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Skin pigmentary anomalies in a mosaic form of partial tetrasomy 3q
  1. Institute of Medical Biology and Human Genetics, University of Graz, Harrachgasse 21/8, A-8010 Graz, Austria
  1. Dr Kroisel, peter.kroisel{at}

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Editor—In the March 1999 issue of the journal, Portnoi et al 1 reported a patient with hyperpigmentation distributed along the lines of Blaschko2 3 with mosaicism for partial tetrasomy for the chromosomal region 3q27-q29. Here we describe a patient who displays a very similar pattern of skin hyperpigmentation (fig 1A, B) associated with mosaicism for a small partial terminal triplication of 3q (fig 2) leading to functional tetrasomy with the following karyotype obtained from lymphocytes: mos 46,XY, trp(3)(q27.1-qter)[47]/46,XY[4]. Both parents were found to have a normal karyotype. The proband is a 5 year old boy, the first child of healthy, unrelated parents. During early pregnancy intrauterine growth retardation was suspected, but no anomalies were recorded during the following months except reduced fetal movements. He was born by caesarean section 3 weeks before the calculated date of birth because of HELLP syndrome. His birth weight and length were 2810 g and 49 cm, respectively. Owing to his pigmentary skin anomalies, soon after birth the diagnosis of a hypomelanosis of Ito was made. He was retarded in all developmental milestones, as he was not able to sit before the age of 8 months or walk before 21 months and started to speak at about 2 years. Coarse facial features (fig 1A) with pronounced supraorbital ridges, broad nasal bridge, long philtrum, large prominent ears, and hypoplastic enamel structures were noted. He has a bilateral single palmar crease, but his father shows this feature on his right hand as well. At the age of 2 years his weight of 12 kg (25th centile), length of 84 cm (10th-25th centile), and head circumference of 50.5 cm (75th centile) indicated disproportionate growth curves. Psychomotor examination showed a general retardation of about 6-8 months. Magnetic nuclear resonance imaging of the brain showed periventricular lesions of the white matter with no further anomalies. Despite our request to perform a skin biopsy from the light and dark pigmented areas of his skin to allow cytogenetic analysis of these tissue samples as well, his parents have so far refused this. Since, currently, there is no medical necessity to perform this type of analysis, we had to respect their wishes.

Figure 1

Clinical features of the patient aged 5 years. (A) Front view. Note hypertelorism and prominent ears. (B) Hyperpigmentation following the lines of Blaschko.

Figure 2

Partial GTG and RTG karyotype of the normal and the derivative chromosomes 3.

At the age of 5 years the proband was investigated again. He is currently 113 cm (50th-75th centile) tall, weighs 19.5 kg (50th-75th centile), and his head circumference is 53.5 cm (90th centile). He is cooperative and understands questions and commands quite well but his articulation is still rather poor despite regular speech therapy. Motor development in particular with regard to fine movements is about two to three years behind normal. At the cytogenetic level, the size of the partially tetrasomic segment seems to be identical to the previously reported case.1 We performed FISH analysis using the same YAC clones (806_d_8, 760_f_3, 781_f_8, 883_d_12) as described to determine how similar at the molecular level the chromosomal breakpoints are. A triplication was confirmed for two YACs (781_f_8 and 883_d_12) whereas the more proximal YAC, 806_d_8, showed only one signal on the rearranged chromosome. Furthermore, the YAC 760_f_3, which is just a few megabases proximal to 781_f_8, does not map to the triplicated region. This indicates that the breakpoint in 3q27.1 is not identical at the molecular level in both patients, but is more distal in our proband. From the hybridisation pattern of the triplicated YAC clones it can be concluded that the terminal triplication on the derivative chromosome 3 occurred because of an insertional inverted duplication (fig 3). FISH analysis using a probe specific for the subtelomeric region of the long arm of chromosome 3 (Vysis) showed additional interstitial signals on the derivative chromosome 3 (results not shown).

Figure 3

Partial metaphase cell showing the localisation of the YAC clone 883_d_12 on the normal and the derivative chromosome 3. Note that the inverted orientation of the inserted fragment was confirmed by the relative position of the hybridisation signals.

The patient described by Portnoi et al 1 was claimed to be the first with a pure partial tetrasomy of 3q but he is of normal intelligence and does not show dysmorphic features. As can be judged from the distribution of normal versus abnormal cells in lymphocytes and skin fibroblasts, in particular from the dark pigmented areas, the percentage of partially tetrasomic cells in their patient is much lower than in our case. This could be the explanation why the proband described here exhibits psychomotor retardation and dysmorphic features. However, the observation of Portnoi et al 1 that in the partial tetrasomic cells for 3q27.1-qter a more intensive skin pigmentation is obvious can clearly be confirmed in the unique karyotype-phenotype constellation present here. It was proposed that because of a gene dosage effect caused by the partial tetrasomy, one or more genes involved in skin pigmentation are responsible for the hyperpigmented brown streaks following the lines of Blaschko (fig 1B). No obvious candidate gene responsible for this effect has been mapped so far to this chromosomal segment; however, the melanoma associated antigen p97gene4 might be involved. Although the partial tetrasomy 3q27.1-qter in both patients is caused by different chromosomal rearrangements, a break in band 3q27.1 must have occurred in both of them during the first postzygotic cell divisions. Molecular studies with mapping of chromosomal breakpoints allowed us to exclude the involvement of a single gene in both affected subjects. In conclusion, partial tetrasomies for an autosomal segment are rare and deserve more attention when they are associated with an unusual phenotype.