Upload
others
View
4
Download
0
Embed Size (px)
Citation preview
Yuva Journal of Medical Science
Vol 2, No 3, September 2016, pg. 77-89
eISSN:2395-6526
www.yjms.in
Page 77
DYSMORPHISM IN CHILDREN
Manasvin Sareen, Nashwa Kamal Shroff , Devendra Sareen
Department of Pediatrics, Geetanjali Medical College and Hospital, Udaipur
DYSMORPHOLOGY
This term is coined by Dr. David Smith in the 1960’s.
Dysmorphology is the study of abnormalities of human form and the mechanism that cause these
abnormalities.
It is estimated that 1 in 40 or 2.5% of newborns have a recognisable malformation or multiple
malformations at birth.
CLASSIFICATION OF BIRTH DEFECTS
Malformation
It is the defect of morphogenesis in an organ or structure due to intrinsically abnormal problem with formation,
growth or differentiation. For example:
1. Hypoplasia of an organ or structure (microtia)
2. Incomplete closure (NTD’s,cleft palate)
3. Incomplete separation (syndactyly)
Malformations are not specific. The same morphologial defect or even a similar pattern of abnormalities may occur as:
An isloated anomaly in an otherwise normal individual.
A feature in a syndrome, sequence or association.
A feature of a chromosome disorder, a single gene defect, multifactorial disorder or secondary to a
teratogenic effect.
Dysplasia
It is abnormal organization of cells into tissues, most often due to single gene defects. For example:
1. Achondroplasia
2. Ectodermal dysplasia
3. Osteogenesis imperfecta
Deformation
It is an alteration in shape or structure of an organ that has differentiated normally. For example:
1. Clubfoot
2. Congenital hip dislocation
3. Craniofacial symmetry
Disruption
It is the structural defect resulting from the destruction of a structure that had formed normally before the insult. For
example:
1. Loss of digit due to amniotic bands
2. Lack of normal limb development due to intrauterine vascular accident.
Yuva Journal of Medical Science
Vol 2, No 3, September 2016, pg. 77-89
eISSN:2395-6526
www.yjms.in
Page 78
Syndrome
It is defined as a pattern of multiple abnormalities that are related by pathophysiology and result from a common
defined etiology. For example:
1. Down syndrome
2. Williams syndrome
3. Turner syndrome
Sequences
It consists of multiple malformations that are caused by a single event that can have many etiologies. For example:
1. Potter sequence – renal dysplasia, pulmonary hypoplasia, facial dimorphisms.
2. Meningomyelocele- club foot, hip dislocation, hydrocephalus.
Association
It refers to a random collection of malformations where there is an unclear relationship among the malformation
such that they do not fit the criteria for a syndrome or sequence.
For example: VACTERL and CHARGE associations
CAUSES OF CONGENITAL MALFORMATIONS
Monogenic (7.5% of serious anomalies)
1. X-linked hydrocephalus
2. Achondroplasia
3. Ectodermal dyplasia
4. Apert disease
5. Treacher collins syndrome
Chromosomal (6% of serious anomalies)
1. Trisomies 21, 18,13, XO , XXY
2. Deletions 4p-, 5p-, 7q-, 13q-, 18p-, 18q-, 22q-
3. Prader-Willi syndrome ( 50% have deletion of chromosome 15)
Maternal infection (2% of serious anomalies)
Intrauterine infections (eg – TORCH)
Maternal illness (3.5% of serois anomalies)
1. Diabetes mellitus
2. Phenylketonuria
3. Hyperthermia
Environmental agents
Polychlrinated biphenyls, herbicides, mercury, alcohol
Medications
Thalidomide, Diethylstilbesterol, phenytoin, warfarin, cytotoxic drugs, ACE inhibitors , Isotretinoin , Valproic acis
Unknown etiologies
Yuva Journal of Medical Science
Vol 2, No 3, September 2016, pg. 77-89
eISSN:2395-6526
www.yjms.in
Page 79
1. Polygenetic – associated with infertility – Anencephaly, Spina bifida, cleft lip , cleft palate, pyloric
stenosis, congenital heart disease
2. Sporadic syndrome complexes- CHARGE synd, VATER synd, Pierre robin syndrome , Prune belly
syndrome
Nutritional
Low folic acid neural tube defects
CAUSES OF DEFORMATION
Most deformations involve the musculoskeletal system .
Fetal movement is required for proper development of the normal musculoskeletal system, and anything
that restricts fetal movement can cause musculoskeletal deformation from intrauterine moulding .
It is important to recognize that deformations can be caused by problems either inrinsic or extrinsic to the
developing fetus.
Two major intrinsic causes are primary neuromuscular disorders and oligohydramnios .
The major extrinsic causes are which lead to restricted fetal movement.
When a fetus is presnt in breech presentation , the incidence of deformations is increased 10-fold.
Uterine factors like uterine shape, volume of amniotc fluid, size and shape of fetus ,presence of more than
one fetus , site of placental implantaion, , presence of abdominal tumours etc.
Most children with extrinsic deformations are completely normal and their prognosis is excellent .
Deformations caused by intrinsic causes have poor prognosis.
CAUSES OF DISRUPTION
Disruption defects are caused by destruction of a previously normally formed part.
2 basic mechansims are involved. One involves entanglement followed by tearing part or amputation of a
normally developed structure , usually a digit, arm, leg by amniotic bands.
The second involves interruption of blood supply which occurs in early gestation, atresia or absence of a
particular part.
If infarction occurs later, necrosis is more likely to be present. Egs include non-duodenal intestinal atresia,
porencephaly etc.
The prognosis for a disruptive defect is determined entirely by the extent and location of tissue loss.
WHO NEEDS A DYSMORPHIC EVALUATION?
1. A history of intrauterine growth retardation or failure to thrive
2. Abnormal growth (short,excessive)
3. Abnormal or unusual facial features
4. Abnormal body and limb proportions or symmetry
5. Major and minor congenital anomalies
6. A relative with problems similar to those of patient
7. A significant regression in developmental process
Yuva Journal of Medical Science
Vol 2, No 3, September 2016, pg. 77-89
eISSN:2395-6526
www.yjms.in
Page 80
APPROACH TO THE DYSMORPHIC CHILD
1. History
2. Physical examination
3. Imaging studies
4. Pattern recognition
5. Laboratory findings
6. Management and genetic counselling
HISTORY
The prenatal history is an important component of history
The pregnancy history of the mother is useful for the recogntion of recurrent miscarriages that may be a
sign of a familial chromosomal disorder
Maternal exposure to teratogenic drugs or chemicals
The pedigree or family history that is necessary to assess the inheritance pattern of a disorder
PHYSICAL EXAMINATION
The essential element of examination is objective assessment of the structure of children
It is also useful to categorize abnormalities as ‘major’ or ‘minor’ birth defects.
Major malformations are those that have medical and social implications,often require surgical repair.
Minor malformations have mostly cosmetic significance
Approximately 155 of newborns have one major anomaly, 0.8% have two major anomalies and 0.5% have
three.
If two minor anomalies are present, the probability of an underlying syndrome or a major anomaly
(congenital heart disease, central nervous sysytem defect) is fivefold in general population.
If three minor anomalies are presnet , the probability that there is a major anaomaly is 20-30%.
Take all routine anthropometric measurements:
Weight
Length/ height
Head circumference
Chest circumference
Mid arm circumference
Uper segment/lower segment ratio
Arm span
Special measurements include:
Hand measurement- middle finger length & palm length, hand length
Foot length
Yuva Journal of Medical Science
Vol 2, No 3, September 2016, pg. 77-89
eISSN:2395-6526
www.yjms.in
Page 81
Facial measurements – inner canthal ,outer canthal ,interpupillary distance, palpebral fissure length
Ear length
Visual and hearing assessment
General: appearance, body shape and size
Head: shape ( brachycephaly , dolichocephaly /scapholocephaly , plagiocephaly), fontanel
size/shape (wide, large, small), sutures (ridges, prominent)
Hair: color, texture, distribution (low/high hairline, whorls)
Eyes shape (almond); palpebral fissures (length, slant), spacing (hypotelorism, hypertelorisim)
Ears: shape (box, simple), position (low-set, posteriorly rotated),lack of helical fold,small
pinna,
Nose: root, bridge (prominent, flat, wide), tip (bulbous, wide),saddle ,upturned
Midface: flat, hypoplastic
Mouth size, shape (down-turned, up-turned), palate (intact, cleft), teeth (wide-spaced, crowded)
Chin: small (micrognathia), prominent (prognathia), recessed (retrognathia)
Neck: length (short, long), webbed, excess skin
Chest: symmetry, size, nipples: shape (inverted), spacing (wide-spaced)
Heart: routine exam for rate, rhythm and murmurs
Abdomen: hepatosplenomegaly, hernias
Genitourinary: Appropriate male/female development, ambiguous genitalia, anal placement
Back: deformities, scoliosis, sacral dimples
Extremities: Fingers - brachydactyly, camptodactyly , arachnodactyly, clinodactyly , polydactyly,
syndactyly.
Crease pattern - Simian crease , bridged upper palmar creases
Foot – partial syndactytly of second and third toes, overlapping toes, wide gap between
hallux and second toe, polydactyly
Upper/Lower extremities - rhizomelic shortening (proximal shortening of limbs),
mesomelic shortening (shortening of forearm), clubfoot (talipes equino varus ), knock
knees (genu valgum), bowlegs (genu varum)
Feet - flat feet (pes planus)
Skin: nevi, hypopigmentation, hyperpigmentation, café-au-lait spots, birth marks, rashes
Neurological: mental status, tone, muscle strength/definition, reflexes, gait
Facies
Flat facies or potter facies
a) Parrot beak nose
b) Micrognathia
Yuva Journal of Medical Science
Vol 2, No 3, September 2016, pg. 77-89
eISSN:2395-6526
www.yjms.in
Page 82
c) Redundant skin , which is a skin fold of tissue extending from the medial canthus across the cheek
d) The ears are slighly low and prssed against the head making them appear large .
Triangular facies
a) High forehead that tapers to a small jaw
b) Micrognathia
c) Prominent nasal bridge
d) Down turning corners of the mouth
Coarse facies
a) Facial expressions lack in refinement
b) Forehead and brows are prominent
c) Puffiness of eyelids
d) The nasal bridge is depresses
e) Anteverted nares and thick upper lip
f) Macroglossia
g) Gums are hypertrophied
Mask like facies
An immobile expressionless fae with starind eyes and slightly open mouth.
RECOGNISING THE PATTERN OF DYSMORPHISM
Presented with facial defect as major features –
a) Treacher collins syndroem
b) Robin sequence
c) Moebius sequence
d) Clef t lip sequence
Presneted as facial limb defect as major features-
a) Oral facial difital syndroem
b) Digeorge syndrome
Limb defect as major features-
a) Holt oram syndrome
b) Fanconi pancytopenia syndrome
c) TAR syndroem
Craniostosis syndrome-
a) Apert syndrome
b) Crouzon syndrome
c) Carpenter syndrome
d) Pfeiffer syndrome
Very small stature without skeletal dysplasia
Yuva Journal of Medical Science
Vol 2, No 3, September 2016, pg. 77-89
eISSN:2395-6526
www.yjms.in
Page 83
a) Rubinstein tayabi syndrome
b) Russel silver syndrome
c) SHORT syndrome
Moderate short stature-
a) Smith lemli opitz syndrme
b) Noonan syndrome
Senile like appearance-
a) Progeria syndrome
b) Werner syndrome
Early overgrowth with associated defect-
a) Fragile X syndorome
b) Beckwith wiedemann syndrome
c) Sotos syndrome
Storage disorder –
a) Mucopolysacharadosis- presented as coarse facies, short stature, corneal clouding, joint contractures.
b) Glycogen storage disorder- failure to thrive, hepatomegaly, recurrent episodes of hypoglycemia etc
REACHING A DIAGNOSIS
Prenatal Diagnosis -
While the majority of children are born without problems, birth defects do occur in 2-3% of all newborns. Prenatal
testing is routinely performed to better determine the health and condition of and unborn fetus. This testing consists
of a number of non-invasive and invasive techniques offered primarily during the 1st and 2
nd trimesters. The
implementation and interpretation of these tests may require the collaboration of multiple specialists including an
obstetrician, maternal-fetal-medicine specialist, genetic counselor, medical geneticist, pediatric surgeon, pediatric
cardiologist, or neonatologist.
Non-invasive Testing
Non-invasive testing consists of maternal serum screening and fetal imaging, such as ultrasonography, magnetic
resonance imaging (MRI), and fetal echocardiography.
Maternal Serum Screening:
Maternal serum screening, previously referred to as the triple screen, uses several biochemical markers to make an
estimate of risk for a number of conditions. Specifically, the level of each maternal marker or specific combination
of markers can be used to calculate the potential risk for aneuploidies, open neural tube defects, abdominal wall
defects, and genitourinary defects. This screening is available to all pregnant women who wish to better define their
personal risk and determine the need for further testing.
1st trimester screening (only available at certified testing centers)
Timing: Performed between 11 weeks to 13 weeks, 6 days
Measures: Free ß-human chorionic gonadotropin (hCG) ,Pregnancy-associated plasma protein (PAPP-A),
Nuchal translucency
Detects:
Chromosome aneuploidies (Trisomy 13, 18, 21 and Turner syndrome)
Yuva Journal of Medical Science
Vol 2, No 3, September 2016, pg. 77-89
eISSN:2395-6526
www.yjms.in
Page 84
85-90% of detection rate of Trisomy 21
Some genetic syndromes associated with increased nuchal thickness (Ex. Noonan syndrome, Smith-Lemli-
Opitz syndrome, skeletal dysplasias)
Cons: Not a diagnostic test
2nd trimester maternal serum screening -
Timing: Performed between 14-22 weeks (depending on lab)
Measures: maternal serum
Human chorionic gonadotropin (hCG)
Alpha-fetoprotein (AFP)
Elevated AFP levels are associated with
Open neural tube defects (ONTD): anencephaly and myelomeningocele
Abdominal wall defects: gastroschisis and omphalocele
Genitourinary defects: congenital nephrosis
Fetal demise
Low levels are associated with an increased risk of Trisomy 21
Unconjugated estriol (uE3)
Inhibin A
Detects:
75-80% of Trisomy 21
60% of Trisomy 18
70-85% of ONTD
*Triple Screen (hCG, AFP, uE3) = 60-65% detection for Trisomy 21
Cons: Not at diagnostic test
Clinical Pearl:
Accurate calculation of personalized risk with maternal serum screening requires:
a) Accurate gestational age - dating error of > 14 days invalidates results
b) Accurate maternal demographics (age, weight, ethnicity)
c) Maternal health information (diabetes, medications)
d) Single vs. multiple fetuses
Ultrasonography:
Ultrasonography is used to assess and monitor fetal growth and development. It allows for the detection of structural
abnormalities. In particular, it can be used in conjunction with maternal serum screening for further evaluation of
specific defects.
High-resolution USG
Timing: Performed at 20 weeks
Benefits: Detects structural abnormalities
Cons: Only detects 30-50% of major birth defects
Yuva Journal of Medical Science
Vol 2, No 3, September 2016, pg. 77-89
eISSN:2395-6526
www.yjms.in
Page 85
Not able to detect chromosomal abnormalities
Invasive testing
Invasive testing consists of chorionic villous sampling (CVS), amniocentesis, and fetal blood sampling. These tests
are diagnostic tests that can be done to determine if a fetus is affected with a chromosomal abnormality, open neural
tube defect, or known genetic abnormality. Because these invasive tests are associated with a risk for miscarriage,
they are only offered to women with pregnancies at increased risk for an abnormality. These women include those
that:
are age 35 years of age or older
have abnormal fetal ultrasound findings
have a positive maternal serum screen
have a family history of a chromosome abnormality
have a previous child with a chromosome abnormality or multiple congenital abnormalities
have had two or more previous spontaneous abortions
are known carriers of an X-linked disorder
are at risk of having a child with a specific genetic disorder
Chorionic Villous Sampling (CVS)
Timing: Performed between 10-12 weeks
Techniques: Transcervical or transabdominal
Benefits:
Early results
99% detection of chromosomal abnormalities
Risks:
1% risk for miscarriage
Increased risk for limb-reduction defects associated with CVS performed prior to 10 weeks gestation.
Cons:
Does not detect all fetal abnormalities
Does not detect open neural tube defects
Amniocentesis
Timing: Performed between 15-22 weeks
Technique: Transabdominal
Benefits:
Less risk for miscarriage (0.5%)
99% detection of chromosomal abnormalities
AFP/AChE level also detects open neural tube defects (98%)
Biochemical or molecular genetic tests can be performed on the cultured amniocytes for specific genetic
conditions
Risks:
0.5% risk for miscarriage
Yuva Journal of Medical Science
Vol 2, No 3, September 2016, pg. 77-89
eISSN:2395-6526
www.yjms.in
Page 86
Increased risk for talipes equinovarus (clubfoot) performed prior to 15 weeks gestation
Cons: Does not detect all fetal abnormalities
Fetal Blood Sampling (Percutaneous Umbilical Blood Sampling (PUBS)
Timing: Performed between 18-22 weeks
Technique: Transabdominal
Benefits:
Most accurate method
Risks:
Greatest risk for miscarriage
Preimplantation Genetic Diagnosis (PGD)
PGD, an alternative to prenatal diagnosis, is an assisted-reproductive technology available for couples at risk for
having a child with a genetic or chromosomal disorder. It involves the use of molecular and cytogenetic techniques
during in vitro fertilization to select for unaffected embryos prior to uterine implantation. Ethical dilemmas raised by
PGD include screening for late-onset diseases (ie Huntington disease) and HLA matching (ie bone marrow donor for
sibling with leukemia).
NEWBORN SCREENING
Goal: Population screening to identify pre-symptomatic newborns at risk for diseases or disorders that if left
untreated can cause significant morbidity and mortality.
Principles:
1. The disorder should be prevalent in the population
2. The screening test should be economic, yet sensitive
3. Treatment for the disorder should be available to prevent morbidity and mortality
Newborns screening began in the 1960s. Since that time it has expanded from testing for a single disorder, PKU, to
testing for several dozen disorders. At this time, each local state government determines which screening tests will
be performed. An up-to-date listing of the newborn screening offered in each state can be found at the National
Newborn Screening & Genetics Resource Center. Newborn screening tests are available for a number of conditions
including endocrinopathies (hypothyroidism, congenital adrenal hyperplasia), hemoglobinopathies (sickle cell
disease), and metabolic disorders (phenylketonuria, galactosemia, and many others), as well as congenital hearing
loss.
With the development of new technology, specifically tandem mass spectrometry , it is now possible to screen for
more than 30 metabolic disorders. Many states are in the process of expanding their newborn screening programs.
However, cost-benefit issues remain an area of active discussion.
As with any screening test, there are false negatives and positives. The newborn screen is not diagnostic and further
definitive testing is required.
A review of the disorders recommended for screening can be found at: Medical References: Recommended
Newborn Screening Tests: 29 Disorders .
LABORATORY
The labooratory evaluation of a dysmorphic child is helpful but complex.
Cytogenetics with Giemsa-banded peripheral leucocyte karyotype (or chromosomal analysis) is the gold
standard and should be performed in most of the evaluations of a dysmorphic child.
Yuva Journal of Medical Science
Vol 2, No 3, September 2016, pg. 77-89
eISSN:2395-6526
www.yjms.in
Page 87
A practical reason for ordering the karyotype early in the diagnostic process is that it typically takes 7-12
days for results .due to many chromosoma abnormalities including derangement of the telomeres of the
chromosomes, assays should detect smallduplications or deletions of the telomeres of chromosome.
FISH (Flourescence in-situ hybridisatio) ans CGH( comparative genomic hybridizatio) are two new
technologies that allow detection of more subtle changes.
In FISH , flourescent lablled probes of known DNA sequence are hybridised to chromosomes that are fixed
ona slide & denatured in place allowing the probe to attach to its complementary sequence .When viewed
with a wavelenght of light that excites the fluoroscent dye, coloured signals are generated allowing
localisation of the probe . FISH probe may consist of a contiguous genomic sequence ,part of
chroomsomeor a whole chromosome. Whole choromosomal probe is also called as painting probe.
CGH is based on FISH technology. DNA from one sample is labelled with red fluorescent dye while DNA
from another is labelled in green. The two are mixed in equal amount & used as chromosomal painting
probe on normal human chromosome. The ratio of red to green fluorescence along each chromosome is
measured . Deviation from expected 1:1 ratio of red to greenwill be detected as change in colour signal in
that region documenting gain or loss of copy number.
CLINICAL INDICATIONS FOR KARYOTYPE ANALYSIS
1. At least one major and two minor malfomations
2. At least two major malformations
3. Developmental or growth retardation with two or more major or minor anomalies
4. Metabolic disorders
Accurate diagnosis allows –
Prognosis
Treatment options
Recurrence risk
MANAGEMENT AND COUNSELLING
1. Management of the affected patient and genetic counselling are essential aspects of the approach to the
dysmorphic patient.
2. Children with Down syndrome have a high incidence of hypothyroidism and children with Achondroplasia
have a high incidence of cervicomedullary junction constriction. Ancipitary guidance and medical
monitoring can improve the quality of life .
3. Hearing aids and correcting the visual problem
4. Enzyme replacement therapies
5. Prognosis of the child depends upon natural history of disease .
6. Risk of recurrence depends upon the cause and pattern of inheritance
7. Chorionic villus sampling or amniocentesis is advised in next pregnancy
8. Risk and prognosis of disease are expained to the parents
EARLY INTERVENTIONAL THERAPIES
Early intervention programmes for infants and toddlers with developmental delay with facial dysmorphism should
begin immediately with focus on gross motor, fine motor, language, and social development.
Yuva Journal of Medical Science
Vol 2, No 3, September 2016, pg. 77-89
eISSN:2395-6526
www.yjms.in
Page 88
Physiotherapy:
The goal of physiotherapy is to ensure that the child avoids developing abnormal compensatory movement for the
physical limitations (e.g., hypotonia, ligamentous laxity, decreased strength, and short arms and legs relative to the
length of the trunk).
Occupational therapy:
This facilitates the development of fine motor skills and mastering self-help skills for independence. These skills
include feeding, dressing, writing, and playing. In addition, infants with hypotonia and feeding issues may receive
occupational therapy with a focus on oral-motor exercise.
Speech and language therapy:
Children with Down Syndrome universally have language delay that is further affected by their low muscle tone,
small mouth with protruding tongue, and open-mouth posture. Difficulties in motor planning and coordinating rapid
movements of the tongue, lips, jaw, and palate affect speech intelligibility. Expressive language is more delayed
than receptive language. Language intervention should begin early and involves the family, and the child's learning
style should be considered when designing a language intervention programme. Pre-language and pre-speech skills
can be addressed even before the child is ready to communicate verbally.
IDENTIFICATION OF ONGOING COMPLICATIONS
Hearing evaluations should be repeated at 6 months, at 12 months, and once a year thereafter. Referral to a
paediatric otolaryngologist is recommended if the tympanic membrane is not visualised and/or otitis media
recurs frequently. In general, placement of pressure equalising tubes (PET) is considered if there are 3 to 5
ear infections in 1 year, or persistent middle ear fluid for 2-3 months. Additionally, children who are prone
to chronic ear disease, it will be important to assess the effects of the multiple sets of PETs that will be
needed.
If the newborn screen is normal, a follow-up for thyroid function (T4 and TSH) is recommended at 6
months and then yearly to identify hypothyroidism. Hyperthyroidism also occurs, but at a lower frequency.
Children with Down Syndrome should have an ophthalmic evaluation by a paediatric ophthalmologist
within the first 6 months of age and yearly thereafter until age 5, then the evaluation will occur every 2
years. Congenital cataracts are seen in 4% of them . The nasolacrimal duct may be obstructed as a
complication of mid-face hypoplasia, but it improves with age. Other abnormalities include strabismus
(23% to 44%), accommodative esotropia, myopia, hyperopia, and blepharitis.
Dental examinations should be done at 2 years of age and continued every 6 months. Dental anomalies
include delayed primary and secondary dentition, missing teeth, small or misshapen teeth, or severe
crowding as a result of a small oral cavity( Hutchinson teeth).
All children with facial dysmorphism should be monitored using the regular growth charts.
Patients with behavioural problems, including inattention, hyperactivity, or withdrawal, should be assessed
for any medical issues discussed above. In certain cases, psycho-pharmacological intervention may be
necessary and should be explored with the child's primary care physician and/or child psychiatrist.
The most common cardiac defects associated with facial dysmorphism are Atrioventricular Septal Defect
(formally called Endocardial Cushion Defect), Ventricular Septal Defect, Persistent Ductus Arteriosus and
Tetralogy of Fallot. Heart surgery to correct the defects is recommended and it must be done before age
five or six months in order to prevent lung damage.
These children should continue to receive general health monitoring with emphasis on medical concerns,
and regular physical examinations and immunisations.
Yuva Journal of Medical Science
Vol 2, No 3, September 2016, pg. 77-89
eISSN:2395-6526
www.yjms.in
Page 89
REFERENCES
1. Nelson text book of pediatrics 20th edition
2. Smith's Recognizable pattern of Human malformation 6th edition
3. Veena kalra pediatric neurology
4. http://bestpractice.bmj.com/best-practice/monograph/700/treatment/step-by-step.html
5. http://www.utmb.edu/pedi_ed/CORE/MedicalGenetics/page_34.htm