Genetic Disorders

Down syndrome
Definition :
Base from Patterson, D (Jul 2009). "Molecular genetic analysis of
Down syndrome.". Human Genetics. 126 (1): 195214.
doi:10.1007/s00439-009-0696-8. PMID 19526251. a b c d e f g h i
j k l m n o p q r Weijerman, ME; de Winter, JP (Dec 2010). "Clinical
practice. The care of children with Down syndrome.". European
journal of pediatrics. 169 (12): 144552. doi:10.1007/s00431-010-
1253-0. PMID 20632187a b c d e f g h i j k l m n o p q r s t u v w x
y z aa ab Malt, EA; Dahl, RC; Haugsand, TM; Ulvestad, IH; Emilsen,
NM; Hansen, B; Cardenas, YE; Skld, RO; Thorsen, AT; Davidsen,
EM (Feb 5, 2013). "Health and disease in adults with Down
syndrome.". Tidsskrift for den Norske laegeforening : tidsskrift for
praktisk medicin, ny raekke. 133 (3): 2904.
doi:10.4045/tidsskr.12.0390. PMID 23381164. Down syndrome
(DS or DNS), also known as trisomy 21, is a genetic disorder
caused by the presence of all or part of a third copy of
chromosome 21. It is typically associated with physical growth
delays, characteristic facial features and mild to moderate
intellectual disability. The average IQ of a young adult with Down
syndrome is 50, equivalent to the mental ability of an 8- or 9-
year-old child, but this can vary widely.
Illustration :
Frequency :
According to the Centers for Disease Control and Prevention,
approximately 6,000 babies are born in the United States each
year with Down syndrome, or approximately 1 out of every 691
live births. Retrieve from
https://www.nichd.nih.gov/health/topics/down/conditioninfo/pages/
risk.aspx
Inheritance pattern :
Most cases of Down syndrome are not inherited. When the
condition is caused by trisomy 21, the chromosomal abnormality
occurs as a random event during the formation of reproductive
cells in a parent. The abnormality usually occurs in egg cells, but
it occasionally occurs in sperm cells. Retrieve from
https://ghr.nlm.nih.gov/condition/down-syndrome.
People who inherit an unbalanced translocation involving
chromosome 21 may have extra genetic material from
chromosome 21, which causes Down syndrome. Like trisomy 21,
mosaic Down syndrome is not inherited. It occurs as a random
event during cell division early in fetal development. Retrieve
from https://ghr.nlm.nih.gov/condition/down-syndrome.
Diagnosis and Management :
Your doctor may suggest that you have tests during pregnancy to
find out if your baby has Down syndrome. You may decide to
have:
Screening tests, such as an ultrasound or a blood test during your
first or second trimester. These can help show if the developing
baby (fetus) is at risk for Down syndrome. But these tests
sometimes give false-positive or false-negative results.
Diagnostic tests, such as chorionic villus sampling or
amniocentesis. These can show if a baby has Down syndrome.
You may want to have these tests if you have abnormal results
from a screening test or if you are worried about Down syndrome.
Sometimes a baby is diagnosed after birth. A doctor may have a
good idea that a baby has Down syndrome based on the way the
baby looks and the results of a
physical exam. To make sure, the baby's blood will be tested. It
may take 2 to 3 weeks to get the test results.
Starting soon after birth, a baby with Down syndrome will be
tested for health problems, such as eye, ear, or thyroid problems.
The sooner these problems are found, the better they can be
managed. Regular doctor visits can help your child stay in good
health.

Your doctor will make a treatment plan that meets your growing
child's needs. For example, most children with Down syndrome
need speech therapy and physical therapy. Teens and adults with
Down syndrome may need occupational therapy to learn job skills
and learn how to live on their own. Counseling may help with
social skills and emotional issues.

Many professionals will help you and your child through life. But
you are vital to your child's success. To help your child:
Learn all you can about Down syndrome. This can help you know
what to expect and how you can help your child.
Find out what type of financial help you can get by contacting
your state's Department of Developmental Disabilities.
Check into resources in your area. For example, many states
provide free early-intervention programs for children with Down
syndrome up to age 3 to help them get off to a good start.
Look into school options for your child. Federal law requires public
schools to provide services to all children with disabilities who are
ages 3 to 21.
Raising a child with Down syndrome has both challenges and
rewards. Remember to take time for yourself. And ask for help
when you need it. Talking to other parents who are raising
children with Down syndrome can be a big help. Ask your doctor
or hospital about parent support groups, or contact a group like
the National Down Syndrome Congress. Retrieve from
http://www.webmd.com/children/tc/down-syndrome-topic-
overview#1 and

Prognosis :
The life expectancy for people with Down Syndrome has
increased substantially. In 1929, the average life span of a person
with Down Syndrome was nine years. Today, it is common for a
person with Down Syndrome to live to age 50 and beyond.
In addition to living longer, people with Down Syndrome are now
living fuller, richer lives than ever before as family members and
contributors to their community. Many people with Down
Syndrome form meaningful relationships and eventually marry.
Now that people with Down Syndrome are living longer, the needs
of adults with Down syndrome are receiving greater attention.
With assistance from family and caretakers, many adults with
Down Syndrome have developed the skills required to hold jobs
and to live semi-independently. Retrieve from
http://www.mychildwithoutlimits.org/understand/down-
syndrome/down-syndrome-prognosis/

Haemophilia
Definition :
Haemophilia, also spelled hemophilia, is a mostly inherited
genetic disorder that impairs the body's ability to make blood
clots, a process needed to stop bleeding. This results in people
bleeding longer after an injury, easy bruising, and an increased
risk of bleeding inside joints or the brain. Retrieve from
https://en.wikipedia.org/wiki/Haemophilia.
Illustration :
Frequency :
Hemophilia A occurs in 1 in 5,000 live male births. Hemophilia A is
about four times as common as hemophilia B. The number of
people with hemophilia in the United States is estimated to be
about 20,000 individuals. The worldwide incidence of hemophilia
is not well known, but estimated at more than 400,000 people.
Retrieve from https://www.hemophilia.org/About-Us/Fast-Facts
Inheritance pattern :
Hemophilia A and hemophilia B are inherited in an X-linked
recessive pattern. The genes associated with these conditions are
located on the X chromosome, which is one of the two sex
chromosomes. In males (who have only one X chromosome), one
altered copy of the gene in each cell is sufficient to cause the
condition. Retrieve from
https://ghr.nlm.nih.gov/condition/hemophilia
Diagnosis and Management :
If doctors suspect hemophilia A or B in a young child, they will do
some simple lab tests. They will take a blood sample, and
measure the amount of factor VIII and factor IX in the blood.
Factor VIII is the protein which is lacking in hemophilia A.
Factor IX is the protein which is lacking in hemophilia B.
The tests will show:
if the person has a bleeding disorder
what kind of bleeding disorder the person has
how severe the bleeding disorder is.

Hemophilia A and B can be divided into three classifications.

CLASSIFICATION LEVEL OF FACTOR VIII
OR IX IN THE BLOOD
Severe Less than 1% of normal
Moderate 1 to 5% of normal
Mild 5 to 30% of norma

One of the lab tests will show how much von Willebrand factor
(VWF) is in the blood. Von Willebrand factor is another of the
proteins in the blood which is important for normal clotting. It acts
as a glue, sticking platelets to the wall of a broken blood vessel. If
the level of VWF is low, then the person has von Willebrand
disease, not hemophilia A or B.
It usually takes 1 to 2 weeks for test results to come back.

Decision-making process
Attitudes about hemophilia often depend on personal experience.
Some carriers have grown up with a close relative who has
complications from the disease. They could belong to a family
with inhibitor problems. They might have seen the consequences
of HIV or hepatitis C in a loved one. They may have witnessed the
pain caused by joint disease. They feel the need for alternatives
to having a child with hemophilia. Religion, personal values and
culture also play a part in decision-making around prenatal
diagnosis and termination of pregnancy. Couples should work
closely with the hemophilia treatment team and genetic
counsellors throughout the prenatal diagnostic process for both
medical and emotional support.
Some couples choose not to have prenatal diagnosis (PND) and
simply want a male baby tested at birth. Others, in order to
prepare themselves, feel they need to know the hemophilia
status, even if they have no intention of terminating the
pregnancy.
Other couples are interested in prenatal diagnosis because
terminating the pregnancy if the baby has hemophiliaas hard as
that decision may be for themis an option. Precautions must be
taken when terminating a pregnancy, as with any surgical
procedure, to avoid bleeding complications. The hemophilia
treatment team must be involved in preparations and follow-up.
Following a termination, counselling should be offered to help
couples cope with the emotional strain.
The genetic counselling session should be tailored to support the
personal values and beliefs of the family so that the couple feel
secure in whatever decision they make. The objective of prenatal
diagnosis is to try and provide carriers and their spouses with
accurate and current information so they can make an informed
decision in a supportive environment. Genetic counsellors protect
the couples autonomy and confidentiality, and provide support
and education. They must be sensitive to the range of values,
cultures, religious beliefs and ethnic differences in our society. In
this way, individuals or families can make decisions that are in
keeping with their value and belief systems.

Medical coverage
Obligate carriers or potential carriers of hemophilia (for example,
a case of no family history but a son already born with
hemophilia) are eligible for prenatal diagnosis. If available in a
laboratory in the province where the family resides, the procedure
is covered by provincial health insurance. Otherwise, a special
request to the provincial Ministry of Health may need to be made
to cover the cost of out-of-province testing.
Prenatal diagnostic options
Ultrasound
Some couples find out the sex of the baby by ultrasound and then
make a decision about invasive testing only if the ultrasound
predicts the baby to be a boy. The sex can generally be predicted
by ultrasound at 16 weeks gestation. Couples should be informed
of the limitations of ultrasound in predicting the sex of the baby.
Chorionic villus sampling (CVS)
The chorion is a membrane that surrounds the developing foetus.
It is located outside of the amniotic membrane. The chorion is a
foetal membrane, that is to say, it originates from the same cells
as the developing baby. The chorion is covered with finger-like
projections called chorionic villi. In early pregnancy, the villi will
implant in the uterus at one point to develop into the placenta,
and the remainder of the villi disappear. CVS can be carried out
after 11 weeks gestation to obtain DNA for analysis. The sample
may be taken either by the vaginal or abdominal route,
depending on where the placenta is located.
Figure 9 from p. 65 of AAC
Vaginal CVS is similar to a pap smear. While an ultrasound is
being done on the abdomen to locate the foetus, a speculum is
inserted into the vagina. A fine tube is then passed through the
cervix and guided to where the placenta is forming. About 10 to
15 milligrams of tissue are aspirated into a syringe. Results can
take up to 3 weeks. The abdominal method is similar to
amniocentesis. CVS is avoided before 11 weeks because of
reports of limb abnormalities occurring when carried out earlier.
The miscarriage rate associated with this procedure is
approximately 1%. CVS is covered by provincial health insurance.
Amniocentesis
Amniocentesis is done after 15.5 weeks. An ultrasound is
performed to locate the placenta and to select a pocket of
amniotic fluid. A thin needle is then inserted through the
abdomen and into the uterus. A small amount of amniotic fluid is
removed. This fluid contains cells that the foetus has shed. In
some circumstances, the cells need to grow before the DNA from
them can be extracted. The risk for complications with the
procedure is 0.5%. Test results take 3 to 4 weeks if cells need to
be grown before the test can be done. Amniocentesis is covered
by provincial health insurance.
The difference between amniocentesis and CVS is that CVS is
done much earlier in pregnancy and thus the results are received
earlier.
As with any medical procedure in a carrier of hemophilia,
precautions must be taken to avoid bleeding complications.
Couples should work closely with the hemophilia treatment team,
including the obstetrician and genetic counsellors throughout the
process for medical and emotional support, including follow-up.
Foetal blood sampling
Foetal blood sampling may be carried out at 18 weeks or more
gestation. A sample is taken from the umbilical vein, under
ultrasound guidance, through a needle inserted into the
abdomen. Blood is taken, and the factor level can be assayed
immediately. It is important to ensure that the sample in the tube
is truly foetal blood and not maternal. A difficult procedure, the
risk of miscarriage is as high as 5%.
Maternal blood test
A new non-invasive method for prenatal diagnosis is at present
being developed. In future, a blood sample taken from the mother
at 7 to 8 weeks gestation will be tested for foetal blood cells. The
foetal male chromosomes will be separated from the mother's
blood and tested for hemophilia. This procedure is still in
development.

Potential psychosocial issues at prenatal diagnosis

If a carrier already has a brother or son with hemophilia and the
results from prenatal diagnosis show that the baby is a boy and
has hemophilia, she may feel ambivalent about stopping a
pregnancy, as she dearly loves her son or brother. By stopping a
pregnancy when the baby is predicted to have hemophilia, she
may feel like she is rejecting her son and/or brother. On the other
hand, she may not know whether she can emotionally handle
having another child with hemophilia. Her own feelings may
conflict with those of her partner.
These are examples of the psychosocial issues that often come up
in a genetic counselling session. A genetic counsellor explores
these feelings with the couple. This may take more than one
counselling session.
In the context of hemophilia, the number of women seeking PND
in the developed world seems to be decreasing with the
successful use of prophylactic treatment. Prophylactic and on-
demand home care has improved the quality of life for young
people with hemophilia and their families, allowing most to grow
up without severe joint disease or other complications. A study in
Sweden showed the main reasons carriers do not use prenatal
diagnosis is that they do not consider hemophilia to be a disorder
serious enough to justify termination of a pregnancy. Having a
child, however, is a personal decision and each woman has the
right to choose what's best for her and her family. Previous
personal experience of hemophilia is still the greatest contributing
factor affecting decisions. Retrieve from
http://www.hemophilia.ca/en/bleeding-disorders/hemophilia-a-
and-b/the-diagnosis-of-hemophilia/
Prognosis :
 Prognosis of haemophlia from What is hemophilia?. NHLBI. July
13, 2013; http://www.nhlbi.nih.gov/health/health-
topics/topics/hemophilia.Robert A Zaiden. Hemophilia A.
Medscape. November 7, 2014;
http://emedicine.medscape.com/article/779322-overview is
Hemophilia can be mild, moderate, or severe, depending on how
much clotting factor is in an affected person's blood. However,
about 70% of patients have the severe form of the disorder.
With appropriate education and treatment, people with
hemophilia can live full and productive lives. Prophylaxis
(preventive measures) and early treatment have dramatically
improved the long-term outlook (prognosis) for people with severe
hemophilia. Replacement therapy has significantly improved life
expectancy, and the availability of therapy at home has improved
quality of life. About 25% of people with severe disease between
6-18 years of age do have below-normal motor skills and
academic performance, and have more emotional and behavioral
problems than others.
The most important life-threatening complications of hemophilia
are intracranial hemorrhage (bleeding within the skull) and
hemorrhages into the soft tissue around vital areas (such as the
airway or internal organs). The lifetime risk of intracranial
bleeding in affected people is 2-8% and accounts for one third of
deaths due to hemorrhage. About 10% of those with severe
hemophilia have intracranial bleeding, with a mortality rate of
30%. Chronic, debilitating joint disease can also develop.
Overall, the mortality rate for affected people is about twice that
of the healthy male population. For severe hemophilia, the rate is
about 4-6 times higher. In some cases the mortality rate depends
on whether any other underlying diseases or conditions are
present.
Iron overload/Hemochromatosis
Definition :
Definition of Iron overload base from Hider, Robert C.; Kong,
Xiaole (2013). "Chapter 8. Iron: Effect of Overload and
Deficiency". In Astrid Sigel, Helmut Sigel and Roland K. O. Sigel.
Interrelations between Essential Metal Ions and Human Diseases.
Metal Ions in Life Sciences. 13. Springer. pp. 229294.
doi:10.1007/978-94-007-7500-8_8a b c Lu JP, Hayashi K. Selective
iron deposition in pancreatic islet B cells of transfusional iron-
overloaded autopsy cases. Pathol Int. 1994 Mar;44(3):194-9.
PubMed PMID 8025661 is also known as hemochromatosis,
indicates accumulation of iron in the body from any cause. The
most important causes are hereditary haemochromatosis (HHC), a
genetic disorder, and transfusional iron overload, which can result
from repeated blood transfusions.
Illustration :
Frequency :
While transfusions deliver vital red blood cells, what some
patients may not realize is that each unit of blood contains 250
milligrams of iron. Generally, a person needs only 1 milligram of
iron a day to replace what is lost from normal body function.
Retrieve from
www.irondisorders.org/Websites/idi/Images/TIOtrifold.pdf
Inheritance pattern :
Types 1, 2, and 3 hemochromatosis are inherited in an autosomal
recessive pattern, which means both copies of the gene in each
cell have mutations. Most often, the parents of an individual with
an autosomal recessive condition each carry one copy of the
mutated gene but do not show signs and symptoms of the
condition.
Type 4 hemochromatosis is distinguished by its autosomal
dominant inheritance pattern. With this type of inheritance, one
copy of the altered gene in each cell is sufficient to cause the
disorder. In most cases, an affected person has one parent with
the condition. Retrieve from
https://ghr.nlm.nih.gov/condition/hereditary-hemochromatosis
Diagnosis and Management :
There are several methods available for diagnosing and
monitoring iron loading including:
Serum ferritin: In males and postmenopausal females, a serum
ferritin value of over 300 ng/mL (670 pmol/L) indicates iron
overload.[16][17][18] In premenopausal females, a serum ferritin
value of over 150 or 200 ng/mL (330 or 440 pmol/L) indicates iron
overload.
Liver biopsy HFE MRI
Serum ferritin testing is a low-cost, readily available, and
minimally invasive method for assessing body iron stores.
However, the major problem with using it as an indicator of iron
overload is that it can be elevated in a range of other medical
conditions unrelated to iron levels including infection,
inflammation, fever, liver disease, kidney disease, and cancer.
Also, total iron binding capacity may be low, but can also be
normal.
The standard of practice in diagnosis of haemochromatosis was
recently reviewed by Pietrangelo. Positive HFE analysis confirms
the clinical diagnosis of haemochromatosis in asymptomatic
individuals with blood tests showing increased iron stores, or for
predictive testing of individuals with a family history of
haemochromatosis. The alleles evaluated by HFE gene analysis
are evident in ~80% of patients with haemochromatosis; a
negative report for HFE gene does not rule out
haemochromatosis. In a patient with negative HFE gene testing,
elevated iron status for no other obvious reason, and family
history of liver disease, additional evaluation of liver iron
concentration is indicated. In this case, diagnosis of
haemochromatosis is based on biochemical analysis and
histologic examination of a liver biopsy. Assessment of the hepatic
iron index (HII) is considered the "gold standard" for diagnosis of
haemochromatosis.
Magnetic resonance imaging (MRI) is emerging as a noninvasive
alternative to accurately estimate iron deposition levels in the
liver as well as heart, joints, and pituitary gland. Retrieve from
Ferritin by: Mark Levin, MD, Hematologist and Oncologist, Newark,
NJ. Review provided by VeriMed Healthcare Netwon Andrea
Duchini. "Hemochromatosis Workup". Medscape. Retrieved 2016-
07-14. Updated: Jan 02, 2016 a b Molar concentration is derived
from mass value using molar mass of 450,000gmol1 for ferritin
labtestsonline.org > TIBC & UIBC, Transferrin Last reviewed on
October 28, 2009.: a b Pietrangelo, Antonello (2010). "Hereditary
Hemochromatosis: Pathogenesis, Diagnosis, and Treatment".
Gastroenterology. 139 (2): 393408.
doi:10.1053/j.gastro.2010.06.013. PMID 20542038.Wood JC,
Enriquez C, Ghugre N, Tyzka JM, Carson
Prognosis :
Affected individuals over age 40 or who have high serum ferritin
levels are at risk for developing cirrhosis. Iron overload increases
the risk of hepatocellular carcinoma. This risk is greater in those
with cirrhosis but is still present in those without cirrhosis.
Significant problems occur in around one in ten. Retrieve from
Crownover, BK; Covey, CJ (Feb 1, 2013). "Hereditary
hemochromatosis.". American family physician. Kowdley, KV
(November 2004). "Iron, hemochromatosis, and hepatocellular
carcinoma.". Gastroenterology.