Journal of Mental Deficiency Research, 1987, 31, 73-79

CASE REPORT

Klinefelter syndrome and associated Fragile-X

syndrome
S. M. PUESCHEL,' M. M. O'BRIEN^ AND T. PADRE-MENDOZA^
'Child Development Center, Department of Paediatrics, -^ Depanmeni of Pathology, Rhode
Island Hospital, Brown University Program in Medicine, Providence, Rhode Island,
^Dr Joseph H. Ladd Center, Department of Mental Healthy Retardation and Hospitals,
State of Rhode Island, USA

ABSTRACT. During screening of male individuals for Fragile-X syndrome in a

residential facility for persons wich mental retardation, the authors found a 21-year-oId
profoundly retarded man who displayed facial features and behaviour suggestive of
Fragile-X syndrome. The chromosome analysis revealed 47,fra(X)(q27)fra(X)(q27)Y.
His physically and intellectually normal sister had 14% of X chromosomes with a fragile
site. Her two sons, who were subsequently examined, were found to have Fragile-X
syndrome.
Thus, the identification of Fragile-X syndrome in the proband during the screening
process of a large institution led to the investigation of the proband's family and the
subsequent diagnosis of Fragite-X syndrome in the proband's two nephews. The
ascertainment of the two affected boys permitted prompt introduction of early
intervention and special education services. Genetic counselling of other at-risk family
members was carried out.

INTRODUCTION
Since the first description of Fragile-X syndrome, an X-linked inherited disorder
associated with mental retardation, dysmorphic features, macro-orchidism and
aberrant behaviours (Turner et al, 1978; Bowen et al., 1978; Howard-Peebles &
Stoddard, 1979; Sutherland & Ashforth, 1979; Jacobs et al, 1979; Turner et al,
1980), numerous reports on this subject have appeared in the medical literature (Opitz
& Sutherland, 1984; Opitz et al, 1985). A recent publication provides an overview of
the clinical characteristics, cytogenetic aspects, behavioural and language dysfunc-
tions, counselling, treatment, and intervention services, as well as other concerns as
they relate to Fragile-X syndrome (Hagerman & McKenzie McBogg, 1983).
This report describes a profoundly mentally retarded young man, who has both
Klinefelter syndrome and Fragile-X syndrome, and his subsequently diagnosed two
nephews, who also are affected with Fragile-X syndrome.

CASE R E P O R T S
Case II-5
The proband was the product of a 36-year-old gravida IV, para III mother who had an
Correspondence: S. M. Pueschel MD PhD MPH, Director, Child Development Center, Rhode
Island Hospital, 593 Eddy Street, Providence, RI 02902, USA
73
74 S. M. Pueschel, M. M. O'Brien and T. Padre-Mendoza

uncomplicated pregnancy and a full-term vaginal delivery. There were no immediate

perinatal complications and the neonatal period was uneventful. His early develop-
ment was significantly delayed: he smiled at one year, sat at 1V2 years, stood at 2 years
and walked independently at V/2 years. He was placed in an institution for mentally
retarded persons at the age of 7 years.
When we examined the proband at the age of 21 years, he displayed the following
dysmorphic features: facial asymmetry, coarse facies, high forehead, large ears with
overfolded helices, large nose, maxillary hypoplasia, malocclusion, high arched palate
and prognathia (Fig. 1). Anthropometric measures included a height of 175 cm
(fiftieth percentile), head circumference of 57-5 cm (seventy-fifth percentile), weight
of 75*3 kg (nintieth percentile), left testicular volume of 23-3 cm"^ and right testicular
volume of 25-7 cm^. His intellectual functioning was in the profoundly mentally
retarded range. He is nonverbal. He exhibited gaze aversion, distractibility and
impulsivity. The results of the endocrine studies are presented in Table 1.
The chromosome analysis revealed the modal number of chromosomes to be 47 per
cell due to an extra X chromosome. Twenty-five of 150 cells were noted to have a
fragile site on one X chromosome and another two cells were found to have a fragile
site on both X chromosomes, as demonstrated in Fig. 2.
Evaluation of the extended family revealed that his half sister (II-3) is physically
and intellectually normal; however, 14%of her cells showed a fragile site on one of the

Fig. 1 Photograph of proband.

Table 1 Hormone determinations of proband

Follicle stimulating hormone 25 [lU/ml (normal 5-25

Luteinizing hormone 325 [lU/ml (normal 6-30 [iU/ml)
Total testosterone 76 pg/ml (normal 80-200 pg/ml)
Free testosterone 441 ng/dl (normal <200 ng/dl)
 Klinefelter syndrome and associated Fragile-X 75

X chromosomes. Her two sons (III-2 and III-3) were noted to have the Fragile-X
syndrome (Fig. 3).

Case III-2
This patient is a 3-year-and-4-month-old boy who was born at full-term via normal

Fig. 2 Arrows indicate the two X-chromosomes with a fragile site.

II

III

Fig. 3 Pedigree of family G:

• Fragile-X syndrome. (J Obligate carrier, [v] Normal karyotype. • O Physically and
mentally normal, not available for karyotyping.
76 S. M. Pueschel, M. M. O'Brien and T. Padre-Mendoza
spontaneous vaginal delivery. His birth weight was 3058 g. There were no
comphcations during pregnancy, labour and delivery, and the neonatal period was
normal. His motor milestones were shghtly delayed but his language development was
significantly retarded. He has recently begun to use single words. He has frequently
exhibited stereotypic and self-injurious behaviours.
The physical examination indicated a length of 96 cm (twenty-fifth percentile),
head circumference of 52 cm (seventy-fifth percentile), and weight of 15-3 kg (fiftieth
percentile). Head banging was observed in response to stress leading to ecchymotic
skin lesions at the mid forehead. Epicanthal folds were present bilaterally. A
tympanostomy tube was in place at the left ear. He has slightly protruding cupped
ears. There were no other dysmorphic features and he appeared to be in good general
health. His neurologic functioning was normal. The left testicular volume was 1 '4 cm^
and the right testicular volume was 1-3 cm^.
During the psychological assessment (Bayley Scales of Infant Development) he
performed at a 17-month level. Nonverbal tasks were at about a 14-month level with
scatters up to 18 months. Language skills were very inconsistent and the patient
required gestural cues to respond to even relatively simple verbal commands. His
receptive language skills were estimated to be at about a 10-month level, and social
and self-help skills were within the 14- to 20-month range.
Significant behaviour problems included hand flapping, head banging, temper
tantrums, inappropriate crying episodes, short attention span and hyperactivity. Part
of this behaviour was thought to be due to poor mothering, the presence of a chaotic
household and marital discord.

Case IIII-3
This l-year-and-7-month-old boy was the 4062 g product of an uncomplicated
full-term pregnancy. The delivery was vaginal and spontaneous, and the neonatal
course was uneventful. Although his motor and social developments were normal, his
language acquisition was delayed.
When the patient was examined, his length was 82 cm (fiftieth percentile), his head
circumference was 48-5 cm (fiftieth percentile) and his weight was U ' l kg (between
the fiftieth and seventy-fifth percentile). The physical examination and the neurologic
assessment were normal, and no outstanding dysmorphic features were identified.
The testicular volume was M cm^ at the left and 1-2 cm^ at the right.
Upon psychological testing, he performed below age expectations. On the Bayley
Scales of Infant Development he earned a mental age estimate of 14 months. His
language skills appeared to be somewhat more delayed than nonlanguage skills. He
used gestures to express his wants. He responded to his name and followed one-step
directions. Occasional head banging was observed. He also exhibited irritability and
crying episodes during the evaluation.

METHODS
Chromosome preparations were made from 72-h cultures of peripheral blood using
the culture medium TC 199 with 5% calf serum, phytohemagglutinin, vitamins and
 Klinefelter syndrome and associated Fragile-X 77

Table 2 Cytogenetic results

Number Number
of cells of cells with
Case Age analyzed Fragile X Karyotype

II-3 26 50 7 46,XX/46,fra(X)(q27)Y
II-5 21 150 25 47,fra{X)(q27)fra(X)(q27)Y
III-2 3 100 3 46,XY/46,fra(X)(q27)Y
III-3 I 50 9 46,XY/46,fra(X)(q27)Y

antibiotics. Standard harvesting and slide preparations were followed by G banding

staining, utilizing a modified Seabright's technique. We examined 50 to 150
metaphases in respective individuals for the presence of Fragile-X chromosomes. The
results of the cytogenetic analyses of the subjects expressing the Fragile-X are shown
in Table 2.

DISCUSSION
Fragile-X syndrome is thought to be the second most common chromosome disorder
associated with mental retardation (Herbst & Miller, 1980). Surveys of institutions for
mentally handicapped have found 2-9% of male residents to be affected with
Fragile-X syndrome (Sutherland, 1979; Carpenter et al., 1982; Blomquist et al.,
1982). It has been estimated that about 8% of all mentally retarded males have this
disorder (Turner et al., 1980; Howard-Peebles et al., 1979). Because of the high
prevalence of Fragile-X syndrome, it has been suggested that a chromosome analysis
be performed in all males with unexplained mental retardation, as well as physically
normal females with mild mental retardation (Sutherland, 1979).
A comprehensive search of the medical literature on Klinefelter syndrome and
associated Fragile-X syndrome uncovered four such previously reported individuals
(Wilmont et al., 1980; Froster-Iskenius et al., 1982; Fryns et al., 1983, 1984). Three
had a karyotype 47,XXY as our patient, whereas one of the four had 46,XY/47,XXY
mosaicism (Fryns et al., 1983). Fryns et al. (1984) also observed the fragile site on
both X chromosomes, as we did in some of our proband's cells, which suggests that
maternal nondisjunction of the Fragile-X chromosome is the putative mechanisms for
the XXY karyotype in these probands. Froster-Iskenius et al. (1982) carried out
replication studies and found that in the majority of metaphases the fragile site was
observed in the early replicating X chromosome.
Two of the reports (Wilmont et ai, 1982; Froster-Iskenius et al., 1982) mentioned
that the degree of mental retardation in their patients with Klinefelter and Fragile-X
syndrome was less severe than usually observed in individuals with Fragile-X
syndrome. This, however, was not the case in this patient who is profoundly mentally
retarded. The testicular size is not provided in the reports on patients with the
combination of Klinefelter syndrome and Fragile-X syndrome. The size of our
78 5. M. Pueschel, M. M. O'Brien and T. Padre-Mendoza

patient's testes were between the testicular size usually noted in Klinefelter syndrome
and that in Fragile-X syndrome.
Whereas mentally retarded patients with macro-orchidism are suspect of having
Fragile-X syndrome, mentally retarded individuals with 'average'-sized testicles
should not be excluded from screening for Fragile-X syndrome as our experience
indicates. Moreover, since testicular enlargement in these patients is primarily
observed after puberty, appreciation of the full clinical expression may be delayed
until adolescence or adult life (Hagerman & McKenzie McBogg, 1983).
Another important consideration relates to the study of male residents in
institutions for persons with mental retardation. As demonstrated in this report, the
identification of Fragile-X syndrome in the proband during the screening process of a
large residential facility led to the investigation of the proband's family (Fig. 3).
Subsequently, the diagnosis of Fragile-X syndrome was made in the proband's two
nephews. The ascertainment of the two affected boys permitted early introduction of
special education services. Moreover, genetic counselling of other at-risk family
members was made possible. Hence, many family members may benefit from the
identification of patients with Fragile-X syndrome by screening mentally retarded
males in institutions.

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 Klinefelter syndrome and associated Fragile-X 79

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Received 6 May 1986; revised 2 July 1986