Eur. J. Psychiat. Vol. 23, N.
° 1, (31-36)
2009
Keywords: Fragile X; 47,XXX; obesity; hyperpha-
gia; affective disorder.
Genetic diagnosis in clinical psychiatry: A case
report of a woman with a 47,XXX karyotype and
Fragile X syndrome
Dr. Anthony M. Vandersteen*
David Moore**
Celia Donaghue***
Dr. Neil MacFarlane****
Dr. Dragana Josifova*
* Guy’s and St. Thomas’ NHS Foundation
Trust, Dept. Clinical Genetics.
** Guy’s and St. Thomas’ NHS Foundation
Trust, Dept. Molecular Genetics.
*** Guy’s and St. Thomas’ NHS Foundation
Trust, Dept. Cytogenetics.
**** Consultant in Adult Developmental
Psychiatry, Honorary Senior Lecturer,
University of Kent.
NEW ZEALAND
UNITED KINGDOM
ABSTRACT – Background and Objectives: A recent report highlighted the importance of
considering a chromosomal abnormality in the differential diagnosis of adult clinical psy-
chiatry. This case report illustrates the importance of considering Fragile X syndrome, an
X-linked genetic disorder associated with psychiatric morbidities.
Methods: A 45 years old woman was referred to the clinical genetics department by her
psychiatrist for investigation of her gross obesity, hyperphagia, learning difficulties and
affective disorder.
Results: Cytogenetic analysis revealed a 47,XXX karyotype. Molecular testing identi-
fied an expansion of approximately 580 repeats in the FRAXA gene carried on two of her
three copies of the X chromosome. Clinical evaluation revealed features consistent with
the Prader-Willi like phenotype of Fragile X syndrome.
Conclusions: It is important to consider molecular and cytogenetic testing in patients
with dysmorphic features, complex neuro-behavioural profile and/or psychotic disorders
in order to establish a causative diagnosis, provide adequate counselling and initiate cas-
cade screening where applicable.
Received 13 March 2008
Revised 17 December 2008
Accepted 19 December 2008
32 ANTHONY M. VANDERSTEEN ET AL.
Introduction been reported for men with FXS with no ev-
idence of chromosome 15q abnormality5.
We present the case of a 45 years old woman
A recent report highlighted the impor- referred to the clinical genetics department
tance of considering a genetic syndrome in for investigation of her gross obesity, hyper-
the differential diagnosis of adults with phagia, learning difficulties and affective
learning difficulties, autism and psychiatric disorder. This combination was consistent
illness1. Most adults with learning difficul- with a diagnosis of Prader-Willi Syndrome
ties have not had specific genetic investiga- and she was referred to the Genetics Ser-
tions, which may reflect previously lower vices for assessment and testing.
availability of testing as well as cultural and
historical divides between healthcare profes-
sionals and those involved in the daily care
of individuals with learning difficulties2. Case Report
Fragile X syndrome (FXS) is the most com-
mon inherited cause of learning difficulties in The patient is the third child of unrelated
men. FXS is caused by expansion (>200 re- parents and is one of non-identical twins
peats) in a CGG repeat sequence of the (Figure 1). Her mother gave no history of
FRAXA gene (Xq27.3). Female pre-mutation illness or substance misuse during pregnan-
carriers (55-200 repeats) are at risk of prema- cy. There was no history of neonatal hypoto-
ture ovarian failure and males of tremor/ataxia nia or feeding difficulties, although irritabil-
syndrome (FXTAS) later in life3. ity in infancy was reported. She achieved
her motor milestones within the expected
FXS is associated with autism spectrum,
time, but presented with speech delay, com-
anxiety and mood disorders, hyperactivity
munication and learning difficulties.
and aggressive behaviours in men3. Women
with FXS may have anxiety, depression, At age of 17 the patient underwent a for-
learning and attention disorders even in the mal assessment which revealed a full scale
presence of normal or above average IQ IQ of 44. A more recent assessment revealed
scores4. A Prader-Willi like phenotype has a full scale IQ of 65 with a particular deficit
Figure 1. Pedigree.
GENETIC DIAGNOSIS IN CLINICAL PSYCHIATRY: A CASE REPORT OF A WOMAN WITH … 33
in verbal reasoning. She never achieved in- of 56cm (50th-75th centile). She had small
dependence and lived in a sheltered accom- hands and feet (shoe size 4) with normal skull
modation under supervision. She was known shape, normal ear morphology and no specific
to have severe hyperphagia with nocturnal dysmorphic features (Figure 2).
food foraging. She manifested an increas-
Cytogenetic analysis involved standard
ingly sexualised behaviour which was be-
G-banded karyotype analysis (Figure 3).
coming of concern to the social services. At
This showed a 47,XXX karyotype (Triple
the age of 41 she developed a psychotic ill-
X), the result was confirmed by multiplex
ness with a severe affective component and
ligation-dependent probe amplification
was under regular psychiatric review. She re-
(MLPA). Quantitative fluorescence Poly-
sponded well to treatment.
merase Chain Reaction analysis (QF-PCR)
The proband’s twin sister and older of four informative markers on the X chro-
brother were also known to have learning mosome (DXS7423, HPRT, DXS1187 and
difficulties. They were not available for as- DXYS287) were consistent with three
sessment in our clinic, however, they were copies of the X chromosome showing a 2:1
known to be of similar stature and build, al- ratio for the maternal to paternal alleles.
though not to the same extent as our patient.
Patient DNA was isolated from EDTA
The patient’s brother had a history of psy-
anticoagulated peripheral blood. Amplifica-
chiatric illness. Unfortunately we were un-
tion of the repeat regions at the FRAXA
able to obtain more detail about their condi-
locus was carried out using standard fluo-
tion. The patient’s mother had a history of
rescent PCR amplification. A single FRAXA
depression but was of normal cognitive abil-
allele corresponding to 33 CCG repeats was
ity, in good general health with no history of
amplified for the index case. Southern blot
premature menopause.
analysis showed an additional discrete band
The patient was tall, with a height of 178cm was present corresponding to a fully methy-
(98th-99.6th centile), weight of 191Kg (>99.8th lated, expanded allele of approximately 580
centile, BMI = 60) and a head circumference repeats (Figure 4) and was significantly dark-
Figure 2. Front view photograph of patient showing non-dysmorphic facial features and obesity.
34 ANTHONY M. VANDERSTEEN ET AL.
Figure 3. Karyotype analysis of the patient (from a blood sample), showing 47,XXX.
Figure 4. Southern Blot analysis of Fragile X alleles for the patient and her mother.
4A: Patient result in lane 2, showing 6.8kb methylated expansion allele; lanes 1 and 3 are normal females*
4B: Mother of patient result in lane 1, showing 3kb unmethylated premutation allele and 5.4kb methylated premutation
allele; lane 2 is a normal female*
* 2.8kb corresponds to the normal unmethylated sized FRAXA allele.
5.2kb corresponds to the normal methylated sized FRAXA allele.
GENETIC DIAGNOSIS IN CLINICAL PSYCHIATRY: A CASE REPORT OF A WOMAN WITH … 35
er than the normal sized bands. Laboratory tion. The patient’s tall stature may be a fea-
testing of the patient’s mother’s blood sam- ture of both Fragile X and Triple X Syn-
ple showed amplification of a normal drome, although we can not exclude the pos-
FRAXA allele corresponding to 34 repeats sibility that there was a significant familial
and a pre-mutation allele of approximately component in this case. Our patient had a rel-
84-92 repeats was detected. Unmethylated atively small head circumference, a feature
and methylated alleles were present in ap- more in keeping with Triple X than with
proximately equal ratios. FRAXE analysis Fragile X syndrome. The latter is more likely
showed normal sized alleles for the index to be associated with macrocephaly9. To our
case and her mother. Unfortunately no sam- knowledge the Prader-Willi Syndrome like
ples were available from the father of the phenotype in females with Fragile X has not
index case. been previously reported in the literature.
The above investigations concluded that In females, X-inactivation takes place
the index case carried three copies of the X early in embryogenesis to provide dosage
chromosome, two of which were maternally compensation. The X-inactivation is usually
inherited, both carrying a full expansion at random resulting in equal representation of
the FRAXA locus. maternal and paternal genes on the X-chro-
mosome. However, skewed X-inactivation
is a well recognised mechanism that may
produce a clinical phenotype of a tradition-
Discussion ally X-linked recessive disorder in carrier
women to the extent that they may present
with a clinical picture very similar to that
To our knowledge an increased associa-
seen in affected males10. In our patient, with
tion of Fragile X syndrome and Triple X has
an assumption of random X-inactivation,
not been reported. A single case report of a
one would expect a probability 2 out of 3 of
woman with Triple X who was found to
each cell line carrying a FRAXA mutation as
carry a single copy of an X chromosome
opposed to 1 out of 2 in female carriers with
with an expanded FRAXA allele and two
a normal chromosome complement. It is
normal copies of the X chromosome was
likely therefore that this dosage effect is the
mentally and physically normal6.
cause of this phenotype.
Nowicki et al.5 described the Prader-Willi
like phenotype in males affected with Frag-
ile X Syndrome: severe behavioural prob-
lems and mental retardation, onset of hyper- Conclusions
phagia between the ages of 1 and 10,
extreme obesity and short stature. Small
This case report highlights the impor-
hands and feet were reported previously in
tance of consideration of cytogenetic and
an original case series7,8.
molecular investigations in patients with a
Our patient presented with features of the complex neuro-behavioural profile and/or
Prader-Willi-like phenotype of Fragile X psychotic disorders, particularly in the pres-
Syndrome including severe cognitive diffi- ence of a family history of learning difficul-
culties, behavioural problems, and morbid ties and/or dysmorphic features. It is impor-
obesity secondary to extreme food consump- tant to compile a detailed family history and
36 ANTHONY M. VANDERSTEEN ET AL.
consider genetic investigations in order to notype of Fragile X Syndrome. J Dev Behav Pediatr 2007;
28(2): 133-138.
establish a causative diagnosis. Although
this may not necessarily alter patient’s man- 6. Fuster C, Templado C, Miró R, Barrios L, Egozcue J.
agement it may prove crucial for other fam- Concurrence of the triple-X syndrome and expression of
the fragile site Xq27.3. Hum Genet 1988; 78: 293.
ily members at risk to have the opportunity
to receive appropriate counselling, take part 7. de Vries BB, Fryns JP, Butler MG, Canziani F,
Wesby-van Swaay E, van Hemel JO, et al. Clinical and
in cascade screening and make informed
molecular studies in fragile X patients with a Prader-Willi-
choice where applicable. like phenotype. J Med Genet 1993; 30(9): 761-766.
8. de Vries BB, Robinson H, Stolte-Dijkstra I, Tjon Pian
Gi CV, Dijkstra PF, van Doorn J, et al. General overgrowth
in the fragile X syndrome: variability in the phenotypic ex-
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Fax: +44-207-188-1369
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