Curs nr.

7
Sindroame de anomalii congenitale multiple (ACM, malformaţii
congenitale)

Definiţie: o anomalie congenitală înseamnă orice defect de

formă, structură sau funcție, inițiat prenatal, indiferent de vârsta la
care a survenit debutul clinic sau când a fost precizat diagnosticul.

Clasificare
După cauze, anomaliile pot fi grupate în patru grupe :
1.Anomalii ale cromozomilor şi ale genelor
2.Anomalii cu cauze teratogene
3.Anomalii multifactoriale
4.Anomalii de cauze necunoscute
Terminologia defectelor morfologice

ţesut cu structura anormală prin formare greşită:

anencefalie, despicăturile de buză / palat, trisomie.
ţesut cu structura normală deformat de forţe externe:
picior strâmb, asimetrii faciale, artrogripoza.
ţesut cu structura normală distrusă: amputaţii în boală
amniotică.
defect cu importanţă cosmetică şi/sau
funcţională şi rata în populaţia generală din acelaşi grup rasial sub
4%.
: defect cu importanţă minimă cosmetică şi/sau
funcţională şi rata în populaţia generală sub 4%.
: defect minor cosmetic şi/sau funcţional cu rata
în populaţia generală mai mare de 4%.
defect morfologic unic care poate fi
malformaţie, deformaţie, distrucţie.
 asociere de anomalii produse în cascada de un defect în
morfogeneza timpurie: sindrom Pierre-Robin. Secvenţa poate fi
izolată sau în cadrul unei sindrom plurimalformativ.
combinaţie ≥ 2 anomalii, fără cauză specifică sau comună:
VATER, CHARGE.
≥ 1 anomalie de dezvoltare care interesează ≥ 2 sisteme,
cu etiologie unică specifică, genetică sau cromozomială: sindrom
Down.

Epidemiologie
 Incidenţa anomaliilor majore: 2% dintre nou-născuţii la
naştere; 5% dintre nou-născuţii cu revelaţie tardivă. Incidenţa
mai mare la avorturile spontane (majoritatea neviabile).
Reprezintă 9% din cauzele de mortalitate perinatală.
 Frecvenţa anomaliilor minore: 1 anomalie minoră: 12% dintre
nou-născuţi; 2 anomalii minore: 0,8% dintre nou-născuţi; ≥ 3
anomalii minore: 0,5% dintre nou-născuţi.
Etiologia anomaliilor majore
1. (o singură genă mutantă):
autozomal dominantă (majoritatea); autozomal recesivă
(mai rare); X-linkată (legată de sex) recesivă (rară); X – linkată
dominantă (excepţională).
!! Nu determină sindroame de anomalii congenitale multiple, dar intră
în diagnosticul diferențial al malformațiilor congenitale când
simptomatologia este prezentă la nou-născut: fibroza chistică (boală
autozomal recesivă) poate produce ileus meconial la fel ca boala
Hirschprung (megacolon congenital – malformație).
2.
a. Aberaţii numerice autozomale (trisomii: 21, 18, 13; monosomii),
sexuale (45 XO – Turner; 47XXY – Klinefelter)
b. Rupturi cromozomiale: deleţii, ruptură/rearanjare, translocaţie: ex.
sindrom cri-du-chat
Riscul de recurenţă este variabil: trisomie 21; nondisjuncţie: 1%;
translocaţie 21/21 maternă: 100%.
 3.
Cele mai frecvente defecte cu ereditate multifactorială sunt:
 anomalii unice majore: defecte tub neural, defecte cardiace
septale, despicătură de buză/palat, stenoza hipertrofică de
pilor, agenezie renală bilaterală, hipospadias, omfalocel,
megalocolon congenital
 deformaţii: picior varus-equin, luxaţie congenitale de şold
Incidenţa în populaţie generală 0,5 – 1 ‰.
- unele au predilecţie de sex: stenoza hipertrofică de pilor la
băieţi, luxaţie de şold la fete
- riscul de recurenţă: 3 – 5 % întotdeauna la rudele de gradul I;
creşte cu numărul de copii afectaţi: după un copil afectat este 4%,
după doi copii afectaţi este 8%.
4. Teratogenitatea

Diabetul zaharat. Incidenţa anomaliilor cardiace, renale, digestive,

osoase şi ale SNC, se ridică la peste 22% la copiii mamelor diabetice
insulino-dependente.
Fenilcetonuria maternă (PKU). Este o maladie genetică
caracterizată prin deficienţa hidroxilazei fenilalaninei, o enzimă
hepatică. Prin urmare are loc creşterea nivelului fenilalaninei în serul
matern, determinând şi creşterea nivelului în serul fetal. Efectele
nedorite (retard mental) ale acestei afecţiuni pot fi prevenite printr-
o dietă săracă în fenilalanină începută înaintea momentului
concepţiei.
Epilepsia este exemplul clasic al afecţiunii care atât prin ea însăşi
cât şi prin tratamentul specific creşte riscul anomaliilor la naştere.
Infecţiile. Expunerea la agenţii infecţioşi virali în timpul sarcinii este
recunoscută a fi o cauză majoră a apariţiei anomaliilor la naştere.

Alcoolism cronic sever (consum zilnic mai mare de 66 ml
alcool pur). Caracteristicile principale ale sindromului alcoolic fetal
cuprind deficienţe de creştere cu debut prenatal, întârziere de
dezvoltare, fante palpebrale scurte, o depresiune infra-nazală cu buza
superioară subţire, multiple anomalii ale articulaţiilor, malformaţii
cardiace.
5. Alţi factori de risc ce pot produce anomalii congenitale:
Factori uterini: oligohidramnios, constrângere uterină (fibrom, gemeni).
Radiaţiile: efecte controversate privind aberaţiile cromozomiale şi
riscul de cancer postnatal.

Momentul producerii anomaliilor şi tipul de defect în unele

malformaţii prin morfogeneza incompletă

Ţesut Anomalia Defect în

SNC Meningomielocel Închidere pol 28 zile
post. tub neural
SNC Anencefalie Închidere pol 26 zile
ant. tub neural
Faţa Despicatura buză Fuziune buză 36 zile
Faţa Despicatură palat Fuziune margini 10
săptămâni
Tub Atrezie de esofag Septare laterală 30 zile
digestiv intestin anterior
Tub Malrotaţia Rotaţia buclei 10
digestiv intestinului intestinului săptămâni
Organe Uter bicorn Fuziune porţiuni 10
genito- Inferioare ducte săptămâni
urinare mulleriene

Hipospadias Fuziune falduri 12

uretrale săptămâni
Inima DSV Închidere sept 9 –10
interventricular săptămâni
Membre Sindactilie severă Separare raze 6 săptămâni
digitale
Diagnosticul prenatal
Alfa fetoproteină maternă: test screening se face la 16-18 săptămâni
de gestaţie. Acest test nu poate fi interpretat după 22 săptămâni vârstă
de gestaţie.
Ecografia: poate detecta anomaliile fătului, ale placentei, lichidului
amniotic şi uterului şi poate monitoriza modificările anatomice,
creşterea prin măsurători în serie.
Amniocenteza: Se recomandă a se efectua la 16-20 săptămâni de
gestaţie. Indicaţii:
 gravidele în vârstă
 anticiparea unui făt cu sindrom Down
 anticiparea unui făt cu defect neural
 ambii părinţi sunt cunoscuţi ca purtători heterozigoţi pentru o
anomalie autosomal recesivă
 mama este putătoare pentru mutația unei anomalii recesive X-
linkată
 pacienta sau partenerul ei prezintă translocaţie cromozomială
  creşterea sau scăderea alfa fetoproteinei la VG 16-18
săptămâni.

Evaluarea nou-născutului malformat

Anamneza:
 sarcina (complicaţii, îmbolnăviri, medicaţie, teratogeni – alcool,
fumat);
 anamneza familială (căsătorii, fratrie, descendenţi,
consangvinitate, malformaţii la alţi membri de familie, vârsta
mamei şi tatălui, născuţi morţi, avorturi) – pedigree-ul trebuie
să conţină bunici, părinţi, fraţi, mătuşi, unchi, veri.
Examenul fizic. Scopul este recunoaşterea semnelor caracteristice
unor anomalii pentru un diagnostic.
 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.