Neonatal Teaching: Approach To The Newborn With Multiple Congenital Abnormalities (MCAs) Flashcards
Multiple Congenital Abnormalities
- Liveborn infants: **3% major congenital abnormalities + **3% minor abnormalities
- 15-20% major congenital abnormalities involve CNS + 15-20% involve heart
- With the improvement in prenatal, intrapartum, postnatal and infant care
—> Proportion of clinical problems attributable to congenital malformations has increased - Difficult diagnostic and management problem
- A lack of familiarity with rare syndromes + seemingly endless lists of disorders with confusing eponyms and complicated arrays of features —> overwhelming to physician —> exacerbated by highly charged emotional environment in which decisions must be made
Etiology:
1. Chromosome abnormalities
- Microscopic
- Submicroscopic
2. Single Gene disorders (AD, AR, X-linked)
3. Multifactorial conditions (Environmental + Genetic)
4. Maternal diseases
5. Maternal exposures
6. Unknown
Pathogenesis:
1. Malformation
2. Deformation
3. Disruption
4. Sequence
5. Association
6. Dysplasia
Phenotype:
1. Physical + Neurological examination
2. Pregnancy history
3. Delivery history
4. Family history
Approach to MCAs
- Physical + Neurological examination
- Head to toe
- Pay attention to detail
- Measurements
- Photographs
- Look at parents for familial traits
- **Major vs Minor abnormalities
- **Single vs Multiple abnormalities - Pregnancy history
- Delivery history
- Family history
Measurements
- Measure major features provides objective information on facial + body characteristics
- Converted to **percentiles / **SD for easy reference and accurate comparison among body parts of patient and among different individuals
Growth parameters:
1. Head circumference
- Microcephaly
- Macrocephaly
- Relative Micro/Macrocephaly (relative to height)
- Familial (measure parents)
- Length
- Preterm babies: Corrected gestational age for all growth measurements until 2 yo
- Physical Examination of MCA
Skull + Face:
1. Skull shape
- Normocephaly
- Dolichocephaly / Scaphocephaly (↑ AP diameter due to premature closure of sagittal suture)
- Plagiocephaly
- Brachycephaly (widened skull due to premature closure of coronal suture)
- Trigonocephaly (triangular skull due to premature closure of metopic suture)
- Holoprosencephaly (failure of cleavage of forebrain (left and right brain))
- Frontal bossing
- Fontanelle, sutures
- Facial general shape + expression (e.g. muscle weakness, CN7 palsy)
- Placement + positioning of facial parts
- Brows
- Synophorus (unibrow)
- Arching of brows - Eye
- Outer + Inner canthal distance
- Interpupillary distance (define hyper/hypotolerism)
- Palpebral fissure length
- Cyclopia
- Hyper/Hypotolerism
- Telecanthi
- Upslanting (midface hypoplasia) / Downslanting eyes (maxillary / zygomatic hypoplasia)
- Epicanthal folds (depressed / low nasal root)
- Coloboma of lids - Ear
- Low set (position lower than outer canthal line to prominent part of occiput)
- Rotation (low set ears often accompanied by posterior rotation —> arrest of migration of ear during development)
- Length (e.g. microtia)
- Preauricular sinus (sporadic / inherited, bilateral likely inherited, AD with reduced penetrance + variable expression, 3-10% syndromal association)
- Ear tags (20% associated anomalies)
- Often associated with renal abnormalities —> Renal USG
—> Renal USG in:
—> Preauricular pits, cup ears, ear tags, malformation / dysmorphic features
—> Family history of deafness, auricular / renal malformations / maternal history of GDM - Mouth
- Lips
- Protruding tongue
- Cleft lip + palate
- Micrognathia / Retrognathia - Nose
- Absence
- Supernumerary
- Long nose
- Broad tip
- Prominent nose
- Narrow bridge
- Depressed bridge
- Smooth philtrum (Fetal alcohol syndrome) - Hair
- Lower posterior hairline (look for neck webbing)
- Hair whorls (>=3 indicate underlying developmental CNS problems)
- Cutis aplasia - Neck
- Webbed neck (lymphedema / cystic hygroma prenatal dried up —> redundant skin at birth) - Limbs
- Rhizomelic (Proximal) / Mesomelic / Acromelic (Distal)
- Arthrogryposis (joint contracture)
- Joint hyperextensibility (Beighton score)
- Hemihypertrophy
Hemihypertrophy
- Very important to know about tumour risk with hemihypertrophy!
- Tumors of embryonal origin: **Wilms’ tumour, **Hepatoblastoma
- ***Beckwith-Wiedemann syndrome (BWS): 7.5% risk
- Isolated hemihypertrophy: 5.9% risk
Screening:
1. Renal ultrasound q3 months until 8 yo
2. Serum AFP q3 months until 5 yo
Major vs Minor Congenital Abnormalities
Major malformation:
- A condition of medical, surgical, cosmetic implications
Minor malformation:
- Less importance and may represent a minor variation
- Some of the abnormalities are not obvious and are only noticeable when we take the measurements and note the percentile
- Minor anomalies may contribute to the diagnosis and can point towards a major congenital abnormality
—> 14% of the newborns were found to have one minor anomaly
—> only 0.8% of the babies had 2 minor anomalies and in this subgroup the frequency of a major defect was 10% (5x more than the control group)
—> >=3 minor anomalies are found in only 0.5% of babies and 90% of them had >=1 major defects
—> Findings **several minor anomalies in the same individual may indicate that a more **serious problem in morphogenesis has occurred
- Most common in areas of complex + variable features such as the ***face, auricles, hands, and feet (∵ complex embryologic development)
- Before ascribing significance to a given minor anomaly in a patient, it is important to note whether it is found in other family members
- Almost any minor defect may occasionally be found as a usual feature in a particular family. This may include clinodactyly, telecanthus, shape and position of the the ears, simian crease etc.
Single vs Multiple abnormalities
- Single Major abnormality: Consider sporadic / multifactorial disorder (i.e. low recurrence risk: <3%) (e.g. cleft lip, clubfoot)
- Multiple Major abnormality: need to rule out chromosomal, monogenic, maternal disease / exposure first (e.g. Down syndrome)
- Pregnancy history
Provides information regarding prenatal onset of congenital abnormalities
- Gestational age:
- Prematurity + Post-maturity (associated with congenital abnormalities) - Onset of fetal activity:
- Usually not felt by mother until about 16-20 weeks (Multiparity: earlier, Primigravida: later)
- Fetal activity increases in amount and intensity from that time, reaches a maximum between 29-38 weeks and then decreases somewhat until delivery
- Indicate ***neurological function
—> Congenital neurological abnormalities often
associated with delayed onset / decreased intensity of fetal activity + localization of fetal movement to one particular quadrant of abdomen
Examples for conditions with abnormal fetal movements:
- Deformation caused by an intrauterine compression (Twins, myoma, septated uterus etc.)
- Congenital muscular dystrophy
- Fetal growth (IUGR)
- Increased incidence of malformations
- Increased incidence of neurological + developmental abnormalities - Amniotic fluid volume
- amniotic fluid is maintained in a ***constant state of equilibrium by fetal urination + fetal swallowing during later part of gestation
- Polyhydramnios:
—> CNS / GI anomalies: difficulties swallowing amniotic fluid
- Oligohydramnios:
—> Placental dysfunction (commonest)
—> Chronic leakage of amniotic fluid
—> Abnormalities in the urinary system as in renal agenesis + urethral obstruction - Fetal USG
- Integrated 1st + 2nd trimester screening (Down syndrome + Aneuploidies)
- First trimester: NT + β-hCG+ PAPP-A (detection rate of 85% for 5% FPR)
- Second trimester: AFP + UE3 + DIA (detection rate of 92% for 5% FPR) - Maternal diseases
- DM (e.g. caudal regression syndrome)
- Myotonic dystrophy
- HT
- PKU
- SLE (e.g. chondrodysplasia punctata (dot like bone growth in cartilage)) - Maternal exposures
- Infection
- Fever
- Exposure to high temp
- Drugs
- Alcohol
- Medications
- Radiation
- Delivery history
- APGAR scores
- Respiratory Status
- Birth parameters (weight, length, OFC)
- Specific Medical Problems (feeding, seizures, cardiac etc.)
- Family history
- 3 generation family history
- Consanguinity, mental retardation, recurrent miscarriages, stillbirths, inherited conditions
- Ethnic background (to identify a need for further screening tests)
- Inherited conditions in siblings / one of the parents
- Consanguinity in the parents increases the chance for an ***AR syndrome in their progeny
- X-linked disorder: a ***male patient with similarly affected male relatives on maternal side
- History of miscarriages, stillbirths, early neonatal deaths (i.e. ***single gene disorders / familial chromosome rearrangement)
- Advanced maternal age: increased risk for fetal ***aneuploidy (i.e. T21, T18, T13 etc.)
- Advanced paternal age: New ***AD conditions (e.g. achondroplasia)
Terminology
- Preimplantation period:
- Ovulation, fertilization, development of blastocyst, inner and outer cell mass and trophoblast
- Until end of 2nd week
- Errors result in a miscarriage rather than malformations - ***Embryonic period:
- 3rd - 8th week post-conception
- Gastrulation: Formation of three germ layers
- Neurolation: Formation of neural tube
- Embryonic development:
—> Morphogenesis (formation of major folds, head,
tail)
—> Organogenesis (Development of body organs)
- Most major malformations arise during this period of organogenesis —> Most important period in clinical settings - Fetal period:
- 3rd month until birth
- Devoted to maturation of tissues + organs + rapid growth of body
- Few, if any malformations arise during this period
Developmental morphologic terminology
- Malformation
- Morphologic defect of an organ / larger region of body that arise because of an **intrinsically abnormal developmental process (i.e. wrong already in the beginning)
- Affect **Morphogenesis + **Organogenesis
- Most malformations would have occurred by **8 weeks gestation
- Earlier it occurs the more complex it is
- Isolated: Spina bifida, Cleft lip, Cleft palate
- Multiple: Down syndrome, Corneila de Lange, William syndrome
- Malformation sequence: A pattern of multiple defects that result from a single primary malformation
—> Sirenomelia (美人魚病): due to vascular accident to lower limb vessels —> no lower limb / renal development —> die in-utero due to renal agenesis)
—> Robin sequence: cleft palate due to small chin —> tongue always pressing against palate
—> Urethral obstruction sequence —> enlarged bladder (may rupture causing urinary ascites) + poor RFT + prune belly syndrome (lax abdomen due to enlarged bladder)
—> Oligohydramnios / Potter sequence —> joint contractures, flat facies - Deformation
- Abnormal form, shape or position of body part caused by mechanical forces acting over prolonged period
- Mechanical forces are external and cause decreased fetal movements
- Examples:
—> Intrauterine constraint / Breech presentation —> Joint contractures
- Evolves after the period of organogenesis is completed
- May be reversible postnatally
- Low recurrence risk - Disruption
- Morphologic defect of organ or larger region resulting from **extrinsic breakdown of / **interference with an originally normal developmental process
- Examples: Amniotic membrane breakdown —> coil around fetus (Amniotic band) —> amputation of limb due to lack of blood supply - Dysplasia
- Abnormal organisation of cells into tissues and its morphologic result (i.e. a process (and the consequence) of dishistogenesis)
- A term most often applied to generalized abnormalities of bone involving epiphyses / metaphyses / diaphyses
- **Skeletal dysplasia: named based on the location of the bony defect such as epiphyseal dysplasia
- Most skeletal dysplasias are associated with **disproportionate short stature - Sequence
- Association
- Non-random occurrence of **>=2 features seen together more frequently than would be expected by chance
- Examples: **VACTERL association
—> Vertebral defects
—> Anal atresia
—> Cardiac defects (VSD most common (Vinson Cheng))
—> Tracheo-esophageal fistula (TOF)
—> Renal anomalies
—> Limb anomalies (Radial anomalies, Preaxial polydactyly, Syndactyly (Vinson Cheng)) - Syndrome
- vs Association
- A recognised pattern of developmentally independent malformations having ***1 etiology
Alpha thalassaemia
Prevalence of (SEA) α-thalassemia deletion in the Asian population: 4.5%
- SEA: –/αα —> i.e. can have baby with no α gene at all
SEA: South East Asia
Organisation of the genome
- Human Genome: ~3,000,000,000bp
- Chromosome: ~150,000,000bp
- Chromosome band: ~10,000,000bp
- Gene (Promoter+exons+introns): ~50,000bp
- Gene (exons): ~3,000bp
- 1 codon: 3bp
- Conventional karyotype: for detecting ***>5M bp changes
- FISH: for detecting ***10000-3M bp changes
- DNA sequencing / PCR: for detecting ***Single - 1000 bp changes (not good for gross abnormalities e.g. copy number variations, deletions, duplications)
- 1000-10000 bp: sometimes can be missed
Karyotype:
- Blood collection in sodium heparin
—> Culture (stimulate T lymphocyte with PHA, usually 72 hours for incubation)
—> Add colchicine to arrest at metaphase
—> Hypotonic soultion to burst cells
—> Drop on slides
—> Stain with Trypsin and Giemsa
—> Fluorescent Microscope analysis
—> Digital capture + analysis
FISH:
- Blood collection in sodium heparin
—> Culture (stimulate T lymphocyte with PHA, usually 72 hours for incubation)
—> Add colchicine to arrest at metaphase
—> Hypotonic soultion to burst cells
—> Drop on slides
—> Hybridise probe to slide
—> Fluorescent Microscope analysis (usually 2 signals, 1 signal: deletion, 3 signals: duplication)
—> Digital capture + analysis
Numerical chromosomal abnormalities
- Down syndrome (47, XX+21)
- Trisomy 18 (47, XY+18)
- Trisomy 13 (47, XX+13)
- Turner syndrome (45X)
- Klinefelter syndrome (47, XXY)
