Second edition

09.qxd 3/10/08 9:39 AM Page 410
410 Congenital, developmental, and other childhood-onset disorders
full mutations. Patients with pre-mutations do not develop
the fragile X syndrome; however, those with full mutations
do. In those with full mutations, transcription of the gene
fails and levels of functional FMRP are low or undetectable.
The relatively minor symptomatology seen in females is due
to random inactivation of the X chromosome, which allows
for some production of FMRP. The fragile X syndrome
derives its name from the fact that when the cells of patients
are cultivated in a medium deficient in thymidine and folic
acid, a fragile site will be found on the long arm of the X chromosome
(Sutherland 1977), which, as might be expected,
corresponds to the location of the expanded CGG repeat.
Interestingly, although both female and male parents with
a premutation may pass a full mutation to their children, this
is far more commonly the case with female parents. The reason
for this is that expansion of a pre-mutation to a full
mutation occurs readily during oogenesis but only rarely
during spermatogenesis.
Magnetic resonance imaging studies have revealed
hypertrophy of the hippocampus with atrophy of the superior
temporal gyrus (Reiss et al. 1994) and atrophy of the
cerebellar vermis (Mostofsky et al. 1998). Autopsy studies
have demonstrated that, although neuronal cell counts are
normal in the cortex, dendritic spines are long and tortuous
in shape (Hinton et al. 1991; Rudelli et al. 1985).
Differential diagnosis
The full clinical syndrome of mental retardation, with or
without autism, and the characteristic facial dysmorphism
(with, in males, macro-orchidism) is distinctive.
Mention should also be made of a condition known as
FXTAS, or fragile X-associated tremor/ataxia syndrome. As
noted earlier, patients with pre-mutations do not develop the
fragile X syndrome. This is not to say, however, that the premutation
is benign, given that those who carry this premutation
are at high risk for developing FXTAS in middle or later
years, with tremor, ataxia, and, in a minority, dementia.
Treatment
The general treatment of mental retardation, autism, and
ADHD is discussed in Sections 5.5, 9.14, and 9.15 respectively.
Importantly, fragile X patients with ADHD respond
well to methylphenidate (Hagerman et al. 1988).
9.7 VELOCARDIOFACIAL SYNDROME
The velocardiofacial syndrome, also known as the 22q11.2
deletion syndrome, is an inherited disorder characterized
by facial dysmorphism, intellectual deficits, and a number
of neuropsychiatric syndromes, most notably a psychosis
phenotypically similar to schizophrenia. First described in
1978 by Shprintzen et al., this disorder is now recognized as
the most common of the microdeletion syndromes, being
found in up to 1 in 4000 live births.
Clinical features
The facial dysmorphism is characterized by hypertelorism,
a large, bulbous nose with a squared-off nasal root, and
micrognathia. Most patients have a degree of velopharyngeal
insufficiency, leading to a hypernasal voice.
About 50 percent of patients suffer from either borderline
intellectual functioning or mental retardation, which is generally
of mild degree (Swillen et al. 1997); perhaps one-fifth
of all patients will also have symptomatology similar to that
seen in ADHD, with varying mixtures of hyperactivity,
impulsiveness, and inattentiveness. Autism has been noted
in a small minority (Fine et al. 2005).
As these patients pass through adolescence into adult
years, up to one-third will develop a psychosis phenotypically
similar to that seen in schizophrenia (Bassett et al.
2003; Gothelf et al. 2007; Murphy et al. 1999), with delusions
and hallucinations. Mood disturbances may also
occur and may be more frequent than psychosis: both
manic or hypomanic episodes (Papolos et al. 1996) and
depressive episodes (Murphy et al. 1999) may occur.
Obsessions and compulsions have also been noted in
roughly one-third of teenagers (Gothelf et al. 2004).
Other clinical features include cardiac defects, hypocalcemia
secondary to hypoparathyroidism, and, in a small
minority, seizures (Kao et al. 2004).
Course
The course is chronic; although some die of cardiac complications,
most live a normal lifespan.
Etiology
This syndrome occurs secondary to a microdeletion at
22q11.2 and is inherited in an autosomal dominant fashion
with variable penetrance (McDonald-McGinn et al. 2001).
Magnetic resonance imaging studies (van Amelsvoort et al.
2004; Bish et al. 2004, Campbell et al. 2006, Eliez et al. 2000,
Kates et al. 2006; Schaer et al. 2006) have revealed atrophy
of the cerebral cortex and white matter, with reduced gyrification
of the cortex; enlargement of the right caudate;
enlargement of the amygdalae; and atrophy of the thalamus.
In the cerebellum, atrophy of the cortex and white
matter is also seen.
Differential diagnosis
In adults, velocardiofacial syndrome must be distinguished
from schizophrenia, bipolar disorder, major
depression, obsessive–compulsive disorder, and ADHD.