Statistics from Altmetric.com
Editor—There are many reports of partial trisomy 8p in the offspring of balanced translocation carriers.1-3 However, in these cases the effect of the partial trisomy is usually masked by the phenotypic consequences of partial monosomy of the partner chromosome.
Partial trisomy for 8p also results from the well known inverted duplication of 8p usually described as inv dup(8)(p11.2p23); this rearrangement, however, also results in partial monosomy for the segment 8p23.1→8pter.4-6 The inv dup(8) is associated with a well defined clinical syndrome,5-9 the childhood phenotype of which includes neonatal feeding problems, hypotonia, structural brain abnormalities, facial dysmorphology, malformed, low set ears, and severe developmental delay. In older patients the facial traits are less characteristic, mental retardation is profound, and spastic paraplegia and orthopaedic problems are frequent. It is known that patients with deletion of 8p23→pter as their sole chromosome abnormality have a near normal phenotype with only mild mental retardation and minimal dysmorphology.10-12 The phenotypic findings of inv dup(8)(p11.2p23) are therefore considered to arise primarily as a result of the duplicated segment 8p21.
More recent reports have described smaller, more distal duplications of 8p in which there is no evidence of any monosomic segment.13-17 Dhooge et al 13 described the transmission of a duplication dup(8)(p22→p23.1) or (p21.3→p22) from a mother to her two children. The associated clinical features were mild mental retardation, short stature, and hypertelorism. Engelen et al 14 described a similar case of transmission of partial trisomy 8p resulting from dup(8)(p22→p23.1) from a mother to her two sons. In this family, mental retardation was mild and there was no growth retardation, only the mother showed slight facial dysmorphology. Barber et al 15recently described seven families with small duplications of 8p23.1 and reviewed five families previously reported in abstract form.16 17 In 10 of the 12 families and 25 of 27 duplication carriers, no phenotypic abnormality was recorded and it was suggested that duplication of 8p23.1 should be considered a cytogenetic anomaly of no established significance. Barber et al 15 described fluorescence in situ hybridisation (FISH) studies with YAC HTY3020 which suggested that this apparent duplication may involve amplification of a small part of 8p23.1.
In this report we describe a mother and her two daughters (fig 1) with minimal dysmorphology and no significant mental retardation, all of whom had duplication of chromosome region 8p23.1. The chromosomes have been studied with G banding and FISH with whole chromosome paint, a subtelomeric probe for 8p, and YAC HTY3020 which maps to 8p23.1.18 19
Patient 1 is the proband who was born in 1995 at term after an uneventful pregnancy and delivery. Birth weight was 3350 g, length 50 cm, and occipitofrontal circumference (OFC) 32 cm. It was noted that she had a smallish head with very mild facial dysmorphism. Karyotyping was requested and chromosome analysis showed an abnormal chromosome 8 with extra material on the short arm. She is the first child of non-consanguineous parents. The healthy father was 32 years old and the mother 30 years old at the time of the proband’s birth. When seen in 1998 at 3 years of age, her weight was 11.6 kg (25th centile), height 88.5 cm (25th centile), and OFC 46 cm (10th centile). She was noted to have bilateral clinodactyly and prominent medial epicanthi. Developmental milestones were within normal limits.
Patient 2 is the younger sister of patient 1. She was born in 1996 at term, following an uncomplicated pregnancy with a birth weight of 3720 g, length 48 cm, and OFC 33 cm. It was noted that she had a smallish head with mild facial dysmorphism and upward slanting palpebral fissures. She also had clinodactyly, bilateral simian creases, and deep skin creases between the first and second toes. She was karyotyped and found to have an abnormal chromosome 8 which was identical to that of her sister. In 1998 at the age of 14 months, she was referred to the Paediatric Clinic at KK Hospital, Singapore for assessment of microcephaly. The developmental assessment was satisfactory; she gained head control at 3 months, sat at 8 months, was walking unsupported at 1 year, and started saying single words at the same time. When seen aged 14 months, her weight was 10 kg (50th centile), height 77 cm (50th centile), and OFC 42 cm (0.7 cm less than the 3rd centile). She was noted to have a small, flattened nose, prominent medial epicanthi, and bilateral clinodactyly. No other dysmorphic features were noted.
Patient 3 is the healthy mother of patients 1 and 2. She had regular education and worked as a sales clerk. Her father, aged 60 years, is healthy and her mother died of a “stroke” at the age of 50. She has four sisters and two brothers of normal intelligence. Her first pregnancy resulted in a spontaneous abortion at 2 months’ gestation. She was karyotyped after the birth of her first child and found to be carrying the same abnormal chromosome 8. On examination in 1998 she was noted to have bilateral clinodactyly and no other dysmorphic features.
Karyotyping was performed on G banded metaphase chromosomes after routine PHA stimulated peripheral blood culture. Synchronisation by thymidine block20 was used to obtain high resolution chromosomes. Chromosome analysis of the three patients showed in each case a karyotype with extra material on the end of the short arm of one chromosome 8 (fig 2). The father of patients 1 and 2 had a normal male karyotype.
FISH with a whole chromosome paint for chromosome 8 (WCP 8) (Cytocell) was performed following the manufacturer’s instructions. The paint hybridised over the total length of both copies of chromosome 8 and not to any other chromosomes, showing that the extra material was derived from chromosome 8.
FISH with a subtelomere probe mapping to locus D8S596 (Oncor) which hybridises to band 8p23→pter was performed according to the manufacturer’s instructions. Results with this probe showed two sets of signals in each of the 20 cells examined, one set of signals on the tip of the normal 8p and one set on the tip of the abnormal 8p. Our interpretation is that both the abnormal and the normal 8 have one copy of the locus D8S596. These results suggest that the rearrangement is interstitial and that telomeric sequences are not involved.
YAC HTY3020 which maps to 8p23.1 was hybridised as previously described15 to metaphases from patients 2 and 3 (fig 3). It showed significant contrast in signal intensity between the homologues of chromosome 8, suggestive of amplification in the abnormal chromosome.
We have described a family showing transmission of a small duplication, dup(8)(p23.1p23.1) from a mother to her two daughters. G banded analysis suggested that the abnormality was a duplication, and application of WCP 8 confirmed that the extra material was indeed derived from chromosome 8. Application of the 8p subtelomere probe mapping to locus D8S596 suggested that the 8p telomeric sequences were not deleted and that the additional material was interstitial. FISH with YAC HTY3020 confirmed the involvement of 8p23.1, the contrast in signal strength between homologues suggesting the possibility of amplified sequences.
The duplication we report is smaller and extends more distally than those described by Dhooge et al 13 and Engelen et al 14 (fig 4). In the family described by Dhoogeet al,13 the duplication of 8p was characterised by G banded analysis and FISH with a whole chromosome paint. In the family described by Engelen et al,14 the duplication of 8p was confirmed by FISH with cosmid probes specific for the region 8p23.1→pter. There was no cytogenetic evidence for deletion of the telomeric sequences in either of these families, neither was it possible to confirm whether the duplication was inverted or direct, although Engelenet al 14 favoured the interpretation of a direct duplication. Barber et al 15 showed gain of distal 8p material by comparative genomic hybridisation which was localised to band 8p23.1 using FISH with YAC HTY3020. The duplication which we report appears identical to the cases described by Barber et al 15 and the karyotype in all three patients has been interpreted as 46,XX,dup(8)(p23.1p23.1).ish dup(8)(p23.1p23.1) (HTY3020++). However, involvement of distal p22 or proximal p23.2 cannot be excluded, especially as this might account for the fine G dark band seen midway between p22 and p23.2 on the duplicated chromosome.
The clinical features noted in the three patients of Dhoogeet al 13 included mild mental retardation, short stature, and hypertelorism, whereas Engelenet al 14 reported mild mental retardation as the only constant finding. Barber et al,15 reviewing 27 carriers of duplication 8p23.1, reported only two subjects with phenotypic abnormality (short stature and developmental delay) and concluded that dup(8)(p23.1) is a cytogenetic anomaly of no established significance. The family we describe shows mild phenotypic features with no mental retardation. Microcephaly, small flattened nose, and prominent medial epicanthi were seen in patient 2 at the age of 14 months. Patient 1 at the age of 3 years showed only prominent medial epicanthi and bilateral clinodactyly. The mother of the two girls had no facial dysmorphology or mental retardation; the only feature seen in adulthood appeared to be bilateral clinodactyly. It would therefore appear that this small duplication has minimal, if any, phenotypic effect and may be unrelated to the slight dysmorphology seen in this family.
Small distal duplications of 8p are an entity quite distinct from the inv dup(8)(p11.2p23) syndrome. The inv dup(8)(p11p23) results in duplication of 8p21→p22 and a clinically recognisable multiple congenital anomalies/mental retardation syndrome with severe clinical effect and reduced reproductive fitness such that transmission does not occur. In contrast, the smaller and more distal duplications of 8p22 and 8p23 result in a much milder phenotype with unaffected reproductive fitness. If the duplication extends no further than 8p23.1 it seems unlikely that there is any associated clinical effect and it should probably be considered a cytogenetic variant of no clinical significance. However, caution is needed in interpretation as duplications extending proximally into band 8p22 are associated with mental retardation.
We thank Dr H Donis-Keller for generating and Dr A Jauch for supplying YAC HTY3020.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.