Common Genetics Problems in Pediatrics

7/28/2019 Common Genetics Problems in Pediatrics

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Common Genetics Problems in

PediatricsShannon Browning MD

November 1, 2006


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Klinefelter Syndrome

Occurs in approximately 1 in 1000 births 80% have the classic 47,xxy karyotype, with 10

% having 46,XY/47XXY mosaicism and another10% having multiple x or Y chromosomes

Results from nondisjunction and is oftenassociated with advanced maternal age

Rarely diagnosed before the onset of puberty


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Most children with KS present initially withbehavior problems , abnormal puberty or

infertility issues Typically taller than average and increased

carrying angle and a relatively wide pelvis

30% will develop gynecomastia during inpuberty


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50% of children have speech delays and25% have motor

All affected males are infertile, althoughthere are rare cases of fertility


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Sickle Cell Disease

Results from a single genetic mutation in whicha nucleotide in the coding sequence of a beta-

globin gene is mutated from adenosine tothymidine

This mutation occurs in the middle of the tripletthat codes for normally glutamic acid as the 6th

AA of the beta-chain of hemoglobin. The singlebase change substitutes Valine for glutamic acid.


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Sickle Cell Disease

The resulting mutated hemoglobin hasdecreased solubility and abnormal

polymerization properties If only 1 beta-globin gene is mutated=heterozygous state which is referred to as sicklecell trait

If both genes are mutated resulting inhomozygous state and called sickle cell anemiaor sickle cell disease.


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Sickle Cell Disease

Prenatal testing for sickle cell has improvedsignificantly over the past 2 decades.

The newborn with sickle cell disease is notanemic initially because of the protective affectsof elevated fetal hemoglobin. Hemolytic anemiadevelops over the 1st 2-4mo.

Chorionic villus sampling can be performed asearly as 9 wks gestation making it an earlieralternative to amniocentesis.


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Teratogens

Accutane embryopathy is associated withembryonic exposure to isotretinoin beyond the

15

th

day after conception and through the end of1st trimester

Isotretinoin is a vitamin A derivative that isadministered orally and used for the treatment

of cystic acne It impedes the normal neural crest migration in

the developing embryo.


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Teratogens

This disruption in the migration of theneural crest cells leads to defects in the

central nervous system, severe earanomalies, conotruncal heart defects andthymic abnormalities

Alcohol can cause all the above mentionedabnormalities with the exception ofthymus abnormalities


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Teratogens

Warfarin embryopathy is a recognizable patternof malformation. Warfarin acts as an

anticoagulant because it is a vitamin Kantagonist. It prevents the carboxylation ofgamma-carboxyglutamic acid which is acomponent of osteocalcin and other vit K

dependent bone proteins. The critical period of exposure is between 6-9

weeks.


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Downs Syndrome

95% of all those affected with DS have trisomy of thechromosome 21

90-95% of these cases are due to maternal meiotic error

with 75% occurring in meiosis I. 3-5% are due topaternal meiotic errors and the remainder are due tomitotic nondisjunction

Recurrence risk estimates are based on empiric data The overall recurrence risk for having a child with any

trisomy is approx 1% added to the mothers age-relatedrisk. As a woman ages the age related risk exceeds therecurrence risk


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CHARGE association

C=coloboma, H=heart defect, A=atresiachoanae, R= retardation of growth postnatally

and development, G=genital anomalies, andE=ear anomalies

Affected individuals must have 4 of the 6features with at least one being coloboma or

atresia choanae There are multiple causes of this association


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Turner Syndrome

The two most common features in girls with TSis short stature and gonadal dysgenesis. Itshould be suspected in any girl of short stature

with unknown cause. Estimated that 1 in 2500 girls are affected Linear growth velocity varies: from birth to 3 yrs

it is normal, from 3-12 yrs velocity decreases,

and after age 12 it decelerates even further. Most affected girls have a 45,X karyotype Diagnosis is based on chromosomal analysis


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Neurofibromatosis Type I

Occurs in 1 in 3000 to 1 in 4000 lives births and isunrelated to gender, ethnicity or geographic location

Autosomal dominant condition

50% of cases are spontaneous mutations in the genethat codes for neurofibromin on chromosome 17.

Males and females are equally affected The recurrence risk to offspring of an affected individual

is 50% This gene abnormality shows full penetrance


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Neurofibromatosis Type I

Caf au lait macules (CALMs) are uniformlypigmented flat spots that range in size from afew mm to as much as 30cm in adults. CALMsincrease in size in proportion to growth.

One or two CALMs are common more than 6raises the concern about NF-1

Of children who present with 6 or more CALMs89% meet the diagnostic criteria for NF-1 within3 years.


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Angelman Syndrome

Affected children are normal at birth They experience global developmental

delay, but speech is affected most. Mostchildren will never speak

They laugh frequently and have an ataxic

gait and often hold their elbows awayfrom their bodies.

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Common Genetics Problems in Pediatrics