-Gruber syndrome varies from 0.07 - 0.75 : 10,000 births. Meckel-Gruber syndrome occurs in all ethnicities although there is increased incidence reported in the Belgian population (3.3 : 10,000), the Finnish population (1.1 : 10,000), and the Ashkenazi Jewish population (0.2 : 10,000). Males and females are affected equally. It is estimated that Meckel-Gruber syndrome accounts about 5% of all neural tube defects.

Etiology

Meckel-Gruber syndrome (OMIM 24900) is a lethal, rare, autosomal recessive condition mapped to 6 different loci in chromosomes 17q21-24 (MKS1), 11q13 (MKS2), 8q21.3-q22.1 (MKS3), 12q21.31-q21.33 (MKS4), 16q12.2 (MKS5), and 4p15.3 (MKS6). This mapping suggests genetic heterogeneity in Meckel-Gruber syndrome.

Differential diagnosis

Trisomy 13 may have similar findings as seen in Meckel-Gruber syndrome. Any fetus, however, with a neural tube defect (particularly an encephalocele) can be considered as a possible Meckel-Gruber syndrome, particularly if the kidneys are abnormal.

Prognosis

Lethal - i
nfants born with Meckel-Gruber syndrome are stillborn or die within a few hours to days after birth.

Recurrence risk

25%.

Management

Pregnancy termination before viability.

Treatment

Currently there is no treatment for this syndrome.



Case reports

During the last six months, we observed three cases of the Meckel Gruber syndrome at State Science Center of Obstetrics and Gynecology, Republic of Uzbekistan.

Case 1

A 22-year-old patient (G2P0A1) presented for sonography at 15 weeks. Her previous pregnancy was terminated six month ago due to Meckel-Gruber syndrome of the fetus at 21st week of pregnancy.

Our examination found an encephalocele involving the posterior fossa with a large posterior fossa cyst protruding from the occiput. Cystic hygroma was also found. The kidneys were echogenic, suggesting cystic dysplasia. Based on these findings, recurrent diagnosis of Meckel-Gruber was made. The patient elected to terminate the pregnancy, and the diagnosis was confirmed after delivery.
 
Image 1: 15 weeks of pregnancy; occipital encephalocele and mild oligohydramnios was present.

  

Image 2: 15 weeks of pregnancy; occipital encephalocele and cystic hygroma.
 

 
Image 3: 15 weeks of pregnancy; polycystic kidneys of the fetus.

 

Image 4: Phenotype of the aborted fetus with the Meckel-Gruber syndrome - occipital encephalocele, absence of nasal bone, low set ears, micrognathia, cystic hygroma, large abdomen, clubbed right foot, no polydactyly.



Case 2

A 31-year-old patient (G4P3) presented for sonography at 20 weeks and 6 days of her pregnancy. Her family and medical histories were unremarkable.

In series of ultrasound images of the fetal brain a large cyst of the choroid plexus, occipital encephalocele as well as mega cisterna magna were found.
 Except polycystic kidneys there was also found a multicystic anechoic alteration in the fetal liver.  We assumed that that cystic structure was a severe fibrotic-cystic lesion of liver. The patient elected to terminate the pregnancy. The autopsy confirmed arrested development of the intrahepatic biliary system at the stage of biliary cylinders with varying degrees of reactive bile duct proliferation, bile duct dilatation, portal fibrosis, and portal fibrous vascular obliteration.

 
Image 5: 21 weeks of pregnancy; a large cyst of choroid plexus, defect of occipital bone and encephalocele.



Image 6: 21 weeks of pregnancy; mega-cisterna magna and hypoplastic cerebellum refer to Dandy-Walker malformation.

  
 
Image 7: 21 weeks of pregnancy; polycystic kidneys.

  

Image 8: 21 weeks of pregnancy; cystic-fibrotic changes of the liver.

  

Image 9: 21 weeks of pregnancy; fibrotic changes of the fetal liver.



Case 3

A 30-year-old woman (G4P3) was referred to our antenatal unit at 31 weeks of gestation for sonographic examination. Her family and medical histories were unremarkable and her marriage wasn’t consanguineous. She has two healthy children, but her previous pregnancy ended by miscarriage in 11-12 weeks. Neither biochemical nor ultrasound screening were carried out in the first trimester. On the series of images occipital encephalocele as well as polycystic kidneys type I was found. Due to severe oligohydramnios the fetus had hypertrophied cardiomyopathy. In 32-33 weeks premature delivery occurred. A boy was born weighting 1200 grams, had prominent encephalocele, microcephaly, micrognathia, large abdomen and hypospadias. Postaxial polydactyly of both feet was also found. The newborn has died 5 minutes after delivery.

Image 10: 31 weeks of pregnancy; ”lemon sign” refers to Arnold-Chiari malformation.



Image 11: 31 weeks of pregnacy; fetal occipital region with occipital encephalocele.

  

Image 12: 31 weeks of pregnancy; polycystic kidneys, small bladder, and oligohydramnios.



Image 13:.31 weeks of pregnancy; hypertrophic cardiomyopathy.





Discussion

Meckel-Gruber syndrome (MKS) is rare genetic disorder characterized by cystic dysplasia of the kidneys (95%), central nervous system abnormalities, particularly occipital encephalocele (80%), anomalies of extremities - polydactyly (75%). Fibrotic changes of the liver may also be present. Newborns with MKS also have abnormal facial features. Another associated abnormalities include micrognathia, cardiac abnormalities, syndactyly, clinodactyly, and clubbed feet.

As the most prominent feature of Meckel-Gruber syndrome is the neural tube defect, the diagnosis of the condition may be missed if other features are not recognized, leading to underestimation of the recurrence risk for the family.

Meckel-Gruber syndrome is caused by changes (mutations) in one of several genes. These genes are called MKS1, MKS2, and MKS3. The genes are located on chromosomes 17, 11, and 8, respectively. MKS is inherited in an autosomal recessive manner. The most likely syndrome to be confused with Meckel-Gruber syndrome is trisomy 13, since 30% of fetuses with trisomy 13 will have enlarged, cystic kidneys and many of them will also have polydactyly and neural tube defects [3, 5]. Karyotyping, therefore, is important in fetuses with this constellation of findings. Although the dismal outcome is the same whether the fetus has, trisomy 13 or Meckel-Gruber syndrome, the recurrence rate is very different - trisomy 13 being mostly a sporadic event with low recurrence rate, versus Meckel-Gruber syndrome with its autosomal recessive pattern.

References

1. Meckel JR. Beschreibung zweier durch sehr alnliche Bildungsaweichung entseller Geschwister. Dtsch Arch Phiol 1898;7:99.
2. Mecke J, Passarge E. Encephalocele, polycystic kidneys and polydactyly as an autosomal recessive trait simulating certain other disorders. Ann Genet 1971;14:97.
3.Opitz, J. M., Howe, J. J.The Meckel syndrome (dysencephalia splanchnocystica, the Gruber syndrome).Birth Defects Orig. Art. Ser. 5: 167-179, 1969.
4.Majewski, F., Stoss, H., Goecke, T., Kemperdick, H.Are bowing of long tubular bones and preaxial polydactyly signs of the Meckel syndrome?Genet. 65: 125-133, 1983. [PubMed: 6654326, related citations]
5.Logan, C. V., Abdel-Hamed, Z., Johnson, C. A.Molecular genetics and pathogenic mechanisms for the severe ciliopathies: insights into neurodevelopment and pathogenesis of neural tube defects.Molec. Neurobiol. 43: 12-26, 2011. [PubMed: 21110233, related citations] [Full Text: Springer]
6.Paavola, P., Salonen, R., Baumer, A., Schinzel, A., Boyd, P. A., Gould, S., Meusburger, H., Tenconi, R., Barnicoat, A., Winter, R., Peltonen, L.Clinical and genetic heterogeneity in Meckel syndrome.Hum. Genet. 101: 88-92, 1997. [PubMed: 9385376, related citations] [Full Text: Springer]
7. Wright, C., Healicon, R., English, C., Burn, J.Meckel syndrome: what are the minimum diagnostic criteria?J. Med. Genet. 31: 482-485, 1994. [PubMed: 8071976, related citations] [Full Text: HighWire Press]
8.G.Pilu,K.Nicolaides,R.Ximenes & Ph.Jeanty. Handbook of Fetal Abnormalities.
9.OMIM.


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