History In 1963, Lejeune et al., High-pitched.Microcephaly. Growth failure Abnormal face.. Mental retardation Facial abnormalities. Multiple congenital.

HistoryHistoryIn 1963, Lejeune et al.,In 1963, Lejeune et al.,

High-pitched.High-pitched.

Microcephaly. Microcephaly.

Growth failureGrowth failure

Abnormal face.. Abnormal face..

Mental retardationMental retardation

Facial abnormalities. Facial abnormalities.

Multiple congenital anomalies. Multiple congenital anomalies.

FrequencyFrequencyincidence incidence 1 in 50,000 livebirths. 1 in 50,000 livebirths. 1.5 in 1000 among individual with mental 1.5 in 1000 among individual with mental retardation. retardation. Mortality/MorbidityMortality/Morbidity 75% die within the first few months of life. 75% die within the first few months of life. 90% die before they are aged 1 year.90% die before they are aged 1 year.Survival to adulthood is possible.Survival to adulthood is possible.RaceRace No known racial predilection exists. No known racial predilection exists. SexSexMale:Female ratio of 0.72. Male:Female ratio of 0.72.

MechanismMechanism Most cases (80-85%) are due to sporadic Most cases (80-85%) are due to sporadic de de novonovo deletion of 5p. deletion of 5p.30-60% of the cases involve 30-60% of the cases involve terminal deletionsterminal deletions with loss of 5p material.with loss of 5p material.Approximately 10-15% of cases result from the Approximately 10-15% of cases result from the unequal segregation of a unequal segregation of a parental balanced parental balanced translocationtranslocation where the 5p monosomy is often where the 5p monosomy is often accompanied by a trisomic portion of the accompanied by a trisomic portion of the genome. genome. Fewer than 10% of cases have Fewer than 10% of cases have other rare other rare cytogenetic aberrationscytogenetic aberrations (eg, interstitial (eg, interstitial deletions, mosaicisms, rings and de novo deletions, mosaicisms, rings and de novo translocations).translocations).The deleted chromosome 5 is paternal in origin The deleted chromosome 5 is paternal in origin in about 80% of the cases.in about 80% of the cases.

Normal Deleted

Cytogenetic analysis

The phenotypes and clinical The phenotypes and clinical

features correlates with the features correlates with the

size of loss region in 5p15.2 size of loss region in 5p15.2

(cri-du-chat critical region).(cri-du-chat critical region).

PhenotypesPhenotypes

Partial MonosomyPartial Monosomy::Cri-du-chat Syndrome (46,-5p)Cri-du-chat Syndrome (46,-5p)

• Mental retardation, abnormal development of glottis and larynx• 1 / 50,000 live births

Characteristic cryCharacteristic cry

Newborns have the characteristic Newborns have the characteristic

mewing cry, which is a high-pitched mewing cry, which is a high-pitched

monochromatic cry that is considered. monochromatic cry that is considered.

Pathognomonic.Pathognomonic.

This cry disappears by the time they This cry disappears by the time they

are aged 2 years.are aged 2 years.

Clinical presentationClinical presentation

1. Speech.1. Speech.

2. Poor suck.2. Poor suck.

3. Motor delays. 3. Motor delays.

4. Failure to thrive.4. Failure to thrive.

5. Severe cognitive. 5. Severe cognitive.

6. Early ear infections.6. Early ear infections.

7. Swallowing difficulties.7. Swallowing difficulties.

8. Early feeding problems.8. Early feeding problems.

Cri-du-ChatCri-du-Chat

Less frequently findingsLess frequently findings Hypospadias,Hypospadias, Inguinal hernia. Inguinal hernia. Dislocated hips. Dislocated hips. Cryptorchidism.Cryptorchidism. Gut malrotation. Gut malrotation. Hydronephrosis.Hydronephrosis. Thymic dysplasia. Thymic dysplasia. Cleft lip and palate. Cleft lip and palate. Talipes equinovarus. Talipes equinovarus. Renal ectopia or agenesis.Renal ectopia or agenesis. Preauricular tags and fistulas. Preauricular tags and fistulas. Clinodactyly of the fifth fingers. Clinodactyly of the fifth fingers. Oligosyndactyly, and hyperextensible joints. Oligosyndactyly, and hyperextensible joints. Rare renal malformations (horseshoe kidneys).Rare renal malformations (horseshoe kidneys). Syndactyly of the second and third fingers and toes. Syndactyly of the second and third fingers and toes.

Causes of death

Pneumonia.Pneumonia.

Aspiration pneumonia.Aspiration pneumonia.

Congenital heart defects.Congenital heart defects.

Respiratory distress syndrome.Respiratory distress syndrome.

Behavioral historyBehavioral history

Behavioral profile includesBehavioral profile includes Aggression. Aggression. Clumsiness. Clumsiness. Hyperactivity. Hyperactivity. Repetitive movements.Repetitive movements. Hypersensitivity to sound.Hypersensitivity to sound. Stereotypic and self-injurious behavior.Stereotypic and self-injurious behavior. Features similar to those of autismFeatures similar to those of autism

Image is of an infant with cri-du-chat syndrome. Image is of an infant with cri-du-chat syndrome. Note a round face with full cheeks, and Note a round face with full cheeks, and

apparently low-set ears apparently low-set ears

• Facial laxity. • Dropped jaw.• Hypertonicity. • Small and narrow face.

Patient with Cri-du-chat syndrome

Father and his child

Conventional cytogeneticConventional cytogenetic

The size of the 5p deletion may vary The size of the 5p deletion may vary

from the entire short arm to only 5p15. from the entire short arm to only 5p15.

A small deletion of 5p may be missed A small deletion of 5p may be missed

by a conventional cytogenetic technique.by a conventional cytogenetic technique.

Chromosomal aberrations = 4 million base pairs = 0.13% of the genome

London

New York

Length of the haploid human DNA

4 million base would be equivalent to 8 km London

In patients with very small deletions. In patients with very small deletions.

The absence of a fluorescent signal The absence of a fluorescent signal

from either the maternal or paternal from either the maternal or paternal

chromosome 5p regions is indicative of chromosome 5p regions is indicative of

monosomy for that chromosomal region.monosomy for that chromosomal region.

Region -specific probe

Orange color represents chromosome 5–specific signal

Green is cri-du-chat locus signal.

Absence of a green signal indicates monosomy for that region (left, interphase cell; right, metaphase chromosome spread).

Late childhood and adolescenceLate childhood and adolescence

Findings includeFindings include

1.1. Deep-set eyes. Deep-set eyes.

2.2. Hypoplastic nasal bridge.Hypoplastic nasal bridge.

3.3. severe mental retardation.severe mental retardation.

4.4. Coarsening of facial features. Coarsening of facial features.

5.5. Prominent supraorbital ridges. Prominent supraorbital ridges.

6.6. Severe malocclusion and scoliosis.Severe malocclusion and scoliosis.

At pubertyAt pubertyFemaleFemale

Menstruate at the usual time.Menstruate at the usual time.

The genital tract is normal in females.The genital tract is normal in females.

Develop secondary sex characteristics.Develop secondary sex characteristics.

MalesMalesTestes are often small. Testes are often small.

Spermatogenesis is normal.Spermatogenesis is normal.

Dentist. Dentist. Urologist.Urologist.Audiologist. Audiologist. Neurologist. Neurologist. Orthopedist. Orthopedist. Cardiologist. Cardiologist. Psychologist. Psychologist. Ophthalmologist. Ophthalmologist. Clinical geneticist. Clinical geneticist. Developmental pediatrician. Developmental pediatrician. Speech language pathologist. Speech language pathologist. Physical and occupational therapist. Physical and occupational therapist.

Consultations

Genetic counselingGenetic counseling

Risk should be assessed Risk should be assessed

based on the type of structural based on the type of structural

rearrangement and its pattern rearrangement and its pattern

of segregationof segregation

Genetic counselingGenetic counselingRecurrence risk for Recurrence risk for affected femaleaffected female is 50%. is 50%.

Recurrence risk for a Recurrence risk for a de novode novo case is 1%. case is 1%.

If a parent is a balanced carrier of a structural If a parent is a balanced carrier of a structural rearrangement, the risk is substantially high.rearrangement, the risk is substantially high.

Rare recurrences in chromosomally normal Rare recurrences in chromosomally normal parents result of gonadal mosaicism for the parents result of gonadal mosaicism for the 5p deletion in one of the parents. 5p deletion in one of the parents.

Prenatal diagnosisPrenatal diagnosis

Routinely performed at 14-16 Routinely performed at 14-16 weeks’ gestation.weeks’ gestation.

Testing for chromosome disorders Testing for chromosome disorders is 99.5% accurate.is 99.5% accurate.

The missed are cases of mosaicism. The missed are cases of mosaicism.

The procedure is associated with a The procedure is associated with a small risk of pregnancy loss (about small risk of pregnancy loss (about 1 in 200 300).1 in 200 300).

AmniocentesisAmniocentesis

TimingTiming

Performed at 10-13 weeks’ gestation.Performed at 10-13 weeks’ gestation.

Limitation and riskLimitation and risk

1.1. Small chance of maternal cell contamination. Small chance of maternal cell contamination.

2. Risk of a fetal loss after the procedure 0.5-1%. 2. Risk of a fetal loss after the procedure 0.5-1%.

3. Accuracy less than 3. Accuracy less than AmniocentesisAmniocentesis

(mosaicism maternal cell contamination)(mosaicism maternal cell contamination)..

Chorionic villus sampling (CVS)Chorionic villus sampling (CVS)

Percutaneous umbilical blood sampling (PUBS)Percutaneous umbilical blood sampling (PUBS)

Is of limited use, except in cases Is of limited use, except in cases dated late in pregnancy. dated late in pregnancy.

Medical Legal PitfallsMedical Legal Pitfalls

Recognize characteristic symptoms and Recognize characteristic symptoms and signs. signs. Refer to a geneticist for genetic Refer to a geneticist for genetic counseling.counseling.Request chromosome analysis of patients Request chromosome analysis of patients with the clinical phenotype of cri-du-chat.with the clinical phenotype of cri-du-chat.Request chromosome analysis of parents Request chromosome analysis of parents to rule out familial translocation.to rule out familial translocation.Offer prenatal diagnosis after the birth of Offer prenatal diagnosis after the birth of an affected child.an affected child.

Failure toFailure to::

PrognosisPrognosisActivityActivity

Activities are limited because of profound mental Activities are limited because of profound mental retardation andretardation and

physical handicaps. physical handicaps.

Patient EducationPatient Education Families are greatly affected. Families are greatly affected. The main contributor to increased family stress is theThe main contributor to increased family stress is thechild's maladaptive behavior. However, these familieschild's maladaptive behavior. However, these familiesalso receive social support from other families, friends,also receive social support from other families, friends,and concerned professionals. and concerned professionals.

Surgical CareSurgical Care

Correction of congenital heart defects may be Correction of congenital heart defects may be indicated. indicated.

Orchiopexy for undescended testes.Orchiopexy for undescended testes. Issues important to anesthetic plan:Issues important to anesthetic plan: Hypotonia. Hypotonia. Temperature maintenance. Temperature maintenance. Anatomical abnormalities of the airway. Anatomical abnormalities of the airway. Mental retardation Congenital heart disease. Mental retardation Congenital heart disease.

Imaging Studies: Imaging Studies:

Skeletal radiographySkeletal radiography– Microcephaly, retromicrognathiaMicrocephaly, retromicrognathia– Cranial base malformations (reduced cranial Cranial base malformations (reduced cranial

base angle and malformed sella turcica and base angle and malformed sella turcica and clivus)clivus)

– Disproportionately short third, fourth, and fifth Disproportionately short third, fourth, and fifth metacarpals and disproportionately long metacarpals and disproportionately long second, third, fourth, and fifth proximal second, third, fourth, and fifth proximal phalanges (frequent)phalanges (frequent)

Laryngeal appearanceLaryngeal appearanceFloppy epiglottis. Floppy epiglottis. Small larynx.Small larynx.Asymmetric vocal cords. Asymmetric vocal cords.

However, the cause of the characteristic cry However, the cause of the characteristic cry cannot be entirely ascribed to the larynx. A cannot be entirely ascribed to the larynx. A developmental field connecting the brain and developmental field connecting the brain and the affected clivus region of the cranial base the affected clivus region of the cranial base with the laryngeal region from which the with the laryngeal region from which the characteristic cry derives may exist. This area of characteristic cry derives may exist. This area of the brain is probably deformed in patients with the brain is probably deformed in patients with cri-du-chat syndrome. The characteristic cry cri-du-chat syndrome. The characteristic cry usually disappears with time.usually disappears with time.

Magnetic resonance imagingMagnetic resonance imaging– Atrophy of the brainstem, atrophic middle cerebellar peduncles and Atrophy of the brainstem, atrophic middle cerebellar peduncles and

cerebellar white mattercerebellar white matter– Possible hypoplasia of cerebellar vermis with enlargement of the Possible hypoplasia of cerebellar vermis with enlargement of the

cisterna magna and fourth ventriclecisterna magna and fourth ventricle

Echocardiography - To rule out structural cardiac Echocardiography - To rule out structural cardiac malformationsmalformationsOther Tests: Other Tests: Swallowing study for feeding difficultySwallowing study for feeding difficultyComprehensive evaluation for receptive and expressive Comprehensive evaluation for receptive and expressive language: Most children have better receptive language than language: Most children have better receptive language than expressive language.expressive language.Developmental testing, referral to early intervention, and Developmental testing, referral to early intervention, and appropriate school placementappropriate school placement

Childhood findingsChildhood findings Include severe mental retardationInclude severe mental retardation Developmental delayDevelopmental delay MicrocephalyMicrocephaly HypertonicityHypertonicity Premature graying of the hair Premature graying of the hair Dropped-jaw, open-mouth expression secondary to Dropped-jaw, open-mouth expression secondary to

facial laxity; short philtrum; malocclusion of the facial laxity; short philtrum; malocclusion of the teeth; scoliosis; short third-fifth metacarpals; and teeth; scoliosis; short third-fifth metacarpals; and chronic medical problems such as upper respiratory chronic medical problems such as upper respiratory tract infections, otitis media, severe constipation, tract infections, otitis media, severe constipation, and hyperactivity.and hyperactivity.