Final Diagnosis -- Multiple Congenital Anomaly/mental Retardation (MCA/MR) Syndrome


Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndrome HALF-CRYPTIC UNBALANCED TRANSLOCATION OF CHROMOSOME FIVE & EIGHTEEN (Fig. 9) resulting in monosomy for 18p telomeric region and trisomy for 5p15 region


Several chromosomal disorders and their associated syndromes have been classified into two categories: abnormalities of chromosome number and defects of chromosome structure. The main abnormalities of chromosomal structure involve duplication or deficiency of a chromosomal region or a combination of both processes. The first deletion or partial trisomy described in humans was 18p in 1963. The most common deletion syndromes involve chromosomes 4p, 5p, 18p, and 18q these were initially described in the 1960s with the increased usage of cytogenetic techniques. However, with the introduction of superior banding techniques, recognition and delineation of many other partial monosomy and partial trisomy syndromes occurred. Several phenotypes and syndromes associated with chromosomal abnormalities have been catalogued with patterns of multiple anomalies and developmental disability.

Chromosome abnormalities have an incidence of 1 in 150 live born infants, and have been attributed to cause a large number of genetic diseases. About 10% of all newborns with a congenital malformation and approximately 15 to 20% of persons with moderate to severe mental retardation have a chromosomal abnormality. Balanced rearrangements such as translocations and inversions occur in about 1 in 500 individuals and unbalanced translocations occur in about 1 in 2000. The phenotypes of chromosome disorders of structure vary considerably because of differences in the size of chromosome duplication or deficiency and the involvement of non-homologous chromosomes.

There is a number of clinical cases with cryptic unbalanced translocations of chromosome ends causing mental retardation. Using conventional GTG-banding, submicroscopic deletions and translocations are difficult to detect. Using molecular methods, cytogenetically invisible rearrangements have been found in 5 - 10% of patients with unexplained mental retardation and even more frequently in children with idiopathic mental retardation and dysmorphic features.

A molecular cytogenetic technique termed multi-probe fluorescence in situ hybridization (FISH) was successfully applied to screen all chromosomes for such telomeric rearrangements. However, this technique requires a significant number of homogenously distributed metaphase spreads since 24 single hybridizations are performed on one slide. On the other hand, multiplex-FISH (M-FISH) proved to be an advanced method for the fast and easy detection of numerical and structural chromosome aberrations by painting all human chromosomes of a single metaphase spread simultaneously in a specific color By this technique whole chromosome painting (WCP) probes are labeled combinatorially using 5 spectrally distinguishable fluorochromes Thus, this method allows to identify genome-wide chromosome rearrangements and to unambiguously determine the origin of marker chromosomes.

The clinical indications for performing cytogenetic analysis have become well established in the last two decades. Most geneticists recommend that cytogenetic analysis should be performed on all children and adults with idiopathic mental retardation even in the absence dysmorphic features. Cytogenetic analysis of parents whose children have structural chromosome abnormalities, such as deletions and duplications, is also indicated, however at times the maternal and/or paternal sample is not available. In our index case the mother was institutionalized for mental disease and the father was not available for work-up.

The chromosomal catalogs and the database of Jablonski provide details of several described abnormalities. Unlike the classical autosomal trisomy syndromes, the phenotypic spectrum of partial monosomy and trisomy conditions varies substantially, contingent on the size of the extra or missing chromosomal segments and whether one or more chromosomes as our index case illustrated.

The chromosome 5p duplication syndrome involves duplication of the short arm of chromosome 5 and is most frequently associated with craniofacial, cardiac, renal, and limb abnormalities, and moderate to severe mental retardation. Dandy-Walker malformation (agenesis of the cerebellar vermis, hydrocephalus, and posterior fossa cyst continuous with the fourth ventricle) does occur in some cases. The phenotype is related to the amount of genetic material duplicated and the specific duplicated segment. Duplication is usually due to unbalanced segregation of a parental autosomal translocation involves the short arm of chromosome 5 and other autosomes. Some of the other duplications involving this region includes: dup(5p)(pter->p13), dup(5)(pter->q13), dup(5)(p13.1->p15.33), dup(5)(pter->p14), inv dup(5)(p14->p15.3), and inv dup(5)(p13.1->p15.3). The critical region responsible for significant abnormalities is believed to be proximal to 5p14.

A study which looked at partial trisomy 5p specifically at proximal 5p as the "critical region" of trisomy of 5p syndrome showed a preponderance for seizures or other brain abnormalities. Several of these patients died at an early age, some had chronic paranoid schizophrenia, all had near normal IQ, and several had minor facial dysmorphology.

Yunnis et al. described two brothers with 5 p partial trisomy. Both had mental retardation, minor facial dysmorphology, and seizures in older brother. The younger brother had a partial trisomy of 5p part with refractory epilepsy, normal early milestones, low IQ partially due to epilepsy and death at 19 years due to complications of epilepsy.

In conclusion, chromosomal abnormalities are common in patients with retardation, congential abnormalities and schizophrenia. Therefore it is important to perform cytogenetic testing on these patients and their families.


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Contributed by Deepak Mohan MD, Deborah Ketterer, Sally Kochmar , Urvashi Surti, PhD

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