genetic disorders fac 2007

Pediatric genetic disordersPediatricsPA-580Fall 2007

http://www.nchpeg.org/index.asp

17 things healthcare professionals should know about genetics

1. Basic human genetics terminology.2. Basic patterns of biological inheritance and variation, within families

and within populations.3. How identification of disease-associated genetic variations facilitates

development of prevention, diagnosis, and treatment options.4. Importance of family history (minimum three generations) in

assessing predisposition to disease.5. Role of genetic factors in maintaining health and preventing disease.6. Difference between clinical diagnosis of disease and identification of

genetic predisposition to disease (genetic variation is not strictly correlated with disease manifestation).

7. Role of behavioral, social, and environmental factors (lifestyle, socioeconomic factors, pollutants, etc.) to modify or influence genetics in the manifestation of disease.

8. Influence of ethno-culture and economics in the prevalence and diagnosis of genetic disease.

17 things healthcare professionals should know about genetics

9. Influence of ethnicity, culture, related health beliefs, and economics in the client’s ability to use genetic information and services.

10. Potential physical and/or psychosocial benefits, limitations, and risks of genetic information for individuals, family members, and communities.

11. The range of genetic approaches to treatment of disease (prevention, gene-based drugs, gene therapy, and pharmacogenomic-based prescribing to match individual genetic profiles).

12. Resources available to assist clients seeking genetic information or services, including the types of genetics professionals available and their diverse responsibilities.

13. Components of the genetic-counseling process and the indications for referral to genetic specialists.

14. Indications for genetic testing and/or gene-based interventions.15. Ethical, legal, and social issues related to genetic testing and recording of genetic

information (e.g., privacy, the potential for genetic discrimination in health insurance and employment).

16. History of misuse of human genetic information (eugenics).17. One’s own professional role in the referral to genetics services, or provision, follow-

up, and quality review of genetic services.

8 skills healthcare professionals should master

1. Gather genetic family-history information, including an appropriate multigenerational family history.

2. Identify clients who would benefit from genetic services.3. Explain basic concepts of probability and disease susceptibility, and

the influence of genetic factors in maintenance of health and development of disease.

4. Seek assistance from and refer to appropriate genetics experts and peer-support resources.

5. Obtain credible, current information about genetics, for self, clients, and colleagues.

6. Use effectively new information technologies to obtain current information about genetics.

7. Educate others about client-focused policy issues.8. Participate in professional and public education about genetics.

http://www.aafp.org/online/en/home/clinical/acf.html

What are the expectations of a PCP?

• Construct and interpret a genogram (family history).

• Assess the information necessary to counsel patients who are considering genetic testing.

• Describe the elements of genetic consultation• Understand ethical, legal and social issues • Provide adequate patient information prior to

testing• Understand how to find information and connect

patients to information resources • Pharmacogenomics

http://www.aafp.org/online/en/home/clinical/acf/genomics/clinobj.html

Objectives • Describe the role of the PA in working with

patients with genetic disorders• Describe the importance of the role of family

history in identifying and determining genetic disorders

• Describe, construct and identify the components of a pedigree

• Review common pediatric genetic disorders• Describe additional resources available to the

clinician and patient

http://content.nejm.org/cgi/reprint/351/22/2333.pdf

Pedigree

• A graphic or diagrammatic representation of family relationships– typically, a pedigree is recorded with standard

symbols and nomenclature that are used to represent individuals and convey information

http://www.ama-assn.org/ama1/pub/upload/mm/464/family_insert02.pdf

Pedigree symbols to know

Patient can create their own pedigree

http://www.hhs.gov/familyhistory/

Take home forms 1

http://www.aafp.org/PreBuilt/acf_fammedhistory.pdf

Take home forms 2

http://www.aafp.org/PreBuilt/acf_diseasechecklist.pdf

Pedigree vs. Genogram • A genogram is a diagram focusing on family

relationships across several generations used primarily by mental health, social health and family health care professionals. – Most genograms include

– Family, emotional, and social relationships

Genogram

SCREEN

http://www.aafp.org/PreBuilt/acf_genomics_screen.pdf

Common pediatricgenetic disorders

• Chromosomal disorders– Trisomy 13, 18, 21– Turners and Klinefelter syndrome

• Mendelian disorders– Marfan syndrome– Cystic fibrosis– Duchenne-Type Muscular Dystrophy

Common pediatric genetic disorders



Chromosomal abnormalities 2° to number

• Result from an error that occurred when an egg or sperm cell were developing

• Why the error?– Unknown

• Nothing that a parent does or doesn’t do before or during pregnancy can cause a chromosomal abnormality in his or her child

http://search.marchofdimes.com/cgi-bin/MsmGo.exe?grab_id=657&page_id=8914176&query=trisomy&hiword=TRISOMIES+trisomy+


• Reproductive cells have only 23 unpaired chromosomes. – When an egg and sperm cell unite, they form

a fertilized egg with 46 chromosomes.• In the process of cell division,

– An error occurs that leaves an egg or sperm cell with too many or too few chromosomes.

• A common type of chromosomal abnormality is called a trisomy

http://search.marchofdimes.com/cgi-bin/MsmGo.exe?grab_id=657&page_id=8914176&query=trisomy&hiword=TRISOMIES+trisomy+

Trisomy• This means that an individual has three copies, instead

of two, of a specific chromosome. • Down syndrome is an example of a trisomy.

– Individuals with trisomy 21 generally have three copies of chromosome 21.

http://www.ds-health.com/trisomy.htm

Trisomy 13 & 18

• 13– 1:12,000 live births

• 18– 1:4000 live births

• These trisomies are usually much more severe than Trisomy 21

• Born with severe mental retardation and many physical birth defects.– Most affected babies die before their first birthday.

Trisomy 21 (Down syndrome )

• The most common of the trisomy disorders– 13

• 1:12,000 live births– 18

• 1:4000 live births– 21

• 1:600 live births

Trisomy 21

• General– Life expectancy: 55 years

• Characteristics– Combination of birth defects

• some degree of mental retardation (mild to severe)• characteristic facial features• heart defects (50% will have these)• GI tract anomalies (15% will have these)• problems with vision and hearing

Trisomy 21 facial features• May have

– eyes that slant upward– small ears that may fold over a

little at the top– mouth may be small, making

the tongue appear large– nose may also be small, with a

flattened nasal bridge. • Some babies have

– short necks– small hands with short fingers– less muscle tone, appear

somewhat "floppy."

Trisomy 21 risk

• Increases with the mother’s age. – 25 yo: 1 in 2000 – 35 yo: 1 in 400– 40 yo: 1 in 100

Risk evaluation• Prenatal testing

– Amniocentesis• After 16th week

– Chorionic villus sampling

• Between 10 – 14th week

• Risk (albeit small)– Infection– Miscarriage– Offered only to women

at increased risk http://www.webmd.com/hw/health_guide_atoz/aa78760.asp

Chorionic villus sampling


• One of the 23 pairs of human chromosomes is called the sex chromosome

• Most common chromosomal abnormalities are those that involve missing or extra sex chromosomes– referred to as X and Y – Females have two X chromosomes– Males have one X and one Y chromosome– Abnormalities

• sexual development• Infertility• growth abnormalities• behavioral and learning problems• most affected individuals live essentially normal lives.

Sex chromosome abnormalities

• Turner syndrome (Monosomy X)– Female have one X chromosome, instead of

two – 1:10,000 females

• Klinefelter syndrome (XXY)– Males have two or more X chromosomes

along with their Y chromosome– 1:1,000 males

Turner syndrome

• General– First described in 1930s– 95% are miscarried– 5% are liveborn– They usually are sterile

• do not undergo normal pubertal changes unless they are treated with sex hormones

Turner syndrome

Stratakis: Endocrinologist, Volume 15(1).January/February 2005.27-36

Turner syndrome

• Children with TS– Issues include

• short stature• bone density • skeletal defects• cardiovascular defects• fertility• management of hormonal replacement

Klinefelter syndrome• General

– First recognition of this syndrome was in 1942– The most common chromosomal disorder associated

with male hypogonadism and infertility – Affected boys

• tend to be tall with normal intelligence– learning disabilities are common

• they have more problems with judgment and impulse control than XY males

– As adults• they produce lower than normal amounts of the male

hormone testosterone (and often are treated with this hormone)

• infertile

Klinefelter syndrome• Physical characteristics

– when present, may include• sparse pubic, facial, and

body hair• underdeveloped muscles• enlarged breasts

(gynecomastia)• may also be taller than

others in their family and have long legs, narrow shoulders, and wide hips

http://yalenewhavenhealth.org/library/healthguide/en-us/support/topic.asp?hwid=zm2596

Klinefelter syndrome

• Most males born with Klinefelter syndrome go through life without being diagnosed– Prepubertal boys have a normal phenotype – Diagnosis, when made, usually occurs in

adulthood

Common pediatric genetic disorders



Mendelian disorders

• Single gene disorders– Inherited genetic disorders– Genes carry instructions for either dominant

or recessive traits• Sometimes the genes are altered in some way,

and a medical disorder results

Mendelian disorders

• Autosomal dominant– a 50 percent chance

(a one-in-two chance) that each child will have the same condition

– dominant disorders often are quite variable, with symptoms ranging from none to severe.

http://ghr.nlm.nih.gov/ghr/picture/autoDominant

Autosomal dominant conditions

• Craniosynostoses syndrome• Osteogenesis • Neurofibromatosis• Marfan syndrome

Autosomal dominant conditions

• Craniosynostoses syndrome– premature fusion of cranial sutures

• Osteogenesis Imperfecta– aka: brittle bone disease

• Neurofibromatosis– subcutaneous neurofibromas

• Marfan syndrome

Neurofibromatosis

Marfan syndrome

• General– First described in 1896– An inherited connective tissue disorder

• can affect the heart, blood vessels, lungs, eyes, bones and ligaments

• symptoms may be mild or severe• may be present at birth or appear in childhood or in adult life

– Most common of inherited disorders of connective tissue

– Incidence: 1 in 5,000

http://www.marchofdimes.com/professionals/14332_1216.asp

Marfan syndrome• Physical characteristics

– tall, slender– loose-jointed– arms and legs may be

unusually long in proportion to the torso

– feet often are flat– spine may be curved

(scoliosis)– the face may be long and

narrow

www.hughston.com/hha/a_12_2_4.htm

Marfan syndrome• Most serious associated

problem and the greatest danger is death – Aortic dissection

• Children and adults with Marfan syndrome are warned to avoid heavy exercise– contact sports and lifting

heavy objects.– yearly or more frequent

echocardiograms are recommended

www.mayoclinic.org/marfan/features.html

Mendelian disorders• Autosomal recessive

– a 25 percent chance (a one-in-two chance) that each of their children will inherit the problem.

– If both parents are carriers of the same recessive gene that can cause a birth defect

– If only one parent passes on the gene for the disorder, the normal gene received from the other parent will prevent expression of the condition.

http://ghr.nlm.nih.gov/ghr/picture/autoRecessive

Autosomal recessive conditions• Sickle cell disease

– a blood disorder that mainly affects people of African-American and Hispanic descent

• Tay-Sachs disease– which causes mental retardation and death mainly in people of

Eastern European Jewish or French Canadian heritage • Phenylketonuria

– a metabolic disorder primarily affecting Caucasians• Cystic fibrosis

– a disorder of the lungs and digestive system affecting mainly people of Northern European Caucasian descent

http://www.marchofdimes.com/pnhec/4439_4136.asp

Autosomal recessive conditions• Sickle cell disease

– 1: 500 African-Americans has the disease• Also affects Arabian, Greek, Maltese, Italian, Sardinian, Turkish and

Indian ancestry • Tay-Sachs disease

– 1: 30 American Jews carries the Tay-Sachs gene • Most frequently in descendants of Central and Eastern European

(Ashkenazi) Jews• Phenylketonuria

– 1: 14,000 is born with PKU/year• The disorder occurs in all ethnic groups

• Cystic fibrosis– 1: 31 Americans carries the CF gene

• 1:32 is born with CF/year• 30,000 children and adults in this country have CF

http://www.marchofdimes.com/pnhec/4439_4136.asp

X-linked inheritance

• An X-linked genetic disease is one that is generally passed on from mother to son. – The genetic abnormality is found on the X

chromosome.– Males inherit the X chromosome from their

mother and the Y chromosome from their father.

– Abnormalities on the X chromosome from the mother will usually manifest as a disease within 50% of her sons.

X-linked inheritance

• Some conditions passed on through X-linked inheritance are:– Hemophilia

• Blood lacking Facto VIII needed for clotting – Red-green color blindness – Duchenne muscular dystrophy

• Muscle weakness and death

Duchene Muscular Dystrophy • One of nine types of muscular dystrophy

– A group of genetic, degenerative diseases primarily affecting voluntary muscles

• Primarily affects boys– Who inherit the disease through their mothers. Women can be

carriers of DMD but usually exhibit no symptoms • Onset

– Early childhood - about 2 to 6 years.• Progression

– All voluntary muscles are affected• including the heart and breathing muscles• survival is rare beyond the early 30s

Duchene Muscular Dystrophy • Characteristics

– myotonia (prolonged muscle spasm) in the fingers and facial muscles

– a floppy-footed, high-stepping gait

– cataracts– cardiac abnormalities– endocrine

disturbances

http://www.ninds.nih.gov/disorders/md/md.htm

So where does a PA go?

http://www.nchpeg.org/

www.geneticalliance.org

References

• Links are provided on all slides for additional information

• Associated readings posted in BB

genetic disorders fac 2007

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