American Journal of Medical Genetics 102:125 135 (2001)

Cohen Syndrome: Essential Features, Natural History,

and Heterogeneity
Satu Kivitie-Kallio1* and Reijo Norio2

1
Departments of Pediatrics and Child Neurology, Hospital for Children and Adolescents, Helsinki University Central
Hospital, Helsinki, Finland
2
Department of Medical Genetics, The Family Federation of Finland, Helsinki, Finland

This article elucidates the clinical picture in

Cohen syndrome (MIM 216550), an autosomal recessive disorder that is overrepresented in Finland. The diagnosis is based on
the typical clinical picture: nonprogressive
psychomotor retardation, motor clumsiness
and microcephaly, typical facial features,
childhood hypotonia and hyperextensibility
of the joints, ophthalmologic ndings of
retinochoroidal dystrophy and myopia in
patients over 5 years of age, and granulocytopenia. In a nationwide study, 29 Finnish
patients were investigated. Magnetic resonance images of the brain with quantitative
structure analyses revealed a relatively
enlarged corpus callosum (CC). The youngest patients had normal EEGs, while all
others had low-voltage EEGs. Of the
patients, 22% had profound, 61% severe, 6%
moderate, and 11% mild retardation. In an
adaptive behavior scale (AAMD), patients
had high scores in the positive domains
(self-direction, responsibility, and socialization), whereas maladaptive behavior was
almost lacking. Only the youngest patients
had unimpaired visual function. Vision
started to deteriorate early but slowly.
Progressive myopia and retinochoroidal
dystrophy were found in all of the patients
over 5 years of age. All of the patients had
isolated granulocytopenia. The heart anatomy was normal. However, decreased left
ventricular function with advancing age
was found. No signicant endocrine
abnormalities were discovered. Fingers

Grant sponsor: Foundation for Pediatric Research, Ulla Hjelt

Fund; Grant sponsor: Finnish Cultural Foundation; Grant
sponsor: Finnish Medical Society Duodecim.
*Correspondence to: Satu Kivitie-Kallio, Hospital for Children
and Adolescents, Helsinki University Central Hospital, 00029
HYKS, Finland. E-mail: satu.kivitie-kallio@hus.
Received 3 January 2001; Accepted 28 March 2001

2001 Wiley-Liss, Inc.

were slender but short, with a typical

metacarpophalangeal pattern prole. The
manifestations vary at different ages. The
Finnish Cohen patients are clinically highly
homogeneous, their disease gene being located on chromosome 8. Heterogeneity probably exists among other patients claimed
to have Cohen syndrome.
2001 Wiley-Liss, Inc.

KEY WORDS: Cohen syndrome; mental

retardation; granulocytopenia; retinochoroidal dystrophy; myopia
INTRODUCTION
In 1968 and 1972, Dr. Michael Cohen and his
collaborators from the United States observed two sibs
and a third patient, respectively, with a previously
unrecognized pattern of abnormalities. In 1973, they
diagnosed these patients with a newly recognized
syndrome [Cohen et al., 1973]. In another report, Carey
and Hall [1978] established Cohen syndrome as a
clinical entity by presenting four new patients with
similar ndings.
In 1968, one of the present authors (R.N.) began to
follow three Finnish patients with abnormalities that
did not t any known syndrome: mental retardation,
distinctive face, slender hands and feet, and signs of
chorioretinal dystrophy. Ten years later, after seeing
the facial pictures of the patients of Carey and Hall
[1978], he realized his patients had Cohen syndrome.
Since then, a large number of patients with Cohen
syndrome have been found in Finland. Six of these were
reported in 1984 [Norio et al., 1984]. They all had
mental retardation, microcephaly, hypotonia, and
clumsiness. They had high-arched or wave-shaped
eyelids; long, thick eyelashes; thick eyebrows; prominent root of nose; short philtrum; open-mouthed
appearance; high, narrow palate; small or absent lobuli
of ears; thick hair and low hairline; narrow hands and
feet; mild syndactylies; and a wide gap between toes 1
and 2. They also had chorioretinal dystrophy and a
previously unpublished feature, granulocytopenia.

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Kivitie-Kallio and Norio

In addition to these reports, over 100 patients have

been reported with the suggested diagnosis of Cohen
syndrome (MIM 216550) [Cohen et al., 1973; Carey and
Hall, 1978; Balestrazzi et al., 1980; Sack and Friedman,
1980; Fryns and Van den Berghe, 1981; Kousseff, 1981;
de Toni and Caero, 1982; Ferre et al., 1982; Friedman
and Sack, 1982; Goecke et al., 1982; Doyard and Mattei,
1983; Fuhrmann-Rieger et al., 1984; Norio et al., 1984;
Mendez et al., 1985; North et al., 1985; Wilson et al.,
1985; Resnick et al., 1986; Sack and Friedman, 1986;
Rizzo et al., 1987; Young and Moore, 1987; Zeller et al.,
1987; Zetler et al., 1987; Mehes et al., 1988; MorenoMontanes et al., 1988; Nambu et al., 1988; Fryns et al.,
1990; Kondo et al., 1990; Kondo et al., 1990; Warburg
et al., 1990; Martinez et al., 1991; Massa et al., 1991;
zturk and Weber, 1991; Steinlein et al., 1991; Higgins
O
et al., 1994; Schlichtemeier et al., 1994; North et al.,
1995; Fryns et al., 1996; Okamoto et al., 1998]. As there
is no test to conrm the diagnosis, these reports are
based on clinical ndings. The pathogenesis of this
pleiotropic syndrome is unknown.
Studies of patients with symptoms clinically similar
to Cohen syndrome have also been published under
other syndrome names. Mirhosseini et al. [1972]
reported on two brothers with pigmentary retinal
degenerations, cataracts, hyperextensible joints, microcephaly, and severe mental retardation. Thirteen years
later Mendez et al. [1985] published a report on two
sisters with ``Mirhosseini-Holmes-Walton syndrome.''
These four patients were clinically very similar to
Cohen patients, and these two syndromes were suggested to be identical [Norio and Raitta, 1986]. In 1994,
Partington and Anderson [1994a] described three
patients without a specic diagnosis as having developmental delay, microcephaly, friendly personality,
myopia, and distinctive facial appearance. A letter to
the editor [Norio, 1994] proposed that these patients
had Cohen syndrome, and this proposal was subsequently accepted by the authors [Partington and
Anderson, 1994b].
Many of the reported patients have been sibs, with
healthy parents. In ve Finnish families the parents
were consanguineous. Thus, Cohen syndrome is considered to be an autosomal recessive disorder. In
Finland, linkage studies were performed with the
assumption of autosomal recessive inheritance, and
the gene was mapped to the long arm of chromosome 8
[Tahvanainen et al., 1994]. The rened mapping of the
Cohen syndrome gene by linkage disequilibrium was
reported, also in Finland, in 1997 [Kolehmainen et al.,
1997]. The haplotype association showed that of the 29
detected Cohen chromosomes, 25 very probably represented one mutation derived from one ancestor. Thus it
seems that the Finnish Cohen patients have one main
mutation and possibly two other rare ones in the same
locus. Very probably this main mutation, together with
the isolated Finnish population structure, caused the
overrepresentation of this disorder in Finland.
Thus far, 34 Cohen syndrome patients have been
diagnosed in Finland. In contrast to the confusing
heterogeneity in the international literature among
patients claimed to have Cohen syndrome, this syn-

drome is highly homogeneous in Finland, both clinically and molecular-genetically. We thus had an
excellent opportunity to undertake a nationwide clinical study of Cohen syndrome.
In this work our aims are to: 1) summarize the results
of the clinical studies of our nationwide evaluation of
Cohen patients in Finland, 2) distinguish essential
features from nonessential ones and dene congruent
diagnostic criteria for this syndrome, 3) evaluate the
natural course of Cohen syndrome at different ages,
and 4) discuss the heterogeneity of the syndrome.
PATIENTS
The core of this nationwide study were the 21
patients with a denite diagnosis of Cohen syndrome
in the les of the Department of Medical Genetics at the
Family Federation of Finland Vaestoliitto. In all of
them, the diagnosis had been made or conrmed by
R.N. along the lines given in the article by Norio et al.
[1984] (see Introduction). Thus, ophthalmologic features also were required for the diagnosis.
To nd more patients, lectures about Cohen syndrome were given and information letters were sent to
neuropediatricians, pediatricians, clinical geneticists,
ophthalmologists, and other medical personnel taking
care of mentally retarded patients. Special effort was
directed at establishing the diagnosis early in infants.
From 1995 to 1997 many suspected cases were referred,
and after careful diagnostic evaluation eight new
evident diagnoses of Cohen syndrome were made.
Twenty-nine patients were invited to participate in
the investigation. Of them, 18 attended the whole study
protocol, nine participated in some of the studies, and
two were included by hospital records only. The ages of
the patients varied from 11 months to 57 years.
Informed consents were obtained from parents and
guardians. The investigations were made at the
Departments of Child Neurology and Pediatrics, Hospital for Children and Adolescents; Departments of
Ophthalmology and Radiology, Helsinki University
Central Hospital; and Department of Pedodontics and
Orthodontics, Institute of Dentistry, University of
Helsinki.
Six case studies had been published previously by
Norio et al. [1984]. Of the 29 patients, 21 had
participated in the rened mapping of the Cohen
syndrome gene by linkage disequilibrium [Kolehmainen et al., 1997].
Clinical evaluation, brain magnetic resonance imaging (MRI) and electroencephalogram (EEG), psychological, ophthalmologic, hematological, endocrine,
cardiac, and radiological studies were performed on
the patients as described earlier [Alaluusua et al., 1997;
Kivitie-Kallio et al., 1997; Kivitie-Kallio et al., 1998;
Kivitie-Kallio et al., 1999a and b; Kivitie-Kallio et al.,
2000].
RESULTS
The clinical manifestations of the 29 patients are
listed in Table I.

Cohen Syndrome

127

TABLE I. Clinical Manifestations (Other Than Ophthalmologic) of 29 Cohen Patients*

Growth and development

Low birth weight (under 3 kg)
Short stature (under 2 SD)
Obesity
Delayed puberty
Reduced fetal activity
Neonatal feeding difculties
Psychomotor retardation
Microcephaly (under 2 SD)
Hypotonia
Hypermobility of joints
Cubitus valgus
Genu valgum
Pes planovalgus
Kyphosis (angle more than 408 or clinically evident)
Scoliosis (angle more than 108)
Motor clumsiness
Craniofacial manifestations
Antimongoloid slant of eyelids
High-arched or wave-shaped eyelids
Long/thick eyelashes
Thick eyebrows
Prominent root of nose
Short philtrum
Prominent upper central incisors
High/narrow palate
Small or absent lobuli of ears
Thick hair
Low hairline
Miscellaneous
Narrow hands and feet
Mild syndactylies
Wide gap between toes 1 and 2
Brisk tendon reexes
Cardiac systolic murmur
Granulocytopenia
High-pitched voice
Cheerful disposition

/n

13/21
12/29
5/29
10/13
9/18
15/20
29/29
29/29
29/29
29/29
7/23
19/25
25/28
20/29
9/23
29/29

62%
41%
17%
77%
50%
75%
100%
100%
100%
100%
30%
76%
89%
69%
39%
100%

13/29
29/29
28/29
25/29
27/29
29/29
21/26
21/26
15/27
29/29
29/29

45%
100%
97%
86%
93%
100%
81%
81%
56%
100%
100%

28/29
12/29
23/28
22/28
7/29
29/29
19/28
29/29

97%
41%
82%
79%
24%
100%
68%
100%

*Bolded entities have the frequency of 100%.

Development
Half of the mothers available for interviewing
(n 18) remembered reduced fetal activity during an
otherwise normal pregnancy. As newborns, the babies
had usually been considered normal, although they
were often smaller than the other children in their
families. Thirteen of 21 patients (62%) with available
data had a birth weight of under 3 kg. Head
circumferences at birth were within normal limits.
Neonatal feeding difculties had been observed in 75%.
All patients had psychomotor retardation, which
appeared not to be progressive. Developmental delay
was noted between 6 to 12 months of age. All
developmental milestones were delayed and children
developed microcephaly. All except one had had good,
sociable contact with other people from a very early
age. Contact smiles had appeared between 6 weeks to
3 months. Twelve of 13 had been reported to be
hypotonic or oppy during the rst months of their
lives. By the age of 1 year all patients were hypotonic.

The infants had been able to turn from prone to

supine between 4 months to 1 year of age, to sit
without support at the age of 10 months to 1.5 years,
and to walk independently by the age of 25 years.
Despite the symptoms of hypotonia they showed
early in life, at least four patients later developed
spasticity in their lower extremities. None had ataxia,
but all had motor clumsiness. Tendon reexes were
brisk in 79%. None of the neurological symptoms
were progressive. Other parts of the routine neurological status were noncontributory. All the patients
learned to speak, but the level of speech competence
varied considerably, even among sibs. The delay in
speech development was often the most prominent
feature in the child's developmental delay. They
uttered their rst words at 15 years of age, and most
but not all could use sentences at 56 years of age.
However, most patients understood speech better than
they could speak themselves. All of our youngest
patients received speech therapy and used sign language successfully.

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Kivitie-Kallio and Norio

Craniofacial Features
One of the inclusion criteria was ``typical facial
features.'' When these features were analyzed in detail,
it was observed that all patients had high-arched or
wave-shaped eyelids, short philtrum, thick hair, and
low hairline. Additionally, 97% had long or thick
eyelashes, 93% had prominent root of nose, 86% had
thick eyebrows, 81% had prominent upper central
incisors, 81% had high or narrow palate, 56% had
small or absent ear lobuli, and 45% had antimongoloid
slant of eyelids. Open-mouth appearance, maxillary
hypoplasia, micrognathia, and defective folding of
earlobes were noted in hospital les. However, the
latter features were not reevaluated, because they are
difcult to estimate with any accuracy without taking
specic measurements.
Miscellaneous Features
Ninety-seven percent of the patients had narrow
hands and feet (judged by inspection, without measurements), 41% had mild syndactylies, 82% had a wide gap
between toes 1 and 2, and 68% had a high-pitched voice.
All had granulocytopenia and 24% had cardiac systolic
murmur. These features will be discussed in detail
later.
MRI Studies of the Brain
No focal signal intensity alterations in the brain were
detected. The relation between the gray and white
matter in all subjects was normal. Quantitative
analyses of internal skull surface, brain stem, and
corpus callosum (CC) revealed a relatively enlarged CC.
Such a nding has not previously been reported to be
associated with mental retardation [Kivitie-Kallio et al.,
1998].
Relatively enlarged CC has not previously been
zturk and
reported in the MRIs of Cohen patients [O
Weber, 1991; Fryns et al., 1996]. However, no measurements were taken. It would be interesting to reevaluate
those images.
MRI studies also conrmed that Cohen syndrome
does not belong to the groups of disorders of dorsal or
ventral induction, proliferation, migration, or myelinization, all of which can only be detected by MRI or
computed tomography (CT). Thus, MRI is valuable in
diagnosis and differential diagnosis. Although MRI
alone cannot conrm the diagnosis, and no denite
measurements can be recommended for clinical use,
any clinical suspicion of Cohen syndrome will be
reinforced if the MRI shows a relatively enlarged CC
in a microcephalic head and normal signal intensities of
gray and white matter.
EEG Studies
None of the patients had had seizures or medication
for epilepsy. The three youngest patients had normal
EEGs. All of the others had low-voltage EEGs. No
irritative spikes or epileptiformic foci were found. Nine

patients had quick beta transients [Kivitie-Kallio et al.,

1999b].
Psychological Tests
All patients had mental retardation, as it was an
obligatory inclusion criterion. Of the 18 tested patients,
22% had profound, 61% severe, 6% moderate, and 11%
mild retardation. In an adaptive behavior scale for
children and adults (AAMD) [Nihira et al., 1975] Cohen
patients had high scores in the positive domains (selfdirection, responsibility, and socialization), while maladaptive behavior was almost lacking [Kivitie-Kallio
et al., 1999b].
The IQ of Cohen patients as assessed in our study
was as low or lower than previously reported.
Obviously, the virtual absence of maladaptive behavior,
and high scores in socialization and responsibility gave
an impression of a higher level of intelligence than the
patients actually had. In many reports the patients are
described as cheerful and sociable [Sack and Friedman,
1980; Fryns and Van den Berghe, 1981; Kousseff, 1981;
Norio et al., 1984], which may be a reection of these
factors.
Ophthalmological Studies
Only the youngest patients under the age of 5 years
had good visual function. Vision started to deteriorate
early but remained relatively good in most patients
until the age of 30. After the age of 40 many patients
were severely visually handicapped, but none were
totally blind. Progressive, often high-grade myopia and
retinochoroidal dystrophy resembling retinitis pigmentosa are essential features in Cohen syndrome. Thus,
the diagnosis of this syndrome can not be made without
them, except in the youngest patients under 5 years of
age. electroretinogram (ERG) is or will be extinguished.
A bull's eye macula appears at varying ages. Other
ndings are strabismus, early lens opacities, shallow
anterior chamber, and iris atrophy [Kivitie-Kallio et al.,
2000].
Hematological Studies
All patients had granulocytopenia, which was mild to
moderate, noncyclic, and not fatal. Bone marrow
examination revealed in all patients a normo- or
hypercellular marrow, often with a left-shifted granulopoiesis. No bone marrow malignancies were seen.
However, patients had increased susceptibility to early
periodontal breakdown, which likely is associated with
the granulocytopenia. Patients had extensive alveolar
bone loss more frequently than the controls (who were
matched for age, sex, and degree of mental retardation).
They also had periodontal pathogenic bacteria more
often than the controls [Alaluusua et al., 1997; KivitieKallio et al., 1997].
Other Studies
In cardiac studies the anatomy of heart was normal
and no tendency to clinically signicant mitral prolapse

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129

TABLE II. Essential and Other Features in Cohen Syndrome

Essential features
Non-progressive psychomotor retardation, motor clumsiness, and microcephaly
Typical facial features: high-arched or wave-shaped eyelids, short philtrum, thick hair, and low hairline
Childhood hypotonia and hyperextensibility of the joints
Ophthalmologic ndings of retinochoroidal dystrophy and myopia in patients over 5 years of age
Periods of isolated granulocytopenia
Findings that strongly support the diagnosis
Long or thick eyelashes, thick eyebrows, prominent root of nose, prominent upper central incisors, high or narrow palate
Relatively enlarged corpus callosum in brain MRI
Low-voltage EEG in patients over 14 years of age
Typical metacarpophalangeal pattern prole
Slender and short ngers
A wide gap between toes 1 and 2
Early lens opacities
Almost total absence of maladaptive behaviour (cheerful disposition)
Nonspecic features that are often seen
Delayed puberty
Short stature
Scoliosis
Kyphosis
Pes calcaneovalgus
Cubitus valgus
Mild syndactylies
Antimongoloid slant of eyelids
Small or absent lobulus of ears

was found. However, a decreased left ventricular

function with advancing age was noticed. In endocrine
studies, no signicant abnormalities were found. However, puberty was late. Obesity and signicantly short
stature were not essential features. Other radiological
studies conrmed kyphosis, scoliosis, and calcaneo
planovalgus to be common features in Cohen syndrome,
but most probably they are secondary to marked
hypotonia. Fingers were slender but short. The metacarpophalangeal pattern prole was typical of this
syndrome [Kivitie-Kallio et al., 1999].
DISCUSSION
Essential Features and Diagnostic Criteria
This patient series was planned in such a way that it
would be as homogeneous as possible. This also means
that atypical and borderline cases were omitted. When
these cases were encountered, they showed several
possible symptoms and signs of the syndrome, but the
general impression was inadequate or some essential
features were lacking, such as ophthalmologic ndings.
Such patients were called ``cohenoid.'' However, in
most cases it was not difcult to draw the line
between real Cohen patients and ``cohenoids.'' Nevertheless, whether the symptoms of some of the omitted
cases had been caused by the same gene remains to
be seen in further studies, after a gene diagnosis is
available.
Table II shows the essential features of Cohen
syndrome, ndings which strongly support the diagnosis, as well as unspecic but frequently noted
features. In a syndrome like this it is not possible to
determine a minimum amount of features required for
the diagnosis.

Suggestions for Diagnostic Procedures

Cohen syndrome should be suspected in children
who, although born at term and healthy, present with
microcephaly and hypotonia by the age of 612 months,
show delay in speech and other developmental milestones, and have nonprogressive mental retardation
and distinctive facial features. A careful ophthalmologic investigation should then be performed, and the
absolute neutrophil count (ANC) should be investigated. If the patient has microcephaly, mental retardation, and developmental delay, and signs of
chorioretinal dystrophy, myopia, and granulocytopenia, no differential diagnostic problems exist because
no other syndrome has this specic combination
[Winter and Baraitser, 2000]. However, MRI of the
brain is especially important in young children, who
may not yet have ophthalmological changes. A relatively enlarged CC supports the diagnosis; furthermore, MRI can exclude many other possible causes of
mental retardation.
If investigations have not been made to detect all the
essential features, differential diagnostic problems
exist. If the patient has mental retardation, retinitis
pigmentosa, and microcephaly, there are about 30
possible syndromes to consider. If the patient has
mental retardation, retinitis pigmentosa, and myopia,
there are 14 possible syndromes [Winter and Baraitser,
2000].
Natural History
Cohen syndrome manifests very differently at different ages. The diagnosis is difcult to make in infants. It
is easiest at school age. In time, the facial features lose

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Kivitie-Kallio and Norio

their most typical characteristics while the ophthalmologic ndings become more and more apparent.

Pregnancy, delivery, and neonatal period.

Pregnancy and delivery are usually normal, though

fetal movements can be weak. As newborns the babies
are considered normal. The characteristic facial features cannot be seen at this age. The head circumference is within normal limits. Granulocytopenia can be
present from birth.
Infancy (01 years). Neonatal feeding problems
are common. Babies are often hypotonic during the rst
months of life. From 612 months of age it becomes
obvious that development is not normal, and children
are brought to a doctor. At that time they have
hypotonia, microcephaly, and delayed developmental
milestones. Most have good, sociable contact from the
beginning and show no signs of autism or cerebral
palsy. Use of sight is normal at this age and they hear
normally. At this age, characteristic facial features are
difcult to recognize. However, the youngest patient
ever diagnosed was 11 months (Fig. 1).
Many parents later remember having been worried
about their children from a very early age, especially if
they had experienced healthy babies before.
Preschool age (26 years). In this period
psychomotor retardation is obvious. Many children
receive physical therapy for motor delay. All patients
learn to walk by the age of 25 years. Speech
development is delayed, but all learn to speak at some

Fig. 1. An 11-month-old boy, the youngest patient diagnosed with

Cohen syndrome.

level, which varies a lot even among sibs. At this age

speech therapy is important. Some patients have
myopia, and sometimes the earliest fundus changes
(pale disc and generally pale fundus with or without
pigment granularity) can be seen. Some have difculties seeing in the dusk. However, most patients have no
ophthalmologic symptoms and ndings at this age.
Because of the obvious developmental delay many
causes of mental retardation are usually excluded by
various tests. EEG is normal. Except for oppiness, no
signs of muscle disease are found. Brain MRI is
considered normal, although CC is relatively enlarged.
Many children with Cohen syndrome have recurrent
upper respiratory infections at this time. Whether this
is a result of granulocytopenia or oppiness and
retardation cannot be judged. However, patients have
no fatal infections, and granulocytes seem to rise
normally in cases of severe bacterial infections. Typical
facial features become more and more characteristic by
5 years of age (Fig. 2). Cohen children at this age are
generally considered to be very beautiful children.
School age (714 years). Patients are not able
to attend normal school; thus they all need special
schools. Mental retardation does not progress and
patients learn new things. Facial features are evident
(Fig. 3), and very often the diagnosis is made at this
age. At this period myopia is always present and signs
of retinochoroidal dystrophy are usually found.
Patients need eyeglasses and like to wear them.
Because of severe pes calcaneovalgus some patients
need orthopedic intervention.
Puberty (1519 years). Puberty is often delayed.
No endocrine abnormalities are found. Patients are
often signicantly short but after pubertal growth
reach short normal (median 2 SD) height. Lowvoltage, nonirritative EEG is found from this age on.
Myopia has often progressed to a malignant level (> 6
diopters). Moderate fundus changes, narrow vessels,
and pigment clumps and bone-spiculae-like pigment
accumulations appear, and patients suffer from nyctalopia and narrowed visual elds. Even teenagers may
have peripheral lens opacities.
Adulthood (2040 years). Facial features
remain recognizable for decades (Fig. 4A); however,
patients show signs of premature aging. Vision deteriorates slowly but remains relatively good in most
patients until the age of 30 years. Young adults have
early nuclear sclerosis.
Middle age (4060 years). The facial features
tend to lose their most characteristic appearance
(Fig. 4D). Patients are usually in good health. However,
decreased left ventricular function with advancing age
may be found. Ophthalmologic changes progress at this
age: the number and size of pigment deposits increases
and approaches the posterior pole by 3540 years of
age. Patients over 45 years of age have severe
retinochoroidal atrophy. A bull's eye macula is seen in
most patients. Most have posterior subcapsular cataract. The iris atrophies and shallow anterior chambers
possibly leading to angle-closure glaucoma may be
seen. However, ophthalmologic abnormalities, though
progressive, do not lead to total blindness.

Cohen Syndrome

131

Fig. 2. Cohen patients at infancy and preschool age. A: A 2-year-old boy. B: A 3-year-old boy. C: A 4-year-old girl. D: Children at our rst course for
Cohen families.

Fig. 3.

Cohen patients at school age. A: A 6-year-old girl. B: A 7-year-old boy. C: A 14-year-old girl. Note the short philtrum. D: A 15-year-old boy.

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Kivitie-Kallio and Norio

Fig. 4.

Adult Cohen patients. A: A 20-year-old male. B: A 26-year old female. C: A 39-year-old female. D: Three sibs aged 45, 39, and 32 years.

Old age (over 60 years). At present, data on this

age group are still lacking. The life span does not seem
to be shortened.
Heterogeneity of the Syndrome
Altogether, over 100 patients have been described as
having Cohen syndrome. In Table III, previously
diagnosed Cohen patients are evaluated according to
the features we consider essential for the syndrome.
Of patients reported outside Finland, 20 [Cohen et al.,
1973; Carey and Hall, 1978; Ferre et al., 1982; Resnick
et al., 1986; Kondo et al., 1990b; Warburg et al., 1990;
zturk and Weber, 1991; Steinlein et al., 1991; Fryns
O
et al., 1996] show the same clinical symptoms as our
patients. Furthermore, four patients described as
having Mirhosseini-Holmes-Walton syndrome [Mirhosseini et al., 1972; Mendez et al., 1985] have symptoms
similar to those of our patients, as do the three patients

described in 1994 by Partington and Anderson. Thus

the ``Finnish'' Cohen syndrome is not solely a Finnish
specialty.
The original patients reported by Cohen et al. [1973]
most probably were similar to the Finnish ones. The
expression ``mottled retina'' probably represents chorioretinal dystrophy. Full certainty cannot be achieved
because these patients have been lost from the followup (Cohen, personal communication).
Ophthalmologic features are important in Cohen
syndrome. Patients claimed to have Cohen syndrome
without the typical ophthalmologic features may not
have the same syndrome as our patients, or the
ophthalmologic investigation may not have been sufcient. Visual symptoms are not easily noticed in
patients with mental retardation, and accurate
ophthalmologic investigation is not easy for ophthalmologists who are not accustomed to coping with
patients with retardation.

Cohen Syndrome

133

TABLE III. Essential Features in 116 Published Patients Claimed to Have Cohen Syndrome*
Typical habitus

Reference

Age/sex

Diagnosis compatible with

Finnish criteria
Mental
(, ?, )
retardation

Microcephaly

Facial

Other

Ophthalmologic ndings
Mottled retina,
chorioretinal
dystophy or ERG
Myopia
abnormality

Granulocytopenia

Balestrazzi et al.
[1980]

11/M
10/M

?
?

No picture

ND
ND

Carey and Hall

[1978]

11/M
5/M
15/M
14/F
18/F
15/M
8/F

ND
ND
ND
ND
ND
ND
ND

Doyard and
Mattei.[1983]

7/F
6/M

ND
ND

Ferre et al.
[1982]

6/F
9/F

ND
ND

Friedman and
Sack [1982]

12/F
7/M
13/M
10/F
16/F

ND
ND
ND
ND
ND

Fryns and Van den

Berghe [1981]
Fryns et al. [1990]
Fryns et al.
[1996]

9/M

ND

15/F
6/F
6/F
3/F
1/F

ND

12/F

ND

11/F
10/F
13/F
4/F

ND
ND
ND
ND

21/M
15/M
15/M
18/M
17/F
12/F
?
?

?
?
?

ND
ND
ND
ND
No
No

Cohen et al.
[1973]

Fuhrmann-Rieger
et al. [1984]
Goecke et al.
[1982]
Higgins et al.
[1994]
Kondo et al.
[1990]
Kousseff [1981]

Martinez et al.
[1991]
Massa et al. [1991]

12/F

ND

Mirhosseini et al.
[1972] (not published as Cohen
syndrome)

28/M
24/M

ND
ND

ND
ND

Mehes et al. [1988]

2/F

ND

Mendez et al.
[1985](not published as Cohen
syndrome)
Moreno-Montanes
et al. [1988]
Nambu et al.
[1988]
North et al. [1985]

18/F
9/F

ND

ND
ND

18/?

ND

No picture

ND

ND

12/F

ND

15/M
16/M
10/F
1/M
8/M
4/F

No
No
No
No
No
No

134

Kivitie-Kallio and Norio

TABLE III. (Continued)
Typical habitus

Reference

Age/sex

North et al. [1995]

Okamoto et al.
[1998]
Partington and
Anderson
[1994]
Resnick et al.
[1986]
Rizzo et al. [1987]
Sack and Friedman [1980]
Sack et al. [1986]a
Schlichtemeier
et al. [1994]
Steinlein et al.
[1991]
de Toni and
Caero [1982]
Warburg et al.
[1990]
Wilson et al. [1985]
Young and Moore
[1987]
Zeller et al. [1987]
Zetler et al. [1987]
zturk and
O
Weber [1991]

Diagnosis compatible with

Finnish criteria
Mental
(, ?, )
retardation

Ophthalmologic ndings

Microcephaly

Facial

Other

Mottled retina,
chorioretinal
dystophy or ERG
Myopia
abnormality

Granulocytopenia

8/F
8/F

?
?

?
?

ND
ND

15/F
3/F
9/F

?
?
?

No picture
No picture
No picture

6/M
4/F
2/F

ND

ND

ND
ND

17/F
10/F

ND
No

12/F
n:o 39

?
?

?
?

ND
ND

13/M
17/F

ND
ND

ND
ND

ND
ND

30/M
28/M

ND
ND

16/F

ND

27/F
10/F

ND

15/M
13/F
10/F
18/M
11/M
7/M

?
?

ND
ND
ND
ND
ND
ND

14/F

*Bolded cases are similar to Finnish patient.

a
39 patients, not individually described.

Future molecular-genetic studies will reveal whether

patients whose symptoms differ from the Finnish
patients have a disease caused by another gene or
different mutations of the gene that has been localized
to the long arm of chromosome 8.
Clinical Consequences of the
Diagnosis of Cohen Syndrome
An exact etiological diagnosis is important for every
individual with mental retardation. A diagnosis of
Cohen syndrome means that the retardation is not
progressive. The exceptionally positive psychic character makes daily life easier than in most other diseases
with mental retardation. The majority of patients may
live at home instead of in an institution. The ophthalmologic features demand adequate eyeglass correction,
bright lighting, safe routes at home and outdoors, and
understanding of the visual problems associated with

this syndrome. Granulocytopenia does not demand

extensive hematological investigations nor does it make
the patient predisposed to severe infections. Genetic
counseling can be based on autosomal recessive
inheritance and will soonwe hopebenet from
molecular-genetic diagnosis.
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