STUDY OF

ABNORMALITIES OF
HUMAN FORM AND THE
MECHANISM THAT
DYSMORPHOLOGY
CAUSED THEM
 MALFORMATION

• primary structural defect arising from a localized error in

morphogenesis and resulting in the abnormal formation of a tissue
or organ
CLASSIFICATION
OF BIRTH DYSPLASIA
DEFECTS • abnormal organization of cells into tissues
(SINGLE
DEFORMATION
PRIMARY
• alteration in shape or structure of a structure or organ that has
DEFECT) differentiated normally

DISRUPTION

• structural defect resulting from the destruction of structure that

had formed normally before the insul
Hennekam RC, Biesecker LG, Allanson JE, Hall JG, Opitz JM, Temple IK, Carey JC, Elements of Morphology Consortium. 2013. Elements of morphology: General terms for congenital anomalies.
Am J Med Genet Part A 161A:2726–2733.
Syndrome
• Pattern of multiple abnormalities that are related by
pathophysiology and result from a single defined
etiology CLASSIFICATION
Sequences OF BIRTH
• Consist of multiple malformations that are caused by DEFECTS
a single event that can have many etiologies (MULTIPLE
Association DEFECTS)
• Nonrandom collection of malformations in which
there is an unclear or unknown relationships among
the malformations
MALFORMATION AND/OR DYSPLASIA

 Caused by interactions of genes and environmental factors

 Many developmental abnormalities are caused by mutations in a single gene and display characteristic mendelian
patterns of inheritance
 Affected genes are often part of evolutionary conserved signal transduction pathways, transcription factors or
regulatory proteins required for key developmental events
DEFORMATION

 Most involve the musculoskeletal system

 Fetal movement is required for the proper development of the normal
musculoskeletal system, and anything that restricts fetal movement can
cause a musculoskeletal deformation from intrauterine molding
 Major intrinsic causes:
 Primary neuromuscular disorders
 Oligohydramnios

 Major extrinsic causes:

 Oligohydramnios from chorionic leakage
 Breech presentation
 Abnormal shape of amniotic cavity
DISRUPTIONS

 caused by destruction of a previously normally formed part.

 Two basic mechanisms are known to produce disruption.
 entanglement followed by tearing apart or amputation of a normally developed structure, usually a digit, arm, or leg, by
strands of amnion floating within amniotic fluid (amniotic bands)
 interruption of the blood supply to a developing part, which can lead to infarction, necrosis, and/or resorption of structures
distal to the insult.
MOLECULAR
MECHANISM OF
MALFORMATION
S
INBORN ERRORS OF
DEVELOPMENT
 History

Physical Examination

APPROACH TO Imaging Studies

DYSMORPHIC
CHILD Laboratory Studies

Diagnosis

Management and Counseling

HISTORY

 Pedigree or family history (3-generation)

 Perinatal history
 Pregnancy history of the mother
 Factors that my relate to deformations or disruptions
 Maternal exposures to teratogenic drugs or chemicals

 Natural history of the phenotype

 Physicians are encouraged to consult experts in teratology and expert information sources such as Teris
(http://depts.washington .edu/~terisweb/teris) to analyze specific potential teratogens.
PHYSICAL EXAMINATION

 Organized and systematic cataloguing of the size and structure

 Major birth defects
 Cause dysfunction or require surgical correction

 Minor birth defects

 Cause neither significant dysfunction nor require surgical correction
IMAGING STUDIES

 Full skeletal survey

 Central nervous system imaging
LABORATORY STUDIES

 Giemsa banded peripheral leukocyte karyotype (chromosome)

analysis
 Gold standard
 Clinical indications for Chromosome
 Array CGH and single nucleotide polymorphism genotyping
Analysis or Array CGH
with copy number variation
 At least 1 major or 2 minor malformations
 Most sensitive method for detection of cytogenomic alterations
 At least 2 major malformations
 Typically takes 7-12 days for results
 Developmental or growth retardation with
 High throughput genomic DNA sequencing (exome sequencing 2 or more major or minor anomalies
or whole genome sequencing)
 Molecular testing should not be performed as a screening test but
instead should be ordered thoughtfully after the differential
diagnosis has been narrowed
 General metabolic screen
DIAGNOSIS

 The clinician should now organize the findings by their specificity into potential developmental pathophysiologic
processes.
 Smith’s Recognizable Patterns of Human Malformation
 computerized database such as the Winter­Baraitser Dysmorphology Database
(www.lmdatabases.com/about_lmd.html)
MANAGEMENT AND COUNSELING

 one of the many benefits of early and accurate diagnosis, because anticipatory guidance and medical monitoring
of patients for syndrome­specific medical risks can prolong and improve their quality of life.
 second major benefit of an accurate diagnosis is that it provides data for appropriate recurrence risk estimates.
 Genetic dis­orders may have direct effects on only one member of the family, but the diagnosis of the condition has
implications for the entire family.