Congenital Malformations (Birth Defects)
Sequence
A single malformation, deformation or event that leads to other abnormalities
Major and minor anomalies
Major - has significant consequence for health or appearance Minor - minimal or no health consequence but may have modest impact on appearance
Malformation syndrome
Pattern of anomalies, at least one of which is morphologic, known or thought to be causally (etiologically) related - More than one tissue, organ, developmental field affected - Syndromic birth defects - associated with other major or minor anomalies that are not secondary - Pattern of multiple features thought to be causally and/or pathogenically related
Causes of syndromic malformations
Chromosomal abnormalities (genomic mutations) Single gene mutations (mendelian disorders) Gestational/prenatal teratogenic effects
Malformation
- Non progressive, congenital morphologic anomaly of a single organ or body part. - Due to an alteration of the primary development program (results from intrinsically abnormal development process) - Can be a single localized defect (isolated cleft lip) or cause a malformation sequence (like hydrocephalus and club foot due to myelomeningocele)
Timing of most structural defects
3-8 weeks (0-2 weeks likely lethal)
Non syndromic cleft palate/lip
Affected individual has no other physical or developmental anomalies and no recognized maternal environmental exposures
Birth defect overview
Affects 2-10% of babies (depends on definition) Leading cause of infant mortality 30-50% of postnatal deaths Birth defect ---- greater chance of illness and long term disability
Deformation
Altered shape or position of a body part due to aberrant mechanical force that distorts an otherwise normal structure.
Minor anomalies
Calvaria shape Ear size Eye spacing or slanting Scalp hair patterning Palmar creases Finger/palm dermal ridge patterns Many syndromes recognizable primarily because of a characteristic pattern of minor anomalies (Down Syndrome) not one major anomaly
Polygenetic
Caused by combined effects of genes at two or more loci Many small additive effects
Disruption - another definition
Destruction of previously normal organ tissue Amniotic bands
Amniotic bands
Disruption
Single vs. multiple anomalies
If there is a single primary defect with secondary or tertiary anomalies (sequence) One or more secondary morphologic anomalies known or presumed to cascade from a single malformation, deformation, disruption, or dysplasia (from single presumed or known anomaly or mechanical factor)
Multifactorial
Environmental factors interact with genetic predisposition -- trait/disorder caused by the combined effects of two or more loci together with environmental factors
Van der Woude Syndrome
Example of a malformation syndrome Lip pits, cleft lip and/or cleft palate AD with variable expression Due to mutation in IRF6 gene on 1q
Syndromic cleft lip/palate
Example of cleft lip and palate as part of a syndrome - Infant with cleft lip and palate due to trisomy 13
Neural tube defects
Failure at any level (anencephaly, meningomyelocele, encephalocele, etc) malformation
Causes of defects
Huge percentage unknown
Ectodermal dysplasias
Many conditions with abnormal development of ectodermal derivatives affecting - skin - sweat pores - hair - teeth - nails - hearing Most are single gene disorders (Mendelian) May be associated with minor anomalies/ dysmorphic features - Sparse hair - Everted lower lip - Thin nails
Syndrome
Means "running together" Pattern of malformations with a known or unknown cause e.g. fetal alcohol
Deformation - human causes
Mechanical force
Robin sequence
Micrognathia, glossoptosis, cleft palate Hypoplasia of mandible before 9 weeks is thought to be initiating process Can be due to in utero constraint, lack of fetal movement, etc.
Dysplasia
Morphologic anomaly arising pre or postnatally from dynamic or ongoing alteration of cellular constitution, tissue organization, or function within a specific organ or a specific tissue type Broadly applies to all abnormalities of histogenesis Tends to be tissue specific, not organ specific
Stickler syndrome
Most common syndrome associated with Robin sequence - it is a hereditary arthro-opthalmopathy -AD -type II and XI collagen gene mutations -myopia, retinal detachment, cataracts -hearing loss -hypotonia, hyper extensible joints, talipes equinovarus, severe arthropathy/arthritis, spondyloepiphyseal dysplasia
Non syndromic malformation
Non syndromic means isolated (only one primary malformation)
Disruption
Non-progressive, congenital morphologic anomaly due to the breakdown of a body structure that had normal development potential
Role of environment
Odds greater with genetic predisposition and an exposure Asthma, emphysema, skin cancer, T2DM, anemia (G6PD)
Potter sequence
Oligohydramnios ---lung hypoplasia and fetal compression with deformations (flat face, talipes) From: -renal agenesis/hypoplasia -amniotic fluid leakage -UT outlet obstruction
Examples of non syndromic malformations
Orofacial clefts NTDs CV malformations Renal agenesis Imperforate anus Diaphragmatic hernia
Minor anomalies from AD traits
Pre auricular tags, pits Polydactyly Clinodactyly Transverse palmar crease
Skeletal dysplasias
Several hundred conditions with abnormal bone and joint development - short bones, long bone deformity, soft bones, etc Most mendelian May have associated malformations May have associated deformations
Achondroplasia
Skeletal dysplasia
Non-syndromic - inheritance
Some familial but most do not follow mendelian pattern Polygenetic or multifactorial (multiple genes + environment) Complex - include intellectual disability, cancer, autism, psychoses, obesity, HTN, Parkinson ----family hx plays a role but not entirely clear
Presence of 3 or more minor anomalies
Suggests the possibility of an underlying, more widespread defect in morphogenesis
Neural tube defect sequence
The NTD (primary malformation) leads to: - Clubfoot (abnormal compression on structures lacking innervation) and decreased ability of fetus to move legs - Hydrocephalus - secondary to NTD (Chiari 2)
Cardiovascular malformations
VSD, PS, conotruncal defects, etc malformation
Talipes deformity
clubfoot deformation
Bowed leg
deformation
Clubfoot
deformation
Conehead from vaginal birth
deformation
Craniofacial asymmetry
deformation
Dislocated hip
deformation
Some contractures
deformation
Some craniosynotosis
deformation
Tibial torsion
deformation
Deformation - cause
frequently from crowding in third trimester
Cleft lip with or without cleft palate
malformation
Posterior cleft palate without cleft lip
malformation
