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Aromatase deficiency is an autosomal recessive disorder that manifest early in embryonal life
with high androgen and low estrogen levels in the female fetus.
Affected newborn girls will have normal internal genitalia and ambiguous or male type external
genitalia ( eg: clitoromegaly, female pseudohermaphrodism).
At puberty, impaired ovarian estrogen synthesis causes primary amenorrhoea, osteoporosis, and
tall stature ( low estrogen delays fusion of epiphysis).
Men with aromatase deficiency have tall stature and osteoporosis but no genital abnormalities.
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In Klinefelter syndrome, Leydig cell dysfunction also occurs and leads to testosterone
deficiency. Gonadotropin (FSH, LH) levels are increased secondary to gonadal failure.
Testosterone deficiency results in development of enunchoid body habitus.
Macroorchidism large jaw and intellectual disability are seen in patients with fragile X
syndrome, an X linked disorder caused by mutations in the fragile X mental retardation 1 gene.
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Xeroderma pigmentosum: skin malignancie, including squamous cell carcinoma, basal ell
carcinoma and malignant melanoma, develop as early as at 5-6 years of life.
Other diseases associated with impaired DNA repair include Fanconi anemia (AR,
hypersensitivity to DNA crosslinking agents) and Bloom syndrome (AR, hypersensitivity to
UV damage and chemotherapeutic agents) among others
Base excision repair is responsible for repairing various non-bulky DNA base alterations,
including depurination, alkylation, oxidation and deamination.
Excessive consumption of dieatary nitrites can promote the deamination of cytosine, adenine
and guanine to form uracil, hypoxanthine and xanthine, respectively.
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Alternative splicing is a normal phenomenon in eukaryotes that greatly increases the
biodiversity of proteins that can be encoded by the genome.
It is thought that at least 70% of the 30000 genes in the human genome undergo alternative
splicing and that on average, a given gene produces 4 alternatively spliced variants.
Variable, Diverse and Joining ( VDJ) gene recombination is a random process that takes place
in the primary lymphoid tissue (the bone marrow for B cells and Thymus for T cells).
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Tumor suppressor genes are involved in multiple processes: including: 1) DNA repair 2)
Cellular differentiation 3) Checkpoint control of the cell cycle 4) Transcription factor regulation
BRCA 1 and 2 are particularly involved in repair of double stranded DNA breaks.
Both BRCA mutations are inherited in an autosomal dominant manner with variable penetrance.
Affected women have a 70-80% lifetime risk for developing breast cancer.
Moreover, their lifetime risk of developing ovarian cancer is also increased by upto 40% ,
although the BRCA 2 gene is less likely to lead to ovarian cancer.
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Homocystinuria has peiotropy. It is characterized by ectopia lentis, mental retardation,
marfanoid habitus and osteoporosis in addition to vascular problems.
 Polyploidy occurs when more than two complete sets of homologous chromosomes exist within
an organism or cell. In a partial hydatiform mole, for example there are cells of nonstandard
ploidy ( typically 69XXX, 69XXY or 69XYY). The chromosomes in this case are derived from
one haploid maternal set and two haploid paternal sets of chromosome.
Genetic linkage describes alleles that tend to be inherited jointly usually because they are
located near one another on the same strand of DNA.
Linkage disequilibrium can occur even if the genes are on different chromosome.
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Mitochondrial disorders follow a maternal inheritance pattern, as an embryos mitochondria are
inherited from the ovum only.
Common medical conditions influenced by multiple genes: 1. Androgenic alopecia 2. Epilepsy
3. Ischemic heart disease 4. Schizophrenia 5. Glaucoma 6. HTN 7. Malignancy 8. Type II DM
The pattern and severity of the baldness varies between males and females, and circulating
androgen levels along with the degree of genetic predisposition are thought to play a prominent
role in determining clinical manifestations.
Androgenic alpecia demonstrates polygenic inheritance with variable penetrance. Key sites of
genetic influence have been identified on the X and Y chromosomes and also on the short arm
of the chromosome 20.
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In X linked recessive inheritence: 1. Affected males will alwayes produce unaffected sons and
carrier daughters 2. carrier females have a 50% chance of producing an affected son or carrier
daughter.
Blotchy red muscle fibres on Gomori trichrome stain are characteristic of the mitochondrial
myopathies.
In these condition, abnormal mitochondria accumulate under the sarcolemma of the muscle
fibres. The fibres have an irregular shape and size on cross section.
EM of the affected muscle reveals an increased number of enlarged, abnormally shaped
mitochondria.
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Mucosal neuromas, are unencapsulated thickened proliferations of neural tissues. MEN 2B is
due to an inherited mutation in RET proto-oncogene.
MEN 2B may be associated with phaechromocytoma and intestinal ganglioneuromas (often
causing assoc constipation)
Tuberous sclerosis is an autosomal dominant syndrome characterized by cutaneous
angiofibromas ( adenoma sebaceum), seizures and mental retardation. Pathological lesion
include CNS hamartomas and benign neoplasms, renal and other visceral cysts and cardiac
rhabdomyomas.
Achondroplasia occurs as a sporadic mutation (due to advanced paternal age) in 85% of cases
and as an inherited autosomal dominant (AD) trait in the remaining 15%.
Renal angiomyolipomas are associated with tuberous sclerosis.
Tuberous sclerosis is characterized by cortical tubers and sub ependymal hamartomas in brain,
with consequent seizures and mental retardation.
 The presence of axillary of inguinal freckles is a cutaneous features of NF-1/
Bony abnormalities of NF-1: sphenoid dysplasia, congenital pseudoarthrosis, and scoliosis.
Expansion of the Huntingtin proteins polyglutamine region results in a gain of function that
leads to pathological interaction with other proteins, including various transcription factors.
Transcriptional repression (silencing) is one of the mechanisms by which mutated huntingtin is
thought to cause disease.
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Given phenotypically normal parents, the probability that a female sibling of a male affected by
an X-linked recessive disease will give birth to an affected child is 1/8.
Classical galactosemia is an autosomal recessive disease.
CFTR mutation are likely responsible for abnormal development of Wolffian structures,
resulting in vasal agenesis and defective sperm transport.
A Dx of CF can be based on elevated sweat chloride levels. If the sweat chloride test is
equivocal, measurement of nasal transepithelial potential difference and genetic testing for
CFTR mutations should be performed to confirm the diagnosis.
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FMR1 normally has 5 to 55 CGG trinucleotide repeats and can potentially expand during
meiosis in oocytes.
Full mutation is characterized by >/= 200 CGG repeats, which causes FMR1 hypermethylation.
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Unbalanced robertsonian translocation account for 2-3% of Down syndrome cases.
Approximately, one third of these cases are due to balanced translocation in one parent. These
balanced translocations are associated with high recurrence risk.
Genetic counseling for the parents is indicated if a translocation is identified in the infant.
Most common translocation in Down syndrome are t (14:21) and t(21:22).
Maternal serum alpha feto protein: 1. open neural tube defects (eg: anencephaly, open spina
bifida) 2. Ventral wall defects ( eg: omphalocele, gastroschisis) 3. Multiple gestation.
MSAFP: Aneuploidies (eg: trisomy 18 and 21)
one common option for screening down syndrome during the second trimester is the Quadruple
screen at 15-18 weeks gestation.
The diagnosis is confirmed by karyotyping fetal cells in the amniotic fluid ( amniocentesis)
Chromosome 21 nondisjunction occurs during oogenesis and is significantly associated with
advanced maternal age.
It is not seen in spermatogenesis or in post zygotic mitotic errors.
Neural tube defects are also associated with increased acetylcholinesterase levels in amniotic
fluid.
Many patients with down syndrome develop early onset Alzheimer dementia ( AD) after age 35.
Characteristic pathologic changes associated with AD involve accumulation of intracellular
neurofibrillary tangles and extracellular amyloid beta plaques.
Neurofibrillary tangles are composed of tau proteins, a primary component of intracellular
microtubules.
 In AD, tau protein is hyperphosphorylated, causing microtubule structures to collapse into
tangles that contribute to global neuronal dysfunction.
Abeta is an abnormal fragment of amyloid precursor protein (APP), which is normally involved
in synaptic formation and repair.
In AD, the protein is not properly cleared and forms amyloid fragments; these then harden into
insoluble plaques that accumulate in brain tissue and vessel walls.
Mutations of the TTR gene result in misfolding and extracellular tissue diposition of
transthyretin proteins ( also known as prealbumin), which can cause familial amyloid
polyneuropathy or familial amyloid cardiomyopathy.
Presynaptic acetylcholine synthesis is reduced in AD due to decreased cerebral content of
choline acetyl transferase. Consequently, acetylcholinesterase inhibitors ( eg: donepezil) are
often used to treat this condition.
Mutations in the gene coding for apolipoprotein E result in impaired synthesis of this protein
and impaired clearance of Abeta from the brain parenchyma. Consequently, apolipoprotein E
mutations are associated with a higher risk for late onset AD.
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The M3 variant of AML, acute promyelocytic leukemia, is associated with the cytogenetic
abnormality t(15:17).
Here the gene for retinoic acid receptor alpha from chromosome 17 is transferred to
chromosome 15 in a location adjacent to the PML ( promyelocytic leukemia) gene.
Fusion of these two genes produces a chimeric gene product PML/RARalpha, which codes for
an abnormal retinoic acid receptor.
Mutations of the genes that code for the epidermal growth factor receptors are associated with
non-small cell lung carcinoma (erbB1), breast cancer (erbB2 aka HER2/neu) and some ovarian
and gastric tumors.
Defective platelet derived growth factor receptor plays a role in the pathogenesis of chronic
myelomonocytic leukemia.
Fragile X: on karyotype analysis of cells cultured in a folate deficient medium, this X linked
disorder shows a discontinuity of staining on the long arm of the X chromosome.
C-myc gene is located in chromosome 8. Translocation between chromosome 8 and
chromosomes coding for the immunoglobulin heavy chain (14), the kappa light chain (2), or the
lambda light chain (22) may result in Burkitt lymphoma.
Mutation of the WT-1 anti-oncogene are associated with the development of Wilms tumor. This
gene is located on chromosome 11.
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Chromosome 22q11.2 deletion is found in 90% of cases of DiGeorge syndrome.
DiGeroge syndrome is associated with at least 15% of cases of interrupted aortic arch, a more
extreme anomaly than aortic coarctation in which the aortic arch is atretic or a segment of the
arch is absent.
Affected patients have poor lower extremity pulses, but respiratory distress, variable cyanosis,
and signs of congestive heart failure will also develop during the first days of life.
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 Histology of Tay sachs typically shows neurons with cytoplasmic distention and lysosomes
with onion skin lamellar lipid rings on electron microscopy.
Patients with Tay sachs eventually develop seizures, blindness and spasticity. Life expectancy is
2-5 years.