Journal of Medical Genetics

Copyright © 1997 by Journal of Medical Genetics.
Volume 34(8)             August 1997             p 702
A study of brothers with Klinefelter syndrome
[Letter To The Editor]

Woods, C. Geoffrey; Noble, Jayne; Falconer, Alaister R.

Yorkshire Regional Genetics Service, Department of Clinical Genetics, Ashley Wing, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK (Woods).
Regional DNA Laboratory, Department of Clinical Genetics, Ashley Wing, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK (Noble).
Department of Paediatrics, Scarborough General Hospital, Woodlands Drive, Scarborough, North Yorkshire YO12 6QL, UK (Falconer).

Outline


Graphics

Klinefelter et al [1] described males with infertility, hypogonadism, and gynaecomastia in 1942. The other clinical features of Klinefelter syndrome are now well delineated but not present in all affected subjects. [2] The live birth prevalence of Klinefelter syndrome is approximately 1 in 1000. [3] The diagnosis is made and confirmed by the cytogenetic finding of 47,XXY. Klinefelter syndrome is considered to be a sporadic disorder resulting from non-disjunction. This is maternal in one half of cases and paternal in the remainder. [4,5] The empirical recurrence risk is negligible as the condition occurs sporadically, with the recurrence risk equal to the birth prevalence, that is, 1 in 1000. Given this, it is not surprising that Klinefelter syndrome is very rarely reported to recur within a family. There are limited reports of sibs with Klinefelter syndrome [6,7] or of twins. [8,9] Therefore we wish to document our clinical, cytogenetic, and molecular findings of a family in which brothers had Klinefelter syndrome.

The older boy was diagnosed as having Klinefelter syndrome at the age of 5 years. He had reduced left elbow supination and radiography showed radioulnar synostosis. Diagnosis was made in the younger sib at the age of 3 years because of undescended testes and a "willowy appearance" similar to his older affected brother. Both had heights approximately on the 50th centile, weights on the 3rd centile, and reduced upper to lower body segment ratios of 0.87 and 0.85. The older sib is at Tanner stage 1 of sexual development at 11 years. Both are otherwise normal on examination, of normal intellectual ability, and neither has any behavioural problems.

Both parents were healthy, normal on examination, and aged 24 years at the time of birth of their first child with Klinefelter syndrome. The couple had no difficulty in conceiving and no recognised pregnancy losses. They are first cousins from the Punjab and are themselves products of first cousin marriages (Figure 1). There are no other family members known to have chromosome anomalies, infertility, or frequent miscarriages.


Figure 1. Pedigree with the males with Klinefelter syndrome shown as filled squares. Cytogenetic analyses and X chromosome genotype results are shown for the nuclear family. The latter were generated using the microsatellite present in intron 13 of the factor VIIIC gene. The results are given as the polymerase chain reaction products measured in base pairs.
Chromosome analysis of peripheral blood lymphocytes was performed on nuclear family members, 50 cells being examined in each case. The brothers with Klinefelter syndrome were non-mosaic 47,XXY, other family members having normal results. X chromosome haplotype analysis was performed using an Applied Biosystems 373 DNA Sequencer and Genescan 672 software. The microsatellite present in intron 13 of the factor VIIIC gene at Xq28 was informative, but nine microsatellites from the dystrophin gene were uninformative. [10] The results are shown in Figure 1; both boys with Klinefelter syndrome had apparently inherited an X chromosome from their father.

These sibs with Klinefelter syndrome had typical clinical features, non-mosaic 47,XXY, and their additional X chromosome was the result of a paternal meiosis I error. Possible explanations for this situation are chance, that the father is a Klinefelter syndrome mosaic which seems unlikely, or that the father has an autosomal recessive disorder affecting meiosis. We have been unable to investigate the family further by single sperm analysis and because no other relative is known to have had a child with aneuploidy.

C Geoffrey Woods

Yorkshire Regional Genetics Service, Department of Clinical Genetics, Ashley Wing, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK

Jayne Noble

Regional DNA Laboratory, Department of Clinical Genetics, Ashley Wing, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK

Alaister R Falconer

Department of Paediatrics, Scarborough General Hospital, Woodlands Drive, Scarborough, North Yorkshire YO12 6QL, UK

REFERENCES^
1. Klinefelter HF, Reifenstein EC, Albright F, et al. Syndrome characterised by gynaecomastia, aspermatogenesis without aleydigism and increased secretion of follicle stimulating hormone. J Clin Endocrinol Metab 1942;2:615. [Context Link]

2. Jones KJ. Smith's recognisable patterns of human malformation. 4th ed. Philadelphia: Saunders, 1988. [Context Link]

3. Nielsen J, Wohlert M. Sex chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Birth Defects 1990;26:209-23. [Medline Link] [Context Link]

4. Jacobs PA, Hassold TJ, Whittington E, et al. Klinefelter's syndrome: an analysis of the origin of the additional sex chromosome using molecular probes. Ann Hum Genet 1988;52:93-109. [Medline Link] [Context Link]

5. Lorda-Sanchez I, Binkert F, Maechler M, Robinson WP, Schinzel AA. Reduced recombination and paternal age effect in Klinefelter syndrome. Hum Genet 1992;89:524-30. [Medline Link] [Context Link]

6. Gustavson KH, Gamstorp I, Meurling S. Bilateral teratoma of testis in two brothers with 47,XXY Klinefelter's syndrome. Clin Genet 1975;8:5-10. [Medline Link] [Context Link]

7. Takayasy J, Kinoshita K, Tsuboi T, Kurihara T. Twins with Klinefelter's syndrome. Lancet 1967;ii:1424. [Context Link]

8. Hatch TR, Moore RJ. Klinefelter syndrome in identical twins. Urology 1985;26:396-7. [Medline Link] [Context Link]

9. Flannery DB, Brown JA, Redwine FO, Winter P, Nance WE. Antenatally detected Klinefelter's syndrome in twins. Acta Genet Med Gemellol 1984;33:51-6. [Medline Link] [Context Link]

10. Laloz MR, McVey JH, Pattison JK, Tuddenham EG. Haemophilia A diagnosis by analysis of hypervariable dinucleotide repeats within the factor VIII gene. Lancet 1991;338:207-11. [Context Link]