Cri-du-chat Syndrome

Cri du chat is the French term for “cat-cry” or “call of the cat.” The term refers to the cat-like cry of a pediatric patient with cri-du-chat syndrome. The condition is a rare genetic disorder caused by deletion mutations on chromosome 5. Cri-du-chat syndrome is more common in females than in males. Aside from the characteristic cry, the condition also presents with dysphagia, low birth weight, poor growth, and severe cognitive, speech, and motor disabilities.

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Epidemiology and Etiology

Epidemiology

  • More common in females, with a ratio of 2:1
  • Incidence ranges from 1 in 15,000–50,000 live births

Etiology

  • Cri-du-chat syndrome is caused by deletions in the terminal short arm of chromosome 5 (can affect from only the region 5p15.3 to the entire short arm of chromosome 5).
    • 5p monosomy, leading to a karyotype of 46,XX or XY,5p‑
    • Partial monosomy 
      • 80% of cases are sporadic (de novo mutations).
      • 10%15% of cases are originated by parental balanced translocation.
      • < 10% of cases are associated with rare cytogenetic aberrations.
  • Deletion in chromosome 5 is paternal in origin in most cases (80%90%).
  • Genes that contribute to cri-du-chat:
    • Telomerase reverse transcriptase gene (hTERT), located at 5p13.33 (the short arm of chromosome 5 at band 13.33), is associated with the phenotypic changes.
    • Semaphorin F gene (SEMA5A) and delta catenin gene (CTNND2) at 5p15.2 are involved in cerebral development.

Clinical Presentation

Symptoms vary and depend on the amount of deleted genetic material.

Neonatal symptoms

  • The syndrome is named for its characteristic “meow-like” cry of affected infants caused by laryngeal and nervous system problems. It lasts for the first few weeks of life.
  • Dysphagia
  • Low birth weight and poor growth, due to:
    • Failure to thrive
    • Feeding problems due to low muscle tone, poor suckling, and gastroesophageal reflux disease (may lead to aspiration pneumonia) 
  • Severe intellectual, speech, and psychomotor disabilities, such as:  
    • Delayed sitting up and walking
    • Clumsiness
  • Hyperactivity, aggression, outbursts, and repetitive movements 
  • Unusual facial features:
    • Microcephaly
    • Hypertelorism, skin tags in front of eyes, epicanthal folds, down-slanting palpebral fissures, and strabismus
    • Small, round face with full cheeks 
    • Flat, wide nasal bridge and short philtrum
    • Micrognathia, down-turned mouth, excessive drooling, cleft lip/palate, and bifid uvula
    • Low-set ears 
  • Hypotonia 
  • Constipation
  • Recurrent infections (e.g., otitis media, respiratory infections, and urinary tract infections [UTIs])
  • Clubfeet, syndactyly, short fingers, and single palmar creases
  • Cardiac defects: 
    • Ventricular septal defect
    • Atrial septal defect
    • Patent ductus arteriosus
    • Tetralogy of Fallot

Symptoms of late childhood and adolescence

  • Intellectual disability
  • Coarsening of facial features with prominent supraorbital ridges, deep-set eyes, and a hypoplastic nasal bridge 
  • Severe dental malocclusion
  • Scoliosis
  • Affected females have normal sexual characteristic development
  • In males, the testes are often small, while spermatogenesis is normal
Criduchat phenotypical features

Phenotypic features associated with cri-du-chat syndrome

Image: “Criduchat” by Paola Cerruti Mainardi. License: CC BY 2.0

Diagnosis and Management

Diagnosis

  • Distinctive cry and associated physical problems lead to clinical suspicion at birth.
  • Genetic counseling and testing (karyotyping) may be offered.
    • If there is high clinical suspicion and the karyotype is normal, order fluorescence in situ hybridization (FISH) to test for similar syndromes.
  • Prenatally, the deletion in chromosome 5 can be detected through genetic analysis of:
    • Amniotic fluid samples
    • Chorionic villi samples

Management

  • No known cure
  • Management aimed at:
    • Maximizing development of affected individuals through speech, physical, and occupational therapy
    • Treating life-threatening conditions (e.g., congenital heart disease)

Prognosis

  • Good upon surviving the first few years of life; morbidity is low
  • Normal life expectancy possible depending on management and therapies

Differential Diagnosis

The following conditions are differential diagnoses of cri-du-chat syndrome:

  • Wolf-Hirschhorn syndrome (Wolf syndrome): a rare chromosomal disorder caused by a partial deletion of the short arm of chromosome 4, especially of band 4p16.3. Associated abnormalities typically include low birth weight, growth retardation, hypotonia, and psychomotor delays and/or disabilities. 
  • Mowat-Wilson syndrome: a genetic condition caused by mutations in the ZEB2 gene, characterized by microcephaly, intellectual disability, delayed development, and Hirschsprung’s disease, among other birth defects and distinctive facial features (e.g., a square-shaped face, deep-set and widely spaced eyes, broad nasal bridge, rounded nasal tip, and a prominent and pointed chin).
  • Patau syndrome (trisomy 13): a genetic syndrome caused by the presence of 3 copies of the 13th chromosome. The condition is characterized by microcephaly, holoprosencephaly, characteristic facial anomalies (e.g., cleft lip/palate, low-set, malformed ears, bulbous nose, small chin, microphthalmia, coloboma), polydactyly, and congenital heart defects.
  • Fetal alcohol spectrum disorders: a group of conditions that can occur in neonates whose mothers consumed heavy amounts of alcohol during their pregnancy. Problems may include characteristic craniofacial changes, short height, low body weight, small head size, poor coordination, low intelligence, behavior problems, and problems with hearing or seeing. 
  • Cohen syndrome: a hereditary disorder with abnormalities that include hypotonia, failure to thrive, microcephaly, joint hypermobility, developmental delay, visual disorders such as myopia and strabismus, and characteristic facial features (e.g., arched eyelids, low hairline, thick eyelashes and eyebrows, high palate).
  • Edwards syndrome (trisomy 18): a genetic syndrome caused by the presence of 3 copies of chromosome 18. Associated abnormalities include microcephaly, myelomeningocele, omphalocele, malformation of visceral organs such as horseshoe kidney and hernias, severe intellectual disability, congenital heart defects, and characteristic facial anomalies (e.g., broad nose, low-set ears, mandibular hypoplasia, cleft lip, and palate).

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