AUTHOR INFORMATION

Section 1 of 11

Authored by Harold Chen, MD, MS, FAAP, FACMG, Chief, Professor, Department of Pediatrics, Section of Perinatal Genetics, Louisiana State University Medical Center

Harold Chen, MD, MS, FAAP, FACMG, is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, American Society of Human Genetics, and Teratology Society

Edited by Ian Krantz, MD, Assistant Professor, Department of Pediatrics, University of Pennsylvania and Children's Hospital of Philadelphia; Robert Konop, PharmD, Director, Clinical Account Management, Ancillary Care Management, 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, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Harold Chen, MD, MS, FAAP, FACMG
Editor's Email:	Ian Krantz, MD

eMedicine Journal, September 30 2005, VOLUME 6, Number 9

INTRODUCTION

Section 2 of 11

Background: In 1963, Lejeune et al described a syndrome of multiple congenital anomalies, mental retardation, microcephaly, abnormal face, and a mewing cry in infants with deletion of a B group chromosome (Bp-), later identified as 5p-. Cri-du-chat syndrome is an autosomal deletion syndrome caused by a partial deletion of chromosome 5p. It 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 because of structural abnormalities of the larynx (such as 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 connecting the brain and the affected clivus region of the cranial base with the laryngeal region from which the characteristic cry derives may exist. This area of the brain is probably deformed in patients with cri-du-chat syndrome. The characteristic cry usually disappears with time.

Frequency:

• In the US: 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, death occurs in 6-8% of the overall population affected with the syndrome. Pneumonia, aspiration pneumonia, congenital heart defects, and respiratory distress syndrome are the most common causes of death.

Race: No known racial predilection exists.

Sex: A significant female predominance exists in affected newborns, with a male-to-female ratio of 0.72.

Age: The condition is detected in newborns and infants because of the catlike cry and dysmorphic features.

CLINICAL

Section 3 of 11

History:

• Characteristic cry


• • Subtle dysmorphism with neonatal complications and a high-pitched cry typically initiate diagnostic evaluation by cytogenetic studies.

  • This distinctive cry is observed in many infants with cri-du-chat syndrome but is not associated with other aneuploidies.

  • About one third of children lose the cry by the time they are aged 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 patients 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 as the result of 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 the 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 low birth weight, hypotonia, microcephaly, growth retardation, a 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, and cardiac defects (eg, ventricular septal defect [VSD], atrial septal defect [ASD], patent ductus arteriosus [PDA], tetralogy of Fallot).
  
  
  
  • Less frequently encountered findings include 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, and hyperextensible joints.
  
  
  
• Childhood: Findings include severe mental retardation; developmental delay; microcephaly; hypertonicity; premature graying of the hair; a 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; and 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, 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 where 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 cases have other rare cytogenetic aberrations (eg, interstitial deletions, mosaicisms, rings and de novo translocations).



• The deleted chromosome 5 is paternal in origin in about 80% of the cases.



• Loss of a small region in band 5p15.2 (cri-du-chat critical region) correlates with all the clinical features of the syndrome with the exception of 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)


• • Localized the region associated with the cry to 1.5 Mb in distal band 5p15.31, between bacterial artificial chromosomes (BACs) containing markers D5S2054 and D5S676.
  
  
  
  • Localized the region associated with the speech delay to 3.2 Mb in band 5p15.32-15.33, between BACs containing markers D5S417 and D5S635.
  
  
  
  • Localized the region associated with the facial dysmorphology to 2.4 Mb in band 5p15.2-15.31, between BACs containing markers D5S208 and D5S2887.
  
  
  

DIFFERENTIALS

Section 4 of 11

Patau Syndrome
Wolf-Hirschhorn Syndrome

Other Problems to be Considered:

Mental retardation syndromes
Multiple congenital anomalies
Other autosomal monosomy and trisomy syndromes

WORKUP

Section 5 of 11

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 by 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 is indicative of 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.
  
  
  
  • Its resolution is limited to approximately 5-10 Mb.
  
  
  
  • The results cannot be mapped directly onto the genome sequence.
  
  
  
• Microarray CGH


• • Microarray CGH uses array elements made from large-insert genomic clones, such as BACS and 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 (frequent)
  
  
  
• Magnetic resonance imaging


• • 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 - To rule out structural cardiac malformations

Other Tests:

• Swallowing study 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 airway of patients with major feeding difficulties

TREATMENT

Section 6 of 11

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 normal parents are most likely 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. 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 corrections. Orchiopexy may be necessary for undescended testes.



• Issues important to anesthetic plan


• • 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 because of profound mental retardation and physical handicaps.

FOLLOW-UP

Section 7 of 11

Prognosis:

• Until recently, little was known about the cognitive function of patients. Recent literature indicates that many children can develop some language and motor skills. These children attain developmental and social skills observed in 5- to 6-year-old children, 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 are 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:


• • National Organization for Rare disorders, Inc. (NORD)
    PO Box 8923
    New Fairfield, CT 06812-8923
    Phone: 800-999-6673
    Fax: 203-746-6481
    E-mail: orphan@nord-rdb.com
  
  
  
  • 5p- Society
    7108 Katella Avenue #502
    Stanton, CA 90680
    Phone: 714-901-1544
    E-mail: fivepminus@aol.com
  
  
  
  • Chromosome Deletion Outreach, Inc. (CDO)
    PO Box 724
    Boca Raton, FL 33429-0724
    Phone: 888-CDO-6880
    E-mail: cdo@worldnet.att.net
  
  
  

MISCELLANEOUS

Section 8 of 11

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



• Physicians and parents should be aware of the range of psychomotor potential difficulties. This helps them make informed decisions concerning home-rearing or institutional placement.

Special Concerns:

• Prenatal diagnosis


• • Amniocentesis, routinely performed at 14-16 weeks’ gestation, remains the criterion standard of invasive diagnostic tests. Testing for chromosome disorders is 99.5% accurate (missing rare cases of mosaicism and providing inaccurate results in the presence of maternal cell contamination). The procedure is associated with a small risk of pregnancy loss (about 1 in 200-300).
  
  
  
  • Chorionic villus sampling (CVS) is performed at 10-13 weeks’ gestation. Earlier testing is thought to be associated with a small risk (1 in 300-1000) of fetal transverse limb deficiency, a small chance of maternal cell contamination, and a 0.5-1% risk of a fetal loss after the procedure. Accuracy (96-98%) is less than that of mid-trimester amniocentesis because of confined placental mosaicism and maternal cell contamination.
  
  
  
  • Percutaneous umbilical blood sampling (PUBS) is of limited use, except in cases dated late in pregnancy. The preimplantation diagnosis is not of any realistic relevance for current care.
  
  
  

TEST QUESTIONS

Section 9 of 11

CME Question 1: What features are most often cited for initiating a diagnostic evaluation using cytogenetic studies for cri-du-chat syndrome?

A: Mewing cry
B: Round face
C: Microcephaly
D: Neonatal complications
E: All of the above

The correct answer is E: The presence of subtle dysmorphism and microcephaly in combination with neonatal complications and a high-pitched mewing cry are the features most often cited for initiating a diagnostic evaluation using cytogenetic studies.

CME Question 2: Which of the following statements is not correct regarding cri-du-chat syndrome?

A: Prevalence is approximately 1 in 50,000 births.
B: The prevalence among individuals with mental retardation is approximately 1.5 in 1,000.
C: A significant male predominance exists.
D: About one third of patients lose the catlike cry by the time the individual is aged 2 years.
E: Severe malocclusion is present.

The correct answer is C: A significant female predominance exists (a male-to-female ratio of 0.72).

Pearl Question 1 (T/F): Recurrence risk after having a child with cri-du-chat syndrome is usually increased significantly.

The correct answer is False: Recurrence risk is negligible unless a parent is a translocation carrier.

Pearl Question 2 (T/F): Facial features of patients with cri-du-chat syndrome change with time.

The correct answer is True: Facial features do change over time. A round face is observed in infancy. A small, narrow, and often asymmetric face is present during childhood. Crowding and coarsened facial features develop during late childhood and adolescence.

Pearl Question 3 (T/F): Fluorescence in situ hybridization (FISH) cytogenetic technique is used to demonstrate submicroscopic translocations in cytogenetically normal parents and affected offspring.

The correct answer is True: FISH using genetic markers that have been precisely localized to the cri-du-chat syndrome locus may be used. The absence of signal from either the maternal or the paternal allele for the marker is indicative of monosomy of 5p15.2.

Pearl Question 4 (T/F): Children with cri-du-chat syndrome do not attain developmental and social skills observed in 5- or 6-year-old children.

The correct answer is False: Many children can attain developmental and social skills observed in 5- or 6-year-old children, 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 are independent in self-care skills.

PICTURES

Section 10 of 11

Caption: Picture 1. Image is of an infant with cri-du-chat syndrome. Note a round face with full cheeks, hypertelorism, epicanthal folds, and apparently low-set ears.
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Caption: Picture 2. Image is of a child with cri-du-chat syndrome. Note hypertonicity, small and narrow face, dropped jaw, and open-mouth expression secondary to facial laxity.
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Caption: Picture 3. Image is the result of a 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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Caption: Picture 4. Cri-du-chat syndrome. G-banded karyotype [46,XX,del(5)(p13)].
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Caption: Picture 5. Cri-du-chat syndrome. G-banded karyotype of a carrier father [46,XY,t(5;17)(p13.3;p13)].
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BIBLIOGRAPHY

Section 11 of 11

• Brislin RP, Stayer SA, Schwartz RE: Anaesthetic considerations for the patient with cri du chat syndrome. Paediatr Anaesth 1995; 5(2): 139-41[Medline].
• Cornish KM, Munir F: Receptive and expressive language skills in children with cri-du-chat syndrome. J Commun Disord 1998 Jan-Feb; 31(1): 73-80; quiz 80-1[Medline].
• Cornish KM, Pigram J: Developmental and behavioural characteristics of cri du chat syndrome. Arch Dis Child 1996 Nov; 75(5): 448-50[Medline].
• Dykens EM, Clark DJ: Correlates of maladaptive behavior in individuals with 5p- (cri du chat) syndrome. Dev Med Child Neurol 1997; 39: 752-756[Medline].
• Fenger K, Niebuhr E: Measurements on hand radiographs from 32 cri-du-chat probands. Radiology 1978 Oct; 129(1): 137-41[Medline].
• Gersh M, Goodart SA, Pasztor LM, et al: Evidence for a distinct region causing a cat-like cry in patients with 5p deletions. Am J Hum Genet 1995 Jun; 56(6): 1404-10[Medline].
• Gersh M, Grady D, Rojas K, et al: Development of diagnostic tools for the analysis of 5p deletions using interphase FISH. Cytogenet Cell Genet 1997; 77(3-4): 246-51[Medline].
• Hodapp RM, Wijma CA, Masino LL: Families of children with 5p- (cri du chat) syndrome: familial stress and sibling reactions. Dev Med Child Neurol 1997 Nov; 39(11): 757-61[Medline].
• Kjaer I, Niebuhr E: Studies of the cranial base in 23 patients with cri-du-chat syndrome suggest a cranial developmental field involved in the condition. Am J Med Genet 1999 Jan 1; 82(1): 6-14[Medline].
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• Niebuhr E: The cat cry syndrome (5p-) in adolescents and adults. J Ment Defic Res 1971 Dec; 15 Pt 4(0): 277-91[Medline].
• Niebuhr E: The Cri du Chat syndrome: epidemiology, cytogenetics, and clinical features. Hum Genet 1978 Nov 16; 44(3): 227-75[Medline].
• Overhauser J, Huang X, Gersh M, et al: Molecular and phenotypic mapping of the short arm of chromosome 5: sublocalization of the critical region for the cri-du-chat syndrome. Hum Mol Genet 1994 Feb; 3(2): 247-52[Medline].
• Overhauser J, McMahon J, Oberlender S, et al: Parental origin of chromosome 5 deletions in the cri-du-chat syndrome. Am J Med Genet 1990 Sep; 37(1): 83-6[Medline].
• Sohner L, Mitchell P: Phonatory and phonetic characteristics of prelinguistic vocal development in cri du chat syndrome. J Commun Disord 1991 Feb; 24(1): 13-20[Medline].
• Wilkins LE, Brown JA, Nance WE, Wolf B: Clinical heterogeneity in 80 home-reared children with cri du chat syndrome. J Pediatr 1983 Apr; 102(4): 528-33[Medline].
• Wilkins LE, Brown JA, Wolf B: Psychomotor development in 65 home-reared children with cri-du-chat syndrome. J Pediatr 1980 Sep; 97(3): 401-5[Medline].
• Zhang X, Snijders A, Segraves R, et al: High-resolution mapping of genotype-phenotype relationships in cri du chat syndrome using array comparative genomic hybridization. Am J Hum Genet 2005 Feb; 76(2): 312-26[Medline][Full Text].

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