Alternative titles; symbols
ORPHA: 564; DO: 0070115;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q22 | Meckel syndrome 1 | 249000 | Autosomal recessive | 3 | MKS1 | 609883 |
A number sign (#) is used with this entry because of evidence that Meckel syndrome type 1 (MKS1) is caused by homozygous or compound heterozygous mutation in a gene encoding a component of the flagellar apparatus basal body proteome (MKS1; 609883) on chromosome 17q22.
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. There is extensive clinical variability and controversy as to the minimum diagnostic criteria. Early reports, including that of Opitz and Howe (1969) and Wright et al. (1994), stated that the classic triad of Meckel syndrome comprises (1) cystic renal disease; (2) a central nervous system malformation, most commonly occipital encephalocele; and (3) polydactyly, most often postaxial. However, based on a study of 67 patients, Salonen (1984) concluded that the minimum diagnostic criteria are (1) cystic renal disease; (2) CNS malformation, and (3) hepatic abnormalities, including portal fibrosis or ductal proliferation. In a review of Meckel syndrome, Logan et al. (2011) stated that the classic triad first described by Meckel (1822) included occipital encephalocele, cystic kidneys, and fibrotic changes to the liver.
Genetic Heterogeneity of Meckel Syndrome
See also MKS2 (603194), caused by mutation in the TMEM216 gene (613277) on chromosome 11q12; MKS3 (607361), caused by mutation in the TMEM67 gene (609884) on chromosome 8q; MKS4 (611134), caused by mutation in the CEP290 gene (610142) on chromosome 12q; MKS5 (611561), caused by mutation in the RPGRIP1L gene (610937) on chromosome 16q12; MKS6 (612284), caused by mutation in the CC2D2A gene (612013) on chromosome 4p15; MKS7 (267010), caused by mutation in the NPHP3 (608002) gene on chromosome 3q22; MKS8 (613885), caused by mutation in the TCTN2 gene (613846) on chromosome 12q24; MKS9 (614209), caused by mutation in the B9D1 gene (614144) on chromosome 17p11; MKS10 (614175), caused by mutation in the B9D2 gene (611951) on chromosome 19q13; MKS11 (615397), caused by mutation in the TMEM231 gene (614949) on chromosome 16q23; MKS12 (616258), caused by mutation in the KIF14 gene (611279) on chromosome 1q32; MKS13 (617562), caused by mutation in the TMEM107 gene (616183) on chromosome 17p13; and MKS14 (619879), caused by mutation in the TXNDC15 gene (617778) on chromosome 5q31.
A great variety of malformations have been observed in Meckel syndrome. A frequent and particularly memorable combination is sloping forehead, posterior encephalocele, polydactyly, and polycystic kidneys. Fraser and Lytwyn (1981) concluded that cystic dysplasia of the kidneys is an obligate feature. Majewski et al. (1983) 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.
Pettersen (1984) described the gross anatomic changes of a newborn infant with the Meckel syndrome and noted differences from trisomy 13. Salonen (1984) reviewed the clinicopathologic findings in 67 cases in Finland, where the disorder is also unusually frequent. She proposed that cystic dysplasia of the kidneys with fibrotic changes in the liver and occipital encephalocele or some other central nervous system malformation are minimum diagnostic criteria. In a review of the pathologic findings in 9 cases, Blankenberg et al. (1987) concluded that a hepatic lesion is a consistent feature: 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. Death occurs in the perinatal period.
Herriot et al. (1991) described 2 sibs and another unrelated infant with Meckel syndrome in which the CNS anomaly was Dandy-Walker malformation (220200). Meckel syndrome type 7 (MKS7) has Dandy-Walker malformation as a more consistent feature.
Walpole et al. (1991) described a family in which 3 nonviable brothers had a variant of Dandy-Walker malformation associated with enlarged cystic dysplastic kidneys and hepatic fibrosis. The presence of these abnormalities in all 3 sibs in the absence of polydactyly and encephalocele suggested that this is a distinct syndrome, but its distinctness from the Meckel syndrome was by no means certain. Di Rocco (1993) suggested that the diagnosis in this case might be carbohydrate-deficient glycoprotein syndrome (CDG; 212065); she proposed that CDG syndrome should be considered in any patient with cerebellar dysplasia and renal or liver abnormalities. Summers and Donnenfeld (1995) described 3 sibs with varying manifestations of Meckel syndrome. The propositus had isolated cystic renal disease. In both of the other sibs, a prenatal diagnosis was made of renal disease, polydactyly, and Dandy-Walker malformation.
Al-Gazali et al. (1996) described an infant with occipital encephalocele, cystic kidneys, and postaxial polydactyly, who also manifested Dandy-Walker malformation. Al-Gazali et al. (1996) suggested that Dandy-Walker malformation should be added to the list of brain defects in Meckel syndrome. Castilla et al. (1998) performed an epidemiologic analysis of the association of polydactyly with other congenital anomalies in 5,927 consecutively born polydactyly cases. Trisomy 13, Meckel syndrome, and Down syndrome (190685) explained 255 of the 338 syndromic polydactyly cases. Down syndrome was strongly associated with first-digit duplication, and negatively associated with postaxial polydactyly.
Clinical Variability
Seller (1981) collated information on phenotypic variability in Meckel syndrome in the published cases: 57% had all 3 major features, which she defined as encephalocele, polycystic kidneys, and polydactyly; 16% had the 2 features found in her 4 cases, i.e., encephalocele and polycystic kidneys; in 9 of 17 families with more than 1 affected sib, manifestation was the same in the affected persons, and in the only other 2 families with 4 affected sibs, expression varied among the sibs.
Simpson et al. (1991) reported on a study in which all cases of confirmed neural tube defects (NTD) in the states of California and Illinois in the years 1985-1987, including liveborn infants as well as cases ascertained during pregnancy, were identified with as complete ascertainment as possible. Mothers were interviewed within 5 months. Among postnatal NTD cases, 14.9% (45/303) had additional anomalies. The frequency of non-NTD-related anomalies was 22.9% (8/35) in encephalocele. The Meckel-Gruber syndrome was the most frequently identified specific syndrome. The high frequency of associated malformations suggested to Simpson et al. (1991) that caution must be exercised before assuming that a given case is polygenic-multifactorial in etiology, especially in cases of encephalocele.
Wright et al. (1994) described 2 sibs, the first of whom presented the classic Meckel syndrome triad, which they defined as encephalocele, postaxial polydactyly, and characteristic cystic changes in the kidney. The second sib showed none of these abnormalities but did show urethral atresia and preaxial polydactyly, 2 features previously described in some patients with Meckel syndrome. For example, 4 of the cases reviewed by Salonen (1984) had urethral atresia. The second sib showed features overlapping those of the entity reported as distal obstructive uropathy with polydactyly by Halal (1986); 2 unrelated stillborn infants had hydronephrosis, hydroureter, and bladder dilatation secondary to urethral obstruction, together with postaxial polydactyly. The 2 sibs illustrated the wide phenotypic spectrum of Meckel syndrome and the difficulty of defining minimum diagnostic criteria.
Nelson et al. (1994) described 3 brothers with Meckel syndrome whose father and his female paternal first cousin had postaxial polydactyly of both feet. They suggested that this represented a mild manifestation of the heterozygous carrier state. They referred to the report of Fitch and Pinsky (1973) who observed a family with postaxial polydactyly along with other possibly heterozygous manifestations. Gulati et al. (1997) reported a family in which 4 individuals had minor malformations related to Meckel syndrome. A sib of the proband had cleft lip and palate, a first cousin of the father had preaxial polydactyly, and her daughter had cleft lip. A second cousin of the mother had syndactyly of all 5 toes of the left foot.
The clinical delineation of MKS had long been confusing, and many authors, e.g., Mecke and Passarge (1971), Hunter et al. (1991), and Genuardi et al. (1993), had called attention to the number of ambiguous and overlapping syndromes that might be included under the general heading of cerebroacrovisceral (CAVE) multiplex syndrome, a designation introduced by Verloes et al. (1992).
Prenatal Diagnosis
In a pregnancy at risk, Pachi et al. (1989) made the prenatal diagnosis by finding at 10 weeks' gestation an abnormal anechoic cystic intracranial image, and at 13 weeks' gestation a skull defect in the occipital area through which part of the brain and meninges protruded into the amniotic cavity as well as abnormally enlarged kidneys.
Karmous-Benailly et al. (2005) speculated that fetuses with an antenatal diagnosis of Meckel or 'Meckel-like' syndrome (see 208540), because of the presence of cystic kidneys and polydactyly and/or hepatic fibrosis but no encephalocele, might be instances of Bardet-Biedl syndrome (BBS; 209900). They sequenced the 8 BBS genes in a series of 13 such cases. In 6, they identified a recessive mutation in a BBS gene: 3 in BBS2 (606151), 2 in BBS4 (600374), and 1 in BBS6 (604896). In addition to these homozygous mutations, they found a heterozygous BBS6 mutation in 3 additional cases. In their series there were no mutations found in BBS1, BBS3 (ARL6; 608845), BBS5, BBS7, or BBS8. The results indicated that the antenatal presentation of BBS may mimic Meckel syndrome.
Numerous examples of affected sibs, concordance in presumedly monozygotic twins (Stockard, 1921), roughly equal occurrence in males and females, and parental consanguinity in some instances (Tucker et al., 1966; Walbaum et al., 1967) make autosomal recessive inheritance quite certain. Simopoulos et al. (1967) described 3 male sibs with polycystic kidneys, internal hydrocephalus, and postaxial polydactyly. The parents were not related. Hsia et al. (1971) described 7 cases in 2 sibships: 2 sets of monozygotic twins in one and 3 sibs in another. Although many of the features suggest trisomy 13, occipital encephalocele has apparently never been observed in the chromosomal aberration. Mecke and Passarge (1971) reported 2 affected sisters. Seller (1981) described a family with 4 affected sibs. Each manifested only 2 of the 3 cardinal signs; all had encephalocele and polycystic kidneys, but none had polydactyly.
Salonen and Norio (1984) found good support for autosomal recessive inheritance; the proportion of affected sibs, corrected for truncate complete ascertainment, was 0.261. No parental consanguinity was found among the Finnish cases, a finding not surprising because of the high frequency of the gene in Finland, the generally low frequency of close marriage in that country and the fact that ancestry was not traced back far enough to find remote consanguinity.
Farag et al. (1990) described the Meckel syndrome in 5 sibs of a Bedouin family, each of whom had occipital encephalocele and polycystic kidneys but lacked polydactyly.
Paavola et al. (1995) mapped the MES locus to 17q21-q24 in a 13-cM region using microsatellite DNA markers. Paavola et al. (1995) found no obligatory recombination between MES and the growth hormone gene (139250). The HOXB gene cluster (e.g., 142968) is located nearby at 17q21-q22 and abnormalities of some of the Hoxb genes in mice lead to multiple malformations bearing some parallels to the MES phenotype. However, Paavola et al. (1995) found obligatory recombinants between the HOXB6 (142961) locus and MES.
Paavola et al. (1999) studied further the location of the genes for Meckel syndrome and mulibrey nanism (253250), which had been mapped to the same region, 17q21-q24. They constructed a bacterial clone contig over the critical region for both disorders. Several novel CA-repeat markers were isolated from these clones, which allowed refined mapping of the MKS and MUL loci using haplotype and linkage disequilibrium analysis. The localization of the MKS locus was narrowed and the entire MKS region was found to fall within the MUL region. However, in the common critical region, the conserved haplotypes were different in MKS and MUL patients. A transcript map was constructed by assigning ESTs and genes, derived from the human gene map, to the bacterial clone contig. Altogether, 4 genes and a total of 20 ESTs were precisely localized.
Paavola et al. (1997) demonstrated clinical and genetic heterogeneity in Meckel syndrome in studies of 1 Italian family, 1 Austrian family (of Turkish origin), and 3 British families (Caucasian, Pakistani, and Bangladeshi). They excluded cosegregation of the disease and marker haplotypes in the Austrian family and in the 3 British families, of which 2 represented classic Meckel syndrome and 1 a somewhat atypical Meckel syndrome phenotype with longer survival of the patient. In the Italian family, with 1 affected child, the affected and unaffected children did not share the same maternal chromosome and thus this family could represent the same allelic disease as the Finnish MKS families. The results suggested locus heterogeneity in Meckel syndrome, a feature previously suspected because of the highly variable clinical phenotype.
Shaheen et al. (2011) identified 3 consanguineous Arab families with Meckel-Gruber syndrome. In 2 of these families, no mutation was identified. While the phenotype in 1 of these families mapped to the MKS3 locus (607361), no mutation was found in the TMEM67 gene (609884). In the other family, homozygosity scan confidently excluded all MKS loci known to that time, indicating that, since compound heterozygosity is unlikely to exist in the setting of first-cousin unions, 2 novel MKS loci are likely to exist in the study population. The remaining family carried a mutation in the TCTN2 gene (see 613846.0001 and MKS8, 613885).
In Finland, Salonen and Norio (1984) found that Meckel syndrome has a birth prevalence of 1:9,000 and a disease gene frequency of 0.01, which is of the same order of magnitude as that of the most common recessive diseases belonging to the 'Finnish disease heritage,' that is, genetic disorders enriched or only encountered in Finland. However, in MES, comparable or even higher incidences are reported from other populations. Lurie et al. (1984) pointed to a relatively high frequency of the syndrome among Tatars in the Soviet Union.
Auber et al. (2007) identified the 29-bp deletion in intron 15 of the MKS1 gene (609883.0001) in 8 of 20 unrelated fetuses diagnosed clinically with MKS. Six cases, consisting of 1 heterozygous and 5 homozygous mutations, had the campomelic variant of the disorder. The carrier frequency of this mutation in the German population was determined to be 1 in 260, and the incidence of MKS was estimated at 1 in 135,000.
Kyttala et al. (2006) identified a gene, which they designated MKS1 (609883), that was mutated in Meckel syndrome families linked to 17q. Expression of the Mks1 gene in mouse embryos, as determined by in situ hybridization, agreed well with the tissue phenotype of Meckel syndrome. Comparative genomics and proteomics data implicated MKS1 in ciliary functions.
Consugar et al. (2007) identified mutations in the MKS1 gene in affected individuals in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All 5 families had the major Finnish deletion mutation (609883.0001): 2 were homozygous, and 3 were compound heterozygous with another pathogenic MKS1 mutation (609883.0004 and 609883.0005). All cases with available data had polydactyly. Five of 17 families had mutations in the TMEM67 gene (609884) consistent with MKS3, and 7 families had no detectable mutation in either MKS1 or TMEM67, suggesting further genetic heterogeneity.
Associations Pending Confirmation
Shamseldin et al. (2020) performed genomic analysis in a cohort of 125 families with ciliopathies, and identified heterozygosity for a 1-bp deletion (c.2603delA) in the CEP295 gene (617728), causing a frameshift predicted to result in a premature termination codon (Gln868ArgfsTer25), in the parents of a fetus (15DG0637) diagnosed with Meckel-Gruber syndrome. Limited clinical information was provided, but the phenotype was tabulated as a stillbirth with encephalocele and dysplastic kidneys, but no polydactyly. The ACMG classification was tabulated as 'variant of unknown significance.' Li et al. (2024) reviewed photographs of the affected fetus and observed a depressed nasal bridge, broad mouth, mild retrognathia, and brachydactyly, suggesting that the fetus had a syndromic disease.
Weatherbee et al. (2009) showed that loss of function of mouse Mks1 resulted in an accurate model of Meckel syndrome, with structural abnormalities in the neural tube, biliary duct, limb patterning, bone development, and the kidney. In contrast to cell culture studies, loss of Mks1 in vivo did not interfere with apical localization of epithelial basal bodies, but rather led to defective cilia formation in most, but not all, tissues. Analysis of patterning in the neural tube and the limb demonstrated altered Hedgehog (Hh) pathway signaling underlying some MKS defects, although both tissues showed an expansion of the domain of response to Shh (600725) signaling, unlike the phenotypes seen in other mutants with cilia loss. Other defects in the skull, lung, rib cage, and long bones were thought likely to be the result of disruption of Hh signaling. Weatherbee et al. (2009) concluded that disruption of Hh signaling may explain many, but not all, of the defects caused by loss of Mks1.
This condition was called dysencephalia splanchnocystica by Gruber (1934); it has been called Gruber syndrome. Opitz and Howe (1969) suggested it be called Meckel syndrome because of the clear description by Johann Friedrich Meckel (1822).
In 1984, the American Journal of Medical Genetics published a large issue devoted mainly to papers on the Meckel syndrome, derived from a Meckel symposium organized by the editor, John M. Opitz, which was held on the bicentennial of the birth of Johann Friedrich Meckel the Younger (1781-1833). (See editorial (1970) and Seidler (1984) for biographical information on Meckel.)
Opitz et al. (2006) gave a further review of the role of Meckel in developmental pathology.
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