1	Common Genetics Problems in Pediatrics Shannon Browning MD November 1, 2006
2	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
3	Klinefelter Syndrome 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
4	Klinefelter Syndrome 50% of children have speech delays and 25% have motor All affected males are infertile, although there are rare cases of fertility
5	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 6^th AA of the beta-chain of hemoglobin. The single base change substitutes Valine for glutamic acid.
6	Sickle Cell Disease 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.
7	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 1^st 2-4mo. Chorionic villus sampling can be performed as early as 9 wks gestation making it an earlier alternative to amniocentesis.
8	Teratogens Accutane embryopathy is associated with embryonic exposure to isotretinoin beyond the 15^th day after conception and through the end of 1^st 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.
9	Teratogens 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
10	Teratogens 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.
11	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
12	CHARGE association C=coloboma, H=heart defect, A=atresia choanae, R= retardation of growth postnatally and development, G=genital anomalies, and E=ear anomalies Affected individuals must have 4 of the 6 features with at least one being coloboma or atresia choanae There are multiple causes of this association
13	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
14	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
15	Neurofibromatosis Type I 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.
16	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.