Ann. Hum. Qerd., Land. (1900), 24, 1.

51 151
With 2 platea
Printed in &eat Britain

Apert’s syndrome (a type of acrocephalosyndactyly)-observations

on a British series of thirty-nine cases*
BY C. E. BLANK, M.B., PH.D.1-
Ga,lton Laboratory, University College London

INTRODUCTION

Acrocephalosyndactyly is a rare developmental deformity characteristially affecting the

head, hands and feet. Any patient with cranial dysplasia of acrocephalic type and syndactyly of
one or more of the extremities may traditionally be described under this heading. Since it was
first described by Apert in 1906 over 150 cases have been reported in the literature. Although
most published cases have been sporadic in occurrence, there are sufficient family data to make a
genetic origin for this conditiop probable, and to suggest the presence of several ‘genes’, each
responsible for a difFerent clinical variety of acrocephalosyndactyly.
It was decided to reinvestigate the problems of definition and etiology and to estimaw the fre-
quency of the condition. Of interest, too, was a possible parental age effect, suggested in Grebe’s
(1944)data and usually ascribed to an increase in the mother’s age ;as Penrose (1957 b) pointed out
the age effect could be explained more satisfactorily as secondary to an increase in the father’s age.
Fifty-four cases of acrocephalosyndactyly, born in Great Britain, were ascertained. Thirty-
four patients were available for examination and in twenty-six of these it was possible to obtain
X-ray photographs of the greater part of the skeleton. Good clinical descriptions, photo-
graphs, X-ray films or post-mortem reports enabled a diagnosis of acrocephalosyndactyly to
be made in the remaining patients, eighteen of whom were dead.
Two main clinical categories : (i) ‘typical’ acrocephalosyndactyly (as originally described by
Apert); and (ii) other types, or ‘atypical’ acrocephalosyndactyly, could be recognized. Inter-
digital osseous union, more especially a mid-digital hand mass with a single nail common to the
second, third and fourth digits, so conspicuous a feature of group (i), was entirely lacking in
group (ii). Every case of acrocephalosyndactyly which has been examined by the author and
almost every case described in the literature may confidently be placed in one or other of thew
two categories.
The present paper is concerned with ‘typical’ acrocephalosyndactyly (henceforth called more
simply Apert’s syndrome), which is the most common type to be reported, both in the literature
and in medical practice. Thirty-nine of the fifty-four cases of acrocephalosyndactyly belong to this
category.
CLINICAL DESCRIPTION OF TWENTY-FOUR CASES, WITH REMARKS ON THE
NECROPSY FINDINQ IN ELEVEN MORE PATIENTS
The following is a summary of the main clinical findings which were observed in the twenty-
four patients with Apert’s syndrome who were examined. More complete descriptions are to be
found in Blank (1959).
*This work formed part of a thesis accepted for the degree of Ph.D., London University.
tIn IWXiPt of a grant from Ule Medical Research Coimcil. Present address : Department of Genetice, The
University, Sheffield.
152 C. E. BLANK
A deformity of the osseous system is the most conspicuous feature of this syndrome. It is
recognizable at birth and characteristically affects the head and extremities.
Although there were many abnormalities of the cranium and face common to all cases, the
relative severity of the different abnormalities varied considerably from patient to patient.
Craniofacial deformity was associated with early and irregular obliteration of cranial sutures
and asymmetry was sometimes quite marked. Crania were short, broad and high (brachy-
cephalic and hypsocephalic) with the highest point of the vault near or anterior to the bregma.
The occiput was generally inconspicuous and the back of the head flattened. The forehead was
generally prominent, more vertical than normal and sometimes there was a swelling in the
position of the metopic suture. This swelling was particularly prominent in the two infants
who were examined, where it was membraneous rather than bony. A swelling could sometimes
be palpated in the region of the bregma. A deep transverse groove above the supra-orbital
ridges was sometimes seen. The lateral walls of the cranium were generally full and two patients
had marked bilateral temporal bulges in the region of the pterion. Parietal eminences were
impalpable. Maxillae were hypoplastic, faces flattened, upper jaws retrognathous and lower jaws
relatively prognathous. Protrusion of the eyeballs (proptosis), increased distance between the
eyes (ocular hypertelorism) and strabismus were frequently marked. The outer canthi lay on a
lower plane than the inner, giving an outward and downward slope to the palpebral fissures.
Noses were short and relatively broad with the classical ‘parrot’ nose often seen. Often the
ears stood out from the head and appeared disproportionately large. Palates were high, alveolar
borders thickened and upper teeth crowded together. Posterior cleft palate was present in six
patients. Hare-lip did not occur.
The second, third and fourth fingers formed a bony mass, the mid-digital mass, with a single
common nail. The first and fifth digits were sometimes free or sometimes joined to this mid-
digital mass by the soft tissues; less frequently union was osseous. Dissimilarities between right
and left hands were generally confined to the finer details ofnail morphology and finger tip or
palmar ridge pattern. I n the feet, the second, third and fourth toes were joined by extensive
soft tissue union. The first and fifth were sometimes free or sometimes joined by the soft tissues
to the second and fourth, respectively. Toe nails were usually separate, but sometimes continuous
on contiguous digits. Although extra ‘first’ metatarsals were present in five patients, well-
defined extra digits were absent. Deformity of the extremities was remarkably symmetrical.
The trunk and lower extremities were of normal, or near normal, length but the upper
extremities were markedly shortened. Lumbar lordosis and other minor deformities of the
thoracic cage, though usually noticeable, were not marked. Deformity of the pectoral girdle
was often marked and abnormalities of the pelvic girdle could be seen on X-ray examination.
Movements at the shoulder and other joints of the upper extremity were almost always limited
and ankylosis of vertebrae common. These deformities were generally more marked in the older
patients.
Some mental impairment, not necessarily amounting to imbecility, was judged to be present
in almost every case.
One of these twenty-four patients died during the period of investigation and was examined
post-morhm ; no visceral abnormalities were apparent. The post-mortem reports of eleven other
patients with the head and extremity deformities of Apert’s syndrome were available. In five
instances the viscera were noted as normal; various abnormalities of the internal organs were
 Apert’s syndrome 153
reported in the remaining six post-mortem reports :polycystic kidneys and thyroid adenoma were
found in case 29; oesophageal atresia of an uncommon type, with a small opening into the
trachea in case 31 ; an unusual kind of pyloric stenosis and absence of normal interlobar lung
fissures in caae 32; an overriding aorta, atrophy of the right and left pulmonary arteries, pul-
monary aplasia, bicornuate uterus and ectopic anus in case 35 ; anomalous duplication of the
superior vena cava, pulmonary stenosis, ventricular septa1 defect, bilateral hydronephrosis and
hydro-ureters with strictures at the ureteric orifices in case 36 ; and cartilage anomalies in the
walls of the trachea and larger bronchi, together with slight endocardia1 fibroelastosis in the
chambers of the left side of the heart described in case 38.
Cases 31, 32, 35 and 36 died in early infancy, case 38 at 15 months (cause of death umscer-
tained) and case 29 at 53 years (fractured skull and subdural haemorrhage). Apart from case 36
(Owen, 1952) none of the eleven cases had been reported in the literature.

BIRTH STATISTICS AND INCIDENCE IN THE GENERAL POPULATION

The true incidence of Apert’s syndrome at birth is difficult to obtain. Diagnoses given early
in life to cases ascertained as adults suggest that these patients are frequently misdiagnosed at
birth. It is possible, indeed probable, that cases of Apert’s syndrome are sometimes included in
obstetric reports under such vague headings as ‘ multiple deformities ’ or ‘congenital ab-
normalities ’. Any estimate, based on obstetric reports alone, of the incidence a t birth of this
condition must be regarded as a minimal value.
A search was made of the obstetric records of a number of London and provincial hospitals.
Where there was a tendency to group everything under the general headings of ‘multiple
deformities’ etc., or individual reports were poorly documented, the records as a group were
discarded. Fifteen London hospitals and eight hospitals in the Midlands and North of England
provided suitable records of 322,182 births. These records cover long periods in the years between
1932 and 1957, though there were gaps in continuity due to war damage, change in hospital
policy and other reasons.
Two cases of acrocephalosyndactyly of Apert type were traced in this way. These infants,
both girls, died within a few hours of birth.
A diagnosis of Apert’s syndrome is well substantiated in one patient (case 31) by a good
clinical description, photographs, X-rays and a post-mortem report. The second patient
(case 35) is less well documented. There are no X-rays, photographs or adequate clinical records.
A post-mortem report lists the following congenital abnormalities : acrocephaly, syndactyly,
ectopic anus, pulmonary aplasia, bicornuate uterus, cleft palate and a congenital heart defect.
The extremities involved and extent of the deformities are not specified. However, cleft palate,
though frequent in Apert’s syndrome has not been observed in atypical acrocephalosyndactyly ;
because of this the author feels justified in grouping this patient as one of Apert’s syndrome.
Total number of births = 322,182.
Number of cases of Apert’s syndrome recognized = 2.
Incidence of the condition at birth, approximately 1 in 160,000.
The first few cases of the author’s series of thirty-nine patients with Apert’s syndrome were
obtained by a search of hospital records, published case r e h n d through the kindness of
personal acquaintances interested in the condition. The majority of cases were ascertained 88 a
154 C . E. BLANK
result of inquiries made of the various specialists throughout Great Britain most likely to meet
with these patients, for example, plastic surgeons, neurosurgeons, paediatriciana and the super-
intendents of mental deficiency institutions. The inquiries were so arranged as to make some
sort of estimate of the efficiency of these methods. It soon became apparent that ascertainment
was far from complete. It seems likely that patients are often not recorded as cases of mro-
cephalosyndactyly at all. Private patients were probably not all reported. Furthermore,
though this does not affect an estimate of the incidence of living patients in the population, it
seems likely that many cases die within a few days or months of birth, before being referred to
the specialists contacted. Again, it is very probable that patients referred many years ago to
specialists no longer practising, were not ascertained. Finally, it is probable that even in a
condition as severe as this, patients are sometimes not referred for specialist opinion because
there is a tendency to assume that nothing can be done. Nevertheless, thirty-nine cases of
Apert’s syndrome were ascertained, twenty-five of these were still alive.
This gives a minimum incidence of approximately 1 in 2,000,000 in the general (living)
population of Great Britain.
Of these twenty-one c w s in this series born in the 10 years between 1948 and 1957, twelve
are now dead, nine patients dying in infancy, five of them within a few days of birth. While the
difference between the estimate of the frequency of Apert’s syndrome at birth, 1 in 160,000
and that in the living population, 1 in 2,000,000, is no doubt, in part due to lack of ascertain-
ment in the living population, it is clear that a high mortality, particularly in early infancy, of
patients with this condition also contributes to the discrepancy between them estimates.

PARENTAL AGE AND BIRTH ORDER

Parental age and birth order data were obtained in thirty-six of the thirty-nine families,
parental age in another and birth order in a thirty-eighth. The parents of the remaining case
were unknown.
The distributions of father’s age at the birth of the propositus, mother’s age at the birth of
the propositus and the position in the family of the propositus are shown in diagrammatic
form and are compared with the corresponding distributions of the ‘general’ population in
Figs. 1 , 2 and 3. The general population figures for maternal age and birth order are those for
England and Wales in 1950 (The Registrar-General’s Xtutisticul Review of England and Wale?
for the year 1950. Part 11, Table I1 (Part I), p. 148). British statistics for father’s age in the
general population are not available; the statistics used are those of the Australian 1953 popu-
lation (Demography,1953, Table 72). Maternal age distributions are v0ry similar in British and
Australian populations. Older parents are more frequent in Apert’s syndrome than in the
general population and propositi tend to be among later births. The modal value for father’s age
occurs at 37 (35-39) years and for mother’s age at 32 (3&34) years; these modal ages are 10 and
5 years older, respectively, than those of the general population.
The independent effect of father’s age, mother’s age and birth order may be studied using the
method of total and partial correlations as indicated by Penrose ( 1 9 5 7 ~ )There
. are six primary
values to be calculated :
(i) the ordinary product moment correlation (N x N) between father’s and motherls ages
(Table 1);
(ii) the product moment correlation (N x N) between father’s age and birth order (Table 2) ;
 Apert’s s y n d r m 155
(iii) the product moment correlation (N x N) between mother’s age and birth order (Table 3);
(iv) the correlation (N x 2) between father’s age and incidence;
(v) the correlation (N x 2) between mother’s age and incidence; and
(vi) the correlation (N x 2) between birth order and incidence.

Father’s age Mother’s age

Fig. 1 Fig. 2
Fig. 1. Percentagefrequency distribution of father’s age in thirty-seven 08888 of Apert’e syndrome
and in a mmpamble population (Australia, 1953). t . ,General population; 0- - -0, Apert’s
syndrome.
Fig. 2. Percentage frequency distribution of mother’s age in thirty-seven caaee of Apert’s syndrome
and in the population (England and Wales). t . , General population; O---O, Apert’s
syndrome.

b
8 10

0
1 2 3 4 5 6 7 8 9 1011
Birth order
Fig. 3. Percentage frequency distribution of birtb .der in thirty-seven caaee of Apert’e syndrome
and in the population (England and Wales). M, Ceneral population; 0---0, Apert’s
syndrome.
 C. E. BLANK
Correlations (i), (ii) and (iii) are derived from various population statistics, i.e. that for (i) the
Australian population figures for 1953, that for (ii) a series of 1025 deliveries at University
College Hospital, London (Galton Laboratory data); and that for (iii) the Registrar-General's

Table 1. Correlation table of father's age and mother's age (Demography, 1953, part of Table 72)
Mother's age
Father's A \

age '7 22 27 32 37 42 47 Totals

17 0.9 0'2 0'0 0'0 0'0 0'0 0'0 1.1
22 5.8 19.1 2.8 0'2 0'0 0'0 0'0 27'9
27 2'0 26.2 29.0 4' 0.4 0'0 0'0 61.7
32 0.3 6.9 21-8 '7'5 2'4 0'2 0'0 49'1
37 0' I 1'4 6.3 12'1 8.2 0-8 0'0 28-9
42 0'0 0.4 1.8 44 5'9 2.4 0' I 15.0
47 0'0 0'I 0.5 1'2 2'0 1'5 0' I 5'4
52 0'0 0 0 0'I 0.3 0.6 0.5 0' I I *6
57 0'0 0'0 0'0 0' I 02 0' I 00 0.4
62 0'0 0'0 0'0 0'0 0'I 0'0 0'0 0' I

Totals 9'I 54'3 62.3 39'9 19.8 5'5 0' 3 191.2

Mean age (last birthday) of father = 31.04,S.D. = 6-79years. Mean age (last birthday) of mother =
27-65,S.D. = 5.84years. Correlation = 0.73.

Table 2. Correlation table of father's age and order of birth (U.C.H. data)
Father's age
Order 17 22 27 32 37 42 47 52 57 62 Totals
ofbirth ,- A
-I

I 8 76 187 147 67 25 I0 2 I 0 523

2 o 18 90 91 50 34 7 2 0 I 293
3 0 2 26 49 21 18 2 0 I 0 119
4 0 0 6 I7 14 7 I 0 0 0 45
5 0 0 5 8 4 2 5 I 0 0 2.5
6 0 0 I 2 5 3 I 0 0 0 12
( > 6) 0 0 0 I 2 3 2 0 0 0 8
Totals 8 96 315 315 163 92 28 5 2 I 1025

Mean age of father = 31.69,S.D. = 6-47years. Mean birth order = 1-86,S.D. = 1-21 years. Cor-
relation = 0.30.

Table 3. Correlation table of mother's age and order of birth (Ewland and Wales)
Order of birth
Mother's , A
1
age I 2 3 4 5 6 7 8 9 10 12 16 Totals
17 22.3 3.2 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 25-7
22 1108 52-5 14.1 2.9 0.5 0.1 0'0 0'0 00 0.0 0.0 0.0 180.9
27 77.9 84.0 37.6 13.8 4.8 1.7 0.5 0.2 0.1 0-0 0-0 0.0 220.6
32 28.5 46.7 29.0 143 6.9 3.6 1.9 0.9 0.4 0.2 0-1 0.0 132.5
37 11.8 21.4 17.6 11.1 6-7 4.3 2.8 1.8 1.1 0.7 0.7 0.0 80.0
42 2.6 4.1 4-3 3'4 2'5 1.8 1-4 1.1 0.8 0.6 1.0 0.1 23-7
47 0'1 0'2 02 0'2 0'2 0'1 0'1 0'1 0'1 0'1 0'2 0'0 I .6

Totals 254.0 212.1 103-0 45'7 21.6 11-6 6-7 4.1 2.5 1.6 2.0 0.1 665.0
Mean age of mother = 28.04, S.D. = 5.97 years. Mean birth order =2-24,P.D. = 1.57 years. Cone-
lation = 049.
 Apert's syndrome 157

Table 4. Distribution of observed cases of Apert's syndrome according to father's age.

Expected numbers based on Australian population data
Father's age Observed Expected
(central age (Apert'S (Australia,
in years) syndrome) 1953) Obs./Exp.
0'00
I7 ( < 0'21
22 5 '40 0.19
27 11-94 0.50
32 9'50 0'74
37 5'59 2.68
42 2.90 1-38
47 I -04 1.92
52
57 4.88
62 0'02

Total 37 36-99 I '00

Mean age 36-19 31.04

S.D. 7.69 6.89
Difference between means = 5.15 f 1.13. Correlation (iv) rfi = 0'34 k 0.07.

Table 5. Distribution of observed cases of Apert's syndrome according to mother's age.

Expected numbers based on data of England and Wales, 1950
Mother's age Observed Expected
(central age (Apert's (England and Wales,
in yeam) syndrome) 1950) Obs./Exp.
I7 ( < 2 0 ) 0 1-43 0'00

22 3 10.06 0.30
27 9 I 2.27 0.73
32 '4 7'37 I -90
37 10 4'45 2.25
42 I 1.32 0.76
47 0 0.09 0'00

Total 37 36.99 I '00

Mean 31-59 28-04

S.D. 4'91 6.05
Difference between means = 3.55 f. 0.98. Correlation (v)rmi = 0.31 f.0.07.

figures for 1950; (iv), (v) and (vi) are given in Tables 4-6. Estimated values of these correlations
and the partial correlations derived from them are tabulated in Table 7.
The partial correlations,
(vii) for constant maternal age and birth order,
(viii) for constant paternal age and birth order, and
(ix) for constant paternal and maternal ages,
indicate that the age of the father is the main factor. When maternal age and birth order are
held constant a significantly positive partial correlation ( + 0-17 f 0.08)is left between father's
age and incidence; whereas, when paternal age and birth order, or paternal age and maternal
age are held constant, no independent effect upon incidence of mother's age or birth order can
be demonstrated.
158 C. E. BLANK

Table 6. Distributions of Apert's syndrome according to order of birth.

Expected numbers based on data of England and Wales, 1950
Observed Expected
(Apert'S (England and Wales,
Birth order syndrome) 1950) Obs./Exp.
I I0 14-13 0.71
2 I1 11.80 0'93
3 7 5'73 1'22
4 3 2.54 1-18
5 3 1'20 2.50
6 I 0.64 1.56
7 2 0.37 5-41

"::I
8
9
I0
12 (11-15)
Total
")
0
0

37
009
0'11

36.98
0'00

I '00
Mean 2.70 2.24
S.D. I -70 1-57
Difference between means = 0.46 L 0.26. Correlation (vi) r b i = 0.14 f 0.08.

Table 7. A comparison of the independent effect of each of three interdependent variables-father's

age, mother's age and birth order--on the incidence of sporadic cases of Apert's syndrome. Correla-
tions between the variables father's age (f )' mother's age (m),order of birth (b),Apert's syndrome (i)
Correlations and partial correlations
(9 r,, = 0 7 3 (ii) ?-,b = 030 (iii) rmb= 0.49
(iv) r,, = 0-34fo.07 (v) rmt= 0-31 f 0 - 0 7 (vi) r b < = 0 - 1 4 f 0 . 0 8
(vii) r,,., = 018 (viii) r,,,,., = 010 (ix) rbt., = 0.04
rft.b = 0'32 rm(.b = 0.28 rb6.m = - 0 . 0 1
rjf.mb = 0.17 rmf.lb = 009 rbd.fm = 0'00

S.E. = f 0.07 or & 0.08 in each of the partial correlations.

Six cases have, in addition to the deformities of the head, hinds and feet characteristic of
Apert's syndrome, developmental defects of the viscera (see above). All six cases were dead
before they came to the author's attention. Although the external morphology of these patients
is not well described, it does not obviously differ from that of the other patients in this series.

Table 8. Parental ages and the differences between them, in four cases .f Apert's syndrome compli-
cated by deformity of viscera cmpared with those of thirty-one cases uncomplicated by known visceral
deformity (two cases are excluded bemuse of suspected, but unconJirmed, visceral deformity)
Father's Mother's Difference
age (f) age (m) (f)- (m)
No. (y-1 (Yew) (Yea@
Uncomplicated cases mean 3I 37'5 31.6 I-5'9
Complicated caaes mean 4 32'75 33'5 - 0.75
Difference -4 7 5 + 1.9 -
t 1-18 0.65 -
D.F. 33 33 -
P 0-24 N.S. 0.51 N.S. -
 Apert’s syndrome 159

Parental age and birth order data of four of the six families to which the cases belong were
available, and an analysis of parental age, Table 8, suggests that these cases as a group differ
from those without known deformity of the viscera in showing a lower father’s age. The dif-
ferences are not, however, statistically significant.

DISCUSSION

The deformities of Apert’s syndrome are grotesque and no patient with these malformations
is known to have married. However, on at least one occasion (van den Bosch, Appendix A) and
probably another (Weech, 1927) a woman with the characteristic deformities of Apert’s SP-
drome has had a child; both children have deformities very similar to those of the parent. No
other person with Apert’s syndrome is known to have had offspring. A genetical origin for this
syndrome seems very probable. This pedigree and the occurrence of only one case in each
sibship-thirty-seven informative sibships in the author’s series, involving thirty-seven
propositi and eighty-seven ‘normal’ sibs (twenty-four of these born after the propositus),
together with the low incidence of parental consanguinity-consanguineous marriage does not
occur in the author’s series and is reported only once in the literature (Book & Hesselvik, 1953)-
strongly suggest a ‘ dominant ’ heredity.
Although strabismus, cleinodactyly and other deformities are occasionally seen among the
parents or sibs of propositi, the frequency of these deformities does not appear to be in excess of
that in the general population and certainly does not suggest possible ‘cas frustes’ of Apert’s
syndrome.
On the hypothesis of a single gene manifest in heterozygous form sporadic cases are due to
new mutation in the germ cells of one or other of the parents; an increase in the parents’ mean
age, attributable wholly to a raised father’s age (see above) fits in well with this hypothesis.
Male and female cases of Apert’s syndrome have been reported with approximately equal
frequency; forty-two males and forty-six females are described in the literature and there are
seventeen new male and twenty new female cases in the author’s series. This does not suggest
a sex-linked or sex-limited trait.
A chromosome count (skin biopsy, case 18) showed no abnormality of chromosome number,
Table 9. No gross chromosomal abnormality was apparent, but this does not rule out the
possibility that a small one, undetectable by present techniques, does exist.

Table 9. Chromosome count in case 18 of Apert’s syndrome

No. of chromosomes in 29 cells
A
r 7
< 45 45 46 47 48 ’48
Frequency - 2 27 - - -
Sex chromosomes X Y . No chromosomal abnormalities apparent.

A t least five well-authenticated families, each with two or more members with the deformities
of atypical acrocephalosyndactyly, are described in the literature (Carpenter, 1901, 1908-9a, b ;
Norvig, 1929; Saethre, 1931; Chotzen, 1932; and Mohr, 1939) and together with two others
described by the author (Blank, 1959) involve at least twenty-two affected individuals. Apert’s
syndrome and atypical acmcephalosyndactyly have never been found together in the same
family. I n the absence of linkage studies the precise genetic relationship of these two categories
 C. E. BLANK
cannot, at present, be ascertained. There is, however, no reason to believe, as some authors have
maintained, that Apert’s syndrome and atypical acrocephalosyndactyly are simply different
manifestations of the same gene in heterozygous form, or are even due to allelic genes.
Cases of Apert’s syndrome with additional deformity of the viscera may simply-represent a
more severe expression of the same gene; may be the manifestation of another allele or alleles;
may be due to mutation at another locus; or may be ‘phenocopies’-developmental deformities
of a non-hereditable nature.
The mutation rate is a measure of the rate of change of chromosomal hereditary material.
It may be defined in a number of ways. In the absence of experimental matings, or of linkage or
cytological studies it is impossible to differentiate between alleles, mutants at different loci and
phenocopies ; or to be certain that we are dealing with ‘point’ mutation rather than chromosomal
aberration. It is, however, possible to estimate, with respect to the abnormality under discussion,
an overall mutation rate. This crude measure is really an estimate of the rate of production of a
zygote of particular clinical type and ignores possible differences in etiology. The mutation rate
is generally expressed per gene per generation. A direct estimate of this overall mutation rate
may be obtained using the formula
m = &I,
where M = the mutation rate per gene per generation; and q = the frequency of sporadic
cases at birth.
Among a total of 322,182 births, two cases of Apert’s syndrome were recognized. Substituting
in the above formula
m = 4 x 2/322,182; or approximately 3 x

This estimate of the rate of mutation at the Apert syndrome ‘locus’ is of the same order of
magnitude as the rates given for some other dominant pathological conditions in man, Table 10.

Table 10. A comparison of the rate of mutation in Aperb’s syndrome with the rates of
mutation i n some other dominant traits i n man, according to various authors
Mutation rate
per million
genes per
Pathological condition generation* Source
Epiloia 8 Gunter & Penrose (1935)
Chondrodystrophy 45 March (1941)
70 Book (1952)
Aniridia 5 Mallenbach (1947)
Microphthalmos (without 5 Sjogren & Lamson (1949)
mental defect)
Retinoblastoma I5 Philip & Sorsby (1944)
23 Nee1 k Falls (1951)
4 VOgel ( 1954)
Partial albinism and 4 Waardenburgh ( I 95 I )
deafness
Acrocephalosyndsctyly 3 Author’s series
(Apert’ssyndrome)
* Data derived from Pearose (1957b).
 Apert’s syndrome 161
It is apparent that the incidence of sporadic cases, or the incidence of mutation to this allele,
is greater the older the father. The relative incidence (the ratio of observed number/expected
number) of sporadic cases of Apert’s syndrome with respect to father’s age is shown in Table 4.
The observed number is obtained from the author’s series and the expected number calculated
from the distribution of father’s age in the Australian 1953 population. Mutation at this locus
is over five times as frequent at the paternal age of 37 (35-39) as at 27 (25-29),
Perhaps these data can be used to distinguish between possible causes of mutation. Penrose
(1955) has indicated the changes in parental age which might be expected if mutation was due
to: ( a )failure to copy the gene correctly at cell division; ( b ) irradiation from natural sources;
and (c) chemical mutagenic agents.
( a ) Where gene mutation is related to the number of cell divisions it might be expected that
the incidence of mutation would show little correlation with maternal age-the number of cell
divisions in the female germ line in man are few compared with the number in the male, where
spermatogenesis continues, though possibly at different rates, throughout reproductive life.
There might well be a strong correlation with paternal age.
The paternal age effect seen in Apert’s syndrome could be interpreted in this manner.
( b ) Where mutation is related to exposure to natural irradiation a much smaller parental age
effect is expected, for example, where the control population mean of father’s age (f,) is 31.0
years and the standard deviation (4.) is 7 years the expected mean of father’s age in the series

fi = fo+v/f = 32.6 years,

and the divergence of the means of paternal and maternal age from the general population is
approximately equal.
This is not the situation observed in Apert’s syndrome.
(c) Haldane has pointed out that chemical mutagens might be produced as toxic by-products
of normal metabolism. In the particular instance cited by Penrose, where mutagenic by-
products accumulate in the germ cells, these by-products would be expected to accumulate to a
greater extent in the female than in the male germ cells. A marked correlation with maternal
age with little or no separate paternal age effect might be expected. This clearly does not apply
to Apert’s syndrome. On the other hand, if these mutagenic substances were produced in the
tissues as a result of normal metabolic processes, the rate of which varied during different stages
in the life cycle (with concomitant changes in concentration of these mutagens in the blood)
and if limited to one sex, an association with parental age similar to that seen in Apert’s syn-
drome might well be produced. Again, mutagenic substances might be produced as a result of
disease processes ; if the disease process was more frequent in older age groups and the female
sex relatively immune, a parental age effect similar to that seen here might well be produced,
Other postulates are, of course, possible; for example, the parents of the patients were
questioned with respect to medical history, occupation, hobbies and dietary habits, and no
association with occupation, disease, drug habit or dietary idiosyncrasy was apparent.
Apert’s syndrome is not the only dominant trait where a marked increase in father’s age at
birth of the propositus (sporadic cases) has been observed, Table 11.
162 C. E. BLANK
Table 11. A comparison of the parental age diflerence observed in Apert’s syndrome
with the diflerences observed in achondroplasia and Marfan’s syndrome
Parental age means
A
I 3
Father Mother Difference
(f1 (m) (f1- (m) SoLirce
Achondroplasia 38.7 32.1 + 6.6
37’7 34‘3 + 3‘4
40-2 33’0 +7.2 Stevenson (1957)
Marfan’s syndrome 35’9 27‘9 + 8.0 Lynas (1958)
Apert’s syndrome 36.9 31.8 + 5’1 Author’s series

SUMMARY
Acrocephalosyndactyly may be divided into two main olinical categories : (i) Apert’s syn-
drome, and (ii) atypical acrocephalosyndactyly.
Apert’s syndrome can be attributed to a single gene in heterozygous form. On this hypothesis
sporadic cases are due to new mutation in the germ cells of one or other parent.
Although it is convenient at present to speak of the syndrome as homogeneous, there are
indications, namely, the difference in parental age distribution between sporadic cases with
severe developmental deformity of the viscera and sporadic cases without known visceral
deformity, that this might not be so.
The incidence at birth of Apert’s syndrome is estimated as approximately 1 in 160,000 and
that in the general population as 1 in 2,000,000. The difference between these estimates is in
part due to lack of ascertainment in the living population and in part due to the high mortality
of these patients, particularly in early infancy.
The rate of mutation at the Apert locus is estimated to be 3 x 10-6 per gene per generation.
There is a marked parental age effect among sporadic cases of Apert’s syndrome; this is
probably due solely to an increase in father’s age.
Apert’s syndrome and atypical acrocephalosyndactyly are probably etiologically unrelated.

I am greatly indebted to Prof. Penrose for his interest and guidance throughout this study and
especially for his advice on the statistical treatment of the parental age data. Thanks are due to
Dr C. A. B. Smith for his guidance on various statistical matters and to Dr D. G. Harnden,
Medical Research Council Unit, Hamell, for a report on the chromosomes of case 18. I would
like to express my gratitude to the many medical practitioners, specialists and general prac-
titioners, who have helped in the ascertainment and investigation of the patients in this series.

REFERENCES
APERT,M. E. (1906). De l’acroc6phalosyndactylie.Bull. SOC. med. H6p. Paris, 23, 131613.
BLANK, C. E. (1959). The genetics of acrocephalosyndactyly. London, Thesis.
BOOK,J. A. (1952). Fr6quence de mutation de la chondrodystrophieet de 1’6pidermolyse bulleuse dans une
population du Sud de la SuBde. J . Genet. hum. 1, 24-6.
BOOK,J. A. & HESSELVIK, L. (1953). Acrocephalosyndactyly. Acta paediat., Stockh., 42, 359-64.
CARPENTER,G. (1901). Two sisters showing malformations of the skull and other congenital abnormalities.
SOC.Study Dis. Child. Rep. 1, 1 1 6 1 8 .
CARPENTER,G. (1908-9a). Case of acrocephaly, with other congenital malformations. Proc. R. SOC.Med.
Sect. for Study Dia. in Child., 2, 45-53.
CARPENTER, G. (1908-93). Case of acrocephaly, with other congenital malformations, autopsy. Proc. R.
SOC.Med. Sect. for Studv L%. in Child., 2, 199-201.
 Plate 1

(4
Mother ( a )& ( h ) and son (c), both exhibiting the dcfnrmities characteristic of Aport’s syndrome.

C . E. BLANK (Facing p . 102)

A n r d s of Hutrun G'enetics, Vol. 24, Y u r t 2 Plate 2

Hnntls and feet of son.

C. E. BLANK
 Apert’s syndrome 163
CHOTZEN, F. (1932). Eine eigenartige familiar8 Entwicklungsstorung. (Akrocephalosyndaktylie, Dysostosis
craniofacialis und Hypertelorismus.) Mschr. Kinderheilk. 55, 97-122.
Demography (1953). Commonwealth Bureau of Census and Statistics. Canberra, Australia.
GREBE,H. (1944). Die Acrocephalosyndaktylie. Eine KlinischatiologischeStudie. 2.KonstLehre, 28,209-61.
GUNTHER, M. & PENROSE, L. S. (1935). The genetics of epiloia. J . Genet. 31, 413-30.
LYNAS, M. A. (1958). Marfan’s syndrome in Northern Ireland: an account of thirteen families. Ann. H u m .
Genet., Lond., 22, 289-309.
MOHR,0. I,. (1939). Dominant acrocephalosyndactyly. Hereditas, Lund, 25, 193-203.
MBLLENBACH, C. J. (1947). Congenital defects in the internal membranes of the eye. Clinical and genetic
aspects. Op. dom. Biol. hered. hum., Kbh., 15.
MBRCH, E. T. (1941). Chondrodystrophic dwarfs in Denmark. Op. dvm. Biol. hered. hum., Kbh., 3.
NEEL,J. V. & FALLS, H. F. (1951). The rate of mutation of the gene responsible for retinoblastoma in man.
Science, 114, 419-22.
NORVIG, J. (1929). To Tilfaelde af Akrocephalosyndaktyli Hos Ssskende. HospituZstidende, 72, 165-78.
OWEN,R. H. (1952). Acrocephalosyndactyly; case with congenital cardiac abnormalities. Brit. J . Radial.
25, 103-6.
PENROSE, L. S. (1955). Parental age and mutation. Lancet, 2, 312-13.
PENROSE, L. S. (1957a). Parental age in achondroplasia and mongolism. Amer. J . H u m . Genet. 9, 167-9.
PENROSE, L. S. (1957 b). Mutationinman. Eflectof Radiation on HumanHeredity,pp. 101-13. Geneva: W.H.0.
PHILIP,U. & SORSBY, A. (1944). Genetical Society (unpublished).
REGISTRAR-GENERAL (1950). Statistical Review of England and Wales.
SAETHRE, H. (1931). Ein Beitrag zum Tunnschiidelproblem. (Pathogenese,Erblichkeit und Symptomato-
logie.) Dtsch. Nervenheilk. 117, 533-55.
SJORGEN, T. & LARSSON, T. (1949). Microphthahnos and anophthalmos with or without coincident oligo-
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STEVENSON, A. C. (1957). Achondroplasia: an account of the condition in Northern Ireland. Amer. J . H u m .
Genet. 9, 81-91.
VOGEL,F. (1954). Uber Genetik und Mutationsrate des Retinoblastoms (Glioma retinae). 2. KonstLehre,
32, 308-36.
WAARDENBURG, P. J. (1951). A new syndrome combining developmental anomalies of the eyelids, eyebrows
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H u m . Genet. 3, 195-253.
WEECH,A. A. (1927). Combined acrocephaly and syndactylism occurring in mother and daughter. A case
report. Johns Hvpk. Hosp. BuU. 40, 73-6.

APPENDIX A
A mother and child; each with the deformities characteristic of Apert’s syndrome
I am most grateful to Dr J. van den Bosch of Leiden for permission to make use of his preliminary
findings relating to the deformities of a 30-year-old mother and her 2-year-old son. I understand that
a more complete description of this important family is being prepared for publication.
It is evident, from his brief description and the accompanying photographs, that parent and child
each have, unquestionably, the deformities of Apert’s syndrome, Pls. 1 and 2.
I n each the head is short, broad and high and the occiput poorly developed; the palate, although not
cleft, is high and the teeth crowded together; the lower jaw protrudes and proper occlusion of the teeth
is prevented; the mother exhibits strabismus. Proptosis is not marked.
Deformity of the extremities is symmetrical and remarkably alike in parent and child; that of the
hands is particularly severe, even for Apert’s syndrome. Fingers and thumbs are fused together to form
a single mass and all toes are joined; five toe nails can be distinguished.
The father of this child is unknown to van den Bosch for the union was extramatrimonial. The
mother is reported to be the first in her family so affected; her father was 27 years old a n d her mother
29 years old a t her birth.
 164 C. E. BLANK
APPENDIX B
Data of thirty-nine cmes of acrocephlosyndactyly born in England, Wales or Scotland
Age at birth of Dates of birth (sibs of propositus)
Dates of birth (if known) propositus
Birth order ,
Case , -A- - (completed Sex
no. Propositus Sex Father Mother Father Mother pregnancies) Brothers Sisters unknown Miscarriages
I 15. g. 57 F I. xii. 21 3.4.24 36 33 3 30. vii. 54 15. xii. s t None known
2 27. iv. 58 F 3. xii. 09 21. XI. 19 48 38 4 19. v:.43 22. i. 40 1 (1948)
6. vn. 49
3 30. jii. 54 F 4. ii. 16 29. xji. 13 38 40 3 18. i. 4 17. j. 46 None known
4 13. IV. 54 M 5 . X. 20 22. v1.23 34 31 2 23. viii. 56 21. IX. 50 None known
4. viii. 55
5 24. v. 52 1' 39 30 3 9. !y. 45 Parents not
2. 111.49 questioned
1953 ,,
6 4. *:33 M 23. iii. 16 13. xi. 20 37 33 3 8. v. 39 20. v11.45 1 (1954)
7 22. v p 52 F 22. x. I 1 21. v+ 13 41 39 3 21. v. 43 12. v. 38 I (1946)
8 23.11.50 F 7.1.20 3. v1.20 31 30 2 14. xii. 47 I(I949)
9 IS. vii.49 F 28. v+ 20 2. V:.ZI 29 28 I None known
I0 11. iv. 48 F 14. v111.05 11.vn.09 43 39 7 13. j: 39 9. v. 37 21. i. 36' None known
29.11.40
16. xi. 41
I1 24. V. 46 M 10. x. 07 23. 18ii: 39 28 2
3- 45 'x.
6. XI. 41 None known
12 30. iii. 46 F 27. vi. 14 31.111. 17 32 29 2 17. IX. 41 14. ii. 48 19. ii. 53 Parents not
(twins) questioned
13 5. viii. 42 P yii. 80
I I. 21.ix. 03 62 39 2 7. vii. 34 None known
I4 27. iii. 40 M 3.18.00 27.11.14 40 26 3 I I. ii. 46 4. vii. 33 None known
3. 10.38
I5 4. Vji. 39 F 26. viii. 02 17. v:.02 37 37 2 14. viii. 27 None known
16 20.111. 35 &I I. x. 07 30. VIU. 04 27 31 2 I934 7. iii. 39 None known
6. v. 41
17 2. X. 35 A1 13. iv. 06 21.iv. 05 29 30 I I(I933)
I(I934)
18 21.x. 36 M 27. vii. 01 2. x. 07 35 29 I None known
I9 26. iv. 29 F 43 29 7 1915 1917 Parents not
I932 1920 questioned
1921
I923
1926
20 15. v: 28 M 17. iii. 98 24. x. 04 30 24 I None known
21 27. XI. 24 F 54 33 I 1931 Parents not
questioned
22 14. v. 22 P 26. i. 86 19. vii. 85 36 37 5 1910 24. vi. 08 None known
x. 20. 25. v1. I 2
12. VI. 24
23 4. iii. 23 hl 45 39 5 '907 None known
1910
1911
1920
24 12. xii. XI 1.' 21. viii. 73 20. iv. 81 38 31 5 ?w5 1906 I(I9d
I907 1910
1912 1913
1916
1920
25 20. vii. 57 M 3. iii. 30 21. ii$30 27 27 I None known
26 15. xii. 46 M 25. xi. 08 30. VLI. 14 38 32 2 30. X. 44 None known
6. p. 50
3.1x. 52
27 4. ii. 50 M 21. viii. 16 17. i..Fo 33 30 I 22. vi. 56 19. v. 52 None known
28 15. v. 55 M 2. x. 19 25. XII. 23 36 31 I None known
29 26. vii. 05 1.' viii. 66 12. i. 69 39 37 6 5 sibs all born before Parents not
propositus questioned
30 30. xi. 51 M 9. iii. 22 13. ix. 25 30 26 2 17.xl.47 I('956)
19.1.54
31 20. xi. 49 P 9. xi. 15 5. ix. 12 34 37 4 1944 I955 I943* Parents not
1946 (twins) uestioned
32 7. iij, 50 M 34 39 2 I. iv. 46 I%efore 1946
33 4. x11. 50 M 16. v. 21 3. vi. 23 30 28 I 4. vii. 52 Parents not
23. iii. 5 6 questioned
34 24. iii. 49 3x I. iv. 10 9. x. 16 39 32 3 1946* None known
13. IX. 47
35 26. x. 55 F 14. i. 32 28. xi. 34 24 21 I Parents not
questioned
36 23. iv. 50 bI Not known Not known Parents not
questioned
37 26. viii. 47 F i 37 22 Not known Not known Parents not
questioned
38 56 P 4 3 sibs born before propositus . Parents not
questioned
39 9. ix. 49 1.' 41 33 2 I sib born before propositus . Parents not
questioned
Still-born or died within a few,,hours of birth.