Trisomy 8 Syndrome

(1)

SUMMARY

Observation of oscilloscopic respiratory sine

wave

with

ventilatory

assist

permits

rapid

diag-nosis and correction of endobronchial intubation.

Continuous

oscilloscopic

monitoring

will

perm

it

early

detection

of

extubation

or

malposition

of

endotracheal

tubes.

MAJ

MICHAEL A. NELSON,

MC,

USA

LTC

GERALD

B.

MERENSTEIN,

MC,

USA

Department

of Pediatrics

Fitzsimons

Army

Medical

Center

Denver, Colorado

ADDRESS FOR REPRINTS: (G.B.M.) Chief, Newborn

Service, Department of Pediatrics, Fitzsimons Army Medical

Center, Denver, Colorado 80240.

The opinions or assertations contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

REFERENCES

1. Kuhns LK, Poznanski AK: Endotracheal tube position in the infant.

J

Pediatr 78:991, 1971.

2. Scanlon JW: Rapid maneuvers to determine location of endotracheal tube in newborn infants.

J

Pediatr 82:1091, 1973.

3. Goldiron JS: Estimation of na.sotracheal tube lengths in neonates. Pediatrics 41:823, 1968.

Trisomy

8 Syndrome

In

1970

we

reported

the

case

of a 2-month-old

boy with a C autosomal trisomy and euploid

mosaicism,

and

suggested,

by

comparison

with

other

cases,

that

this

chromosome

imbalance

might

result

in a definite

syndrome.’

It has

now

been

determined

by

Giemsa

banding

studies

that

the

trisomy

which

is present

involves

a number

8 member,

and

a follow-up

of this

case

is presented.

In addition, a review of all published cases of

authenticated

trisomy

8 suggests

that

this

specific

anomaly

leads

to

a

distinct

clinical

syndrome

involving

mild

psychomotor

retardation,

bone

and

joint

anomalies,

and

other

visceral

defects.

The

condition

is benign

in comparison

with

other

autosomal

trisomies.

CASE REPORT

This patient presented initially with the following features: a large, asymmetric head with flattening of the

right occipitotemporal area, abnormally shaped ears, unila-teral corneal opacity, broad-based nose, high arched palate, retrognathia, short weak neck, bilateral contracttires of all fingers, unilateral single palmar flexion crease with both clinodactyly and camptodactyly, short fourth metacarpals,

cortical thickening of femur shafts, clavicles and ribs, short first metatarsals, prominent plantar creases, cutaneous syndactyly between the second and third toes, abnormal

EEC in the left temporoparietal area, atnal septal defect with increased pulmonary vasculature, hepatomegaly, unila-teral communicating hydrocele, unilaterally nonvisualized kidney on intravenous pyelogram, and abnormal urine amino acid analysis.

He has been regularly followed over the past six years and in general his health and physical growth have been good.

He is very active. Developmental milestones have been

normal with the exception of speech which was delayed and remains very poorly articulated. His disposition is agreeable in spite of bouts of “bad temper.”

FIG. 1. Picture of the child with number 8 trisomy/euploid mosaicism at 5#{189}years of age.

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Ad

#{149}‘‘

Ii

LI

C

II

k’

191 tP

DII

t4

H

E

1 Li

F

fl!.

e

a

1 xY

FIG. 2. Karyotype of a typical trypsin-Giemsa banded metapha.se plate showing 47 chromosomes, an XY sex complement, and a number 8 trisomy.

Current Status

Physical examination when he was 6 years 5 months old revealed the following morphological features: The head is large (543/4 cm in circumference) and asymmetric (Fig. 1). Facial anomalies now include the following: asymmetry, corneal opacity, broad-based pug nose, elevated left corner of mouth, lower lip eversion, high-arched palate, prominent right mental protuberance, and pale hemangioma on chin. The ears are markedly abnormal, with a large and anteriorly rotated lobule, a marked thick, curled antehelix, a helix which is normal superiorly but protuberant and fused with the antehelix in the lower part.

He has an elongated, cylindrical body with very narrow chest and hips (height, 121.3 cm; weight, 20.79 Kg). Addi-tional truncal peculiarities include “pigeon chest,” asym-metric flaring lower rib cage, spina bifida of the first three thoracic vertebrae, and prominent sacroiliac joints. There is a small umbilical hernia, a slightly firm, moderately enlarged liver, a fixed split second heart sound, and a grade Il/VI systolic murmur along the left sternal border radiating toward the back. There is increased pulmonary vascularity on X-ray and right ventricular hypertrophy on EGG, suggesting an atrial septal defect with possible pulmonary stenosis. External genitalia are normal. Blonde, downy hair is abundant on the neck, arms, and back. Tonicity is normal.

Upper extremity examination reveals flexion contracture of the last three fingers on the right hand and of the second

through fifth on the left (he is left-handed), palmar creases marked in the thenar area and deep but supple in the areas of finger contractures, and bridged right transverse palmar lines. Dermatoglyphics reveals an unusual number of arches on the finger tips (five of ten), a high pattern intensity on the palms, and normally placed axial triradii. Lower extremities show large knee joints with protniding medial epicondyles, large epiphyses, and narrow, hyperconvex patellae, genu vanis with medially curved tibias, flexion contractures of the third through fifth toes on the right and fourth and fifth toes on the left, mild cutaneous syndactyly of the second and third toes, and mildly hypoplastic toe nails. The plantar surfaces are strikingly unusual: a very deep cleft-like crease begins in a sharp angle between the first and second.toes and

extends about one third the length of the plantar surface.

Similar though shorter and shallower creases exist between the second and third and the third and fourth toes. Other body joints appear normal.

He is well-coordinated, alert, and aware of his surround-ings, with no overt evidence of retardation. Psychological

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TABLE

I

DATA FROM Sn.mms OF 15 PATIENTS Wrrji SPECIFICALLY IDENTIFIED NUMBER 8 TRISOMY

Authors

A geat

Publication Sex

Birth-wezg t

(gm)

Parental Age (yr)

M F Tiues Studied Karyotypes

-Cassidy Ct al. 6 yr 6 mo M 4,026 22 . . . Blood/marrow 46XY/47XY+8

Caspersson et al.’

1 1 1 yr M 4,030 20 22 Blood 47XY+8

2 16 yr 9 mo M 3,940 33 36 Blood/skin 46XY/47XY+8

3 27 yr

F

2,870

42

44 Blood 46XX/47XX+8

4 13 yr M 2,770 35 35 Blood (3

x

)/skin

(3x)

47XY+8

Tuncbilek

et al.4 3 yr M . . .

Blood

46XY/47XY+8

deGrouchy et al.’ 11 yr M 4,000 42 40 Blood/skin 46XY/47XY+8

Malpeuch

et al. 14 wk F 3,250 28 25 Blood 46XX/47XX+8

Atkins at al.7 & Riccardi et al.8

1 9 yr F . . . 31 33 Blood 46XX/47XX+8

2 10 yr M 2,380 33 35 . . . 46XY/47XY+8

Bijlsma

e’t al.’

1 5 yr M 3,400 30 30 Blood/skin 46XY/47XY+8#{176}

2 1 yr F 2,790 34 29 Blood 46XX/47XX+8

Kakati et al.’#{176} 12 wk F . . .

Blood

47XX+8

Laurent et al.’1

1 22 yr M . . . Blood/skin 46XY/47XY+8

2 26 yr M . . . Blood/skin 46XY/47XY+8

Jacobsen et al.”

1 8 yr 9 mo M 3,250 31 31 Blood (3 X

) /skin

47XY+8

2 5 yr M 3,000 35 51 Blood/skin 46XY/47XY+8

#{176}All

blood

cells

studies

were

uniformly + 8.

Speech and hearing evaluation revealed a severe articula-tion immaturity and a mild-to-moderate delay in language ability, possibly related to a rather severe deficit in imme-diate auditory memory. No structural abnormality in the oral mechanism was found, but there is a mild unilateral conduc-tive hearing loss, suggesting middle ear pathology.

Chemistry

All values of an SMA-18 were normal except for a

moderate increase in serum lactic dehydrogenase and alkaline phosphatase. Quantitative analysis of serum and

urinary amino acids showed persistence of a modest hyper-glycinuria (310 mg/gm of creatinine) with a normal serum glycine level (2.33 mg/100 ml; normal range, 0.42 to 4.41 mg/100 ml). There was only a trace of proline in the urine,

however, and no free hydroxyproline. In the serum, the

proline level was normal (2.29 mg/100 ml; normal range,

0.59 to 3.34 mg/100 ml) and trace amounts of free hydroxy-proline were present. The blood and urinary levels of other

amino acids were normal except for a slight elevation of the

urinary phosphoethanolamine (98 mg/gm of creatinine). As stated in our original report,’ it seems likely that the iminoaciduria noted at 2 months merely represented a slight exaggeration of the physiologic “immaturity” of the newborn kidney.

CYTOGENETIC

STUDIES

Conventional

peripheral

blood

cultures

again

indicated

46,

XY/

47,

XY,

+

C mosaicism,

but

the

relative

proportion

of

euploid

cells

was

higher

than

in the

initial

studies

of

1968

(30

2n

cells

out

of 55).

Metaphases of phytohemagglutinin-stimulated

blood

cultures

were

also

treated

by

the

Giemsa

banding

method

of Gallimore

and

Richardson.2

In

brief,

air-dried

acetic-acid-methanol-fixed

cells,

pretreated

by

.075

M KC1

for

five

minutes,

were

subjected to .05% bactotrypsin Difco for five to

ten seconds at

4 C,

kept

for

90 minutes

in

2

x

SSC

at 60 C, and

then

stained

in

Gurr’s

R 66

“improved”

Giemsa

for

90 minutes.

The

banding

pattern

of

euploid

cells

(five

preparations)

appeared

normal.

In

the

analysis

of cells

with

47

chromosomes (seven preparations), the banding

pattern

consistently

revealed

the

presence

of

a

supernumerary

number

8 member,

as

shown

in

Figure 2.

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1234567891011121314151617

BRAIN

ABNORMALITY

( I)

KIDNEY

ANOMALIES

(h)

VESSEL

& HEART

ANOMALIES

OTHER

SKELETAL

ANOMALIES(g)

VERTEBRAL

&

RIB

ANOMALIES(f)

DEEP

PLANTAR

CREASES

TOE

ANOMALIES(e)

ABNORMAL

PALMAR

CREASES(d)

FINGER

ANOMALIES(c)

MICRO-

OR

RETRO-GNATHIA

LIP

PROMINENT

OR

EVERTED

PALATE

ANOMALY

ABNORMAL

NOSE(b)

EYE

ANOMALIES

(a)

ABNORMAL

EARS

ABNORMAL

HEAD

SHAPE

THIN

BODY

HABITUS

DELAYED

MOTOR

DEVELOPMENT

DELAYED

AND/OR

POOR

SPEECH

MENTAL

RETARDATION

NUMBER

OF

CASES

FIG. 3. Graph illustrating the major recurring signs observed in proven cases of number 8 trisomy. Shaded areas represent the

number of cases affected with the indicated sign or symptom as compared to the total number in which a specific reference was made. Key: a, strabismus in seven cases; b, eight have pug noses with flat bridge and broad base; c, nine with clinodactyly and

five with camptodactyly; d, seven with markedly deep creases and two with a single crease; e, seven with flexion deformities of toes;

f,

seven with spina bifida and three with extra ribs; g, four with abnormal patellae, five with nondigital joint contractures, and four with bone thickening; h, four with hydronephrosis; i, four with abnormal EEGs and two with agenesis of corpus

callosum.

DISCUSSION

In

the

past,

reports

of

isolated

cases

of

C

trisomies have presented variable clinical

pic-tures,

and

only

some

of those

cases

appeared

to

have

features

in

common.

Recently,

improved

cytogenetic techniques, allowing positive

identi-fication of specific C group members, have

demonstrated that certain

C autosomal

trisomies

involve a number 8 member. A search of the

literature has revealed 17 cases of authenticated

number

8 trisomy

to

date,

including

the

present

one

(Table

I).13120

In

13 of

these

cases,

this

trisomy has been found associated with euploid

mosaicism. In two of four cases where mosaicism

was not discovered, chromosomal studies were

performed

in

only

one

tissue,

peripheral

blood,

and

mosaicism

cannot

definitely

be

ruled

out.3’#{176}

In

the

other

two

cases

both

blood

and

skin

were

examined

without

evidence

of

312

It is

probable

that

differences

in the

extent

of

mosai-cism may be reflected in the severity or benignity

of deformations in individual patients. Yet, a

survey

of

these

cases

has

shown

sufficient

uniformity

of

signs,

symptoms,

and

anomalies

among the patients to delineate a clinical

syndrome.

#{176}Casespublished by Laurent et a!.” and by de Gouchy et al.5

(5)

In

general,

the

recurrent

features

are

as follows

(Fig.

3).

The

body

is

narrowly

built

and

of

a

variable

but

often

normal

height.

The

head

is

large

and

somewhat

abnormally

shaped

as are

the

ears;

the

nose

is broad-based

and

pugged;

stra-bismus

and

high-arched

or

cleft

palate

are

frequently

evident.

Skeletal

anomalies

are

usually

present

and

involve

the

ribs,

vertebrae,

and

patellae.

The

pelvis

is narrow,

and

cortical

thick-ening

of bones

is often

observed.

Joint

contract-ures

and

limitations,

which

may

either

progress

or

regress

with

age,

are

commonly

found.

Fingers

and

toes

exhibit

clinodactyly

and

frequently

camptodactyly

and

other

anomalies.

One

poten-tially

diagnostically

significant

finding

is

the

presence

of

unusually

deep

palmar

and

plantar

creases.

Noteworthy

dermatoglyphic

findings

include

an

increased

incidence

of

arches

on

the

finger

tips,

a high

palmar

pattern

intensity,

and

a

tnradius

which

is commonly

displaced

upwards

on

the

palm.’49”2”3

Abnormal

EEG

and

agenesis

of

the

corpus

callosum

are

frequently

reported.

Important

psychomotor

developmental

features

include

a

mild-to-moderate

mental

and

motor

retardation,

usually

with

delayed

and

poorly

articulated

speech.

Emotional

control

is

poor.

Figure

3 is

a

graphic

summary

of

the

most

frequent

abnormalities

found

among

the

trisomy

8 patients.

Chromosome

number

8 trisomy,

which

is often

found

in

association

with

euploid

mosaicism,

contrasts

with

the

other

autosomal

trisomies

in

several

respects.

The

parental

age,

with

three

known

exceptions,

is in

the

20’s

and

early

30’s

(Table

I).

The

birthweight

is

generally

within

normal

limits

(Table

I).

Statural

development

is

not,

as a rule,

reduced

or delayed.

Finally,

mental

retardation

is usually

moderate.

Thus,

with

a

few

exceptions,

the

syndrome

appears

relatively

benign

in

comparison

with

other

autosomal

trisomies,

and

seems

to allow

the

patients

to

lead

relatively

normal

lives.

These

facts

may

be

attributable

to

the

frequency

of

euploid

mosaicism

in the

syndrome

or possibly

to

genetic

peculiarities

of

the

number

8 chromo-some.

So

far,

only

one

locus,

that

coding

for

glutathione

reductase,

has

been

mapped

on

chro-mosome

8.’

The

identification

of trisomy

8 may

be

too

recent

and

the

number

of recognized

cases

too

few

to

permit accurate assessment of the

long-term

prognosis.

It is hoped

that

documentation

of

the

features

which

have

been

commonly

observed

among

these

seventeen

proven

cases

of trisomy

8 will

facilitate

recognition

of the

condition

and

a

better

assessment

of its

prognostic

implications.

ADDENDUM:

Since

submission

of

this

manu-script,

an

abstract

has

been

published

which

briefly describes three more cases of trisomy 8

and suggests

that

the

condition

is clinically

iden-tffiable.

The

proposed

criteria

are

in

agreement

with

those

which

we

have

set

forth.15

SUZANNE

B.

CASSIDY,

M.S.

Buuut

J.

MCGEE,

B.S.

J

AN VAN

Eys,

M.D.,

PH.D.

WALTER

E.

NANCE, M.D., PH.D.

ERIC ENGEL,

M.D.,

PH.D.

Departments

of Medicine

and

Pediatrics

Vanderbilt

University

School

of Medicine

Nashville,

Tennessee

Supported by a grant from Maternal and Child Health

Services, Public Health Service grant 1 P01 GM21054-01, and a grant from the National Foundation-March of Dimes. Ms. Cassidy was supported in part by the Howard Hughes

Medical Institute.

ADDRESS FOR REPRINTS: (E.E.) Department of

Medi-cine, Vanderbilt University School of Medicine, Nashville,

Tennessee 37232.

REFERENCES

1. van Eys

J,

Nance WE, Engel E: C autosomal trisomy with mosaicism: A new syndrome. Pediatrics

45:665, 1970.

2. Gallimore PH, Richardson CR: An improved banding technique exemplified in the karyotype analysis of two strains of rat. Chromosoma 41:259, 1973. 3. Caspersson T, Lindsten

J,

Zech L, et al: Four patients

with trisomy 8 identified by the fluorescence and Giemsa banding techniques.

J

Med Genet 9:1,

1972.

4. Tuncbilek E, Atasu M, Say B: Dermatoglyphics in trisomy 8. Lancet 2:821, 1972.

5. deGrouchy

J,

Turleau C, Leonard C: Etude en fluores-cence d’une trisomie C mosaique, probablement 8:46 XY/47,XY,?8+. Ann Genet 14:69, 1971. 6. Malpuech C, Dutrillaux B, Fonck Y, et al: Trisomie 8 en

mosaique. Arch Fr Pediatr 29:853, 1972.

7. Atkins L, Holmes LB, Riccardi VM: Trisomy 8.

J

Pediatr 84:302, 1974.

8. Riccardi VM, Atkins L, Holmes LB: Absent patellae, mild mental retardation, skeletal and genitourinary anomalies, and C group autosomal mosaicism.

J

Pediatr 77:664, 1970.

9. Bijlsma JB, Wijffels JCHM, Tegelaers WHH: C8 trisomy mosaicism syndrome. Helv Paediatr Acta 27:281,

1972.

10. Kakati 5, Nihill M, Sinha AK: An attempt to establish trisomy 8 syndrome. Humangenetik 19:293, 1973.

11. Laurent C, Robert JM, Grambert

J,

Dutrillaux B: Observations cliniques et cytogenetiques de deux adultes trisomiques C en mosaique: Individualisa-tion du chromosome supernumeraire par la tech-nique moderne de denaturation: 47,XY,?8 + . Lyon

Med 226:827, 1971.

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syndrome: Report of two further cases. Ann Genet 17:87, 1974.

13. Penrose LS: Dermatoglyphic patterns in a case of trisomy 8. Lancet 1:957, 1972.

14. Kucherlapati RS, Nichols EA, Creagan RP, et al: Assign-ment of the gene for glutathione reductase to human chromosome 8 by somatic cell hybridiza-tion. Read before the American Society of Human Genetics, Portland, Oregon, October 1974. 15. Bass HN, Crandall BF: Trisomy 8-an identifiable

syndrome. Read before the American Society of

Human Genetics, Portland, Oregon, October 1974.

ACKNOWLEDGMENT

We are most indebted to Susan Lewis, Ph.D., psychologist, Vanderbilt Child Psychiatric Division, for the child’s psycho-motor evaluation.

Epileptiform

Activity

in the

Electroencephalogram

Induced

by

Lithium

Carbonate

Lithium

salts

have

been

used

in the

prophylaxis

of

manic-depressive

disease

in

adults,’2

in

the

treatment

of

episodic

behavior

disturbances

in

children,34

and

recently

in

the

treatment

of

thyrotoxicosis. Side effects of therapy with

lithium

salts

have

been

frequent

at

toxic

blood

levels

(>

1.5 mEq/liter)

but

rare

at

therapeutic

blood

levels

(0.8

to

1.5 mEq/liter).6

This report describes the development of

paroxysmal

electroencephalographic

abnormali-ties

in

a

child

under

treatment

with

lithium

carbonate

for

a behavior

disturbance.

Such

parox-ysmal activity has not been described previously

during

lithium

carbonate

therapy.

CASE REPORT

This white boy was the 2,920-gm product of a normal pregnancy, labor, and repeat Cesarean section delivery in a 39-year-old gravida 2 woman. Growth and development were normal with walking at 1 1 months and speaking three-word sentences at 2 years. At the age of 6#{189}years he was hospitalized for presumed encephalitis after a three-week history of peculiar fidgeting mannerisms, excessive activity,

and staggering gait. He was unable to sit still, he talked continuously with a marked dysarthria, and he was severely ataxic. Admission lumbar puncture revealed clear and color-less cerebrospinal fluid containing 154 mononuclear cells per

cubic millimeter with a protein level of 37 mg/dl; bacterial

FIG. 1. EEC performed prior to instituting lithium carbonate therapy (patient receiving no medications).

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1975;56;826

Pediatrics

Suzanne B. Cassidy, Barbara J. McGee, Jan Van Eys, Walter E. Nance and Eric Engel