Common Genetics Problems in Pediatrics

Common Genetics Problems in Pediatrics
Presentation lecture by:Shannon Browning MD

Klinefelter Syndrome

* Occurs in approximately 1 in 1000 births
* 80% have the classic 47,xxy karyotype, with 10 % having 46,XY/47XXY mosaicism and another 10% having multiple x or Y chromosomes
* Results from nondisjunction and is often associated with advanced maternal age
* Rarely diagnosed before the onset of puberty
* Most children with KS present initially with behavior problems , abnormal puberty or infertility issues
* Typically taller than average and increased carrying angle and a relatively wide pelvis
* 30% will develop gynecomastia during in puberty
* 50% of children have speech delays and 25% have motor
* All affected males are infertile, although there are rare cases of fertility

Sickle Cell Disease

* Results from a single genetic mutation in which a nucleotide in the coding sequence of a beta-globin gene is mutated from adenosine to thymidine
* This mutation occurs in the middle of the triplet that codes for normally glutamic acid as the 6th AA of the beta-chain of hemoglobin. The single base change substitutes Valine for glutamic acid.
* The resulting mutated hemoglobin has decreased solubility and abnormal polymerization properties
* If only 1 beta-globin gene is mutated= heterozygous state which is referred to as sickle cell trait
* If both genes are mutated resulting in homozygous state and called sickle cell anemia or sickle cell disease.
* Prenatal testing for sickle cell has improved significantly over the past 2 decades.
* The newborn with sickle cell disease is not anemic initially because of the protective affects of elevated fetal hemoglobin. Hemolytic anemia develops over the 1st 2-4mo.
* Chorionic villus sampling can be performed as early as 9 wks gestation making it an earlier alternative to amniocentesis.

Teratogens

* Accutane embryopathy is associated with embryonic exposure to isotretinoin beyond the 15th day after conception and through the end of 1st trimester
* Isotretinoin is a vitamin A derivative that is administered orally and used for the treatment of cystic acne
* It impedes the normal neural crest migration in the developing embryo.
* This disruption in the migration of the neural crest cells leads to defects in the central nervous system, severe ear anomalies, conotruncal heart defects and thymic abnormalities
* Alcohol can cause all the above mentioned abnormalities with the exception of thymus abnormalities
* Warfarin embryopathy is a recognizable pattern of malformation. Warfarin acts as an anticoagulant because it is a vitamin K antagonist. It prevents the carboxylation of gamma-carboxyglutamic acid which is a component of osteocalcin and other vit K dependent bone proteins.
* The critical period of exposure is between 6-9 weeks.

Down’s Syndrome

* 95% of all those affected with DS have trisomy of the chromosome 21
* 90-95% of these cases are due to maternal meiotic error with 75% occurring in meiosis I. 3-5% are due to paternal meiotic errors and the remainder are due to mitotic 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 mother’s age-related risk. As a woman ages the age related risk exceeds the recurrence risk

Turner Syndrome

* The two most common features in girls with TS is short stature and gonadal dysgenesis. It should 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

Neurofibromatosis Type I

* Occurs in 1 in 3000 to 1 in 4000 lives births and is unrelated to gender, ethnicity or geographic location
* Autosomal dominant condition
* 50% of cases are spontaneous mutations in the gene that 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
* Café au lait macules (CALMs) are uniformly pigmented flat spots that range in size from a few mm to as much as 30cm in adults. CALMs increase in size in proportion to growth.
* One or two CALMs are common more than 6 raises the concern about NF-1
* Of children who present with 6 or more CALMs 89% meet the diagnostic criteria for NF-1 within 3 years.

Angelman Syndrome

* Affected children are normal at birth
* They experience global developmental delay, but speech is affected most. Most children will never speak
* They laugh frequently and have an ataxic gait and often hold their elbows away from their bodies.

Common Genetics Problems in Pediatrics.ppt