Clinical approach to the dysmorphic neonate

Clinical approach to the dysmorphic
Contact:
Dr. Bernhard Steiner, Médecin Adjoint, Children‘s Hospital
bernhard.steiner@luks.ch
Chinderarztpraxis, Ruopigenring 37, 6015 Luzern
steiner@geneticus.ch
newborn
Genetics in Neonatology
Cantonal Hospital Lucerne, 15 th of January 2013

Major congenital anomalies
At birth: 2 – 3 %
At age 5: 4 – 6 %
Minor congenital anomalies
At birth: 15 %
Clinical approach to the dysmorphic newborn

Major malformations.
Major versus minor anomalies
Those that have medical & /or social implications.
Often require surgical repair.
Minor malformations.
Have sometimes cosmetic significance.
Normal variants.
From J. Graham: Smith‘s Recognizable Patterns of Human Deformation (2007)

The importance of minor anomalies
„Minor anomalies“ are indicators for
relevant „major anomalies“
(malformations of organs, mental
retardation).
• Ultrasound of the brain
• Ultrasound of the heart
• Ultrasound of the abdomen
• Examination of the eyes
• Examination of the ears
From J. Graham: Smith‘s Recognizable Patterns of Human Deformation (2007)

Causes of human malformations
Cause Percent Incidence
Genetic 15-25
Chromosome 10-15
Single gene 2-10
Multifactorial 20-25
Environmental 8-12
Maternal diseases 6-8
Uterine / plazental 2-3
Drug / chemicals 0.5-1
Twinning 0.5-1
Unknown 40-60
From Stevenson and Hall: Human Malformations And Related Anomalies (2006)

History of intrauterine
developement
Clinical approach to the dysmorphic newborn
Accurate diagnosis
Allow for decision making
and communicating:
Prognosis.
Treatment options.
Occult abnormalities.
Recurrence risk.
Pathogenesis.

Possible teratogenic exposures
Results of diagnostic procedures (ultrasound, AC)
Complications (bleeding, fever)
Fetal Movement (time of onset, force)
Amount of amniotic fluid
History of intrauterine developement
Weeks of gestation

From Moore and Persaud: The Developing Human (1998)
Timetable of human development

Gestation
Complications of labour
Fetal presentation
Mode of delivery
Neonatal status:
• force, breathing, measurements, seizures
Newborn course:
• feeding, anomalies, complications,
resuscitation
Perinatal information
Pre-natal vs. post-natal onset of developmental problems

Three generation family history
Ask for:
• Birth defects
• Other genetic disease
• Multiple miscarriages
• Parental ages and health status
• Consanguinity and geographic origin
Family History

The major types of problems in morphogenesis
Malformation Deformation Disruption Dysplasia
From J. Graham: Smith‘s Recognizable Patterns of Human Deformation (2007)

Clinical approach to the dysmorphic newborn
Malformation
Disruption
Deformation
Interrelationships between malformations,
deformations, and disruptions

Problems in morphogenesis: disruption
Disruptions
Morphological alterations of structures after
formation
Due to destructive processes
vascular accidents ⇒ bowel atresias
amnion rupture sequence ⇒ limb defects
Recurrence risk low.

Ionisation (X-Ray, radioactivity)
Hyperthermia
Infections
Teratogenic (drugs, alcohol)
Metabolic
Vascular disruption
Amnion rupture sequence
Causes of disruption
From J. Graham: Smith‘s Recognizable Patterns of Human Deformation (2007)

From Moore and Persaud: The Developing Human (1998)
Timetable of human development

Deformations
Due to mechanical forces that mold
a part of fetus over a prolonged
period of time
- Clubfeet due to compression in
the amniotic cavity
- Often involve the musculoskeletal
system and may be
reversible postnatally
Problems in morphogenesis: deformation

Breech position
Dolichocephalic deformation of the head due
to intrauterine breech position.
Trisomy 18

Maternal risk factors
Primigravida
Small maternal size
Small uterus
Uterine malformation
Uterine fibromata
Small maternal pelvis
Fetal risk factors
Oligohydramnios
Large fetus
Multiple fetuses
Risk factors for fetal constraint

The non-random clinical association among deformations
From J. Graham: Smith‘s Recognizable Patterns of Human Deformation (2007)

Deformations related to breech presentations
From J. Graham: Smith‘s Recognizable Patterns of Human
Deformation (2007)

Disorders predisposing to breech presentation
3% of all births with breech presentations
23% of all newborns with malformations
with breech positions
From J. Graham: Smith‘s Recognizable Patterns of Human
Deformation (2007)

Problems in morphogenesis: malformation
Malformations
Occur during formation of structures
Complete or partial absence
Alterations of its normal configuration
The exact mechanism is mostly
unknown. Error in embryonic cell
proliferation, differentiation,
migration, programmed death and
cell to cell communication.
Recurrence risk unknown.

Development of lymphatic system
The early developing lymph channels drain into the venous system (approx. 8 week).

Development of lymphatic tissue

Development of lymphatic tissue

Development of lymphatic tissue

Dermal ridges of fingertips and simian crease
From J. Graham: Smith‘s Recognizable Patterns of Human Deformation (2007)

Evaluation of cleft palate

Brain and hair
developement:
13 th and 18 th week
Hair pattern and intrauterine brain growth
From J. Graham: Smith‘s Recognizable Patterns of Human Deformation (2007)

Hair pattern and intrauterine brain growth
Frontal «up-sweep»
or
cow lick

Hair pattern and intrauterine brain growth

Hair pattern and intrauterine brain growth

Systematic clinical evaluation
Anthropometry Height, weight, head circumference, arm span, US/LS ratio
The further measurements deviates from the normal centile ranges, the greater the
change of making a genetic diagnosis
Head Shape, size, anterior and posterior fontanelle, forehead and temporal region
Hair Colour, texture, hair whorl pattern, hair line, growth
Eyes Slant, intercanthal distance, shape, size, cornea, sclera, iris (colour, coloboma),
fundus
Ears Size, position, shape
Mouth region Size, shape, palate (narrow, high arched, cleft), alveolar ridges, lips (thick, thin, cleft,
shape), Philtrum (small, long, simple, prominent)
Chin & Malar region Micrognathia, retrognathia, hypoplasia of malar region
Neck Short, long, webbed
Chest Shape, inter nipple distance, sternum
Hands & Upper
limbs
Shape, fingers, nails, clinodactyly, limb lengths, carrying angle
Feet & Lower limbs Shape, toes, big toe abnormalities, sandal gap, limb lengths, hip dislocation, edema
Skin Colour, texture, hirsutism, sweating, pigmentary abnormalities

Where to find reference data
Greenwood growth references
– Greenwood genetic center
– http://www.ggc.org

ABase

ABase

Eyes
Slant, inner and outer
canthal distance, shape, size,
cornea, sclera, iris (colour,
coloboma), fundus

Inner canthal distance
Outer canthal distance
Interpupillary distance
Telecanthus, hyper- and hypotelorism

Telecanthus, hyper- and hypotelorism

Size, position, shape
Ear pit!
Ears

Hypoplastic ear
Microtia
Ears

Ears

P P
Ear position / ear rotation
• Ear position
- location of the superior attachment of the pinna
- measurement
- line through inner and outer canthi
- line between the outer canthus and the most
prominent part of the occiput
• Ear rotation
- rotation of the median longitudinal axis of the external
auricle
- measurement
- Frankfurt horizontal plane – medial longitudinal axis
of the ear, connecting the two most remote points
- normal rotation: 17-22 degrees
R

22 o
Ear position / ear rotation

Size
Shape
Palate (narrow, high arched, cleft)
Alveolar ridges,
Lips (thick, thin, cleft, shape)
Philtrum (small, long, simple, prominent)
Mouth

Micrognathia
Retrognathia
Hypoplasia of malar
region
Chin

Short
Long
webbed
Neck

Hand and fingers
Shape, fingers, nails,
clinodactyly, limb lengths,
carrying angle

Sandal gap
Feet

Syndactyly of toes
Sign for reduced
intrauterine movements,
but also a frequent
unspecific sign.
Described in 325 different
traits.
Feet

Neurologic examination

Etiology / pathogenesis /phenotype
Pierre-Robin-Sequence
Oligohydramnios Extrinsic mandibular deformation
Neurogenic hypotonia Lack of mandibular exercise
Growth deficiency Intrinsic mandibular hypoplasia
Connective tissue disorder Intrinsic mandibular hypoplasia and failure of
connective tissue penetration across palate

most syndromes are
polytypic
The importance of databases
The diagnostic process in clinical dysmorphology is difficult !
large number of syndromes
low prevalence of
most syndromes
increasing knowledge
in modern genetics
Need for databases to collect information about:
summaries of clinical features
family studies of Mendelian disorders
key journal references
information of research progress about gene localisation and locus
identification

MIM
since 1966
OMIM
since 1985
The importance of MIM and OMIM
McKusick, V.A. Mendelian Inheritance in Man and its online version, OMIM. Am J Hum Genet 80, 588-604 (2007).

Online “expert” systems with free access
Orphanet.
www.orpha.net
Syndroc.
www.syndroc.ch
The Phenomizer.
http://compbio.charite.de/phenomizer

Commercial “expert” systems
London Medical Databases, Winter–Baraitser
Dysmorphology Database.
www.lmdatabases.com
POSSUMweb.
www.possum.net.au
SynDiag.
members.tripod.com/~kolosov

Clinical approach to the dysmorphic newborn

Thank you for your attention!