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 Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, low birth weight, poor growth, and severe cognitive, speech, and motor disabilities.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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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 Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm of chromosome 5 (can affect from only the region 5p15.3 to the entire short arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). 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 Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). 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 Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System problems. It lasts for the first few weeks of life.
  • Dysphagia
  • Low birth weight and poor growth, due to:
    • Failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive
    • Feeding problems due to low muscle tone Muscle tone The state of activity or tension of a muscle beyond that related to its physical properties, that is, its active resistance to stretch. In skeletal muscle, tonus is dependent upon efferent innervation. Skeletal Muscle Contraction, poor suckling, and gastroesophageal reflux disease Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease (may lead to aspiration pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin tags in front of eyes, epicanthal folds, down-slanting palpebral fissures, and strabismus Strabismus Strabismus is the misalignment of the eyes while fixating the gaze on an object. Strabismus can be idiopathic, but it may also be caused by cerebral palsy, uncorrected refractive errors, and extraocular muscle or cranial nerve dysfunction. Strabismus
    • Small, round face with full cheeks 
    • Flat, wide nasal bridge and short philtrum
    • Micrognathia, down-turned mouth, excessive drooling, cleft lip Cleft lip The embryological development of craniofacial structures is an intricate sequential process involving tissue growth and directed cell apoptosis. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate. As the most common craniofacial malformation of the newborn, the diagnosis of a cleft is clinical and usually apparent at birth. Cleft Lip and Cleft Palate/ palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate, and bifid uvula
    • Low-set ears 
  • Hypotonia 
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Recurrent infections (e.g., otitis media, respiratory infections, and urinary tract infections Urinary tract infections Urinary tract infections (UTIs) represent a wide spectrum of diseases, from self-limiting simple cystitis to severe pyelonephritis that can result in sepsis and death. Urinary tract infections are most commonly caused by Escherichia coli, but may also be caused by other bacteria and fungi. Urinary Tract Infections [UTIs])
  • Clubfeet, syndactyly, short fingers, and single palmar creases
  • Cardiac defects: 
    • Ventricular septal defect
    • Atrial septal defect Atrial Septal Defect Atrial septal defects (ASDs) are benign acyanotic congenital heart defects characterized by an opening in the interatrial septum that causes blood to flow from the left atrium (LA) to the right atrium (RA) (left-to-right shunt). Atrial Septal Defect
    • Patent ductus arteriosus Patent ductus arteriosus The ductus arteriosus (DA) allows blood to bypass pulmonary circulation. After birth, the DA remains open for up to 72 hours and then constricts and involutes, becoming the ligamentum arteriosum. Failure of this process to occur results in patent ductus arteriosus (PDA), a condition that causes up to 10% of congenital heart defects. Patent Ductus Arteriosus (PDA)
    • Tetralogy of Fallot Tetralogy of Fallot Tetralogy of Fallot is the most common cyanotic congenital heart disease. The disease is the confluence of 4 pathologic cardiac features: overriding aorta, ventricular septal defect, right ventricular outflow obstruction, and right ventricular hypertrophy. 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 Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. 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 Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). 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 Patau syndrome Trisomy 13, or Patau syndrome, is a genetic syndrome caused by the presence of 3 copies of chromosome 13. As the 3rd most common trisomy, Patau syndrome has an incidence of 1 in 10,000 live births. Most cases of Patau syndrome are diagnosed prenatally by maternal screening and ultrasound. More than half of the pregnancies result in spontaneous abortions. Patau Syndrome (Trisomy 13) (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 Cleft lip The embryological development of craniofacial structures is an intricate sequential process involving tissue growth and directed cell apoptosis. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate. As the most common craniofacial malformation of the newborn, the diagnosis of a cleft is clinical and usually apparent at birth. Cleft Lip and Cleft Palate/ palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate, low-set, malformed ears, bulbous nose Nose The nose is the human body's primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Anatomy of the 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 Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care. 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 Strabismus Strabismus is the misalignment of the eyes while fixating the gaze on an object. Strabismus can be idiopathic, but it may also be caused by cerebral palsy, uncorrected refractive errors, and extraocular muscle or cranial nerve dysfunction. Strabismus, and characteristic facial features (e.g., arched eyelids, low hairline, thick eyelashes and eyebrows, high palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate).
  • Edwards syndrome Edwards syndrome Edwards syndrome, or trisomy 18, is a genetic syndrome caused by the presence of an extra chromosome 18. The extra chromosome is either from 3 full copies of chromosome 18 or an additional segment of chromosome 18. As the 2nd most common trisomy, Edwards syndrome is seen in 1 out of every 5,500 live births. Edwards Syndrome (Trisomy 18) ( trisomy 18 Trisomy 18 Edwards syndrome, or trisomy 18, is a genetic syndrome caused by the presence of an extra chromosome 18. The extra chromosome is either from 3 full copies of chromosome 18 or an additional segment of chromosome 18. As the 2nd most common trisomy, Edwards syndrome is seen in 1 out of every 5,500 live births. Edwards Syndrome (Trisomy 18)): a genetic syndrome caused by the presence of 3 copies of chromosome 18. Associated abnormalities include microcephaly, myelomeningocele, omphalocele Omphalocele Omphalocele is a congenital anterior abdominal wall defect in which the intestines are covered by peritoneum and amniotic membranes. The condition results from the failure of the midgut to return to the abdominal cavity by 10 weeks' gestation. 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 Nose The nose is the human body's primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Anatomy of the Nose, low-set ears, mandibular hypoplasia, cleft lip Cleft lip The embryological development of craniofacial structures is an intricate sequential process involving tissue growth and directed cell apoptosis. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate. As the most common craniofacial malformation of the newborn, the diagnosis of a cleft is clinical and usually apparent at birth. Cleft Lip and Cleft Palate, and palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate).

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