Weitzman Newborn Screening Part 2 2019

Pediatric Genetics
Newborn Screening Part 2
Mark Korson, MD
VMP Genetics, LLC
Leah Burke, MD
University of Vermont

Weitzman Institute Learning Academy Pediatric Genetics
The NERGN project is supported by the Health
Resources and Services Administration (HRSA) of the
U.S. Department of Health and Human Services
(HHS) under grant number UH7MC30778; New
England Regional Genetics Network; total award
amount: 1.5 million; 100% from governmental
sources. This information or content and
conclusions are those of the author and should not
be construed as the official position or policy of, nor
should any endorsements be inferred by HRSA, HHS
or the U.S. Government.

4
Disclosures
We do not have anything to disclose.

5
Learning Objectives
• Describe the history of newborn screening and how
new disorders are added
• Understand the significance of an abnormal newborn
screen
• Define the role(s) of the primary care physician in the
newborn screening process
• Apply learned principles to adapted case studies

CHCI Profile:
 Founding year: 1972
 Hubs/Locations: 15/210
 Patients per year: 100,000

Session Date
March 18, 2019: Autism Spectrum Disorder: Genetic and Neurological Perspectives
Session Time
1 p.m. to 2:30 p.m. EST
To register: https://www.weitzmaninstitute.org/nergn-cip-registration

Leah W. Burke, MD
Mark Korson, MD
Today’s Presenters
Addiction 101—Session 2: Trauma-Informed Care| 2/21/19

NEWBORN SCREENING – PART I
• The evolution of newborn screening
• How a disease gets approved for screening
• The logistics of the newborn screen
• The resources available to clinicians to help manage an
abnormal result

NEWBORN SCREENING – PART II
• WELCOME!
• Today - real cases to highlight some of the issues that
arise with an abnormal result

Call from the NB Screening Lab!
The infant’s screen shows the following abnormalities:
• Total galactose = 50 mg/dL (NL<14)
• GALT enzyme = absent
• Amino acids = High MET, PHE, TYR

SECONDARY MARKER
PRIMARY MARKER

GALACTOSE
UDP-
GLUCOSE
UDP-
GALACTOSE
GLUCOSE-1-PO4GALACTOSE-1-PO4

GALACTOSE
UDP-
GLUCOSE
UDP-
GALACTOSE
GLUCOSE-1-PO4
GALT
GALACTOSE-1-PO4
LIVER DISEASE
SEPSIS RISK

GALACTOSE
UDP-
GLUCOSE
UDP-
GALACTOSE
GLUCOSE-1-PO4
GALT
GALACTOSE-1-PO4
GALACTITOL
CATARACTS

GALACTOSEMIA
HOMOCYSTINURIA ?
PHENYLKETONURIA ?
TYROSINEMIA ?

This is all likely due to the
patient’s galactosemia.
PHE, TYR, MET are non-
specifically elevated due to liver
dysfunction.
PHE
HOMOGENTISIC
4-OH-PPA
TYR
MALEYL-AcAC
FUMARYL-AcAC

This is all likely due to the
patient’s galactosemia.
PHE, TYR, MET are non-
specifically elevated due to liver
dysfunction.
PHE
HOMOGENTISIC
4-OH-PPA
TYR
MALEYL-AcAC
FUMARYL-AcAC
INHIBITED

The baby is now 6 days old.
Born to a 32 yr old woman, G3/P2→3, following an
unremarkable pregnancy and vaginal delivery at term.
Discharged home on day 2, breastfeeding. Slightly jaundiced
at discharge.

You saw the baby in the office for jaundice the day before.
Total bilirubin =11.8 mg/dL.
The baby is still breastfeeding.

Your office calls today for an update. She is still jaundiced,
maybe more so.
The mother says the baby is not feeding as vigorously today
as yesterday.

At your office, the infant is floppy and drowsy, rousing only
for brief periods of time.
Mucous membranes are moist. Significantly icteric.
Liver edge is felt 3 cm below the right costal margin. No
spleen palpable.

The baby is referred to the ED for evaluation!
Liver functions:
• AST=413, ALT=555
• Bili: total/direct=18.8/1.3
CBC: Hgb=13.9 g/dL, Hct=41%, WBC=25.2, Platelets=102
• Differential: neutrophils=81%, bands=10%
Electrolytes: Na=144, K=5.1, Cl=115, HCO3=15
Urinalysis: pH=6.5, gluc/keto/prot negative
Urine reducing substances - strongly positive

Which ONE of the following is your immediate concern at
this time?
A. Liver failure
B. Sepsis
C. Irreversible cataracts
D. Stroke
E. Kidney failure

Which ONE of the following should you do before
performing a lumbar puncture in this case?
A. Cranial ultrasound
B. Repeat bloodwork
C. Start antibiotics with gram-negative coverage
D. Coagulation studies
E. Feed with a lactose-free formula

Coags: PT=17.2 sec, INR=1.4, PTT>60 sec
Blood cultures – positive for E. coli
CSF, urine cultures – negative
Responds to antibiotic therapy; the baby recovers.
Water droplet cataracts noted by slit-lamp exam;
regressed after a soy diet is initiated.
Lab abnormalities resolve within 2-3 days.

The newborn male is the 2nd child born to non-
consanguineous parents, following a normal pregnancy
and delivery.
Birth weight=2950 grams, length=51 cm.
Alert and active, feeding well.
Discharged home on day 2.

Call from the NB Screening Lab on day 4:
• Elevation in citrulline
• Elevation in argininosuccinic acid
• Elevation in CIT/ASA ratio
There is a concern about a urea cycle defect.

Call from the NB Screening Lab on day 4:
• Elevation in citrulline
• Elevation in argininosuccinic acid
• Elevation in CIT/ASA ratio
There is a concern about a urea cycle defect.
SECONDARY MARKER
PRIMARY MARKERS

AMMONIA
CARBAMYL
PHOSPHATE
UREA
ORNITHINE
ARGININE
ARGININOSUCCINIC
ACID
CITRULLINE

UREA CYCLE DISORDERS
• Neonatal-onset urea cycle defects can be associated with
feeding difficulties, seizures, progressive lethargy, and
coma.
• Late-onset variants may be associated with clinical
decompensations associated with infections or
following a dietary protein load.

You call the family.
The baby is breastfeeding vigorously every 2-3 hours.
The parents are shocked by the news; they had no idea
there was anything wrong with their baby.

At this point, which ONE of the following is your next
recommendation?
A. Have the baby seen in the Metabolic Clinic today
B. Have the baby seen by the PCP tomorrow
C. Have the baby go directly to the ED
D. Repeat the newborn screening test
E. Order blood amino acids to confirm the
abnormality

Among the following lab tests, which ONE would be the
most helpful regarding the patient’s immediate
management?
A. Amino acids (blood)
B. Organic acids (urine)
C. Acylcarnitines (blood)
D. Ammonia
E. Lactic acid

If the ammonia is elevated, what might be classically
abnormal about the vital signs?
A. Tachycardia
B. Bradycardia
C. Tachypnea
D. Apnea
E. Hypertension

The ammonia level measures 320 µmol/L (NL<95)
Repeat four hours later  352

Management in the NICU:
• Protein feedings are held
• Fluids given: 10% dextrose-1/4 normal saline at
1.5x maintenance rate
• IV medications to clear waste nitrogen
(Na benzoate–Na phenylacetate, L-arginine)
• Monitor ammonia and amino acids

The baby does well. The ammonia levels normalize within
24-36 hours.
Once normal, feeding is begun; the diet is limited in natural
protein to the RDI for protein.
Oral medications are provided that
help to clear waste nitrogen.
Courtesy of Mark Korson, MD

WHY WE DO NEWBORN SCREENING….
Before newborn screening, this baby would
have presented clinically:
• Poor feeding  altered mental
status  coma, even death
Neurodevelopmental sequelae correlate with
the duration of encephalopathy
hyperammonemia.
Courtesy of Mark Korson, MD

A newborn baby was diagnosed with meconium ileus at birth
• Meconium ileus is a bowel obstruction that occurs when the
meconium is thicker and stickier than normal meconium
• Most infants with meconium ileus have a disease called
cystic fibrosis
The newborn screen came back screen positive for CF, BUT
only one mutation was found (delta F508)
Sweat chloride testing (gold standard for diagnosis)
was also positive for CF
49

YOU GET MORE HISTORY
The couple had had carrier screening for cystic fibrosis (CF)
during the pregnancy
The mother had been found to have a common CF mutation
(delta F508) and the father’s screening test was negative
50

WHAT IS GOING ON?
A. The baby does not really have cystic fibrosis
B. The reported father is not the biological father (misattributed
paternity)
C. The genetic testing done in newborn screening is incomplete
D. The samples were switched
51

A. The baby does not really have cystic fibrosis
B. The reported father is not the biological father (misattributed
paternity)
C. The genetic testing done in newborn screening is incomplete
D. The samples were switched
52
WHAT IS GOING ON?

NEWBORN SCREENING FOR CYSTIC FIBROSIS
Newborn screening for CF involves first testing for elevated
immunoreactive trypsinogen (IRT), an indicator of pancreatic
insufficiency
When an elevated IRT is found, reflex testing of a panel of
CF mutations is done
53

GENETIC TESTING FOR CF
More than 1500 mutations have been described in the
gene for cystic fibrosis
Both carrier screening and newborn screening only tests
for a handful of those
Trust the clinical picture and get the geneticist involved
to explain discrepancies

FOLLOW-UP TESTING IN THIS CASE
Baby had sequencing done of the whole CF gene and was
found to have a second rare mutation
Father was subsequently tested and found to carry the rare
mutation
55

A female patient is born by elective repeat C-section to a
31 year old woman, G2/P1→2, at 38 weeks gestation
following a pregnancy. Had premature labor briefly at
29 weeks, treated with terbutaline, bed rest. Birth
weight=2880 grams.
Feeds well on cow’s milk formula.
Kept in the NICU because of maternal complications
(fever, infection).

Routine newborn screen is positive for C14:1, indicative
of very long chain acyl CoA dehydrogenase (VLCAD)
deficiency.
C14:1 is short-hand for an unsaturated fatty that is
14 carbons long and esterified to carnitine, and
therefore identified by tandem mass spectrometry.
C2-C6 – short chain
C6-C10 – medium chain
C12-C18 – long/very long chain

LCFA
MCFA
SCFA
12-18 C
6-10 C
<6 C Acetyl
CoA
Ketones
Mitochondrion
L-carnitine
+ LCFA
LONG CHAIN
FATTY ACID OXIDATION DEFECTS

VERY LONG CHAIN ACYL CoA DEHYDROGENASE
(VLCAD) DEFICIENCY
• Fasting intolerance
• Encephalopathy with fasting/catabolism
• Muscle involvement:
• Rhabdomyolysis
• Muscle weakness
• Cardiomyopathy

Blood for acylcarnitine analysis sent – normal.
The baby continues to feed well. There are no symptoms
of concern.
Liver functions are normal.
Echocardiogram is normal.

At this point, which ONE of the following most closely
represents the counseling you provide to the parents?
A. The NB screen is a false positive
B. The follow-up testing is not definitive and further
testing needs to be done
C. The baby does not have VLCAD deficiency

The C14:1 normalizes because the baby gains weight 
less catabolic  the fatty acid intermediates normalize.
The baby remains at risk for developing symptoms.
Further testing options:
• Blood acylcarnitines during an infection
• VLCAD enzyme testing
• Fatty acid oxidation testing in fibroblasts
• VLCAD DNA sequencing

SO I CAN’T ALWAYS
TRUST A NORMAL
REPEAT SPECIMEN
FROM THE NB
SCREENING LAB??

If the NB Screening Lab asks for a repeat specimen, trust a
normal result.
If the Lab recommends a metabolic referral, diagnostic
testing is necessary.
When in doubt, consult a geneticist.

An infant female is born following an unremarkable
pregnancy. Mother is a 34 years old G2/P01/SA1. The
baby is delivered by cesarean section. Birth
weight=3250 grams.
Mild jaundice, not requiring phototherapy.
Discharged home, bottle-feeding a cow’s milk formula.

The NB Screening Lab calls on day 7.
There is an elevated level of C3, could be indicative of
propionic acidemia
• C3=4.1 (NL<0.8)
• C3/C0=14 (NL<2)
C3 is short-hand for an unsaturated fatty that is 3
carbons long (propionate) and esterified to carnitine,
and therefore identified by tandem mass spec

The NB Screening Lab calls on day 7.
There is an elevated level of C3, could be indicative of
propionic acidemia
• C3=4.1 (NL<0.8)
• C3/C0=14 (NL<2)
C3 is short-hand for an unsaturated fatty that is 3
carbons long (propionate) and esterified to carnitine,
and therefore identified by tandem mass spec
SECONDARY MARKER
PRIMARY MARKER

PROPIONIC ACIDEMIA
• A defect in organic acid metabolism
• In its most severe form, it can be associated with feeding
difficulties, progressive lethargy, seizures, and coma
• A milder variant, it might be associated with vomiting,
lethargy, as well as clinical and biochemical
decompensation

You call the parents and they are concerned because the
baby is gagging with some feeds, and has vomited
earlier. He has been crying most of the last 4-5 hours.
You recommend the baby go to the ED where the baby
is found to be listless and hypotonic.
The baby is not well-hydrated. He is tachypneic and
mottled.

Appropriate laboratory testing is likely to identify which ONE
of the following combinations:
1. Metabolic acidosis
2. Ketosis
3. High ammonia
4. Neutropenia
5. Thrombocytopenia
Combinations of abnormal results:
A. 1, 2, 3
B. 1, 3
C. 2, 4
D. 4 only
E. 1, 2, 3, 4, 5

Actual lab results:
• Blood gases: pH=7.21, pCO2=21, pO2=42, HCO3=9
• CBC: Hgb=13, Hct=38.4, WBC=3.1, Plts=71
• WBC diff: Neutrophils=25%, bands=2%
• Electrolytes: Na=134, K=4.7, Cl=99, HCO3=10
• Anion gap= 25
• NH3= 320 μmol/l (NL<95)
• Urinalysis: pH=5, gluc neg, prot neg, ketones 4+

The infant’s metabolic crisis improves with the
following approach:
• IV dextrose
• Removal of ammonia
• Restriction of protein
• Calorie supplementation

You get a call from the newborn screening lab your patient
has a positive newborn screen for SCID
They tell you that the TRECs are low
78

POSITIVE SCREEN FOR SCID
<125 copies/uL of TREC (Reference range is >200 copies/uL)
This information was on the newborn screening result:
• “Babies with severe combined immunodeficiency have a blockage or
T-cell development, resulting in functional deficiencies in both T & B
cells. T-cell counts approach zero in affected newborns, and this is
reflected by a lack of T-cell receptor excision circles in blood. TREC
analysis revealed that this infant has a low number of TRECs and
therefore is at risk for an immunodeficiency. Referral to a specialist for
a complete blood count, flow cytometry, evaluation, and genetic
counseling is recommended”.
79

WHAT DO YOU DO NOW?
A. See the baby in your office as soon as possible
B. Admit the baby immediately to the hospital
C. Call the geneticist
D. Call the immunologist
80

A. See the baby in your office as soon as possible
B. Admit the baby immediately to the hospital
C. Call the geneticist
D. Call the immunologist
81
WHAT DO YOU DO NOW?

83
Int. J. Neonatal Screen. 2017

FOLLOW-UP ON THE CASE
Mildly decreased numbers of T-cells were found on further
testing
No evidence of SCID
Some developmental delays and hypotonia were noted
Referral to a geneticist resulted in a diagnosis of
22q deletion syndrome
84

85
Int. J. Neonatal Screen. 2017

Which ONE of the following is the proper response when
receiving a call from the NB Screening Lab?
A. Dammit! They’re calling again!
B. They’re always asking for another specimen!
C. Hang up and don’t answer the phone when they call
back!
D. As if my life isn’t hard enough!
E. Thank you for calling.

NB screening is a screen, not a diagnostic test.
Remember:
• The (ACMG) ACT sheets and algorithms
• Other educational resources
Concerns? Questions?  call a geneticist!
SUMMARY

RESOURCES FOR INFORMATION: NEWBORN SCREENING
https://www.babysfirsttest.org/

RESOURCES FOR INFORMATION: CONDITIONS
Genereviews.org
https://newenglandconsortium.org/

Weitzman Newborn Screening Part 2 2019

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