Transcript Minor anomaly - Stanford Medicine

CLINICAL MEDICAL GENETICS
GENETICS 202
Jon Bernstein
Department of Pediatrics
October 29, 2015
Session Goals
Gain familiarity with the field of clinical medical genetics
◦ A developmental biology, biochemistry and genetics
clinic
 Understand the meaning of “dysmorphology” and its
role in clinical diagnosis
◦ Relating genotypes to phenotypes
◦ Introduction to the identification of zebras (or
precision medicine)

Lecture Outline

The rapidly changing landscape of medical genetics

Dysmorphology/Systematic phenotyping
◦ Major and minor anomalies
◦ Categories of anomalies
 Malformation, deformation, disruption
◦ Constellations of anomalies
 Association, sequence, syndrome

Clinical cases
◦ Modern clinical genetics
◦ Bioinformatics support for matchmaking – precision medicine
Genetics from a Medical Education Perspective
Learned in Pre-clinical
curriculum
Clinical Curriculum
Residency, Fellowship….
Learned in Pre-clinical curriculum
Clinical Curriculum
Residency, Fellowship….
Learned in Pre-clinical
curriculum (mostly fall
quarter) and occasionally
thereafter.
Genotype
Environment
Phenotype
Genetic testing and
family history
The medical history
Assessing the patient
(Physical Exam, Lab Tests, Imaging, Pathology, Physiologic studies)
Clinical Genetics
•Obstetrics
•Pulmonology
•Cardiology
•Hematology
•Oncology
•Gastroenterology/Hepatology
•Psychiatry
•Immunology
•Neurology
•Otolaryngology
•Endocrinology
•Primary Care
•Medical Genetics
• Biochemical genetics
• Dysmorphology
Clinical Medical Genetics


Dysmorphology
Biochemical genetics
◦ Inborn errors of metabolism
◦ Lysosomal disorders
◦ Mitochondrial disease
Allusions to dysmorphology in GENE202
Filamin A related disorders in molecular
genetics
 Teratology segment of reproductive genetics
lecture

◦ Warfarin embryopathy
Allusions to dysmorphology in DBIO

Hereditary hearing loss
◦ Waardenburg syndrome

Skeletal dysplasias
◦ Achondroplasia
◦ Cleidocranial dysplasia

Ectodermal dysplasia
◦ Ectodermal dysplasia, anhidrotic

Disorders of sex development
◦ Campomelic dysplasia

Teratology
◦ Fetal alcohol syndrome
Situations Prompting Consideration of Syndromes that May
Have Recognizable Dysmorphic Features

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One or more anomalies
Growth aberration
Cranial size/contour
abnormalities
Neurologic problems
Ectodermal defects
Orthopedic problems

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Abnormal genitalia/sexual
development
Unusual behavior, activity
or speech
Phenotype variation from
family
Hearing/vision loss
A clinical case – from lecture #1

18 year old young
woman with a long,
complicated medical
history including bone
marrow failure and
pulmonary disease.
http://www.genereviews.org

http://www.wheelessonline.com
Making the diagnosis

Search OMIM for bone
marrow, lung, skin, nails

Three out of the top 5
results are forms of
dyskeratosis congenita.
One phenotype/disease multiple modes of
inheritance
 Dyskeratosis congenita can show the following
modes of inheritance
◦ Autosomal dominant
◦ Autosomal recessive
◦ X-linked recessive
At GeneReviews.org , originally from Macmillan Publishers
Ltd: Nature Genetics, Savage SA, Connecting complex
disorders through biology, 44:238-40, copyright 2012
Dysmorphology

The study of
abnormal form

The medical specialty
of evaluating patients
with abnormal
physical features
What is a dysmorphic feature

Normal structure of abnormal size, proportion or
shape
◦ Smooth philtrum
◦ Variant palmar creases
◦ Upslanting palpebral fissures

Feature not normally present
◦ Ear tag
◦ Extra digit
◦ Supernummerary nipple
Elements of Morphology

http://elementsofmorphology.nih.gov/
Categories of dysmorphic features
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Minor anomaly
◦ Features that differ from family, racial/ethnic background or the
general population
 Most found as “low frequency normals” in general population (e.g.
Down syndrome- small ears, epicanthal folds, upslanting eyes,
transverse palmar crease, incurved 5th fingers)
◦ No major surgical or cosmetic importance
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Major anomaly
◦ Indication for medical or surgical intervention, or cosmetic importance
◦ Cleft lip, cleft palate, structural heart disease, microtia
Importance of Minor Anomalies

Specific minor anomalies may be markers for occult major
malformations
◦ Sacral tags, birthmarks

Many syndromes are defined by a pattern of specific minor
anomalies
◦ Fetal alcohol syndrome
◦ Marfan syndrome

Three or more minor anomalies associated with increased risk
of a major malformation (congenital heart defect, cleft palate
for example)
Identification of anomalies
Careful physical examination required
 Found more frequently in areas of the body
that are more variable and complex

◦ 70% found on either the hands or face
Variant palmar creases
“Hockey Stick Crease” as
seen in Fetal Alcohol
Syndrome
Single transverse crease
as seen in Down
syndrome
Stanford Medical Genetics
http://elementsofmorphology.nih.gov/
Decreased creases as
seen in fetal hypokinesia
http://elementsofmorphology.nih.gov/
The Lip-Philtrum Guide
•
Microcephaly, short stature, small weight for age (all
< 5th %ile)
Hoyme, 2006, Pediatrics, Diagnosis of FAS by 1996 IOM Criteria, PMID: 15629980
Making a diagnosis

Sifting through information to find a unifying
explanation(s) for
◦ History
◦ Exam
◦ Studies
 Radiology
 EKG
 Sweat test
◦ Laboratory Tests
Clinical case #1: Dysmorphology/Phenotyping in
the era of whole genome sequencing
A newborn boy is noted to be small for gestational age. He
experiences episodes of low blood sugar in the nursery.
 With age he is short for age, has delayed tooth eruption,
frequent sinopulmonary infections and hearing loss


Has array CGH, a variety of single gene tests and eventually
whole exome sequencing
Facial dysmorphology
Avila, Magali, et al. Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: towards recommendation for molecular
testing and management. Clinical Genetics (2015).
Dyment DA et al. Mutations in PIK3R1 Cause SHORT Syndrome. Am J Hum Genet.
2013 Jul 11;93(1):158-66. Epub 2013 Jun 27. PMID: 23810382
Revisiting the exome

c.1945C>T variant in PIK3R1
◦ Not reported on initial analysis
 Not predicted to be deleterious
 Mutation was not yet in databases
Review -- Factors to consider / actions to take in
establishing a genetic diagnosis
◦ Does phenotype match that in other affected individuals
◦ Mode of inheritance
◦ Number of mutations/variants identified (2 for recessive)
 Confidence in designating variants as mutation
 Informatics, segregation, literature/databases
◦ Configuration/phase of mutations (cis vs trans for
recessive)
 If not enough mutations found – is there more testing that
should be done
Multiple lines of evidence to support a diagnosis

The clinical history, physical exam and other findings
should match the diagnosis supported by genetic
information.
Categorizing congenital anomalies/dysmorphic
features
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Malformation
Deformation
Disruption
Considering congenital differences in a
developmental context can be helpful in
developing a differential diagnosis.
 Cause/mechanism and timing
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Malformation

Congenital heart defect or cleft lip
and palate

Structural defects arising form an
intrinsically abnormal
developmental process

More likely to have a genetic
component to etiology
www.cdc.gov
Deformation

Abnormality of structure arising
from mechanical forces on an
otherwise normally formed
structure or tissue
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Club foot, overlapping toes,
unusual head shape
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Positional plagiocephaly
http://www.nlm.nih.gov/medlineplus
http://www.springerimages.com
Disruption
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Structural defects resulting from the
destruction or interruption of
intrinsically normal tissue
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Affect a group of tissues in a specific
anatomic distribution that does not
follow usual pattern of embryologic
development
◦ Limb reduction anomalies from amniotic
bands
◦ Intestinal atresia caused by vascular
insufficiency
Constellations of anomalies and their origins
Association
 Sequence
 Syndrome

◦ Genetic
◦ Epigenetic
◦ Teratogenic
Origins of congenital anomalies

Association
◦ Nonrandom occurrence of multiple anomalies that
cannot be explained by chance alone and for which
no consistent etiology can be established
◦ 6 to 8 anomalies comprise core features; rarely are all
anomalies present in 1 individual
Origins of congenital anomalies

Sequence
◦ Anomalies due to single problem in morphogenesis
that leads to cascade of subsequent events
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Syndrome
◦ Recognizable recurring pattern of multiple anomalies;
all cases due to a single identifiable etiology
The story of CHARGE
Sanlaville and Verloes, EJHG, 2007
www.chargesyndrome.org
Case #2
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A young man is noted to have
spontaneous keloids and a
history of mitral valve disease
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Exome sequencing reveals a
variant of unknown
significance in the FLNA gene,
c.4726G>A (p.G1576R)
Pedigree
Case #3 Brachydactyly and bronchomalacia
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Newborn boy requires intubation
for respiratory failure
◦ Has a very pliable bronchial tree that
essentially collapses on itself
◦ His father was hospitalized for
several weeks as an infant for similar,
but milder findings
◦ Both the child and the father have
short digits and hallux valgus
Matchmaking
Making matches – and discoveries
Data Sharing from Stanford
The Autism Spectrum
Autism
Fragile X
Isolated or syndromic / Essential or complex
An emerging map of autism spectrum disorders
16p11.2
Deletion
22q13 Deletion
22q11 Deletion
Timothy
Syndrome
15q13 Deletion
Fragile X
Idiopathic Autism?
PTEN
Lecture Summary
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Genetic understanding of diverse disease processes is
rapidly increasing
Dysmorphology refers to the study of abnormal form
and the application of this study to medical care
Major and minor anomalies
◦ Malformations, deformations, disruptions
◦ Associations, sequences and syndromes
Human phenotype ontology
Lecture Summary

Clinical lessons – thinking about syndromes and diagnoses in
general
◦ Critically assess all of the available information
 Consider that each piece of information may or may not be
accurate and may or may not be related to an underlying
etiology for the patient’s condition
 Importance of the basic sciences
◦ Analogous to planning and interpreting the results of an
experiment
Lecture Summary
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Careful observation can lead to
◦ Diagnosis
◦ Improved therapy
◦ New discoveries
The role of clinical description/phenotyping in the
interpretation of genomic information
Value of systematic sharing of high quality data
Medical Genetics – The Medical Specialty

At Stanford
◦ Clinical Clerkship – Pediatrics 301A
 Dysmorphology, biochemical genetics, cancer genetics, clinical laboratory genetics
◦ Medical Genetics Residency Program
 Entry after one year of training in any primary specialty
◦ Clinical laboratory fellowships
◦ Center for Undiagnosed Diseases

Beyond Stanford
◦ The American Board of Medical Genetics
 www.abmg.org
◦ The American College of Medical Genetics (and Genomics)
 www.acmg.net (Video on Genetics Residency http://youtu.be/oh_S6zmMcm8)
◦ The American Society of Human Genetics
 www.ashg.org
Review Question
Which of the following is expected to arise most
consistently in the first trimester of pregnancy
A. Malformation
B. Deformation
C. Disruption
D. Sequence