Clinical approach to the dysmorphic newborn

Genetics in Neonatology
Cantonal Hospital Lucerne, 15th of January 2013
Contact: Dr. Bernhard Steiner, Mdecin Adjoint, Childrens Hospital bernhard.steiner@luks.ch Chinderarztpraxis, Ruopigenring 37, 6015 Luzern steiner@geneticus.ch

Clinical approach to the dysmorphic newborn

Major congenital anomalies

At birth: At age 5: 23% 46%

Minor congenital anomalies

At birth: 15 %

Major versus minor anomalies

Major malformations.
Those that have medical & /or social implications. Often require surgical repair.

Minor malformations.
Have sometimes cosmetic significance.

Normal variants.
From J. Graham: Smiths 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: Smiths Recognizable Patterns of Human Deformation (2007)

Causes of human malformations

Cause
Genetic Chromosome Single gene Multifactorial Environmental Maternal diseases Uterine / plazental Drug / chemicals Twinning Unknown

Percent Incidence
15-25 10-15 2-10 20-25 8-12 6-8 2-3 0.5-1 0.5-1 40-60
From Stevenson and Hall: Human Malformations And Related Anomalies (2006)

Clinical approach to the dysmorphic newborn

History of intrauterine developement

Accurate diagnosis
Allow for decision making and communicating: Prognosis. Treatment options. Occult abnormalities. Recurrence risk. Pathogenesis.

History of intrauterine developement

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

Weeks of gestation

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

Three generation family history

Ask for: Birth defects Other genetic disease Multiple miscarriages Parental ages and health status Consanguinity and geographic origin

The major types of problems in morphogenesis

Malformation

Deformation

Disruption

Dysplasia

From J. Graham: Smiths Recognizable Patterns of Human Deformation (2007)

Clinical approach to the dysmorphic newborn

Malformation Deformation Disruption

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.

Causes of disruption

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

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 musculoskeletal 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

From J. Graham: Smiths Recognizable Patterns of Human Deformation (2007)

Deformations related to breech presentations

From J. Graham: Smiths 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: Smiths 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: Smiths Recognizable Patterns of Human Deformation (2007)

Evaluation of cleft palate

Hair pattern and intrauterine brain growth

Brain and hair developement: 13th and 18th week

From J. Graham: Smiths 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 Shape, size, anterior and posterior fontanelle, forehead and temporal region Colour, texture, hair whorl pattern, hair line, growth Slant, intercanthal distance, shape, size, cornea, sclera, iris (colour, coloboma), fundus Size, position, shape Size, shape, palate (narrow, high arched, cleft), alveolar ridges, lips (thick, thin, cleft, shape), Philtrum (small, long, simple, prominent)

Head Hair Eyes Ears Mouth region

Chin & Malar region Micrognathia, retrognathia, hypoplasia of malar region Neck Chest Short, long, webbed Shape, inter nipple distance, sternum

Hands & Upper Shape, fingers, nails, clinodactyly, limb lengths, carrying angle limbs 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

Telecanthus, hyper- and hypotelorism

Inner canthal distance

Outer canthal distance

Interpupillary distance

Telecanthus, hyper- and hypotelorism

Ears

Size, position, shape Ear pit!

Ears

Hypoplastic ear

Microtia

Ears

Ear position / ear rotation

P P R

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

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

Pierre-Robin-Sequence

Oligohydramnios Neurogenic hypotonia Growth deficiency Connective tissue disorder

Extrinsic mandibular deformation Lack of mandibular exercise Intrinsic mandibular hypoplasia Intrinsic mandibular hypoplasia and failure of connective tissue penetration across palate

The importance of databases

most syndromes are polytypic

low prevalence of most syndromes

The diagnostic process in clinical dysmorphology is difficult !

large number of 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

The importance of MIM and OMIM

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).

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, WinterBaraitser 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!