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Lecture no.

Common Multiple Congenital Anomaly (MCA)


An MCA syndrome can be defined as multiple primary defects (eg,

malformation, anomaly) in different geographic but not necessarily different
embryologic body areas. Multiple anomalies can sometimes occur within a
geographic/embryologic field such as the midline as in holoprosencephaly, in
which hypotelorism and cleft lip/palate often occur in association with the
midline brain defect.
Subtle anomalies are no less important diagnostically and often require
close scrutiny of the parents' and siblings' features.
Only a few MCA syndromes are life-threatening in the neonatal period.
It is important to note, however, that malformations are the most common
cause of death at this critical point in the life span.

I. Clinical presentation. Table 4-1 lists symptoms and signs that

should alert the clinician to the possibility of cryptogenic malformations or
disorders. Obviously, if overt malformations are present, an MCA syndrome
will be immediately recognized and diagnostic efforts will shortly follow.
However, if external features of the disorder are subtle or nonspecific and
the usual procedures associated with intensive newborn support have been
started, findings may go unrecognized early.
Each manifestation listed in Table 4-1 is more common in infants with
MCA syndromes. Table 4-2 list the more common neonatal MCA syndromes,
many of which share some of the features set forth in Table 4-1.


Decreased or unusual fetal activity
Abnormal fetal problem/position
Abnormalities of size: SGA or LGA, microcephaly or macrocephaly,
large or irregular abdomen, small chest, limb-trunk disproportion, asymmetry
Abnormalities of tone: hypotonia, hypertonia
Abnormalities of position: joint contractures, fixation of joints in
extension, hyperextension of joints
Midline aberrations: hemangiomas, hair tufts, dimples or pits
Problems of secretion, excretion, or edema: no urination, no passage of
meconium, chronic nasal or oral secretions, edema (nuchal, pedal,
generalized, ascites)
Symptoms: unexplained seizures, resistant or unexplained respiratory
Metabolic disorders: resistant hypoglycemia, unexplained hypo- or
hypercalcemia, polycythemia, hyponatremia, thrombocytopenia
TABLE 7-2.
Trisomy 21 (Down syndrome)
Trisomy 18 (Edwards' syndrome)
Trisomy 13 (Patau's syndrome)
45,X (Turner's syndrome)
Potter's oligohydramnios sequence
Amniotic band syndrome
Pierre Robin sequence
VATER association
CHARGE association
Beckwith's syndrome
Fetal alcohol syndrome
Infant of a diabetic mother
Infectious diseases

II. General approach to diagnosis. Early and accurate

documentation of physical characteristics, including photographs, is
essential. If the infant is critically ill, confirmatory tests (chromosome studies,
renal or brain ultrasonography, brain computed tomography/magnetic
resonance imaging [CT/MRI] scan, or echocardiography) become a priority
equal in importance to ongoing therapy.
The basis of diagnosis of MCA syndromes in the neonate is knowing
which disorders are most common plus documenting the physical
manifestations and appropriate exclusion tests such as chromosomal
analysis. Diagnostic problems also occur because immediate efforts tend to
emphasize therapy. Nevertheless, diagnosis will often facilitate or guide
therapy in a more efficient manner. If clinical geneticists or dysmorphologists
are locally available, they should be asked to examine the infant as soon as
possible after delivery.

III. Chromosomal syndromes. Chromosomal syndromes are by far

the most common MCA syndromes diagnosed in the neonatal period.
A. Trisomy 21 (Down syndrome)
1. Incidence. Trisomy 21 is by far the most common MCA syndrome,
occurring in about 1 in 600 live births. Only ~80% of cases are diagnosed
accurately in the newborn nursery, which means that there is a 20% rate of
diagnostic error for this most common cause of MCA and mental retardation.
The reason for missing the diagnosis is probably that most of the features of
trisomy 21 may occur as isolated features in otherwise normal infants.
2. Physical findings. Findings include hypotonia, upward eye slant,
epicanthus, hypotelorism, a tendency to protrude the tongue, Brushfield's
spots, a single transverse palmar crease, redundant nape of neck skin, and
short, incurved fifth fingers. Although each of these features may occur in
normal individuals, it is the combination of features forming a recognizable
pattern that usually permits early diagnosis.
3. Associated anomalies include congenital heart defects, particularly
of the atrioventricular canal, and increased frequency of duodenal atresia,
esophageal atresia, and imperforate anus. Patients may have many
immediate medical problems because of these anomalies.
4. Hypotonia may be associated with breathing difficulties, poor
swallowing, and aspiration.

B. Trisomy 18 (Edwards' syndrome)

1. Incidence. About 1 in 5000 live births.
2. Morbidity. Highly lethal within the first 3 months of life. 10% survive
the first year.
3. Physical findings. Manifested by prenatal and postnatal growth
deficiency, micrognathia, overlapping digits, congenital heart disease (95%
incidence, usually complex), abnormal ears, short sternum, ptosis, rocker-
bottom clubfeet, and generalized hypertonicity.
4. Other anomalies of 10% frequency include tracheoesophageal fistula
or esophageal atresia, hemivertebra, radial hypoplasia or aplasia,
omphalocele, and spina bifida.
C. Trisomy 13 (Patau's syndrome)
1. Incidence. About 1 in 7000 live births.
2. Morbidity. Highly lethal within the first 3 months of life. Survival
beyond the first year is rare.
3. Physical findings. Manifested by cleft lip and palate, polydactyly,
scalp cutis aplasia, a bulbous nose, microphthalmos, and congenital heart
disease (95% frequency, usually complex).
4. Other anomalies include cystic kidneys, hooked penis (in males),
midline cleft lip with holoprosencephaly, and rocker-bottom clubfeet.

D. 45,X (Turner's) syndrome

1. Incidence. About 1 in 2000 live-born females.
2. Morbidity. The 45,X syndrome is usually compatible with survival if
the child reaches term. Ninety-five percent of conceptions are miscarried or
3. Physical findings. Neck webbing, pedal and nuchal edema, shield
chest, coarctation of the aorta, and short stature are the hallmarks of this
IV. Nonchromosomal syndromes

A. Oligohydramnios sequence (Potter's oligohydramnios

1. Incidence. This syndrome is the second most common MCA (1 in
4000 live births). Most cases are nonsyndromic and have a 2-7% recurrence
risk, depending on the specific urinary tract defect. Some may be associated
with the prune-belly syndrome (absent abdominal musculature, urinary tract
abnormalities, and cryptorchidism) if the kidneys were hydronephrotic early
in gestation and later decompress, leaving a wrinkled abdomen and the
effects of oligohydramnios (pulmonary hypoplasia and Potter's sequence).
About 5% of cases are part of an MCA syndrome with primary defects outside
the urinary system.
2. Morbidity. Almost all of these infants die.
3. Pathophysiology. Renal agenesis leads to decreased production of
amniotic fluid (oligohydramnios). Deficient amniotic fluid is believed to be
responsible for associated pulmonary hypoplasia.
4. Clinical presentation
a. History. The history of oligohydramnios must be solicited from the
obstetrician. Anuria is typically present in the newborn.
b. Placental examination. The placenta must be examined for
yellowish plaques (amnion nodosum).
c. Physical findings. Unexplained and highly refractory respiratory
distress coupled with pneumothoraces, clubfeet, hyperextensible
fingers, large cartilage-deficient ears, lower inner eye folds, and a
beak nose are classic manifestations associated with prolonged and
severe oligohydramnios.
5. Diagnosis is usually confirmed by renal ultrasonography and autopsy
disclosure of the urinary tract abnormality. It is advisable to perform
chromosome studies on the propositus to exclude a chromosomal basis for
the disorder. The recurrence risk depends on the specific syndrome
diagnosis. Parents should have renal ultrasonograms. Future pregnancies
should be monitored by ultrasonography unless the risk of recurrence is
definitely ruled out.

B. Amniotic band syndrome

1. Incidence. About 1 in 2000 to 1 in 4000 live births. Because in some
newborns many body areas are involved and because the bands dissipate
before delivery in 90% of cases, the diagnosis is often missed or a
misdiagnosis is made.
2. Pathophysiology. This syndrome is poorly understood, but the effects
of early amnion rupture with entanglement of body parts in bands or strands
of amnion are well appreciated. The resulting biomechanical forces can
cause deformities of the limbs, digits, and craniofacies. Viscera that are
normally outside the fetus in early embryonic development may be hindered
in their return, giving rise to omphalocele and other anomalies.
3. Physical findings
a. Extremities. Limb and digit amputations, constrictions, and distal
b. Craniofacies. Facial clefts and encephaloceles.
c. Viscera. Omphalocele, gastroschisis, and ectopia cordis.
4. Placental examination. It is always important to examine the
placenta, but especially so in these cases. The amnion is often small, absent,
or rolled into strands. Not all amniotic bands cause intrauterine problems.
Ultrasound studies of routine pregnancies have identified amniotic bands
that were not attached to the fetus. Follow-up of these pregnancies has
revealed normal newborns.
5. Management. Surgical removal of the constricting band and plastic
surgical reconstruction should be done if possible.

C. Pierre Robin sequence

1. Incidence. About 1 in 8000 live births.
2. Pathophysiology. The basis of this sequence is severe hypoplasia of
the mandible, which does not support the tongue. The accompanying
glossoptosis results in severe upper airway obstruction and early intrauterine
cleft palate.
3. Clinical presentation. These infants have a short jaw (micrognathia)
or receding chin associated with cleft palate. Respiratory distress secondary
to upper airway obstruction may occur. Low-set ears are also present.
4. Management. Positioning the infant in the prone position with the
head lower than the rest of the body works in mild cases. Obturators made
from a cast of the palate work in mild to severe cases when the infant
accepts the apparatus. Intubation, tracheostomy, and suturing of the tongue
tip to the lower gingiva are effective temporary measures for glossoptosis
when nothing else works. As the mandible grows out, the glossoptosis
eventually will resolve. Oral feedings may result in choking or respiratory
distress, and gavage feedings or gastrostomy tube feedings may be needed.
Most cases of Pierre Robin sequence are nonsyndromic and have little or no
recurrence risk.

V. Miscellaneous syndromes

A. VATER association
1. Incidence. About 1 in 5000 live births.
2. Clinical presentation. Major features include vertebral anomalies,
anal atresia, tracheoesophageal fistula, esophageal atresia, and radial
defects. The V in VATER can also represent vascular (cardiac) defects and the
R, renal defects, because these two areas are also commonly involved. The
presence of additional features, except for atresia of the small intestine and
occasional hydrocephalus, rules out a diagnosis of VATER association. This
nonrandom association is usually not of genetic origin and requires exclusion
of other similar disorders, including chromosomal syndromes.

B. CHARGE association
1. Incidence. Although it does not occur as frequently as the VATER
association, the CHARGE (coloboma, heart disease, choanal atresia, retarded
growth and development with or without CNS anomalies, genital anomalies
with or without hypogonadism, ear abnormalities or deafness) association is
common, occurring in 1 in 10,000 to 1 in 15,000 live-born infants. CHARGE
often presents as a medical emergency because about half of the patients
have choanal atresia, serious heart defects, and swallowing difficulties.
2. Clinical presentation
a. Choanal atresia. The infant may present with unexplained
respiratory distress. The posterior nares can be blocked unilaterally or
bilaterally as well as being stenotic.
b. Associated anomalies. Patients with CHARGE association also have
heart defects, small ears, retinal colobomas, and cleft lip and palate; males
have micropenis. A smaller percentage have unilateral facial palsies and
swallowing difficulties, the latter potentially as lethal as choanal atresia.
Postnatal growth deficiency and psychomotor delay round out the major
features of this nonrandom and nongenetic association.
3. Diagnosis. Any newborn with unexplained breathing difficulties
should have nasogastric tubes passed through its nasal passages,
particularly if there are multiple congenital anomalies. Exclusion of other
similar entities and chromosomal disorders is essential before the diagnosis
of CHARGE association can be accepted.

C. Beckwith's syndrome
1. Clinical presentation
a. Physical findings typically include LGA (large for gestational age)
infants with macroglossia and omphalocele, but ~20% of patients have only
one or neither of these features. Unilateral limb hypertrophy may also be
b. Laboratory findings. Refractory hypoglycemia is frequently present
regardless of the presence of external features and should immediately raise
the possibility of Beckwith's syndrome.
2. Management. Making the diagnosis early in the postnatal period and
immediate institution of aggressive hypoglycemic therapy may prevent
mental retardation.

VI. Teratogenic malformations

A. Fetal alcohol syndrome (FAS) may be suspected on the basis

of the phenotype alone (short palpebral fissures; epicanthal folds; a flat nasal
bridge; a long, simple philtrum; a thin upper lip; and small, hypoplastic nails)
or may present only as a small for gestational age infant. It may also present
with microcephaly. FAS also has an increased association with congenital
heart defects. A thorough history of maternal drug intake is important to rule
out a teratogenic cause of multiple anomalies and mental retardation.

B. Infants of diabetic mothers (IDMs)

1. Incidence. These infants are at 3 times the risk for malformations
compared with the offspring of nondiabetic mothers. IDMs present with
anomalies in ~1 in 2000 consecutive deliveries.
2. Clinical presentation. The well-known malformations are sacral
agenesis, femoral hypoplasia, heart defects, and cleft palate. Others include
preaxial radial defects, microtia, cleft lip, microphthalmos,
holoprosencephaly, microcephaly, anencephaly, spina bifida, hemivertebra,
urinary tract defects, and hallucal polydactyly. Some IDMs have many
anomalies, which may not be recognized as related to maternal diabetes.
Improved diabetic control during gestation dramatically reduces the
incidence of IDM-related malformations but does not reduce it back to

C. Infectious (prenatal) diseases such as rubella,

cytomegalovirus, and toxoplasmosis can cause anomalies such as
microcephaly, hydro-/macrocephaly, cataracts, microphthalmia, and heart
defects. These defects can be confused by single gene or chromosome
abnormalities. Any neonate who has these features with no obvious cause
should have TORCH studies and a brain scan.

VII. Genetic counseling for MCA syndromes is complex and

requires a great deal of sensitivity. First, it is important to have a secure
diagnosis, if one is possible. The next step is to establish the parents'
understanding of the entire situation and what they have been told by other
professionals. Recurrence risk figures and the availability of prenatal
diagnosis for subsequent pregnancies are mandatory areas to cover.

1. What is the most common MCA syndrome?

2. What signs and symptoms association suggests Down syndrome in


3. What MCA syndrome is only found in female infants?

4. What MCA syndrome presents with respiratory distress that is

relieved when the infant is placed in prone position?

5. What MCA syndromes can often present with omphalocele?

6. What association includes choanal atresia?

Answers to questions

1. Trisomy 21

2. Hypotonia, upward eye slant, epicanthus, hypotelorism, a tendency

to protrude the tongue, single transverse palmar crease.

3. Turners syndrome.

4. Pierre-Robin sequence.

5. Trisomy 18, amniotic band syndrome, Beckwiths syndrome.

6. CHARGE association.