genetic osce for dnb pdiatric

Genetics -OSCEGenetics -OSCE
Dr. Kashmiri PDr. Kashmiri P BadbadeBadbade

Policies regarding genetic testing of children The AAP recommendations includePolicies regarding genetic testing of children The AAP recommendations include
the followingthe following

11. Established newborn screening tests should be reviewed and evaluated periodically to permit. Established newborn screening tests should be reviewed and evaluated periodically to permit
modification of the program or elimination of ineffective components. The introduction of newmodification of the program or elimination of ineffective components. The introduction of new
newborn screening tests should be conducted through carefully monitored research protocols.newborn screening tests should be conducted through carefully monitored research protocols.
 2. Genetic tests, like most diagnostic or therapeutic endeavors for children, require a process of2. Genetic tests, like most diagnostic or therapeutic endeavors for children, require a process of
informed parental consent and the older child's assent. Newborn screening programs are encouragedinformed parental consent and the older child's assent. Newborn screening programs are encouraged
to evaluate protocols in which informed consent from parents is obtained. The frequency of informedto evaluate protocols in which informed consent from parents is obtained. The frequency of informed
refusals should be monitored. Research to improve the efficiency and effectiveness of informedrefusals should be monitored. Research to improve the efficiency and effectiveness of informed
consent for newborn screening is warranted.consent for newborn screening is warranted.
 3. The AAP does not support the broad use of carrier testing or screening in children or3. The AAP does not support the broad use of carrier testing or screening in children or
adolescents. Additional research needs to be conducted on carrier screening in children andadolescents. Additional research needs to be conducted on carrier screening in children and
adolescents. The risks and benefits of carrier screening in the pediatric population should beadolescents. The risks and benefits of carrier screening in the pediatric population should be
evaluated in carefully monitored clinical trials before it is offered on a broad scale. Carrier screeningevaluated in carefully monitored clinical trials before it is offered on a broad scale. Carrier screening
for pregnant adolescents or for some adolescents considering pregnancy may be appropriate.for pregnant adolescents or for some adolescents considering pregnancy may be appropriate.
 4. Genetic testing for adult-onset conditions generally should be deferred until adulthood or until4. Genetic testing for adult-onset conditions generally should be deferred until adulthood or until
an adolescent interested in testing has developed mature decision-making capacities. The AAPan adolescent interested in testing has developed mature decision-making capacities. The AAP
believes that genetic testing of children and adolescents to predict late-onset disorders isbelieves that genetic testing of children and adolescents to predict late-onset disorders is
inappropriate when the genetic information has not been shown to reduce morbidity and mortalityinappropriate when the genetic information has not been shown to reduce morbidity and mortality
through interventions initiated in childhood.through interventions initiated in childhood.
 5. Because genetic screening and testing may not be well understood, pediatricians need to provide5. Because genetic screening and testing may not be well understood, pediatricians need to provide
parents the necessary information and counseling about the limits of genetic knowledge andparents the necessary information and counseling about the limits of genetic knowledge and
treatment capabilities, the potential harm that may be done by gaining certain genetic information,treatment capabilities, the potential harm that may be done by gaining certain genetic information,
including the possibilities for psychological harm, stigmatization, and discrimination, and medicalincluding the possibilities for psychological harm, stigmatization, and discrimination, and medical
conditions and disability and potential treatments and services for children with genetic conditions.conditions and disability and potential treatments and services for children with genetic conditions.
Pediatricians can be assisted in managing many of the complex issues involved in genetic testing byPediatricians can be assisted in managing many of the complex issues involved in genetic testing by
collaboration with geneticists, genetic counselors, and prenatal care providers.collaboration with geneticists, genetic counselors, and prenatal care providers.
 6. The AAP supports the expansion of educational opportunities in human genetics for medical6. The AAP supports the expansion of educational opportunities in human genetics for medical
students, residents, and practicing physicians and the expansion of training programs for geneticstudents, residents, and practicing physicians and the expansion of training programs for genetic
professionals.Email to Colleague Print Versionprofessionals.Email to Colleague Print Version

 What is Human Genome ProjectWhat is Human Genome Project,?,?
 What is HaploidWhat is Haploid
 What is Diploid.What is Diploid.
 What is GenotypeWhat is Genotype
 What is PhenotypeWhat is Phenotype

 Human Genome ProjectHuman Genome Project, Gene mapping is performed by genetic linkage, Gene mapping is performed by genetic linkage
analysis, which is based on the principle that alleles at two genetic loci that areanalysis, which is based on the principle that alleles at two genetic loci that are
located near one another will segregate together in a family unless they arelocated near one another will segregate together in a family unless they are
separated by genetic recombinationseparated by genetic recombination

HaploidHaploid -Reproductive or germline cells contain one copy (N) of this genetic-Reproductive or germline cells contain one copy (N) of this genetic
complementcomplement
 DiploidDiploid. somatic (non-germline) cells contain two complete copies (2N). somatic (non-germline) cells contain two complete copies (2N)
 GenotypeGenotype- is the genetic constitution of an individual and refers to which- is the genetic constitution of an individual and refers to which
particular alternative version (allele) of a gene is present at a specific locationparticular alternative version (allele) of a gene is present at a specific location
(locus) on a chromosome.(locus) on a chromosome.
 PhenotypePhenotype-is the observed structural, biochemical, and physiologic characteristics-is the observed structural, biochemical, and physiologic characteristics
of an individual, determined by the genotype, and refers to the observed structuralof an individual, determined by the genotype, and refers to the observed structural
and functional effects of a mutant allele at a specific locusand functional effects of a mutant allele at a specific locus

 Identify the structureIdentify the structure
 MethodMethod
 ImportanceImportance

 MicroarraysMicroarrays
 Have been developed that permit tens or hundreds of thousands ofHave been developed that permit tens or hundreds of thousands of
genes to be analyzed on a small glass chip.genes to be analyzed on a small glass chip.
 Patterns of gene expression provide signatures for particular diseasePatterns of gene expression provide signatures for particular disease
states, such asstates, such as
 cancer,cancer,
 In response to therapyIn response to therapy
 Microarray containing 36,000 oligonucleotides. The microarray wasMicroarray containing 36,000 oligonucleotides. The microarray was
exposed to RNA from normal fibroblasts (labeled red; see arrows) andexposed to RNA from normal fibroblasts (labeled red; see arrows) and
fibroblasts from a patient with Niemann-Pick disease, type C (labeledfibroblasts from a patient with Niemann-Pick disease, type C (labeled
green).green). ArrowsArrows point to regions in which there was a strongpoint to regions in which there was a strong
hybridization signal with either normal or disease RNA. Thishybridization signal with either normal or disease RNA. This
microarray was used to search for genes that are highly expressed inmicroarray was used to search for genes that are highly expressed in
the fibroblasts of patients.the fibroblasts of patients.

•Identify the genetic predominanceIdentify the genetic predominance
give six examples of the samegive six examples of the same

 Autosomal dominant pedigreeAutosomal dominant pedigree
 Male & female are equally affacted.Male & female are equally affacted.
 Autosomal dominant inheritance is determined by the presence of oneAutosomal dominant inheritance is determined by the presence of one
abnormal gene on one of the autosomes (chromosomes 1–22).abnormal gene on one of the autosomes (chromosomes 1–22).

characteristics –characteristics –
 Transmitted in a vertical (parent to child) pattern, appearing in multipleTransmitted in a vertical (parent to child) pattern, appearing in multiple
generations.generations.
 An affected individual has a 50% (1 in 2) chance of passing on theAn affected individual has a 50% (1 in 2) chance of passing on the
deleterious genes fordeleterious genes for eacheach pregnancy, and therefore of having a childpregnancy, and therefore of having a child
affected by the disorder. This is referred to as theaffected by the disorder. This is referred to as the recurrence riskrecurrence risk forfor
the disorder.the disorder.
 Unaffected individuals (family members who do not manifest the trait)Unaffected individuals (family members who do not manifest the trait)
do not pass the disorder to their children.do not pass the disorder to their children.
 Males and females are equally affected.Males and females are equally affected.
 The finding of male-to-male transmission essentially confirmsThe finding of male-to-male transmission essentially confirms
autosomal dominant inheritanceautosomal dominant inheritance

 If no history of an affected family member still the individualIf no history of an affected family member still the individual
is affectedis affected
 new mutationnew mutation
 incomplete penetranceincomplete penetrance -not all individuals who-not all individuals who
carry the mutation have phenotypiccarry the mutation have phenotypic
manifestations-manifestations- skipped generation,skipped generation,
 variable expressionvariable expression -mutation will manifest the-mutation will manifest the
disorder to different degreesdisorder to different degrees
 somatic mutationssomatic mutations -spontaneous genetic-spontaneous genetic
mutations occur not in the egg or sperm that formsmutations occur not in the egg or sperm that forms
a child but rather in a cell in the developinga child but rather in a cell in the developing
embryo.embryo.

ExamplesExamples
 Neurofibromatosis
 Tuberous sclerosis
 Von willebrand’s disease
 Acute intermittent porphyria
 Marfans syndrome
 Achondroplasia
 Hereditory sperocytosis
 Facio-scapulo-humeral muscular dystrophy
 Huntington chorea
 Charcoot marries tooth
 Ehler danlos
 OI

IdentifyIdentify
5 examples5 examples

A pedigree illustrating the inheritance pattern of an autosomal recessiveA pedigree illustrating the inheritance pattern of an autosomal recessive
disorder. Affected individuals are represented by shading anddisorder. Affected individuals are represented by shading and
heterozygotes by partial shading.heterozygotes by partial shading.
 AlbunismAlbunism
 Ataxia telangectesiaAtaxia telangectesia
 Crigler-najjar symdromCrigler-najjar symdrom
 CFCF
 Wilson’s d.Wilson’s d.
 GalactosemiaGalactosemia
 PKUPKU
 N-P D.N-P D.
 Sickle cell dsSickle cell ds
 ThalassemiaThalassemia
 Aplastic anemiaAplastic anemia
 Fanconis anemiasFanconis anemias

A pedigree showing the inheritance of an X-linked recessive condition. Solid symbolsA pedigree showing the inheritance of an X-linked recessive condition. Solid symbols
represent affected individuals, and dotted symbols represent heterozygous carriers. Onlyrepresent affected individuals, and dotted symbols represent heterozygous carriers. Only
females can transmit the disorder to their sons. Fathers transmit trait to all daughters.females can transmit the disorder to their sons. Fathers transmit trait to all daughters.
 Hemophilia A & BHemophilia A & B
 GG66 PD defPD def
 Hunter s.Hunter s.
 Neurogenic DINeurogenic DI
 Lesch _ Nyhan s.Lesch _ Nyhan s.
 DMDDMD
 Colour blindnessColour blindness

X- link dominantX- link dominant
 Both male and female are affectedbut moreBoth male and female are affectedbut more
sever in malessever in males
 Affected father transfer it to all daughters &Affected father transfer it to all daughters &
affected mother transfer it bothaffected mother transfer it both
 ExamplesExamples
 Incontinentia pigmentiIncontinentia pigmenti
 VDRR(hypophosphatemic)VDRR(hypophosphatemic)
 Melnick needle’s s.Melnick needle’s s.

SITUATIONS WITH HIGH PROBABILITY OF
GENETIC DISEASE
1.Family history of genetic disorder or chronic
disease
2.Prenatally diagnosed fetal anomalies
3.Positive newborn metabolic screening test
4.Multiple congenital anomalies
5.Neurodevelopmental disorders
6.Perinatal or neonatal death
7.Acute life-threatening event
8.Disorders of growth
9.Multisystem disorders

The karyotype of a male with three copies of chromosome 21 or trisomyThe karyotype of a male with three copies of chromosome 21 or trisomy
21. Note the arrangement of the chromosomes from largest to smallest21. Note the arrangement of the chromosomes from largest to smallest
1/600–800 births1/600–800 births
 Hypotonia, flat face, upward and slanted palpebralHypotonia, flat face, upward and slanted palpebral
fissures and epicanthic folds, speckled irisesfissures and epicanthic folds, speckled irises
(Brushfield sports);varying degrees of mental and(Brushfield sports);varying degrees of mental and
growth retardation;dysplasia of the pelvis, cardiacgrowth retardation;dysplasia of the pelvis, cardiac
malformations, and simian crease;short, broad hands,malformations, and simian crease;short, broad hands,
hypoplasia of middle phalanx of 5th finger, duodenalhypoplasia of middle phalanx of 5th finger, duodenal
atresia, and high arched palate;5% of patients withatresia, and high arched palate;5% of patients with
Down syndrome are the result of a translocation—Down syndrome are the result of a translocation—
t(14q21q), t(15q21q), and t(13q21q)—in which thet(14q21q), t(15q21q), and t(13q21q)—in which the
phenotype is the same as trisomy 21 Down syndromephenotype is the same as trisomy 21 Down syndrome

Write features in hand & footWrite features in hand & foot
 Write features in handWrite features in hand

 Additional Disorders in Children with Down SyndromeAdditional Disorders in Children with Down Syndrome
 Duodenal atresia Annular pancreas TracheoesophagealDuodenal atresia Annular pancreas Tracheoesophageal
fistula Hirschsprung disease Short stature Shortfistula Hirschsprung disease Short stature Short
sternum Brachycephaly Delayed fontanel closure Threesternum Brachycephaly Delayed fontanel closure Three
fontanels Frontal sinus hypoplasia Peripheral joint laxity Atlantoaxialfontanels Frontal sinus hypoplasia Peripheral joint laxity Atlantoaxial
instability (C1–C2 subluxation) Exaggerated space between 1st and 2ndinstability (C1–C2 subluxation) Exaggerated space between 1st and 2nd
toes Mottled skin in infancy Dry coarse skin in adolescencetoes Mottled skin in infancy Dry coarse skin in adolescence IncreasedIncreased
Risk for Development ofRisk for Development of Leukemia:AML,Leukemia:AML,
ALL Myelodysplasia Transient lymphoproliferative syndrome CeliacALL Myelodysplasia Transient lymphoproliferative syndrome Celiac
disease Hypothyroidism Diabetes mellitus Obesity Refractivedisease Hypothyroidism Diabetes mellitus Obesity Refractive
errors Strabismus Mitral valve prolapse Conductive and/or sensorineuralerrors Strabismus Mitral valve prolapse Conductive and/or sensorineural
hearing loss Obstructive sleep apnea Epilepsy Alzheimerhearing loss Obstructive sleep apnea Epilepsy Alzheimer
disease Conduct oppositional disorders ADHDdisease Conduct oppositional disorders ADHD

 What are the common physical characteristicsWhat are the common physical characteristics
of children with Down syndrome?of children with Down syndrome?

 Upslanted palpebral fissures with epicanthal foldsUpslanted palpebral fissures with epicanthal folds
 Small, low-set ears with overfolded upper helicesSmall, low-set ears with overfolded upper helices
 Short neck with excess skin folds in newbornsShort neck with excess skin folds in newborns
 Prominent tongueProminent tongue
 Flattened occiputFlattened occiput
 Exaggerated gap between first and second toeExaggerated gap between first and second toe
 HypotoniaHypotonia

 Are Brushfield spots pathognomonic for DownAre Brushfield spots pathognomonic for Down
syndrome?syndrome?
 What is the chance that a newborn with aWhat is the chance that a newborn with a
simian crease has Down syndrome?simian crease has Down syndrome?

 No.No. Brushfield spots are speckled areas that occur inBrushfield spots are speckled areas that occur in
the periphery of the iris. They are seen in about 75%the periphery of the iris. They are seen in about 75%
of patients with Down syndrome but also in up to 7%of patients with Down syndrome but also in up to 7%
of normal newborns.of normal newborns.
 A single transverse palmar crease is present in 5% ofA single transverse palmar crease is present in 5% of
normal newborns. Bilateral palmar creases are foundnormal newborns. Bilateral palmar creases are found
in 1%. These features are twice as common in malesin 1%. These features are twice as common in males
as they are in females. However, about 45% ofas they are in females. However, about 45% of
newborn infants with Down syndrome have a singlenewborn infants with Down syndrome have a single
transverse crease. Because Down syndrome occurs intransverse crease. Because Down syndrome occurs in
1 in 800 live births, the chance that a newborn with a1 in 800 live births, the chance that a newborn with a
simian crease has Down syndrome is onlysimian crease has Down syndrome is only 1 in 601 in 60..

 What proportion of infants with DownWhat proportion of infants with Down
syndrome have congenital hypothyroidism?syndrome have congenital hypothyroidism?
 What other conditions of increased risk shouldWhat other conditions of increased risk should
not be overlooked during early infancy?not be overlooked during early infancy?
 . What is the expected intelligence quotient. What is the expected intelligence quotient
(IQ) of a child with Down syndrome?(IQ) of a child with Down syndrome?

 About 2% (1 in 50) as compared with 0.025% (1 in 4,000) for allAbout 2% (1 in 50) as compared with 0.025% (1 in 4,000) for all
newborns. This emphasizes the importance of the state-mandatednewborns. This emphasizes the importance of the state-mandated
newborn thyroid screennewborn thyroid screen
 conditions of increased riskconditions of increased risk
 Congenital heart disease: A-V canal defects, ventriculoseptal defectsCongenital heart disease: A-V canal defects, ventriculoseptal defects
 Gastrointestinal malformations: Duodenal atresia, tracheoesophageal atresiaGastrointestinal malformations: Duodenal atresia, tracheoesophageal atresia
 Congenital hypothyroidismCongenital hypothyroidism
 Lens opacities/cataractsLens opacities/cataracts
 Hearing lossHearing loss
 CryptorchidismCryptorchidism
 The IQ range is generally 25-50, with a mean reported IQ of 54;The IQ range is generally 25-50, with a mean reported IQ of 54;
occasionally, the IQ may be higher. Intelligence deteriorates duringoccasionally, the IQ may be higher. Intelligence deteriorates during
adulthood, with clinical and pathologic findings consistent withadulthood, with clinical and pathologic findings consistent with
advanced Alzheimer disease. By age 40, the mean IQ is 24.advanced Alzheimer disease. By age 40, the mean IQ is 24.

 Down syndrome is a risk factor for whatDown syndrome is a risk factor for what
malignancy?malignancy?
 What is the genetic basis for Down syndrome?What is the genetic basis for Down syndrome?
 What chromosomal abnormalities are relatedWhat chromosomal abnormalities are related
to maternal age?to maternal age?
 Does advanced paternal age increase the riskDoes advanced paternal age increase the risk
of having a child with trisomy 21?of having a child with trisomy 21?
 Which is technically correct: Down'sWhich is technically correct: Down's
syndrome or Down syndrome?syndrome or Down syndrome?

 LeukemiaLeukemia
 The syndrome can be caused by trisomy of all or part of chromosome 21:The syndrome can be caused by trisomy of all or part of chromosome 21:
 Full trisomy 21: 94%Full trisomy 21: 94%
 Mosaic trisomy 21: 2.4%Mosaic trisomy 21: 2.4%
 Translocation: 3.3%Translocation: 3.3%
 All trisomies and some sex chromosomal abnormalities (except 45X andAll trisomies and some sex chromosomal abnormalities (except 45X and
47, XYY).47, XYY).
 There does not appear to be an increased risk of Down syndromeThere does not appear to be an increased risk of Down syndrome
associated with paternal age until after age 55. Some studies have noted anassociated with paternal age until after age 55. Some studies have noted an
increased risk of having children with Down syndrome after this age,increased risk of having children with Down syndrome after this age,
although others have not. The reports are controversial, and the statisticalalthough others have not. The reports are controversial, and the statistical
analysis needed to perform such a study is cumbersome. It is known thatanalysis needed to perform such a study is cumbersome. It is known that
approximately 10% of all trisomy 21 cases derive the extra chromosome 21approximately 10% of all trisomy 21 cases derive the extra chromosome 21
from the father.from the father.
 In 1866, John Langdon Down, physician at the Earlswood Asylum inIn 1866, John Langdon Down, physician at the Earlswood Asylum in
Surrey, England, described the phenotype of a syndrome that now bears hisSurrey, England, described the phenotype of a syndrome that now bears his
name. However, it was not until 1959 that it was determined that thisname. However, it was not until 1959 that it was determined that this
disorder is caused by an extra chromosome 21. The correct designation isdisorder is caused by an extra chromosome 21. The correct designation is
Down syndromeDown syndrome..

 What genetically inherited disease has theWhat genetically inherited disease has the
highest known mutation rate per gamete perhighest known mutation rate per gamete per
generation?generation?
 Which disorders with ethnic and racialWhich disorders with ethnic and racial
predilections most commonly warrantpredilections most commonly warrant
maternal screening for carrier status?maternal screening for carrier status?

 Neurofibromatosis.Neurofibromatosis. The estimated mutation rate for this disorder is 1.3 ×The estimated mutation rate for this disorder is 1.3 ×
10-4 per haploid genome. The clinical features are café-au-lait spots and10-4 per haploid genome. The clinical features are café-au-lait spots and
axillary freckling in childhood followed by the development ofaxillary freckling in childhood followed by the development of
neurofibromas in later years. There is approximately a 10% risk ofneurofibromas in later years. There is approximately a 10% risk of
malignancy with this condition, and mental deficiency is common.malignancy with this condition, and mental deficiency is common.
 These are-These are-
 Tay-Sachs diseaseTay-Sachs disease
 Familial dysautonomiaFamilial dysautonomia
 Gaucher diseaseGaucher disease
 Canavan diseaseCanavan disease
 Bloom syndromeBloom syndrome
 Fanconi anemiaFanconi anemia
 Nieman-Pick disease (type A)Nieman-Pick disease (type A)
 Mucolipidosis IVMucolipidosis IV
 Cystic fibrosisCystic fibrosis
 Sickle cell anemiaSickle cell anemia
 Alpha- and beta-thalassemiaAlpha- and beta-thalassemia

 Which syndromes are associated withWhich syndromes are associated with
advanced paternal age?advanced paternal age?
 What is the most common genetic lethalWhat is the most common genetic lethal
disease?disease?

 Advanced paternal age is well documented to beAdvanced paternal age is well documented to be
associated withassociated with new dominant mutationsnew dominant mutations
 The mutation rate in fathers who are >50 years old is fiveThe mutation rate in fathers who are >50 years old is five
times higher than the mutation rate in fathers who are <20times higher than the mutation rate in fathers who are <20
years old.years old.
 Autosomal dominant new mutations that have beenAutosomal dominant new mutations that have been
mapped and identified, includingmapped and identified, including
 achondroplasiaachondroplasia,,
 Apert syndromeApert syndrome,,
 Marfan syndromeMarfan syndrome..
 Cystic fibrosisCystic fibrosis (CF).(CF).

 What are the "fat baby" syndromes?What are the "fat baby" syndromes?
 . What is the "H3O" of Prader-Willi. What is the "H3O" of Prader-Willi
syndrome?syndrome?
 What syndrome is associated with unprovokedWhat syndrome is associated with unprovoked
outbursts of laughter?outbursts of laughter?
 What syndrome is associated with unprovokedWhat syndrome is associated with unprovoked
outbursts of laughter?outbursts of laughter?
 Name the two most common forms ofName the two most common forms of
dwarfism that are recognizable at birth.dwarfism that are recognizable at birth.

 Prader-Willi (obesity, hypotonia, small hands and feet)Prader-Willi (obesity, hypotonia, small hands and feet)
 Beckwith-Wiedemann (macrosomia, omphalocele, macroglossia, earBeckwith-Wiedemann (macrosomia, omphalocele, macroglossia, ear
creases)creases)
 Sotos (macrosomia, macrocephaly, large hands and feet)Sotos (macrosomia, macrocephaly, large hands and feet)
 Weaver (macrosomia, accelerated skeletal maturation, camptodactyly)Weaver (macrosomia, accelerated skeletal maturation, camptodactyly)
 Bardet-Biedl (obesity, retinal pigmentation, polydactyly)Bardet-Biedl (obesity, retinal pigmentation, polydactyly)
 Infants of diabetic mothersInfants of diabetic mothers
 Hyperphagia, hypotonia, hypopigmentation,Hyperphagia, hypotonia, hypopigmentation, andand obesityobesity
 Angelman syndromeAngelman syndrome
 Thanatophoric dwarfism:Thanatophoric dwarfism: This is the most common, but it is aThis is the most common, but it is a lethallethal
chondrodysplasia that is characterized by flattened, U-shaped vertebral bodies;chondrodysplasia that is characterized by flattened, U-shaped vertebral bodies;
telephone-receiver-shaped femurs; macrocephaly; and redundant skinfolds thattelephone-receiver-shaped femurs; macrocephaly; and redundant skinfolds that
cause a pug-like appearance.cause a pug-like appearance. ThanatophoricThanatophoric means death-loving (an aptmeans death-loving (an apt
description). The incidence is 1 in 6,400 births.description). The incidence is 1 in 6,400 births.
 Achondroplasia:Achondroplasia: This is the most commonThis is the most common viableviable skeletal dysplasia, occurringskeletal dysplasia, occurring
1 in 26,000 live births. Its features are small stature, macrocephaly, depressed1 in 26,000 live births. Its features are small stature, macrocephaly, depressed
nasal bridge, lordosis, and a trident handnasal bridge, lordosis, and a trident hand

 What syndrome is associated with CATCH22?What syndrome is associated with CATCH22?
 List the syndromes and malformationsList the syndromes and malformations
associated with congenital limbassociated with congenital limb
hemihypertrophy. ?hemihypertrophy. ?

 This acronym has been used to describe the salient features of DiGeorge/velocardiofacialThis acronym has been used to describe the salient features of DiGeorge/velocardiofacial
syndrome:syndrome:
CC
 Congenital heart diseaseCongenital heart disease
AA
 Abnormal faceAbnormal face
TT
 Thymic aplasia/hypoplasiaThymic aplasia/hypoplasia
CC
 Cleft palateCleft palate
HH
 HypocalcemiaHypocalcemia
22: Microdeletion of chromosome 22q11 The cardiovascular lesions frequently22: Microdeletion of chromosome 22q11 The cardiovascular lesions frequently
encountered are tetralogy of Fallot, truncus arteriosis, interrupted aortic arch, right-encountered are tetralogy of Fallot, truncus arteriosis, interrupted aortic arch, right-
sided aortic arch, and double-outlet right ventricle. Any infant with any of thesesided aortic arch, and double-outlet right ventricle. Any infant with any of these
cardiovascular lesions should be screened for DiGeorge/velocardiofacial syndrome.cardiovascular lesions should be screened for DiGeorge/velocardiofacial syndrome.
 THESE ARE-THESE ARE-
 Beckwith-Wiedemann syndromeBeckwith-Wiedemann syndrome
 Conradi-Hünermann syndromeConradi-Hünermann syndrome
 Klippel-Trenaunay-Weber syndromeKlippel-Trenaunay-Weber syndrome
 Proteus syndromeProteus syndrome
 NeurofibromatosisNeurofibromatosis
 Hypomelanosis of ItoHypomelanosis of Ito
 CHILD syndrome (congenital hemidysplasia, ichthyosiform erythroderma, limbCHILD syndrome (congenital hemidysplasia, ichthyosiform erythroderma, limb
defects)defects)

 What are the most common microchromosomeWhat are the most common microchromosome
deletion syndromes?deletion syndromes?
 What are the cardinal features of AlagilleWhat are the cardinal features of Alagille
syndrome?syndrome?

 DiGeorge/velocardiofacial syndrome (DGS/VCF)DiGeorge/velocardiofacial syndrome (DGS/VCF)
 Prader-Willi syndrome (PWS)Prader-Willi syndrome (PWS)
 Angelman syndrome (AS)Angelman syndrome (AS)
 William syndrome (WS)William syndrome (WS)
 Alagille syndromeAlagille syndrome
 Rubinstein-Taybi syndrome (RTS)Rubinstein-Taybi syndrome (RTS)
 Wilms' tumor-aniridia-ambiguous genitalia-mental retardation syndromeWilms' tumor-aniridia-ambiguous genitalia-mental retardation syndrome
(WAGR)(WAGR)
 Miller-Dieker syndromeMiller-Dieker syndrome
 In about 90% of cases, a history of prolonged neonatal jaundice due to paucity ofIn about 90% of cases, a history of prolonged neonatal jaundice due to paucity of
intrahepatic ducts (and occasionally extrahepatic ducts)intrahepatic ducts (and occasionally extrahepatic ducts)
 Cardiac lesions occur in 85% of cases and are predominantly peripheral pulmonicCardiac lesions occur in 85% of cases and are predominantly peripheral pulmonic
stenosis, but might include pulmonary valve stenosis, partial anomalous venousstenosis, but might include pulmonary valve stenosis, partial anomalous venous
drainage, ASD, or VSDdrainage, ASD, or VSD
 In about 90% of cases, anterior ocular segment dysgenesis, particularly posteriorIn about 90% of cases, anterior ocular segment dysgenesis, particularly posterior
embryotoxonembryotoxon
 Bilateral or unilateral optic disc drusen in 80-90% of casesBilateral or unilateral optic disc drusen in 80-90% of cases
 Hemivertebrae or butterfly vertebrae in about 90% of casesHemivertebrae or butterfly vertebrae in about 90% of cases
 Autosomal dominant mode of inheritance, with incomplete penetranceAutosomal dominant mode of inheritance, with incomplete penetrance
 Mutations detected in the Jagged1 gene in the majority of patientsMutations detected in the Jagged1 gene in the majority of patients
 Deletion of chromosome 20p11 in a small percentage of patientsDeletion of chromosome 20p11 in a small percentage of patients

 What are the reasons that a disease might beWhat are the reasons that a disease might be
genetically determined but the family historygenetically determined but the family history
would be negative?would be negative?

 Autosomal recessive inheritanceAutosomal recessive inheritance
 X-linked recessive inheritanceX-linked recessive inheritance
 Genetic heterogeneity (e.g., retinitis pigmentosa mayGenetic heterogeneity (e.g., retinitis pigmentosa may
be transmitted as autosomal recessive or dominant orbe transmitted as autosomal recessive or dominant or
X-linked recessive)X-linked recessive)
 Spontaneous mutationSpontaneous mutation
 NonpenetranceNonpenetrance
 Expressivity (i.e., variable expression)Expressivity (i.e., variable expression)
 Extramarital paternityExtramarital paternity
 Phenocopy (i.e., an environmentally determined copyPhenocopy (i.e., an environmentally determined copy
of a genetic disorder)of a genetic disorder)

 How are structural dysmorphisms categorized?How are structural dysmorphisms categorized?

 Malformation:Malformation: A problem of poor formation (likelyA problem of poor formation (likely
genetically based) in which the abnormality is present at thegenetically based) in which the abnormality is present at the
onset of development (e.g., hypoplastic thumbs of Fanconionset of development (e.g., hypoplastic thumbs of Fanconi
syndrome)syndrome)
 Disruption:Disruption: An extrinsic destructive process interferes withAn extrinsic destructive process interferes with
previously normal development (e.g., thalidomide causingpreviously normal development (e.g., thalidomide causing
limb abnormalities)limb abnormalities)
 Deformation:Deformation: An extrinsic mechanical force causesAn extrinsic mechanical force causes
abnormalities that are usually asymmetrical (e.g,. breechabnormalities that are usually asymmetrical (e.g,. breech
position causing tibial bowing and positional club feet)position causing tibial bowing and positional club feet)
 Dysplasia:Dysplasia: An abnormal cellular organization or function thatAn abnormal cellular organization or function that
generally affects only a single tissue type (e.g., cartilagegenerally affects only a single tissue type (e.g., cartilage
abnormalities that result in achondroplasia)abnormalities that result in achondroplasia)

 What are the principal kinds of morphologicWhat are the principal kinds of morphologic
defects in infants with multiple anomalies?defects in infants with multiple anomalies?

 Developmental or polytopic field defect:Developmental or polytopic field defect: A pattern of anomalies derived from theA pattern of anomalies derived from the
disturbance of a single region or part of an embryo that responds as a coordinateddisturbance of a single region or part of an embryo that responds as a coordinated
unit to extrinsic or intrinsic influences. Field defects are believed to be derivativesunit to extrinsic or intrinsic influences. Field defects are believed to be derivatives
of a single malformative or disruptive process. For example, if the rostralof a single malformative or disruptive process. For example, if the rostral
mesoderm is disturbed early during development, multiple anomalies of the headmesoderm is disturbed early during development, multiple anomalies of the head
and face can occur.and face can occur.
 Sequence:Sequence: A pattern of multiple anomalies derived from a single known (orA pattern of multiple anomalies derived from a single known (or
presumed) prior anomaly or mechanical factor. For example, the entity ofpresumed) prior anomaly or mechanical factor. For example, the entity of
micrognathia, glossoptosis, and cleft soft palate is more properly called the Pierremicrognathia, glossoptosis, and cleft soft palate is more properly called the Pierre
Robin sequence (rather than syndrome), because the small mandible likely causesRobin sequence (rather than syndrome), because the small mandible likely causes
the developing tongue to be pushed posteriorly, which does not allow the posteriorthe developing tongue to be pushed posteriorly, which does not allow the posterior
palatal shelves to close properly.palatal shelves to close properly.
 Syndrome:Syndrome: The nonrandom occurrence of multiple anomalies with such anThe nonrandom occurrence of multiple anomalies with such an
increased frequency that a pathogenetically causal relationship (often of unknownincreased frequency that a pathogenetically causal relationship (often of unknown
cause) is felt to be involved. For example, chromosomal syndromes (e.g., Down)cause) is felt to be involved. For example, chromosomal syndromes (e.g., Down)
have characteristic clinical features.have characteristic clinical features.
 Association:Association: The nonrandom occurrence of multiple anomalies without a knownThe nonrandom occurrence of multiple anomalies without a known
field defect, sequence initiator, or causal relationship but with such a frequency thatfield defect, sequence initiator, or causal relationship but with such a frequency that
the malformations have a statistical connection.the malformations have a statistical connection.

1.1. Describe the most common anomalyDescribe the most common anomaly
associations.associations.
2.2. How do clinodactyly, syndactyly, andHow do clinodactyly, syndactyly, and
camptodactyly differ?camptodactyly differ?
3.3. Where is the Darwinian tubercle located?Where is the Darwinian tubercle located?

1.1. Are-Are-
CHARGECHARGE
 CColoboma of the eye,oloboma of the eye, hheart defects,eart defects, aatresia of the choanae,tresia of the choanae, rretardation (mental andetardation (mental and
growth),growth), ggenital anomalies (in males), andenital anomalies (in males), and eear anomaliesar anomalies
MURCSMURCS
 MMüllerian duct aplasia,üllerian duct aplasia, rrenal aplasia, andenal aplasia, and ccervicothoracicervicothoracic ssomite dysplasiaomite dysplasia
VATERVATER
 VVertebral,ertebral, aanal,nal, ttracheoracheoeesophageal, andsophageal, and rrenal orenal or rradial anomaliesadial anomalies
VACTERLVACTERL
 VATER anomalies plusVATER anomalies plus ccardiac andardiac and llimb anomaliesimb anomalies
 Clinodactyly:Clinodactyly: Curvature of a toe or finger (usually the fifth) as a result ofCurvature of a toe or finger (usually the fifth) as a result of
hypoplasia of the middle phalanx, which is the last fetal bone to develophypoplasia of the middle phalanx, which is the last fetal bone to develop
in the hands and feet. Normal curvature can consist of up to 8° of inwardin the hands and feet. Normal curvature can consist of up to 8° of inward
turning; curvature beyond this is considered a minor anomaly.turning; curvature beyond this is considered a minor anomaly.
Syndactyly:Syndactyly: An incomplete separation of the fingers (usually 3rd andAn incomplete separation of the fingers (usually 3rd and
4th) or toes (usually 2nd or 3rd).4th) or toes (usually 2nd or 3rd).
Camptodactyly:Camptodactyly: Abnormal persistent flexion of fingers or toes.Abnormal persistent flexion of fingers or toes.
1.1. Also called theAlso called the auricular tubercleauricular tubercle, this is a cartilaginous bump on the, this is a cartilaginous bump on the
upper part of the outer ear below and posterior to the helix. It is a minorupper part of the outer ear below and posterior to the helix. It is a minor
variant that should not be considered an anomaly.variant that should not be considered an anomaly.

 Identify?Identify?
 Write syndromWrite syndrom
associated withassociated with
it?it?

 Chromosomal syndromes (most commonlyChromosomal syndromes (most commonly
trisomy 13, 4p-, 13q-)trisomy 13, 4p-, 13q-)
 TriploidyTriploidy
 CHARGE association,CHARGE association,
 Goltz syndrome,Goltz syndrome,
 Rieger syndrome.Rieger syndrome.
 Wilms tumor (aniridia)Wilms tumor (aniridia)

Identify .Identify .
Give diagnosis.Give diagnosis.

What is FISH?What is FISH?
 FFluorescenceluorescence iinn ssituitu hhybridization (FISH) is a molecular cytogeneticybridization (FISH) is a molecular cytogenetic
technique that is used to identify abnormalities of chromosome number ortechnique that is used to identify abnormalities of chromosome number or
structure using a single-stranded DNA probe (for a known piece of DNAstructure using a single-stranded DNA probe (for a known piece of DNA
or chromosome segment). The probe is labeled with a fluorescent tag andor chromosome segment). The probe is labeled with a fluorescent tag and
targeted to a single-strand DNA that has been denatured in place on atargeted to a single-strand DNA that has been denatured in place on a
microscope slide. The use of fluorescent microscopy enables the detectionmicroscope slide. The use of fluorescent microscopy enables the detection
of more than one probe, each of which is labeled with a different color. Anof more than one probe, each of which is labeled with a different color. An
example of the use of FISH is for the rapid prenatal diagnosis of trisomiesexample of the use of FISH is for the rapid prenatal diagnosis of trisomies
with the use of amniotic fluid or chorionic villi testing using interphasewith the use of amniotic fluid or chorionic villi testing using interphase
cells from cultured specimens and probes for the most commoncells from cultured specimens and probes for the most common
chromosomal abnormalities (13, 18, 21, X, and Y). Although interphasechromosomal abnormalities (13, 18, 21, X, and Y). Although interphase
FISH for prenatal diagnosis has low false-positive and false-negative rates,FISH for prenatal diagnosis has low false-positive and false-negative rates,
it is considered investigational and is used only in conjunction withit is considered investigational and is used only in conjunction with
standard cytogenetic analysis.standard cytogenetic analysis.

 46, XY,46, XY,
 t(4:8),t(4:8),
 (p21;q22)-(p21;q22)-
 What does it all mean?What does it all mean?

 46:46: Normal number of chromosomesNormal number of chromosomes
 XY:XY: Genetic maleGenetic male
 t(4:8):t(4:8): The first set of parentheses refers to theThe first set of parentheses refers to the
chromosomes. The symbol in front indicates thechromosomes. The symbol in front indicates the
change:change: tt stands for reciprocal translocation,stands for reciprocal translocation, deldel forfor
deletion,deletion, dupdup for duplication, andfor duplication, and invinv for inversion.for inversion.
 (p21;q22):(p21;q22): The second set of parentheses refers to theThe second set of parentheses refers to the
bands on the chromosomes. The short arm symbol isbands on the chromosomes. The short arm symbol is
pp; the long arm symbol is; the long arm symbol is qq..

 What is the proper way to test for low-set ears?What is the proper way to test for low-set ears?
 This designation is made when the upper portion of the ear (helix) meets theThis designation is made when the upper portion of the ear (helix) meets the
head at a level below a horizontal line drawn from the lateral aspect of thehead at a level below a horizontal line drawn from the lateral aspect of the
palpebral fissure. The best way to measure is to align a straight edge betweenpalpebral fissure. The best way to measure is to align a straight edge between
the two inner canthi and determine whether the ears lie completely below thisthe two inner canthi and determine whether the ears lie completely below this
plane In normal individuals, approximately 10% of the ear is above this planeplane In normal individuals, approximately 10% of the ear is above this plane..

 IdentifyIdentify
 Give clinical featureGive clinical feature

 Facial appearance of a child with trisomy 13Facial appearance of a child with trisomy 13
 Cleft lip often midline;Cleft lip often midline;
 flexed fingers with polydactyly;ocularflexed fingers with polydactyly;ocular
 hypotelorism,hypotelorism,
 bulbous nose;bulbous nose;
 low-set malformed ears;low-set malformed ears;
 small abnormal skull;small abnormal skull;
 cerebral malformation,cerebral malformation,
 especiallyespecially
 holoprosencephaly;holoprosencephaly;
 microphthalmia,microphthalmia,
 cardiac malformations;cardiac malformations;
 scalp defects;hypoplastic or absent ribs;scalp defects;hypoplastic or absent ribs;
 visceral and genital anomaliesvisceral and genital anomalies
 95% die by 6 month95% die by 6 month
 5% survive by > 6 month5% survive by > 6 month

Give karyotype and clinical featuresGive karyotype and clinical features
of followingof following
 Trisomy 8Trisomy 8
 TetrasomyTetrasomy

 Trisomy 8-Trisomy 8-
 47, XX/XY,+847, XX/XY,+8
 Growth and mental deficiency are variable. The majority of patients areGrowth and mental deficiency are variable. The majority of patients are
mosaics. The presence of deep palmar and plantar furrows is characteristicmosaics. The presence of deep palmar and plantar furrows is characteristic
 47, XX/XY,+947, XX/XY,+9
 The majority of patients are mosaics. Clinical features include craniofacialThe majority of patients are mosaics. Clinical features include craniofacial
(high forehead, microphthalmia, low-set malformed ears, bulbous nose)(high forehead, microphthalmia, low-set malformed ears, bulbous nose)
and skeletal (joint contractures) malformations and heart defects (60%).and skeletal (joint contractures) malformations and heart defects (60%).
 47, XX/XY,+1647, XX/XY,+16
 The most frequently observed autosomal aneuploidy in spontaneousThe most frequently observed autosomal aneuploidy in spontaneous
abortions. The recurrence risk is negligible.abortions. The recurrence risk is negligible.
 Tetrasomy-Tetrasomy-
 47, XX/XY, +i(12p)47, XX/XY, +i(12p)
 Known as Pallister-Killian syndrome. Sparse anterior scalp hair, eyebrows,Known as Pallister-Killian syndrome. Sparse anterior scalp hair, eyebrows,
and eyelashes, prominent forehead, chubby cheeks, long philtrum withand eyelashes, prominent forehead, chubby cheeks, long philtrum with
thin upper lip and cupid-bow configuration Polydactyly and streaks ofthin upper lip and cupid-bow configuration Polydactyly and streaks of
hyper/hypopigmentation have been reportedhyper/hypopigmentation have been reported

 Trisomy 18:Trisomy 18:
 overlapping fingers and hypoplastic nails.overlapping fingers and hypoplastic nails.
 rocker-bottom feet (protruding calcanei).rocker-bottom feet (protruding calcanei).
 Male infant with trisomy 18 at age 4 days. Note prominent occiput,Male infant with trisomy 18 at age 4 days. Note prominent occiput,
micrognathia, low-set ears, short sternum, narrow pelvis, prominent calcaneus,micrognathia, low-set ears, short sternum, narrow pelvis, prominent calcaneus,
and flexion abnormalities of the fingers.and flexion abnormalities of the fingers.
 Low birthweight,Low birthweight,
 closed fists with index finger overlapping the 3rd digit and the 5th digit overlappingclosed fists with index finger overlapping the 3rd digit and the 5th digit overlapping
the 4th,the 4th,
 narrow hips with limited abduction,narrow hips with limited abduction,
 short sternum, small nipplesshort sternum, small nipples
 rocker-bottom feet,rocker-bottom feet,
 microcephaly, prominent occiput, micrognathia,microcephaly, prominent occiput, micrognathia,
 Cardiac(VSD, PDA, and ASD) and renal malformations, andCardiac(VSD, PDA, and ASD) and renal malformations, and
 mental retardation;mental retardation;
 95% of cases are lethal in the 1st yr95% of cases are lethal in the 1st yr
 Hypoplastic nailsHypoplastic nails
 Inguinal or abdominal herniasInguinal or abdominal hernias
 Premature birth, polyhydramniosPremature birth, polyhydramnios
 MicrognathiaMicrognathia
 Prominent occiputProminent occiput
 Tight palpebral fissuresTight palpebral fissures
 Narrow nose and hypoplastic nasal alaeNarrow nose and hypoplastic nasal alae
 Narrow bifrontal diameterNarrow bifrontal diameter
 95% die by 1 yr95% die by 1 yr
 5% survive by >1 yr5% survive by >1 yr

 A, Child with velocardiofacial syndromeA, Child with velocardiofacial syndrome
(deletion 22q11.2).(deletion 22q11.2).
 B, Child with Prader-Willi syndrome (deletionB, Child with Prader-Willi syndrome (deletion
15q11–13).15q11–13).
 C, Child with Angelman syndrome (deletionC, Child with Angelman syndrome (deletion
15q11–13).15q11–13).
 D, Child with Williams syndrome (deletionD, Child with Williams syndrome (deletion
7q11.237q11.23

 4p-4p-
 5p-5p-
 9p-9p-
 18q-18q-

 4p- Wolf-Hirschhorn syndrome.4p- Wolf-Hirschhorn syndrome.
 5p- Cri-du-chat syndrome5p- Cri-du-chat syndrome
 9p- The main features are craniofacial9p- The main features are craniofacial
dysmorphology with trigonocephalydysmorphology with trigonocephaly
 18q- hypotonia with “froglike”position18q- hypotonia with “froglike”position

 GiveGive
clinicalclinical
featuresfeatures

Turner's syndromeTurner's syndrome
 Redundant nuchal skinRedundant nuchal skin (A)(A) andand
 puffiness of the handspuffiness of the hands (B)(B) and feetand feet (C)(C)
 45,X45,X
 Short stature Congenital lymphedema Horseshoe kidney PatellaShort stature Congenital lymphedema Horseshoe kidney Patella
dislocation Increased carrying angle of elbow Madelung deformitydislocation Increased carrying angle of elbow Madelung deformity
(chondrodysplasia of distal radial epiphysis) Congenital hip(chondrodysplasia of distal radial epiphysis) Congenital hip
dislocation Scoliosis Widespread nipples Shield chest Redundant nuchaldislocation Scoliosis Widespread nipples Shield chest Redundant nuchal
skin (in utero cystic hygroma) Low posterior hairline Coarctation ofskin (in utero cystic hygroma) Low posterior hairline Coarctation of
aorta Bicuspid aortic valve Cardiac conductionaorta Bicuspid aortic valve Cardiac conduction
abnormalities Hypoplastic left heart syndrome? Gonadal dysgenesisabnormalities Hypoplastic left heart syndrome? Gonadal dysgenesis
(infertility, primary amenorrhea) Gonadoblastoma (if Y chromosome(infertility, primary amenorrhea) Gonadoblastoma (if Y chromosome
material present) Learning disabilities (nonverbal perceptual motor andmaterial present) Learning disabilities (nonverbal perceptual motor and
visuospatial skills) [in 70%] Developmental delay (in 10%) Socialvisuospatial skills) [in 70%] Developmental delay (in 10%) Social
awkwardness Hypothyroidism (acquired in 15–30%) Type 2 diabetesawkwardness Hypothyroidism (acquired in 15–30%) Type 2 diabetes
mellitus (insulin resistance) Strabismus Cataract Red-greenmellitus (insulin resistance) Strabismus Cataract Red-green
colorblindness (as in males) Recurrent otitis media Sensorineural hearingcolorblindness (as in males) Recurrent otitis media Sensorineural hearing
loss Inflammatory bowel disease Celiac disease?loss Inflammatory bowel disease Celiac disease?

Noonan syndromeNoonan syndrome
 InheritanceInheritance
 Clinical featuresClinical features
 MutationMutation

 Autosomal dominantAutosomal dominant
 mutation inmutation in PTPN1,PTPN1, which encodes a nonreceptor tyrosinewhich encodes a nonreceptor tyrosine
kinase (SHP-2) on chromosome 12q24.1.kinase (SHP-2) on chromosome 12q24.1.
 Features common to Noonan syndrome include short stature,Features common to Noonan syndrome include short stature,
low posterior hairline, shield chest, congenital heart disease,low posterior hairline, shield chest, congenital heart disease,
and a short or webbed neck. In contrast to Turner syndrome,and a short or webbed neck. In contrast to Turner syndrome,
Noonan syndrome affects both sexes and has a differentNoonan syndrome affects both sexes and has a different
pattern of congenital heart disease.pattern of congenital heart disease.
 Short stature Failure to thrive EpicanthalShort stature Failure to thrive Epicanthal
folds Ptosis Hypertelorism Low nasal bridge Downwardfolds Ptosis Hypertelorism Low nasal bridge Downward
slanting palpebral fissures Myopia Nystagmus Low-setslanting palpebral fissures Myopia Nystagmus Low-set
auricles Dental malocclusion Low posterior hairline Shortauricles Dental malocclusion Low posterior hairline Short
webbed neck Shield chest Pectus excavatum orwebbed neck Shield chest Pectus excavatum or
carinatum Scoliosis Cubitus valgus Pulmonary valvecarinatum Scoliosis Cubitus valgus Pulmonary valve
stenosis Hypertrophic cardiomyopathy Atrial septal defectstenosis Hypertrophic cardiomyopathy Atrial septal defect
(ASD) Tetralogy of Fallot Cryptorchidism Small(ASD) Tetralogy of Fallot Cryptorchidism Small
penis Bleeding disorders, including thrombocytopeniapenis Bleeding disorders, including thrombocytopenia

 At birthAt birth (A)(A) and at 4 yr of ageand at 4 yr of age (B).(B). Note the shortNote the short
palpebral fissures; long, smooth philtrum withpalpebral fissures; long, smooth philtrum with
vermillion border; and hirsutism in the newbornvermillion border; and hirsutism in the newborn
 A,A, Note bilateral ptosis, short palpebral fissures,Note bilateral ptosis, short palpebral fissures,
smooth philtrum, and thin upper lip.smooth philtrum, and thin upper lip. B,B, ShortShort
palpebral fissures are sometimes more noticeable inpalpebral fissures are sometimes more noticeable in
profile. Head circumference is second percentileprofile. Head circumference is second percentile
 Skull: Microcephaly, midface hypoplasiaSkull: Microcephaly, midface hypoplasia
 Eyes: Short palpebral fissures, epicanthal folds, ptosis,Eyes: Short palpebral fissures, epicanthal folds, ptosis,
strabismusstrabismus
 Mouth: Hypoplastic philtrum, thin upper lip, prominentMouth: Hypoplastic philtrum, thin upper lip, prominent
lateral palatine ridges, retrognathia in infancy, micrognathialateral palatine ridges, retrognathia in infancy, micrognathia
or relative prognathia in adolescenceor relative prognathia in adolescence
 Nose: Flat nasal bridge, short and upturned noseNose: Flat nasal bridge, short and upturned nose

• Describe the characteristic features of the fetal
hydantoin syndrome?

 Craniofacial:Craniofacial: Broad nasal bridge, wide fontanel,Broad nasal bridge, wide fontanel,
low-set hairline, broad alveolar ridge, metopiclow-set hairline, broad alveolar ridge, metopic
ridging, short neck, ocular hypertelorism,ridging, short neck, ocular hypertelorism,
microcephaly, cleft lip/palate, abnormal or low-setmicrocephaly, cleft lip/palate, abnormal or low-set
ears, epicanthal folds, ptosis of eyelids, coloboma,ears, epicanthal folds, ptosis of eyelids, coloboma,
and coarse scalp hairand coarse scalp hair
 Limbs:Limbs: Small or absent nails, hypoplasia of distalSmall or absent nails, hypoplasia of distal
phalanges, altered palmar crease, digital thumb, andphalanges, altered palmar crease, digital thumb, and
dislocated hipdislocated hip
 Approximately 10% of infants whose mothers tookApproximately 10% of infants whose mothers took
phenytoin (Dilantin) during pregnancy have a majorphenytoin (Dilantin) during pregnancy have a major
malformation; 30% have minor abnormalities.malformation; 30% have minor abnormalities.

 What is the nature of the mutation in fragile XWhat is the nature of the mutation in fragile X
syndrome?syndrome?
 What are the associated medical problems ofWhat are the associated medical problems of
fragile X syndrome in males?fragile X syndrome in males?
 What is the outcome for girls with fragile X?What is the outcome for girls with fragile X?

1.1. Tripplet repeat expantion syndromTripplet repeat expantion syndrom
2.2. Expansion of trinucleotide repeat sequences. When the lymphocytes ofExpansion of trinucleotide repeat sequences. When the lymphocytes of
an affected male are grown in a folate-deficient medium and thean affected male are grown in a folate-deficient medium and the
chromosomes examined, a substantial fraction of X chromosomeschromosomes examined, a substantial fraction of X chromosomes
demonstrate a break near the distal end of the long arm.demonstrate a break near the distal end of the long arm.
3.3. Ex: fragile X Syndrom, myotonic dystrophy , huntingtons ds,Ex: fragile X Syndrom, myotonic dystrophy , huntingtons ds,
spinocerebellar disorder.spinocerebellar disorder.
4.4. Medical problems-Medical problems-
1.1. Flat feet (80%),Flat feet (80%),
2.2. macroorchidism (80% after puberty),macroorchidism (80% after puberty),
3.3. mitral valve prolapse (50-80% in adulthood),mitral valve prolapse (50-80% in adulthood),
4.4. recurrent otitis media (60%),recurrent otitis media (60%),
5.5. strabismus (30%),strabismus (30%),
6.6. refractive errors (20%),refractive errors (20%),
7.7. seizures (15%), andseizures (15%), and
8.8. scoliosis (>20%).scoliosis (>20%).
5.5. Heterozygous females who carry the fragile X chromosome have moreHeterozygous females who carry the fragile X chromosome have more
behavioral and developmental problems (including attention deficitbehavioral and developmental problems (including attention deficit
hyperactivity disorder), cognitive difficulties (50% with an IQ in thehyperactivity disorder), cognitive difficulties (50% with an IQ in the
mentally retarded or borderline range), and physical differencesmentally retarded or borderline range), and physical differences
(prominent ears, long and narrow face). Cytogenetic testing is(prominent ears, long and narrow face). Cytogenetic testing is
recommended for all sisters of fragile X males.recommended for all sisters of fragile X males.

 KEY POINTS: FRAGILE X SYNDROMEKEY POINTS: FRAGILE X SYNDROME
1.1. Most common cause of inherited mentalMost common cause of inherited mental
retardationretardation
2.2. Prepubertal: Elongated face, flattened nasalPrepubertal: Elongated face, flattened nasal
bridge, protruding earsbridge, protruding ears
3.3. Pubertal: MacroorchidismPubertal: Macroorchidism
4.4. Heterozygous females: 50% with IQ in theHeterozygous females: 50% with IQ in the
borderline or mentally retarded rangeborderline or mentally retarded range
5.5. First recognized trinucleotide repeat disorderFirst recognized trinucleotide repeat disorder
u
b
e
r
t
a
l
:
M
a
c
r
o
o
r
c
h
i
d
i
s
m
4.H
e
t

 KaryotypeKaryotype
 Clinical featuresClinical features
 IncidenceIncidence

 KLINEFELTER SYNDROMEKLINEFELTER SYNDROME
 47,XXY47,XXY
 1/500 newborn1/500 newborn
 mosaic patterns:mosaic patterns:
 46,XY/47,XXY,46,XY/47,XXY,
 46,XY/48,XXYY,46,XY/48,XXYY,
 45,X/46,XY/47,XXY, or 46,XX/47,XXY.45,X/46,XY/47,XXY, or 46,XX/47,XXY.
 Rarely, occurrence of more than two X chromosomesRarely, occurrence of more than two X chromosomes
may result in Klinefelter variants:may result in Klinefelter variants:
 48,XXXY,48,XXXY,
 49,XXXYY,49,XXXYY,
 49,XXXXY,49,XXXXY,
 50,XXXXYY,50,XXXXYY,
 47,XXY/48,XXXY,47,XXY/48,XXXY,
 47,XXY/49,XXXXY, or 48,XXYY karyotype47,XXY/49,XXXXY, or 48,XXYY karyotype

46,XY -A normal male
46,XX- A normal female
47,XX,+13 -A female with an extra chromosome 13 (trisomy 13)
47,XXY- A male with two X chromosomes and one Y chromosome
(Klinefelter syndrome)
46,XX,del(4)(p16) -A female with a terminal deletion and a breakpoint at
band 4p16
45,XX,(15;21)(q10;q10) -A female with a robertsonian translocation
involving chromosomes 15 and 21
46,XX,(15;21)(q10;q10),t21- A female with an unbalanced robertsonian
translocation between chromosomes 15 and 21, resulting in trisomy 21
46,XY,t(9;22)(q34;q11) -A male karyotype with a balanced reciprocal
translocation between chromosomes q and 22, with breakpoints at bands
9q34 and 22q11, generating the Philadelphia chromosome rearrangement
47,XY,+21/46,XY -A male with mosaicism for trisomy 21

 Aneuploidy Deviation of the chromosome number from that characteristic for the species. In the human, aAneuploidy Deviation of the chromosome number from that characteristic for the species. In the human, a
chromosome complement that is not an exact multiple of the haploid number (chromosome complement that is not an exact multiple of the haploid number (nn) (23 chromosomes), eg, 46) (23 chromosomes), eg, 46
chromosomes.chromosomes. AutosomeAny chromosome other than the sexAutosomeAny chromosome other than the sex
chromosomeschromosomes
 BandingThe illumination of various intrachromosomalBandingThe illumination of various intrachromosomal
bands and/or regions of varying intensity by procedures ofbands and/or regions of varying intensity by procedures of
differential staining. The most commonly used proceduresdifferential staining. The most commonly used procedures
are Q-, G-, C-, R- and T-banding.are Q-, G-, C-, R- and T-banding.
 BreakpointLocation of a break in a chromatid orBreakpointLocation of a break in a chromatid or
chromosome denoted by the exact band involved.chromosome denoted by the exact band involved.
 Diploidy (2Diploidy (2nn)State of having two full sets of homologous)State of having two full sets of homologous
chromosomes (ie, containing the number of chromosomeschromosomes (ie, containing the number of chromosomes
present in somatic and primary germ cells). Each speciespresent in somatic and primary germ cells). Each species
has a characteristic number (2has a characteristic number (2nn), with the haploid number), with the haploid number
((nn) being present in the gamete (sperm or ovum). In) being present in the gamete (sperm or ovum). In
humans, 2humans, 2nn = 46.= 46.

 List 5 diseases which need AN screeningList 5 diseases which need AN screening
 Methods of screeningMethods of screening
 Tripple test componentTripple test component
 Quadriple testQuadriple test
 Combined testCombined test
 Integrated testIntegrated test
 Name the 4 condition in which MSAFP isName the 4 condition in which MSAFP is
increasedincreased

genetic osce for dnb pdiatric

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Viewers also liked

Viewers also liked (15)

Similar to genetic osce for dnb pdiatric

Similar to genetic osce for dnb pdiatric (20)

More from mandar haval

More from mandar haval (20)

Recently uploaded

Recently uploaded (20)

genetic osce for dnb pdiatric