Turner's syndrome mosaicism in patients with a normal blood lymphocyte karyotypeBMJ 1999; 318 doi: https://doi.org/10.1136/bmj.318.7187.856 (Published 27 March 1999) Cite this as: BMJ 1999;318:856
- Cristina Azcona, research fellow,
- Philippe Bareille, research fellow,
- Richard Stanhope, consultant ()
- Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children and Middlesex Hospital (UCLH), London WC1N 8AA
- Correspondence to: Dr Stanhope
- Accepted 26 June 1998
Most doctors believe that a normal blood lymphocyte karyotype excludes the diagnosis of Turner's syndrome. However, there are patients whose dysmorphic features strongly suggest Turner's syndrome, but whose lymphocyte karyotype is normal. In the past, these patients have probably been labelled inappropriately as having Noonan's syndrome. In a girl with some of the clinical features of Turner's syndrome—growth failure,1 gonadal dysfunction, cardiovascular abnormalities, renal anomalies, a webbed or short neck, or both, cubitus valgus, and nail dysplasia, 2 3 —it is important to make an accurate diagnosis. Turner's syndrome has serious sequelae throughout life—especially with regard to hypertension, oestrogen replacement, infertility, and skeletal integrity.
We describe four patients who had features of Turner's syndrome (see table), but whose lymphocyte karyotype was normal. All had more than just short stature. The patients in cases 1, 3, and 4 had other clinical features of Turner's syndrome, while the girl in case 2 had no dysmorphic features but a pattern of growth failure typical of Turner's syndrome. The girls subsequently underwent skin biopsy for fibroblast culture and chromosome analysis. In one patient (case 3), an initial lymphocyte karyotype was reported as normal (46, XX), but a second investigation showed 2 out of 100 cells had a 45, XO Turner's syndrome karyotype after the analysis of skin fibroblasts.
Clinical features of Turner's syndrome in patients with a normal lymphocyte karyotype point to the necessity of assessing the karyotype in other tissues, notably the skin. A skin biopsy for fibroblast analysis is quick and easy to perform, and leaves only a small scar. We diagnosed Turner's syndrome in four girls who had a normal lymphocyte karyotype, but in whom chromosomal analysis of skin fibroblasts showed Turner's mosaicism. The discrepancies between the blood and skin karyotypes found in our patients mean that previous cases of Turner's syndrome have been undiagnosed or misdiagnosed.
We suggest that in some cases of Turner's syndrome the abnormal cell lines die out in the bone marrow, thereby leaving the 46, XX cell line. This phenomenon may be explained by the rapid cell turnover in the bone marrow. It is well known that the distribution of the constituent karyotype in tissues differs in patients with a mosaic chromosome complement. However, restriction of monosomy X to specific tissues such as skin, 4 5 endometrium,5 and ovary6 is unusual.
Turner's syndrome is believed to occur in 1 per 2500 liveborn girls, and in approximately one third of cases analysis shows mosaics on the lymphocyte karyotype.7 Normal lymphocyte karyotypes with chromosomal aberrations in skin fibroblast cultures have probably been observed in some cytogenetic laboratories, but have rarely been reported. Thus, doctors may be unaware of the indications for chromosomal analysis of a second tissue in some patients.
Although rare, mosaicism limited to certain tissues has been described previously in disorders such as trisomy 21, 8 9 trisomy 8 mosaicism,10 and triploidy.11 The factors influencing survival of an aneuploid cell line in given tissues are unknown, as are the mechanisms by which mosaicism occurs. Several observations in vivo 12 13 and in trisomy 8 mosaicism10 suggest that aneuploid cell lines may be lost over time in lymphocytes of people who have persistent euploid/aneuploid mosaicism in skin fibroblasts. Our observations contradict the assumption that the determination of blood karyotype is an absolute test, and the principles we have described may well be applicable to other chromosomal disorders.
Turner's syndrome should be suspected in any girl with two or more of the clinical features of that disorder. For example, growth failure in a girl with short stature or primary ovarian failure or osteoporosis in a short woman are indications for skin karyotype determination if the blood chromosome complement is normal. In conclusion, we believe that Turner's syndrome is such an important diagnosis that some patients with a normal lymphocyte karyotype warrant cytogenetic evaluation of a second tissue, usually the skin, when this diagnosis is strongly suspected.
Contributors: RS coordinated the study and had the original idea for performing skin biopsies in girls when there was suspicion of Turner's syndrome; he is guarantor for the paper. CA and PB collected the data and wrote the manuscript.
Funding CA was funded by the Fundación Ramón Areces, Spain. PB was funded by the Child Growth Foundation. We are grateful to Serono (UK) for secretarial support.