I Med Genet 1992; 29: 407-411

Distal 8p deletion (8p23.1-+8pter): a commondeletion?

R Hutchinson, M Wilson, L Voullaire

AbstractThe clinical manifestations and cytoge-netic details of five patients with a denovo deletion of the short arm of chro-mosome 8, del(8)(p23), are described.Of the four surviving children all hadmild mental retardation and subtle facialanomalies; three of the five had cardiacabnormalities. The clinical features seenin these patients are compared with thoseof three previous single case reports withdel(8)(p23), and with patients describedas having the '8p -' syndrome associatedwith del(8)(p21).The findings in these patients suggest

that major congenital anomalies, es-pecially congenital heart defects, are fre-quent even in small distal 8p deletions,but facial dysmorphism may be subtleand mental retardation less severe thanin those with deletions associated withmore proximal breakpoints.The five patients were detected within a

four year period, suggesting that thisdeletion syndrome is relatively frequent.The possible mechanisms for the forma-tion of terminal deletions are discussed.

An '8p - 'syndrome has been described associ-ated with partial deletion of the short armof chromosome 8, del(8)(p21).1 The features ofthis syndrome include mental retardation, post-natal growth retardation, dysmorphic facies,and congenital heart defect. Terminal deletionof a smaller segment of 8p (8p23.1 -+pter) hasrecently been reported in three patients withless marked phenotypic abnormalities.24

Victorian ClinicalGenetics Services,Murdoch Institute,Royal Children'sHospital, FlemingtonRoad, Parkville,Victoria 3052,Australia.R HutchinsonM WilsonL Voullaire

Correspondence toMs Voullaire.Received 18 June 1991.Revised version accepted1 October 1991.

We describe five further patients with thisdistal deletion, and compare their clinicalfeatures with those previously reported.

Case reportsCASE 1This 8 year old girl (fig 1) was delivered atterm after a normal pregnancy. There wereepisodes of staring and eye fluttering in theneonatal period suggesting seizures: EEG andcerebral ultrasounds were normal. She sat at 6months, walked at 15 months, and has persist-ing fine motor and coordination problems. Sherarely vocalised in infancy, produced her firstrecognisable word after the age of 2 years andat 8 years had limited speech abilities but couldconduct simple conversations. She had a leftconvergent strabismus associated with hyper-metropia which improved with correctivelenses. Pubic hair was noted from the age of 7years, attributed to premature adrenarche. Sheis described as affectionate, extremely activeand distractable, easily frustrated, and some-times aggressive.On examination at the age of 8 years 7

months her OFC was 52 cm (50th centile),height 134-5 cm (90th centile), and weight433 kg (>97th centile). Her face was round,with broad cheeks and a relatively narrowforehead. Her palpebral fissures were slightlyupward slanting, her eyelashes were long, andshe had prominent eyebrows. Her nasal bridgewas high, her nose small, and the upper lip wasthin and tented. Her hands were small withtapered, pudgy fingers and her feet were shortand broad. Tanner stage 2 pubic hair waspresent, but there were no other signs of

Figure 1 Case I at 8 years of age: note broad cheeks, high nasal bridge, and puffy tapering fingers.

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puberty or virilisation. General clinical exam-ination was otherwise normal.

CASE 2This male child (fig 2) was the second child ofhealthy parents. Apart from first trimesterhyperemesis, the pregnancy and delivery werenormal. Fetal ultrasound at 36 weeks had sug-gested mild dilatation of the cerebral vent-ricles, but no increase in ventricular size wasfound on cerebral ultrasound at birth and at 1month. Episodic vomiting attacks, at intervalsof weeks to months, occurred from the age of 2weeks. These episodes typically lasted two tothree days and were associated with frequentvomiting, lethargy, and a dazed appearance.No metabolic abnormalities were detected. In-travenous pyelogram and micturating cystour-ethrogram, performed after a urinary tractinfection at the age of 2 months, were normal.A cerebral CT scan showed partial agenesis ofthe corpus callosum with dilatation of thetemporal and occipital horns of the lateralventricles and wide separation of the bodies ofthe lateral ventricles. Cardiac catheterisation,performed at 19 months for investigation of anasymptomatic cardiac murmur, showed mildpulmonary valve stenosis and a small patentforamen ovale. He sat unaided at 8 months,walked at 17 months, and spoke his first wordsafter the age of 2 years.On examination at the age of 3 years 9

months his weight was 14-4kg (3rd to 10thcentile), height 95 5 cm (10th centile), andOFC 51 2cm (50th centile). His overall de-velopmental function was equivalent to 2-5years and his neurological examination wasnormal apart from a tendency to drool.Minor facial anomalies noted were dolicho-

cephaly, high and prominent forehead, highnasal bridge, long philtrum, prominent pre-maxilla, high palate, retrognathia, and poster-iorly rotated ears with poor definition of thesuperior crus of the antihelix. Apart from mildpectus carinatum, pes planus, and a systoliccardiac murmur, general physical examinationwas normal.

Figure 2 Case 2 at 3 years 9 months and case 4 at 2 years 2 months of age.

CASE 3This 4 year old girl (fig 3) was born at term ofa pregnancy associated with poor maternalweight gain, and her low birth weight wasattributed to placental insufficiency. Gavagefeeding was required for several days in theneonatal period. At 6 weeks she presented withpoor feeding, cyanosis, and congestive cardiacfailure. Investigations showed mild ventricularseptal defects, Ebstein's anomaly, patent duc-tus arteriosus, and pulmonary hypertension.She underwent ligation of the PDA and pul-monary artery banding at 7 weeks and furthersurgery at 12 months. An intravenous pyelo-gram performed after a urinary tract infectionat 10 months showed mild right hydronephro-sis (ultrasound at 4 years showed that this hadresolved). She required surgical correction of aleft convergent strabismus; subsequent visualacuity was normal.On examination at the age of 4 years, her

height was 97 cm (10th centile), weight 15 kg(10th centile), and OFC 45 cm (< 3rd centile).She had a broad forehead, laterally upswepteyebrows, high, broad nasal bridge, smallanteverted nose, broad cheeks, wide mouth,thin upper lip, and posteriorly angulated ears.Her hands were small with tapered fingers,clinodactyly, and a single right transverse pal-mar crease. She had pes planus and prominentheels. She had mild to moderate develop-mental delay, was extremely active, sleptpoorly, had frequent tantrums, and was de-scribed as affectionate but difficult to control.

CASE 4This boy (fig 2) was the product of a pregnancyassociated with mild pre-eclampsia in the thirdtrimester and delivery was by LSCS at termfor fetal distress in labour; Apgar scores were 3and 9. His first feed precipitated a cyanoticepisode; oesophageal atresia with tracheo-oes-pageal fistula was diagnosed and repaired onday 1. He was observed to have preaxial poly-dactyly of the left hand, a left undescendedtestis, and widely separated first and secondtoes. Chest x ray showed 13 pairs of ribs andextra thoracic vertebrae. Renal ultrasoundstudies showed horsehoe kidneys and bilateralureteric reflux. Echocardiogram and cerebralultrasound were normal. Subsequently, he hashad good general health, but has mild tomoderate developmental delay.On examination at the age of 2 years 7

months his height was 86 cm (3rd to 10thcentile) and weight 12 8 kg (10th to 25th cent-ile). He had a narrow forehead, narrow down-ward slanting palpebral fissures, broad nasalbridge, and widely spaced nipples, but generalexamination was otherwise normal.

CASE 5This infant was delivered at term by emerg-ency LSCS for fetal bradycardia with Apgarscores of 6 and 8. Clinical features includednarrow and receding forehead, prominent pre-maxilla, micrognathia, low set ears, and singletransverse palmar creases.

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Distal 8p deletion (8p23.1-+8pter): a common deletion?

Figure 3 Case 3 at 4 years of age: note broad cheeks, high nasal bridge, smalljaw, and puffy fingers.

Central cyanosis developed on day 1, andcardiological investigations showed a completeAV canal, common AV valve, double outletright ventricle, small left ventricle, and severepulmonary stenosis. A right subclavian to rightpulmonary artery shunt was performed on day3. Cranial ultrasound showed no cerebralstructural abnormality. The infant's clinicalcourse was complicated by cardiac arrhyth-mias, recurrent right upper lobe collapse/consolidation, necrotising enterocolitis, andmultiple episodes of leukemoid reaction andfever, suggesting sepsis. Death occurred at 11weeks. Necropsy was not performed.

CYTOGENETIC STUDIESMitotic cells were obtained from PHA stimu-lated peripheral blood lymphocytes (perman-ent cell lines were not established). Metaphasechromosomes were examined after GTLbanding at the 550 band level. In each patientdeletion of the short arm ofone chromosome 8,del(8)(p23), was observed in an otherwise nor-mal karyotype (fig 4). In case 4 the paternalkaryotype was normal, but the mother was notstudied. In all other cases parental chromo-somes were found to be normal.

DiscussionWe have described five patients with partialdistal deletion of 8p (8pter-+p23.1). Threepatients had chromosome analysis at less than1 year of age because of major anomalies anddysmorphic features. The main indication inthe other two cases, ascertained at 2 years 8months and 7 years 6 months, was develop-mental delay. Congenital heart defects werepresent in three of the five patients and afurther patient had multiple anomalies includ-ing oesophageal atresia with fistula, polydac-tyly, and costovertebral anomalies. No obviousfacial dysmorphism was present except in case5; all other patients had minor facial anomal-ies. Although as a group there was no consist-ent facies, two unrelated subjects (cases 1 and3) presented a very similar facial appearance,characterised by strabismus, high nasal bridgewith broad nasal root, short nose, broadcheeks, small jaw, and low set, posteriorly

8 del(8i 8 del(8

Figure 4 Partial karyotypes of the five patientsshowing the normal and deleted chromosomes 8 afterGTL banding.

rotated ears; both had puffy, tapering fingers.These patients showed a marked resemblancein facial appearance, behavioural characteris-tics, and degree of developmental delay to thepatient with del(8)(p23) reported by Blennowand Brondum-Nielsen.2

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Hutchinson, Wilson, Voullaire

Comparison of the clinical features of our

five patients with del(8)(p23) and three otherspreviously reported with a similar deletion(table) suggests that although there is not a

consistent phenotype, frequent features in-clude developmental delay/mild to moderatemental retardation, behavioural problems(hyperactivity, poor concentration), congenitalheart defects, strabismus, and minor facial anddigital anomalies. Comparison with the clin-ical manifestations of patients with del(8)(p21)shows that the latter group was more likely to

have pre- and postnatal growth deficiency,including microcephaly, and mental retarda-tion was more severe. Congenital heart defectand genitourinary anomalies were common inboth groups. Facial dysmorphism was more

pronounced in the del(8)(p21) patients, butwas non-specific. Epicanthic folds and broad,flat nasal bridge were reported in the majoritywith del(8)(p21), but were not seen in our

patients; rather, the nasal bridge was high.It has been suggested that this smaller ter-

minal deletion may not have any major pheno-typic effect.3 This is not supported by our

findings. Although facial dysmorphism isslight, congenital heart defects, genitourinaryabnormalities, and other major malformationshave been described in over half of thereported patients. Variation in breakpointwithin band 8p23 might be responsible for theobserved variability in clinical presentation inpatients with a cytogenetically similar dele-tion.The deletion seen in these patients is detect-

able at the 400 band level (ISCN) but whenroutine chromosome diagnosis is undertakenusing trypsin banded chromosomes the dele-tion involves partial loss of a light terminal

band and hence it is easily overlooked. Trypsinbanding of longer chromosomes giving a 550band pattern shows the dark band, 8p23.2,within the light band 8p23 and the deletion ofthis dark band is readily observed. This re-

quirement for routine analysis at the 550 bandlevel may explain why it has only recently beendescribed. Children with cardiac defects andmental retardation who had chromosomalanalysis in the past, but not at the 550 bandlevel, may warrant repeat chromosomal invest-igation.The five cases presented here were detected

in a four year period in a laboratory perform-ing predominantly paediatric cytogeneticsand carrying out approximately 1500 chromo-somes analyses annually, drawn from a popu-

lation with an annual birth rate of 60 000. Thissuggests that the deletion may in fact be relat-ively common and have an incidence rate com-

parable to that of the deletion of 5p associatedwith the cri du chat syndrome.

Following the findings of Muller5 andMcClintock6 that terminal deletions producedby X irradiation or physical breakage were

unstable and liable to rejoining, Muller5 postu-

lated the presence of telomeres to explain thespecial properties of the ends of chromosomesthat gave them stability and suggested thatstable terminal deletions were in fact intersti-tial and resulted from two breaks. It has fol-lowed that the stable de novo terminal dele-tions seen in the clinical situation are assumedto result from a two break rearrangement withthe second break occurring close to the telo-mere. However, certain terminal deletions, forexample of 5p, 4p, 18p, 18q, and now appar-

ently also 8p, occur more frequently as de novo

deletions than as unbalanced translocations,

Clinical manifestations in patients with distal 8p deletions.

Blennowand Dobyns

Fryns Brondum- Pecile et al'et al' Nielsen2 et a!4 Case 1 Case 2 Case 3 Case 4 Case 5 Total (10 patients)

del(8)(p23) del(8)(p23) del(8)(p23) del(8)(p23) del(8)(p23) del(8)(p23) del(8)(p23) del(8)(p23) del(8)(p21)

Mat age, pat age 24, 24 28, 30 39, 31 27, 27 25, 37 25, 27 32, 32 33, 34Birth weight (g) 3150 3430 2680 4300 3000 2230 2660 3160 3/8* 9/10*Mental retardation + + + + + + + + 8/8 10/10Hyperactivity/ + + - + - + + - 5/8 ...

behaviour problemsPostnatal growth - - - - - - + N/A 1/7 6/10

deficiencyMicrocephaly - - + - - + - - 2/8 7/10High, narrow forehead - + ... + - - + + 4/7 7/10Epicanthic folds - - - - - - - - 0/8 8/10Upward slanting - + - - - + - - 2/8 ...

palpebral fissuresStrabismus - + - + - + - - 3/8 ...

High nasal bridge ... + - + + + + - 5/7 ...

Wide, flat nasal bridge - - + - - - - 1/8 6/10Short nose - - + + - + - - 3/8 5/10Broad cheeks - + + + - + + - 5/8 ...

Thin upper lip - - + + - + + - 4/8Retrognathia/small + + + + + + + + 8/8 5/10

jawLow set/post + - + + - + + + 6/8 6/10

angulated/malformed ears

Puffy hands/feet ... - + + - + + - 4/7 2/10Pes planus ...- + + + - 3/6 ...

Broad chest/wide set + - + + + + + - 6/8 3/10nipples

Congenital heart - - + - + + - + 4/8 7/10defect

Genitourinary + - - - + + + - 4/8 5/10anomalies

Other malformations - - Diaphragmatic Premature Agenesis - TOF, - 4/8 ...

hernia adrenarche corpus polydactyly,callosum skeletal abn

* No with low birth weight

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Distal 8p deletion (8p23.1 -.8pter): a common deletion?

which suggests that they may not be the resultof random breakage and exchange involvingtwo breaks.Terminal deletions could occur by a re-

combinational mechanism involving unevencrossing over between sister chromatids,or intrachromosomally, by looping out ofthe interstitial region. Such recombinationalerrors might be facilitated by repeat sequencesnear the telomere and within the chromosome.Such mechanisms have been proposed toexplain interstitial deletion of 15ql 1.2 associ-ated with the Prader-Willi syndrome and thepresence of direct and inverted repeatedDNA sequences have been shown in the region15q1 1-13.7

Alternatively, stable terminal deletionsmight be formed following a single break ifhealing occurs to add a telomere. Molecularanalysis of a patient with a truncated chromo-some 16 has shown that healing of a terminallydeleted chromosome can occur.8 This mightinvolve the action of telomerase or occurby recombinational replication mechanismswhere repeats from the telomere of one chro-mosome are copied to that of another.9 Recentevidence'0 suggests that telomerase may oper-ate in the germ cells to add telomeres to theends of chromosomes. Thus, it is possible thata terminal deletion occurring at a particularstage in the development of a germ cell could

be healed by the action of telomerase. Thishealing might be dependent upon the site ofthe initial break, as specific sequences might beneeded in the proximity of the break to permitthe addition of telomeric sequences by telo-merase.8

1 Dobyns WB, Dewald GW, Carlson RO, Mair DD, MichelsVV. Deficiency of chromosome 8p2l.l1-8pter: case re-port and review of the literature. Am J Med Genet1985;22: 125-34.

2 Blennow E, Brondum-Nielsen K. Partial monosomy 8pwith minimal dysmorphic signs. J Med Genet 1990;27:327-9.

3 Fryns JP, Kleczkowska A, Vogels A, Van Den Berghe H.Normal phenotype and slight mental retardation in denovo distal 8p deletion (8pter-.8p23. 1:). Ann Genet(Paris) 1989;32:171-3.

4 Pecile V, Petroni MG, Fertz MC, Filippi G. Deficiency ofdistal 8p-: report of two cases and review of the liter-ature. Clin Genet 1990;37:271-8.

5 Muller HJ. The remaking of chromosomes. In: Studies ingenetics: selected papers of HJ' Muller. New York: Bloom-ington University Press, 1969:384-408.

6 McClintock B. The production of homozygous deficienttissues with mutant characteristics by means of the aber-rant mitotic behaviour of ring-shaped chromosomes.Genetics 1938;23:315-76.

7 Donlon TA, Lalande M, Wyman A, Bruns G, Latt SA.Isolation of molecular probes associated with the chromo-some 15 instability in the Prader-Willi syndrome. ProcNati Acad Sci USA 1986;83:4408-12.

8 Wilkie AOM, Lamb J, Harris PC, Finney RD, Higgs DR.A truncated chromosome 16 associated with a thalassae-mia is stabilized by addition of telomeric repeat(TTAGGG)n. Nature 1990;346:868-71.

9 Wang S-S, Zakian VA. Telomere-telomere recombinationprovides an express pathway for telomere acquisition.Nature 1990;345:456-8.

10 Hastie ND, Dempster M, Dunlop MG, Thompson AM,Green DK, Allshire RC. Telomere reduction in humancolorectal carcinoma and with ageing. Nature 1990;346:866-8.

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