2013 - Clinical Approach to the Dysmorphic Newborn

Contact: Dr. Bernhard Steiner, Médecin Adjoint, Children‘s [email protected]

Chinderarztpraxis, Ruopigenring 37, 6015 [email protected]

Clinical approach to the dysmorphic newborn

Genetics in Neonatology

Cantonal Hospital Lucerne, 15th of January 2013


�Major congenital anomalies

At birth: 2 – 3 %At age 5: 4 – 6 %

� Minor congenital anomalies

At birth: 15 %

Major versus minor anomalies

From J. Graham: Smith‘s Recognizable Patterns of Human Deformation (2007)

Major malformations.

Those that have medical & /or social implications.

Often require surgical repair.

Minor malformations.

Have sometimes cosmetic significance.

Normal variants.

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

Causes of human malformations

From Stevenson and Hall: Human Malformations And Related Anomalies (2006)

Cause Percent IncidenceGenetic 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


History of intrauterine

developement

Accurate diagnosisAllow for decision making

and communicating:

Prognosis.

Treatment options.

Occult abnormalities.

Recurrence risk.

Pathogenesis.

History of intrauterine developement

Weeks of gestation

Possible teratogenic exposures

Results of diagnostic procedures (ultrasound, AC)

Complications (bleeding, fever)

Fetal Movement (time of onset, force)

Amount of amniotic fluid

Timetable of human development

From Moore and Persaud: The Developing Human (1998)

Perinatal information

Gestation

Complications of labour

Fetal presentation

Mode of delivery

Neonatal status:

• force, breathing, measurements, seizures

Newborn course:

• feeding, anomalies, complications,

resuscitation

Pre-natal vs. post-natal onset of developmental problems

Family History

Ask for:

• Birth defects

• Other genetic disease

• Multiple miscarriages

• Parental ages and health status

• Consanguinity and geographic origin

Three generation family history

The major types of problems in morphogenesis

Malformation Deformation Disruption Dysplasia



Disruption

Interrelationships between malformations,

deformations, and disruptions

Malformation

Deformation

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.

Causes of disruption


� Ionisation (X-Ray, radioactivity)

� Hyperthermia

� Infections

� Teratogenic (drugs, alcohol)

� Metabolic

� Vascular disruption

� Amnion rupture sequence

Timetable of human development

From Moore and Persaud: The Developing Human (1998)

Problems in morphogenesis: deformation

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 musculo-

skeletal system and may be

reversible postnatally

Breech position

Dolichocephalic deformation of the head due

to intrauterine breech position.

Trisomy 18

Risk factors for fetal constraint

Maternal risk factors

� Primigravida

� Small maternal size

� Small uterus

� Uterine malformation

� Uterine fibromata

� Small maternal pelvis

Fetal risk factors

� Oligohydramnios

� Large fetus

� Multiple fetuses

The non-random clinical association among deformations


Deformations related to breech presentations

From J. Graham: Smith‘s Recognizable Patterns of Human

Deformation (2007)

Disorders predisposing to breech presentation

From J. Graham: Smith‘s Recognizable Patterns of Human

Deformation (2007)

3% of all births with breech presentations

23% of all newborns with malformations

with breech positions

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



Dermal ridges of fingertips and simian crease


Evaluation of cleft palate

Hair pattern and intrauterine brain growth


Brain and hair

developement:

13th and 18th week


Frontal «up-sweep»

or

cow lick



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

Ears

Size, position, shape

Ear pit!

Ears

MicrotiaHypoplastic ear

Ears

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

P PR

Ear position / ear rotation

>22o

Mouth

Size

Shape

Palate (narrow, high arched, cleft)

Alveolar ridges,

Lips (thick, thin, cleft, shape)

Philtrum (small, long, simple, prominent)

Chin

Micrognathia

Retrognathia

Hypoplasia of malar

region

Neck

Short

Long

webbed

Hand and fingers

Shape, fingers, nails,

clinodactyly, limb lengths,

carrying angle

Feet

Sandal gap

Feet

Syndactyly of toes

Sign for reduced

intrauterine movements,

but also a frequent

unspecific sign.

Described in 325 different

traits.

Neurologic examination

Etiology / pathogenesis /phenotype

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

Pierre-Robin-Sequence

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 featuresfamily studies of Mendelian disorderskey journal referencesinformation of research progress about gene localisation and locus

identification

most syndromes arepolytypic

OMIM since 1985

MIM since 1966

McKusick, V.A. Mendelian Inheritance in Man and its online version, OMIM. Am J Hum Genet 80, 588-604 (2007).

The importance of MIM and OMIM

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


Thank you for your attention!

Documents

2013 - Clinical Approach to the Dysmorphic Newborn