MILLER-DIEKER SYNDROME CHROMOSOME REGION, INCLUDED
MDCR, INCLUDED
MDLS
Monosomy 17p13.3
Lissencephaly due to 17p13.3 deletion
Telomeric deletion 17p
MDS CHROMOSOME 17p13.3 DELETION SYNDROME, INCLUDED
Chromosomal anomaly with epilepsy as a major feature
-Rare neurologic disease
Classic lissencephaly
-Rare developmental defect during embryogenesis
-Rare genetic disease
-Rare neurologic disease
Partial monosomy of the short arm of chromosome 17
-Rare developmental defect during embryogenesis
-Rare genetic disease
Features of the Miller-Dieker syndrome include classic lissencephaly (pachygyria, incomplete or absent gyration of the cerebrum), microcephaly, wrinkled skin over the glabella and frontal suture, prominent occiput, narrow forehead, downward slanting palpebral fissures, small nose and chin, cardiac ... Features of the Miller-Dieker syndrome include classic lissencephaly (pachygyria, incomplete or absent gyration of the cerebrum), microcephaly, wrinkled skin over the glabella and frontal suture, prominent occiput, narrow forehead, downward slanting palpebral fissures, small nose and chin, cardiac malformations, hypoplastic male extrenal genitalia, growth retardation, and mental deficiency with seizures and EEG abnormalities. Life expectancy is grossly reduced, with death most often occurring during early childhood (summary by Schinzel, 1988). Lissencephaly means 'smooth brain,' i.e., brain without convolutions or gyri. Deletion of or mutation in the LIS1 gene (PAFAH1B1; 601545) appears to cause the lissencephaly because point mutations have been identified in this gene in isolated lissencephaly sequence (ILS; see 607432). Facial dysmorphism and other anomalies in Miller-Dieker patients appear to be the consequence of deletion of additional genes distal to LIS1. Toyo-oka et al. (2003) presented evidence that the gene whose deletion is responsible for the greater severity of Miller-Dieker syndrome compared to isolated lissencephaly is the gene encoding 14-3-3-epsilon (YWHAE; 605066).
For rapid diagnosis, Batanian et al. (1990) used PCR in connection with probe YNZ22 (D17S5), a highly polymorphic, variable number tandem repeat (VNTR) marker previously shown to be deleted in all patients with MDS, but not in patients ... For rapid diagnosis, Batanian et al. (1990) used PCR in connection with probe YNZ22 (D17S5), a highly polymorphic, variable number tandem repeat (VNTR) marker previously shown to be deleted in all patients with MDS, but not in patients with isolated lissencephaly sequence. Analysis of 118 normal persons revealed 12 alleles (differing in copy number of a 70-bp repeat unit) ranging in size from 168 to 938 bp. Pollin et al. (1999) evaluated the risk of abnormal pregnancy outcome in carriers of balanced reciprocal translocations involving the MDS critical region in 17p13.3. Fourteen families were ascertained on the basis of an affected index case. In these 14 families, 38 balanced translocation carriers had 127 pregnancies, corrected for ascertainment bias by the exclusion of all index cases and carriers in the line of descent to the index cases. An abnormal phenotype, an unbalanced chromosome constitution, or both, were found in 33 of the 127 (26%) pregnancies: 15 of 127 (12%) had MDS and an unbalanced karyotype with del(17p); 9 of 127 (7%) had a less severe phenotype with dup(17p); and 9 were unstudied, although MDS with der(17) was usually suspected based on early death and multiple congenital anomalies. When unexplained pregnancy losses, including miscarriages and stillbirths, were excluded from the total, 33 of 99 (33%) pregnancies were phenotypically or genotypically abnormal. The overall risk of abnormal pregnancy outcome of 26% was in the upper range of the reported risk for unbalanced offspring of carrier parents ascertained through liveborn aneuploid offspring. The risk increased to 33% when unexplained pregnancy losses were excluded from the total.
Miller (1963) described this condition in a brother and sister who were the fifth and sixth children of unrelated parents. The features were microcephaly, small mandible, bizarre facies, failure to thrive, retarded motor development, dysphagia, decorticate and decerebrate ... Miller (1963) described this condition in a brother and sister who were the fifth and sixth children of unrelated parents. The features were microcephaly, small mandible, bizarre facies, failure to thrive, retarded motor development, dysphagia, decorticate and decerebrate postures, and death at 3 and 4 months, respectively. Autopsy showed anomalies of the brain, kidney, heart, and gastrointestinal tract. The brains were smooth with large ventricles and a histologic architecture more like normal fetal brain of 3 to 4 months' gestation. Dieker et al. (1969) described 2 affected brothers and an affected female maternal first cousin. They also emphasized that this should be termed the lissencephaly syndrome because malformations of the heart, kidneys, and other organs, as well as polydactyly and unusual facial appearance, are associated. Reznik and Alberca-Serrano (1964) described 2 brothers with congenital hypertelorism, mental defect, intractable epilepsy, progressive spastic paraplegia, and death at ages 19 and 9 years. The mother showed hypertelorism and short-lived epileptiform attacks. Autopsy showed lissencephaly with massive neuronal heterotopia, and large ventricular cavities of embryonic type. (The findings in the mother made X-linked recessive inheritance a possibility.) The patients of Reznik and Alberca-Serrano (1964) may have suffered from a disorder distinct from that described by Miller (1963) and Dieker et al. (1969). All patients with the Miller-Dieker syndrome are severely retarded. None learned to speak. They may walk by 3 to 5 years but spastic diplegia with spastic gait is evident. As in other forms of stationary forebrain developmental anomalies, decerebrate posturing with head retraction emerges in the first year of life. Dobyns et al. (1983) stated that the most characteristic finding on computerized tomography is complete failure of opercularization of the frontal and temporal lobes, and that this most likely accounts for bitemporal hollowing. (Opercularization is formation of the parts of the lobes that cover part of the insula.) The form of lissencephaly in the Miller-Dieker syndrome was designated classic or type I lissencephaly by Dobyns et al. (1984). It is characterized by microcephaly and a thickened cortex with 4 rather than 6 layers. Bordarier et al. (1986) pointed out that agyria was considered a rare malformation until the recent progress in neuroradiology. Selypes and Laszlo (1988) described the Miller-Dieker syndrome in a 12-year-old boy with a de novo terminal deletion of 17p13. He had growth retardation, microcephaly, ptosis of the left eyelid, low-set ears, prominent philtrum, thin upper lip, clinodactyly of the fifth fingers, and atrial septal defect. Lissencephaly was demonstrated by computerized tomography. MDS is a severe neuronal migration abnormality. Dobyns et al. (1988) found the most consistent features of the facies in MDLS to be bitemporal hollowing, prominent forehead, short nose with upturned nares, prominent upper lip, thin vermilion border of the upper lip, and small jaw. Agenesis of the corpus callosum was demonstrated by computerized tomography in about 90% of cases. The cerebellum was normal in all. Striking midline calcifications were found in most patients with visible chromosomal change. Allanson et al. (1998) reported pattern profiles on 5 children with MDLS and 25 children and adolescents with isolated lissencephaly sequence. The patients with ILS at all ages showed reduced head circumference and a wide and flat face with a broad nose and widely spaced eyes. In the age group of 6 months to 4 years of age, there was similarity between the pattern profiles of ILS and MDLS, with a correlation coefficient of 0.812 (p less than 0.001). In MDLS there are a few distinguishing features, including brachycephaly, a slightly wider face, and a considerably shorter nose. Allanson et al. (1998) concluded that given the striking similarity of the pattern profiles, the principal diagnostic discriminators are qualitative features, specifically the tall, furrowed forehead and the long, broad thickened upper lip in MDLS. They also concluded that their observations were consistent with the concept of additional gene(s) telomeric to LIS1 contributing to the facial phenotype of MDLS.
Ledbetter et al. (1988) described 2 variable number tandem repeat (VNTR) probes that revealed a 15-kb region containing HTF islands that are likely to be markers of expressed sequences. Use of these probes showed homology to chromosome 11 ... Ledbetter et al. (1988) described 2 variable number tandem repeat (VNTR) probes that revealed a 15-kb region containing HTF islands that are likely to be markers of expressed sequences. Use of these probes showed homology to chromosome 11 in the mouse. Because of the close location of MDCR to tumor antigen p53 (TP53; 191170) and MYHSA1 (160730) in man, the homologous locus in the mouse is probably close to the corresponding loci in that species. Several neurologic mutants in the mouse map to that region. In 2 MDS patients with normal chromosomes, a combination of somatic cell hybrid, RFLP, and densitometric studies demonstrated deletion of polymorphic anonymous probes in the paternally derived chromosome 17 (VanTuinen et al., 1988). This demonstration of submicroscopic deletion suggests that all MDS patients may have deletions at the molecular level. In an addendum, the authors stated that 3 additional MDS patients without cytogenetically detectable deletions had been found to have molecular deletions and that 'to date' 13 of 13 MDS patients had molecular deletions. Using anonymous probes, Schwartz et al. (1988) likewise found molecular deletions in 3 MDS patients, 2 of whom had no visible abnormalities of chromosome 17. None of the 3 RFLP loci studied was absent in a case of lissencephaly without MDS. Ledbetter et al. (1989) found that in all of 7 patients 3 overlapping cosmids spanning more than 100 kb were completely deleted, thus providing a minimum estimate of the size of the MDS critical region. A hypomethylated island and evolutionarily conserved sequences were identified within this 100-kb region--indications of the presence of one or more expressed sequences potentially involved in the pathophysiology of this disorder. Reiner et al. (1993) cloned a gene called LIS1 (lissencephaly-1) in 17p13.3 that is deleted in Miller-Dieker patients. Nonoverlapping deletions involving either the 5-prime or the 3-prime end of the gene were found in 2 patients, identifying LIS1 as the disease gene. The deduced amino acid sequence showed significant homology to beta subunits of heterotrimeric G proteins, suggesting that it may be involved in a signal transduction pathway crucial for cerebral development. Since haploinsufficiency appears to lead to the syndrome, half the normal dosage of the gene product is apparently inadequate for normal development. It may be that improper proportions of beta and gamma subunits of a G protein disturb formation of the normal protein complex, as in hemoglobin H disease, which is caused by an imbalance in the ratio of alpha- to beta-globin. About 15% of patients with isolated lissencephaly and more than 90% of patients with Miller-Dieker syndrome have microdeletions in a critical 350-kb region of 17p13.3. Genotype/phenotype studies are necessary to explain the phenotypic differences. Neer et al. (1993) commented on the nature of the newly found gene and the usefulness of identifying families of genes and the proteins they encode. Platelet-activating factor (PAF) is involved in a variety of biologic and pathologic processes (Hanahan, 1986). PAF acetylhydrolase, which inactivates PAF by removing the acetyl group at the sn-2 position, is widely distributed in plasma and tissue cytosols. One isoform of PAF acetylhydrolase present in bovine brain cortex is a heterotrimer comprising subunits with relative molecular masses of 45, 30, and 29 kD (Hattori et al., 1993). Hattori et al. (1994) isolated the cDNA for the 45-kD subunit. Sequence analysis revealed 99% identity with the LIS1 gene, indicating that the LIS1 gene product is a human homolog of the 45-kD subunit of intracellular PAF acetylhydrolase. The results raised the possibility that PAF and PAF acetylhydrolase are important in the formation of the brain cortex during differentiation and development. Kohler et al. (1995) searched for microdeletions in 17p13.3 in 5 patients with lissencephaly-1, typical features of Miller-Dieker syndrome and apparently normal karyotypes. Analysis of loci D17S5 and D17S379 by PCR and FISH revealed a deletion in 3 of the 5 cases. No deletion was observed in the other 2. Given the almost identical clinical picture of the 5 patients, the great variation in the molecular findings argued against Miller-Dieker syndrome being a contiguous gene syndrome. Chong et al. (1996) characterized the LIS1 gene (PAFAB1B1; 601545), demonstrating the presence of 11 exons. SSCP analysis of individual exons was performed on 18 patients with isolated lissencephaly sequence (ILS; see 607432) who showed no deletions detectable by FISH. In 3 of these patients, point mutations were identified: a missense mutation, a nonsense mutation, and a 22-bp deletion at the exon 9-intron 9 junction predicted to result in a splicing error. The findings confirmed the view that mutations of LIS1 are the cause of the lissencephaly phenotype in ILS and in the Miller-Dieker syndrome. Together with the results of deletion analysis for other ILS and Miller-Dieker syndrome patients, these data are also consistent with the previous suggestion that additional genes distal to LIS1 are responsible for the facial dysmorphism and other anomalies in MDS patients. Cardoso et al. (2003) completed a physical and transcriptional map of the chromosome 17p13.3 region from LIS1 to the telomere. Using FISH, Cardoso et al. (2003) mapped the deletion size in 19 children with ILS (607432), 11 children with MDS, and 4 children with 17p13.3 deletions not involving LIS1. Cardoso et al. (2003) showed that the critical region that differentiates ILS from MDS at the molecular level can be reduced to 400 kb. Using somatic cell hybrids from selected patients, Cardoso et al. (2003) identified 8 genes consistently deleted in patients classified as having MDS: PRP8 (607300), RILP (607848), SREC (SCARF1; 607873), PITPNA (600174), SKIP (603055), MYO1C (606538), CRK (164762), and 14-3-3-epsilon (YWHAE; 605066). These genes defined the telomeric MDS critical region, which contains additional genes distal to LIS1 that are responsible for the clinical features that distinguish MDS from ILS. In addition, deletion of the CRK and YWHAE genes delineated patients with the most severe lissencephaly grade. Deletion of the ABR gene (600365), which is outside the MDS critical region, was associated with no apparent phenotype. On the basis of recent functional data and the creation of a mouse model suggesting a role for YWHAE in cortical development, Cardoso et al. (2003) suggested that deletion of 1 or both of these genes in combination with deletion of LIS1 may contribute to the more severe form of lissencephaly seen only in patients with Miller-Dieker syndrome. - Chromosome 17p13.3 Deletion Syndrome Nagamani et al. (2009) reported 5 patients with 17q13.3 deletions involving YWHAE but not PAFAH1B1, 2 with deletion including PAFAH1B1 but not YWHAE, and 1 with deletion of YWHAE and mosaic for deletion of PAFAH1B1. Three deletions were terminal, and 5 were interstitial; all were de novo. Patients with deletions including YWHAE but not PAFAH1B1 had significant growth restriction, cognitive impairment, and shared craniofacial features, including tall vertex, prominent forehead, broad nasal root, and epicanthal folds. Brain imaging was abnormal in all but 1 individual. The most common brain imaging abnormalities included prominent Virchow-Robin spaces, periventricular and white matter signals, Chiari I malformation, and abnormal corpus callosum. Patients with deletions including PAFAH1B1 but not YWHAE presented with seizures, significant developmental delay, and classic lissencephaly. Growth restriction was not observed in 1 patient with deletion of YWHAE, suggesting that another gene, perhaps CRK, may be involved in growth regulation. The interstitial genomic rearrangements were likely generated by diverse mechanisms. Mignon-Ravix et al. (2009) reported a patient with developmental delay and facial dysmorphism who was found to have a heterozygous deletion of 394 to 411 kb on chromosome 17p13.3. The mother did not carry the deletion, and the father was not available for study. At age 3 years 7 months, the boy had macrocephaly and facial anomalies reminiscent of MDS, including high forehead with bitemporal hollowing, hypertelorism, epicanthus, downslanting palpebral fissures, anteverted nares, pronounced cupid bow, and small low-set posteriorly rotated ears with irregular helices. Brain MRI showed pronounced hypoplasia of the corpus callosum with posterior agenesis and ependymal and periventricular nodular heterotopias, mostly in the occipital areas. Anterior regions displayed malformation of cortical development with polymicrogyric like appearance of the frontal lobes associated with foci of pachygyria and subcortical heterotopias. The deleted region contained 5 genes: TIMM22 (607251), ABR, BHLHA9 (615416), TUSC5 (612211) and YWHAE, but only haploinsufficiency of YWHAE was considered to be pathogenic. The phenotype was similar to that described in heterozygous Ywhae-deficient mice (see Toyo-oka et al., 2003). The facial features in this patient also suggested that genes located in this region could contribute to the facial phenotype of MDS. Bruno et al. (2010) identified 8 unrelated individuals with microdeletions at chromosome 17p13.3. One patient had a complex deletion and duplication. All except 1 were de novo and included the YWHAE gene, which was found in an affected sib and a less severely affected mother. The smallest deletion was 328 kb in size, and all breakpoints were distinct. In a comparison with previous studies (Mignon-Ravix et al., 2009 and Nagamani et al., 2009), Bruno et al. (2010) determined that the delineated critical region spanned approximately 258 kb and included 6 genes: TUSC5, YWHAE, CRK, MYO1C, SKIP and part of PITPNA. YWHAE was considered to play a large role in the phenotype, and CRK was the likely candidate for growth restriction. The variable phenotype included postnatal growth retardation and mild facial features such as laterally extended eyebrows, infraorbital folds, broad nasal tip, maxillary prominence and prominent upper and/or lower lip. The 2 affected sibs had developmental delay, but their mother who had the deletion had normal cognition; facial features in this family were minimal. Brain MRI performed in 5 individuals showed no evidence of lissencephaly, but showed mild structural anomalies in the white matter.