Indian Pediatrics - Editorial

Letters to the Editor

Indian Pediatrics 2003; 40:917-919

Combined Down and Klinefelter Syndrome

A 3-month-old male, born to non-consanguineous parents was referred for chromosomal analysis because of dysmorphic features. Mother’s age was 26 years and father was 29 years old. The child had growth retardation with microcephaly, hypertelorism, slanted eyes, depressed nasal bridge, protruding tongue, simian crease, and undes-cended testes. Thyroid stimulating hormone (TSH) level was found to be high (7.0 MIU/mL) compared to control (0.2-5.1 MIU/mL), T3 and T4 levels were within normal range. Chromosomal analysis using GTG banding from PHA stimulated cultures revealed 48,XXY+21 karyotype in all the metaphases scored. Chromosomal analysis of parents was found to be normal. Fluorescence in situ hybridization (DISH) analysis was performed on interphase nuclei and metaphases using centromeric (X and Y) and locus specific (21q22.13-q22.2) probes. The probes for the study were purchased from Vysis (UK) and FISH was done according to the manufacturers instructions with minor modifications. FISH analysis showed XXY and chromosome 21 fluorescence signals in all metaphases and interphase cells confirmed no indication of mosaicism.

Trisomy 21 occurs due to non-disjunction of 21 chromosome during gametogenesis in one of the parents. The occurrence of double aneuploidy is a rare phenomenon and only few reports are available on trisomy 21 and XXY sex chromosomes in children with Down syndrome (DS)(1,2). The first case of double aneuploidy was reported by Ford and associates who examined a patient with an XXY and trisomy 21 karyotype(3). Down or Klinefelter syndrome (KS) is a relatively common chromosomal abnormality. The coincidence rate of Klinefelter and DS in the same individual is not known and earlier studies have estimated the incidence of combined Down and KS to be 0.7 × 10–5(4). Neonatal survey data indicate that the incidence of XXY, +21 double aneuploidy at birth is higher than expected from the incidence of either alone. However, recent coincidence rate of double aneuploidy in Down syndrome is not known. Patients with DS have been reported to have a incidence of abnormalities of sexual development including micropenis and small testes. In our case child had typical features of DS but no Klinefelter features were observed since the child was three months old and in KS typical physical phenotype is evident only in later age. Young children with KS have behavioural problems and learning disabilities only. Short stature of DS and tall stature of KS may have additive effect(2). Yamaguchi, et al.(4) reported a mosaic DS-KS karyotype where majority of cell lines were with XXY and the child had abnormalities of external genitalia. Ambiguous genitalia like phallus is also reported in DS with 47,XX+21/47,XXY karyotype(5). In cases of double aneuploidy involving autosomes and sex chromosomes, clinical manifestation of the autosomal abnormality are usually predominant and those of the sex chromosomal abnormality tend to be missing. However, FISH studies are essential in such cases to detect low rate of mosaicism which helps in better genetic counseling.

V. Babu Rao,
K. Ghosh,
Institute of Immunohematology (ICMR),
13th Floor, New Multistoryed Building,
KEM Hospital Campus, Parel,
Mumbai 400 012,
India.

References

1. Hobbs A, Seabright M, Mould S. Two cases of trisomy 21 and one XXY case with a typical clinical features. Hum Genet 1977; 38: 239-244.

2. Hou JW, Wang TR. Double aneuploidy with Downs - Klinefelter’s syndrome. J Formos Med Assoc 1996; 95: 350-352.

3. Ford CE, Jones KW, Miller OJ, Mittowoch U, Penrose LS, Ridler M, et al. The chromosomes in a patient showing both mongolism and the Klinefelter syndrome. Lancet 1959; 1: 709.

4. Yamaguchi T, Hamasuna R, Hasui Y, Katida S, Osada Y. 47XXY/48XXY, +21 chromosomal mosaicism presenting as hypospadias with scrotal transposition. J Urol 1989; 142: 797-798.

5. Jyothy A, Kumar KSD, Rao GNM, Rao VB, Swarna M, Umadevi B, et al. Cytogenetic studies of 1001 Down syndrome cases from Andhra Pradesh, India. Indian J Med Res 2000; 111: 133-137.