Common Genetics Problems in Pediatrics

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Common Genetics Problems in Pediatrics

• Shannon 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 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

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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

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Klinefelter Syndrome

• 50 of children have speech delays and 25 have
  motor
• All affected males are infertile, although there
  are rare cases of fertility

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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.

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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.

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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.

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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.

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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

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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-carboxyglutami
  c acid which is a component 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
  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
  mothers age-related risk. As a woman ages the
  age related risk exceeds the recurrence risk

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CHARGE association

• Ccoloboma, Hheart defect, Aatresia choanae, R
  retardation of growth postnatally and
  development, Ggenital anomalies, and Eear
  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

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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

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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

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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.

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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.