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