Genetics -OSCEGenetics -OSCE

Dr. Kashmiri P Dr. Kashmiri P BadbadeBadbade

Policies regarding genetic testing of children The AAP recommendations include Policies 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 new modification 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 of 2.    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 encouraged informed 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 informed to 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 informed refusals 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 or 3.    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 and adolescents. 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 be adolescents. 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 screening evaluated 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 until 4.    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 AAP an 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 is believes 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 mortality inappropriate 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 provide 5.    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 and parents 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 medical including 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 by Pediatricians 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 medical 6.    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 genetic students, residents, and practicing physicians and the expansion of training programs for genetic professionals.Email to Colleague Print Version professionals.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 are analysis, 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 are located 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

complement complement

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 location particular 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 structural of 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

Microarrays Microarrays Have been developed that permit tens or hundreds of thousands of Have 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 disease Patterns of gene expression provide signatures for particular disease

states, such as states, such as cancer, cancer, In response to therapy In response to therapy

Microarray containing 36,000 oligonucleotides. The microarray was Microarray containing 36,000 oligonucleotides. The microarray was exposed to RNA from normal fibroblasts (labeled red; see arrows) and exposed to RNA from normal fibroblasts (labeled red; see arrows) and fibroblasts from a patient with Niemann-Pick disease, type C (labeled fibroblasts from a patient with Niemann-Pick disease, type C (labeled green). green). ArrowsArrows point to regions in which there was a strong point to regions in which there was a strong hybridization signal with either normal or disease RNA. This hybridization signal with either normal or disease RNA. This microarray was used to search for genes that are highly expressed in microarray was used to search for genes that are highly expressed in the fibroblasts of patients. the fibroblasts of patients.

Identify Identify

•Identify the genetic predominance Identify the genetic predominance give six examples of the same give 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 one Autosomal 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 multiple Transmitted 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 the An affected individual has a 50% (1 in 2) chance of passing on the deleterious genes for deleterious genes for eacheach pregnancy, and therefore of having a child pregnancy, and therefore of having a child affected by the disorder. This is referred to as the affected by the disorder. This is referred to as the recurrence riskrecurrence risk for for 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 confirms The finding of male-to-male transmission essentially confirms

autosomal dominant inheritance autosomal dominant inheritance

If no history of an affected family member still the individual If 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 phenotypic carry the mutation have phenotypic manifestations- manifestations- skipped generation,skipped generation,

variable expressionvariable expression -mutation will manifest the -mutation will manifest the disorder to different degrees disorder to different degrees

somatic mutationssomatic mutations -spontaneous genetic -spontaneous genetic mutations occur not in the egg or sperm that forms mutations occur not in the egg or sperm that forms a child but rather in a cell in the developing a 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

IdentifyIdentify5 examples5 examples

A pedigree illustrating the inheritance pattern of an autosomal recessive A pedigree illustrating the inheritance pattern of an autosomal recessive disorder. Affected individuals are represented by shading and disorder. Affected individuals are represented by shading and

heterozygotes by partial shading.heterozygotes by partial shading.

AlbunismAlbunism Ataxia telangectesia Ataxia 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 Thalassemia Thalassemia Aplastic anemiaAplastic anemia Fanconis anemiasFanconis anemias

A pedigree showing the inheritance of an X-linked recessive condition. Solid symbols A pedigree showing the inheritance of an X-linked recessive condition. Solid symbols represent affected individuals, and dotted symbols represent heterozygous carriers. Only represent 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 GG6 6 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 more Both 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 both affected 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 trisomy The 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 births 1/600–800 births

Hypotonia, flat face, upward and slanted palpebral Hypotonia, flat face, upward and slanted palpebral fissures and epicanthic folds, speckled irises fissures 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, cardiac growth 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, duodenal hypoplasia of middle phalanx of 5th finger, duodenal atresia, and high arched palate;5% of patients with atresia, 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 the t(14q21q), t(15q21q), and t(13q21q)—in which the phenotype is the same as trisomy 21 Down syndrome phenotype 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  Tracheoesophageal Duodenal atresia  Annular pancreas  Tracheoesophageal

fistula  Hirschsprung disease  Short stature  Short fistula  Hirschsprung disease  Short stature  Short sternum  Brachycephaly  Delayed fontanel closure  Three sternum  Brachycephaly  Delayed fontanel closure  Three fontanels  Frontal sinus hypoplasia  Peripheral joint laxity  Atlantoaxial fontanels  Frontal sinus hypoplasia  Peripheral joint laxity  Atlantoaxial instability (C1–C2 subluxation)  Exaggerated space between 1st and 2nd instability (C1–C2 subluxation)  Exaggerated space between 1st and 2nd toes  Mottled skin in infancy  Dry coarse skin in adolescence  toes  Mottled skin in infancy  Dry coarse skin in adolescence  Increased Increased Risk for Development ofRisk for Development of  Leukemia:AML,   Leukemia:AML, ALL  Myelodysplasia  Transient lymphoproliferative syndrome  Celiac ALL  Myelodysplasia  Transient lymphoproliferative syndrome  Celiac disease  Hypothyroidism  Diabetes mellitus  Obesity  Refractive disease  Hypothyroidism  Diabetes mellitus  Obesity  Refractive errors  Strabismus  Mitral valve prolapse  Conductive and/or sensorineural errors  Strabismus  Mitral valve prolapse  Conductive and/or sensorineural hearing loss  Obstructive sleep apnea  Epilepsy  Alzheimer hearing loss  Obstructive sleep apnea  Epilepsy  Alzheimer disease  Conduct oppositional disorders  ADHDdisease  Conduct oppositional disorders  ADHD

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

Upslanted palpebral fissures with epicanthal folds Upslanted palpebral fissures with epicanthal folds Small, low-set ears with overfolded upper helices Small, low-set ears with overfolded upper helices Short neck with excess skin folds in newborns Short neck with excess skin folds in newborns Prominent tongue Prominent tongue Flattened occiput Flattened occiput Exaggerated gap between first and second toe Exaggerated gap between first and second toe Hypotonia Hypotonia

Are Brushfield spots pathognomonic for Down Are Brushfield spots pathognomonic for Down syndrome?syndrome?

What is the chance that a newborn with a What 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 in Brushfield 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% of A single transverse palmar crease is present in 5% of normal newborns. Bilateral palmar creases are found normal newborns. Bilateral palmar creases are found in 1%. These features are twice as common in males in 1%. These features are twice as common in males as they are in females. However, about 45% of as they are in females. However, about 45% of newborn infants with Down syndrome have a single newborn infants with Down syndrome have a single transverse crease. Because Down syndrome occurs in transverse crease. Because Down syndrome occurs in 1 in 800 live births, the chance that a newborn with a 1 in 800 live births, the chance that a newborn with a simian crease has Down syndrome is only simian crease has Down syndrome is only 1 in 601 in 60. .

What proportion of infants with Down What proportion of infants with Down syndrome have congenital hypothyroidism? syndrome have congenital hypothyroidism?

What other conditions of increased risk should What 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 all About 2% (1 in 50) as compared with 0.025% (1 in 4,000) for all newborns. This emphasizes the importance of the state-mandated newborns. 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 defects Congenital heart disease: A-V canal defects, ventriculoseptal defects Gastrointestinal malformations: Duodenal atresia, tracheoesophageal atresia Gastrointestinal malformations: Duodenal atresia, tracheoesophageal atresia Congenital hypothyroidism Congenital hypothyroidism Lens opacities/cataracts Lens opacities/cataracts Hearing loss Hearing loss Cryptorchidism Cryptorchidism

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 during occasionally, the IQ may be higher. Intelligence deteriorates during adulthood, with clinical and pathologic findings consistent with adulthood, 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 what Down 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 related What chromosomal abnormalities are related

to maternal age? to maternal age? Does advanced paternal age increase the risk Does 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's Which 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 and All trisomies and some sex chromosomal abnormalities (except 45X and 47, XYY).47, XYY).

There does not appear to be an increased risk of Down syndrome There does not appear to be an increased risk of Down syndrome associated with paternal age until after age 55. Some studies have noted an associated 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 statistical although others have not. The reports are controversial, and the statistical analysis needed to perform such a study is cumbersome. It is known that analysis needed to perform such a study is cumbersome. It is known that approximately 10% of all trisomy 21 cases derive the extra chromosome approximately 10% of all trisomy 21 cases derive the extra chromosome 21 from the father. 21 from the father.

In 1866, John Langdon Down, physician at the Earlswood Asylum in In 1866, John Langdon Down, physician at the Earlswood Asylum in Surrey, England, described the phenotype of a syndrome that now bears Surrey, England, described the phenotype of a syndrome that now bears his name. However, it was not until 1959 that it was determined that this his name. However, it was not until 1959 that it was determined that this disorder is caused by an extra chromosome 21. The correct designation is disorder is caused by an extra chromosome 21. The correct designation is Down syndromeDown syndrome. .

What genetically inherited disease has the What genetically inherited disease has the highest known mutation rate per gamete per highest known mutation rate per gamete per generation? generation?

Which disorders with ethnic and racial Which disorders with ethnic and racial predilections most commonly warrant predilections 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 and 10-4 per haploid genome. The clinical features are café-au-lait spots and axillary freckling in childhood followed by the development of axillary freckling in childhood followed by the development of neurofibromas in later years. There is approximately a 10% risk of neurofibromas 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 disease Tay-Sachs disease Familial dysautonomia Familial dysautonomia Gaucher disease Gaucher disease Canavan disease Canavan disease Bloom syndrome Bloom syndrome Fanconi anemia Fanconi anemia Nieman-Pick disease (type A) Nieman-Pick disease (type A) Mucolipidosis IV Mucolipidosis IV Cystic fibrosis Cystic fibrosis Sickle cell anemia Sickle cell anemia Alpha- and beta-thalassemia Alpha- and beta-thalassemia

Which syndromes are associated with Which syndromes are associated with advanced paternal age? advanced paternal age?

What is the most common genetic lethal What is the most common genetic lethal disease? disease?

Advanced paternal age is well documented to be Advanced paternal age is well documented to be associated with associated with new dominant mutationsnew dominant mutations The mutation rate in fathers who are >50 years old is five The mutation rate in fathers who are >50 years old is five

times higher than the mutation rate in fathers who are <20 times higher than the mutation rate in fathers who are <20 years old. years old.

Autosomal dominant new mutations that have been Autosomal dominant new mutations that have been mapped and identified, including mapped 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 unprovoked What syndrome is associated with unprovoked

outbursts of laughter? outbursts of laughter? What syndrome is associated with unprovoked What syndrome is associated with unprovoked

outbursts of laughter? outbursts of laughter? Name the two most common forms of Name 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, ear Beckwith-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 mothers Infants of diabetic mothers

Hyperphagia, hypotonia, hypopigmentation,Hyperphagia, hypotonia, hypopigmentation, and and obesityobesity Angelman syndromeAngelman syndrome

Thanatophoric dwarfism:Thanatophoric dwarfism: This is the most common, but it is a This 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 that telephone-receiver-shaped femurs; macrocephaly; and redundant skinfolds that cause a pug-like appearance. cause a pug-like appearance. ThanatophoricThanatophoric means death-loving (an apt means 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 common This is the most common viableviable skeletal dysplasia, occurring skeletal dysplasia, occurring 1 in 26,000 live births. Its features are small stature, macrocephaly, depressed 1 in 26,000 live births. Its features are small stature, macrocephaly, depressed nasal bridge, lordosis, and a trident hand nasal bridge, lordosis, and a trident hand

What syndrome is associated with CATCH22? What syndrome is associated with CATCH22? List the syndromes and malformations List the syndromes and malformations

associated with congenital limb associated with congenital limb hemihypertrophy. ?hemihypertrophy. ?

This acronym has been used to describe the salient features of DiGeorge/velocardiofacial This acronym has been used to describe the salient features of DiGeorge/velocardiofacial syndrome: syndrome:

C C Congenital heart disease Congenital heart disease

A A Abnormal face Abnormal face

T T Thymic aplasia/hypoplasia Thymic aplasia/hypoplasia C C Cleft palate Cleft palate

H H HypocalcemiaHypocalcemia

22: Microdeletion of chromosome 22q11 The cardiovascular lesions frequently 22: 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 these sided 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 syndrome Beckwith-Wiedemann syndrome Conradi-Hünermann syndrome Conradi-Hünermann syndrome Klippel-Trenaunay-Weber syndrome Klippel-Trenaunay-Weber syndrome Proteus syndrome Proteus syndrome Neurofibromatosis Neurofibromatosis Hypomelanosis of Ito Hypomelanosis of Ito CHILD syndrome (congenital hemidysplasia, ichthyosiform erythroderma, limb CHILD syndrome (congenital hemidysplasia, ichthyosiform erythroderma, limb

defects) defects)

What are the most common microchromosome What are the most common microchromosome deletion syndromes? deletion syndromes?

What are the cardinal features of Alagille What 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 syndrome Alagille syndrome Rubinstein-Taybi syndrome (RTS) Rubinstein-Taybi syndrome (RTS) Wilms' tumor-aniridia-ambiguous genitalia-mental retardation syndrome Wilms' tumor-aniridia-ambiguous genitalia-mental retardation syndrome

(WAGR) (WAGR) Miller-Dieker syndrome Miller-Dieker syndrome

In about 90% of cases, a history of prolonged neonatal jaundice due to paucity of In 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 pulmonic Cardiac lesions occur in 85% of cases and are predominantly peripheral pulmonic stenosis, but might include pulmonary valve stenosis, partial anomalous venous stenosis, but might include pulmonary valve stenosis, partial anomalous venous drainage, ASD, or VSD drainage, ASD, or VSD

In about 90% of cases, anterior ocular segment dysgenesis, particularly posterior In about 90% of cases, anterior ocular segment dysgenesis, particularly posterior embryotoxon embryotoxon

Bilateral or unilateral optic disc drusen in 80-90% of cases Bilateral or unilateral optic disc drusen in 80-90% of cases Hemivertebrae or butterfly vertebrae in about 90% of cases Hemivertebrae or butterfly vertebrae in about 90% of cases Autosomal dominant mode of inheritance, with incomplete penetrance Autosomal dominant mode of inheritance, with incomplete penetrance Mutations detected in the Jagged1 gene in the majority of patients Mutations detected in the Jagged1 gene in the majority of patients Deletion of chromosome 20p11 in a small percentage of patients Deletion of chromosome 20p11 in a small percentage of patients

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

Autosomal recessive inheritance Autosomal recessive inheritance X-linked recessive inheritance X-linked recessive inheritance Genetic heterogeneity (e.g., retinitis pigmentosa may Genetic heterogeneity (e.g., retinitis pigmentosa may

be transmitted as autosomal recessive or dominant or be transmitted as autosomal recessive or dominant or X-linked recessive) X-linked recessive)

Spontaneous mutation Spontaneous mutation Nonpenetrance Nonpenetrance Expressivity (i.e., variable expression) Expressivity (i.e., variable expression) Extramarital paternity Extramarital paternity Phenocopy (i.e., an environmentally determined copy Phenocopy (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 (likely A problem of poor formation (likely genetically based) in which the abnormality is present at the genetically based) in which the abnormality is present at the onset of development (e.g., hypoplastic thumbs of Fanconi onset of development (e.g., hypoplastic thumbs of Fanconi syndrome) syndrome)

Disruption:Disruption: An extrinsic destructive process interferes with An extrinsic destructive process interferes with previously normal development (e.g., thalidomide causing previously normal development (e.g., thalidomide causing limb abnormalities) limb abnormalities)

Deformation:Deformation: An extrinsic mechanical force causes An extrinsic mechanical force causes abnormalities that are usually asymmetrical (e.g,. breech abnormalities 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 that An abnormal cellular organization or function that generally affects only a single tissue type (e.g., cartilage generally 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 morphologic What 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 the A pattern of anomalies derived from the disturbance of a single region or part of an embryo that responds as a coordinated disturbance 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 derivatives unit to extrinsic or intrinsic influences. Field defects are believed to be derivatives of a single malformative or disruptive process. For example, if the rostral of a single malformative or disruptive process. For example, if the rostral mesoderm is disturbed early during development, multiple anomalies of the head mesoderm 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 (or A pattern of multiple anomalies derived from a single known (or presumed) prior anomaly or mechanical factor. For example, the entity of presumed) prior anomaly or mechanical factor. For example, the entity of micrognathia, glossoptosis, and cleft soft palate is more properly called the Pierre micrognathia, glossoptosis, and cleft soft palate is more properly called the Pierre Robin sequence (rather than syndrome), because the small mandible likely causes Robin sequence (rather than syndrome), because the small mandible likely causes the developing tongue to be pushed posteriorly, which does not allow the posterior the 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 an The nonrandom occurrence of multiple anomalies with such an increased frequency that a pathogenetically causal relationship (often of unknown increased 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 known The nonrandom occurrence of multiple anomalies without a known field defect, sequence initiator, or causal relationship but with such a frequency that field 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 anomaly Describe the most common anomaly associations. associations.

2.2. How do clinodactyly, syndactyly, and How 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 and etardation (mental and

growth), growth), ggenital anomalies (in males), and enital anomalies (in males), and eear anomalies ar anomalies MURCSMURCS MMüllerian duct aplasia, üllerian duct aplasia, rrenal aplasia, and enal aplasia, and ccervicothoracic ervicothoracic ssomite dysplasia omite dysplasia VATERVATER VVertebral, ertebral, aanal, nal, ttracheoracheoeesophageal, and sophageal, and rrenal or enal or rradial anomalies adial anomalies VACTERLVACTERL VATER anomalies plus VATER anomalies plus ccardiac and ardiac and llimb anomaliesimb anomalies

Clinodactyly:Clinodactyly: Curvature of a toe or finger (usually the fifth) as a result of Curvature of a toe or finger (usually the fifth) as a result of hypoplasia of the middle phalanx, which is the last fetal bone to develop hypoplasia 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 inward in 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 and An 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 the Also 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 minor upper 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 syndrom Write syndrom

associated with associated with it?it?

Chromosomal syndromes (most commonly Chromosomal 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? FFluorescence luorescence iin n ssitu itu hhybridization (FISH) is a molecular cytogenetic ybridization (FISH) is a molecular cytogenetic

technique that is used to identify abnormalities of chromosome number or technique that is used to identify abnormalities of chromosome number or structure using a single-stranded DNA probe (for a known piece of DNA structure using a single-stranded DNA probe (for a known piece of DNA or chromosome segment). The probe is labeled with a fluorescent tag and or chromosome segment). The probe is labeled with a fluorescent tag and targeted to a single-strand DNA that has been denatured in place on a targeted to a single-strand DNA that has been denatured in place on a microscope slide. The use of fluorescent microscopy enables the detection microscope slide. The use of fluorescent microscopy enables the detection of more than one probe, each of which is labeled with a different color. An of 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 trisomies example of the use of FISH is for the rapid prenatal diagnosis of trisomies with the use of amniotic fluid or chorionic villi testing using interphase with the use of amniotic fluid or chorionic villi testing using interphase cells from cultured specimens and probes for the most common cells from cultured specimens and probes for the most common chromosomal abnormalities (13, 18, 21, X, and Y). Although interphase chromosomal 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 with it 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 chromosomes Normal number of chromosomes XY:XY: Genetic male Genetic male t(4:8):t(4:8): The first set of parentheses refers to the The first set of parentheses refers to the

chromosomes. The symbol in front indicates the chromosomes. The symbol in front indicates the change: change: tt stands for reciprocal translocation, stands for reciprocal translocation, deldel for for deletion, deletion, dupdup for duplication, and for duplication, and invinv for inversion. for inversion.

(p21;q22):(p21;q22): The second set of parentheses refers to the The second set of parentheses refers to the bands on the chromosomes. The short arm symbol is bands 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 the This 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 the head 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 between palpebral 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 this the 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 . .

Identify Identify Give clinical featureGive clinical feature

Facial appearance of a child with trisomy 13 Facial appearance of a child with trisomy 13 Cleft lip often midline;Cleft lip often midline; flexed fingers with polydactyly;ocular flexed 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, especially especially holoprosencephaly;holoprosencephaly; microphthalmia,microphthalmia, cardiac malformations;cardiac malformations; scalp defects;hypoplastic or absent ribs;scalp defects;hypoplastic or absent ribs; visceral and genital anomalies visceral 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 features Give karyotype and clinical features of followingof following

Trisomy 8 Trisomy 8 Trisomy 9 Trisomy 9 Trisomy 16 Trisomy 16 Tetrasomy Tetrasomy

Trisomy 8-Trisomy 8- 47, XX/XY,+847, XX/XY,+8 Growth and mental deficiency are variable. The majority of patients are Growth 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 Trisomy 9-Trisomy 9-

47, XX/XY,+947, XX/XY,+9 The majority of patients are mosaics. Clinical features include craniofacial The 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%).

Trisomy 16-Trisomy 16- 47, XX/XY,+1647, XX/XY,+16 The most frequently observed autosomal aneuploidy in spontaneous The 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 with thin and eyelashes, prominent forehead, chubby cheeks, long philtrum with thin upper lip and cupid-bow configuration Polydactyly and streaks of 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, micrognathia, Male infant with trisomy 18 at age 4 days. Note prominent occiput, micrognathia,

low-set ears, short sternum, narrow pelvis, prominent calcaneus, and flexion low-set ears, short sternum, narrow pelvis, prominent calcaneus, and flexion abnormalities of the fingers. abnormalities of the fingers.

Low birthweight, Low birthweight, closed fists with index finger overlapping the 3rd digit and the 5th digit overlapping the closed fists with index finger overlapping the 3rd digit and the 5th digit overlapping the

4th, 4th, narrow hips with limited abduction,narrow hips with limited abduction, short sternum, small nipples short 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 yr 95% of cases are lethal in the 1st yr Hypoplastic nails Hypoplastic nails Inguinal or abdominal hernias Inguinal or abdominal hernias Premature birth, polyhydramnios Premature birth, polyhydramnios Micrognathia Micrognathia Prominent occiput Prominent occiput Tight palpebral fissures Tight palpebral fissures Narrow nose and hypoplastic nasal alae Narrow nose and hypoplastic nasal alae Narrow bifrontal diameter Narrow bifrontal diameter 95% die by 1 yr95% die by 1 yr 5% survive by >1 yr5% survive by >1 yr

A, Child with velocardiofacial syndrome A, Child with velocardiofacial syndrome (deletion 22q11.2). (deletion 22q11.2).

B, Child with Prader-Willi syndrome (deletion B, Child with Prader-Willi syndrome (deletion 15q11–13). 15q11–13).

C, Child with Angelman syndrome (deletion C, Child with Angelman syndrome (deletion 15q11–13). 15q11–13).

D, Child with Williams syndrome (deletion D, Child with Williams syndrome (deletion 7q11.23 7q11.23

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 craniofacial 9p- The main features are craniofacial

dysmorphology with dysmorphology with trigonocephalytrigonocephaly

18q- hypotonia with “froglike”position 18q- hypotonia with “froglike”position

Identify Identify Give Give

clinical clinical featuresfeatures

Turner's syndrome Turner's syndrome Redundant nuchal skin Redundant nuchal skin (A)(A) and and puffiness of the hands puffiness of the hands (B)(B) and feet and feet (C)(C)

45,X 45,X Short stature  Congenital lymphedema  Horseshoe kidney  Patella Short stature  Congenital lymphedema  Horseshoe kidney  Patella

dislocation  Increased carrying angle of elbow  Madelung deformity dislocation  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 nuchal dislocation  Scoliosis  Widespread nipples  Shield chest  Redundant nuchal skin (in utero cystic hygroma)  Low posterior hairline  Coarctation of skin (in utero cystic hygroma)  Low posterior hairline  Coarctation of aorta  Bicuspid aortic valve  Cardiac conduction aorta  Bicuspid aortic valve  Cardiac conduction abnormalities  Hypoplastic left heart syndrome?  Gonadal dysgenesis abnormalities  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 and material present)  Learning disabilities (nonverbal perceptual motor and visuospatial skills) [in 70%]  Developmental delay (in 10%)  Social visuospatial skills) [in 70%]  Developmental delay (in 10%)  Social awkwardness  Hypothyroidism (acquired in 15–30%)  Type 2 diabetes awkwardness  Hypothyroidism (acquired in 15–30%)  Type 2 diabetes mellitus (insulin resistance)  Strabismus  Cataract  Red-green mellitus (insulin resistance)  Strabismus  Cataract  Red-green colorblindness (as in males)  Recurrent otitis media  Sensorineural hearing colorblindness (as in males)  Recurrent otitis media  Sensorineural hearing loss  Inflammatory bowel disease  Celiac disease?loss  Inflammatory bowel disease  Celiac disease?

Noonan syndrome Noonan syndrome

InheritanceInheritance Clinical features Clinical features MutationMutation

Autosomal dominant Autosomal dominant mutation in mutation in PTPN1,PTPN1, which encodes a nonreceptor tyrosine which 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, and low posterior hairline, shield chest, congenital heart disease, and a short or webbed neck. In contrast to Turner syndrome, Noonan a short or webbed neck. In contrast to Turner syndrome, Noonan syndrome affects both sexes and has a different pattern of syndrome affects both sexes and has a different pattern of congenital heart disease. congenital heart disease.

Short stature  Failure to thrive  Epicanthal Short stature  Failure to thrive  Epicanthal folds  Ptosis  Hypertelorism  Low nasal bridge  Downward folds  Ptosis  Hypertelorism  Low nasal bridge  Downward slanting palpebral fissures  Myopia  Nystagmus  Low-set slanting palpebral fissures  Myopia  Nystagmus  Low-set auricles  Dental malocclusion  Low posterior hairline  Short auricles  Dental malocclusion  Low posterior hairline  Short webbed neck  Shield chest  Pectus excavatum or webbed neck  Shield chest  Pectus excavatum or carinatum  Scoliosis  Cubitus valgus  Pulmonary valve carinatum  Scoliosis  Cubitus valgus  Pulmonary valve stenosis  Hypertrophic cardiomyopathy  Atrial septal defect stenosis  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 birth At birth (A)(A) and at 4 yr of age and at 4 yr of age (B).(B). Note the short Note the short palpebral fissures; long, smooth philtrum with palpebral fissures; long, smooth philtrum with vermillion border; and hirsutism in the newborn vermillion 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, Short Short palpebral fissures are sometimes more noticeable in palpebral fissures are sometimes more noticeable in profile. Head circumference is second percentile profile. Head circumference is second percentile

Skull: Microcephaly, midface hypoplasia Skull: Microcephaly, midface hypoplasia Eyes: Short palpebral fissures, epicanthal folds, ptosis, Eyes: Short palpebral fissures, epicanthal folds, ptosis,

strabismus strabismus Mouth: Hypoplastic philtrum, thin upper lip, prominent lateral Mouth: Hypoplastic philtrum, thin upper lip, prominent lateral

palatine ridges, retrognathia in infancy, micrognathia or palatine ridges, retrognathia in infancy, micrognathia or relative prognathia in adolescence 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, metopic low-set hairline, broad alveolar ridge, metopic ridging, short neck, ocular hypertelorism, ridging, short neck, ocular hypertelorism, microcephaly, cleft lip/palate, abnormal or low-set microcephaly, cleft lip/palate, abnormal or low-set ears, epicanthal folds, ptosis of eyelids, coloboma, ears, epicanthal folds, ptosis of eyelids, coloboma, and coarse scalp hair and coarse scalp hair

Limbs:Limbs: Small or absent nails, hypoplasia of distal Small or absent nails, hypoplasia of distal phalanges, altered palmar crease, digital thumb, and phalanges, altered palmar crease, digital thumb, and dislocated hip dislocated hip

Approximately 10% of infants whose mothers took Approximately 10% of infants whose mothers took phenytoin (Dilantin) during pregnancy have a major phenytoin (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 X What is the nature of the mutation in fragile X syndrome? syndrome?

What are the associated medical problems of What 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 syndrom Tripplet repeat expantion syndrom 2.2. Expansion of trinucleotide repeat sequences. When the lymphocytes of an Expansion of trinucleotide repeat sequences. When the lymphocytes of an

affected male are grown in a folate-deficient medium and the chromosomes affected male are grown in a folate-deficient medium and the chromosomes examined, a substantial fraction of X chromosomes demonstrate a break near examined, a substantial fraction of X chromosomes demonstrate a break near the distal end of the long arm.the distal end of the long arm.

3.3. Ex: fragile X Syndrom, myotonic dystrophy , huntingtons ds, spinocerebellar Ex: fragile X Syndrom, myotonic dystrophy , huntingtons ds, spinocerebellar disorder. 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%), and8.8. scoliosis (>20%).scoliosis (>20%).

5.5. Heterozygous females who carry the fragile X chromosome have more Heterozygous females who carry the fragile X chromosome have more behavioral and developmental problems (including attention deficit behavioral and developmental problems (including attention deficit hyperactivity disorder), cognitive difficulties (50% with an IQ in the mentally hyperactivity disorder), cognitive difficulties (50% with an IQ in the mentally retarded or borderline range), and physical differences (prominent ears, long retarded or borderline range), and physical differences (prominent ears, long and narrow face). Cytogenetic testing is recommended for all sisters of fragile and narrow face). Cytogenetic testing is recommended for all sisters of fragile X males. X males.

KEY POINTS: FRAGILE X SYNDROMEKEY POINTS: FRAGILE X SYNDROME1.1. Most common cause of inherited mental Most common cause of inherited mental

retardation retardation

2.2. Prepubertal: Elongated face, flattened nasal Prepubertal: Elongated face, flattened nasal bridge, protruding ears bridge, protruding ears

3.3. Pubertal: Macroorchidism Pubertal: Macroorchidism

4.4. Heterozygous females: 50% with IQ in the Heterozygous females: 50% with IQ in the borderline or mentally retarded range borderline or mentally retarded range

5.5. First recognized trinucleotide repeat disorder First recognized trinucleotide repeat disorder

1.Most common cause of inherited mental retardation 2.Prepubertal: Elongated face, flattened nasal bridge, protruding ears 3.Pubertal: Macroorchidism 4.Heterozygous females: 50% with IQ in the borderline or mentally retarded range 5.First recognized trinucleotide repeat disorder

Identify Identify KaryotypeKaryotype Clinical featuresClinical features Incidence Incidence

KLINEFELTER SYNDROME KLINEFELTER SYNDROME 47,XXY 47,XXY 1/500 newborn 1/500 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 chromosomes Rarely, 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 karyotype 47,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 4p1645,XX,(15;21)(q10;q10) -A female with a robertsonian translocation involving chromosomes 15 and 2146,XX,(15;21)(q10;q10),t21- A female with an unbalanced robertsonian translocation between chromosomes 15 and 21, resulting in trisomy 2146,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 rearrangement47,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, a Aneuploidy 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 sex AutosomeAny chromosome other than the sex chromosomeschromosomes

BandingThe illumination of various intrachromosomal BandingThe illumination of various intrachromosomal bands and/or regions of varying intensity by procedures of bands and/or regions of varying intensity by procedures of differential staining. The most commonly used procedures differential 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 or BreakpointLocation 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 chromosomes chromosomes (ie, containing the number of chromosomes present in somatic and primary germ cells). Each species present 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 is Name the 4 condition in which MSAFP is

increasedincreased