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 Lubbock;3Genetics Coordinator, Maternal-Fetal Medicine and
Genetics, Texas Tech University Health Sciences Center at Amarillo;4Pediatric Clinical Nurse Specialist in Genetics and
Coordinator of the Down Syndrome Clinic, Department of Genetics, Children’s Medical Center of Dallas5Women’s Health
Nurse Practitioner, Maternal-Fetal Medicine and Genetics, Texas Tech University Health Sciences Center at
Amarillo;6Pediatric 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@mostgene.org
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 (REYDAR=Recognize, 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
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
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 >6000 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
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
Suspicion of genetic disease underlying this unusual infant led to
referral and genetic counseling for this autosomal dominant disease—
mother’s guilt about her accident was assuaged and she learned she
had a 50% chance each of her future children would have OI
• 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
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
Genetic disease can be defined by abnormal
genes, tissues, or chromosomes (genetic testing)
Categories of genetic or congenital disease
Disease category1
Number of
diseases
Aggregate
frequency2
Shortened
lifespan
Major
handicap
(%)
Mendelian
> 4500
1
++3
+++
Chromosomal
> 100
0.5
++++
++++
Multifactorial
> 100
5-10
++
+++
Metabolic errors
> 500
0.3
+++
++++
Syndromes
> 1000
0.7
+++
++++
Isolated anomalies
> 200
2-3
+
++
Total
> 5000
10-12
++
+++
• 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.
Sickle cell anemia is
recessive, requiring
both β-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
• OI is caused by one abnormal
allele at a collagen gene
(genotype Oo)
• Different phenotypes of OI
relate to different collagen
alleles
• The >6000 Mendelian
diseases thus relate to a
similar number of different
genes and abnormal alleles.
• Characterization of abnormal
alleles provides DNA testing—
few of the >1600 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
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 early–onset
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
REYDAR of common pediatric presentations
Recognition → Category → Referral ↔ Medical home
• Case 1N, 3N—newborns with poor feeding,
unusual appearance
• Case 4N—Newborn with deterioration and
lethargy
• Case 5K—Child with hypotonia and motor
delays
• Case 6K—First-grader with school problems
• Case 7K—Boy with tall stature
• Case 8K—Girl with intermittent acidosis and
fatigue
(see Chapter 1)
REYDAR of common pediatric presentations
Recognition to category to referral and management
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?
Poor breast-feeding may signal
syndromes or congenital disorders
Case 1N (cont): Important history was that this
child was mother’s second--her child was the
problem, not her breast-feeding. The child’s
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 WolfHirschhorn syndrome. Recognition of H&P
signals was the key to REYDAR, not
knowledge of a rare disease.
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?
• The infant’s 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 child’s diagnosis?
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.
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
disorders—e.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)
Cloned DNA segment
from target chromosome
13
18
21
X
Y
FISH probes
Fluorescent label
13, X, Y
No culture or need for
metaphase spreads
18
21
Male with
trisomy 13
• 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
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 child’s teacher felt she
was a discipline problem due to attention deficit or conduct disorder and
suggested possible medication therapy. Do you agree?
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.
• 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.
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), ShprintzenDiGeorge spectrum (22q), and ~15 others.
• Consider chromosomes in any child with unexplained mental disability
and/or multiple birth defects, couples with >2 miscarriages, prenatal
diagnosis for women over age 35
See Chapter 7 for more information
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?
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 enzymes—inborn 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?
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 < 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
Inborn errors of metabolism
• Over 300 disorders with overall frequency 1 in 600.
• Nearly all are Mendelian autosomal or X-linked recessive—
the 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
• 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 disorder—suspect
new gene mutations or chromosome
aberrations.
Case 7K—A 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
Case 6A, cont
The family history shows
numerous relatives with heart
problems on the father’s
side. The father (individual
III-2) is not unusually tall (5’
10”) and has no eye or heart
problems. However, the
father’s brother (individual III1) developed aortic dilation
and insufficiency at age 39,
was 6’ 5” tall, and had a lean
build with flat feet and
inguinal hernias.
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.
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.
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)
• 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
Multifactorial Disorders
Table 4.1. Multifactorial Disorders in the United States
Disorder or
category
Cause of
death
Prevalence
Numbers
affected
(rank)
(%
population)
(millions)
Hereditability
[Genetic risk factors]
(high ++++ to low +)
Heart disease
1
3
7
++ [Cholesterol uptake]
Cancer
2
5
6
++ [Oncogenes]
Stroke
3
<1
0.6
+ [Cholesterol, blood
clotting]
Accidents
4
<1
3
+
Diabetes
mellitus
7-8
4
11
++ [Insulin secretion,
action]
Suicide
8-9
<1
0.1
++ [Schizophrenia,
alcoholism]
Congenital
anomalies*
9-10
5
3
++ [Developmental genes]
[Alcohol and drug use]
*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)
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
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)
Review Questions
•
A.
B.
C.
D.
E.
•
A.
B.
C.
D.
E.
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 breastfeeding 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
•
A.
B.
C.
D.
E.
•
A.
B.
C.
D.
E.
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
Questions 5-6
•
•
•
A.
B.
C.
D.
E.
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
6. Which of the following birth defects would
be most likely to occur in this situation?
A. Congenital heart defect
B. Omphalocele
C. Anencephaly
D. Tracheo-esophageal fistula
E. Anal atresia
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
(> 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.
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).
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 cc—see 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.