FAMILIAL
DE
LANGE
SYNDROME
WITH
CHROMOSOME
ABNORMALITIES
Arthur Falek, Ph.D., Rina Schmidt, M.D., and George A. Jervis, M.D.
Department of Medical Genetics, New York State Psychiatric Institute, New York City, and Research Department, Letchworth Village, ThielLc, New York
(Submitted May 21; accepted for publication June 30 1965.)
Supported in part by United States Atomic Energy Commission Contract AT (30-1) 3381.
ADDRESS: (A.F.) Georgia Mental Health Institute, Emory University, 1256 Briarcliff Road, N.E., Atlanta, Georgia.
PEDIATRICS, Vol. 37, No. 1, Part I, January 1966
92
T
HE eponym de Lange syndrome is usedto denote a peculiar form of mental re-tardation characterized by a cluster of
mi-nor malformations. Described for the first
time in 1933 by Comelia de Lange of Am-sterdam as “Typus degenerativus
Amstelo-damensis,” the condition has attracted spo-radic and cursory attention during the following three decades.’8 It was only within the past two years that there has been a considerable renewal of interest in
de Lange syndrome with the almost simul-taneous publication of three extensive studies19” in the English and American
literature. The experience of several ob-servers suggests that the condition is not as rare as previously thought. In fact, during the past two years more cases have been
recorded in the world literature than in all of the previous thirty years.2236
The clinical features of de Lange syn-drome are well established, and include
characteristic face with bushy eyebrows, long curved eyelashes, low forehead, large and depressed bridge of nose, nostrils tilted upwards, increased distance between nose and upper lip and small chin. Eyes may
show the antimongoloid slant. Ears are in-serted low. Palate is arched, teeth irregular, and mandible underdeveloped. Neck is short and posterior hairline low. There is abundant lanugo and often hirsutism of
the trunk. Upper extremities are frequently short and micromelia and defective devel-opment of hands is occasionally observed. Usually the thumb is placed more proxi-mally than normal and there is limited
ex-tension of the elbow. Clinodactyly of the fifth finger and simian line are often seen.
The feet show partial webbing of the second and third toes. Congenital mal-formation of the heart has been noted in a number of cases. Diagnosis is not difficult
in typical cases once a few other forms of mental retardation are ruled out. However,
the etiological factors responsible for de
Lange syndrome are still largely unknown. The genetic hypothesis of a dominant
mutation has been advanced and would
account for the usually sporadic occurrence
of the ti3T On the other hand,
it has also been suggested that the
syn-drome may be due to a recessive autosomal
gene.29 Familial occurrence, however, is the exception and parental consanguinity is re-ported in only one case. Because of some similarities between Down’s and de Lange
syndromes, the possibility of a chromoso-mal etiology has been suggested. In the
latter disorder, however, normal karyotypes are described in the majority of cases, and
chromosome anomalies are reported in only
seven unrelated patients.20’ 24. 29, 30,34
This communication describes the clini-cal and cytogenetic findings in a kindred with four cases of clinically typical de Lange syndrome. Chromosomal
abnormali-ties have been observed in the affected chil-dren, one of their parents, and several immediate relatives.
CASE REPORTS AND FAMILY STUDY
In December, 1963, a mother of two severely
retarded children requested genetic counseling.
Information ascertained during the interview
in-dicated that this 34-year-old woman was in her
ninth pregnancy. Both she and her husband, age
35, were found to be in good health. No
no evidence of consanguinity. Of her previous eight pregnancies, tile first child, a girl, died at the
age of 9 months, two other children, both boys,
were living and well at the ages of 1 1, and 4, the
9- and 5-year-old girls were severely retarded,
there was one male stillbirth and two early
mis-carriages. The two affected girls looked strikingly
alike in their general appearance as vell as in
their facial features. Furthermore, the mother
re-ported that her first child who died in infancy, as
well as a maternal male first cousin of her children,
resembled to a great extent the two affected
children.
Case 1 (J. H.)
This 9-year-old female was born at term after an
uneventful pregnancy. She was third in line of
birth. Birth weight was 4.1 kg and length 51 cm.
Birth was normal and no paranatal complications
were recorded. Umbilical hernia was noted in
infancy and was surgically repaired at 2 years of
age. The infant displayed a weak cry and had
difficulties in feeding. Psychomotor retardation
was obvious by the first year of life. She sat up at
11 months and began to walk at 3 years and 2
months. There was some word recognition at 4
years of age, but it was not until after 5 years
of age and following speech therapy that she was
able to repeat a few simple words. At no time
was visual impairment suspected. Distorted facial
features were obvious since early age and a
diag-nosis of gargoylism was repeatedly made.
On physical examination the height was 127
cm (10th percentile ), the weight 32.1 kg (75th
percentile ). Condition of general nutrition was
good. As shown in Figure 1, facial features were
somewhat grotesque with bushy eyebrows
con-fluent over the midline, low forehead covered
with lanugo, deeply set eyes, and pug nose. The
eyelashes were very long and abundant. The ears
were rather large and placed low. There was a
large space between nose and upper lip and mild
micrognathia. Palate was high, teeth irregularly
spaced, and uvula showed a bifid tip. Pupils
reacted normally to light and accommodation.
Corneas and lenses were clear. Fundi showed
no abnormalities. Vision was estimated
approxi-mately 20/70 in each eye. On audiometric
exami-nation there was some evidence of loss of hearing,
air conduction tests showing 70 dh on the right
and 30 on the left, but co-operation was limited
and neither pure tone nor bone conduction tests
could be performed because of the low mental
level. Circumference of head was 50 cm. Neck
was short. Thyroid could be easily palpated and
appeared of normal size. There was no deformities
of the chest aside from mild dorsal lordosis. There
FIG. 1. Case 1
(J.
H.).was hirsutism of the back and extremities. Lungs
and heart showed no abnormalities. Abdomen was
protruding but neither liver nor spleen was
en-larged. Upper extremities appeared of normal
configuration. There was no limitation in the
extension of the elbows. Hands were rather large,
thumbs were placed low and the fifth finger was
curved medially. There was no simian line. Legs
were not deformed but the feet appeared short
and there was a distinct webbing between second
and third toe bilaterally. Muscular function, tone,
and trophism of the extremities showed no
ab-normalities. A positive Babinski sign could be
demonstrated.
On psychological exaniination, using the
Stan-ford-Binet, Form L, the mental age was 2 years,
6 months at a chronological age of 9 years 4
months, with an I.Q. of 26. It was felt that the
child’s I.Q. might be somewhat higher, but
prob-ably not above 30. Her behavior was described by
the mother as presenting no special problems. She
was a pleasant, outgoing, co-operative child
with-in her obvious intellectual limitations.
X-ray examination of the skull showed no
abnormalities. The sella was of normal
configura-tion. Spinal vertebrae were not distorted. Ribs
were not enlarged. Hands showed none of the
metacarpal and phalangic changes seen in
gargoy-lism. The middle phalanx of the fifth finger
ap-peared hypoplastic and the presence of clinodactyly
was confirmed. The second toes were long and
Laboratory findings were non-contributory:
Hemoglobin 14.3 gm/100 ml, WBC 5,700 with
normal (lifferential count, no Reilly bodies, normal
sedimentation rate, blood calcium 10.5 mg/100
ml, phosphorus 4.5%, BUN 12 mg/100 ml, blood
sugar 95 mg/100 ml, cholesterol 125 mg/100 ml,
PBI 5.5 iog/100 ml. Electrophoresis and immune
electrophoresis of the serum showed no
abnor-malities. Urine examination showed no albumin,
no sugar, and no acetone. Mucopolysaccharides
determined with DiFerrante method” were 12
mg/gm creatinine, a normal value. Paper
chromato-gram of amino acids of serum and urine revealed no
abnormal pattern. Electroencephalogram and
elec-trocardiogram were within normal limits.
Case 2 (M. H.)
The younger sib of Case 1 was a female 5 years
of age. There was a negative gestational and
para-natal history. Birthweight was 3.3 kg and length
46 cm. The peculiar facial features similar to her older sib were obvious shortly after birth. There
was, in addition, a systolic murmur over the
pre-cordium. The child throve poorly and feeding was
difficult. Psychomotor development appeared even
more retarded than in her older sister. She sat up
at 2 years, and at 5 years was still unable to stand
or to walk and was not toilet trained. No speech
had developed and her utterances were limited to a
few unintelligible sounds. Convulsive seizures
de-scribed as grand mal had been noted at varying
intervals. Their total number was 15-20 according
to the parents. The child had been examined by
several physicians, who had made the diagnosis of
gargoylism.
On physical examination the height was 97 cm
(less than 3rd percentile), weight 15.4 kg (3rd
percentile). Condition of general nutrition was
good. The grotesque facial features were
charac-teristic (Fig. 2); heavy confluent eyebrows, low
forehead with lanugo, long eyelashes, pug nose,
wide upper lip, mild micrognathia, high palate,
irregular teeth, and partially bifid uvula. There
was convergent strabismus and irregular horizontal
nystagmus; marked myopia was present but fundi
were otherwise unremarkable. Grossly adequate hearing at monaural levels was suggested from
increased eye movements. Ears were placed low.
Neck was short and dorsal lordosis was present.
The back and limbs showed moderate hirsutism.
There was a systolic murmur in the third inter-costal space but no enlargement of heart. Cyanosis
was not present, not even during crying. Hands
showed low-placed thumbs and clinodactyly of
fifth finger. There was no limitation in extension
of elbow and no simian line. Bilateral webbing of
second and third toe was present. Neurological
examination showed no impairment of motility of
the various segments, although the child was
un-FIG. 2. Case 2 (M. H.).
able to walk. Feet were in equinovarus position.
Deep tendon reflexes were overactive and
incon-stant. Babinski signs were noted.
Psychological examination, using the Gesell test,
showed at the age of 60 months a motor score of
12-18 months, an adaptive behavior of 15-18
months and a personal-social development of
15-18 months. Language production was absent. The
I.Q. was therefore at about the same level as that
of the older sister.
X-ray examination showed the minor
abnor-malities of the fifth finger and second toe as noted
in Case 1. There was, in addition, evidence of
horseshoe kidney with double right ureter. Spina
bifida occulta was also observed.
Laboratory findings were within normal limits:
Hemoglobin 11.7 gm/100 ml, WBC 7,600 with
normal differential count, no Reilly bodies, normal
sedimentation rate, blood calcium 9.7 mg/100 ml
phosphorus 5 mg/100 ml, glucose 102 mg/100 ml,
cholesterol 140 mg/100 ml, PBI 6 iog/100 ml.
Urine contained no albumin, no sugar, no ketonic
substances. Mucopolysaccharides were 14 mg/gm
creatinine. Electroencephalogram could not be
per-formed because of lack of co-operation.
Electro-cardiogram presented evidence of semi-horizontal
heart.
Case 3 (K. H.)
The oldest sib died at the age of 9 months, but
4.
1
t
“
‘, d.u-i \:‘
Fie. 3. The three affected siblings in infancy.
I
jsisters.
for study. She was born at terni after normal
de-livery. Birth weight was 3.4 kg. She failed to thrive
and at 6 months her weight was only 5.2 kg (less
than 3rd I)ercelltile ). Clinical records reported her
as a severely retarded odd-looking female child
with impaired vision who displayed the heavy
con-fluent eyebrows, low hairline, hirsutism, and pug
nose characteristic of the two other sibs (Fig. 3).
She had a grade 2 systolic murmur. Convulsive
seizures were observed on several occasions. Death
ensued at 9 months following acute
bronchopneu-monia. Postmortem diagnoses were congenital
de-feet of heart (ventricular and auricular septum
de-feet and overriding aorta), hypertrophy of right
auricle and ventricle, bronchopneumonia,
emacia-tion, and internal hydrocephalus. The only
micro-scopie abnormality mentioned concerned the
pituitary gland. This was said to show “almost
complete absence of mature basophilic and
acido-philic cells, most of the cells consisting of un
differentiated chromophobe elements.”
nystagmus and internal strabismus were noted.
Palate was high and teeth irregular. There was
marked hirsutism of the body with irregular patches
of baldness. Neck was short, there was a dorsal
scoliosis, umbilical hernia, and bilateral
crvptor-chidism. Curved little finger, low insertion of thumb
and webbing of the second and third toes were
Case 4 (D. Y.)
A male, age 14 years, a maternal first cousin of
Cases 1, 2, and 3, was seen in a mental institution.
His weight at birth was 3.7 kg and length 51 cm.
lie was said to have been cyanotic at birth because
of the cord being wrapped around the neck.
How-ever, his neonatal history was apparently
unre-markable. Development was slow and severe
re-tardation became apparent in infancy. He had been
suffering from frequent grand mal attacks since
early childhood. At 14 years he was untidy and
had no speech. His height was 141 cm (less than
3rd percentile), weight 41.9 kg (10th percentile).
The facial features bear close resemblance to those
of his cousins (Fig. 4): confluent eyebrows,
(lee!)-set eves, low forehead, low-set ears, pug nose, wide
lIl)l)C lip space, and mild micrognatliia. Bilateral
PEDIGREE OF THE H FAMILY
de Lange Syndrome with Chromosome Abnormalities
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. CLINICALLY AFFECTED, ABNORMAL CHROMOSOME PATTERN WITH PARTIAL TRISOMY
0
CLINICALLY AFFECTED, DIED PRIOR TO CHROMOSOME ANALYSISCLINICALLY NORMAL, BALANCED TRANSLOCATION CARRIER
c: CLINICALLY NORMAL WITH NORMAL CHROMOSOME PATTERN
CD REPORTED CLINICALLY NURMCL
o- STILLBORN OR DIED IN INFANCY
S MISCARRIAGE
Fic. 5. Pedigree of the family. De Lange syndrome with chromosome abnormalities.
present. Spleen and liver were not palpable.
The electroencephalogram showed frequent high
voltage paroxysmic discharges. These were
char-acterized either by multiple spikes and a large
wave, or by two per second “spike and wave” complexes.
Other Family Members
The other members of the kindred were clincally
normal (Fig. 5). However, some minor
abnormali-ties were noted. The mother (11-6) showed web-bing of the second and third toe. Her three normal
children (111-17, 22, 24) and all of her sisters and
brothers, including the father of Case 4 (11-3), showed similar webbing. The brothers of Cases
1, 2, and 3 (111-17, 22), as well as both of the
maternal uncles (11-3, 5) and a normal first
cousin ( 111-12 ), have a mild degree of confluent
eyebrows.
Chromosome Analysis
The karotype from peripheral blood cultures#{176}
in Cases 1, 2, and 4 showed a modal number of
46 chromosomes ( Table I). However, an abnormal
pattern was consistently present, characterized by
a loss of a small acrocentric chromosome of the C group (No. 21-22) and an additional
meta-centric chromosome resembling, but somewhat
smaller than, chromosome E 16 (Fig. 6).
0 The procedure used was a modification of the
technique described by Moorhead and his
col-leagues.’
TABLE I
CHROMOSOME Couxis OF AFFECTED ChILDREN
Total No. Cells Counted
Less than C/or.
4I
Chr.
45 Chr.
46
C/zr.
47
Chr.
More I/ian 47 Chr.
Modal
No.
Case 1 (J.H.)
Case
(M. H.)
Case 4
(D.Y.)
100
45
37
4
3
1
5
1
..
12
4
1
71
37
34
7
..
1
1
..
..
46
46
46
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CASE NO. 113,7633,34
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CASE NO. 123,9330
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%‘ ‘1
FIG. 6. Karyotypes of affected children showing
similar chromosomal abnormalities.
The father of Cases 1, 2, and 3 had a normal
karotype, but in the mother (11-6) the karotype
was similar to that of her affected children, and, in
addition, there was an apparent deletion of one of
the A 3 chromosomes so that it consistently
re-sembled one of the large C group chromosomes
( Fig. 7). Of the phenotypically normal sibs of Cases 1, 2, and 3, the oldest (111-17) carried the
3 #{149}
j144 4
‘
4
FIG. 7. Deviant chromosornal pattern displayed by
mother of three affected siblings.
xx
4 a;4,lb,m
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‘:
(“);:‘ ‘4”;#{231}’s..,
FIG. 8. Abnormal karyotype displayed by
pheno-typically normal brother of affected siblings.
FIG. 9. Consistent chromosome pattern found in
phenotypically normal carriers.
chromosomal aberration similar to his mother ( Fig.
8), while the two younger sibs had normal
chromo-soines.
Of the six surviving sibs of the mother of Cases
1, 2, and 3, two brothers (11-3, 5) and two sisters
98
hers ( Fig. 9 ). One of the brothers ( 11-3 ) is the
father of Case 4. The other has a phenotypically normal son (111-12 ) with a carrier chrorno:ome pattern.
COMMENT
The diagnosis of de Lange syndrome is based on a cluster of minor physical ab-normalities, none of which when con-sidered singly is either specific or very rare. As in the diagnosis of Down’s syndrome, it
is the combination of these minor abnor-malities rather than any single one which makes it possible to arrive at a diagnosis,
and considerable diagnostic significance should be attached to the presence of mental retardation and physical underde-velopment.
The cases described here showed almost all the main physical abnormalities with
the exception of limited extension of elbow.
There was also the characteristic history of failure to thrive and the impairment of physical development. However, a
remark-able exception from the large majority of cases was the normal birth weight of all four cases. The low I.Q. was in keeping with the diagnosis of the syndrome. Con-vulsive manifestations as seen in Cases 2,
3, and 4 have been reported only occasion-ally in de Lange syndrome.
Gargoylism and hypothyroidism were considered in the differential diagnostic work-up because the patients were referred
with these diagnoses. However, skeletal changes characteristic of gargoylism were
missing; there were no Reilly bodies in the white cells, no hepatosplenomegaly, and the amounts of mucopolysaccharides in the urine were within normal limits. There were no clinical signs of cretinism;
more-over, protein-bound iodine and cholesterol values were normal.
Disturbances of endocrine function have
been reported in a few cases. Defect in thyroid function is reported by Willemin Clog,5 Zweymuller,lI and Schlesinger et al.19
The last two investigators also found some evidence of pituitary dysfunction. In this respect the finding of almost complete
ab-sence of mature basophilic and acidophilic
cells in our Case 3 may be of significance.
However, the examination was made in
an-other laboratory and no slides were
avail-able. Hart et al.,32 on the other hand, found no histological change in the pituitary gland. The few autopsy reports available in the literature offer no clue as to the causation of the condition.
The etiology of de Lange syndrome is unknown. The possibility that the condition is due to genetic factors has been
con-sidered by many investigators. A dominant mutation was suggested by Ptacek et al. and 232 which would account for the
usually sporadic occurrence of the
condi-tion, but is not consistent with the findings in the kindred here reported. Opitz et al.29
have presented some evidence that this
syn(lrOme is due to an autosomal recessive
gene.
The possibility of a chromosomal abnor-mality in de Lange syndrome has been in-vestigated in recently published cases.
Normal chromosomal patterns have been reported, and the consensus of opinion is that the condition is not associated with karyotype alteration. However, Geudeke
et al.24 observed in one affected child a
consistent deletion of the long arm of one of the B group chromosomes apparently
translocated on to a G group chromosome.
The translocation chromosome was found to be similar in shape, though somewhat smaller in size, to the chromosomes of the
D group. Jervis and Stimson2#{176} and other
in-230, 34 have reported the
pres-ence of an extra small chromosome frag-ment in some of their karyotypes.
This is the first study of a family with de Lange syndrome in which chromosomal abnormalities are observed in both parents and children. Cytogenetic evidence ob-tamed from blood cultures of three affected
NORMAL
E!1E!UE
3 .NORMAL CHROMOSOME 3
3. CHROMOSOME 3 WITH DELETION
G.CHROMOSOMES 2I AND 22
T. TRANSLOCATION CHROMOSOME
. CHROMOSOMES OF CARRIER CARRIER
I#{149}H.I\
LiLI
‘E!1EE
‘-+--G GROUP-. ‘-G GROUP-.B POSSIBLE OFFSPRING OF CARRIER x NORMAL MATING
I
CARRIERU
AFFECTED NOT VIABLEPF
LL!1
EI
kE
FIG. 10. Hypothesis of formation and transmission of chromosonie abnormalities in the familial de Lange
syndrome.
normal complement of chromosome ma-terial. The affected children on the other hand have an excess of chromosome ma-terial seemingly derived from chromosome
A 3
(
Fig. bA). The partial trisomy of genetic material is constantly associated in this family with the clinical picture of de Lange syndrome. It is possible that the many miscarriages in this pedigree arepro-duced by embryos carring a deleted A 3, no translocation chromosome and four nor-mal G group chromosomes
(
Fig. lOB)
. Itwill be necessary, of course, to study more familial cases with similar chromosomal deviations in order to confirm this hy-pothesis. As previously indicated by Ptacek and his colleagues, the normal finding in most cases does not exclude the possibility that the excess material is to be found in all such cases, but the fragments are too
small to be detected. The fragments re-ported by some investigators would lend
weight to this hypothesis. Contradictory evi-dence is available only from the study of the abnormal chromosomes in the child de-scribed by Geudeke and his colleagues. We
do not have evidence for a deletion similar to theirs in our family. Like their finding,
however, we do have a loss of one of the
G group chromosomes and a new
trans-location chromosome. Geudeke and his associates suggested that there is no rela-tionship between the aberrant karyotype and the clinical syndrome. Whether cause and effect are independent of chromosomal rearrangement or related in some manner
to linear rearrangements of the genes on the chromosomes is, of course, not proven.
To what extent their finding is pertinent to ours will have to await observations in
additional cases.
dlistin-guishing the deleted A 3 chromosome from
the large C group chromosomes. At present, the deleted chromosome is so similar to both X and 6 that there is difficulty in
classifying them.
The basic question which arises is
whether all cases of this syndrome have a common etiology.
SUMMARY
Familial de Lange syndrome is described in three siblings and a maternal first cousin.
A new chromosomal aberration has been
found in this family in all affected children
and in 7 unaffected carriers. Karyotypic
differences between carriers and their
affected children present evidence of an
ex-cess of some chromosome A 3 material producing the clinical disorder.
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2. de Lange, C. : Nouvelle observation du “Typus
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Acknowledgments
We wish to express our appreciation to Miss
Lois Simpkins, Miss Jean Nolan and Mrs. Lame
Ruut for their devoted technical assistance, and to
Drs. William Paradowski, Elliot Osserman and
Raymond L. Pfeiffer, Mrs. Shulamith Kastein and
Miss S. Morgan for their special clinical studies.
We should also like to thank Dr. Henry Burkhardt
for permission to use the postmortem data on Case
3, and Dr. M. DeLuca and the staff of Munson
State Hospital for their help in the evaluation of
Case 4. Special credit is also due the personnel of
the United States Navy, Air Force and Army Medi-cal Corps for the facilities furnished to us during the course of this study. Finally, we should like to acknowledge the patient co-operation of members
of the family described in this report.
CARING FOR YOUR DISABLED CHILD, by
Ben-jamin Spock and Marion 0. Lerrigo. New York: The Macmillan Company, 1965, 373 pp., $4.95.
At a first glance, Dr. Spock’s most recent effort appears to be a collection of self-evident
facts, well-worn clich#{233}sand repetitions-the
reader has the feeling that he has heard all of this before.
However, when the reviewer reread the open-ing sentences and realized that the text is aimed, not at the pediatrician or trained worker in the field, but at the guilty, anxious, and often desperate parent, then the full value of this
work became apparent.
This book is not intended nor does it
im-press one as a “cookbook” to help the anxious but well-meaning parent to become a more anxious fledgling diagnostician. On the
con-trary, the authors make it unmistakably clear
that their intent is to complement the advice and guidance of well-trained specialists rather than to replace them.
Several areas are worthy of particular note. A section is included discussing mechanical aids to enable the handicapped child to fully exploit his capabilities. This is the best dis-cussion of its kind in the currently available
literature in my opinion. The many
time-proven devices and suggestions offered were
obviously obtained from the experience of a
multitude of workers and families and will
prove an invaluable aid to the reader.
The authors develop the concept that the rehabilitation of a disabled child must be
suited to the ability of the particular child
and not to any preconceived stereotyped plan. Emphasis is placed on the necessity of
ac-cepting certain limitations and exploiting
strengths. While these beliefs are by no means
unique and underly any worthwhile
rehabili-tation program, their inclusion in a text that will no doubt have widespread popular
ap-peal, will aid immeasurably in their general
acceptance by parents.
The physician caring for a child with a
dis-ability will find this text to be a valuable
ad-junct to his care. It will serve to expand
par-ents’ knowledge and understanding of the
problems and help them to anticipate future
difficulties. It will give rise to questions on the
part of the parents but the answers to these
questions will serve not only to further the
parents’ understanding but to establish better
communication and rapport between parent
and physician. If the latter is achieved, this book will have contributed immeasurably to the care of the disabled child.
