Presented at the European Chromosome Conference, Vienna, July 1999

Case Report
After a chorionic Villus sample had revealed an apparently normal female karyotype on direct preparation, this patient was referred to this department at birth with bladder extrophy, unusual streaked skin pigmentation and ambiguous genitalia.

Cytogenetic Results
Peripheral Blood:

The peripheral blood sample at birth revealed an abnormal female karyotype (fig 1)

46,XX,add(10)(p15). ish add(10)(wcp4+) de novo

The additional material on the short arm of chromosome 10 was shown by Fluorescence In Situ Hybridisation (FISH) studies to be derived from chromosome 4 material (fig 3), and it was deduced from the banding pattern to most likely be 4q31.1 - 4qter. This anomaly therefore, is a derivative chromosome 10 of the rearrangement t(4;10)(q31.1;p15). As both parents were shown to have normal karyotypes this was considered to be a 'de novo' event.

Fig 1. Peripheral blood karyotype:
46,XX,add(10)(p15). ish add(10)(wcp4+) de novo.
(Click on image to enlarge)

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Skin Biopsies:
Biopsies taken from pigmented and non-pigmented areas of the patient's skin showed the following Cytogenetic results
(confirmed by Molecular Cytogenetics-fig 3):

Pigmented Skin - 46,XX,idic(10)(qter-p15::p15-qter)/46,XX,der(10)t(4;10)

Non-Pigmented Skin - 46,XX, idic(10)(qter-p15::p15-qter)

As the anomalies seen in PB and skin were not detected prenatally these are believed to be post Zygotic events.

Fig 2. Skin biopsy karyotype:
46,XX, idic(10)(qter-p15::p15-qter).
Click on an image to enlarge

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Possible Mechanism of Origin of Chromosome Abnormality
It is postulated that this patient began embryonically with an apparently normal female karyotype as detected in the Chorionic Villus sample (CVS). A post zygotic mitotic anomaly lead to the formation of the t(4;10) of which the der(4)t(4;10) was subsequently lost leaving only the add(10)(p15) or der(10)t(4;10)(q31.1;p15) detectable in the peripheral blood and in a mosaic form in the pigmented tissue. This rearranged chromosome 10 then underwent a series of events, the process being postulated as 'Uing' or U-type exchange first described in 1989 by Wik Sjostedt et al (Hereditas 1989;111:115-123). This U-type exchange event involves chromosome breakage, in this case breakage at the translocated chromosome 4 end of the derived chromosome 10 followed by a subsequent reunion between the sister< chromatids. This event is thought to be generated by an abnormal event in DNA replication. The result being the idic(10)(qter-p15::p15-qter)(fig 4) detected in both the pigmented skin in a mosaic form and in the non-pigmented skin as the sole abnormality.

Fig 3. Mechanism for U-type exchange.
(Click on an image to enlarge)

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Skin Pigmentation
The pigmentary anomalies in this case have resulted directly from the presence of a mosaic cell line. Numerous and diverse chromosomal abnormalities have been reported in patients with pigmentary anomalies distributed along the lines of Blaschko, which are linear areas of skin differentiated from adjoining skin only by a difference in pigmentation. They are aligned along the axis of limbs and circumferentially around the trunk, and are thought to represent the tracts of migration of melanocytes. Blaschko lines also show genetic mosaicism, characteristically present in peripheral blood lymphocytes and/or skin fibroblasts cultures. Chromosomal aberrations may conclude in abnormalities of pigmentation as a result of the altered expression of genes in the pigmentary pathway which map to a number of different chromosomes. Our case confirms the relationship between chromosomal mosaicism and anomalous skin pigmentation, particularly as lines of Blaschko are followed. This stresses the importance in these cases of careful evaluation of cells which should include a lymphocyte karyotype and karyotypes from skin biopsies from both dark and light skin.

Fig 4. C-band image of idic(10).
Click on an image to enlarge

We postulate that in this case the pigmentary anomalies may have resulted directly from the altered expression or gene dosage effect of specific pigmentation genes or regulators of pigmentation localised on chromosome 10.

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