Lecture no.

Common Multiple Congenital Anomaly (MCA) Syndromes

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 7-1 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 7-2 list the more common neonatal MCA syndromes, many of which share some of the
features set forth in Table 7-1.

TABLE 7-1. SYMPTOMS AND SIGNS IN NEONATES THAT MIGHT INDICATE CRYPTOGENIC
MULTIPLE CONGENITAL ANOMALY SYNDROME
 Prenatal
Oligohydramnios
Polyhydramnios
Decreased or unusual fetal activity
Abnormal fetal problem/position
 Postnatal
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 distress
 Metabolic disorders: resistant hypoglycemia, unexplained hypo- or hypercalcemia,
polycythemia, hyponatremia, thrombocytopenia
TABLE 7-2.
→ THE MOST COMMON CHROMOSOME DISORDERS DIAGNOSED IN THE
NEONATAL PERIOD
Trisomy 21 (Down syndrome)
Trisomy 18 (Edwards' syndrome)
Trisomy 13 (Patau's syndrome)
45,X (Turner's syndrome)
→ THE MOST COMMON NONCHROMOSOMAL DEFORMATION OR DISRUPTION
SEQUENCES DIAGNOSED IN THE NEONATAL PERIOD
Potter's oligohydramnios sequence
Amniotic band syndrome
Pierre Robin sequence
→ OTHER MCA SYNDROMES OF SPECIAL INTEREST IN THE NEONATE
VATER association
CHARGE association
Beckwith's syndrome
→ TERATOGENIC SYNDROMES COMMONLY SEEN IN NEONATES
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 stillborn.
3. Physical findings. Neck webbing, pedal and nuchal edema, shield chest, coarctation of
the aorta, and short stature are the hallmarks of this disorder.
 IV. Nonchromosomal syndromes

A. Oligohydramnios sequence (Potter's oligohydramnios sequence)

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 swellings.
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 seen.
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 baseline.
 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.

Questions

1. What is the most common MCA syndrome?

2. What signs and symptoms association suggests Down syndrome in neonates?

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. Turner’s syndrome.

4. Pierre-Robin sequence.

5. Trisomy 18, amniotic band syndrome, Beckwith’s syndrome.

6. CHARGE association.