When to Suspect a Genetic Syndrome

BENJAMIN D. SOLOMON, MD, and MAXIMILIAN MUENKE, MD

National Human Genome Research Institute, Bethesda, Maryland

Family physicians should be able to recognize findings on physical examination and history
that suggest the presence of a genetic syndrome to aid in the diagnosis and treatment of poten-
tially affected patients, as well as subspecialty referral. General themes that can alert family
physicians to the presence of genetic conditions include dysmorphic features that are evident on
physical examination; multiple anomalies in one patient; unexplained neurocognitive impair-
ment; and a family history that is suggestive of a hereditary disease. The presence of one obvi-
ous malformation should not limit the full evaluation, because additional, subtler findings will
often be important in the differential diagnosis. Taking an accurate three-generation family
history is invaluable when considering a genetic syndrome. Important elements include the age
and sex of family members; when family members were affected by disease or when they died;
the ethnic background; and if there is consanguinity. Genetic subspecialists can assist family
physicians in diagnosis, suggest additional testing and referrals if warranted, help direct medi-
cal care, and provide counseling for affected patients and their families. (Am Fam Physician.
2012;86(9):826-833. Copyright © 2012 American Academy of Family Physicians.)

A
lthough many genetic conditions impairment; and a family history that is sug-
are individually rare, they are com- gestive of a hereditary disease.
mon in aggregate and place a great
burden on affected patients and Dysmorphic Features
the medical system.1-3 Congenital malforma- Dysmorphic features may result from a per-
tions (many of which are related to genetic turbation of human development.9 This per-
disturbances) occur in approximately 5 per- turbation can be a direct effect of a genetic
cent of live-born infants; a much higher pro- mutation or can indirectly involve a genetic
portion of conceptions are affected by genetic disturbance, such as in the case of gestational
anomalies.4,5 In one study, an estimated 79 of exposure to a teratogen. Figures 1A through 1I
1,000 live-born infants were found to have a are examples of dysmorphic features that
genetic syndrome and/or congenital malfor- can be found on physical examination that
mation by 25 years of age.6 may be helpful in the diagnosis of genetic
Prompt recognition of features suggestive syndromes.
of genetic conditions can improve the selec- A full dysmorphology examination is best
tion of appropriate, cost-effective diagnos- conducted by a trained clinical geneticist;
tic tests; the performance of well-informed a primary care physician should conduct a
genetic counseling related to issues such as thorough physical examination.9-12 An essen-
prognosis and future family planning; and tial component of the physical examination
timely referral to subspecialists.7,8 There- for genetic syndromes is comparison with
fore, it is important for family physicians to established normative values. In addition
be able to recognize general themes that can to weight, height, and head circumference,
suggest the presence of a genetic syndrome examples of other important measurements
and identify patients who would benefit include interpupillary distance (the distance
from referral to clinical geneticists. between the center of the pupils) if a mid-
General themes that can alert family phy- line defect is suspected (as in the case of
sicians to the presence of genetic conditions holoprosencephaly, the most common mal-
include dysmorphic features; multiple anom- formation of the human forebrain), or the
alies in one patient that may be related to a size of the limbs in the case of a skeletal dys-
unifying cause; unexplained neurocognitive plasia.7,13 These values must be interpreted
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 Genetic Syndrome

in the context of the patient’s longitudinal folds are also a normal finding in many per-
growth, as well as the family background. sons of Asian or Native American descent.7,14
The absence or presence of certain features Recently, an effort has been made to codify
in family members can be a clue that a feature physical descriptors, which can help with
is either pathologic or merely a familial or communication and establishment of the
ethnic variant. For example, inner epicanthal differential diagnosis.10
folds (small folds of skin over the medial eyes) The presence of one obvious malforma-
can occur in persons with Down syndrome, tion should not limit the full evaluation,
and are also described in more than 50 other because additional, subtler findings will
syndromes, including Noonan syndrome, often be important in the differential diag-
Rubinstein-Taybi syndrome, and Smith- nosis. For example, a newborn might be
Lemli-Opitz syndrome. However, epicanthal immediately noted to have a cleft palate,

A B C

D E F

G H I

Figure 1. Examples of dysmorphic features that can be found on physical examination that may be helpful in the diag-
nosis of genetic syndromes. (A) A black infant presents with pigmentary anomalies in the context of a genetic condi-
tion; notice the hypopigmented tips of the hair. (B) An iris coloboma can be associated with many genetic syndromes,
or can occur as an isolated feature. (C) A single maxillary central incisor can occur in conditions that include midline
deficits, and can be a clue to the presence of accompanying brain malformations. (D) A small ear with an overfolded
helix can be a familial variant or can occur as part of a genetic syndrome. (E) Fifth-finger clinodactyly (incurving of the
fifth finger) occurs in many genetic conditions, and is classically seen in persons with Down syndrome. (F) An unusual
shape of the digits, such as tapered digits, can occur in many conditions; this patient has Coffin-Lowry syndrome. (G)
Various types of syndactyly (fusion) of the fingers or toes may be seen; second- and third-toe syndactyly, which occurs
in Smith-Lemli-Opitz syndrome, is shown here. (H) Examination of the skin is an important part of the physical exami-
nation; this child with neurofibromatosis 1 has multiple café au lait macules. (I) This lesion, visible with a Wood lamp,
has irregular borders and is typical of sporadic café au lait macules.

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Genetic Syndrome

which has a broad differential diagnosis. A Table 1 lists resources that can be helpful
patient with a cleft palate; hypocalcemia; a in establishing a differential diagnosis based
ventricular septal defect; and subtle physi- on the presence of several distinct features.
cal features, such as a broad nasal root, over-
folded helices of the ears, and long, narrow Neurocognitive Impairment
fingers and toes, likely has 22q11.2 deletion In many genetic conditions, neurocognitive
syndrome (formerly called DiGeorge syn- impairment may be the first and most obvi-
drome), which has a prevalence of approxi- ous sign of disease.19 Genetic conditions can
mately one in 4,000 live births.15 produce neurocognitive impairment in a
number of different ways, including via struc-
Cluster of Findings tural brain malformations, aberrant signaling
Many genetic conditions are suggested involving genes that play important neuro-
through a combination of clinical fea- logic roles, and inborn errors of metabolism,
tures, including the physical appearance of the latter of which can cause neurologic dis-
the patient, laboratory abnormalities, and ease because of an inadequate amount of a
aspects of family history.14 For example, an needed substrate or accumulation of a toxic
adolescent presenting for a sports physi- metabolite. Phenylketonuria, galactosemia,
cal examination who is noted methylmalonic acidemia, and maple syrup
An essential component of
to have arachnodactyly (long, urine disease are examples of conditions
thin fingers) and pectus exca- caused by inborn errors of metabolism that
the physical examination
vatum, and whose father died are included in newborn screening.20,21 In the
for genetic syndromes is
of an aortic dissection would assessment of developmental delay and/or
comparison with estab-
be suspected of having Marfan neurocognitive impairment, neuroimaging is
lished normative values.
syndrome.16 Short stature and warranted when a structural, degenerative, or
thumb anomalies in a child metabolic process is suspected.19,20
who also has aplastic anemia may suggest Neurocognitive impairment related to
Fanconi anemia, and confirmation would be genetic conditions may be recognized in
important to institute surveillance for long- childhood; however, some conditions, such as
term complications.17 Huntington disease or some types of Charcot-
There are several possible explanations Marie-Tooth disease, as well as familial forms
for the presence of a cluster of findings in of complex disorders, such as Parkinson dis-
a patient with a genetic syndrome. One ease and Alzheimer disease, may manifest
common reason is pleiotropy, in which a much later in life.22-25 Key historical items
mutation in a single gene results in multiple should include the degree and type of dysfunc-
effects on separate organ systems. For exam- tion; the timing, both in terms of when the
ple, in Holt-Oram syndrome, sometimes dysfunction was first noticed as well as how the
called heart-hand syndrome, mutations in impairment has changed with time (including
the gene TBX5 cause congenital heart and whether or not there has been regression, or
limb malformations.18 Another possible loss of developmental milestones); and if there
explanation for the presence of a cluster of are any recognized triggers.
findings is that the patient has a contiguous Inborn errors of metabolism, such as
gene syndrome, in which he or she has dele- phenylketonuria, deserve special attention,
tions (missing genetic material) or duplica- largely because medical interventions in these
tions (extra genetic material) involving a disorders can be especially important for pre-
certain portion of a chromosome. Because venting neurocognitive impairment.20,21 For
all genes in the deleted or duplicated inter- example, it may be necessary to remove a type
vals are affected, the involvement of many of food source that cannot be properly metab-
genes can result in a complicated clinical olized (phenylalanine in the case of phenylke-
picture. The 22q11.2 deletion syndrome is tonuria). These interventions may influence
a well-known example of a contiguous gene the degree of cognitive impairment, and can
syndrome.15 be a matter of life or death.

828 American Family Physician www.aafp.org/afp Volume 86, Number 9 ◆ November 1, 2012
 Genetic Syndrome

Suspicious Family History cancer types in familial adenomatous pol-

Taking an accurate three-generation family yposis; breast and ovarian cancer and other
history (Figure 226,27) is important when a cancer types in BRCA1- or BRCA2-related
genetic syndrome is suspected or identified. cancer), early or unusual onset of a relatively
Genetic counselors can be invaluable in this common condition such as cardiac disease
regard.26,28 It is critical to consider all health- (e.g., familial hyperlipidemia, inherited
related issues, even if they do not appear to arrhythmia), or a history of unusual reac-
be directly connected to the primary condi- tions to a certain medication (e.g., severe or
tion. For example, genetic syndromes may be life-threating reactions to anesthetic agents,
suggested by a preponderance of early can- such as what may occur in patients with suc-
cer diagnoses (e.g., colon cancer and other cinylcholine esterase deficiency).26,29,30

Table 1. Web-Based Resources for Clinical Genetics

Resource Web address Description

American Academy of Family http://www.aafp.org Provides links to published resources pertaining to genetics,
Physicians including key articles and resources for patients, in the “AFP By
Topic” module on genetics: http://www.aafp.org/afp/genetics
American Academy of http://www.aap.org Provides guidelines and algorithms on the management of relatively
Pediatrics common genetic conditions in the “Committee on Genetics”
section: http://www2.aap.org/visit/cmte18.htm
American College of Medical http://www.acmg.net Provides many resources, including algorithms for treating affected
Genetics patients and managing abnormal newborn screening test results
(http://www.acmg.net/AM/Template.cfm?Section=ACT_Sheets_
and_Confirmatory_Algorithms&Template=/CM/HTMLDisplay.
cfm&ContentID=5661), and a database of available regional
genetic services (http://www.acmg.net/GIS/)
ClinicalTrials.gov http://clinicaltrials.gov Registry of federally and privately supported clinical trials, including
those dedicated to determining the genetic causes of disease,
conducted in the United States and internationally
GeneTests http://www.ncbi.nlm.nih. Expert-written reviews, which include contact information for the
gov/sites/GeneTests authors of each article, on many genetic conditions, as well as
links to clinical and research laboratories that provide testing
Genetics Home Reference http://ghr.nlm.nih.gov Provides many resources, including short descriptions of conditions
and explanations of genetic terms; may be a useful source for
families with less familiarity with medical terminology
London Medical Databases http://www.lmdatabases. Series of searchable databases of genetic conditions; can be
com/about_lmd.html especially useful for developing a differential diagnosis
(subscription required)
National Human Genome http://elements A source for newly standardized terms used in human
Research Institute’s Elements ofmorphology.nih.gov dysmorphology, with links to source articles
of Morphology: Human
Malformation Terminology
National Organization for http://www.rarediseases. Serves patients with rare diseases; includes links to support groups,
Rare Disorders org/ ways to apply for help (with treatment costs), booklets on a
few disorders, and links to physicians with expertise in specific
disorders
Online Mendelian Inheritance http://www.ncbi.nlm.nih. Database of genes associated with human disease, as well as
in Man gov/omim conditions with proven and hypothetical genetic underpinnings;
searchable by multiple phenotypic and genetic terms
Possum Web http://www.possum. Dysmorphology database consisting of multiple malformations, and
net.au/ (subscription metabolic, teratogenic, chromosomal, and skeletal syndromes,
required) which can be useful for the establishment of a differential diagnosis

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Genetic Syndrome

77 70 79 65
Breast cancer Myocardial “Old age” “Cancer”
Hypertension infarction

54 49 48 52
Hypercholes- Motor vehicle
terolemia crash 56
Hypertension < 10 weeks
Non–insulin-
dependent diabetes

22 23 23
Insulin-dependent Attention-deficit/ Asthma
diabetes hyperactivity disorder Ventricular septal
Major depressive defect (status post-
disorder repair in infancy)

2 P 14 weeks
Congenital
heart disease

Figure 2. Example pedigree for a (relatively small) family that may be affected with a hypothetical genetic syndrome
showing history of first-, second-, and third-degree relatives of the proband. In this situation, a 14-week fetus of unknown
sex (marked with a “P” for “proband” or “propositus,” and indicated with an arrow; the “P” inside the diamond [for
“pregnancy”] indicates the fetal status) has been prenatally identified as possibly being affected by a genetic condition
because of the presence of congenital heart disease. The proband has a healthy sister two years of age. The mother, who
is 23 years of age, is affected by attention-deficit/hyperactivity disorder and major depressive disorder. The proband’s
mother has a dizygotic twin brother with asthma who also had congenital heart disease in the form of a ventricular septal
defect that was repaired in infancy (his symbol is shown in solid black to indicate that he, like the proband, had a congeni-
tal cardiac malformation). The maternal grandfather is healthy at 52 years of age. The maternal grandfather is separated
from the maternal grandmother (almost no medical history, including her current age, is known about the maternal
grandmother, who was adopted). With another partner, about whom few details are known, the maternal grandmother
had a spontaneous abortion at less than 10 weeks’ gestation; the sex was not known. A maternal great-aunt, who is 56
years of age, has hypertension and non–insulin-dependent diabetes mellitus. She did not have children (by choice). The
maternal great-grandparents are both deceased; the maternal great-grandmother is described as dying of “old age”
at 79 years of age, and the maternal great-grandfather died of “cancer” (more specifics unknown) at 65 years of age.
The father is 22 years of age and has insulin-dependent diabetes. The paternal grandmother is 49 years of age and has
hypercholesterolemia. The paternal grandfather died in a motor vehicle crash at 48 years of age; details of his family his-
tory are not known. The paternal great-uncle is healthy at 54 years of age, but is infertile (for unknown reasons). The
paternal great-grandmother is 77 years of age and has breast cancer and a history of hypertension. The paternal great-
grandfather died at 70 years of age of a myocardial infarction. Other details not shown here could include the ethnicity
of the family, which could have a bearing on the frequency of certain conditions, as well as the age at which the previ-
ously mentioned conditions were diagnosed (such as the age at which the paternal great-grandmother received the
breast cancer diagnosis). In taking the family history, it would also be important to ascertain the presence of conditions
possibly related to that of the proband, including the presence of consanguinity, any type of congenital malformations,
and cognitive impairment manifesting in childhood.26 Pedigree symbols are reviewed in reference 27.

830 American Family Physician www.aafp.org/afp Volume 86, Number 9 ◆ November 1, 2012
 Genetic Syndrome
Table 2. Types of Genetic Tests

Test Description Applications/comments

Biochemical assays Many types available, Some can be performed only on certain tissue types, and only by certain
depending on the specialized laboratories
condition Because the selection of the type of assay is critical, a biochemical workup is
often best directed by a subspecialist in inborn errors of metabolism
FISH (fluorescence Microscope-based As with karyotyping (see below), FISH testing is used in many situations, but
in situ hybridization) study of a specific is now often replaced with microarray
testing chromosomal region
Karyotype Microscope-based study Used in many situations, including prenatally, in cancer genetics, and in
of chromosomes patients with neurocognitive impairment and/or congenital malformations;
in many situations, karyotyping is being replaced by microarray
Microarray Study of overall genomic Contains similar information to karyotyping, but is analyzed through
material different technology, and at much higher resolution
Unlike karyotyping, microarray will not typically diagnose balanced
translocations, and may return more information that is of unclear clinical
significance
Sequencing Base-by-base Traditionally, a single gene or small group of genes would be sequenced if a
examination of a mutation affecting that gene was suspected; however, new technologies
portion of genetic now make simultaneous large-scale sequencing of many genes more
material possible than before

Important elements include the age and sex locate a regional geneticist through the
of family members; when family members American College of Medical Genetics Web
were affected by disease or when they died; the site at http://www.acmg.net/GIS/.
ethnic background; and if there is any consan- For other patients, the diagnosis is made
guinity, which may give evidence for the pres- through genetic testing. There is a wide array
ence of a recessive condition. Many genetic of tests that may be used.8 The choice of test
diseases will present differently in terms of depends on the nature of the condition, the
timing, clinical features, and even the chance expense and availability of the test, and the
of being affected at all, depending on the age specific clinical scenario (for example, the
and sex of the person. Knowing these facts testing strategy may be different if a con-
may also help determine the likely inheritance dition were suspected in an adult versus a
pattern, and can be helpful in calculating the fetus). Ultimately, whether or not a patient
recurrence risk. Some conditions are more or family elects to undergo
common in certain ethnicities, such as Tay- testing is a matter of personal In many genetic conditions,
Sachs disease in persons of Ashkenazi Jewish choice, and patients should be neurocognitive impairment
descent and sickle cell disease in persons of counseled regarding what a test
may be the first and most
African descent.26,31 Taking a thorough family may or may not reveal.
obvious sign of disease.
history may require patients to contact rela- Table 2 lists selected genetic
tives to help provide key details. Additionally, tests. In addition to these spe-
when physicians are attempting to diagnose a cialized tests, however, physicians should be
patient with dysmorphic features, they may be aware that many genetic conditions are sus-
aided by the now almost ubiquitous presence pected or confirmed by commonly ordered
of advanced handheld devices that can store tests, such as plain radiography, complete
photographs of family members. blood count, or a basic metabolic panel. For
example, wormian bones might be visible in
Genetic Testing and Referral a radiographic image of the skull in a patient
Some genetic conditions are diagnosed on with osteogenesis imperfecta, and thrombo-
clinical grounds. Geneticists can assist in cytopenia would be evident in a patient with
diagnosis, suggest additional testing and Wiskott-Aldrich syndrome.32,33 Family phy-
referrals if warranted, help direct medical sicians can work in conjunction with genetic
care, and provide counseling for affected subspecialists when performing appropriate
patients and their families. Physicians can diagnostic and confirmatory testing.

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Genetic Syndrome

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence
Clinical recommendation rating References Comments

A full dysmorphology examination is best conducted by C 9-12 —

a trained clinical geneticist; a primary care physician
should conduct a thorough physical examination.
In the assessment of developmental delay and/ C 19, 20 Discussion with a radiologist or
or neurocognitive impairment, neuroimaging is neurologist may assist with the choice
warranted when a structural, degenerative, or of imaging modality.
metabolic process is suspected.
A three-generation family history should be obtained C 26, 28 A combination of open-ended and
when a genetic syndrome is suspected or identified. specific questions is useful to ascertain
Genetic counselors can be invaluable in this regard. the presence of relatively common
conditions (such as those that involve
cancer or neurocognitive disturbances);
it also allows for identification of
medical issues that “run in the family.”

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-
oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.
org/afpsort.xml.

Certain resources may be helpful in Eunice Kennedy Shriver National Institute of Child Health
determining the type of genetic testing that & Human Development; Figure 1H is courtesy of Douglas
R. Stewart, MD, National Cancer Institute; and Figure 1I is
is recommended and available (Table 1). For courtesy of Douglas R. Stewart, MD, National Cancer Insti-
example, the GeneTests Web site (http:// tute, and John Crawford, National Institutes of Health.
www.ncbi.nlm.nih.gov/sites/GeneTests) can
be used to find a laboratory that conducts The Authors
testing for a certain genetic condition,
BENJAMIN D. SOLOMON, MD, is a staff clinician in the
and the National Institutes of Health– Medical Genetics Branch of the National Human Genome
based ClinicalTrials.gov Web site (http:// Research Institute, Bethesda, Md.
clinicaltrials.gov) can help locate relevant
MAXIMILIAN MUENKE, MD, is the chief of the Medical
research studies, which can also be a useful Genetics Branch and the director of the Medical Genet-
way to find physicians with expertise in a ics Residency Training Program at the National Human
rare disorder. Genome Research Institute.

Data Sources: A PubMed search was completed in Clini- Address correspondence to Maximilian Muenke, MD,
cal Queries combining the key terms genetics, primary Medical Genetics Branch, National Human Genome
care, and referral. The search included meta-analyses, Research Institute, 35 Convent Dr., Room 1B203, MSC
randomized controlled trials, clinical trials, and reviews. 3717, Bethesda, MD 20892-3717 (e-mail: mamuenke@
Also searched were the Agency for Healthcare Research mail.nih.gov). Reprints are not available from the
and Quality, the Cochrane database, the Institute for authors.
Clinical Systems Improvement, and the National Guideline
Author disclosure: No relevant financial affiliations to
Clearinghouse database. Search date: August 16, 2011.
disclose.
This work was supported by the Intramural Research Pro-
gram of the National Human Genome Research Institute,
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