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Pediatrics: Genetics and Metabolic Disease > Genetics
Cri-du-chat Syndrome
Article Last Updated: Jul 16, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, Pathology, Director of Perinatal Genetics and Genetic Laboratory Services, Louisiana State University Medical Center; Laboratory Director, Hema-Con Cancer Cytogenetics Laboratory, Gainesville, Florida
Harold Chen is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Human Genetics, and Teratology Society
Editors: Ian Krantz, MD, Department of Pediatrics, Assistant Professor, University of Pennsylvania and Children's Hospital of Philadelphia; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System; Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
cat cry syndrome, chromosome deletion 5p syndrome, monosomy 5p syndrome, (Bp-), 5p-, partial deletion of chromosome 5p, 5p deletion, 5p monosomy, growth failure, microcephaly, facial abnormalities, mental retardation, catlike cry, mewing cry, laryngeal hypoplasia, floppy epiglottis, small larynx, asymmetric vocal cords, pneumonia, congenital heart defects, respiratory distress syndrome, cri-du-chat syndrome, aneuploidies, feeding problems, failure to thrive, ear infections, cognitive delay, speech delay, motor delay, hyperactivity, self-injurious behavior, hypotonia, hypertelorism, epicanthal folds, down-slanting palpebral fissures, strabismus, down-turned mouth, flat nasal bridge, micrognathia, low-set ears, short fingers, single palmar creases, cardiac defects, cleft lip and palate, preauricular tags, preauricular fistulas, thymic dysplasia, gut malrotation, megacolon, inguinal hernia, dislocated hips, cryptorchidism, hypospadias, renal malformations, clinodactyly of the fifth fingers, talipes equinovarus,pes planus, syndactyly of the second and third fingers and toes, oligosyndactyly, hyperextensible joints, short philtrum, malocclusion of the teeth, scoliosis, short third-fifth metacarpals, transverse flexion creases, distal axial triradius
Background
In 1963, Lejeune et al described a syndrome consisting of multiple congenital anomalies, mental retardation, microcephaly, abnormal face, and a mewing cry in infants with a deletion of a B group chromosome (Bp-), later identified as 5p-.1 Cri-du-chat syndrome is an autosomal deletion syndrome caused by a partial deletion of chromosome 5p and is characterized by a distinctive, high-pitched, catlike cry in infancy with growth failure, microcephaly, facial abnormalities, and mental retardation throughout life.
Pathophysiology
A partial deletion of the short arm of chromosome 5 is responsible for the characteristic phenotype. The characteristic cry is perceptually and acoustically similar to the mewing of kittens. This unusual cry is due to structural abnormalities of the larynx (eg, laryngeal hypoplasia) and CNS dysfunction. The laryngeal appearance may be normal or may exhibit marked anatomical abnormalities such as floppy epiglottis, small larynx, and asymmetric vocal cords. However, the cause of the characteristic cry cannot be entirely ascribed to the larynx. A developmental field may connect the brain and the affected clivus region of the cranial base with the laryngeal region from which the characteristic cry derives. This area of the brain is probably deformed in patients with cri-du-chat syndrome. The characteristic cry usually disappears over time.
Frequency
United States
The estimated prevalence is about 1 in 50,000 live births. The prevalence among individuals with mental retardation is about 1.5 in 1000.
Mortality/Morbidity
With contemporary interventions, the chance of survival to adulthood is possible. Currently, the mortality rate of cri-du-chat syndrome is 6-8% in the overall population. Pneumonia, aspiration pneumonia, congenital heart defects, and respiratory distress syndrome are the most common causes of death.
Race
No racial predilection has been found.
Sex
A significant female predominance is observed in affected newborns, with a male-to-female ratio of 0.72:1.
Age
The condition is detected in newborns and infants because of the catlike cry and dysmorphic features.
History
- Characteristic cry
- Subtle dysmorphism with neonatal complications and a high-pitched cry typically prompt diagnostic evaluation using cytogenetic studies.
- Many infants with cri-du-chat syndrome have this distinctive cry, but it is not associated with other aneuploidies.
- About one third of children no longer exhibit the catlike cry by age 2 years.
- Developmental history: Early feeding problems are present because of swallowing difficulties; poor suck; failure to thrive; early ear infections; and severe cognitive, speech, and motor delays. Almost all affected individuals have these problems.
- Behavioral history
- Behavioral profile includes hyperactivity, aggression, tantrums, stereotypic and self-injurious behavior, repetitive movements, hypersensitivity to sound, clumsiness, and obsessive attachments to objects. Some of these problems are more pronounced in individuals with lower cognitive-adaptive levels and with histories of previous medication trials.
- Features similar to those of autism and social withdrawal may be more characteristic of individuals who have a 5p deletion due to an unbalanced segregation of a parental translocation. However, children with cri-du-chat syndrome are able to communicate their needs, socially interact with others, and have some degree of mobility.
Physical
- Neonatal period
- Newborns have a characteristic mewing cry, a high-pitched monochromatic cry that is considered pathognomonic for this syndrome.
- Neonatal complications include poor sucking, need for incubator care, respiratory distress, jaundice, pneumonia, and dehydration.
- In addition, common findings include the following:
- Low birth weight
- Hypotonia
- Microcephaly
- Growth retardation
- Round face with full cheeks
- Hypertelorism
- Epicanthal folds
- Down-slanting palpebral fissures
- Strabismus
- Flat nasal bridge
- Down-turned mouth
- Micrognathia
- Low-set ears
- Short fingers
- Single palmar creases
- Cardiac defects (eg, ventricular septal defect [VSD], atrial septal defect [ASD], patent ductus arteriosus [PDA], tetralogy of Fallot)
- Less common findings include the following:
- Cleft lip and palate
- Preauricular tags and fistulas
- Thymic dysplasia
- Gut malrotation
- Megacolon
- Inguinal hernia
- Dislocated hips
- Cryptorchidism
- Hypospadias
- Rare renal malformations (eg, horseshoe kidneys, renal ectopia or agenesis, hydronephrosis)
- Clinodactyly of the fifth fingers
- Talipes equinovarus
- Pes planus
- Syndactyly of the second and third fingers and toes
- Oligosyndactyly
- Hyperextensible joints
- Childhood
- Findings include the following:
- Severe mental retardation
- Developmental delay
- Microcephaly
- Hypertonicity
- Premature graying of the hair
- Small, narrow, and often asymmetric face
- Dropped-jaw, open-mouth expression secondary to facial laxity
- Short philtrum
- Malocclusion of the teeth
- Scoliosis
- Short third-fifth metacarpals
- Children with cri-du-chat syndrome also have chronic medical problems such as upper respiratory tract infections, otitis media, severe constipation, and hyperactivity.
- Late childhood and adolescence
- Findings include severe mental retardation, microcephaly, coarsening of facial features, prominent supraorbital ridges, deep-set eyes, hypoplastic nasal bridge, severe malocclusion, and scoliosis.
- Affected females reach puberty, develop secondary sex characteristics, and menstruate at the usual time. The genital tract is usually normal in females, except for a report of a bicornuate uterus.
- In males, the testes are often small, but spermatogenesis is thought to be normal.
- Dermatoglyphics
- Transverse flexion creases
- Distal axial triradius
- Increased whorls and arches on digits
Causes
- Most cases (80-85%) are due to sporadic de novo deletion of 5p (15.3->15.2).
- Approximately 10-15% of cases result from the unequal segregation of a parental balanced translocation in which the 5p monosomy is often accompanied by a trisomic portion of the genome. The phenotypes in these individuals may be more severe than in those with isolated monosomy of 5p because of this additional trisomic portion of the genome.
- Most cases involve terminal deletions with 30-60% loss of 5p material. Fewer than 10% of patients have other rare cytogenetic aberrations (eg, interstitial deletions, mosaicisms, rings and de novo translocations).
- Approximately 1-2% of cases have recombinations that involve a pericentric inversion in one of the parents.
- A mechanism that involves dicentric chromosome formation with subsequent breakage and telomere healing during meiosis was recently proposed to explain the rare cases in which a parental paracentric inversion likely results in a viable terminal deletion.
- The deleted chromosome 5 is paternal in origin in about 80% of cases.
- Loss of a small region in band 5p15.2 (cri-du-chat critical region) correlates with all clinical features of the syndrome except for the catlike cry, which maps to band 5p15.3 (catlike critical region). The results suggest that 2 noncontiguous critical regions contain genes involved in this condition's etiology.
- High-resolution mapping of genotype-phenotype relationships in cri-du-chat syndrome using array comparative genomic hybridization (CGH) has provided the following findings:
- The region associated with the cry was localized to 1.5 Mb in distal band 5p15.31, between bacterial artificial chromosomes (BACs) that contain markers D5S2054 and D5S676.
- The region associated with the speech delay was localized to 3.2 Mb in band 5p15.32-15.33, between BACs that contain markers D5S417 and D5S635.
- The region associated with the facial dysmorphology was localized to 2.4 Mb in band 5p15.2-15.31, between BACs that contain markers D5S208 and D5S2887.
Patau Syndrome
Wolf-Hirschhorn Syndrome
Other Problems to be Considered
Mental retardation syndromes
Multiple congenital anomalies
Other autosomal monosomy and trisomy syndromes
Lab Studies
- Conventional cytogenetic studies: The size of the 5p deletion may vary from the entire short arm to only 5p15. A small deletion of 5p may be missed using a conventional cytogenetic technique.
- High-resolution cytogenetic studies: Look for a small deletion of 5p.
- Fluorescence in situ hybridization
- Molecular cytogenetic studies using fluorescent in situ hybridization (FISH) allow the diagnosis to be made in patients with very small deletions. FISH uses genetic markers that have been precisely localized to the area of interest.
- The absence of a fluorescent signal from either the maternal or paternal chromosome 5p regions indicates monosomy for that chromosomal region.
- Chromosome CGH
- Chromosome CGH is capable of screening the entire genome for DNA copy-number alterations in a single hybridization.
- The resolution is limited to approximately 5-10 Mb.
- The results cannot be directly mapped onto the genome sequence.
- Microarray CGH
- Microarray CGH uses array elements made from large-insert genomic clones, such as BACs and phage artificial chromosomes (PACs).
- This method has sufficient measurement precision to permit reliable detection of single-copy aberrations affecting individual clones.
Imaging Studies
- Skeletal radiography
- Microcephaly, retromicrognathia
- Cranial base malformations (reduced cranial base angle and malformed sella turcica and clivus)
- Disproportionately short third, fourth, and fifth metacarpals and disproportionately long second, third, fourth, and fifth proximal phalanges (common)
- MRI
- Atrophy of the brainstem, atrophic middle cerebellar peduncles and cerebellar white matter
- Possible hypoplasia of cerebellar vermis with enlargement of the cisterna magna and fourth ventricle
- Echocardiography - Used to rule out structural cardiac malformations
Other Tests
- Swallowing study to assess for feeding difficulty
- Comprehensive evaluation for receptive and expressive language (Most children have better receptive language than expressive language.)
- Developmental testing, referral to early intervention, and appropriate school placement
Procedures
- Gastrostomy in infancy to protect the airway in patients with major feeding difficulties
Medical Care
- Care is supportive. No treatment exists for the underlying disorder.
- Genetic counseling
- Female patients are fertile and can deliver viable affected offspring, with an estimated recurrence risk of 50%.
- Recurrence risk for a de novo case is 1% or less. Rare recurrences in chromosomally healthy parents are probably the result of gonadal mosaicism for the 5p deletion in one of the parents.
- If a parent is a balanced carrier of a structural rearrangement, the risk is substantially high. The risk should be assessed based on the type of structural rearrangement and its pattern of segregation.
- Chronic medical problems such as upper respiratory tract infections, otitis media, and severe constipation require appropriate treatment.
- Use the relatively good receptive skills to encourage language and communicative development rather than relying on traditional verbal methods.
- Early stimulation and introduction to sign language are effective means of developing communication skills (50% of children are able to use sign language to communicate).
- Behavior modification programs may be successful in managing hyperactivity, short attention span, low threshold for frustration, and self-stimulatory behaviors (eg, head-banging, hand-waving).
Surgical Care
- Correction of congenital heart defects may be indicated. Medical problems involving minor malformations such as strabismus and clubfoot may be amenable to surgical correction. Orchiopexy may be necessary in patients with undescended testes.
- Issues important to anesthetic plan include the following:
- Anatomical abnormalities of the airway
- Congenital heart disease
- Hypotonia
- Mental retardation
- Temperature maintenance
Consultations
- Clinical geneticist
- Developmental pediatrician
- Neurologist
- Cardiologist
- Ophthalmologist
- Dentist
- Orthopedist
- Psychologist
- Physical and occupational therapist
- Speech language pathologist
- Audiologist
- Urologist
Diet
No special diet is required.
Activity
Activities are limited in patients with profound mental retardation and physical limitations.
Currently, drug therapy is not a component in the standard of care for this syndrome. See Treatment.
Deterrence/Prevention
See Special Concerns.
Prognosis
- After the first years of life, the mortality (10%) and morbidity rates are low. About 75% of deaths occurred during the first months of life, and as many as 90% occurred within the first year.
- Recent improvements in management and rehabilitation programs have resulted in increased psychomotor development, improved autonomy, and better social adaptation.
- Until recently, little was known about the cognitive function of patients with cri-du-chat syndrome. Recent literature indicates that many children can develop some language and motor skills. These children attain the developmental and social skills commonly observed in children aged 5-6 years, although their linguistic abilities are seldom as advanced. Older, home-reared children are usually ambulatory, able to communicate verbally or through gestural sign language, and independent in self-care skills.
Patient Education
- Families are greatly affected. The main contributor to increased family stress is the child's maladaptive behavior. However, these families also receive social support from other families, friends, and concerned professionals. Up-to-date information about the syndrome and other resources should be made available. The following sources of information are available:
Medical/Legal Pitfalls
- Failure to recognize characteristic symptoms and signs
- Failure to refer to a geneticist for evaluation and genetic counseling
- Failure to request chromosome analysis of patients with the clinical phenotype of cri-du-chat
- Failure to request chromosome analysis of parents to rule out familial translocation
- Failure to offer prenatal diagnosis after the birth of an affected child
- Failure to properly inform parents about the range of psychomotor potential difficulties, which would help them make informed decisions concerning home-rearing or institutional placement
Special Concerns
- Genetic counseling
- Most persons with cri-du-chat syndrome have a de novo deletion, and the risk of recurrence in these individuals is practically negligible. However, the possibility of gonadal mosaicism in one of the parents cannot be excluded, even if no recurrence has been reported.
- In patients with a balanced familial translocation, the recurrence risk is higher. The reproductive risk for producing unbalanced offspring for carriers of translocations that involve 5p ranged from 8.7-18.8%.2 The risk for male and female carriers is the same.
- Prenatal diagnosis
- Prenatal diagnosis of fetuses with cri-du-chat syndrome has been reported in families with a balanced familial translocation.
- Prenatal diagnosis of de novo 5p deletions is not common but has been reported in patients with the following conditions
- Nonimmune hydrops fetalis
- Isolated bilateral ventriculomegaly
- Fetal choroid cysts associated with an abnormal maternal serum human chorionic gonadotrophin level
- Microcephaly with cerebellar hypoplasia (a fetus with 5p- mosaicism)
- Dandy-Walker syndrome with agenesis of the corpus callosum
- Not all 5p deletions result in the cri-du-chat phenotype. Individuals with short terminal deletions in 5p15.3 may show only a mild or moderate psychomotor retardation. Interstitial and apparently unbalanced deletion in 5p14, detected with prenatal diagnosis indicated for advanced maternal age, resulted in a completely normal phenotype traced through 6 individuals in 3 generations.3
| Media file 1:
Infant with cri-du-chat syndrome. Note the round face with full cheeks, hypertelorism, epicanthal folds, and apparently low-set ears. |
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| Media file 2:
Child with cri-du-chat syndrome. Note the hypertonicity, small and narrow face, dropped jaw, and open-mouth expression secondary to facial laxity. |
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| Media file 3:
Fluorescent in situ hybridization (FISH) study of a patient with cri-du-chat syndrome. FISH photograph shows deletion of a locus-specific probe for the cri-du-chat region. Spectrum orange color represents chromosome 5–specific signal and spectrum green is cri-du-chat locus signal. Absence of a green signal indicates monosomy for that region (left, interphase cell; right, metaphase chromosome spread). |
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| Media file 5:
G-banded karyotype of a carrier father [46,XY,t(5;17)(p13.3;p13)]. |
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Cri-du-chat Syndrome excerpt Article Last Updated: Jul 16, 2007
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