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Editor—Since the initial case of partial trisomy 6q was reported by de Grouchy et al,1 2 at least 23 additional cases have been published. The majority of these cases represent the abnormal segregation of a balanced parental chromosome translocation. While trisomy 6q patients do have some common characteristics, the inconsistent phenotypic features are usually attributed to an accompanying area of monosomy. Most often the deleted area is the terminal band of the recipient chromosome,3-13 although longer deletions have also been reported.14-16 Only deletion of the short arm of acrocentric chromosomes are without clinical effect, as these are the nucleolar organiser regions (NOR) containing the ribosomal genes which are present in multiple copies within the genome. Robertsonian translocation carriers, who lack two NORs, are phenotypically normal. Hence, trisomy 6q patients who lack one NOR2 17-20 can be regarded as cases of “pure” trisomy 6q, together with cases of insertion21 22 and duplication23-25 of 6q material.
We report a pair of sibs who carry der(7)ins(7;6)(q21.11;q22.1q23.3)mat, as confirmed by fluorescence in situ hybridisation (FISH). Their phenotypes are compared with other cases of “pure” partial trisomy 6q.
Case 1, the proband (II.3, fig 1) is an ethnic Chinese male. He was born at term, weighing 3345 g, to a 32 year old, gravida 7, para 2 female and a 38 year old male. He was referred aged 7 years because of his dysmorphic features and because he was failing in school. The proband's mother had had four spontaneous first trimester miscarriages before the birth of her four children. There was no known consanguinity or previous history of congenital abnormality in the family, neither was there any history of recurrent spontaneous miscarriages in the parent's sibs.
Physical examination showed central obesity with weight (30 kg) on the 97th centile. Height (124.2 cm) was between the 90th and 97th centile but the head circumference (52 cm) was on the 50th centile. Additional craniofacial dysmorphism consisted of brachycephaly, a flat facial profile, bushy, pointed eyebrows, mild hypertelorism, downward slanting palpebral fissures, a flat nasal bridge with anteverted nares, severe midfacial hypoplasia, and a bow shaped mouth with thick lips. Bilateral clinodactyly was also present. He had noisy breathing and a tendency to mouth breathe. The mother noted that he snored loudly but there were no complaints of daytime somnolence. He had been slow in attaining developmental milestones and was found to be educationally subnormal with an IQ of 50 ± 8. A two dimensional echocardiogram, performed because of the presence of a systolic murmur, was normal. Permission to publish clinical photographs was refused.
Case 1 was evaluated for obstructive sleep apnoea (OSA) using standard polysomnography. This showed no significant obstructive apnoea. Sleep efficiency was satisfactory. There was no paradoxical inward rib cage movement during inspiration, desaturations, or bradycardia documented.
Case 2 (II.2, fig 1) is the older sister of case 1. She was also born at term by normal delivery and weighed 3175 g. She was seen at 17 years of age. Her height (155.3 cm) was between the 25th and 50th centile and her weight (40.8 kg) was between the 3rd and 10th centile. She had brachycephaly, a flat facial profile, bushy, pointed eyebrows, mild hypertelorism, a flat nasal bridge with anteverted nares, midfacial hypoplasia, a bow shaped mouth, and bilateral clinodactyly. Her craniofacial features were similar to, but milder than, those of her brother. In comparison to him, she did not have downward slanting palpebral fissures or obesity and had thin lips with a long philtrum. Her secondary sexual development was found to be normal. She did not consent to formal IQ testing but was noted to have been slow in attaining developmental milestones and had left school without academic credits. She did not consent to be photographed.
Peripheral blood lymphocytes were cultured from all available family members using a thymidine synchronisation technique. The father and sib II.4 were 46,XY. The mother's karyotype was interpreted as 46,XX,ins(7;6)(q21.11;q22.1q23.3), which represents a balanced direct insertion of chromosome 6q22.1→6q23.3 into band q21.11 on chromosome 7 (fig 2). Cases 1 and 2 were found to carry the mother's altered chromosome 7, namely der(7)ins(7;6)(q21.11;q22.1q23.3)mat, in addition to two normal copies of chromosome 6, which represents trisomy for the region 6q22.1→6q23.3. FISH, conducted according to the manufacturer's instructions and performed with a chromosome 6 paint and chromosome 6q telomeric sequences, confirmed the presence of trisomy 6 and the interstitial nature of the insertion (fig 3).
The external clinical features and karyotype of the 11 previously published cases of “pure” partial trisomy 6q, together with the present cases, are summarised in table 1. The eight cases on the left hand side (group I) have in common an overlap of the region 6q26→6q27. The five cases on the right hand side of the table (group II) represent varied areas of partial trisomy 6q (fig 4). The cases comprise nine males and four females. In both our family and those previously described,21 22 the inherited insertion was maternal in origin. Of the inherited translocations with deletion of ribosomal material, two were paternal17 18 and three were maternal in origin.2 19 20 In two cases,23 25 the observed duplication was de novo and in one case24 the origin was not able to be determined.
All cases, sufficiently old to assess, exhibited some form of mental retardation and in all cases the majority of the dysmorphism was craniofacial. Despite the relatively large areas of duplicated genetic material, major organ malformation does not appear to be frequently involved in the partial trisomy 6q syndrome. Only two cases17 20 died in infancy, both from complications arising from cardiac anomalies; the oldest reported case21was 19 years old. Group I cases, with the overlap of 6q26→6q27, are characterised by growth retardation, microcephaly, micrognathia, and a short webbed neck. These features are not often found in the group II cases, which adds weight to 6q26→6q27 being the critical region for this phenotype. This was first suggested by Turleau and de Grouchy2 and was further defined by Brøndum-Nielsenet al,25 whose patient lacked duplication of the 6q27 telomeric sequences. Midfacial hypoplasia is observed only in our patients and that of Henegariuet al,24 which may or may not be related to the common breakpoint at 6q23.3. A sleep study was performed in case 1 to exclude OSA in view of his symptoms (noisy breathing, snoring, poor school performance) and the association between midfacial hypoplasia and obstructive sleep apnoea.26 Despite the severe midfacial hypoplasia, case 1 did not have OSA.
To our knowledge, trisomy for the region 6q22.1→6q23.3 has not been previously reported. We observed the phenotype to be quite different from that recorded in cases which have an overlap of the 6q26→6q27 region. Traits in common to subjects with different areas of trisomy are probably the result of perturbation of multifactorial gene interaction. The currently known genes for disorders (deafness, argininaemia, cardiomyopathy, and hereditary persistence of fetal haemoglobin), proteins (phospholamban, myristoylated alanine rich protein kinase C substrate, protein L-isoaspartate O-methyltransferase, glucocorticoid regulated kinase, immunodeficiency virus type I enhancer binding protein-2, immune interferon receptor, transcription factor 21, and connective tissue growth factor), and DNA sequences (six-twelve leukaemia gene and non-coding transcript in T cells) within 6q22.1→6q23.3 do not appear to be related to the observed features. While the phenotype must represent the effect of the triplicated genes in this area, there remains much to be discovered about the mechanisms involved.
This investigation was supported by grant (RP 3690022/N) from the National Medical Research Council of Singapore.