Congenital Anomalies/Dysmorphology

Question 1

What are the clinical goals of dysmorphology?

Answer 1

accurately diagnose a child with a birth defect
suggest further diagnostic evaluation
give prognostic information about the range of outcomes that can be expected
develop a plan to manage expected complications
provide family with an understanding of the causation
give recurrence risk to parents and other relatives

Question 2

Describe major anomalies and provide examples.

Answer 2

anomalies of medical, surgical, or cosmetic significance

eg. CHD, cleft palate, ectopia cordis

Question 3

Describe minor anomalies and provide examples.

Answer 3

anomalies of little to no known medical significance

eg. skin tags, single transverse palmar crease, overlapping toes, clinodactyly

Question 4

What causes congenital anomalies?

Answer 4

genetic (eg. HOXD13 mutations affect homeobox gene which causes a combo of syndactyly and polydactyly) and/or environmental factors (eg. exposure to retinoic acid can cause anomalies such as microtia and CNS defects, including polymicrogyria and hydrocephalus)

Question 5

What are the three main categories of congenital anomalies?

Answer 5

malformations
deformations
disruptions

Question 6

Define malformations and provide examples.

Answer 6

due to an intrinsically abnormal developmental process
occur during the formation of a structure (complete or partial absence, alterations of normal configuration)
eg. holoprosencephaly, CHD, neural tube defects (sometimes), cleft lip

Question 7

Define deformations and provide examples.

Answer 7

due to extrinsic forces impinging physically on the fetus during development
due to mechanical forces that mold part of the fetus over a prolonged period of time
especially common in the second trimester
often involves musculoskeletal system
most present at birth and resolve spontaneously or can be treated with external fixation devices
Eg. clubfoot, congenital hip dislocation, plagiocephaly, dolichocephaly

Question 8

What is dolichocephaly?

Answer 8

deformation of the head most commonly due to intrauterine breech position

Question 9

Define disruptions and provide examples.

Answer 9

results from destruction or irreplaceable normal fetal tissue
morphological alterations of structures after formation
low recurrence risk
Eg. vascular accidents leading to bone atresias or amniotic band disruption –> limb defects

Question 10

What factors increase risk for fetal constraint?

Answer 10

Maternal (primagravida, small maternal size, small uterus, uterine malformation, uterine fibromata, small maternal pelvis)
Fetal (oligohydramnios, large fetus, multiple gestations)

Question 11

Define dysplasia and provide examples.

Answer 11

abnormal tissue organization (microscopic structure)

Eg. abnormal bone growth –> skeletal dysplasias, abnormal growth of connective tissue –> ectodermal dysplasia

Question 12

What is Achondroplasia?

Answer 12

caused by AD mutations in the FGFR gene
results in short stature, rhizomelic shortening of limbs, macrocephally, and characteristic facial features (frontal bossing, midface retrusion)
about 80% are de novo

Question 13

Define association and provide examples.

Answer 13

non-random occurance of several morphological defects not identified as a sequence or syndrome
in general, the etiology is not defined
Eg. VACTERL association

Question 14

What is VACTERL association?

Answer 14

Vertebral (misshapen vertebrae, fused vertebrae, and extra/missing vertebrae), Anal anomalies (anal atresia), Cardiac, Tracheo-Esophageal fistula, Renal anomalies, Limb anomalies (poorly developed/missing thumbs, underdeveloped forearms and hands)
mostly sporatic, etiology unclear but may have both genetic and environmental factors

Question 15

Define sequence and provide examples.

Answer 15

a pattern of anomalies in which a single known defect in development causes a cascade of subsequent abnormalities
can be part of a syndrome or isolated event
Eg. Potter Sequence, Pierre Robin Sequence

Question 16

What is Potter Sequence?

Answer 16

caused by oligohydramnios secondary to renal agenesis or other renal anomalies that reduce urine output production
decrease volume of amniotic fluid restricts fetal movements causing characteristic features of flat facies, depression of nasal tip, abnormal ear folding, wrinkled skin, and malposition of the feet (including clubfoot deformities)

Question 17

What is Pierre Robin Sequence?

Answer 17

primary anomaly is micrognathia –> superior displacement of tongue –> failure of palatal shelves to close –> “U” shaped cleft with glossoptosis

Question 18

Define syndrome and give exampels.

Answer 18

a group of anomalies occurring together with a specific common etiology: genetic (chromosomal or single gene), environmental (alcohol), or complex (1+ genetic and/or environmental factor)
eg. CHARGE syndrome

Question 19

What is CHARGE syndrome?

Answer 19

Coloboma, Heart defects, choanal Atresia, Retarded growth and development, Genital abnormalities, Ear anomalies
many other symptoms
clinical diagnosis requires 4 major symptoms, or 3 major and 3 minor symptoms
major symptoms are coloboma, choanal atresia, cranial nerve dysfunction, and characteristic ear

Question 20

Name the categories of genes that are known to be associated with malformation syndromes or isolated anomalies.

Answer 20

transcription factors (34%)
enzymes (19%)
structural proteins (18%)
receptors (9%)
tumor suppressor (5%)

Question 21

Define teratogen and provide examples.

Answer 21

a drug that alters normal fetal formation
~4-6% of birth defects are due to exposure to teratogens in the environment
includes maternal illness and infection
response to teratogens is highly individual
Eg. TORCH (Toxoplasmosis, Other [syphilis, varicella zoster, parovirus B19], Rubella, CMV, Herpes), physical agents (radiation/heat exposure), drugs and chemical agents

Question 22

What influences teratogen response?

Answer 22

maternal genotype
fetal genotype
dose
route
time of exposure

Question 23

What is Maternal DM?

Answer 23

risk for congenital malformations related to the severity of the disease
women with Insulin-dependent DM OR uncontrolled non-insulin dependent DM have 2-3X incidence of congenital anomalies
increased risk of macrosomia with shoulder dystocia, clavicular fractures, or Erb’s palsy (often 10lb + babies)
increased risk for pregnancy and newborn complications
increased risk from malformations (ureter duplex, situs inversus, CNS defects/caudal regression)

Question 24

What is Maternal PKU?

Answer 24

associated with microcephaly, ID, and CHD

androgen producing tumors or adrenal glands or ovaries can cause virilization of female fetus

Question 25

What is thalidomide?

Answer 25

antinausea and sleeping aid (no longer used)

caused amelia and meromelia (total or partial absence of extremities), intestinal atresia, cardiac abnormalities

Question 26

What is Fetal Alcohol syndrome?

Answer 26

most common major teratogen to which a fetus is likely exposed
1st trimester –> facial dysmorphisms
2nd half of pregnancy –> growth defects
causes growth retardation, microcephaly, mild ID, short palpebral fissures, short nose, smooth philtrum, thin upper lip, small distal phalanges, hypoplastic finger nails, and cardiac defects (VSD most common)

Question 27

What is Fetal Anticonvulsant syndrome?

Answer 27

~0.4% of pregnant women take anticonvulsants during pregnancy (sodium valproate, phenytoin, carbamazepine, phenobarbitol)
treatment with anticonvulsants in pregnancy leads to an overall 2-3 fold increase risk of congenital malformation compared to risk of general population
risk of anticonvulsant therapy must be weighed with risk of seizure-induced morbidity and mortality for both mother and fetus)
major malformations include heart defects, hypospadias, clubfoot, and clefting
risk of NTDs is ~5% with valproate exposure
other malformations include microcephaly, growth retardation, midface myoplasia, and hypoplasia of fingers