Pure partial trisomy of the short arm of chromosome 5

Marie Odile Rethore1,2, Mane Christine de Blois2, Marie Peeters2, P.Popowski3, C.Pangalos2, and J. Lejeune2

Hum Genet (1989) 82:296-298

Résumé :

Summary : We describe a male infant with multiple dysmorphic features who is trisomic for chromosome segment 5p13.32 ? 5p14.2 as a result of recombination aneusomy. His father is a balanced carrier of an inverted insertion of this chromosome segment. The clinical features of this patient are compared with those of other patients with isolated partial 5p trisomy reported in the literature.




Monosomy 5p (cri-du-chat syndrome), first described in 1963 by Lejeune et al., is a well-recognized clinical entity, and the diagnosis can readily be made at birth. The diagnosis of trisomy 5p, however, is more difficult and usually made only on chromosome analysis. We report the case of a child tri-somic for chromosome segment 5p13.32 ? 5p14.31 due to a re-combination aneusomy (Lejeune and Berger 1965).


Case report


Clinical history

The propositus (IV 2, Fig. 1) was born on January 20, 1987 at 39 weeks gestation, following an uneventful pregnancy. At birth he weighed 3000 g and measured 47 cm, and his head cir-cumference was 36.5 cm. Both parents (III 6 and III 7) were in good health. The mother had had one spontaneous miscarriage at 8 weeks of pregnancy (in 1985). The family pedigree was unremarkable except for the child III 1 (a son of the paternal uncle of the propositus), who was born with hydrocephalus and who died a few hours after birth.

Fig.l. - Family pedigree. White square with black dot : 46,XY,inv ins(5)(p15.12;p14.2;p14.3), Black square : 46,XY,der(5)(p15.12;p14.2;p13.31)pat

Fig. 2. Propositus at 2 months of age

When examined at 2 months of age (Fig. 2), the propositus weighed 4300 g (P 10-25) and measured 51 cm (< P5), and his head circumference was 40 cm (P 50-75). Generalized hypotonia was noted. His forehead was high with retraction of the temporal regions, which contrasted with his round face and prominent cheeks. The occipital bone was protuberant. His upper eyelids were puffy, and epicanthal folds were present. The palpebral fissures were small due to mild blepharophimosis and were horizontally slanted. The irides were blue and cryptic, and he had coloboma of the iris and retina bilaterally. His nose was short with a broad, flat bridge and large septum, through which ran a median groove. The pillars of the philtrum were poorly marked. His mouth was small with a short upper lip and a thick, everted lower lip. Glossoptosis was present, due to posterior positioning of the tongue. He showed micro-retrognathia. His ears were low set. The superior border of the helix was horizontal bilaterally. The left antihelix formed a single crest, which ended with one prominent fold. Just behind the antitragus a small unusual pitlike cutaneous depression was noted; the superior half of the pinna hung down loosely.

His neck was short and wide. His abdomen, was prominent secondary to hypotonia. An umbilical hernia and major diastasis recti were noted. The testes were in the scrotum; the penis was large and angulated. He had bilateral clubfoot. The toes of his right foot were irregularly implanted and overlapped, the first toe overlapping the second and the fourth overlapping the third. In both hands the flexion creases were normal. His fingers were long, with a radial loop on the thumb and IV, and arches on II, III and V, bilaterally.

At 1 year of age the child weighed 9000 g (P 10-25) and measured 74.5cm (P 25), and his head circumference was 49.5cm (P 95). His skull was turricephalic with depression of the temporal regions. His face, especially the cheeks, appeared infiltrated. Developmental milestones were only slightly delayed: he smiled, had social contact, and sat without support, but did not stand; he was capable of only monosyllabic vowel sounds. The D.Q. (Brunet-Lezine) was 75.



Cytogenetic analysis (Figs. 3, 4) of the proband's peripheral blood lymphocytes revealed a male karyotype with 46 chromosomes. In all the mitoses analyzed, the short arm of one chromosome 5 was too long. After RHG-banding, it was seen that band 5p15.1 was too marked and that zone 5p14 was slightly elongated. The other chromosomal segments appeared normal.

The maternal karyotype was normal. The paternal karyotype analyzed by RHG-banding revealed that in spite of normal total arm length, the short arm of one of the chromosomes was structurally abnormal. Band 5p15.1 was too prominent (as observed in the propositus), whereas band 5p13.3 was extremely small. The other chromosomes were normal. Karyotype analyses done in prometaphase (Viegas-Pequignot and Dutrillaux 1978) showed that both father and son had a chromosomal anomaly that was limited to the short arm of one chromosome 5. As is seen in Fig. 3. the paternal karyotype analyzed by RHG-banding showed an exaggeration of band 5p15.1, reduction of band 5p13.3, and a very minute, colored band at 5p14.2, which was absent on the normal homologous chromosome. This arrangement could arise from three breakpoints (at 5p13.31, 5p14.3, and 5p15.12) and inverted translation of chromosome segment 5p13.32 ? 5p14.2, the segment 5p125.11 ? 5p14.3 keeping its normal centromeric orientation.

During paternal meiosis, the translated and inverted segment (13.32-14.2) could remain unpaired, forming translation loops (see Fig.3A). One chromatid exchange (or an odd number of exchanges) in the paired segment (14.3-15.11) could have produced the recombinant chromosome observed in the propositus. A double loop figure could also have occurred if the inverted translated segment also pairs (see Fig.3B). If the single chromatid exchange (or odd number of exchanges) in segment (14.3-15.11) produced the recombinant chromosome, then the propositus is trisomic only for chromosome segment 5p13.32 ? 5p14.2 (46,XY, inv ins(5)(pter ? p15;12: :p13.32 ? p14.2::p15.11 ? p14.3:: 13.31 ? qter). The balanced inversion-insertion described in the proband's father was also found in the paternal grandfather (II3, Fig. 1) and in the paternal great uncle (II3). The rest of the kindred could not be examined.

Fig. 3. - Meiotic pairing and crossing-over in an inv ms(5)(pter ? p15.12::p13.32 ? p14.2::p15.11 ? p14.3::13.31 ? qter) resulting in recombinant chromosome 5 with duplication of the 5p13.32-^5p14.2 segment. A Simple translation loops, B double-loop figure

Fig.4a,b* - Chromosomes 5: a of the proband; b of the father. The arrows show the abnormal chromosomes. R bands and G bands



Cases of isolated trisomy or monosomy resulting from a parental translation and subsequent recombination aneusomy have been reported (Lejeune and Berger 1965). Review of the literature revealed nine cases similar to our observation. Five of these cases showed inverted insertion (Gustavson et al. 1988; Kajii et al. 1987; Martin et al. 1985; Palmer et al. 1977; Wyandt et al. 1980), and one case, an intrachromosomal direct shift (Therkelsen et al. 1973); in the remaining cases (Cohen et al. 1983; Narahara 1987; Pai et al. 1983) the displaced segments were so small that they precluded any interpretation pertaining to their centromeric orientation. In three of the reported cases, translation of the chromosomal segment occurred within the chromosome arm (Kajii et al. 1987; Nara" hara 1984; Wyandt et al. 1980). Parental translation was of maternal origin in five cases and of paternal in the remaining four observations.

Since the first reported observation of trisomy 5p in 1964 (Gustavson et al. 1964; Lejeune et al. 1964) about forty other cases have been reported. Most of the cases arise from translocations involving the short arm of chromosome 5 and another autosome. These partial trisomies for the short arm of chromosome 5 are therefore associated with other chromosomal disequilibriums.

We were able to find nine other reports of isolated trisomy 5p. Six of these were complete 5p trisomies (Brimblecombe et al. 1977; Carnevale et al. 1982; Cordero et al. 1977; Kunze et al. 1980; Leschot and Lim 1979; Orye et al. 1983); and resulted either from the formation of an isochromosome for the short arm of one chromosome 5 or from a translocation of 5p onto the centromere of an acrocentric chromosome. Klecz-kowska et al. (1987) reported a patient with an isolated partial trisomy 5p resulting from a tandem duplication of segment 5p13.1 ? 5p15.3. This polymalformed infant had hydrocephalus, agenesis of the corpus callosum, abnormal fixation of the jejunum and of the ascending colon, hypoplastic polycystic kidneys, and small adrenal glands with marked cortical hypoplasia. Marked hypertelorism, narrow palpebral fissures with a mongoloid slant, poorly lobulated ears, and microretrognathia were noted. The limbs were long and slender and both thumbs were in fixed adduction. The patient had bilateral clubfeet but no other skeletal anomalies were documented on X-ray.

The patient reported by Gustavson et al. (1988), trisomic for segment 5p13 ? 5p15, had moderate macrocephaly, a prominent forehead, and a protruding occiput. The nose was short with a broad, flat nasal bridge. The photograph (Fig. 2) of the child shows, as in our patient, a wide nasal septum with a median groove. The patient had alternating convergent strabismus, luxation of the right hip, and equinovarus deformity of the feet. At age 5 years her I.Q. was 45. A CT scan showed slight enlargement of the ventricles without hydrocephaly.

A case of trisomy 5p resulting from a de novo tandem duplication was reported by Chia et al. (1987). The patient was trisomic for the distal portion of the short arm of chromosome 5: 5p14 ? 5pter. Dysmorphic features were minimal (bifid tip of the tongue, bilateral genu valgus, and slightly wide-spaced nipples), and the developmental delay was mild (IQ of 68 at age 4 2/12 years).

The clinical picture of our patient is very similar to the one described by Gustavson et al. (1988) and is less severe than that reported by Kleczkowska et al. (1987), whose patient also had macrocephaly, small palpebral fissures, hypertelorism, micrognathia, and equinovarus deformity of the feet.

From these observations and as already suggested by Leschot and Lim (1979) and by Orye et al. (1983), it would seem that the clinical severity of trisomy 5p is due not only to the length of the duplicated segment, but perhaps essentially to trisomy for all or part of segment 5p13.



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