Congenital malformations - Edocr

18 PART I GENERAL CONSIDERATIONS
In patients with several of the cardinal features
of the disorder, identification of a CHD7 mutation
provides a definitive diagnosis and allows
for appropriate anticipatory guidance and genetic
counseling to families that would be much
more difficult otherwise.
Biochemical Testing
Biochemical testing may be helpful in evaluating
infants with specific malformations or patterns of
malformations but, like molecular testing, needs
to be targeted to a specific diagnosis. There are
a few inherited metabolic disorders that produce
malformations in multiple organ systems as a
result of far-reaching metabolic effects on early
fetal development. An excellent example of this
is the Smith-Lemli-Opitz syndrome which represents
a defect in cholesterol biosynthesis and is
associated with low levels of total serum cholesterol
and marked elevations of the cholesterol
precursor 7-dehydrocholesterol. In its severe
form, this disorder is associated with dysmorphic
facial features, cleft palate, syndactyly, polydactyly,
genital anomalies, and mental retardation.
Another example is Zellweger syndrome,
associated with multiple peroxisomal enzyme
deficiencies as a result of a defect in peroxisomal
assembly. Patients with this disorder have a characteristic
pattern of multiple minor dysmorphic
features including a large fontanel, tall forehead,
epicanthal folds, Brushfield spots, anteverted
nares, excess skin folds on the nape of the neck,
simian creases, and camptodactyly. Cardiac septal
defects may be present and there is always
profound hypotonia. Because many of the findings
superficially resemble those seen in Down
syndrome, the latter disorder may be initially considered.
Other inborn errors of metabolism that
are more typically associated with a “metabolic
presentation” are known to be linked to specific
congenital malformations, reflecting the effect of
the metabolic derangement in utero. An example
of this is the fact that approximately 40% of infants
with nonketotic hyperglycinemia, who typically
present with a neonatal encephalopathy, are also
found to have agenesis of the corpus callosum.
Infants with pyruvate dehydrogenase or other
disorders associated with congenital lactic acidosis
often have dysmorphic facial features resembling
those observed in association with fetal alcohol
syndrome. Patients with the severe form of
glutaric aciduria type II, while presenting with
severe metabolic acidosis, hypoglycemia, and
hyperammonemia, also often exhibit dysmorphic
features including hypospadias, cystic kidneys,
and abnormal facial features. The setting of hydrops
fetalis is another circumstance in which
biochemical testing can be helpful. While there
are many nongenetic causes of hydrops, the differential
diagnosis of nonimmune hydrops includes
both multiple malformation syndromes
such as chromosomal abnormalities and Noonan
syndrome and storage disorders such as infantile
Gaucher disease, congenital disorders of glycosylation,
GM1 gangliosidosis, sialidosis, and mucolipidosis
II (I-cell disease), among others.
Follow-up
In some cases in which an infant is identified as
having multiple congenital malformations, a specific
diagnosis cannot be established in the immediate
neonatal period despite appropriate clinical
evaluation and testing. In these cases, follow-up
should be arranged with a clinical geneticist. It
may be possible to establish a diagnosis at a later
time as more information comes to light through
followup of the infant’s growth and development
and medical progress. The appearance of a normal
child changes very significantly over time and
the same is true of the dysmorphic features associated
with many malformation syndromes. A diagnosis
that was not recognizable in a newborn
may become apparent in an older infant or toddler.
Follow-up is equally important for children
with an established diagnosis of a genetic disorder
or birth defect syndrome since there are often
associated medical concerns for which periodic
surveillance is important. For some disorders,