PROGNOSIS IN NEWBORN INFANTS WITH X-CHROMOSOMAL ABNORMALITIES

(1)

(

Received September 14; revision accepted for publication November 24, 1970.)

This is contribution Number 426 of the Eleanor Roosevelt Institute for Cancer Research, Department

of Biophysics.

This study was supported by National Institutes of Health U.S. Public Health Services Grants

HD-00622-06 and HS-00269-02, by the National Foundation Birth Defects Center Grant C-26, and by a

grant from the Genetics Foundation.

PRESENT ADDRESS: (E.E.) Department of Pediatrics, The University of Texas Medical School at San

Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78229.

ADDRESS FOR REPRINTS: (A.R.) Department of Biophysics, University of Colorado Medical Center,

4200 E. 9th Avenue, Denver, Colorado 80220.

Pzn rATlucs, Vol. 47, No. 4, April 1971

681

PROGNOSIS

IN

NEWBORN

INFANTS

WITH

X-CHROMOSOMAL

ABNORMALITIES

Eleanor Eller, M.D., William Frankenburg, M.D., Mary Puck, M.A., and

Arthur Robinson, M.D.

From the Eleanor Roosevelt Institute for Cancer Research, Department of Biophysics, and the

Depart inent of Pediatrics, University of Colorado Medical Center, Denver, Colorado

ABSTRACT. Sex-chromosomal aberrations occur

with a relatively high frequency and have been as-sociated with mental retardation, perceptual prob-lems, psychopathology, and growth abnormalities.

Identification of this possibly high risk group at

birth enables the study of their growth and

devel-opment to determine if and when they deviate

from normal. Routine screening of the chromatin

constitution of 21,214 consecutive newborn infants

has identified 32 babies with gross X chromosome

abnormalities. Three died in the newborn period.

During the past 5 years, 27 children have been

followed from birth. The evaluation process

con-sists of semiannual and annual physical and

de-velopmental examinations, psychological testing,

growth measurements, pedigree analysis,

dermato-glyphic analysis, home environment evaluation,

and, in mosaics, repeated chromosome analysis.

The patients with 45,X karyotypes have classical

physical signs. The other patients have normal

phenotypes, although several have minor physical

manifestations such as clinodactyly and epicanthic

folds. Overall development in all except two

pa-tients has been within normal limits. In mosaics,

there is a tendency for the abnormal cell line to

disappear. Pediatrics, 47:681, 1971, NEWBORN

IN-FANTS, X CHROMOSOMAL ABNORMALITIES,

NONDIS-JUNCTION.

PPROXIMATELY 1% of all live-born

in-fants have gross chromosomal

aberra-tions, many of which are associated with

major physical and mental defects.1

Aberra-tions of the sex chromosomes, which

con-stitute about 50% of all chromosomal

ab-normalities, generally cause less serious

somatic effects than do those of autosomes.

Only in the infant with Turner’s syndrome

is there a readily recognized clinical

pic-ture. However, sex chromosomal errors

have been associated with a variety of

be-havioral and mental disorders.2#{176}

Most of the previously studied patients

with X chromosomal abnormalities (X-CA)

have been identified because of individual

problems or through screening of

nonran-domly selected populations, such as

resi-dents of institutions for the mentally

retarded or emotionally disturbed.8’1116

Several studies on more normal populations

such as women admitted to a general

hospi-tal,2,1720 have identified subjects with

X-CA, but who had normal phenotypes,

in-tellect, and behavior. Due to a lack of

suffi-cient large random samples, the prognosis

of X-CA individuals is therefore unknown.

Comparison of the incidence of X-CA in

in-stitutionalized patients with incidences in

unselected newborn infants suggests that

X-CA newborn infants are at a significantly

increased risk for developmental or

emo-tional problems.28 A long-term follow-up

study of a large population of randomly

de-termined affected newborns is of

impor-tance to determine the frequency of minor

as well as major variations in normal

(2)

TAI3LE I

NuSIBF:it AND IN(II)EN(E 01’ N. CL1IIOIIOSOIIAL

ANOMALIES IN 21,214 NEwB0I6N INFANTS*

0Males: 1080.5. Females: 10,409.

TABLE II

Data

* Involving .5th finger.

-t 1)efined as at least two Stali(lard deviations above the mean in tables published by Pryor.52 +

to study more carefully the time of onset

and their nature.

PATIENTS AND METHODS

From January 1, 1964, to January 31,

1970, a total of 21,572 newborn infants at

three Denver hospitals were screened for

X-CA l)y examination of the amniotic sex

chromatin pattern in placentas routinely

ob-tamed from all deliveries. This method of

screening is used instead of the buccal

smear for convenience and because of its

greater sensitivity, particularly in detection

of mosaicisni.5#{176} Babies evidencing a

dis-crepancy between sex chromatin

constitu-tion and phenotypic sex are carefully

checked by a series of tests including

corn-plete karyotypic analysis of cells cultured

from the peripheral blood.20 Obviously,

newborn infants with a 47,XYY karyotype

are missed.

When a definite chrornosomal diagnosis

is established, the child’s physician is

noti-fied, and, with his consent, the test results

are discussed with the parents. They are

told that an abnormality was noted in the

cells of their infant. In some cases a

chro-mosomal abnormality is mentioned but the

word sex chromosome is not specified. They

are told that some children with these

ab-normalities have learning problems, such as

perceptual problems, and others do not.

lucide nee Follow-up

.

I bnoruolly .\‘umber

Detected I!

-

F

-

Ex-pired

--- lol-lotted

47,XXX 9 .09 --- 9

47,XXY 8 .07 i 6

45,X I .03 1

45X/46,XX 8 .08

---

6

45,X/46,XX/47XXX 1 .01

---

I

46XX/17,XXX I .01

---

I

46,XY/47XXY 1 .01

--

-

1

46.XXq- 1 .01

-

I

‘Iotal I4 .08 - 3 17

They are asked to include their child in our

follow-up study-to gain information about

the condition and to provide appropriate

help if problems are detected.

Pregnancy and birth histories, family

pedigree, physical examination, and

derina-toglyphic analysis are completed during the

first year of life. Each child is reevaluated

annually. Detailed measurements made at

each visit include height, weight, sitting

height, arm span, head circumference, chest

circumference, chest diameter, internipple

distance, intercanthal and interpupillary

distance, and testicular size. Parents are

en-couraged to discuss questions and feelings

P11ioIc.ki, CI1.%RM’rERIsTIcs OF 9 47,XXX PATIENTS (AGES f-5 YEARS)

Patients

(liIIo(laetyly* Epicanthic folds

Wide-set eyest

Iiicoordinatioii Pectus carinatunl

Bilateral plaziovalgus IlymeflIll stenosis tretlIral stenosis Overlapping toes

.\‘.(‘. Dli. P.M. D.S. C.B.

+ + + + +

+ + +

+ +

+ + +

+ +

s.J-.

E.B. TI?. (‘-1.

+ +

(3)

‘FABLE IV

Piiysit-i (‘IIAIIA(’TElIISTI(S OF 6 45, X/46,XX

PATIENTS (AGES TO 3 NEARS)

Patients

1)atu

-

- --

--

---

-

-(.11’. L.E. .1.11. S.JJ’. T.P. II.!!.

(‘linodactyly +

Epicanthal folds +

Wide-set eyes + + +

Short stature +

Ine’oordination +

ARTICLES 683

TABLE III

PHYSICAL CHARACTERISTICS OF 8 47,xxy PATIENTS

(AGES TO 5 YEARS)

Patients

Data -

-

---I1.L.* li.S. J..1. (S. Dl’. K.D. KU’. .1.)!.

Small and/or soft testes + + + + +

(‘linodactyly + + +

Wide-set eyes + +

‘fall stature +

(‘left palate, glossoptosis and small mandible +

Patent ductus arteriosus +

Preauricular pits +

Abnormal ear helices +

* l)ied.

they have about their child. The sex

chro-matin status of available family members is

established by buccal smear. Children with

mosaicism have had repeat chromosome

analyses of peripheral blood and skin

fibro-blasts.

Patients are evaluated at 6, 12, 18, 24,

and 36 months with the Revised Yale

Developmental Schedules. This test is a

composite of the Gesell Developmental

Schedules with selected items from the

Stan-ford-Binet, Merril Palmer, and Hetzer Wolf

examinations. At age 3 years and 5 years the

Graham Einhart perceptual test is

per-formed, while at 4 and 6 years the

Stanford-Binet is administered. The examiners

ad-ministering these tests, although aware of

the diagnosis, were not aware of the results

of previous evaluations.

Since environmental factors affect a

child’s development, the amount of home

stimulation is assessed using the STIM

scale devised by Caldwell.21 This inventory

assesses the frequency and stability of adult

contact, the amount of developmental and

vocal stimulation, the emotional climate,

and the availability of play material.0

RESULTS

Thirty-two infants with X-CA have been

detected. Table I lists the types of

abnor-malities, their number, and incidence. Two

infants with Klinefelter’s syndrome and one

with Turner’s syndrome expired in the

new-horn period.20 Two patients have been lost

to follow-up. Information on five patients is

incomplete. Of the patients followed, seven

are less than 2 years of age, twelve are

be-tween 2 and 4 years of age, and eight arc

between 4 and 6 years of age.

Among the nine trisomy X patients, the

most frequently noted minor anomalies

were clinodactyly, epicanthal folds, and

wide-set eyes (Table II). Two of the

chil-dren (N.C. and P.M.f) have each had one

febrile seizure.

The findings among the eight 47,XXY

pa-tients are listed (Table III). One testicular

biopsy was performed at 18 months during

0 A total score of 73 can be achieved. A mean of

50 has been reported for families from lower

socio-economic levels and a mean of 59 for middle-class

families.

(4)

684

‘l’ABLE V

lIF;-T1IoI-NcF:1’11;LoGu.k1I1 IC FINDINGS Ox

(_‘ii I L1)ItEN VITII N CIIHo\1oSo\IA I

:IA LFOICtIATIONS

PT Koryolype U’s) EE(; (outrncntst

J.t XXV 6 \VNI’ I’oorly (irgattized Awake

Cs xxv 4

ur xxv 4 WNI

K% XXV 3 \%NI Mature

JM XXV I WN1 Mature

AS XO 5 WNI Severely Distorted Sleep

NM X() 5 WNI Severely Distorted Sleep

i,:t XXq- 3 WNL Severely Distorted Sleep

NC XXX 6 WNI.

DII XXX 5 WNI. At. Cerebral Fast Activity

PM XXX 4 WNI

DS XXX 4 WNL Poorly Organized

CR XXX 3 \\N1 Poorly Organized

sv xxx a \\-NI Poorly Organized

ER XXX 1 WNI. Sleei MO(leratel3 Distorted

TB XXX I ‘t\Nl

CA XXX I WNI

LE XO/XX 4 WNL

SW XO/XX 3 WNL Slightly 1)istorted Sleep

JB XO/XX 3 WNL Slight DisorganLation Awake

LII XY/XXY Abnormal

S\Vithiii normal limits.

tCriteria for rea(litlg are described by Metcalf.’8

a hernia repair

(

K.D.

)

. Histologic findings

were similar to those reported in older

pre-pubertal males with Kinefelter’s syndrome23

-absence of germinal or mitotic activity in

the seminiferous tubules and relative

fail-ure of lumen development. Two children

have died-one with cleft palate,

glossopto-sis, hyaline membrane disease, and

prema-thrity, and one with a patent ductus

arterio-sus. The surviving six boys are healthy.

Of six patients with 45,X/46,XX

karyo-types ages M2 to 3% years,

(

Table IV

),

none

has the classical features of Turner’s

syn-drome. Growth measurements are normal

except in one girl whose height is below the

3rd percentile. General health is also

nor-mal.

Two girls with 45,X karyotype have

typi-cal physical features of Turner’s syndrome.

A third died at 13 days of age with

coarcta-lion of the aorta. All three had prominent

dorsal pedal edema at birth.

The three females in the study with other

X-CA have normal phenotypes. The male

with Klinefelter’s mosaicism has a seizure

disorder of undetermined etiology.

Careful prenatal histories fail to suggest

any significant environmental factors. (In

two mothers there was increased abdominal

x-ray exposure prior to conception. Three

mothers were on oral contraceptives within

3 months of conception). Detailed pedigree

analyses yielded no information that could

be considered significant.

Dermatoglyphic analyses in 17 patients

show some individual unusual features. The

only consistent finding is the previously

re-ported decreased digital ridge counts and a-b

ridge counts in patients with trisomy X.24,25

Buccal smears in 24 parents and 16

sib-lings are normal.

Electroencephalograms have thus far

been performed on 21 patients (Table V).

These will be reported in detail in a

sepa-rate communication. One child (XX/XXY

mosaic) has epilepsy with a nonspecifically

but definitely abnormal EEC. It is of

inter-est that the two subjects with 45,X and one

with 46,XXq- (all monosomic for the short

arm of X chromosome

)

have severely

dis-torted sleep patterns.

Chromosome analyses have been

re-peated in the mosaic patients (Table VI).

All but one of six patients have shown some

diminution of the aneuploid line with time.

The significance of this finding in this small

series is unknown. If this trend is present in

a larger series, it may explain the occasional

occurrence of individuals who

phenotypi-cally resemble a specific chromosomal

dis-ease but who have normal karyotypes.

0th-ers have reported the same phenomenon.2720

The developmental or intelligence

quo-tients for all the children studied have been

within normal limits except one girl with

Turner’s syndrome whose IQ is 57, and one

girl with

47,XXX

whose IQ is 63 (Table

VII) . Two other triplo-X patients have

scores below one standard deviation from

the norm-78 and 79. Two of these children

have a very low STEM scale score

suggest-ing environmental deprivation as a possible

(5)

ARTICLES 685

TABLE VI

FOLLOW-ui’ (‘iIRouosoME ANALYSES IN PATI ENTS WITh MOSAICISM

N (liromosoinal -I tta;nalws Patient

1t Eram (New Born) Repeat Exams

Blood Blood Skin -It Tints

Number of cells

Counted

#{182}-1neuploid

Number of Cells

Counted

Number line -C d of Cells

‘ Counted

#{182}.1neuploid

45,X/46.XX i.E. .1.11. SW. ‘II’. 11.11. 40 80 30 49 60 48 % 7.5% 27 % 14 % 10 % 50 80 80 29 St) 40

20 %

-1.5% 50

9

-3.4% 21)

6 %

-7.5% -10% -10% -3years 1year 2years 2years years n4years

45,X.’46,XX’47.XXX PA. SI 45,X 19%

47,XXX 6%

- - 49 45,X 0% 47,XXX 6%

3years

46XX’47,XXX 1.11. 60 5 % 40 0 ‘ 29 0% 4years

No standard test of emotional

develop-ment has been administered. However,

clinical observation during the

psychologi-cal and physical evaluations indicate that

eight seem excessively shy, three are

de-pressed

(

but come from poorer home

envi-ronments

) ,

one is moderately hyperactive,

and one shows developmental deviation in

interpersonal relations.

DISCUSSION

The study of patients with X-CA

identi-fled through screening of unselected

new-born infants rather than through screening

of nonrandom populations is essential in

determining the incidence and natural

his-tory of these conditions.

It is evident that the ultimate emotional

and intellectual development of these

chil-dren may be modified by the parents being

informed of the initial test results, by the

physician’s awareness of the diagnosis, by

repeated examinations of the patient, and by

intervention if problems become evident. It

was only after much deliberation that the

decision was made to tell parents of their

baby’s abnormality. It is felt they have the

right to know, especially since the condition

might be associated with future problems.

It is also felt that telling the parents is

nec-essary to permit continued follow-up and

the exchange of information with other

medical personnel, particularly in the event

of a family moving from the vicinity.

Paren-tal anxiety undoubtedly can affect

parent-child relationships. Parental reactions vary

all the way from apparent unconcern to

ov-erprotectiveness and defensiveness. Some

parents express concern about the reaction

of their child to testing, possibly thereby

expressing their own anxiety about the

re-sults of the tests. These anxieties have

usu-ally decreased as parents have observed

normal development in their child. Only

one family, college educated, was not

in-formed of the diagnosis at their physician’s

request, until the infant was 6 months of

age. This child was trisomy-X and is

func-tioning in the dull normal range. The

par-ents resent not being told sooner and more

completely about their child’s potential

problems.

There may be a tendency for parents to

provide greater stimulation to these

chil-dren as a result of repeated developmental

tests which are performed in their presence.

However, in those cases where the STIM

Scale was administered there was no

cvi-dence of increased stimulation.

So far, there has been minimal

therapeu-tic intervention. Three children have

(6)

Patient Karyotypt Age at Last

l’est Type of Test Mental Age I.Q. Slit,, Score

NI). 47,XXV 2 O/1 1LY. 6/12 13

K.W. 47,XXY

,z

1/12 RY. ‘2 I/I 100 40

D.’f. 47,XXY 3 1/1 S.lLt S 1/li 97

c.s. 47.XXY 4 1/1t S.B. 5 6/I 133 60

J.A. 47,XXY 5 1/1Z S.B. 4 8/1 91

‘l’.B. 47,XXX 1 0/12 lt.Y. 1 0/1 98 60

E.B. 47,XXX 1 6/1’2 R.Y. I 0/1 63 40

CA. 47,XXX I 7/H lt.Y. 1 7/1 100 46

CII. 47,XXX 2/1 R.Y. 2 3/1 104 64

S.\’. 47,XXX 2 8/1 lt.Y. 2 1/1 79

P.M. 47,XXX 3 11/1 S.D. 3 1/1Q 78 54

D.H. 47,XXX 4 0/1, S.B. 3 9/l2 90

I).S. 47,XXX 4 0/1 S.B. S 7/1 88 61

NC. 47,XXX 6 t/1 S.B. 6 p2/12 103

11.11. 45,X/46,XX 6/12 R.V. 6/1 103

L.E. 45,X/46,XX 2 0/1 S.B. 2 0/1 106 34

S.W. 45,X/46,XX 2/1 R.Y. 1 10/1 86

J.B. 45,X/46,XX 3 0/1 S.B. 3 6/1 113 59

c.W. 45,X/b6,XX 4 0/1 SB. 3 9/1 9

P.A. 45,X/46,XX/47,XXX 3 0/1 1LY. 3 6/1 117

J.B. 46.XX/47,XXX 4 11/1 SB. 5 0/12 100 44

NC. 45X 4 11/12 S.B. 3 0/1 57

AS. 45X 5 0/12 SB. 5 4/1 107

L.Mc. 46,XXq- 3 0/1’2 S.B. 3 7/1 106 55

* Revised Yale l)evelopmental.

t Stanford-Bitiet.

on our recommendation. Preschool

place-ment has been suggested for several

chil-dren with withdrawn behavior. Public

Health nurse referrals for regular home

vis-itation have been made for four children

with poor home environments.

The results of our studies to date show no

striking trends in the physical, intellectual,

and emotional development of X-CA

pa-tients but minor variations from normal are

present which ‘arrant close follow-up.

Ex-cept for the girls with Turner’s syndrome,

the phenotypes of the children are

nor-mal. The occurrence of clinodactyly,

epi-canthic folds, or wide set eyes in seven of

nine triplo-X patients is very much more

frequent than in an unselected newborn

population. #{176} The small and soft testes of

the Klinefelter’s patients would probably

have been overlooked on routine

examina-tion if the physician were unaware of the

diagnosis. It is very unlikely the aberration

would have been suspected in any of these

patients, other than the 45,X patients, on

the basis of physical examination or history.

Retardation is evident in one girl with

Turner’s syndrome and in one with 47,XXX.

The measured intellectual development of

the 22 other children is within normal

range. There is concern, however, about

two of these children, but future follow-up

will be necessary to verify any significant

abnormality. None of the children has

clearly defined emotional problems, but

possible tendencies in several patients will

need observation over a period of time.

In mosaic patients who have had repeat

chromosome analysis, the results indicate a

tendency for the aneuploid line to decrease.

This finding may explain some cases of

phe-TABLE VII

(7)

ARTICLES 687

nocopies of chromosomal conditions in

pa-tients with normal appearing chromosomes.

The role of etiologic factors in these

con-ditions has been discussed in previous

pa-ers.31

CONCLUSIONS

WTe have presented a preliminary report

of a series of babies with sex-chromosomal

malformations identified at birth. Early sex

chromatin screening is the only way to

identify this potentially high risk group. No

abnormal patterns have yet appeared.

Con-tinned follow-up with the addition of more

intensive perceptual testing and studies of

personality and behavioral development

may identify more subtle disorders. Sibling

studies will be used for comparisons.

Hope-fully, it will be possible to intervene

effec-tivelv when indicated and minimize serious

pathology.

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3. Carron, D. C., and Vander Stoep, L. R. :

Per-sonalitv and intelligence in Turner’s

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4. Money, J., and Cranoff, D. : IQ and the

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(8)

NOTED BY T. E. C., JR., M.D.

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Med. Genet., 6:310, 1969.

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30. Marden, P. M., Smith, D. W., and McDonald,

M. J.: Congenital anomalies in the newborn

infant, including minor variations. J. Pediat., 64:357, 1964.

31. Robinson, A., Goad, W. B., Puck, T. T., and

Harris, J. S.: Studies on chromosomal

non-disjunction in man III. Amer. J. Hum.

Ge-net., 21:466, 1969.

Acknowledgment

The authors are grateful to Dr. David R. Metcalf

for his interpretation of the EEC’s. We also wish

to acknowledge the help of Mrs. Rosanna Lagace

in obtaining STIM scores.

SOME

FORGOTTEN

PEDIATRIC DISEASES-WHAT EVER HAPPENED TO THEM?

Diseases, like everything else, often fall out of

favor and in time some well known to older

gen-erations of physicians are dropped entirely from

contemporary textbooks. A sampling of diseases

which have faded into oblivion is given below.

Their names may evoke nostalgic remembrances

especially among those of us who remember

pediatric practice in the pre-antibiotic era.

1. Barlow or Cheadle’s disease

2. B#{252}hl’sdisease

3. F#{233}d#{233}or Riga’s disease 4. Parrot’s disease 5. Paltauf’s disease 6. Czerny’s disease

7. Duroziez’s disease 8. Kirkland’s disease

9. Winckel’s disease

(9)

1971;47;681

Pediatrics

Eleanor Eller, William Frankenburg, Mary Puck and Arthur Robinson

ABNORMALITIES