Unilateral Partial Adactyly in Down's Syndrome

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Unilateral

Partial

Adactyly

in Down’s

Syndrome

Siegfried M. Pueschel, M.D., M.P.H., and Patricia O’Donnell, B.A.

From the Developmental Evaluation Clinic, Children’s Hospital Medical Center, and the Department of Pediatrics, Harvard Medical School, Boston, Massachusetts

ABSTRACT. During a six-month period three children with

Down’s syndrome presented with a unique unilateral hand

dysplasia. Epidemiological investigations did not uncover a special etiological agent responsible for the formation of the partial adactyly. Pediatrics, 54:466, 1974, DOWN’S SYN-DROME, UNILATERAL PARTIAL ADACTYLY.

The subsequent delivery was uneventful. The baby weighed 2.9 kg. Down’s Syndrome and right hand dysplasia were

diagnosed shortly after birth and the chromosomal analy-sis revealed trisomy G, while her parents had normal

karyograms. The neonatal period was normal. There are

no family members with skeletal anomalies and/or Down’s

syndrome. The patient has a 15-year-old normal stensister.

Patient 2

Many phenotypical characteristics have been

de-scribed in Down’s syndrome since Langdon Down

published his observations in 1866.13 “Additional”

congenital anomalies have been recognized at an

increased frequency during the past decades.4’5

Stubby hands with shortened fingers and

brachy-dlinodactyly of the fifth digit are often noted, and

syndactyly is occasionally observed; yet other

path-ological features of the distal extremities are rare.6

There are only a few reports describing reduction

malformations of extremities in children with

Down’s syndrome.” Two patients with Down’s

syndrome presenting limb abnormality were

fol-lowed at Children’s Hospital in Los Angeles.8 Only

one account of a unilateral partial adactyly was

un-covered in the literature.9

This paper describes a distinct unilateral

dyspla-sia of digits 2 to 5 observed in three out of 20

children with Down’s syndrome admitted to a

special study at Children’s Hospital Medical

Cen-ter, Boston, during a six-month period.10

SUBJECTS Patient 1

J. D., a 9-month-old white girl, was born to unrelated

parents; the father was 43 years and the mother was 39 years of age at the time of J. D.’s birth. The antenatal period was complicated by a viral illness at the end of the first month of gestation. No medication was taken

other than acetaminophen intermittently and a multiple

vitamin preparation throughout gestation. At 38 weeks of

pregnancy spontaneous labor Started. Because of fetal bradycardia, oxytocin was administered to accelerate labor.

D. C., a 12-month-old white boy, was born to a

24-year-old gravida IV, pam III mother. Prior to conception she had taken contraceptive medications (ethynodiol

din-cetate combined with mestranol) for six years, and during pregnancy salicylic acid and a decongestant containing

phenacetin, acetaminophen, phenylpropanolamine and

phenyltoloxamine was administered sporadically. The mother

did not experience any complications throughout gestation.

At term, irregular and slow fetal heart beats were noted and a cesarean section was performed. The infant’s birth

weight was 2.7 kg. He was diagnosed as a “small-for-dates infant” with Down’s syndrome and an anomaly of his left hand. A subsequent chromosomal study reported 47 chromosomes with an extranumerary G-chromosome. In addition a pectus carinatum deformity of the chest and congenital heart disease were noted. The latter involves a

large interventricular septal defect with significant left to

right shunting and resulting pulmonary artery

hyperten-Sion. During the neonatal period the infant developed

jaundice; he received phototherapy. The family history is

negative for chromosomal disorders and skeletal anomalies. There is no consanguinity. The patient’s three siblings are normal.

Patient 3

D. B., a 6-month-old white boy, was born to young parents; the father was 29 years and the mother was 2.5 years of age. The antenatal period was uncomplicated. The

(Received August 20; revision accepted for publication

Sep-tember 14, 1973.)

This investigation was supported in part by MCHS Project

928 and by NICHD grant HDO 5341-03, U.S. Department

of Health, Education and Welfare.

ADDRESS for REPRINTS: (S.M.P.) Developmental Eval-uation Clinic, The Children’s Hospital Medical Center, 300

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J.D. ‘

D.C.

J.D.

D.C.

D.B. . D.B.

ARTICLES 467

Fic. 1. Unilateral partial adactyly in three children with Down’s syndrome.

mother occasionally took an analgetic containing salicylic acid, acetaminophen, salicylamide and caffeine and a multi-pie vitamin preparation with ferrous sulfate from the third

month to the end of pregnancy. Three weeks prior to the

estimated date of confinement the mother delivered a baby boy weighing 2.8 kg. Phenotypical anomalies compatible

with Down’s syndrome and a right hand deformity were

noted. Also this child’s karyogram showed trisomy 21. Both parents’ chromosomes were normal. Mild jaundice was ob-served during the otherwise uncomplicated neonatal course. A paternal grandfather’s cousin had Down’s

syn-drome. No musculoskeletal anomalies are known to have occurred in this family.

Photographs of the patients’ hand malformations

demon-strate the nearly identical unilateral partial adactyly in all

three (Fig. 1). As noted, the first digit in all three

in-stances appears to be unaffected. The remaining

rudimen-tary digits are of various lengths and structure.

The radiological study of the patients’ bony structures revealed broad flaring ilia, decreased acetabular angles, and hypoplasia of the nasal bones. There were no additional skeletal anomalies other than the involved limb malforma-tions

(

Fig. 2). The radiograph of J. D.’s right hand shows the absence of phalanges 2 to 5 and metacarpals 2 to 4. A rudimentary fifth metacarpal is noted. Also D. C. has no visible phalanges of the second to fifth digits on the

left hand. The third and fourth metacarpals are shortened while the second and fifth metacarpals are of normal size. In addition small calcified structures distal to metacarpals

Fic. 2. Radiographs of the three Down’s syndrome children

with unilateral partial adactyly.

3 and 4 give the appearance of a stippled epiphysis. The

radiograph of D. B.’s right hand depicts normal

metacar-pals and in addition rudimentary proximal phalanges of fingers 2 and 5. The osseous structures of the first digit

were interpreted as normal in all three children. Also, the

opposite hand of each patient does not display any ab-normalities.

Epidemiological investigations included geographical and

seasonal considerations, occupation of parents and environ-mental conditions. Since the time interval from the fourth

to the seventh postovulatory week is of utmost significance in the formation of the distal extremities,1’ particular at-tention was directed to the first two months of pregnancy. Emphasis was placed on. factors such as radiation, smoking,

infections, inadequate nutrition, ingestion of toxic substances or medications and other aspects conceivably interfering

with normal embryogenesis. This in-depth search for a suitable etiological explanation and for common

denomina-tors failed to yield any positive results. Of questionable

significance is the fact that the mothers of all three infants

had worked in local hospitals of different towns as nurses or nurses’ aides. None of them, however, had been exposed to radiation, unusual infections, or other identifiable

path-ologic circumstances.

DISCUSSION

The recognition of an increased frequency of a

distinct congenital anomaly among a group of

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dren with the same chromosomal disorder

chal-lenged the investigators to search for underlying

etiological and pathogenetic mechanisms. A

corn-prehensive study of this phenomenon is of

import-ance for the following reasons: (1) prompt

epi-demiological investigation could lead to early

iden-tification of involved causative factors and avoid

unnecessary further occurrence of anomalies; and

(2) it is also conceivable that during such studies

one might find clues which could be helpful to

explain etiological factors in trisomy 21.

A critical review of the pertinent literature on

terato1ogy,136 congenital anomalies,4’172’ and

Down’s syndrome3’522 was carried out in an

at-tempt to elucidate the etiology of the described

malformation. Specifically, reports dealing with

con-genital deformities of the upper extremities2729

were studied and several investigators most

experi-enced with limb abnormalities and Down’s

syn-drome9’3085 were contacted. Known syndromes

with limb anomalies including Poland’s syndrome

were reviewed but their symptomatology was not

identical with the clinical picture of our patients.

There are many theories concerning possible

etiological and pathogenetic mechanisms leading to

malformation of the extremities. Some skeletal

anom-alies have predominandy genetic causes and there

are many known syndromes with Mendelian

in-heritance. Freire-Maia pointed out that simple

genetic mechanisms are of relatively little

import-ance in the etiology of congenital limb deficiencies,

however.’7 Since there is no family member of the

three respective patients afflicted with a similar

anomaly, a “dominant” genetic cause is highly

un-likely in our children.

An alternative theory links the chromosomal

aber-ration in trisomy 21 to the observed hand

malfor-mation, since this particular anomaly has not been

reported to occur in euploid patients.7 Although

one cannot disprove this hypothesis one would

expect this abnormality to occur more often in

Down’s syndrome should there exist an association

between the aneuploidy and hand dysplasia.

Le-jeune’#{176} did not find a single child of his 4,000

Down’s syndrome patients with this particular

malformation, nor did other workers in this field

encounter unilateral partial adactyly in any of their

Down’s syndrome patients135 except one.9 Also

Schonenberg and Pfeiffer do not believe that the

chromosomal aberration in Down’s syndrome is

causally related to the hand anomaly, but rather a

coincidental event.

The reexamination of the chromosomal

struc-tures of our three patients did not uncover any

findings distinct from the karyograms of other

pa-tients with Down’s syndrome-trisomy 21.

During the past century many congenital

anom-alies of the extremities had been attributed to

amniotic bands which allegedly prevented the

normal development of an involved limb.’6

Ball-antyne also ascribed the primary abnormality to

the amnion36 and Torpin extended this view and

hypothesized an early rupture of the amnion

re-suiting in extraneous strands which then could

strangulate the distal extremity.37 Streeter rejected

this theory of amniotic bands causing limb

defor-mines and in turn presented evidence that

endog-enous degeneration within the mesenchymal and

subcutaneous connective tissue occurs due to the

inherent “defect in the germ plasma.”88 Since the

examinations of the three placentas did not show

any such structures, one cannot attribute the

ob-served malformations in the presented patients to

causation by amniotic bands. Furthermore, the

ap-pearance of the anomalies themselves (Fig. 1) does

not suggest strangulation by amniotic strands, and

also the bony abnormalities (Fig. 2) would be

difficult to explain on this basis.

Teratogenetic agents are known to produce

con-genital anomalies when given during a “sensitive

period” of antenatal development. In animal

ex-periments many drugs and other environmental

causes have been shown to interfere with normal

em-bryogenesis.2’ Over 30 “teratogens,” including

vita-mins, amino acids, nucleic acid antagonists,

alkalat-ing agents, caffeine, nicotine, and salicylates, have

been implicated in mimicking the effect of

thalido-mide in the development of the limbs.13

In man only a few environmental factors have

been identified as causing malformations. It has

been suggested that genotype of both mother and

embryo is of importance in determining the

vulner-ability of the developing organism to a specific

teratogen.13

Investigation of the maternal histories in our

pa-tients did not provide evidence that teratogens were

operative during the critical period of

embryo-genesis. Although all three mothers worked as

nurses, so far no common denominators were

de-tected and no teratogenic agents were found in

their immediate environment which could account

for the occurrence of this limb malformation.

SUMMARY

A unique unilateral anomaly of the hand has

been observed in three Down’s syndrome children

during a six-month period. This prompted a review

of the subject-related literature and a thorough

epidemiological study in an attempt to investigate

underlying etiological aspects and pathogenetic

mechanisms possibly involved in the formation of

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ARTICLES

469

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ACKNOWLEDGMENT

We are indebted to Dr. A. C. Crocker, Director of the Developmental Evaluation Clinic, for his support, guidance and advice. Furthermore, we are grateful to Dr. R. H. Wil-kinson for the review and interpretation of the radiological findings, and to Mrs. K. Dale for the chromosome analysis.

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1974;54;466

Pediatrics

Siegfried M. Pueschel and Patricia O'Donnell