Genetics for Nurses in Pediatric Disciplines

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Genetics for Nurses in Pediatric Disciplines

• A guide to recognition and referral of congenital
  and genetic disorders
• AUTHORS
• Golder N. Wilson MD PhD,1 Vijay Tonk PhD,2
• REVIEWERS
• Shirley Karr BSN RN,3 Joanna K. Spahis BSN CNS,4
  Shirley Myers,5 RNC, MSN, FNP, and Sherry
  Letalian RN6
• 1Clinical Professor of Pediatrics, Texas Tech
  University Health Science Center at Lubbock and
  Private Practitioner, KinderGenome Genetics,
  Dallas Texas 2Professor of Pediatrics and
  Obstetrics-Gynecology Director, Cytogenetics
  Laboratory, Texas Tech University Health Science
  Center at Lubbock3Genetics Coordinator,
  Maternal-Fetal Medicine and Genetics, Texas Tech
  University Health Sciences Center at
  Amarillo4Pediatric Clinical Nurse Specialist in
  Genetics and Coordinator of the Down Syndrome
  Clinic, Department of Genetics, Childrens
  Medical Center of Dallas5Womens Health Nurse
  Practitioner, Maternal-Fetal Medicine and
  Genetics, Texas Tech University Health Sciences
  Center at Amarillo6Pediatric Clinic Coordinator,
  Department of Pediatrics, Texas Tech University
  Health Sciences Center, Lubbock
• Acknowledgement
• This presentation was designed as part of the
  GEN-ARM (Genetics Education Network for Nursing
  Assessment, Recognition, and Management) for the
  Mountain States Region Genetics Collaborative
  (MSRGCC) contact www.mostgene.org or Ms. Joyce
  Hooker at joycehooker_at_mostgene.org

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Genetic Disorders are Common
Genetic diseases affect 5-10 of children Nurses
can recognize and refer genetic disorders without
need for esoteric genetic knowledge We will now
present cases where your nursing skills and
alertness (REYDARRecognize, EYDentify, Assess,
Refer) can greatly benefit children with genetic
diseases. These cases will introduce you to
simple principles of genetics that will give you
confidence in recognizing these patients and
foster a medical home These cases and
principles are geared to the nursing genetics
primer and resources on the GENARM CD
3
Think genetics when something is unusual or
extreme

• Case A A term AGA newborn product of a pregnancy
  with little prenatal care has an enlarged and
  distorted head, blue-gray sclerae (whites of the
  eyes), and deformed limbs. X-rays show multiple
  fractures, and the mother blames this on an auto
  accident at 7 months gestation. Do you agree?

Newborn with large head and deformed bones with
fractures by x-ray
4
This unusual presentation should prompt REYDAR
for a genetic disease

• More detailed family history would be useful,
  although many genetic disorders occur as new
  changes (new mutations)
• The symptoms of blue sclerae and multiple
  fractures could be searched on the website Online
  Mendelian Inheritance in Man (go to
  http//www.ncbi.nlm.nih.gov/entrez/ or enter OMIM
  in search engine). They point to a disorder
  called osteogenesis imperfecta (166210
• OMIM contains gt6000 diseases that can be searched
  by symptom, name, or number associated databases
  contain genetic education, medical literature
  (PubMed), and even the complete human genome
  sequence/gene map.
• Also useful is the companion database
  www.genetests.org that lists testing (when
  available) for the particular genetic disease (go
  to the clinical laboratory section and search by
  disease name

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Suspicion of genetic disease underlying this
unusual infant led to referral and genetic
counseling for this autosomal dominant
diseasemothers guilt about her accident was
assuaged and she learned she had a 50 chance
each of her future children would have OI
The family history indicated that the mother and
other relatives had mild features of osteogenesis
imperfecta or brittle bone disease (see Chapter 2)
Family history
Pedigree
6

• Note that simple recognition and assessment of
  possible genetic disease, not sophisticated
  knowledge, optimized nursing care of this family.
  
• Nurses with additional interest in genetics can
  learn to construct pedigrees, interpret
  inheritance mechanisms, and provide recurrence
  risks for the parents (genetic counseling)
• Nurses are ideally positioned to be genetic
  counselors with their hands-on contact, emphasis
  on education, and focus on prevention
• Read chapters 2-4 in the primer to acquire the
  skills for genetic counseling

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Genetic disease can be defined by abnormal genes,
tissues, or chromosomes (genetic testing)
Categories of genetic disease relate to the steps
from gene to family (genetic hierarchy)

• A family has people with unusual symptoms
• A person has abnormal form or function (disease)
• A tissue (cell to organ) has abnormal structure
  (metabolic disorders)
• A chromosome is extra or missing (chromosome
  disorders)
• Several genes (plus environment) are abnormal
  (multifactorial disorders or susceptibilities)
• A gene (DNA to RNA to protein) is abnormal
  (Mendelian disorders

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Categories of genetic or congenital disease
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• Mendelian diseases like osteogenesis imperfecta
  have distinctive family patterns
• The pattern of affected relatives is caused by
  transmission of single genes, each with a unique
  position (locus) on the chromosome.
• The paired chromosomes 1-22 and XX in females
  imply paired genes except for X and Y genes in
  the male
• Dominant or recessive diseases result when one or
  both gene partners (alleles) are abnormal.
• Abnormal alleles can be predicted (genetic risks)
  and sometimes diagnosed through their abnormal
  DNA sequence or RNA/protein expression.

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• Sickle cell anemia is recessive, requiring both
  ß-globin alleles to be abnormal (SS versus AS
  trait or AA normal).
• Sickle cell anemia can be predicted (25 risk for
  next child) and tested (abnormal S protein or
  gene)
• Other inherited anemias can be related to
  different abnormal globin alleles (C, D, E,
  thassemias).

A or S
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• OI is caused by one abnormal allele at a collagen
  gene (genotype Oo)
• Different phenotypes of OI relate to different
  collagen alleles
• The gt6000 Mendelian diseases thus relate to a
  similar number of different genes and abnormal
  alleles.
• Characterization of abnormal alleles provides DNA
  testingfew of the gt1600 characterized disease
  genes are available to the clinic.
• Simultaneous analysis of multiple genes (DNA
  chips, arrays) is not yet practical in the way
  that karyotypes define any abnormal chromosomes

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Know categories, not rare diseases

• Mendelian diseases reflect transmission of single
  genes (abnormal alleles) DNA diagnosis

• Single genes altering development cause birth
  defects and syndromes
• Single genes altering enzyme pathways cause
  inborn errors of metabolism
• Single genes altering organ function(s) produce
  extreme or earlyonset
• examples of common disease (e.g.,
  neonatal diabetes)

Multifactorial diseases reflect multiple abnormal
genes plus environment DNA/HLA markers
Many genes altering development cause isolated
birth defects like cleft palate Many genes
altering enzyme pathways cause common metabolic
diseases (e.g., adult-onset
diabetes, hyperlipidemia) Many genes altering
organ function(s) produce adult diseases (e.g.,
schizophrenia)
Chromosomal diseases imbalance multiple genes
and cause multiple birth defects Karyotype
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REYDAR of common pediatric presentations
Recognition ? Category ? Referral ? Medical home

• Case 1N, 3Nnewborns with poor feeding, unusual
  appearance
• Case 4NNewborn with deterioration and lethargy
• Case 5KChild with hypotonia and motor delays
• Case 6KFirst-grader with school problems
• Case 7KBoy with tall stature
• Case 8KGirl with intermittent acidosis and
  fatigue
• (see Chapter 1)

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Case 1N. Newborn with feeding problems(see
Chapter 1 of primer)A term female infant
exhibited slow growth in the last trimester of
pregnancy but had normal ultrasound studies.
After normal delivery and borderline low birth
weight (5 lbs), the mother reported difficulty
breast-feeding. Lactation education and
reassurance were given and the infant was
discharged with mild jaundice and a weight loss
of 5 from her birth weight. Was this
management appropriate?What additional history
might have been helpful?
REYDAR of common pediatric presentations
Recognition to category to referral and
management
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Poor breast-feeding may signal syndromes or
congenital disorders
Case 1N (cont) Important history was that this
child was mothers second--her child was the
problem, not her breast-feeding. The childs low
muscle tone and subtle facial changes
(down-slanting palpebral fissures, broad nasal
bridge, down-turned corners of the mouth) led to
evaluation after discharge with chromosome
studies that showed deletion of the number 4
short arm (4P- or Wolf-Hirschhorn syndrome.
Recognition of HP signals was the key to REYDAR,
not knowledge of a rare disease.
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A birth defect (VSD) plus other signs

• Case 3N A term male infant with a heart murmur
  was found to have a ventricular septal defect
  without failure but had continuing lethargy, low
  muscle tone, poor latch for breast-feeding and
  difficulty stooling. What else should be
  considered?

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• The infants facial appearance was slightly
  unusual and raised the question of Down syndrome
  (OMIM 190685), which would explain the low
  muscle tone and poor feeding. Single palmar
  creases were noted on the hands as well as wide
  spaces between the first and second toes. What
  testing would be most useful in determining the
  childs diagnosis?

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• Routine chromosome analysis (karyotype) will show
  the extra chromosome 21 that is characteristic of
  Down syndrome which normally requires at least
  5-7 days for results.

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• Now a rapid FISH test is available that does not
  require stimulation of white blood cell division
  and gives results within 2-4 hours. Rapid FISH
  highlights chromosomes commonly involved in
  disorderse.g., 13 (Patau syndrome), 18 (Edwards
  syndrome), or 21 (Down syndrome), showing three
  versus the normal two FISH signals in each cell
  nucleus (X and Y probes also show Turner syndrome
  or document sex in cases of ambiguous genitalia)

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• RULE Do not blame neonatal feeding problems on
  inexperience/adjustment without considering a
  congenital/genetic disorder
• RULE Consider congenital/genetic disorders in
  children with several physical variations (minor
  anomalies) and/or unusual facial appearance

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Case 6K. A first-grader with school problems
A 6-year-old girl is having trouble keeping up in
the first grade because of distractibility and
poor comprehension. She had some problems
breast-feeding and later needed speech therapy.
Her school nurse noted a somewhat unusual facial
appearance with narrow eyes, long face, and
prominent nose she also had long fingers and a
faint heart murmur. The childs teacher felt she
was a discipline problem due to attention deficit
or conduct disorder and suggested possible
medication therapy. Do you agree?
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• The subtle facial changes, speech delay, and
  school problems suggest mild mental
  disability--such children may be labeled as
  unmotivated or hyperactive unless the underlying
  congenital problem is recognized. This child had
  the Shprintzen-DiGeorge spectrum (OMIM 192430),
  proven by FISH testing showing submicroscopic
  chromosome 22 deletion (her parents were normal).
  Referral to cardiology showed a small cardiac
  defect and arrythmia medication was needed, but
  not for the learning problem.

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• RULE Look for additional physical variations
  (minor anomalies like single palmar crease) in
  children with apparently isolated birth defects
  because syndromes imply multiple problems and
  higher genetic risks
• RULE School problems may reflect cognitive
  disabilities due to genetic conditions rather
  than behavior or psychosocial problems.

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Chromosome disorders

• Miscarriages (50-60), liveborn children (0.5),
  cancer tissue (many have diagnostic changes)
• Over 200 pediatric diseases due to extra or
  missing chromosome or parts of chromosomes (p
  small or q long arms)
• Hallmarks are multiple major or minor anomalies
  (unusual appearance) with mental disability
• Most recognized by a routine karyotype, but FISH
  is required to detect submicroscopic deletions
  (e.g., DiGeorge) or the 3 of suspect children
  who have changes on subtelomere FISH after normal
  karyotypes
• Individual submicroscopic deletions are found in
  Williams (7q), hereditary retinoblastoma (13q),
  Prader-Willi (15q), Shprintzen-DiGeorge spectrum
  (22q), and 15 others.
• Consider chromosomes in any child with
  unexplained mental disability and/or multiple
  birth defects, couples with gt2 miscarriages,
  prenatal diagnosis for women over age 35
• See Chapter 7 for more information

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Case 4N Sudden deterioration and unusual odor in
a newborn after 24 hours of feeding.

• A term newborn male with appropriate birth weight
  had an uncomplicated vaginal delivery with good
  Apgar scores. The child fed avidly for 24 hours
  but slowly become lethargic and less active. The
  nurse noted jaundice and documented a cutaneous
  bilirubin of 8.0 mg , mostly indirect. Review of
  the family history showed that the couple had 3
  living children with 2 prior infant deaths of
  unknown cause they came from the same small town
  in Mexico. The nurse also detected an unusual
  sweet smell to the urine and notified the
  pediatrician when the child became jittery and
  would not feed. What is the most likely disease
  category?

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Inborn errors of metabolism

• Metabolic diseases in children can have acute,
  intermittent, or insidious presentations. Unlike
  diabetes mellitus or metabolic syndromes in
  older children with obesity, early onset
  metabolic disorders are often due to abnormal
  genes that encode defective enzymesinborn errors
  of metabolism. Acute inborn errors involve
  derangements of small molecules and often
  manifest when a newborn is removed from the
  maternal metabolism (delivery) and required to
  break down foodstuffs on its own. Many acute
  metabolic disorders have similar symptoms of
  lethargy, low tone, and jitteriness progressing
  to coma due to low blood sugar, acidosis,
  inability to make energy, or high ammonia. What
  screening tests are indicated to investigate an
  acute metabolic disorder?

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Inborn errors of metabolism

• The standard newborn screen in Texas detects the
  acute metabolic disorders phenylketonuria (PKU--
  OMIM 261600) and galactosemia (OMIM 230400) as
  well as sickle cell anemia (OMIM 603903),
  congenital adrenal hyperplasia (OMIM 201910,
  others), and hypothyroidism (OMIM 218700,
  others).
• The expanded or supplemental newborn screen
  (employing in part an acylcarnitine profile) uses
  mass spectrometry to detect up to 50 additional
  acute metabolic disorders and is being adopted by
  most states.
• The supplemental screen along with blood sugar,
  electrolytes, pH, and ammonia was obtained in
  this infant, showing a low sugar (45 mg ),
  elevated anion gap (sodium plus potassium
  concentration minus chloride and bicarbonate ?
  12-14), acidosis (pH lt 7.2), and abnormal
  acylcarnitines. These findings plus certain
  elevated blood amino acids (leucine, isoleucine,
  valine) suggested a diagnosis of maple syrup
  urine disease and led to successful dietary
  treatment of the metabolic disorder

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Inborn errors of metabolism

• Over 300 disorders with overall frequency 1 in
  600.
• Nearly all are Mendelian autosomal or X-linked
  recessivethe abnormal alleles cause their
  encoded enzyme to be defective with build-up of
  chemicals before the block and deficiency of
  those after the block
• Children with inborn errors usually have a normal
  appearance with abnormal blood chemistries (low
  glucose, anion gap, high ammonia, high lactic
  acid)
• Early recognition is key before organ damage
  occurs from acidosis, seizures, or chemical
  build-up dietary treatment is often available

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• RULE Suspect acute metabolic disorders in
  normal-appearing infants who decompensate after
  feeding look for hypoglycemia, acidosis, or high
  ammonia.
• RULE The lack of a family history does not
  exclude a genetic disordersuspect new gene
  mutations or chromosome aberrations.

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Case 7KA boy with tall stature
. A pediatric nurse conducts a school physical
on a 6-year-old boy who is very tall for his age.
He has a height beyond the 97th centile despite
average weight and head circumference, and his
parents are not tall. The nurse notes other
findings including an aged facial appearance, lax
joints, heart murmur, and concave chest. The
nurse suspects a genetic condition, and documents
a family history
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Case 6A, cont

• The family history shows numerous relatives with
  heart problems on the fathers side. The father
  (individual III-2) is not unusually tall (5 10)
  and has no eye or heart problems. However, the
  fathers brother (individual III-1) developed
  aortic dilation and insufficiency at age 39, was
  6 5 tall, and had a lean build with flat feet
  and inguinal hernias.

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Disorders with extreme tall stature (gigantism),
short stature (dwarfism), or failure to thrive
are often genetic

• Diagnosis Marfan syndrome (154700)
• Suspicion of the disorder led to protection from
  collision or high-intensity sports and led to
  cardiac studies demonstrating aortic dilatation.
  The boy and affected family members have a 50
  risk to transmit the disease with each child.

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Case 9P. Adolescent female with unplanned
pregnancy

• A 16-year-old female was referred to obstetric
  clinic from the emergency room after a diagnosis
  of malnutrition and a positive pregnancy test.
  She had been brought in by the police for
  vagrancy and alcoholism, exhibiting poor hygiene
  and nutrition on examination. Fetal ultrasound
  revealed a fetus of about 3 months gestation with
  very small head circumference, abnormal head
  shape, and intrauterine growth retardation. Her
  obstetric RN recognized two likely diagnoses, and
  referred her to maternal-fetal medicine for
  evaluation including level II ultrasound.

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• The fetal growth changes would be consistent with
  fetal alcohol syndrome but the severe
  microcephaly suggested anencephaly (OMIM 206500,
  others). Of growing importance in pediatrics is
  preconception care, illustrated here by the fact
  that folic acid taken early in pregnancy lowers
  the incidence of neural tube defects like
  anencephaly or spina bifida by 2/3. As with
  maternal diabetes, prevention must begin before
  planning the pregnancy since a missed period may
  not be noticed until 3-4 weeks after conception
  (after the primitive streak stage)

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• RULE Pregnancy planning and preconception
  counsel are important priorities because
  recognition of pregnancy by a missed period (3-4
  weeks embryonic age) may be too late for
  preventive measures

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Multifactorial Disorders
Table 4.1. Multifactorial Disorders in the
United States
Ranks first for neonatal causes of death
approximate scale (100 of predisposition
due to genetic factors as for Mendelian
disorders) to (20 of predisposition due to
genetic factors)
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Multifactorial Disorders

• Most isolated birth defects like cleft palate,
  hypospadias, heart defects, spina bifida
• Many common diseases like diabetes mellitus,
  hypertension, mental illness
• Multiple genes involved, giving lower
  transmission risks (about 3 for offspring of
  affected parent, sibling to affected child)
• Therapeutic goals are to manipulate environment
  (e.g., folic acid) either generally or for
  specific high-risk individuals identified by
  associated DNA markers (more diverse and
  sensitive than HLA haplotypes

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Multifactorial disorders For some (e.g.,
coronary artery disease), single genes of major
effect (e.g., those regulating cholesterol) are
good risk markers)
Recognizing at-risk children or adolescent
females provides important opportunities for
nursing education and prevention (see chapter 4)
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Review Questions

• 1. A term female infant to a 37-year-old mother
  with three prior children has a low birth weight
  and a poor latch for breast-feeding the first 24
  hours of life. Mother had first trimester
  maternal serum screening (quad screen) that was
  normal. Your assessment of the baby reveals an
  unusual facial appearance with a broad nose and
  extra skin folds on the neck. Based on the
  history, which of the following is the most
  likely reason for poor breast-feeding in this
  child
• Maternal incompetence
• Autosomal dominant disorder in mother
• X-linked recessive disorder in child
• Chromosomal disorder in child
• Multifactorial disorder in child
• 2. Prior to receiving test results, the most
  important aspect of care along with evaluating
  the feeding problem is
• Genetic counseling regarding recurrence risk
• Genetic counseling regarding prenatal diagnosis
• Supportive counseling for future mental
  retardation
• Supportive counseling for probable birth defects
• Supportive counseling explaining the management
  plan

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• 3. A female infant demonstrates inconsistent
  bottle feeding and exaggerated jaundice with a
  total bilirubin of 14 at day 2 of life. Your
  assessment reveals the infant is less responsive
  than early on your shift, and you note decreased
  muscle tone with a poor suck. The prenatal
  history is normal except that the mother and
  father are from Pakistan and are second cousins.
  Which of the following conditions would be most
  likely in this infant?
• Chromosome disorder
• Biliary atresia
• Inborn error of metabolism
• Lactose intolerance
• Multifactorial disorder
• 4. As the infant is being evaluated, a
  grandparent brings documentation from Pakistan
  showing a prior child of this couple died with a
  diagnosis of maple syrup urine disease. Which of
  the following would resources would provide
  information on the inheritance of this disorder?
• Online Mendelian Inheritance in Man
• GeneTests
• Alliance of Genetic Support Groups
• ISONG
• ACOG

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Questions 5-6

• 5-6. A 21-year-old female was referred to
  obstetric clinic from the emergency room after a
  diagnosis of malnutrition and a positive
  pregnancy test. She had been brought in by the
  police for vagrancy and alcoholism, exhibiting
  poor hygiene and nutrition on examination. She
  also was affected with cystic fibrosis, having a
  milder disease course, and a sister had a child
  with spina bifida. Fetal ultrasound revealed a
  fetus of about 3 months gestation with very small
  head circumference, abnormal head shape, and
  intrauterine growth retardation.
• 5. The poor malnutrition and unplanned pregnancy
  caused the young woman to miss the following
  standards of care
• Amniocentesis because of higher risks for
  chromosome abnormalities and cystic fibrosis
• Triple/Quad screening with ultrasound to screen
  for fetal chromosome abnormalities
• Preconception counsel including provision of
  vitamins with folic acid
• Prosecution because of suspected alcoholism
  causing damage to the fetus
• Preimplantation genetic diagnosis of to avoid the
  high risk for fetal cystic fibrosis

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• 6. Which of the following birth defects would be
  most likely to occur in this situation?
• Congenital heart defect
• Omphalocele
• Anencephaly
• Tracheo-esophageal fistula
• Anal atresia

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Answers 1-D 2-E

• Questions 1-2.
• Difficulty breast feeding by an experienced
  mother should prompt concern about a congenital
  disorder. The history of advanced maternal age
  (gt 35) together with an unusual appearance in the
  child warrants consideration of a chromosome
  disorder. (answer 1D). First trimester quad
  screen plus ultrasound will detect as many as 87
  of fetuses with Down syndrome but sampling of
  fetal cells (e.g., chorionic villus sampling or
  amniocentesis) with karyotyping is required for
  definitive diagnosis of fetal chromosome
  disorders.

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Answers 3-C 4-A

• Questions 3-4
• The difficulty feeding with progressive lethargy
  and family history of parental consanguinity
  (relatedness) suggest a metabolic disorder (see
  Chapters 2 and 10). Information on genetic
  disorders such as maple syrup urine disease can
  be found in Online Mendelian Inheritance in Man
  (enter OMIM in browser).

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Answers 5-C 6-C

• Questions 5-6
• The importance of preconception counsel is
  recognized by the American College of Obstetrics
  and Gynecology (ACOG). Provision of folic acid
  prior to conception (the embryo will be at least
  3 weeks along when mother misses her menstrual
  period) lowers the risk of neural tube defects
  (spina bifida, anencephaly) by 2/3. Neural tube
  defects exhibit multifactorial determination (see
  Chapter 4) with increased risk (0.5-1) to
  relatives. The woman is affected with cystic
  fibrosis (219700--autosomal recessive) and would
  be a homozygote (genotype ccsee Chapter 3) but
  the father would be unlikely to be a carrier (at
  least 19/20 chance) and thus there would be no
  indication for prenatal diagnosis. A planned
  pregnancy could have included carrier screening
  for cystic fibrosis in the father.