Meckel syndrome is a rare autosomal recessive lethal condition characterized by central nervous system malformations (typically occipital meningoencephalocele), postaxial polydactyly, multicystic kidney dysplasia and ductal proliferation in the portal area of the liver. Other malformations frequently include microphthalmia, cleft lip and palate, bowing of long bones, heart defects, and genital anomalies, including micropenis. Complete or partial situs inversus and other laterality defects, such as dextrocardia, have been reported in some cases. Meckel syndrome is a heterogeneous autosomal recessive disorder for which three loci have been mapped: MKS1 on 17q, MKS2 on 11q, and MKS3 on 8q. Comparison of the clinical features of MKS3-linked cases with those of MKS1- and MKS2-linked kindreds suggests that polydactyly (and possibly encephalocele) are less common in MKS3-linked families.
Cystic dysplasia of the kidneys is an obligate feature for the diagnosis. Prenatal diagnosis can be done now as early as 10 weeks' gestation due to improvements in ultrasonography. Amniocentesis may reveal elevated amniotic alpha-fetoprotein due to encephalocele. If the pregnancy goes to term, death occurs in the perinatal period. Pulmonary hypoplasia is the leading cause of death.
Although Meckel syndrome is rare, it is the most frequently diagnosed specific syndrome in cases of malformations associated with neural tube defects.
Khaddour et al. (2007) identified a novel polymorphism (c.507-19T>C) in intron 4 of the MKS3 gene in a Lebanese case with Meckel syndrome.
Khaddour et al. (2007) identified a novel polymorphism (c.1575+53G>A) in intron 15 of the MKS3 gene in a Mauritanian case with Meckel syndrome.
Khaddour et al. (2007) studied a Meckel syndrome case from a non-consanguineous family originating from Morocco. This case was found to have polydactyly, cystic kidneys, microcephaly, occipital encephalocele and epidydymal cysts. At the molecular level, this case was found to be a compound heterozygote for MKS3 mutations. This case was found to carry the missense mutation c.1336G>C (p.D446H) in exon 13 of the MKS3 and a c.2439G>A mutation located at the last base of exon 23 that, although it did not change the amino acid (p.A813A), abolished the donor splice site following in silico analysis. In addition to that, Khaddour et al. (2007) identified a novel polymorphism, c.2952A>G (A984A), in exon 28 of the MKS3 gene in a Moroccan patient.
[See: United Arab Emirates > Smith et al., 2006].
Khaddour et al. (2007) studied a consanguineous Palestinian family with two siblings affected with Meckel syndrome. Both of them were found to have cystic kidneys and one of them was found to have cleft palate. Clinical analysis of these cases and other MKS3 mutated cases studied also in this investigation revealed variable brain phenotypes. Interestingly, in this Palestinian family, one sibling was found to have an occipital encephalocele, whilst the other affected sibling was found to have an isolated Dandy-Walker malformation as the brain malformation. At the molecular level, one of these siblings was found to be homozygous for splice site mutation, c.1065+1delG, in exon 10 of the MKS3 gene.
Khaddour et al. (2007) identified a novel polymorphism, c.1665-109_1665-108insT, in intron 16 of the MKS3 gene in a Tunisian case with Meckel syndrome.
Smith et al. (2006) reported a consanguineous Emirati family of Omani origin with one individual affected with MKS3. The affected individual had occipital encephalocele, Dandy-Walker cysts, renal cystic dysplasia, hepatic developmental defects (hepatic fibrosis, bile duct proliferation, ductal plate malformation), and left-hand postaxial polydactyly. At the molecular level, this patient was found to be homozygous for a 2-bp deletion in exon 3 of the MKS3 gene, 383-384delAC, causing a frameshift beginning at his128 with premature stop at residue 140 (H128fsX140). Each of the first-cousin parents was heterozygous for the mutation.