VOL. ii6, No. 3
FAMILIAL ACROCEPHALOSYNDACTYLY
(PFEIFFER SYNDROME)*
By RONALD M. SALDINO, M.D.,f HOWARD L. STEINBACH, M.D.,t and
Downloaded from www.ajronline.org by 50.116.19.84 on 03/18/16 from IP address 50.116.19.84. Copyright ARRS. For personal use only; all rights reserved CHARLES J. EPSTEIN, M.D.
SAN FRANCISCO, CALIFORNIA
ACROCEPHALOSYNDACTYLY (ACS) the cold. Neither the parents nor other mem-
A I is a descriptive term applied to a bers of the patient’s family had similar mal-
group of closely related genetic diseases formations of the skull or extremities.
characterized by a premature fusion of the On physical examination, the skull was de-
cranial sutures and a varied degree of creased in anteroposterior diameter and the
syndactyly. In recent years, several dis- forehead was wide and prominent. The circum-
tinct varieties of ACS have been separated ference of the head measured i cm. and the
from the classic type described by Apert’ inner canthal distance 40 mm. The eyes pro-
in 1906. Although
typic overlay exists, truded slightly, and the patient wore eyeglasses
considerable pheno- because of hyperopia (Fig. I, A and B). Hypo-
these syndromes are plasia of the maxillary region with a “parrot-
caused by distinct genes, and correct gene- beaked” nose was apparent. The palate was
on an accurate
tic counseling depends narrow and the alveolar ridges were wide. The
diagnosis.
clinical and roentgenographic the clinical and teeth were irregularly placed and some of the
This report describes anterior teeth were missing. Duplicated upper
roentgenographic features in a mother and canines had been removed previously. Supina-
her children who had a dominantly in-
tion of the forearms was limited and cubitus
herited, familial variety of acrocephalosyn- valgus was present. Brachydactyly, broad
dactyly as described by Pfeiffer.2’ thumbs, and radially deviated terminal pha-
langes were noted in the hands. A painful bony
nodule was present on the distal phalanx of the
REPORT OF CASES right thumb and there was a moderate clino-
CASE I. A 30 year old mother of 3 was born dactyly of the fifth fingers. Dermatoglyphics
were normal. The great toes were broad, and
with a prominent forehead, broad thumbs and
toes, and webbing between the second and third there was a partial soft-tissue syndactyly that
toes of both feet. She did not receive any spe- involved the second and third toes, bilaterally.
cific treatment for these abnormalities, and In general, all the long bones of the arms and
physical and mental development was normal. hands appeared short. Height of the patient
At the age of 20 years, the patient delivered a was I 52 cm. Routine clinical laboratory values
child (Case II) that resembled the mother in of the blood chemistry were unremarkable.
several respects. A second child, born when the Roentgenographic Findings (Fig. 2-5). The
mother was 21 years of age, was normal. The roentgenograms of the skull demonstrated the
third child (Case in) was born when the mother typical features of premature fusion of the
cranial sutures, with increased height and flat-
was 25 years old, and this child also had anom-
alies of the head and extremities similar to those tening of the frontal and occipital bones, and
of the mother. One year later, the mother ex- shortened anterior and posterior diameters.
perienced a single grand mal seizure. An elec- Minimal increase in the convolutional markings
troencephalogram was said to have been abnor- of the skull, upward slanting of the lesser
mal and she was treated with Dilantin and sphenoid wings, a deepened sella turcica, and a
Gemonil without recurrence of the seizures. The small posterior fossa were also shown. An ap-
parent assimilation of the atlas at the base of
mother complained of pain in her hips, elbows,
shoulders, and hands which was not associated the skull was noted. Maxillary hypoplasia was
with swelling or redness, but was aggravated by pronounced and resulted in prognathism.
* From the Departments of Radiology,f and Pediatrics, University of california School of Medicine, San Francisco, California.#{149}
Supported by USPHS grant AM02589 and a grant from the National Foundation March of Dimes.
Currently Clinical Associate, Department of Radiology, National Institutes of Health, Bethesda, Maryland.
§ Recipient of a Career Development Award from the National Institute of Child Health Development, USPHS..
6o9
6io R. \l. Saldino, H. L. Steinbach and C. J. Epstein NOVEMBER, i972
Downloaded from www.ajronline.org by 50.116.19.84 on 03/18/16 from IP address 50.116.19.84. Copyright ARRS. For personal use only; all rights reserved 1’ic;. i. Case 1. (4 and B) Views of face and head showing maxillary hypoplasia,
prominence of the eves, wide forehead, and increased inner canthal distance.
The roentgenograms of the hands showed a
generalized brachydactyly. The greatest de-
gree of shortening was in the middle phalanges.
especially those of the index and little fingers,
Complete fusion of the proximal and distal pha-
lanx of the left thumb and partial fusion of the
interphalangeal joint of the right thumb were
noted. The thumbs were broad and deviated
radially. The articular cartilage of all the inter-
phalangeal and metacarpophalangeal join ts was
narrowed. No fusion of the carpal bones was
demonstrated. A bone island was present in the
distal left ulna. Significantly, no osseous syn-
dactyly was demonstrated.
The roentgen findings in the feet were a gen-
eralized brachyphalangia with absence of the
middle phalanges of all the toes and partial
fusion of the proximal and distal phalanges of
the great toes. The first metatarsal was greatly
shortened and extremely broad. Multiple tarsal
‘ .. coalitions were noted, with calcaneocuboid fu-
FIG. 2. Case I. Lateral view of the skull showing
typical changes of acrocephaly. The size of the -- -
skull is increased and the frontal and occipital increased. Pronounced maxillary hypoplasia is
present.
bones are flat. The depth of the sella turcica is
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\OL. ii#{243N}o, . j
Familial
Acrocephalosyndactyly
(Pfeiffer Syndrome)
611
612 R. M. Saldino, H. L. Steinbach and C. J. Epstein NOVEMBER, 1972
Downloaded from www.ajronline.org by 50.116.19.84 on 03/18/16 from IP address 50.116.19.84. Copyright ARRS. For personal use only; all rights reserved l’1G. 4. Case I. (A and B) Frontal, and (C) oblique projections of the feet. The first metatarsals are markedly
broadened and deformed, especially on the right. The interphalangeal joints of the broadened and short-
ened great toe are fused. The middle phalanges are absent bilaterally, and multiple tarsal bones have fused.
word at 7 months, she did not walk until 2 years of all fingers, abnormally wide thumbs, and
of age. At 3 years she required glasses because slight clinodactyly of both fifth fingers were
of severe hyperopi a. Thereafter development observed. Dermatoglyphics were normal. The
appeared normal and she progressed well in great toes were broad and a soft-tissue syn
school. At years of age, petit mal and grand dactyly of both second toes extended as far
mal seizures began ; these were treated with distally as the nails (Fig. 7). The patient’s
phenobarbital and Gemonil. Also at 9 years, height was 137 cm. Although formal testing was
strabismus was corrected surgically. not done, mentation appeared somewhat slow.
On physical examination, the patient’s re- However, her teacher stated that the child’s
semblance to her mother was striking. The con- school work was above average.
formation of the skull was similar and the cir- Roentgenographic Findings (Fig. 8-13). Skull
cumference of the head was 52.8 cm. The inner roentgenograms were obtained at 8 and 10
canthal distance was 37 mm. and there was years of age. Previous craniectomy defects were
marked antimongoloid slant to the eyes. Pro- noted along the coronal and lambdoid sutures
nounced maxillary hypoplasia was noted and bilaterally. Metallic clips about the foramen
the mouth was held open. The alveolar ridges magnum had been placed during the previous
were wide and the palate was narrow but high surgical procedures because of premature cran-
(Fig. 6). The teeth were crowded and ortho- ial synostosis and Arnold-Chiari malformation.
dontic procedures had been performed to cor- The frontal bone was increased in height and
was flat, and the coronal diameter of the skull
rect malalignment. The ears were low-set but
normal in conformation. External rotation of was increased. The lesser sphenoid wings slanted
the elbows was limited markedly. Shortening upward and were unusually dense. A shallow
VOL. ii6, No. 3 Familial Acrocephalosyndactyly (Pfeiffer Syndrome) 613
Downloaded from www.ajronline.org by 50.116.19.84 on 03/18/16 from IP address 50.116.19.84. Copyright ARRS. For personal use only; all rights reserved FIG. 6. Case II. High narrow palate with wide
alveolar ridges. The lateral incisors have been re-
moved because of crowding of the teeth.
lanx of the thumb showed a partially assimi-
lated anomalous ossification center in the distal
portion. No fusion ofthe carpal bones was noted
or bony fusion of the pilalanges. The thumbs
were abnormally broad. At the age of 8 years,
the roentgenograms of the feet demonstrated
hypoplasia of the middle phalanges and absence
of the epiphyses of the distal and middle pha-
FIG. 7. Case II. Broad great toes with extensive
soft-tissue syndactyly of the second and third toes
bilaterally.
614 R. M. Saldino, H. L. Steinbach and C. J. Epstein NoVEMBER, 1972
extremely broad and short, especially on the
left side. The epiphysis of the left first meta-
tarsal was deformed and medially placed. Early
fusion was seen of the deformed medial cunei-
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bones. The navicular and middle cuneiform
were fused Oil the right side. Solid calcaneocu-
boid fusion was present bilaterally.
Roentgenograms at the age of 10 years dem-
onstrated a progressive synostosis of the previ-
ously described early fusions with the calcaneo-
cuboid fusion forming one solid mass, and mul-
tiple coalitions between the cuneiforms, navi-
cular, and first 3 metatarsals. The middle and
distal phalanges had not yet fused.
In the roentgenogram ofthe elbowjoint, con-
siderable hypoplasia of all the bones was seen.
The normal anterior angulation of the distal
humeral condyles was absent and the radial
head was hypoplastic. The epiphysis of the
proximal radius was extremely small and flat.
In the lumbar spine, the intervertebral disk be-
tween the fourth and fifth lumbar vertebrae was
narrow and the posterior elements were fused.
The right twelfth rib was hypoplastic. Coxa
valga, abnormal widening of the symphysis, and
hypoplasia of the greater trochanters were seen
in roentgenograms of the pelvis. could
No significant roentgen abnormalities
be detected in the chest, knees, lower extremi-
ties, forearms, humeri, or femora. The acromial
process of the scapula appeared unusually large.
CASE III. This patient, the 5 year old daughter
ofCase I, had malformations similar to those of
her sister and mother. During the first year of
life, premature fusion of the coronal suture was
noted and craniectomies were performed. Early
development was slightly delayed and the child
did not walk until 17 months. Mental develop-
ment, however, was considered normal there-
after.
On physical examination, the patient’s face
11G. 8. Case II. (A) Lateral and (B) frontal projec- resembled that of her mother and sister (Fig.
tions of the skull. The postoperative defects are 14, A and B). The forehead was bulging and a
the result of craniectomy performed because of surgical bony defect was noticeable. The head
Arnold-Chiari malformation and premature su- measured 45.4 cm. in circumference and the
tural synostosis. Severe maxillary hypoplasia, inner canthal distance was 30 mm. The right
crowding of the teeth, and narrowing of the palate ear was slightly low-set. The alveolar ridges
are present. were wide and the palate was deep. Only the
right upper incisor, which had been capped, re-
langes. An anomalous ossification center was mained in the jaw. The lower teeth were placed
present in the proximal phalanx of the great irregularly. External rotation of the forearm
toe which was abnormally wide and consider- was moderately limited and full extension of the
ably shortened. The first metatarsal was also elbow could not be attained. The thumbs were
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616 R. M. Saldino, H. L. Steinbach and C. J. Epstein NOVEMBER, 1972
fusion of the distal phalanges with com-
plete syndactyly, and usually a single nail
( synorchia). Hoover et al.’3 have described
in detail the malformations in o cases of
Downloaded from www.ajronline.org by 50.116.19.84 on 03/18/16 from IP address 50.116.19.84. Copyright ARRS. For personal use only; all rights reserved Apert ACS. In these, severe premature
synostosis of the cranial sutures resulted
in the classic “tower skull.” Other asso-
ciated anomalies, such as mental retarda-
tion, maxillary hypoplasia, limited motion
of the elbows, and visual difficulties were
often present. Other causes of secondary
craniosynostosis have been reviewed by
Duggan and co-workers.1#{176}
All of the other variations of acrocephalo-
syndactyly were called atypical ACS. In
none of these variants was the severe in-
terdigital osseous fusion seen that is char-
Ik
A
I
-.
11G. 10. Case II. (A and B) Anteroposterior and (C
and D) oblique projections of the feet. The first 11G. II. Case II. Lateral view of the cervical spine.
metatarsals are severely deformed and an unusual Hypoplasia of the posterior elements of the first
epiphysis of the proximal phalanx of the great toe cervical vertebra is noted; patient had Arnold-
is present. The epiphyses of the distal and middle Chiari malformation. Complete fusion of the
phalanges are absent, probably prior to their posterior elements of the fifth and sixth cervical
fusion. The calcaneocuboid and multiple other vertebrae and partial fusion of the anterior inter-
tarsal and metatarsal bones are fused. vertebral body are noted.
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VOL. ii6, No. 3
, Familial Acrocephalosyndactyly
a (Pfeiffer Syndrome)
617
6i R. M. Saldino, H. L. Steinbach and C. J. Epstein NOVEMBER, 1972
Downloaded from www.ajronline.org by 50.116.19.84 on 03/18/16 from IP address 50.116.19.84. Copyright ARRS. For personal use only; all rights reserved 11G. 14. Case III. (A and B) Views of face and head showing maxillary hypoplasia,
wide forehead, and increased inner canthal distance.
cilaracteristic of the Pfeiffer syndrome in-
dude I flat nasal bridge, hypertelorism,
antimongoloid slant of the palpebral fis-
sures, high-arched palate, varus deformities
of the great toes, brachmesophalangia,
trapezoidal shape of the proximal phalanx
of the thumb, and a deformed, wide first
metatarsal. The mother and affected sib-
lings of this report had all these features.
Additional roentgenographic features found
in this family, not reported previously in
cases of the Pfeiffer syndrome included:
Arnold-Chiari malformation (Case ii), con-
genital fusions of the cervical spine (Cases
II and III) and of the lumbar spine (Cases i
and ii), coxa valga (Cases i, II, and III),
and widening of the svmphvsis pubis
FIG. 15. Case III. A broad thumb, markedly short-
ened second and fifth middle phalanges, and ab-
normal distal end of the proximal phalanx
thumb are seen in the hand. of the
\OL. ii6, \o. 3 Familial Acroceplialosvndactylv (Pfeiffer Syndrome) 619
(Cases I, II, and iii). All these features ex-
cept the Arnold-Chiari malformation have
been described previously in tile typical
Apert syndrome.6’7’23
Downloaded from www.ajronline.org by 50.116.19.84 on 03/18/16 from IP address 50.116.19.84. Copyright ARRS. For personal use only; all rights reserved Another prominent feature in the 3 mem-
bers of this family was the severe coalition
of the tarsal bones. Fusions of the tarsal
bones were described in previousl re-
ported cases of the Pfeiffer syndrome, but
not emphasized.’7’38 Schauerte and St-
Aubin25 stressed the progressive nature of
11G. 17. Case iii. Fusion of the posterior elements
of the third and fourth cervical vertebrae.
the svnosteoses ill tile classic .Apert syn-
drome and presented examples of this con-
dition in the feet, hands, and cervical
spine. Points of roentgenographic interest
besides the fusion of tarsal bones and
vertebrae include hvpoplasia of the elbow
and shoulder joint, fusion of the inter-
phalangeal joints of the thumbs, and se-
lective shortening of the middle phalanges
of the index and little fingers.
Except for one report,25 all of the types
of ACS are inherited in an autosomal
dominant manner.3’4’20’23’32 When PolY-
dactyly accompanies ACS, then the in-
heritance may be autosomal recessive or
dominant (Carpenter’s5 and Noack’s18 syn-
drome, respectively).31 Nearly all of the
earlier reports of ACS were those of spora-
die new mutations. The cases described by
Weech,36 van den Bosch33 (typical ACS)
ACS)
and Waardenburg et al.3’ (atypical
presented familial examples.
11G. i6. Case III. (A) Anteroposterior and (B) lateral In 1964 Pfeiffer2’ presented a familial
views of the foot showing absence of the epiphyses example of atypical ACS, and further re-
of the distal and middle phalanges before fusion ports by Zippel and Sch#{252}ler,38 Martsolf
has taken place. The first metatarsal is short and et al.,17 and others, have established the
broad, and the shortened great toes are greatly
widened. 1)evelopmental anomalies of the tarsal entitV as a genetically distinct form of
bones that lead to fusion are present. The cal- atypical ACS. Recognition of a familial
caneus and cuhoid are fused solidi v. form of ACS in the ‘oung infant is of
620 R. i\l.Saldino, H. L. Steinbach and C. J. Epstein NOVEMBER, 1972
specific chromosomal abnormality cannot
be correlated with the Apert syndrome. In
the family with Pfeiffer syndrome herein
reported, ho dl romosom e abnorm ali ties
Downloaded from www.ajronline.org by 50.116.19.84 on 03/18/16 from IP address 50.116.19.84. Copyright ARRS. For personal use only; all rights reserved were detected. In other instances of this
syndrome, Pfeiffer,21’22 and Zippel and
Sch#{252}ler8 reported that their analysis also
disclosed norm al ch romosomes. Other
causes of the Apert syndrome have been
suggested. Pilosebaceous abnormalities of
the forearms (acne vulgaris) in 7 postpu-
bertal patients with the Apert syndrome
were reported by Solomon et al.27 Since
forearm acne is rare, the authors con-
sidered abnormal androgen metabolism as
a possible etiologic factor in the Apert svn-
drome.
Other syndromes that frequently mani-
fest broad thumbs and broad great toes
are distinguished easily from the Pfeiffer
syndrome by the lack of acrocephaly. The
malformations of the thumb and great toe
in the Ru binstei n-Taybi syndrome24’29’3#{176}
may be similar to those of the Pfeiffer
FIG. i8. Case III. Widening of the symphysis pubis syndrome. The frontodigital syndrome,’6
and bilateral coxa valga.
the oto-palato-digital syndrome,15 Len ‘s
pleonosteosis,’ and Type B brachydactyly32
also ma\’ include similar digital abnor-
obvious value in the prompt, correct gene- mali ties. The acrocephalopolysyndactyly
tic counseling of parents. The risk of oc-
currence in offspring of affected individuals
is 50 per cent and there is no evidence for
incomplete penetrance (unaffected individ-
uals who carry the gene).
The etiology of acrocephalos’ndactyly is
not known. Blank4 and Frerichs” impli-
cated an increased paternal age-a known
phenomenon in new mutant cases of
achondroplasia.
Recently, Dodson et al.9
described a typical case of the Apert svn-
drome which was associated with a Group
A chromosomal aberration. In their review
of chromosomal analysis in patients with
ACS, 3 abnormal chromosomes were dis-
covered among 20 patients examined. All
of these were in the typical form of ACS
(Apert syndrome). Although all of the
aberrations in ACS involved the Group A FIG. 19. Case III. Lateral view of the elbow demon-
strates generalized hypoplasia of the bones of the
chromosome, the described abnormalities elbow.
in each patient were different, and a
\OL. ii6, No. 3 Familial Acrocephalosvndactvl\? (Pfeiffer Syndrome) 621
syndromes described by Carpenter5 and by tions. A.M.A. Am. 7. Dis. (Jhild., 1971, 12!,
Noack included cranial and digital ab- 393-400.
normalities, but these syndromes are recog- ,1. BARTSOCAS, C. S., WEBER, A. L., and CRAW-
nizable by the presence of preaxial poly- FORD, J. I). Acrocephalosyndactyly type :
Chotzen’s syndrome. 7. Pediat., 1970, 77,
Downloaded from www.ajronline.org by 50.116.19.84 on 03/18/16 from IP address 50.116.19.84. Copyright ARRS. For personal use only; all rights reserved dactyly. The delta phalanx described by 267-272.
J ones” is closely related to the deformities 4. BLANK, C. E. Aperts syndrome type of acro-
in the great toe ofour patients. cephalosyndactyly-observa tions on British
Although the malformations of acro- series of thirty-nine cases. Ann. Human
Genet., 1960,24, 151-164.
cephalosvndactvly are predominantly of 5’ CARPENTER, G. Two sisters showing malforma-
the head and distal extremities, a gen- tions of skull and other congenital abnormal-
eralized skeletal dysplasia is clearly pres- ities. Rep. Soc. Study Dis. Child, ioi, 1,
ent. Deformities may be present in the I I 0- 1 I 8.
shoulder, elbow, pelvis, hips, and spine,623’37 6. COHN, B. N. True oxycephaly with syndactyl-
ism: case report. Am. 7. Surg., 1945, 68,
as in this family with the Pfeiffer syndrome. 7’ COOPER, R. Acrocephalosyndactyly with report
Actually, a generalized mesodermal defect of case. Brit. 7. Radiol., 1953, 26, 533-538.
is present in the Apert syndrome, with ab- 8. CROME, L. Critique of current views on acro-
normal viscera, cleft palate, chamber- cephaly and related conditions. 7. Ment. Sc.,
angle abnormalities, other ocular problems, 1961, 107, 459-474.
9. l)oDsox, W. E., Mu5ELE5, M., KENNEDY,
and bifid uvula.4’26’32 J. L., JR., and AL-AISH, M. Acrocephalosyn-
The clinical and roentgenographic
fea- dactylia associated with chromosomal trans-
tures of congenital ring constrictions of the location. A.M.A. Am. 7. Dii. Child., iyo,
digits, secondary to mechanical and amnio. 120, 360-362.
tic bands, are superficially similar to de- 10. DUGGAN, C. A., KEENER, E. B., and GAY, B. B.,
J R. Secondary craniosynostosis. AM. J. ROENT-
formities in the Apert syndrome, but they GENOL., RAD. THERAPY & NUCLEAR MED.,
can and should be differentiated.2’35 1970, 109, 277-293.
I 1. FRERICHS, C. T. Apert’s syndrome. Nebraska
SUMMARY M. 7., 1967,52, 491-495.
12. GORLIN, R. J., and SEDANO, H. Acrocephalosyn-
A family with acrocephalosyndactyly, dactyly (Apert’s syndrome). Mod. Med., 1969,
which differs from classic Apert’s syn- 37, 235-237.
drome, has been described. 13. HOOVER, G. H., FLATT, A. E., and WEIss, M. W.
Hand and Apert’s syndrome. 7. Bone & Joint
The autosomal dominant manner of in-
Surg., 1970, 52-A, 878-895.
heritance and the lack of interdigital 14. JONES, G. B. Delta phalanx. 7. Bone & Joint
osseous fusion clearly differentiates it from Surg., 1964, 46-B, 226-228.
Apert’s syndrome. Other characteristic I 5. LANGER, L. 0., JR. Roentgenographic features of
features include broad thumbs and great oto-palato-digital (OPD) syndrome. AM. J.
ROENTGENOL., RAD. THERAPY & NUCLEAR
toes, normal intelligence, and only mild MED., 1967, 100, 63-70.
soft-tissue syndactyly. i6. MARSHALL, R. E., and SMITH, D. W. Fronto-
Additional roentgen findings are pre- digital syndrome: dominantly inherited dis-
sented and a differential diagnosis is dis- order with normal intelligence. 7. Pediat.,
cussed. 1970,77, 129-133. J. B., CARPENTER,
17. MARTSOLF,
J. T., CRACCO,
Howard L. Steinbach, M.D. G. G., and O’HAitA, A. E. Pfeiffer syndrome:
Department of Radiology unusual type of acrocephalosyndactyly with
University of California San Francisco broad thumbs and great toes. A.M.A. Am. 7.
San Francisco, California 94122 Dis. Child., 1971, 12!, 257-262.
i8. NOACK, M. Em Beitrag zum Krankheitsbild der
Kin-
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m#{233}md.. hOp. Paris, 1906, 23, 13 10-1330. synostosis_syndactylism. AM. J. ROENTGENOL.,
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311- 320. J. ROENTGENOL., RAD. THERAPY & NUCLEAR
22. PFEIFFER, R. A. Associated deformities of head MED., 1965, 93, 362-366.
and hands. Birth Defects Original Article 31. TEMTAMY, S. A. Carpenter’s syndrome: acro-
Series, 1969, 5, No. ,, pp. 18-34. cephalopolysyndactyly : autosomal recessive
23. PILLAY, V. K. Acrocephalosyndactyly in Singa- syndrome. 7. Pediat., I 966, 69, I I I- I 20.
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Joint Surg., 1964, 46-B, 94-101. formations. Thesis, Johns Hopkins Univer-
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