dental developmental pathology /certified fixed orthodontic courses by Indian dental academy

Developmental Pathology
INDIAN DENTAL ACADEMY
Leader in continuing dental education
www.indiandentalacademy.com


Cytogenetics
• Examination of chromosomes under the
microscope
• Necessary to induce cells to undergo
mitosis in order to see individual
chromosomes
• Molecular cytogenetic techniques (e.g.,
FISH) can be performed on interphase
cells (cells that are not actively dividing)

Reasons to do a cytogenetic study
• Diagnose constitutional disorders
– I.e., disorders present at birth -- classic example is
trisomy 21 (Down syndrome)
– Typically involve more than one cell line

• Add further diagnostic or prognostic
information to a diagnosis of an acquired
disorder
– I.e., diseases that are NOT constitutional -- these
are most commonly malignancies
– Typically involve only the cell line or tissue
involved by the malignancy

48-hour culture; overnight exposure to colcemid

72-hour culture; several hours’ colcemid;
ethidium bromide added


Basic Terminology
• Constitutional Chromosomal
Abnormalities
• Acquired Chromosomal Abnormalities
• Numerical abnormalities
• Structural abnormalities
– Balanced
– Unbalanced


Karyotype -- Blood


Karyotype -- Marrow


FISH diagram (scanned)


Fluorescence in s itu hybridization
(FISH)
• Specimen is collected as previously described
for each tissue type
• Indications for FISH include:
– Microdeletions (e.g., Prader-Willi, Angelman and
DiGeorge syndromes)
– Cryptic translocations (e.g., t(12;21))
– Cancer translocations (e.g., BCR-abl, PML-RARA)
and rearrangements (e.g., MLL)
– Enumeration of chromosomes or detection of
translocations or rearrangements in interphase
nuclei

Clinical History
• Approximately 32 weeks’ gestation
• Abnormalities detected on ultrasound:
– Abnormal head shape
– Frontal bossing
– Clenched fists


Newest method -- array-based
Comparative Genomic Hybridization
• DNA is extracted from patient
• DNA from patient and sex-matched
control are labeled in different colors
• Labeled DNA is hybridized to a chip
(microarray) on which are
oligonucleotides spaced across the
genome (density or spacing of oligos
depends on platform)
• Results in ratio of patient to control at
these loci

Array CGH
• Used to detect abnormalities too small
to be seen under the microscope (each
G-band can contain hundreds of genes)
• Can detect only unbalanced
rearrangements (e.g., deletions,
duplications)
• Balanced rearrangements (e.g.,
inversions, insertions) will NOT be
detected by array-CGH

Specimen to draw for a cytogenetic study?
• SODIUM heparin tube
• Recommend at least 1 ml (3 if poss)


Trisomy (one extra chromosome)
• Typically arises from a nondisjunction error in
either meiosis I, meiosis II or mitosis (if due to
amitotic error, the trisomy is mosaic)
• Most autosomal trisomies arise from maternal
nondisjunction errors
– Strong correlation between increasing maternal
age and risk for nondisjunction
– Advanced Maternal Age (AMA) is the most
common reason for referral for a prenatal
chromosome study
– 95% of trisomy 21 is due to maternal
nondisjunction errors

Major “viable” trisomies
• Chromosome 13 (obsolete name, Patau
synd)
• Chromosome 18 (obsolete name, Edward
synd)
• Chromosome 21 (Down synd)
• All other chromosomes have been reported in
trisomic state; unless mosaic, virtually
uniformly fatal in utero or shortly after birth

Trisomy 21 (1 in 800 live births;
incidence greater if mat. age >35)
•
•
•
•
•
•

Hypotonia
Short neck with loose skin at nape
Flat nasal bridge
Brushfield spots around edge of iris
Epicanthal folds
Short, broad hands with single transverse
palmar crease
• Congenital heart disease
• Mental retardation
• Increased riskwww.indiandentalacademy.com
for leukemia

Thompson & Thompson, Genetics in Medicine, 7th ed, p. 91

Trisomy 13 (1 in 15-25000 live births)
• Growth retardation
• Severe central CNS malformations
(e.g., holoprosencephaly)
• Microcephaly
• Cleft lip, cleft palate
• Polydactyly
• Congenital heart, renal and
genitourinary malfomations

Trisomy 18 (1 in 7500 live births)
• Severe cardiac malformations
• Low-set, malformed ears
• Characteristic clenched fist (2nd and
5th digits overlap)
• Rocker-bottom feet
• Mental retardation
• Increased maternal age is a risk factor

Sex chromosome numerical abnormalities
• Male

– Klinefelter (47,XXY): 1/1000 males
– 47,XYY: 1/1000 males
– 46,XX males: 1/20,000 males

• Female
–
–
–
–

Turner (45,X): 1/5000 females
Trisomy X (47,XXX): 1/1000 females
46,XY females: 1/20,000 females
Androgen insensitivity (testicular
feminization): 1/20,000 females

Klinefelter syndrome
• Tall, thin body habitus; long legs
• Signs of hypogonadism at puberty
– Small testes, underdeveloped secondary
sex characteristics

• May have gynecomastia
• Almost always infertile
• May be mosaic for a normal (or other
abnormal) cell line

Turner syndrome
• Approx. 99% of 45,X conceptions die in
utero; livebirth approx 1/4000 females
• Approx. 50% cases 45,X; remainder are
mosaic for another cell line, either
46,XX or with a structurally abnormal X
(e.g., isochromosome Xq)


Turner syndrome
•
•
•
•

Short stature
Broad chest with widely spaced nipples
Gonadal dysgenesis (e.g., streak gonads)
Webbed neck (from lymphedema during fetal
life)
• Lymphedema of dorsum of feet
• Low posterior hairline
• Renal and cardiovascular abnls, incl.
coarctation of aorta

Microdeletion/microduplication syndromes
• Very small (sometimes visible by Gbanding, sometimes not) deletions
• Result from unequal crossing over
between homologous regions on
chromosomes during meiosis
• Typically confirmed by FISH


Microdeletion syndromes


DiGeorge/velocardiofacial
syndromes
• Characteristic craniofacial features
• Varying degrees of mental retardation
may be a feature
• Conotruncal heart defects (e.g.,
tetralogy of Fallot, pulmonary atresia,
absent pulmonary valve)
• Over 30 different genes in this region,
so phenotype dependent on size of
deletion

Prader-Willi/Angelman syndromes
• Both due to a deletion within the proximal
long arm of a chromosome 15
• Manifestations depend on which
chromosome 15 is deleted: the 15 that
came from the patient’s mother or the 15
that came from the patient’s father:
– IMPRINTING
– Need specialized molecular studies to
determine which homolog is deleted

Cassidy SB et al, 2000, Am J Med Genet 97:136

Prader-Willi
•
•
•
•

Severe hypotonia in infancy
Hypogonadism
Feeding difficulties in infancy
Over time, feeding difficulties resolve and
hyperphagia ensues --> extreme foodseeking behavior
• Obesity
• Mild mental retardation, learning difficulties,
behavioral issues

Angelman
• Severe mental retardation and
developmental delay
• Jerky, ataxic gait (“puppet”-like)
together with characteristic arm position
• Paroxysms of inappropriate laughter
• Virtually absent speech

Marfan syndrome
• Autosomal dominant connective tissue
disorder due to mutations in fibrillin 1
(FBN1) gene
• FBN1 encodes an extracellular matrix
glycoprotein
• Wide-ranging systemic effects:
– Skeletal, ocular, pulmonary, skin

• Clinical diagnosis; heterogeneity of
gene makes identification of causative
gene extremely difficult

Marfan
•
•
•
•
•
•
•
•
•

Tall stature, arachnodactyly
Pectus excavatum
Joint laxity
Narrow palate
Ectopia lentis
Mitral valve prolapse
Aortic dilatation, dissection
Pulmonary blebs, pneumothorax
Striae

Cystic Fibrosis
• Autosomal recessive: patients have
mutations in both CFTR (CF
transmembrane conductance regulator
gene) alleles
• Predominantly dz of northern
Europeans, with carrier rate approx 1 in
29 (incidence of dz approx 1/2500)
• Lungs and exocrine pancreas primarily
affected
• Increased sweat chloride
concentrations

CF Clinical Features
• Pulmonary findings

– Very thick secretions, recurrent infections, COPD
and bronchiectasis

• Pancreatic findings

– Decreased secretion of pancreatic enzymes such
as trypsin and lipase (pts can take supplements)

• Other features: meconium ileus in 10-20%
newborns with CF
• CBAVD: Congenital bilat absence of vas
deferens (some pts with absent to very mild
features of CF may present with infertility)

Fragile X syndrome
• X-linked mental retardation syndrome
due to unstable CGG repeats in
promoter region of FMR1 gene on very
distal long arm of X chromosome
• Prevalence 16-25/100,000 in gen pop;
most common cause of inherited mental
retardation


Fragile X
• Due to expansion of repetitive sequences (similar
disorders: Huntington, myotonic dystrophy, various
ataxias)
• CGG repeat in 3’ untranslated region of FMR1
gene:
–
–
–
–

5-40 repeats: normal
41-58 repeats: gray zone
59-200 repeats: premutation
>200 repeats: full mutation

• This expansion occurs during maternal meiosis (so
mothers of Fragile X pts have premutations); risk of
expansion to full mutation increases with size of
premutation

Fragile X clinical features
• Both males and females can manifest
features (usually more pronounced in males
as no other copy of normal X)
• Moderate mental retardation (usu. milder in
females)
• Hyperactivity, hand flapping or biting, temper
tantrums
• Post-pubertal males: long face, prominent jaw
and forehead, large ears, large testes (FMR1
is normally expressed in testes)

From: geneticsmodules.duhs.duke.edu

Duchenne Muscular Dystrophy
• X-linked progressive myopathy due to
mutations or deletions within the DMD
gene
• Incidence: approx 1/3500 male births
• DMD encodes dystrophin, expressed in
muscle (smooth, cardiac and skeletal)
• Mutations lead to partially functional or
nonexpressed dystrophin (severity of
disease based in part on expression
status of dystrophin)

DMD clinical features
• Progressive muscle degeneration and
weakness
• Begins with hip girdle and neck flexors,
begins to spread distally
• Usually manifests by age 5 (Gowers
maneuver) and have calf pseudo-hypertrophy
• Cardiac findings present in approx 95% pts;
chronic heart failure in 50%
• Confined to wheelchair by age 12 or so
• Median age at death is 18 years

From: medgen.genetics.utah.edu

References
• Nussbaum RL, McInnes RR, Willard HF.
Tho m p s o n & Tho m p s o n G e ne tic s in M d ic ine
e
(7 th e d ). Elsevier Saunders, 2007.

– Excellent in-depth introduction to clinical genetics.

• Jones KL. Sm ith’s Re c o g niz a ble Pa tte rns o f
Hum a n M lfo rm a tio n. Elsevier Saunders,
a
2006.

– Outstanding guide, with many pictures and
differential diagnoses, of many genetic syndromes
and abnormalities. Lists of syndromes associated
with various clinical findings (e.g., dental and
maxillofacial abnormalities).

• www.genetests.org

– Very well-written and updated reviews under the
section, GeneReviews.

Thank you
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