Are bowing of long tubular bones and preaxial polydactyly signs of the Meckel syndrome?

We describe four cases with signs resembling those of Meckel syndrome. Two cases demonstrated postaxial polydactyly; one case, preaxial polydactyly; and one case, pre- and postaxial polydactyly. Since there is at least one other reported case with preaxial polydactyly, it may be a rare sign of the Meckel syndrome. In all four cases, various degrees of bowing of the long tubular bones were observed. Since at least two cases exhibited typical Meckel syndrome and since in a few further reported cases X-ray examination revealed bowing of long tubular bones, this sign is considered to be a further, hitherto not well recognized sign of the Meckel syndrome, and not grounds for delineation of a new syndrome. An extensive review of the literature revealed, that shortened and bowed extremities may be present in about one-sixth of all cases with Meckel syndrome.     

Antenatal presentation of Bardet-Biedl syndrome may mimic Meckel syndrome

Bardet-Biedl syndrome (BBS) is a multisystemic disorder characterized by postaxial polydactyly, progressive retinal dystrophy, obesity, hypogonadism, renal dysfunction, and learning difficulty. Other manifestations include diabetes mellitus, heart disease, hepatic fibrosis, and neurological features. The condition is genetically heterogeneous, and eight genes (BBS1-BBS8) have been identified to date. A mutation of the BBS1 gene on chromosome 11q13 is observed in 30%-40% of BBS cases. In addition, a complex triallelic inheritance has been established in this disorder--that is, in some families, three mutations at two BBS loci are necessary for the disease to be expressed. The clinical features of BBS that can be observed at birth are polydactyly, kidney anomaly, hepatic fibrosis, and genital and heart malformations. Interestingly, polydactyly, cystic kidneys, and liver anomalies (hepatic fibrosis with bile-duct proliferation) are also observed in Meckel syndrome, along with occipital encephalocele. Therefore, we decided to sequence the eight BBS genes in a series of 13 antenatal cases presenting with cystic kidneys and polydactyly and/or hepatic fibrosis but no encephalocele. These fetuses were mostly diagnosed as having Meckel or "Meckel-like" syndrome. In six cases, we identified a recessive mutation in a BBS gene (three in BBS2, two in BBS4, and one in BBS6). We found a heterozygous BBS6 mutation in three additional cases. No BBS1, BBS3, BBS5, BBS7, or BBS8 mutations were identified in our series. These results suggest that the antenatal presentation of BBS may mimic Meckel syndrome.     

Gross anatomical studies of a newborn with the Meckel syndrome

A male infant with the Meckel syndrome was studied anatomically. The findings were compared with those from eight trisomy-13 cases to determine whether or not the superficial similarities between the two syndromes were matched by similarities in the internal variations. Emphasis was on the head and limbs. In the head, major differences were found in the nasal bones, mandible, and tongue. In the limbs, the skeletal variations were more severe in the Meckel syndrome infant, but he lacked the muscle variations diagnostic of trisomy 13.     

Prenatal diagnosis of Meckel syndrome

Summary The three main features of Meckel syndrome are encephalocele, polycystic kidneys, and polydactyly. Prenatal diagnosis of a fetus with Meckel syndrome was made in the 16th week of gestation by means of amniotic fluid alpha₁ fetoprotein estimation. The indication for amniocentesis was a previous child with an occipital meningocele and polycystic kidneys. Interpretation of the alpha₁-fetoprotein value (240 g/ml) was difficult due to fetal blood contamination. Prenatal diagnosis is indicated in any pregnancy following the birth of a child with only two major symptoms of Meckel syndrome.     

Clinical and genetic heterogeneity in Meckel syndrome

Meckel syndrome (MKS) is a lethal malformation syndrome characterised by posterior meningoencephalocele, polycystic kidneys, fibrotic changes of the liver, and polydactyly. We have previously shown a linkage to chromosome 17q in 17 Finnish Meckel families. In this study we have analysed one Italian, one Austrian (of Turkish origin) and three British MKS families (Caucasian, Pakistani, and Bangladeshi families) for linkage to the MKS locus on chromosome 17q22–q24. We did not observe co-segregation of the disease and marker haplotypes in the Austrian family or in the three British families, of which two represented classical MKS and one a slightly atypical MKS phenotype with longer survival of the patient. In the Italian family the affected and non-affected children did not share the same maternal chromosome and thus this family could represent the same allelic disease as the Finnish MKS families. These results suggest locus heterogeneity in Meckel syndrome – a feature previously suspected based on the highly variable clinical phenotype. Received: 2 June 1997 / Accepted: 12 June 1997     

TCTN3 Mutations Cause Mohr-Majewski Syndrome

Orofaciodigital syndromes (OFDSs) consist of a group of heterogeneous disorders characterized by abnormalities in the oral cavity, face, and digits and associated phenotypic abnormalities that lead to the delineation of 13 OFDS subtypes. Here, by a combined approach of homozygozity mapping and exome ciliary sequencing, we identified truncating TCTN3 mutations as the cause of an extreme form of OFD associated with bone dysplasia, tibial defect, cystic kidneys, and brain anomalies (OFD IV, Mohr-Majewski syndrome). Analysis of 184 individuals with various ciliopathies (OFD, Meckel, Joubert, and short rib polydactyly syndromes) led us to identify four additional truncating TCTN3 mutations in unrelated fetal cases with overlapping Meckel and OFD IV syndromes and one homozygous missense mutation in a family with Joubert syndrome. By exploring roles of TCTN3 in human ciliary related functions, we found that TCTN3 is necessary for transduction of the sonic hedgehog (SHH) signaling pathway, as revealed by abnormal processing of GLI3 in patient cells. These results are consistent with the suggested role of its murine ortholog, which forms a complex at the ciliary transition zone with TCTN1 and TCTN2, both of which are also implicated in the transduction of SHH signaling. Overall, our data show the involvement of the transition zone protein TCTN3 in the regulation of the key SHH signaling pathway and that its disruption causes a severe form of ciliopathy, combining features of Meckel and OFD IV syndromes.     

Multiple congenital anomalies syndrome with multicystic renal dysplasia,postaxial polydactyly and lumbosacral meningocoele. Difficulties in nosological classification and genetic counseling

In this report we describe a 17 weeks old female fetus with a lumbosacral meningocoele, multicystic renal dysplasia (Potter type IIb) and postaxial polydactyly type A at the left hand and left foot. There was no hepatic fibrosis. Although multicystic renal dysplasia and postaxial polydactyly are often present in the Meckel syndrome, a lumbosacral neural tube defect is not a typical finding in this syndrome.     

What is the function of centrioles?

The function of centrioles has been controversial and remains incompletely resolved. This is because centrioles, in and of themselves, do not directly perform any physiological activity. Instead, their role is only to act as a jig or breadboard onto which other functional structures can be built. Centrioles are primarily involved in forming two structures-centrosomes and cilia. Centrioles bias the position of spindle pole formation, but because spindle poles can self-organize, the function of the centriole in mitosis is not obligatory. Consequently, lack of centrioles does not generally prevent mitosis, although recent experiments suggest acentriolar spindles have reduced fidelity of chromosome segregation. In contrast, centrioles are absolutely required for the assembly of cilia, including primary cilia that act as cellular antennae. Consistent with this requirement, it is now becoming clear that many ciliary diseases, including nephronophthisis, Bardet-Biedl syndrome, Meckel Syndrome, and Oral-Facial-Digital syndrome, are caused by defects in centriole-associated proteins.     

A newborn child with karyotype 47,XX,+der(12) (12pter→12q12::8q24→8qter),t(8;12) (q24;q12) pat

Summary A case of Meckel or Gruber syndrome is reported, together with a survey of the relevant literature of recent years (1971–1977), in reference to a probably autosomal recessive inheritance of this malformation.     

Prenatal diagnosis of genetically determined early manifestation of autosomal dominant polycystic kidney disease?

Summary A case of an unusually early manifestation of autosomal dominant polycystic kidney disease (ADPKD) is reported that was prenatally diagnosed by ultrasound. The ultrasonographic picture showed greatly enlarged kidneys and increased echogenicity that was indistinguishable from cases of autosomal recessive polycystic kidney disease or Meckel syndrome without further information. Because of two further cases of early manifestation of ADPKD within the family reported (brother and cousin), as well as several other familial cases reported in the literature, we postulate that genetic factors are involved (modifying alleles). When repeated observations of familial cases of early manifestations of ADPKD are made, genetic counseling should be considered.     

Johann Friedrich Meckel, Jr. as founder of scientific teratology

n the occasion of the 150th anniversary of his death, the scientific work of the famous German anatomist Johann Friedrich Meckel (1781 to 1833) in Halle is appreciated. The Younger Meckel is counted to the most outstanding figures in the history of anatomy and medicine in the first third of 19th century. According to his founded knowledges in the normal, comparative, and pathologic anatomy and embryology he was able to give a scientific argument of malformations first of all in the history of medicine and biology. The edition of Meckel's Handbook of Pathologic Anatomy (in German language; 1st vol. 1812) is the birth of scientific teratology. Through his contributions to teratology Meckel directly participated in the raising of general pathology and pathologic anatomy to scientific disciplines. Meckel's interceding for C. F. Wolff's theory of epigenesis, not at last by translation of Wolff's paper "De formatione intestinorum" (1768 to 1769) into the German language, accelerated the development of the general and special embryology during the 19th century. In the contemporary medicine the succeeding eponyms are reminding of the imposing German physician and anatomist: the Meckel's diverticulum of ileum (1809), the Meckel's cartilage of the mandibular arch (1820) and the so-called Meckel syndrome (1822).     

The ciliary transitional zone and nephrocystins

Loss of cilia and ciliary protein causes various abnormalities (called ciliopathy), including situs inversus, renal cystic diseases, polydactyly and dysgenesis of the nervous system. Renal cystic diseases are the most frequently observed symptoms in ciliopathies. Cilia are microtubule-based organelles with the following regions: a ciliary tip, shaft, transitional zone and basal body/mother centriole. Joubert syndrome (JBTS), Meckel Gruber syndrome (MKS) and Nephronophthisis (NPHP) are overlapping syndromes. Recent studies show that JBST and MKS responsible gene products are localized in the transitional zone of the cilia, where they function as a diffusion barrier, and control protein sorting and ciliary membrane composition. Nephrocystins are gene products of NPHP responsible genes, and at least 11 genes have been identified. Although some nephrocystins interact with JBST and MKS proteins, proteomic analysis suggests that they do not form a single complex. Localization analysis reveals that nephrocystins can be divided into two groups. Group I nephrocystins are localized in the transitional zone, whereas group II nephrocystins are localized in the Inv compartment. Homologs of group I nephrocystins, but not group II nephrocystins, have been reported in C. reinhardtii and C. elegans. In this review, we summarize the structure of the ciliary base of C. reinhardtii, C. elegans and mammalian primary cilia, and discuss function of nephrocystins. We also propose a new classification of nephrocystins.     

Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome

Meckel syndrome (MKS) is a rare autosomal recessive lethal condition characterized by central nervous system malformations, polydactyly, multicystic kidney dysplasia, and ductal changes of the liver. Three loci have been mapped (MKS1–MKS3), and two genes have been identified (MKS1/FLJ20345 and MKS3/TMEM67), whereas the gene at the MKS2 locus remains unknown. To identify new MKS loci, a genomewide linkage scan was performed using 10-cM–resolution microsatellite markers in eight families. The highest heterogeneity LOD score was obtained for chromosome 12, in an interval containing CEP290, a gene recently identified as causative of Joubert syndrome (JS) and isolated Leber congenital amaurosis. In view of our recent findings of allelism, at the MKS3 locus, between these two disorders, CEP290 was considered a candidate, and homozygous or compound heterozygous truncating mutations were identified in four families. Sequencing of additional cases identified CEP290 mutations in two fetuses with MKS and in four families presenting a cerebro-reno-digital syndrome, with a phenotype overlapping MKS and JS, further demonstrating that MKS and JS can be variable expressions of the same ciliopathy. These data identify a fourth locus for MKS (MKS4) and the CEP290 gene as responsible for MKS.     

Whole exome sequencing identified a homozygous novel variant in CEP290 gene causes Meckel syndrome

Meckel syndrome (MKS) is a pre‐ or perinatal multisystemic ciliopathic lethal disorder with an autosomal recessive mode of inheritance. Meckel syndrome is usually manifested with meningo‐occipital encephalocele, polycystic kidney dysplasia, postaxial polydactyly and hepatobiliary ductal plate malformation. Germline variants in CEP290 cause MKS4. In this study, we investigated a 35‐years‐old Chinese female who was 17+1 weeks pregnant. She had a history of adverse pregnancy of having foetus with multiple malformations. We performed ultrasonography and identified the foetus with occipital meningoencephalocele and enlarged cystic dysplastic kidneys. So, she decided to terminate her pregnancy and further genetic molecular analysis was performed. We identified the aborted foetus without postaxial polydactyly. Histological examination of foetal kidney showed cysts in kidney and thinning of the renal cortex with glomerular atrophy. Whole exome sequencing identified a novel homozygous variant (c.2144T>G; p.L715^*) in exon 21 of the CEP290 in the foetus. Sanger sequencing confirmed that both the parents of the foetus were carrying this variant in a heterozygous state. This variant was not identified in two elder sisters of the foetus as well as in the 100 healthy individuals. Western blot analysis showed that this variant leads to the formation of truncated CEP290 protein with the molecular weight of 84 KD compared with the wild‐type CEP290 protein of 290 KD. Hence, it is a loss‐of‐function variant. We also found that the mutant cilium appears longer in length than the wild‐type cilium. Our present study reported the first variant of CEP290 associated with MKS4 in Chinese population.     

Allelic somatic mutations may explain vascular twin nevi

Summary Vascular twin nevi, i.e., telangiectatic nevus and nevus anemicus occurring together and adjacent to each other, can be explained as twin spots resulting from a somatic recombination. It is so far unclear, however, whether the postulated underlying autosomal recessive mutations are allelic. This problem can be approached by studying another cutaneous phenotype, phacomatosis pigmentovascularis. Within this diagnosis, several authors have reported the simultaneous occurrence of three different birthmarks, viz., a pigmentary nevus, a telangiectatic nevus and a nevus anemicus. These cases can also be explained as a twin-spot phenomenon, provided two of these nevi are considered allelic traits. The two vascular nevi are most probably allelic, whereas the pigmentary nevus may be a nonallelic component of this syndrome. In conclusion, phacomatosis pigmentovascularis provides circumstantial evidence suggesting allelism of somatic mutations giving rise to two different vascular nevi.     

Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle

Meckel syndrome (MKS) is a lethal malformation disorder characterized classically by encephalocele, polycystic kidneys, and polydactyly. MKS is also one of the major contributors to syndromic neural tube defects (NTDs). Recent findings have shown primary cilia dysfunction in the molecular background of MKS, indicating that cilia are critical for early human development. However, even though four genes behind MKS have been identified to date, they elucidate only a minor proportion of the MKS cases. In this study, instead of traditional linkage analysis, we selected 10 nonrelated affected fetuses and looked for the homozygous regions shared by them. Based on this strategy, we identified the sixth locus and the fifth gene, CC2D2A (MKS6), behind MKS. The biological function of CC2D2A is uncharacterized, but the corresponding polypeptide is predicted to be involved in ciliary functions and it has a calcium binding domain (C2). Immunofluorescence staining of patient's fibroblast cells demonstrates that the cells lack cilia, providing evidence for the critical role of CC2D2A in cilia formation. Our finding is very significant not only to understand the molecular background of MKS, but also to obtain additional information about the function of the cilia, which can help to understand their significance in normal development and also in other ciliopathies, which are an increasing group of disorders with overlapping phenotypes.     

Cerebral gigantism: report on two familial cases (author's transl)

Two cases of cerebral gigantism occurring in related boys (cousins of 3rd degree) are discussed. It is difficult to argue from these cases in favour of a precise type of hereditary transmission. The hypothesis of a dominant trait with weak penetrance cannot be excluded. A genetic heterogeneity of the Sotos syndrome is very likely.     

Delineation of two distinct 6p deletion syndromes

Deletions of the short arm of chromosome 6 are relatively rare, the main features being developmental delay, craniofacial malformations, hypotonia, and defects of the heart and kidney, with hydrocephalus and eye abnormalities occurring in some instances. We present the molecular cytogenetic investigation of six cases with 6p deletions and two cases with unbalanced translocations resulting in monosomy of the distal part of 6p. The breakpoints of the deletions have been determined accurately by using 55 well-mapped probes and fluorescence in situ hybridization (FISH). The cases can be grouped into two distinct categories: interstitial deletions within the 6p22–p24 segment and terminal deletions within the 6p24–pter segment. Characteristics correlating with specific regions are: short neck, clinodactyly or syndactyly, brain, heart and kidney defects with deletions within 6p23–p24; and corneal opacities/iris coloboma/Rieger anomaly, hypertelorism and deafness with deletions of 6p25. The two cases with unbalanced translocations presented with a Larsen-like syndrome including some characteristics of the 6p deletion syndrome, which can be explained by the deletion of 6p25. Such investigation of cytogenetic abnormalities of 6p using FISH techniques and a defined set of probes will allow a direct comparison of reported cases and enable more accurate diagnosis as well as prognosis in patients with 6p deletions. Received: 29 July 1998 / Accepted: 28 October 1998     

Conserved Genetic Interactions between Ciliopathy Complexes Cooperatively Support Ciliogenesis and Ciliary Signaling

Mutations in genes encoding cilia proteins cause human ciliopathies, diverse disorders affecting many tissues. Individual genes can be linked to ciliopathies with dramatically different phenotypes, suggesting that genetic modifiers may participate in their pathogenesis. The ciliary transition zone contains two protein complexes affected in the ciliopathies Meckel syndrome (MKS) and nephronophthisis (NPHP). The BBSome is a third protein complex, affected in the ciliopathy Bardet-Biedl syndrome (BBS). We tested whether mutations in MKS, NPHP and BBS complex genes modify the phenotypic consequences of one another in both C. elegans and mice. To this end, we identified TCTN-1, the C. elegans ortholog of vertebrate MKS complex components called Tectonics, as an evolutionarily conserved transition zone protein. Neither disruption of TCTN-1 alone or together with MKS complex components abrogated ciliary structure in C. elegans. In contrast, disruption of TCTN-1 together with either of two NPHP complex components, NPHP-1 or NPHP-4, compromised ciliary structure. Similarly, disruption of an NPHP complex component and the BBS complex component BBS-5 individually did not compromise ciliary structure, but together did. As in nematodes, disrupting two components of the mouse MKS complex did not cause additive phenotypes compared to single mutants. However, disrupting both Tctn1 and either Nphp1 or Nphp4 exacerbated defects in ciliogenesis and cilia-associated developmental signaling, as did disrupting both Tctn1 and the BBSome component Bbs1. Thus, we demonstrate that ciliary complexes act in parallel to support ciliary function and suggest that human ciliopathy phenotypes are altered by genetic interactions between different ciliary biochemical complexes.