Manuscript received: March 30, 2005; Initial review completed: June 6, 2005;
Revision accepted: November 24, 2005.

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Abstract:

We present here the first case of constitutional tetrasomy 18p from India. A 3-year-old female with developmental delay and dysmorphic features revealed 47,XX,+mar karyotype. The small meta-centric marker chromosome was identified as i(18p) with m-FISH followed by m-BAND. Parents and a normal sibling of the proband revealed normal karyotype. There was history of mental retardation and dysmorphic features in four cases on paternal side; however, their karyotype was also normal.

Key words: FISH, Tetrasomy.

Chromosome analysis is indicated for conditions like mental retardation, dysmorphic features etc. Within the limits of conventional cytogenetics, various gross chromosomal anomalies are identified. In addition to this, other cryptic and rare constitutional chromosome anomalies are also increasingly uncovered with molecular cytogenetic techniques since the last decade. A patient with dysmorphic features and delayed development was referred to our laboratory for chromosomal analysis. Tetrasomy of 18p was established with the help of molecular cytogenetics. We wanted to study extended family members with a history of mental retardation to see if similar chromosomal marker was involved.

An 8-month-old female child was referred for chromosomal analysis due to suspected congenital anomaly. The age of the parents at the time of patients’ birth were 30 and 32 years for mother and father respectively. The ultrasonography during pregnancy was normal. Her length, weight and head circumference were within the normal limits. Her urine analysis for reducing substance was normal and FeCl3 test was normal. The results of ultrasonography and fundus examination were also normal. There was no weight gain until the age of 6 months, however, later it was normal. Clinical examination revealed several dysmorphic features. With reference to the percentage of patients with one of 50 different phenotypic features listed in table on the website(1), the presence of the features in index patient was recorded. These features included, develop-mental delay, low set ears, small head, high arched palate, small mouth and chin, epicanthic folds, crossed eyes, long philtrum, down-slanting eyes, asymmetric face, hyper telorism, and hypotonia.

Her family history was remarkable with four cases of mental retardation from paternal side. The paternal aunt, 36/F is mentally retarded (IQ 60) having schizophrenia, dysmorphic features and short stature. Other relatives from previous generations, 40/F, 42/M are siblings with low IQ / mild mental retardation and socially less developed, the male relative is married, with no children. Another relative, a 16/F also has mental retardation.

Karyotypic analysis of above mentioned four affected relatives, and normal individuals i.e. parents, a sibling, and paternal grandfather was normal. Conventional cytogenetic studies were carried out as per standard methods. M-FISH and M-BAND were carried out as per manufacturer protocol (Metasystems, Germany) at Germany.

Based on the results of detailed cytogenetic analysis, the condition was diagnosed as tetrasomy of 18p (Fig. 1a and 1b), a known condition from the western countries, but reported for the first time from India. The family is registered on the web site(1) and useful literature was made available to the mother after translation in local language.

Fig. 1a. M-FISH karyotype depicting three copies of chromosome 18.

Fig. 1b. M-band image depicting tetrasomy of 18p.

In order to arrive at an accurate diagnosis of genetic condition, the conventional cytogenetics needs to be substantiated with molecular methods. Use of m-FISH and m-BAND could simultaneously determine the origin and copy number of the chromosomal fragment in the marker i.e., tetrasomy of 18p. Use of multiplex fluorescent PCR has been reported previously, which gives additional information regarding parental origin of the marker(2). Both paternal(3), and maternal(2,4) origin has been reported. The abnormality of chromosome 18 is either inherited(5) or de novo(6,7).

Pooling the data helps learn about genotype / phenotype correlations and aid in the recognition and diagnosis of tetrasomy 18p. Even in a relatively well-defined condition like Down syndrome, intrinsic variability of the phenotype has been observed. Similarly, tetrasomy 18p seems to display marked variability of phenotypic characteristics. However, combining certain common characteristics may point to a unique picture of an individual with tetrasomy 18p; as a firm definition of the phenotype of tetrasomy 18p has not been reached unlike Down syndrome. It is important to put on record such rare cases of genetic conditions, as there are relatively small numbers of cases in such category of chromo-some anomalies that provides opportunity to explore the mechanisms of anomalies that may be generalizable to other conditions.

1. The chromosome 18 registry and research society. URL: http://www.chromosome18.org

2. Irwin DL, Bryan JL, Chan FY, Matthews PL, Healey SC, Peters M, Findley I. Prenatal diagnosis of tetrasomy 18p using multiplex fluorescent PCR and comparison with a variety of techniques. Genet Test. 2003; 7: 1-6.

3. Eggermann T, Engels H, Apacik C, Moskalonek B, Muller-Navia J, Schwanitz G, Stengel-Rutkowski S. Tetrasomy 18p caused by paternal meiotic nondisjunction. Eur J Hum Genet 1997; 5: 175-177.

4. Boyle J, Sangha K, Dill F, Robinson WP, Yong SL Grand maternal origin of isochromosome 18p present in two maternal half-sisters. Am J Med Genet 2001: 101: 65-69.

5. Abeliovich D, Dagan J, Levy A, Steinberg A, Zlotogora J. Isochromosome 18p in a mother and her child. Am J Med Genet.1993; 46: 392-393.

6. Back E, Toder R, Voiculescu I, Wildberg A, Schempp W. De novo isochromosome 18p in two patients: cytogenetic diagnosis and confirmation by chromosome painting. Clin Genet. 1994; 45: 301-304.

7. Eggermann T, Engels H, Moskalonek B, Nothen MM, Muller-Navia J, Schleiermacher E, Schwanitz G, Stengel-Rutkowski S. Tetrasomy 18p de novo: identification by FISH with conventional and microdissection probes and analysis of parental origin and formation by short sequence repeat typing. Hum Genet. 1996 ; 97: 568-572.