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A rare, lethal, genetic, multiple congenital anomaly disorder characterized by the triad of brain malformation (mainly occipital encephalocele), large polycystic kidneys, and polydactyly, as well as associated abnormalities that may include cleft lip/palate, cardiac and genital anomalies, central nervous system (CNS) malformations, liver fibrosis, and bone dysplasia.
ORPHA:564Classification level: Disorder
Prevalence is estimated at 1/38,500 births in Europe. However, birth prevalence is higher in specific populations such as in Finland (1/9,000), Kuwaiti Bedouin populations (1/3,500), Gujarati Indians (1/1,300), and in Qatar (1/5,000). No gender predilection is reported.
Fetuses affected by Meckel syndrome (MKS) survive only a few days to a few weeks at the most, or die in utero. The main CNS features include occipital encephalocele, hydrocephalus, anencephaly, holoprosencephaly, as well as Dandy-Walker. Large polycystic kidneys with cystic dysplasia are a constant feature of Meckel syndrome. Hepatic dysgenesis and liver fibrosis are frequent. Polydactyly may affect all four extremities and is typically postaxial (80%) or very rarely preaxial. Affected individuals have pulmonary hypoplasia secondary to oligohydramnios. Cleft lip and palate, microphthalmia and micrognathia may be observed. Cardiac malformations may include atrial septal defect, aorta coarctation, patent arterial duct, and valvular pulmonary stenosis. Incomplete development of internal and external genitalia, and cryptorchidism in males are common.
Defective ciliary biology underlies MKS. Mutations in many different cilia-related genes have been associated with this disorder, often in the context of consanguineous unions. Most of these genes are also responsible for Joubert syndrome, leading to the concept that MKS is the extreme lethal phenotype of Joubert syndrome.
Diagnosis may be made on fetal ultrasonography showing occipital encephalocele and dysplastic kidneys. Two of the three major malformations or two other anomalies along with one classical feature are sufficient for diagnosis of MKS. Autopsy may also be required. The disorder is often detected before the 14th gestational week. Molecular genetic testing can be used to confirm the diagnosis or to guide genetic counseling.
Differential diagnoses include trisomy 13, Bardet-Biedl syndrome, Hydrolethalus, and Smith-Lemli-Opitz Syndrome.
Prenatal diagnosis by ultrasonography is possible starting from 12 weeks of pregnancy. Encephalocele, cystic kidneys and polydactyly may be detected.
MKS is inherited in an autosomal recessive manner. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
No treatment is currently available for Meckel syndrome which has a constantly fatal outcome.
MKS is lethal in utero or in the very early neonatal period with pulmonary hypoplasia and kidney failure as the main causes of early demise.