Linda Ikuta, MN, RN, CCNS, PHN, and Ksenia Zukowsky, PhD, APRN, NNP-BC ❍ Section Editors

❍ Section Editor

Clinical Issues in Neonatal Care

Important Considerations in the

Initial Clinical Evaluation of the
Dysmorphic Neonate
Patroula Smpokou, MD; Brendan C. Lanpher, MD; Kenneth N. Rosenbaum, MD

ABSTRACT
Background: The approach to clinical evaluation of the dysmorphic neonate can be challenging and multifaceted. It
requires specialized knowledge of rare diagnoses and awareness of immediate versus long-term needs for the newborn
and the family.
Purpose: This review summarizes important considerations in the initial evaluation of genetic syndromes, which can
present in the neonatal period with variable aspects of dysmorphism.
Methods:  An overview of the literature in this area is provided.
Findings/Results:  Several overlapping areas of concern for working with this population are addressed, including com-
munication with the family, fundamentals of the physical examination, common genetic disorders, syndromes, as well as
palliative care and end of life decision making for the newborn in the context of family needs.
Implications for Practice: The initial approach for the neonatal practitioner needs to focus on various aspects of the
newborn's care, including medical stabilization, determining whether immediate laboratory or imaging studies are
needed, careful physical examination with particular attention to detail, appropriate and timely communication with the
family, and knowledge of various specific aspects of rare diseases.
Implications for Research:  More research is needed to better understand how to best support the newborn born with
dysmorphia or a rare disease. Particular attention needs to be focused on strategies to best support the family who is
often in crisis during the neonatal period.
Key Words:  dysmorphism, dysmorphic features, dysmorphic neonate, genetic evaluation, genetic syndrome

T
he clinical genetic evaluation of a neonate sus-
pected of having an underlying syndromic
diagnosis can be complex, multifaceted, and
emotionally burdensome to the family. In the neona-
tal nursery or intensive care setting, the initial
approach is extremely important. Many consider-
ations must be addressed when contacting specialists
for consultations and communicating specific con-
cerns to the family.
Fundamental to this initial approach (for all neo-
natal practitioners—nurses, nurse practitioners,
physician assistants, and neonatologists) is a clear
and well-rounded knowledge and appreciation for
the complexity of this evaluation, the correct
approach to assessing dysmorphia in the setting of a
recent birthing process, and the uncertainties arising
Author Affiliations: Division of Genetics & Metabolism, Children's
National Health System, Washington, DC (Drs Smpokou, Lanpher, and
Rosenbaum); and Department of Pediatrics, The George Washington
School of Medicine & Health Sciences, Washington, DC (Drs Smpokou,
Lanpher, and Rosenbaum).
The authors declare no conflicts of interest.
Correspondence: Patroula Smpokou, MD, Division of Genetics &
Metabolism, Children's National Health System, 111 Michigan Ave NW,
Ste 1950, Washington, DC 20010 (psmpokou@childrensnational.org).
DOI: 10.1097/ANC.0000000000000216
from a potential genetic diagnosis and related
testing.1,2 Moreover, the critical aspects of an initial
assessment for life-threatening complications that
need immediate attention and treatment need to be
addressed. And most importantly careful and sensi-
tive ways of communicating those concerns to the
family are vital to the care of these infants in the
context of families.
This review presents a practical approach and
important considerations in the initial evaluation of
a neonate with possible dysmorphia and suspected
syndromic diagnosis from the perspective of the neo-
natal clinician.
COMMUNICATING CONCERNS WITH
THE FAMILY
When a neonatal clinician encounters a possibly dys-
morphic neonate, the first response is often self-
doubt. Assessing dysmorphism has subjective ele-
ments that are often triggered by clinical experience
and expertise. Key points in the initial communica-
tion with the family include the following:
1. First congratulate the family on the birth of the
baby. This is very important and tremendously
appreciated by families. This is a very special

248 Advances in Neonatal Care • Vol. 15, No. 4 • pp. 248-252

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 Clinical Approach to the Dysmorphic Neonate 249

time for the family regardless of whether the
newborn ultimately has a genetic diagnosis.
2. Point out the positives without being overly or
falsely reassuring.
3. Be honest about your concerns. Families appre-
ciate honesty and the genuine honesty of the
neonatal provider builds trust.
4. Do not mention specific diagnoses or syn-
dromes by name initially unless there is a great
deal of confidence in the diagnosis. When any
uncertainty exists, it is preferable to speak in
general terms. Initial words used by neonatal
clinicians tend to stick in the parents’ minds
even if they ultimately are refuted.
5. Assess the educational and cognitive level of
the family and use words that make sense to
them. Scientific terms are rarely useful initially
and only create additional anxiety.
6. Reassure the family that you will keep them
informed and updated (and do so).
7. Ask for their permission to have their newborn
evaluated by a specialist, such as a clinical
geneticist. The family must be informed about
this planned assessment before a geneticist
arrives. Some families are not ready for this and
timing becomes important.
8. Treat the newborn like any other “typical” or
“normal” infant. Families are very sensitive to
body language and word choice, which can
unintentionally reveal your underlying senti-
ment about their newborn.
9. Avoid separating the newborn from the par-
ents, if at all possible. Most dysmorphic syn-
dromes do not pose an immediate threat to the
newborn's health unless major malformations
are present that need close monitoring and/or
management.
FUNDAMENTALS OF THE
DYSMORPHOLOGY EVALUATION
Assessment for dysmorphology or dysmorphic cra-
niofacial features can be quite subjective and requires
expertise, experience, and attention to detail. The
term “dysmorphic” implies the presence of abnor-
mal features as compared with what is considered
“normal.”2,3 To overcome some of the subjectivity in
this process, several more objective, clinical tools

TABLE 1.  Select Genetic Syndromes and Their Associated Clinical and Laboratory Phenotype
Characteristic Clinical/Laboratory
Genetic Syndrome Findings Laboratory Testing
Down syndrome CHD, hypotonia, organ malforma- Chromosome analysis, FISH
tions (eg, renal)
Edwards syndrome (trisomy 18) IUGR, CHD, short sternum, overlap- Chromosome analysis, FISH
ping fingers, hypertonia
Patau syndrome (Trisomy 13) CL/CP, CHD, brain malformations, Chromosome analysis, FISH
polydactyly
Turner syndrome (45,X) CHD (eg, aortic coarctation), Chromosome analysis, FISH
hydrops, lymphedema, webbed
neck, skeletal/renal malformations
22q11 deletion syndrome (Velocar- CHD (eg, TOF), CL/CP, hypotonia, Chromosome analysis, FISH, chro-
diofacial syndrome) hypocalcemia, immune deficiency mosome microarray
Noonan syndrome Macrosomia, CHD (eg, VSD, ASD, Gene sequencing
PVS), HCM, hydrops, lymphede-
ma, hypotonia, webbed neck
Neurofibromatosis type 1 Multiple CALS, hypotonia Gene sequencing
Williams syndrome CHD (eg, SVAS), hypotonia, failure Chromosome analysis, FISH, chro-
to thrive, hypercalcemia mosome microarray
Prader–Willi syndrome Severe hypotonia, hypogenitalism 15q11 methylation studies
(males), failure to thrive
Beckwith–Wiedemann syndrome Macrosomia, omphalocele, mac- 11q15 methylation studies
roglossia, hypoglycemia
Craniosynostosis syndromes Craniosynostosis (often coronal), Gene sequencing
(Pfeiffer, Apert, Crouzon syn- characteristic facial and/or ex-
dromes) tremity features
Abbreviations: ASD, atrial septal defect; CALS, café-au-lait spots; CHD, congenital heart disease; CL/CP, cleft lip/cleft palate; FISH,
fluorescence in situ hybridization; HCM, hypertrophic cardiomyopathy; IUGR, intrauterine growth restriction; PVS, pulmonary valve
stenosis; SVAS, supravalvular aortic stenosis; TOF, tetralogy of fallot; VSD, ventricular septal defect.

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 250 Smpokou et al

have been developed by experienced clinical dys-
morphologists to assist in categorizing and system-
atically organizing various facial characteristics.
Charts to plot the length, distance, or rotation of
different physical characteristics and organs are
published and utilized by clinical geneticists to
objectively categorize the physical assessments.3 The
distance between the eyes, the length and rotation of
the ears, the length of the philtrum, the length of the
fingers, the palms or soles, the distance between the
nipples, or the chest circumference can all be accu-
rately measured and plotted on graphs against
empirically derived normal measurements.2,3 This
approach can be useful when a subjective assessment
is in doubt or needs confirmation.
Appreciation of the dynamic nature of the dys-
morphology examination is essential. Craniofacial
features can change dramatically early in life. Edema
and mechanical pressure, for example, can distort or
alter the newborn's true facial features, resulting in
deformation of the face. A history of maternal uter-
ine malformation, oligohydramnios, prenatal sub-
stance exposure, atypical in-utero positioning, or
prematurity suggest that the newborn's features
should be reassessed after these external influences
have been resolved.1,2
Owing to the dynamic nature and subjectivity
inherent to the assessment of craniofacial features,
photographs or videos sometimes are useful to docu-
ment these features for purposes of comparison or to
seek alternative opinions. With the family's permis-
sion, neonatal practitioners, particularly those in
more remote settings where clinical geneticists are
not readily available for in-person consultations,
should consider this approach.4-7
Documentation of assessment findings is critical.
In the current healthcare environment of work-hour
rules and frequent practitioner hand-offs, docu-
menting all abnormal findings in the medical record
is the only practical way to achieve consistency.
When describing craniofacial features that appear
“abnormal,” specific terms and anatomical land-
marks are employed to “paint a picture” without
actually drawing a picture.4 Such terms as down-
slanting palpebral fissures, telecanthus, hyper-
telorism, wide nasal bridge, wide forehead, and low-
set ears are often used to describe findings.2,3
Documenting a detailed and systematic examination

TABLE 2.  Select Large Molecule Inherited Metabolic Disorders and Associated Clinical and
Laboratory Phenotypes
IMD Group
(Examples) Typical Organ Malformations
Mitochondrial Brain, heart
(PDHC defi-
ciency)
Sterol (SLOS, MA) Multiple organs (brain, cardiac,
kidneys, facial clefting, geni-
tal, extremity in SLOS); liver
disease, skin rash in MA
Peroxisomal Hydrops, multiple organs
(Zellweger syn- (brain, heart, kidneys, hear-
drome) ing, retinopathy, cataracts,
liver disease, skeletal)
Lysosomal storage Hydrops, skeletal (dysostosis
(Hurler syn- multiplex, contractures), car-
drome) diac, ocular (corneal cloud-
ing), brain, organomegaly
(liver, spleen), hematologic
CDG Hydrops, multiple organs
(brain, heart, kidneys, GI,
hearing, retinopathy, liver
disease, skeletal), organo-
megaly, skin
Copper transport Brain, skeletal, skin
(Menkes disease)
Abbreviations: CDG, congenital disorders of glycosylation; GI, gastrointestinal; IMD, inherited metabolic disorder; MA, mevalonic
aciduria; PDHC, pyruvate dehydrogenase complex; SLOS, Smith—Lemli–Opitz syndrome; VLCFA, very long-chain fatty acids.
Characteristic
Biochemical Findings Typical Dysmorphism
High lactate, pyruvate, High forehead, epicanthal
alanine, metabolic folds, short and upturned
acidosis nose, long philtrum
Low total cholesterol, Micrognathia, ocular ptosis,
elevated 7DHC (SLOS), short/upturned nose, 2-3
abnormal liver func- toe syndactyly (SLOS); high
tion, high urine meva- forehead, dolichocephaly,
lonic acid (MA) low-set ears, thin lips (MA)
Abnormal liver function, High forehead, large fonta-
abnormal VLCFA, bile nels, micrognathia, ear
acids anomalies
Abnormal liver function, Coarse face, short/upturned
anemia, thrombocyto- nose, ear anomalies
penia
Abnormal liver function, Variable, abnormal “fat pads”
coagulopathy, abnor-
mal immune function
Low serum copper, Long/narrow face, bitemporal
ceruloplasmin narrowing, myopathic ex-
pression, cutis laxa, “kinky”/
hypopigmented hair

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with attention to describing only what is observed
(without interpretation) is encouraged.4,5
COMMON GENETIC DIAGNOSES AND
ASSOCIATIONS
In certain genetic conditions, recurrent associa-
tions have emerged that can guide the initial evalu-
ation and management of the neonate, even before
specialist consultation is available. For example,
some congenital heart defects are more often asso-
ciated with one syndrome than another. Certain
physical examination findings, such as severe
hypotonia or hydrops fetalis, should trigger the
consideration of a different set of genetic diagno-
ses.4-7 Table 1 outlines some of the most common
genetic syndromes and their associated clinical and
laboratory findings.
Summary of Recommendations for Practice and Research
What we know:
What needs to be studied:
What we can do today:
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ANC-D-15-00053.indd 251
Clinical Approach to the Dysmorphic Neonate 251
RARE METABOLIC-DYSMORPHIC
SYNDROMES
Special consideration needs to be given to a group of
rare genetic disorders that affect the metabolism of
large molecules. In their most severe forms, these
disorders can present in the neonatal period. To this
group of dysmorphic-metabolic syndromes belong
certain mitochondrial disorders (eg, pyruvate dehy-
drogenase complex deficiency), sterol/cholesterol
pathway disorders (eg, Smith–Lemli–Opitz syn-
drome and mevalonic aciduria), peroxisomal disor-
ders (eg, Zellweger syndrome), lysosomal storage
disorders (eg, mucopolysaccharidoses), congenital
disorders of glycosylation, and copper transport dis-
orders (eg, Menkes disease).6 Neonates with small
molecule inherited metabolic disorders (IMDs), such
as organic acidemias or urea cycle disorders,
• The initial communication with the family is critical; clinicians must
be honest and sensitive to set the tone for future communication.
• Parents should not be separated from their babies, if at all possible.
• Assessment for dysmorphology can be quite subjective and requires
expertise, experience, and attention to detail.
• Documentation is important to achieve consistency among the
healthcare team.
• Some genetic conditions are characterized by common associations
that can guide the evaluation of the neonate.
• The evaluation of the neonate with a possible large or small molecule
disorder should be guided by a clinical geneticist.
• Best practices for team approaches to the care of the neonate with a
possible rare disease, particularly the use of a single spokesperson;
• Best practice approaches to communication with families of different
cultures;
• How to prepare the family for the long-term challenges they face with
a child who has a rare disease;
• The potential value of remote telemedicine consultation for the
evaluation and diagnosis of neonatal rare diseases;
• Best practices for palliative care for infants whose conditions can be
symptomatically managed only or are lethal.
• Keep up to date important contact information for rare disease
experts, metabolic specialists, and clinical geneticists prominently
displayed so that valuable time is not wasted looking for these
details.
• Acknowledge the critical nature of communication, both verbal and
nonverbal, used with families during the period of uncertainty while
a neonate is being evaluated for a rare disease.
• Guide neonatal caregivers to available resources for the systematic
evaluation and diagnosis of neonates with possible rare diseases/
genetic disorders.
• Emphasize a team approach to preparing the neonate with a rare
disease for discharge so that the care transition to outpatient
providers is smooth and important aspects of care are not neglected.
• Encourage caregivers to become knowledgeable about patient
advocacy resources, registries, clinical trial information, and support
groups for families of infants with rare diseases.
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 252 Smpokou et al
typically present with early and catastrophic (if not
treated immediately) neurologic symptoms and spe-
cific biochemical findings within the first few days
or weeks of life. Newborns with IMDs that affect
large molecules can present with facial dysmorphia,
major organ malformations, and biochemical distur-
bances in the first few days to weeks of life and typi-
cally have a severe and progressive clinical course
and poor long-term neurologic outcomes.6,7 To eval-
uate for large and small molecule disorders, consul-
tation with an experienced clinical geneticist is para-
mount so that appropriate genetic and biochemical
testing is ordered and unnecessary interventions are
avoided (eg, cardiac or other surgeries in a neonate
with severe neurologic outcome and poor progno-
sis). Specific clinical findings that are associated with
select rare metabolic-dysmorphic syndromes are
summarized in Table 2.8,9
SPECIAL CONSIDERATIONS:
PALLIATIVE CARE AND END-OF-LIFE
DECISIONS
Certain genetic diagnoses suggest a different approach
to management of the neonate owing to the severe,
progressive course of the disease and poor long-term
prognosis. Genetic syndromes with increased risk for
immediate or short-term, multi-organ, lethal compli-
cations include Patau syndrome (trisomy 13),
Edwards syndrome (trisomy 18), and certain large
molecule IMDs.5-7 Consultation with multiple spe-
cialists becomes important to address each involved
organ and decide on the best course of action. At the
same time, the poor prognosis brings about a differ-
ent set of discussions surrounding the extent of inter-
ventions, which, in the long-term, will not improve
life expectancy. In these cases, quality of life takes
precedence over extraordinary measures to postpone
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ANC-D-15-00053.indd 252
the neonate's inevitable death. Palliative care, hospice
care, and limitation of care are often discussed. Par-
ents or guardians must make the most appropriate
decisions for their families and infants; however, the
genetic and other specialists are responsible for pro-
viding accurate, realistic, and honest information
concerning the long-term outlook for these neonates
and the potential effects of any interventions.
SUMMARY
In caring for a neonate with a suspected genetic diag-
nosis, the neonatal clinician must have a clear under-
standing and appreciation of the multiple aspects of
evaluating and managing a genetic diagnosis.
Knowledge of specific genetic conditions can serve
as a foundation to a well-rounded, professional, and
comprehensive approach to the initial evaluation
and management of the dysmorphic neonate.4,7 In
circumstances involving potentially lethal diagnoses,
the practitioner must be knowledgeable and com-
fortable engaging with the assistance of geneticists
and other specialists to provide the best possible care
to the newborn and family.
References
1. Aase JM. Diagnostic Dysmorphology. New York, NY: Plenum
Medical Book Company; 1990.
2. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of
Human Malformation. 7th ed. Philadelphia, PA: WB Saunders; 2013.
3. Gripp KW, Slavotinek AM, Gall JG, Allanson JE. Handbook of Physical
Measurements. 3rd ed. Oxford, England: Oxford University Press; 2013.
4. Firth H, Hurst JA. Oxford Desk Reference Clinical Genetics. Oxford,
England: Oxford University Press; 2005.
5. Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson
Genetics in Medicine. 8th ed. Philadelphia, PA: WB Saunders; 2015.
6. National Newborn Screening & Genetics Resource Center. http://
genes-r-us.uthscsa.edu/resources.htm. Accessed April 2, 2015.
7. Onlilne Mendelian Inheritance in Man. http://www.omim.org/.
Accessed April 2, 2015.
8. Burton BK. Inborn errors of metabolism in infancy: a guide to diagno-
sis. Pediatrics. 1998;102:e69.
9. Nyhan WL, Barshop BA, Ozand PT. Atlas of Metabolic Diseases. 2nd
ed. Oxford University Press; 2005.
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