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Deletion and duplication of the adenomatous polyposis coli gene resulting from an interchromosomal insertion involving 5(q22q23.3) in the father

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Editor—Chromosomal rearrangements occur at a low frequency in the general population and chromosomal insertions occur at an estimated frequency of 1 in 5000 newborn infants.1 Adjacent segregation of interchromosomal insertions results in a deletion or duplication of the inserted segment or more complicated imbalances through a recombination event at meiosis. In the case presented here, a balanced interchromosomal insertion between chromosomes 5 and 10, 46,XY,dir ins(10;5)(q25;q22q23.3), was carried by the father. Theoretically this insertion involves less than 1% of the haploid autosomal length and therefore a fetus with either a duplication or deletion is likely to be viable unless there are essential genes in this segment that are deleterious in an aneuploid conceptus. Generally deletions are more deleterious than duplications and there are few published cases where the clinical features of a duplication and deletion for the same chromosomal region have been described within the same family.2 3

In this paper we report four cases of a 5q22q23.3 deletion and one case of a duplication for the same region which includes theAPC gene. All of the aneuploid offspring were within the same generation and the clinical features associated with 5q22q23.3 deletion with a similar genetic background will be compared with published cases.

Lymphocytes were cultured by standard methods including semi-synchronisation with thymidine and preparations were analysed using G banding.4 Fluorescence in situ hybridisation (FISH) of the chromosome preparations involved YAC probe 37HG4 containing a 2.3 kb fragment of cDNA from theAPC gene which recognises anMspI polymorphism.5 TheAPC gene has been localised to the subband 5q22.1.5 Standard FISH procedures were used and have been published elsewhere.6 FISH images were viewed using computer enhanced image analysis systems (Vysis).

The family were investigated on the birth of the proband. The parents were first cousins of Asian origin and the mother did not speak any English. At the birth of the second child the father was 34 and the mother 21 years of age. They have three clinically normal children (first, third, and eighth pregnancies, II.1, II.3, and II.8) although the chromosome constitution of one of them is unknown (II.1). However, the remaining five pregnancies resulted in chromosomally abnormal offspring (fig 1).The parents had genetic counselling after the birth of their second child (case I, II.2) and further follow up of family members was declined.

Figure 1

Diagrammatic summary of clinical features in the family. The father (I.2) carries the interchromosomal insertion. N=normal karyotype.

In case 1 (II.2) the pregnancy was uneventful and the infant was delivered at term. At birth his Apgar score was 3 at one minute, 6 at five minutes, and 9 at 10 minutes. Intubation failed as the vocal cords could not be visualised owing to the malformed head and neck. His birth weight was 1860 g and head circumference 34 cm. Physical examination showed cleft palate, micro-osmia, anteverted nostrils, micrognathia, downward slanting palpebral fissures, talipes equinovarus, polydactyly (nine toes on the right foot), low set ears, bilateral VII cranial nerve palsy, and ulnar deviation of the fingers (fig 2). He was also tachypnoeic from birth with chest wall recession and irregular respiratory effort. Chest x ray showed clear lungs. Septic and TORCH screen were normal. Arterial blood gases showed a mild metabolic acidosis. ECG was normal. The tachypnoea remained unexplained. The proband was initially nursed in oxygen but later tolerated air. The child showed restricted movement of all limbs. At 16 days an x ray showed a fractured right humerus with callous surrounding a fracture of the right clavicle. No pathological cause was found. He was extremely irritable, with a paucity of spontaneous movement and inability to feed without a nasogastric tube.

Figure 2

(A) Case II.2 at birth and (B) polydactyly and talipes of the right foot. (All photographs reproduced with permission.)

On day 23 he became deeply cyanosed with breathing even more laboured than previously and died suddenly the same day. Necropsy was declined on religious grounds.

The patient's karyotype showed a deleted chromosome 5, 46,XY,del(5)(q22q23.3). Investigation of the parents' blood indicated that the mother had a normal female karyotype. However, the father had an interchromosomal insertion of the 5q22q23.3 segment into chromosome 10, 46,XY,dir ins(10;5)(q25;q22q23.3) (fig 3).

Figure 3

A diagrammatic representation of the interchromosomal direct insertion between chromosomes 5 and 10 in the father.

The proband's karyotype was therefore 46,XY,der(5)dir ins(10;5)(q25;q22q23.3)pat.

With case 2 (II.3, fig 1), the mother had an amniocentesis at 17 weeks' gestation; a normal male chromosome constitution was reported and the pregnancy continued to term. The baby had no dysmorphic features at birth and examination at 5 years of age showed a unilateral simian crease, clinodactyly, and a right undescended testis. An orchidopexy was later performed.

With case 3 (II.4, fig 1), the parents initially declined prenatal diagnosis but ultrasound scan at 19 weeks' gestation showed hydrocephalus and lumbosacral spina bifida. The pregnancy was terminated at 22 weeks' gestation after cytogenetic analysis of amniotic cells showed an abnormal karyotype, 46,XY,der(5)dir ins(10;5)(q25;q22q23.3)pat. At necropsy the fetus weighed 280 g, crown-rump length was 17.0 cm, and head circumference 24.5 cm. External examination showed frontal bossing and a large head. The lumbar meningomyelocele was confirmed but the fetus also had borderline hydrocephalus, a horseshoe kidney, and bilateral talipes. No heart, lung, or brain abnormalities were evident, but the lung, adrenal, and thymus showed congestion.

With case 4 (II.5, fig 1), the mother presented in the second trimester and ultrasound scan at 21+4 weeks' gestation showed a normal sized fetus for gestation. The head circumference was 18.6 cm, BPD 53 cm, and the heart, spine, and diaphragm appeared normal. However, polydactyly (six toes on each foot), bilateral talipes, and arthrogryposis of the elbows and fingers were evident, and a pterygium at each elbow was suspected on ultrasound. A fetal blood sample was taken for cytogenetic studies and analysis showed a male fetus with the der(5). FISH studies using the APC probe showed only one signal in all divisions examined, 46,XY,der(5)dir ins(10;5)(q25;q22q23.3).ish der(5)dir ins(q25;q22q23.3)(37HG4−) (fig 4). The parents elected to terminate the pregnancy.

Figure 4

FISH using YAC probe 37HG4 showing a single signal (arrowed) in a metaphase from II.2.

With case 5 (II.6, fig 1), the mother presented in the second trimester and an ultrasound scan at 19 weeks' gestation was normal. Prenatal diagnosis was declined. The male child, born at term weighing 2700 g, was clinically normal on initial assessment. Blood was sent for karyotyping at birth by the paediatricians because of the previous family history. Neonatal blood showed a male child with a duplication of 5q22q23.3, 46,XY,der(10)dir ins(10;5)(q25;q22q23.3)pat (fig 5). FISH using the APC probe showed three signals on blood interphase cells, nuc ish 5q22.1(37HG4x3). Detailed examination of the child after cytogenetic investigation showed a third fontanelle, bilateral clinodactyly, a unilateral simian crease, and an undescended left testis. No other dysmorphic features were evident. The child was developmentally normal at 2 years of age.

Figure 5

FISH using chromosome 5 paint showing a duplication of chromosome 5 material inserted into chromosome 10.

In the pregnancy of case 6 (II.7, fig 1), the mother underwent initial ultrasound examination at 20 weeks' gestation. This showed talipes, polydactyly, and arthrogryposis. Cytogenetic analysis of the amniotic fluid showed a female fetus with a der(5), 46,XX,der(5)dir ins(10;5)(q25;q22q23.3)pat. The parents elected to continue the pregnancy and a dysmorphic child was born at term. The child had a cleft palate, downward slanting palpebral fissures, clenched fists, restricted hip movement, polydactyly of the right foot (six toes), hirsutism, talipes, micrognathia, and low set ears (fig 6). She also had similar respiratory difficulties to case 1. Examination at 3 months showed further dysmorphism including developmental delay, glossoptosis, barrel shaped chest, abnormal lumbosacral spine, increased tone, simple left ear, unilateral accessory auricle, and epicanthic folds. The child had to be fed by nasal tube as she was unable to feed orally. The child died at 11 months of age and necropsy was declined.

Figure 6

(A) Case II.7 at birth and (B) polydactyly and talipes of the feet.

With case 7 (II.8, fig 1), the mother declined prenatal diagnosis but serial ultrasound appeared normal and growth was satisfactory. The pregnancy and birth were uncomplicated. A male child was born at term and the Apgar scores were 8 at one minute and 9 at five minutes. There were no dysmorphic features at 8 weeks of age except unilateral clinodactyly which was also present in the mother. The karyotype was normal, 46,XY.

The oldest male child (II.1) has not been karyotyped but his growth and development are normal.

Interchromosomal insertions are individually rare events and in this family both a deletion and duplication of the inserted region were viable. Interchromosomal insertions involve three break rearrangements and theoretically such insertions can lead to aneusomy via two mechanisms, segregation or recombination. However, observed aneusomies have mostly resulted from segregation7 and only exceptionally from recombination.8 In this family adjacent 1 segregation of the insertion has provided a unique study of four monosomy 5q22q23.3 offspring with a similar genetic background and a clinically normal child with a duplication of 5q22q23.1. There has been one other reported case of a (10;5) interchromosomal insertion and this gave rise to an infant with duplication of a more proximal region of 5q(q13q22).9

Of the previous 27 cases where a deletion of 5q13-31 has been published, 24 have arisen de novo11 13-31 and three were recombinants from an intrachromosomal insertion.10 12 As far as we are aware this is the first reported case of deletion 5q resulting from segregation of an interchromosomal insertion in the parent.

Earlier publications have described either a distal 5q22 or proximal deletion of 5q13 because of the similarity of the bands in 5q. Consistent clinical features associated with deletion of distal 5q22-q31 include developmental delay, low birth weight, failure to thrive, decreased fetal movement, polyhydramnios, camptodactyly, small mouth, high arched palate, micrognathia, hypertelorism, downward slanting palprebal fissures, short stature, head circumference above 35 cm, frontal bossing, epicanthic folds, depressed nasal bridge, anteverted nostrils, low set ears, short neck, cleft palate (50% cases), head and heart abnormalities (50% cases), talipes, simian crease, and mental and motor retardation. Other clinical features less frequently observed were dislocation of the hips (28%), thin upper lip (28%), carp shaped mouth (28%), and repeated respiratory and urinary infections (43%).32 The four cases described here all had talipes and arthrogryposis while case 1 also had low birth weight, failure to thrive, depressed nasal bridge, micro-osmia, anteverted nostrils, low set ears, micrognathia, carp shaped mouth, cleft palate, downward slanting palpebral fissures, single simian crease, short neck, mental retardation and recurrent respiratory infections. Case 3 had skull enlargement, frontal bossing, and low set ears while case 6 had cleft palate, downward slanting palprebal fissures, low set ears, and respiratory problems. Only three published cases have a similar breakpoint (5q22q23.3) to the deletion cases described here and two had mental retardation, multiple epidermoid cysts, long midface, and APC.12 A third case19 described an adult with a bossed, high forehead, long philtrum, high arched palate, joint laxity, long fingers, and APC. Interstitial deletions of 5q22 have been reported in adults with polyposis coli but as the cases described here have a larger deletion involving 5q23.3 they are unlikely to survive to adulthood when APC would be evident.

Several consistent features between the cases presented in this paper and previously published cases of a deletion of 5q22q23.3 include arthrogryposis and talipes, suggesting that some limb development genes as well as APC are localised to this chromosomal region. One of the malformations displayed by cases 1, 4, and 6 was polydactyly. In view of the proposed role ofAPC in some forms of apoptosis and the function of the Drosophila homologues ofAPC, β-catenin, and GSK3β in segment polarity and other aspects of cell fate,33 the finding of polydactyly in this family is of interest. Mice carrying the Apcmutation have been seen to display digital abnormalities, but polydactyly is not a frequent finding in patients with deletions of the APC locus and may therefore be a consequence of genes other thanAPC in the family presented here.34

Reports of duplication for the distal 5q segment are rare, as many are a result of an unbalanced segregation of a translocation and are also deleted for another chromosome. Case 5 and that of Gilgenkrantz et al 9 are unique in that they are both the result of familial insertion. Three patients with a duplication of 5q22q23.3 have been reported and were all clinically dysmorphic with developmental delay. Features included microcephaly, psychomotor and mental retardation, small ears, strabismus, sloping, enlarged forehead, prominent nasal bridge, small chin, disproportionately long arms, esotropia, spasticity, and episodes of self mutilation.32 Patients with a more distal duplication have features which include low birth weight, brachycephaly, clinodactyly, facial anomalies with protruding nose, and enlarged forehead.32 Case 5 is unusual in that duplication of a segment of 5q22q23.3 incorporating a known gene has occurred without obvious phenotypic effect at 4 years of age. The child had a simian crease, clinodactyly, and undescended testis, but these features are also found in normal subjects; this is supported by the presence of the same phenotype in one of the sibs (case 2) who had a normal karyotype. The presence of an extra copy ofAPC could have a longer term effect especially in the colorectum. This child is effectively a natural experiment and if no phenotypic abnormalities of the colorectum occur then this would have implications for the safety of gene therapy for FAP in that an extra copy of APC in a colonocyte is not harmful.

Ultrasonography is becoming an increasingly more useful tool for detecting pregnancies at risk for a chromosome abnormality or genetic disorders. However, for couples with a known chromosome rearrangement, prenatal diagnosis is essential if a viable offspring with an abnormal clinical outcome is likely. It is also recommended that cases of clinically normal subjects with unbalanced karyotypes are published so that an informed decision can be made by parents prenatally when a similar rearrangement is identified. This paper presents such an example, as duplication of 5q22q23.3 may not result in clinical abnormality.


The authors would like to thank Simon Roth who referred the proband to the Cytogenetics Department and Helwyn Morgan for referring subsequent prenatal samples. The ideogram was produced using Applied Imaging software.