Genetics other:

In Kallmanns syndrome, there is an absence of GnRH secretory neurons from the hypothalamus due to
defective migration from the olfactory placode. These patients have central hypogonadism and anosmia.
Given phenotypically normal parents, the probability that a female sibling of a male affected by an Xlinked recessive disease will give birth to an affected child is 1/8.
The probability that an autosomal recessive disease will be transmitted to a child can be calculated from the
maternal and paternal pedigrees. An unaffected individual (with unaffected parents) who has a sibling
affected by an autosomal recessive condition has a two thirds chance of being a carrier for that condition.
A complete mole results from fertilization of an ovum that is devoid of genetic material and subsequent
reduplication of the paternal genetic complement giving a characteristic 46 XX genotype.
Xeroderma pigmentosum develops due to a defect in DNA excisional repair. This disease is characterized
by increased sensitivity to UV radiation and a high incidence of all forms of cutaneous malignancy.
Common findings in Down syndrome include mental retardation facial dysmorphism and cardiac defects
95% of cases are caused by the presence of an extra chromosome 21(trisomy). Less commonly unbalanced
Robertsonian translocations or mosaicism may be responsible.

Down syndrome is associated with characteristic physical exam findings such as a flattened facies,
epicanthal folds, oblique palpebral fissures, single palmar crease, shortened fifth digit, large tongue and
others. Congenital heart defects, especially endocardial cushion defects, are common in children with
Downs syndrome. The majority of cases occur due to maternal meiotic nondisjunction.
Diminished femoral pulses compared to brachial pulses, symptoms of inadequate perfusion of the lower
extremities during ambulation, and enlarged intercostal arteries in a child/young adult are typical of adulttype congenital coarctation of the aorta. Turners syndrome is associated with coarctation of the aorta in
girls. A variety of other autosomal and sex chromosomal inherited disorders are associated with
cardiovascular developmental defects and/or pathology. The major associations are as follows:
Down syndrome endocardial cushion defects (ostium primum ASD regurgitant atrioventricular valves)
DiGeorge syndrome tetralogy of Fallot and interrupted aortic arch
Friedreich's ataxia hypertrophic cardiomyopathy
Marfan syndrome cystic medial necrosis of the aorta
Tuberous sclerosis valvular obstruction due to cardiac rhabdomvomas
Congenital hypothyroidism presents soon after birth with hypotonia, poor feeding, jaundice, macroglossia,
constipation and umbilical hernia. It should be diagnosed as early as possible to prevent the development of
mental retardation.
Patients with both sporadic and hereditary (associated with Von Hippel-Lindau disease) renal cell
carcinomas are found to have deletions of the VHL gene on chromosome 3p.
A pedigree involving a female index case (proband), affected father, and affected paternal grandmother
most likely corresponds to autosomal dominant or X-linked dominant inheritance. Androgenetic alopecia is
the most common cause of hair loss in both males and females and is generally inherited as an autosomal
dominant or polygenic disorder.
The cytogenetic defect t(15;17) is associated with acute promyelocytic leukemia (AML type M3).
Translocation of the gene for the retinoic acid receptor alpha from chromosome 17 to chromosome 15 leads
to formation of the fusion gene PML/RAR. This abnormal fusion gene product inhibits differentiation of
myeloblasts and triggers the development of acute promyelocytic leukemia.
After participating in this learning exercise you should be able to calculate the probability that a child of
parents from two populations with different mutant allele carrier frequencies will inherit an autosomal
recessive disease.

Trisomy 21 (47, XX, +21) is detectable by cytogenetic karyotype analysis and is the most common cause of
congenital mental retardation. Patients with Down syndrome are 20-40 times more likely to develop ALL
than the general population.
Trisomy 21 (Down syndrome) is characterized by mental retardation, facial dysmorphism, single palmar
crease, endocardial cushion defects, and duodenal atresia. Affected individuals have an increased risk of
AML-M7 and ALL in childhood and early Alzheimer disease in adulthood.
A variety of genetic disorders can result in facial and/or palatal malformations, including deletions of the
long arm of chromosome 22. However deletions involving the long arm of chromosome 22 are also
associated with DiGeorge syndrome (congenital thymic and parathyroid aplasia, congenital cardiovascular
anomalies).
Primary amenorrhea in a patient with fully developed secondary sexual characteristics suggests the
presence of an anatomic defect in the genital tract, such as imperforate hymen or Mllerian duct
abnormalities.
Klinefelter syndrome is characterized by hypogonadism, eunuchoid habitus, small firm testes, and genotype
47 XXY.
1. Elevated alpha-fetoprotein levels are seen in multiple gestation neural tube defects (including spina
bifida anencephaly), and abdominal wall defects.
2. In contrast Down syndrome is associated with low alpha-fetoprotein levels in maternal serum and
amniotic fluid. The definitive prenatal diagnosis is made by karyotyping of fetal cells.
47 XXY is the most common karyotype producing Klinefelter syndrome. Patients present with tall stature,
small firm testes, azoospermia and gynecomastia. Mild mental retardation may be present.

Pleiotropy describes instances where multiple phenotypic manifestations result from a single genetic
mutation. Most syndromic genetic illnesses exibit pleiotropy.
Renal angiomyolipoma is a benign tumor composed of blood vessels, smooth muscle, and fat. Bilateral
renal angiomyolipomas are associated with tuberous sclerosis, an autosomal dominant condition.
Turners syndrome (45 XO) manifests in the neonate with lymphedema and cystic hygromas. Short stature,
primary amenorrhea and coarctation of the aorta are the other important clinical features of Turners
syndrome in adults.
In X-linked recessive inheritance, male children of unaffected parents contract the disease. There is no
male-to-male transmission. G6PD deficiency, which causes an acute hemolytic anemia in reaction to
oxidant drugs, follows this pattern.
The presence of lactic acidosis and ragged red skeletal muscle fibers histologically suggest a mitochondrial
myopathy. There may be variable clinical expression of mitochondrial DNA defects in different affected
family members due to heteroplasmy, which is the coexistence of both mutated and wild type versions of
mitochondrial genomes in an individual cell.
Genomic imprinting refers to the phenomenon in which an offspring's genes are expressed in a parent
specific manner. Genomic imprinting is produced by DNA methylation. which is an epigenetic process in
which genes can be silenced by the attachment of methyl groups to cytosine residues in the DNA molecule.
Achondroplasia is an autosomal-dominant disorder. The transmission of autosomal disorders statistically
occurs in 50% of the offspring of an affected parent.
Follicular lymphoma is a non Hodgkin lymphoma of follicular B lymphocytes. Patients with follicular
lymphoma characteristically have a translocation between chromosomes 14 and 18 which causes Bcl 2
overexpresslon. Bcl 2 is considered a proto-oncogene because it has anti apoptotic effects.

Neonates with Edwardss syndrome (47, XX, +18) have small jaws (micrognathia), small eyes
(microphthalmia), and malformed and low-set ears. Note that rocker- bottom feet are seen, as with Patau
syndrome (trisomy 13). The presence of clenched hands with overlapping fingers is considered one of the
distinguishing features of this syndrome.

The presence of rod-shaped intracytoplasmic inclusions known as Auer rods is characteristic of

many forms of acute myeloblastic leukemia (AML). The MS variant of AMLI acute
promyelocytic leukemia, is associated with the cytogenetic abnormality (15:17).
Down syndrome (trisomy 21) occurs in approximately 1 in 730 live births. The majority of
fetuses with this chromosomal defect die in utero. The triple marker test, quadruple marker
test, and integrated test allow for Down syndrome screening. Amniocentesis and chromosomal
analysis of fetal cells can be used to verify the diagnosis.

Aspirin irreversibly inhibits COX 1 and COX 2. COX 2 is an inducible enzyme that is normally
undetectable in most tissues except in the case of inflammation.
Lymphedema is a characteristic finding in a fetus afflicted with Turner syndrome (45, XO). The
lymphedema can vary in severity, ranging from edema of the hands and feet to hydrops
fetalis. Other common fetal Turner syndrome abnormalities include coarctation of aorta and
horseshoe kidney.
Trisomy 13 (Patau syndrome) most often occurs secondary to nondisjunction during maternal
meiosis I. A severe condition trisomy 13 is strongly associated with cleft lip and palate,
polydactyly, rocker-bottom feet and holoprosencephaly.

In most cases of CF, the mutation in the CFTR gene product causes defective posttranslational folding and glycosylation. The result is degradation of the CETR integral
membrane protein before it reaches the cell surface.
Patients with Turner syndrome may have karyotype 45, XO (complete monosomy),
45X0/46XX (mosaicism), or 46XX (with partial deletion of one X chromosome). Mosaicism
appears to account for a majority of cases of Turner syndrome.

Sweat chloride concentrations over 60 mmol/L are found in patients with cystic fibrosis (CH)
F5O8 is the most common CFTR mutation found in patients with CR This mutation impairs
post-translational processing of the CRTR gene transcript. The result is degradation of the
gene product before it can be transported to the cell surface, causing complete absence of
CETR protein from the apical membrane of exocrine duct epithelial cells.
Phenotypic mixing refers to co-infection of a host cell by two viral strains resulting in progeny
virions that contain nucleocapsid proteins from one strain and the genome of the other strain.
Since there is no change in the underlying viral genomes (no genetic exchange) the next
generation of virions reverts to their original, unmixed phenotypes.

Genome recombination between two defective viruses co-infecting the same host cell can yield
a cytopathic wild-type genome. Recombination is gene exchange that occurs through the
crossing over of two double-stranded DNA molecules. Reassortment describes the mixing of
genome segments in two or more segmented viruses that infect the same host cell.
On average autosomal recessive conditions affect 25% of offspring of asymptomatic
heterozygous carrier parents. Classical galactosemia is an autosomal recessive disease.
Mental retardation, eczema, and a mousy or musty body odor in a toddler are signs of
phenylketonuria (PKU). Most infants with PKU are born to two heterozygous carrier parents.
The probability that heterozygous carrier parents will transmit an autosomal recessive disease
like PRU to a child is 1/4.
Streak ovaries amenorrhea and infertility are the gonadal manifestations of Turners
syndrome. This condition is associated with short stature webbed neck, low posterior hairline
and coarctation of the aorta.