Second edition

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Other associated disorders include Hashimoto’s thyroiditis,
acute myeloid leukemia, diabetes mellitus, chronic
obstructive pulmonary disease, and breast cancer.
Pre-pubertally, hormone levels are generally within
normal limits, but after puberty, abnormalities become
apparent with a low testosterone level and an elevated
follicle-stimulating hormone level.
Karyotyping will reveal one or more extra X chromosomes.
Course
The evolution of the clinical picture is usually complete by
adult years.
Etiology
Klinefelter’s syndrome occurs secondary to non-disjunction
during either spermatogenesis or oogenesis, resulting in the
presence of one or more extra X chromosomes. The most
common karyotype is 47,XXY; in about 10 percent of
cases, mosaicism is present, with a 46,XY/47,XXY karyotype.
Rarely, more severe abnormalities may occur, yielding
karyotypes such as 48,XXXY or 49,XXXXY.
Although much of the symptomatology of Klinefelter’s
syndrome can be explained on the basis of primary hypogonadism
secondary to a progressive fibrosis of the testes,
it is clear that hypogonadism alone is not sufficient to
explain all of the neuropsychiatric features of the disorder,
such as mental retardation (Pasqualini et al. 1957;
Wakeling 1972). Recent MRI studies have indicated a mild
global cerebral atrophy (Giedd et al. 2007; Itti et al. 2006);
however, the mechanism underlying this is not certain.
Differential diagnosis
When fully expressed, the clinical picture in adults is distinctive.
Diagnostic difficulties may arise in partial cases,
and the correct diagnosis may be revealed only incidentally
during a work-up for infertility or erectile dysfunction.
Treatment
Testosterone treatment improves libido and erectile function,
and tends to help with energy and overall outlook (Nielsen
et al. 1988); infertility, however, persists. Gynecomastia may
require surgical correction. Developmental disabilities and
mental retardation are treated in the usual fashion.
9.6 FRAGILE X SYNDROME
The fragile X syndrome is one of the most common causes
of mental retardation in developed countries. Although the
9.6 Fragile X syndrome 409
classic picture of mental retardation with a characteristic
facial dysmorphism is far more common and severe in
males, females may also be affected.
Clinical features
The classic syndrome (Baumgardner et al. 1995; Finelli et al.
1985; Wisniewski et al. 1985c), as noted, is most evident in
males and is characterized by mental retardation, a characteristic
dysmorphic facies, and macro-orchidism. Mental
retardation ranges from mild to severe. Autistic features,
such as gaze avoidance, are present in most cases, and a
minority will have the full syndrome of autism; ADHD is also
seen in a minority. Dysmorphic features include a long, narrow
face, prognathism, a high forehead, and large ears (De
Arce and Kearns 1984). Macro-orchidism is a constant
feature in post-pubertal males and may also be seen in a
minority during childhood (Chudley and Hagerman 1987;
De Arce and Kearns 1984). Seizures, either complex partial
or grand mal, occur in a significant minority (Finelli et al.
1985; Musumeci et al. 1999; Sabaratnam et al. 2001;
Wisniewski et al. 1985c). Other features include hyperextensible
joints and mitral valve prolapse (Chudley and
Hagerman 1987), and in a minority there may also be hyperreflexia
and Babinski signs (Finelli et al. 1985). Incomplete
penetrance may occur in males, and some may be of normal
intelligence; in these cases, however, elements of developmental
dysphasia, with both receptive and expressive deficits,
are common, and most post-pubertal males will also have
macro-orchidism.
Females with the fragile X syndrome tend to have much
milder cases. Mental retardation is seen in only about 50
percent and tends to be of mild degree; facial dysmorphism
is seen in only a small minority.
Genetic testing is available.
Course
Although there is some evidence that, in males, intellectual
functioning may undergo a decline in late childhood or
early adolescence (Dykens et al. 1989), it appears that, for
the most part, the clinical picture becomes set in adolescence
and generally remains stable thereafter.
Etiology
The fragile X syndrome occurs secondary to mutations in the
FMR1 gene on the long arm of the X chromosome (Verkerk
et al. 1991), which codes for a protein known as the fragile X
mental retardation-1 protein (FMRP). This gene normally
contains a sequence of CGG trinucleotide repeats containing
anywhere from 5 to 55 triplets. An expansion of this
sequence to include from 55 to 200 repeats is known as a premutation,
whereas expansions to over 200 triplets constitute