Familial Transmission of a Small SupernumeraryMarker Chromosome 8 Identified by FISH:An Update

H. Rothenmund,1 A.E. Chudley,1,2 and A.J. Dawson1,2*1Department of Human Genetics, University of Manitoba, Winnipeg, Manitoba, Canada2Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada

A father and his 2 daughters were previ-ously determined to carry a small, supernu-mary marker chromosome [Chudley et al.,1983]. The origin of this marker could not bedetermined by standard cytogenetic tech-niques. In this study, fluorescence in situhybridization (FISH) studies identified themarker chromosome as a pericentric de-rivative of chromosome 8. The father haslow grade mosaicism for this marker and isphenotypically normal. Both daughters arenon-mosaic and show developmental delaysand somewhat differing clinical findings.The phenotypes of the 2 sisters are com-pared with those previously reported for su-pernumerary der(8) patients. This is thefirst report of familial transmission of a su-pernumerary der(8) marker chromosome.Am. J. Med. Genet. 72:339–342, 1997.© 1997 Wiley-Liss, Inc.

KEY WORDS: FISH; marker chromosome;partial trisomy 8; mosaicism

INTRODUCTION

Partial trisomy 8 is associated with a phenotype thatresembles full trisomy 8 syndrome and comprises along face, thick everted lower lip, high protruding fore-head, deep palmar and plantar skin furrows, abnormaltoe posture, hypoplastic or absent patellae, and renal,vertebral, genital, and urethral abnormalities [Fine-man et al., 1979; Walker and Bocian, 1987]. We reporton a family in which the father and 2 daughters carrya supernumerary marker chromosome [Chudley et al.,1983] identified as a der(8) with fluorescence in situhybridization (FISH).

CLINICAL REPORT

The oldest daughter (III-1 [Chudley et al., 1983]) wasborn with a right duplicated thumb. The pregnancywas normal and birth weight was 3.65 kg. Renal ultra-sound and electrocardiograms were normal. All motormilestones were achieved at the appropriate ages.Apart from recurrent otitis media and plantar warts,her health has been good. She was noted to have de-velopmental delays at an early age. At 10 yearsWISC-R testing showed a verbal score of 60, a perfor-mance score of 46, and a full scale score of 50. Sheattends a functional life skills program for the mentallyhandicapped at a local high school and has participatedin a work placement program at a local bakery. She hasexhibited some abnormal, autistic-like behaviors withunusual shyness, immaturity, withdrawal, anxiety,tension, and perseveration of topics. These have im-proved with time. She has difficulties with additionand subtraction but can recognize several words. Atage 17 years, she was cooperative; her height was 170.5cm (90th centile), weight was 67 kg (75th centile) andOFC was 55 cm (40th centile), and she had no anoma-lies.

The youngest daughter (III-2 [Chudley et al., 1983])was born at term. She weighed 4.0 kg and was noted tohave coarctation of the aorta which was repaired at 5days. Chromosome studies at that time identified a su-pernumerary marker chromosome. Subsequently, thesame marker was demonstrated in her older sister andin a mosaic state in her father. This child is functioningat a higher level and has fewer autistic-like behaviorsthan her sister. She attends a special education pro-gram in a local high school. She is a pleasant, respect-ful, and cooperative student who gets along well withher peers. She is shy in new situations, is naive, andcan be easily led. She has poor speech and languagedevelopment and has poor awareness of necessary lifeskills. She does have a habit of picking sores on herskin. She has difficulties with math. She is able towrite at an elementary level. She is involved in a vol-untary work placement program. At age 15 years, shehad no anomalies. Her height was 165 cm (75th cen-tile), weight 56 kg (50th centile), and OFC 53 (10thcentile).

*Correspondence to: Dr. A.J. Dawson, Cytogenetics Laboratory,685 William Avenue, Winnipeg, Manitoba, Canada R3E 0Z2.E-mail: adawson@cc.umanitoba.ca

Received 9 January 1997; Accepted 22 May 1997

American Journal of Medical Genetics 72:339–342 (1997)

© 1997 Wiley-Liss, Inc.

The father (II-2 [Chudley et al., 1983]) is now 45years old. Apart from high myopia, he is in good health.He graduated from university with a masters degree.Physical findings were normal. His height was 192 cm(>95th centile), weight was 86 kg (85th centile) and hisOFC was 58.5 cm (95th centile).

MATERIALS AND METHODSCytogenetic and FISH Studies

Peripheral blood samples were re-obtained from thetwo sibs and their parents. Chromosomes were pre-pared by standard techniques and Q-banded. One hun-dred metaphases were examined to determine the cur-rent marker frequency. Oncor (Gaithersburg, Mary-land) digoxigenin-labelled Coatasome probes wereused for FISH analysis. In situ experiments were per-formed as outlined in the manufacturer’s protocol [On-cor, 1994]. The slides were mounted in antifade solu-tion with propidium iodide for counterstaining. The hy-bridization signals appeared yellow and the remainingchromosomal DNA red.

RESULTS

The current frequency of the marker (Fig. 1) wasfound to be 98%, 97%, and 10% for the 1st and 2nddaughters and the father, respectively. FISH analysisdetermined the marker to be a derivative of the peri-centric region of chromosome 8 (Fig. 2). The result-

ing karyotype of the daughters is interpreted as47,XX,+mar.ish der(8)(wcp 8+). The father’s karyotypeis 46,XY[90]/47,XY,+mar[10].ish der(8)(wcp8+). Break-points could not be determined due to the minute sizeof the marker chromosome.

DISCUSSION

Previous cytogenetic studies documented the pres-ence of a small supernumerary chromosome in bothdaughters and their father [Chudley et al., 1983]. Thismarker could not be identified by standard cytogenetictechniques. Current FISH analysis identified themarker as a derivative of the pericentric region of chro-mosome 8. The fluctuation in marker frequency in thedaughters is interpreted as a reflection of cultural ar-tefact. However, the father was found to carry themarker in 10% of his cells as compared to the initiallyreported frequency of 27% [Chudley et al., 1983]. Thisreduction in frequency likely reflects the phenomenomof preferential marker loss after successive cell divi-sions [Bernstein et al., 1978].

Complete trisomy 8 is a known cytogenetic syndromebut mosaicism is much more common [Schinzel, 1983].Patients with a supernumerary marker of a small peri-centric region of chromosome 8 have been reported pre-viously [Melnyk and Dewald, 1994; Spinner et al.,1995; Butler et al., 1995]. These patients have a phe-notype that is nonspecific but is described as consistentwith that seen in patients with mosaic trisomy 8 syn-drome. The phenotype of mosaic trisomy 8 includesskeletal, cutaneous, and facial anomalies. Ankylosedlarge joints, clubfoot, absent or hypoplastic patellae,

Fig. 1. Q-banding demonstrating the supernumary marker chromo-some (arrow).

Fig. 2. Hybridization of Coatasome 8 Whole Chromosome Probe to thenormal chromosomes 8 (right) and the supernumerary marker (left).

340 Rothenmund et al.

and arachnodactyly/brachydactyly appear to be pre-sent in some form in most patients. Deep grooves in thepalms and soles are virtually diagnostic in infancy butbecome less prominent with age. The face is charater-ized by a prominent, pouting lower lip and small jaw.Mental retardation may be present but is often mildand may remain undetected.

The clinical findings of the 2 daughters in thepresent study reflect the variable effects of partialtrisomy 8 mosaicism. These 2 sisters, both carriers ofthe identical supernumerary der(8) marker, have dif-ferent clinical phenotypes. The oldest daughter is moreseverely mentally and behaviorly handicapped andpresented with preaxial polydactyly as the only majorsomatic anomaly. Her younger sister had a cardiacanomaly but no minor anomalies. Both girls andtheir father tend to be slim with a long trunk. Theoldest daughter and father are tall which may be afamilial trait. The phenotypic presentation of our casesis compared with that in the literature (Table I).Without the availability of FISH technology, wewould not have predicted the chromosome origin ofthe marker. Retrospectively, some of the findingscould have suggested a chromosome 8 origin (slendertrunk, relatively normal facial appearance). Thisidentification has finally allowed some degree of clo-sure with respect to the original studies over 15years ago, thus allowing us to provide more specificprognostic implications and information to the family.This study supports the observation that the charac-

teristics of mosaic trisomy 8 syndrome cannot be cor-related to particular duplicated regions of chromo-some 8 [Walker and Bocian, 1987]. The phenotypicvariability of this syndrome is extensive [Kurytka etal., 1988] and it is difficult to predict physical growthand development when a der(8) marker chromosome isdetected.

ACKNOWLEDGMENTS

We thank Dr. A. Danilkewicz for providing clinicalinformation and for originally referring the family, Di-ane Riordan for her expert technical assistance, andthe family for their patience and persistent cooperationwith this study.

REFERENCES

Bernstein R, Hakim C, Hardwick B, Nurse GT (1978): Significance of de-tection of extra metacentric microchromosome in amniotic cell culture.J Med Genet 15: 136–142.

Butler MG, Roback EW, Allen GA, Dev VG (1995): Identification of a ringchromosome as a ring 8 using fluorescent in-situ hybridization (FISH)in a child with multiple congenital anomalies. Am J Med Genet 57:494–495.

Chudley AE, Zheng HZ, Pabello PD, Shia G, Wang HC (1983): Familialsupernumerary microchromosome mosaicism: Phenotypic effects andan attempt at characterization. Am J Med Genet 16:89–97.

Fineman RM, Ablow RC, Breg WR, Wing SW, Rose JS, Rothman SLG,Warpinski J (1979): Complete and partial trisomy of different seg-

TABLE I. Manifestations of Supernumerary Ring/Marker Chromosome 8

Melnyk & Dewald[1994]

Spinner et al.[1995]

Butler et al.[1995]

Rothenmund et al. [1997]; Chudley et al. [1983]

II-1 III-1 III-2

Age at diagnosis 15 months 7 months 3 days 30 years 4 years At birthReasons for referral Developmental

delay, hypotoniaDevelopmental

delay, skeletalanomalies

Poor suck, minorfacial anomalies

Affecteddaughters

Developmentaldelay

Cardiacanomalies

Height (%) 25 75 95 >95 90 75Weight (%) 75 5 90 25 75 50OFC (%) <5 95 60 95 40 10Neurological status Developmental

delay, seizuresLanguage delay − − Developmental

delay; autisticbehaviors

Developmentaldelay

Facial anomalies +a +b +c − − −Deep plantar creases − + − − − −Cardiac anomalies − − − − − +Renal anomalies − Malrotation,

thickened extrarenal pelvis, mildrt hydronephorsis

Rt hydronephrosis,bilateral v-ureflux

− − −

Genital anomalies − − Absent clitoris − − −Limb anomalies − Camptodactyly, foot

deformities,hypoplasticpatellae, narrowdiaphyses, longbones

Bilateralclinodactyly,Sprengeldeformity

− Rt preaxialpolydactyly

−

Skeletal anomalies − Extra lumbarvertebrae, bifidvertebrae

− − − −

Long, slender trunk − + + + + +Mosaicism − + + + − −

aDeep set eyes, round face, upslanted palpebral fissures, epicanthus, downturned mouth.bSimple ears, everted lower up, prominent forehead.cProminent forehead, epicanthus, deep set eyes, small palpebral fissures, low posterior hairline, high-arched palate, abnormal ears.

Marker Chromosome 8 Trisomy 341

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Kurytka ZE, Krzywka R, Piatkowska E, Radwin M, Pietrzyk JJ (1988):Trisomy 8 mosaicism 8 syndrome. Two cases demonstrating variabilityin phenotype. Clin Ped 27:557–564.

Melnyk AR, Dewald G (1994): Identification of a small supernumerary ringchromosome 8 by fluorescent in-situ hybridization in a child with de-velopmental delay and minor anomalies. Am J Med Genet 50:12–14.

Oncor (1994): Chromosome In-Situ Hybridization System for Tissue,Whole Cells or Metaphase Chromosomes; Fluorescence/Light Micros-copy. Oncor, Inc.

Schinzel A (1983): ‘‘Catalog of Unbalanced Chromosome Aberrations inMan.’’ Berlin: Walter de Gruyter and Co., pp 1–7.

Spinner NB, Grace KR, Owens NL, Sovinsky L, Pellegrino JE, McDonald-McGinn D, Zackai E (1995): Mosaicism for a chromosome 8-derivedminute marker chromosome in a patient with manifestations of tri-somy 8 mosaicism. Am J Med Genet 56:22–24.

Walker AP, Bocian M (1987): Partial duplication 8q12→q21.2 in sibs withmaternally derived insertion and reciprocal translocations: Case re-ports and review of partial duplications of chromosome 8. Am J MedGenet 27:3–22.

342 Rothenmund et al.