GENETIC DISORDERS

Pathology review course

Hispanic Health Professional Association of NY

Rassull Suarez MD
GENETIC DISORDERS
Involving extra autosomic chromosome
Involving chromosomal deletions
Involving sexual chromosome
Mendelian disorders
Autosomal recessive disorders
Autosomal dominant disorders
Triplet repeat mutations
Genomic imprinting
GENETIC DISORDERS
Involving extra
autosomic chromosome
Pataus
syndrome
(trisomy 13)
Edwards
syndrome
(trisomy 18)
Down
syndrome
(trisomy 21)
GENETIC DISORDERS
How do trisomies occur?
Meiotic non-
disjunction
(95%)
Robertsonian
translocation
(4%)
Mosaicism
during
embryogenesis
(1%)
M
E
I
O
S
I
S

Nromal
M
E
I
O
T
I
C

N
O
N
-
D
I
S
J
U
N
C
T
I
O
N

Abnormal
GENETIC DISORDERS
Robertsonian
translocation
occurs between
chromosomes:
13
14 18
21
R
O
B
E
R
T
S
O
N
I
A
N

T
R
A
N
S
L
O
C
A
T
I
O
N

GENETIC DISORDERS
Patau Syndrome
Trisomy 13

Mental retardation
Cleft lip and palate
Cardiac defects (VSD, ASD)
Polycystic kidneys
Omphalocele
Microcephaly
Micrognatia
Microphtalmia
Holoprosencephaly
Polydactyly
Most die in 1st year of life
P
A
T
A
U






Microcephalia
Micropthtalmia
Single eye
GENETIC DISEASE
Edwards Syndrome
Trisomy 18
Mental retardation
low set ears
micrognathia
Congenital heart defects
(VSD, ASD, PDA)
Overlapping flexed fingers
Rocker bottom feet
Poor prognosis


GENETIC DISORDERS
Down syndrome
Trisomy 21
Duodenal Atresia (double bubble
sing)
Brushfield spots
Endocardial cushion defects
Single simian crease
Single flexion crease
Increase risk of ALL
Alzheimers disease
Hirschsprung dissease

GENETIC DISORDERS
Down syndrome
Labs:
-HCG
Inhibin A
Estriol
-Fetoprotein

DOWN SYNDROME
KARYOTYPE OF DOWN
DEFECTS INVOLVING CHROMOSOMAL DELETIONS
Cri-du-chat
Deletion of 5p
High pitch cry
Mental retardation
Congenital heart disease
Colombomas
Microcephaly
Large segment deletion



DISORDERS INVOLVING SEX CHROMOSOMES
Klinefelter syndrome
47 XXY
Meiotic nondisjunction
Male Hypogonadism
LABS:
FSH and LH
Testosterone
Testicular atrophy
Infertility
High pitch voice
Gynecomastia
Female distribution of hair



TURNER SYNDROME
45 xo
Female Hypogonadsm
No barr bodies present
Failure to develop secondary sexual
characteristics
Short stuture
Wide-spaced nipples
Atrophic, streaked ovaries
Primary amenorrhea
Infertility
Cystic hygroma
Preductal Aortic coartation
Bicuspid aortic valve
Hydrops fetalis

PSEUDOHERMAPHRODITES
True Hermaphrodite
Presence of both testicular and
ovarian tissue
Very uncommon even on the test
Female Pseudohemaphroditism
Normal Genetic sex (XX)
Internal organs are normal
Ambiguos or virilized external
genitalia
Causes:
Congenital adrenal hyperplasia
Androgen producing tumors
Externous androgens
PSEUDOHERMAPHRODITES
Male pseudohemaphroditism
Genetic sex normal (XY)
Phenotype; Ambiguous genitalia
Causes:
Complete androgen insensitivity syndrome
Undescended testes (need to be removed)
Precences of uterus
Blind vaginal
Testosterone, DHT, FSH, LH
5 a reductase deficiency
Ambiguous genitalia until puberty
Testosterone, FSH, DHT


MENDELIAN DISORDERS
Characterized by single gene mutation
Point mutation
Silent mutation: same amino acid
Missense mutation: different aminoacid (larger protein)
Nonsense mutation : Stops production of protein
Frameshift mutation : Deletion or insertion of bases
(triplets)
Pattern of inheritance
Autosomal recesive
Autosomal Dominant
X- Linked

AUTOSOMAL RECESSIVE
Cystic fibrosis
Most common lethal disease on caucasians
Defect on a Chloride channel CFTR
(misfolding)
Located on chromosome 7
Deletion of phenilalanine at position 508
Clinical manifestations
Infections with staph and pseudomona
Bronchiectasis
Pancreatic insufficiency (leading to
malabsorbtion)
Absence of Vas Deferens
Meconium ileus
Dx- Chloride sweat test, DNA probes
Tx- N-acetylcysteine, Vit ADEK,
AUTOSOMA RECESSIVE DISORDERS
Phenylketonuria (PKU)
Phenylalanine Hydroxilase deficiency
Deficiency of other Hydroxylases (Dopamine
hrydroxilase, serotonin hydroxilase ect)
Mental retardation
Albinism
Musty odor
Rx- diaetary resriction of phenilalanine
Alkaptonuria (Ochronosis)
Deficiency of Homgentistic acid Oxidase
Results in accumulation of homogentistic acid
Back urine, black bones and cartilages
Early onset of degenerative arthritis
OCHRONOSIS
AUTOSOMAL RECESIVE DISORDERS
Albinism
Tyrosinase deficiency
Increase risk of basal cell
carcinoma
Squamous cell carcinoma
Glycogen storage diseases
Von gierkes disease
Pompes disease
McArdles disease
LYSOSOMAL STORAGE DISEASES
LYSOSOMAL STORAGE DISEASES
GAUCHERS DISEASE
AUTOSOMAL DOMINANT DISORDERS
Marfan Syndrome
ED Syndrome
Neurofibromatosis
NF1, NF2
Caf-au-late spots
Increase risk of
Pheocromositoma
Meningiomas
Bilateral acustic neuroma (NF2)
Optic gliomas
Ependimoma


VON HIPPEL LINDAU SYNDROME
VHL tumor supressor gene
Chromosome 3
Retinal and cerebellar hemangioblastoma
Cyst in liver, pancreas and liver
Bilateral renal cell carcinoma
TRIPLET REPEAT MUTATIONS
Fragile X Syndrome
CGG repeats
FMR gene
Elongated face and jaw
Large ears
Macro-orchidism
Anticipation
Huntington's disease
Chromosome 4
CAG repeats
Atrophy of the caudate nuclei
Choreiform movements
Death

FAMILIAL HYPERCHOLESTEROLEMIA
HYPERCHOLESTEROLEMIA
GENOMIC IMPRINTING
GENOMIC IMPRINTING