69Med Genet 1994;31:694-701

Asymmetry and skin pigmentary anomalies inchromosome mosaicism

C G Woods, A Bankier, J Curry, LJ Sheffield, S F Slaney, K Smith, L Voullaire,D Wellesley

AbstractWe report six persons mosaic for a chro-mosome anomaly. All were mentally re-tarded and dysmorphic. Unilateral orasymmetrical features were found in allcases, in one an unusual transverse ter-minal limb anomaly, and in the othersvarious degrees of hemiatrophy of the leftside of the body. Five of the subjects hadskin pigmentary anomalies which weredistributed in the lines of Blaschko. Theabnormal cell lines found were ring chro-mosome 22, trisomy 22, a large acrocentricmarker, a deletion of 18q, a deletion of 8q,and triploidy. In four cases the clinicaldiagnosis was only confirmed by skin bi-opsy. In one case low level mosaicism inblood was fortuitously detected because ofcytogenetic fragile X screening and con-firmed in a skin biopsy. The sixth case wasof dynamic mosaicism of a non-mosaicdeletion 18q with a chromosome 18 derivedmarker present in a proportion of cells.Chromosome mosaicisn may cause subtleand asymmetrical clinical features andcan require repeated cytogenetic in-vestigations. The diagnosis should be act-ively sought as it enables accurate geneticcounselling to be given.

(J Med Genet 1994;31:694-701)

Murdoch Institute forResearch into BirthDefects, RoyalChildren's Hospital,Flemington Road,Parkville, Melbourne,Victoria 3052,AustraliaC G WoodsA BankierL J SheffieldL Voullaire

Regional CytogeneticLaboratory, ChurchillHospital, Oxford, UKJ CurryK Smith

Department ofClinical Genetics,Churchill Hospital,Oxford, UKS F SlaneyD Wellesley

Correspondence toDr Woods.

Received 1 February 1994Revised version accepted forpublication 27 April 1994

It is important for the physician to be aware ofthe spectrum of clinical features that chro-mosome mosaicism can cause. As the diagnosisusually requires multiple tissue sampling theymust discriminatingly select which patients toinvestigate. Chromosome mosaicism may pres-ent as a recognised phenotype such as Pallister-Killian/12p tetrasomy, and Down's mosaicism,or as a dysmorphic intellectually disabled per-son often with a normal lymphocyte chro-mosome analysis. Whereas most chromosomalmosaics described have a symmetrical pheno-type, a minority are reported to have asym-metrical and ipsilateral dysmorphic features.We describe six persons mosaic for a chro-mosome anomaly. These are illustrative of theimportance of asymmetrical features in alertingthe clinician to the diagnosis and of the easewith which the confirmatory abnormal cell linemay escape detection if only lymphocyte cy-togenetic studies are performed.

In chromosomal mosaicism the abnormalcell line(s) contains a cytogenetically detectablechromosomal anomaly and the other cell lineusually has a normal chromosome constitution.The incidence of chromosomal mosaicismcausing significant phenotypic effects is un-

known, but is likely to be greater than 1 in10 000. This estimate is extrapolated from the0-1% to 0 3% incidence of chromosomal mo-saicism at amniocentesis, '-3 and that the in-cidence of Down's mosaics is 1-5 per 10 000(as 5% of cases are reported to be mosaics anda further 5% of cases are the result of a mitoticerror4). It seems likely that chromosomal mo-saicism is underdiagnosed.Mosaics and chimeras are composed of two

or more cell lines. In mosaics the cell linesoriginate from one zygote, but in chimerasmore than one zygote is involved. For thepurposes of this paper, however, we use theterm mosaic rather more broadly to indicate aperson with two demonstrably different celllines but not necessarily to indicate their zygoticorigin.

Case reportsCASE 1A 3 year old boy was referred because of de-velopmental delay and a congenital mal-formation of the left hand, both of unknownaetiology. The parents were healthy, unrelated,Afro-Caribbeans who were normal on ex-amination and had no scalp defects. The fatherwas 22 years of age at the time of birth andthe mother 18 years. They had no other chil-dren but the mother subsequently had a normalgirl with a different partner.The pregnancy was complicated by in-

termittent vaginal bleeding in the first and sec-ond trimester. The mother did not have achorionic villus sampling. A male child wasborn at 38 weeks' gestation with a birth weightof 2400 g. At birth he was noted to have anabnormal small left hand. During the first yearof life three surgical procedures were un-dertaken to increase the function of the lefthand. When seen at the age of 3 years he wasassessed to be globally moderately de-velopmentally delayed; in particular his speechwas limited to a few indistinct words.At the age of 3 years his height was 102 cm

(90th centile) and his head circumference51 cm (50th centile). He was not dysmorphic(fig 1 a). There were patches of depigmentationover his entire skin surface which had beenpresent since early infancy. He had a 1-2 cmwide streak of hyperpigmented skin runningfrom the midline of his mid thoracic back tothe left axilla (fig lb). The limbs were normalapart from the left hand which had a hypoplasticthumb, fused second and third digits, and miss-ing ulnar border (fig 1 c). Neurological ex-amination was normal.

Cytogenetic analysis of PHA stimulated

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Asymmetry and skin pigmentary anomalies in chromosome mosaicism

Figure 1 Case 1. (a) Face and upper body, (b) Left upper back showing ahyperpigmented skin streak radiating from the midline around to the axilla. (c) Ableft hand with a hypoplastic thumb, fused second and third digits, and missing ulnborder of the hand. The right hand was normal.

blood lymphocytes showed 146 cellsnormal male karyotype and five cells Mabnormal karyotype, 46,XX,r(22). Theblast culture from normal coloured skin s11 cells out of 60 to have ring chromoso:Parental lymphocyte karyotypes were n

CASE 2A 14 year old girl was referred for agenetics opinion. She had multiple con

anomalies, multiple exostoses, and moderatemental retardation, but no unifying diagnosis.A cytogenetic analysis of blood lymphocyteshad been normal on two occasions. The parentswere healthy, unrelated, Afro-Caribbeans, themother being 32 and the father 31 years of agewhen their daughter was born. The motherhad three other healthy children all by differentfathers.Pregnancy and delivery were normal and she

was born at term with a birth weight of 3000 g.She fed poorly as a neonate and at five weeksbecame tachypnoeic. Investigation showed acyanotic Fallot's tetralogy. Treatment was med-ical and a ventricular septal defect was repairedat 11 years of age. She has attended a special

1 a school having static moderate mental re-tardation. Short stature was noted in the firstyear of life and has persisted. Bony outgrowthswere noted in the second year which progressedto multiple exostoses by 4 years of age. Nonehas caused discomfort but a thoracic lumbarscoliosis has developed. Because of increasingsize, an exostosis was removed from the rightfibula head at the age of 12 years. Histologyconfirmed a benign osteochondroma of thefibula.On examination her height was 131 cm and

head circumference 49 cm, both much less thanthe 3rd centile. Her forehead was bossed, herears were small, simple, and low set, her eye-brows had a lateral flair and were tented up-wards, and the lower lateral eyelids werepartially deficient (fig 2a). The fourth and fifth

1 b metacarpals of both hands appeared short, themiddle phalanges fusiform, and the fifth fingerbrachydactylic (fig 2b). Over the scapula area ofher right shoulder were linear hyperpigmentedstreaks running from her spine to her arm.Over her mid back was hyperpigmented "U"and "W" shaped patterning more or less sym-metrically distributed about the midline. Herleft leg and foot were smaller than her right by4 and 1 cm, respectively. Running down theback of both her legs were linear hy-popigmented streaks (fig 2c). Investigationshowed a bone age of 7 years at the chro-nological age of 13 years. A CT brain scan wasnormal.Lymphocyte karyotypes were normal, 46,

XX, on two separate examinations. A skinbiopsy ofnormally pigmented skin showed mo-

1 c saicism with 77/80 cells showing a large in-terstitial deletion of the long arm of one

5normal chromosome 8, 46,XX,del(8) (q21q24). Onar detailed reanalysis of blood, one cell out of 200

examined was found to have the same deletion.Parental lymphocyte karyotypes were normal.

with avith an CASE 3fibro- A 13 year old girl was referred for evaluation

,howed who had severe scoliosis, fits, precocious pu-me 22. berty, and mild mental retardation. The parentsLormal. were healthy, unrelated, and white, both aged

20 at the time of birth. They have no otherchildren.The pregnancy and labour were normal and

clinical delivery was at term of a 2400 g female infant.Lgenital Both feet were inturned, but only one required

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Woods, Bankier, Curry, Sheffield, Slaney, Smith, Voullaire, Wellesley

2a

I

II

Figure 2. Case 2. (a) Dysmorphic facies showing epicanthic folds and tented eyebro(b) Back of the legs showing tramline hypopigmented streaks running down the legs.(c) Hands showing brachydactyly, fusiform appearance, and fifth finger clinodactyly.

splinting for the first six weeks of life to achievenormal positioning.A scoliosis was noted at 18 months. Spinal

x rays did not show any vertebral anomalies.The scoliosis progressed and a thoracic fusionwas performed at 10 years. At the age of 5years transient hyperthyroidism developedwhich responded to carbimazole. At 6 yearssigns of precocious puberty began with en-largement of the right breast and were followedby growth of pubic hair and onset of mensesat 9 years. Hormone studies were compatiblewith an early and sustained puberty. At 8 yearsher stature was on the 90th centile and herbone age was 13 years. Grand mal fits startedat 6 years. At the age of 8 years absence attacksalso developed. At 10 years an EEG showed aleft centrotemporal focus and an MRI scanshowed that the right hippocampus and leftcerebellar hemisphere were mildly atrophic.On examination at the age of 13 years her

height was 138 cm (

Asymmetry and skin pigmentary anomalies in chromosome mosaicism

3a

A

3b

ii A

I' I

3d

1.:

Figure 3 Case 3. (a) Facies with asymmetry caused by left sided hypoplasia.(b) Hands. Both are of the same size and show brachydactyly, short fifth metacarpals,and fifth finger clinodactyly. (c) Right upper arm showing hypopigmented linear skinstreaks. (d) Lower back showing a patchy midline vascular naevus and hypopigmentedstreaks radiating from the midline.

genital anomalies were noted. Cleft palate wasrepaired at 1' years and a pharyngoplasty of arigid soft palate performed at 11 years. Narrowexternal auditory meati and vesicular ab-normalities resulted in moderate bilateral deaf-ness. A cardiac murmur was investigated and anasymptomatic ventricular septal defect found.

In the first two years of life lateral nystagmuswas evident for which no cause was found. Thenystagmus gradually abated and her vision wasassessed as normal. She had mild static mentalretardation. Her teeth did not start eruptinguntil 15 months and at 15 years the first den-tition was not complete. Periods had not startedat 15 years.On examination at 15 years she had a mildly

dysmorphic, asymmetrical face, the left sidebeing hypoplastic. She had a brown right pupiland green left pupil. She had small handsand feet with bilateral simian creases and longtapered fingers with broad nails. She had abroad band of hyperpigmented skin about thelower abdomen, the upper margins slopingfrom the flanks down to the umbilicus (fig 4A).Above and parallel to the upper margin ofthe hyperpigmented region were a number ofhyperpigmented streaks. The right leg waslonger than the left, 48 cm compared to 81 cm,and the right foot was larger than the left.

Cytogenetic analysis showed the same mo-

Figure 4 Case 4 showing the torso with a broadhypopigmented band around the abdomen coming down tothe umbilicus from the flanks with streaking on the rightupper border under the axilla.

saic karyotype at 15 years as was seen at 3 yearswith the marker present in six of 50 cells.Molecular cytogenetic investigations suggestthat it is derived from chromosome 18 (re-ported elsewhere). Parental lymphocyte karyo-types were normal.

CASE 5A boy who was severely mental retarded, short,and had asymmetrical dysmorphic features wasreferred for diagnosis. The parents were un-related and white. The father was 28 years oldand suffered from multiple sclerosis and themother was 30 years old at the time of the birthof their only child.The pregnancy was complicated by pre-ec-

lamptic toxaemia and low oestriol levels in thethird trimester. The baby was delivered byelective caesarean section at 38 weeks in goodcondition. Birth weight was 1450 g (

Woods, Bankier, Curry, Sheffield, Slaney, Smith, Voullaire, Wellesley

testicle was undescended. He was severely de-velopmentally delayed and was moderately hy-potonic. A skeletal survey showed generalisedosteoporosis and cotton reel shaped vertebraewith narrower anterior-posterior diameterswith long pedicles, likened to flying buttresses.At 3 years his anterior fontanelle was still

open and the appearance of macrocephaly andbody asymmetry were more marked. Grandmal epilepsy had developed as had flexion con-tractures of all large joints and a lumbar sco-liosis. Scalp hair was sparse and his teeth werewidely spaced with a number missing. Chro-mosome analysis of blood lymphocytes wasnormal on two separate analyses. A skeletalsurvey showed short left fourth and fifth toephalanges and no left fibula. CT scan of thebrain showed slightly increased CSF spacesaround and within the brain but no structuralanomalies. At 9 years a right thoracolumbarkyphosis scoliosis was treated by luque fusionfrom the sacrum to T4.At 10 years the patient was reviewed. His

height was still on the 3rd centile, weight onthe 10th centile, and head circumference on the50th centile. The asymmetry and dysmorphicfeatures are shown in fig 5. The patient wasseverely mentally retarded having learnt to

Figure 5 Case 5. (a) Both hands showing left sided 2/3 finger syndactyly. (b) Faceshowing deep set, prominent eyes, left sided hypoplasia. (c) View of the whole personshowing the smaller left side offace, left arm, and left leg.

stand at the age of 4 but had never walkedindependently and had no expressive or re-ceptive language. He died at 15 years of agefrom a chest infection.

Repeat blood karyotyping was normal, 46,XX. Skin biopsy for fibroblast karyotypingshowed triploidy, 69,XXY, in 29 of 30 cells.The remaining cell had the karyotype 45,XY,- 15. The father's lymphocyte karyotype was46,XY. The mother's lymphocyte karyotype atthe age of 40 showed 42 of 50 cells were 46,XX, three cells were 45,X, four cells were 47,XXX, and one cell was 48,XXXX.

CASE 6A 19 year old girl was referred as having Turn-er's syndrome despite cytogenetic analysisshowing a normal lymphocyte karyotype, 46,XX, on three separate occasions. The parentswere healthy, unrelated, Asians, the motherbeing 38 and the father 39 years of age whentheir daughter was born. Oftheir three children,the first child was a male who died ofrespiratorydistress syndrome at 35 weeks' gestation, thesecond is the index case, and the third is ahealthy 17 year old female.

In the latter two months of the pregnancythere had been poor fetal growth of unknowncause. Spontaneous labour occurred at termand a female weighing 2000 g was born ingood condition. She was noted to be mildlydysmorphic, with a murmur and a left clubfoot.An asymptomatic ventricular septal defect

closed spontaneously at 2 years. Left talipesequinovarus was successfully treated by tendontransfers at the age of 3 years. Severe left sidedsensorineural deafness of unknown aetiologywas detected at 4 years. By 5 years it was notedthat her left leg was 1 cm shorter than her right.She had mild mental retardation, numericalcalculations being particularly weak, and at-tended a normal school.

She was investigated at the age of 16 yearsbecause of persistent disproportionate shortstature. Her right hand bone age was less thanthe 3rd centile. As her left leg was shorterthan her right, a leg lengthening procedure wasperformed at the age of 16 years. Radiologicalinvestigation at that time had confirmed herhypoplastic left leg, and to a lesser extent leftarm, and also showed a shallow left acet-abulum.At the age of 18 years primary amenorrhoea

was investigated. Although the diagnosis ofTurner's syndrome had been suggested, cy-togenetic analysis was 46,XX on three oc-casions. She had high basal levels of FSH (81U/l) and LH (27 U/l) which rose even higheron an LHRH test, indicating primary ovarianfailure. During an episode of acute abdominalpain a laparotomy was performed. This showeda normal vagina and cervix, and a small uteruswhich was unicomuate on the right side witha normal round ligament and fallopian tubebut streak gonad. On the left side a smallgolf ball-like structure (thought to represent avestigial hemiuterus) was found attached to anormal round ligament, vestigial fallopian tube,and a streak gonad.

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Asymmetry and skin pigmentary anomalies in chromosome mosaicism

When examined at the age of 19 years shewas short (

Woods, Bankier, Cuny, Sheffield, Slaney, Smith, Voullaire, Wellesley

in our cases. Once established the pigmentarychange is stable. This is in marked contrast tothe important differential diagnosis of mentalretardation in persons with spalB incontinentiapigmenti where there is evolution, erythema,blistering, verucous change, hyperpigment-ation, and hypopigmentation.36 Skin pigment-ary dysplasia distributed along the lines ofBlaschko can occur in a number of other con-ditions, such as in female carriers of some Xlinked disorders, like chondrodysplasiapunctata and anhidrotic ectodermal dysplasia,and also mosaic distributions of single genemutations, like McCune Albright/polyostoticfibrous dysplasia/GNAS 1 mutations leading toincreased activity.3738

In only two of six cases was the diagnosisof chromosome mosaicism apparent from theinitial lymphocyte chromosome analysis. Thesefindings are typical with the blood often beinga poor tissue in which to search for a mosaicabnormal cell line. If detailed analysis of fivelymphocytes is performed, only mosaicismof >38% would be excluded with 90% con-fidence.39There are many reports of the abnormal cell

line being only detected in fibroblasts.5313240-42If present, the site of spalB is often used as aguide to the site for skin biopsy. This may bean erroneous assumption as the fibroblasts andmelanocytes have different embryological de-rivations and paths of migration in the de-veloping embryo. Skin pigmentary anomaliesmay be caused by melanocyte defects alone andmay not be induced by fibroblast abnormalities.The lines of Blaschko are thought to representthe tracts of migration of melanocytes.43-5 Me-lanocyte culture would clearly be the mostdesirable diagnostic modality to assess cases ofsuspected chromosome mosaicism with spalB,especially as both the melanocytes and neur-ones derive from the neural tube. Skin biopsiesdid not detect all cases of suspected chro-mosome mosaicism as illlustrated by 10 of 19persons reported by Glover et a123 who hadblood, normal skin, and hypopigmented skinexamined cytogenetically,23 and five of 13 per-sons described by Sybert et al,5 and in twofurther cases we investigated who were mentallyretarded and dysmorphic with asymmetricalfeatures and spalB. Biopsies at more than oneskin site may be required to show the abnormalcell line or to show that it is not just a culturalartefact.46 Usually, however, the mosaic cellline is present in similar proportions at differentsites of sampling.23 Keratinocyte cultures haverecently been shown to be of use in detectingcovert chromosome mosaicism, confirming onecase detected by fibroblast culture showing ahitherto undetected trisomy 7 cell line butfailing to find an XY/XO mosaic line presentin fibroblasts.3"The findings of a number of different but

apparently balanced translocations in case 3 isan unusual finding, but has been previouslyreported in chromosome mosaicism.474 We areunsure whether the clincal features are causedby the chromosome mosaicism or are theconsequence of an undiagnosed primarydefect. Similar cytogenetic findings have also

been reported in incontinentia pigmenti andWerner's progeria syndrome.49 Subjects withsignificant mental retardation, microcephaly,and mosaicism for multiple differentaneuploidies have been described. This entityis thought to be an autosomal recessive disorderof mitosis.""The finding of chromosome mosaicism has

implications for the individual subject and fam-ily. The value ofknowing a specific diagnosis ina child with intellectual disabilities and multiplemalformations is obvious. A diagnosis not onlyclarifies the patient's management but defin-itely helps to alleviate the guilt so common toparents who wonder whether they have causedthe birth defects by some omission or com-mission during the pregnancy. An exact pre-diction of phenotype is not possible as theproportion of the abnormal cell line in onetissue may give little guidance to its recurrencein other tissues, for instance the brain.52 Forthe families, given that the parents have normalcytogenetic analyses and that multiple differentaneuploides were not found, recurrence risk issmall.

We would like to thank Dr J Hurst for allowing us to reportone of her patients and Professor D M Danks, Dr R J MGardner, and V Petrovic for helpful comments in the preparationof this manuscript.

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