Cri Du Chat Syndrome

Etiology

Cri-du chat results from either a partial or complete deletion of chromosome 5p. Most of the deletions occur de novo. The deletions occur as random events during the formation of reproductive cells in early fetal development. Around 80% to 90% are paternal in origin, which can arise from a chromosomal breakage during gamete formation. The remaining 10% to 15% result from unbalanced parental translocation. Moreover, 80% to 90% of cases result from terminal deletions of chromosome 5, while 3% to 5% are due to an interstitial deletion. Mosaicism, inversions, and ring chromosomes are less common mechanisms.[2]

Epidemiology

Although cri du chat is considered a rare disorder, it is 1 of the most common chromosomal anomalies. The incidence ranges from 1 in 15,000 to 1 in 50,000 liveborn infants. The incidence in females is slightly higher than in males. The exact incidence and prevalence worldwide and among races has not been established. Similarly, specific risk factors associated with prenatal events or parental age are unclear. However, there are occasional reports of parental exposure to radiation, hyperemesis, anorexia, and toxemia.[3]

Pathophysiology

Patients demonstrate phenotypic and genotypic variability. Research has revealed that partial deletion of the short arm of chromosome 5 causes the characteristic phenotype. The phenotype is identifiable despite variations in deletion size, which have led to a theory that a critical region is responsible for the characteristic feature in hemizygosity. The region identified is 5p15.2, and individuals with a deletion of chromosome 5 that does not include this region do not show a typical phenotype and, in some cases, are even normal.

Cytogenetic studies have helped identify 2 regions, 5p15.3, responsible for the characteristic cry, and 5p15.2, responsible for the other significant clinical findings. Similarly, other areas have been identified for additional features, such as speech retardation and dysmorphism. Therefore, clinical manifestations depend on the deletion of the critical area. Another crucial factor in the manifestation is the size, type of deletion, and whether it is interstitial or terminal. The most characteristic feature of this disease is high-pitched crying, and the pathogenesis is attributable to the anatomical alteration of the laryngeal morphology, which may be a result of:

• A small, floppy epiglottis
• Hypoplasia of the larynx
• A narrow or diamond-shaped larynx
• Abnormal airspace in the posterior area during phonation

However, not all patients with abnormal crying have the above features. Therefore, there may be neurological changes as well.[3]

History and Physical

Neonatal Period

In the neonatal period, the most characteristic finding is a high-pitched, monotonous cry, which usually disappears within the first few months of life. The cry is not limited to this syndrome alone and is known to accompany a few other neurological disorders. Newborns also exhibit low birthweight and microcephaly, as well as asphyxia, muscle hypotonia, and impaired suction. These lead to impaired growth and development during the first few years of life. Reports of recurrent respiratory and intestinal infections exist.[3]

General Characteristics

(a) Craniofacial Malformations

• Microcephaly
• Moon face
• Hypertelorism
• Prominent epicanthic folds
• Large nasal bridge
• Downturned corners of the mouth
• Short philtrum
• Premature gray hair
• Abnormal transverse flexion creases

 Uncommonly:

• Downward slanting palpebral fissures
• Low-set ears
• Narrow auditory ducts
• Preauricular tags
• Deafness
• Myopia and cataracts
• Hypersensitivity of pupils to methacholine
• Hypospadias and cryptorchidism

With increasing age, the following features change:

• Hypotonia in the neonatal period is replaced with hypertonia
• Prominent microcephaly
• Prominent supraorbital arch
• Dental malocclusions
• Moon face changes into a more narrow vertical face in adulthood

(b) Other Anomalies That Might Be Present

• Hypersensitivity to sound
• Cardiac disorders, including congenital heart defects
• Cutaneous hemangioma
• Renal pathology

(c) Orofacial Abnormalities

• High palate
• Mandibular microretrognathia
• Hypoplasia of the enamel
• Chronic periodontitis

(d) Developmental and Behavioral Manifestations

• Hyperactivity
• Self-injurious behavior
• Repetitive movements
• Gentle personality
• Obsessive attachment to objects
• Comprehension of speech is better than their ability to express or communicate[2]

Evaluation

Antenatally 

Cri du chat is diagnosable via amniocentesis during the antenatal period, where the deletion of chromosome 5 is visible. The structural abnormalities are observable sonographically. Also, fetuses who show mosaicism may display fetoplacental and feto-amniotic chromosomal abnormalities along with microcephaly and cerebellar hypoplasia.[3][4][5][6]

Postnatally

A diagnosis can be made based on clinical findings. The occurrence of specific characteristic findings such as microcephaly, low birth weight, moon face, muscle hypotonia, and a cat-like cry together should raise clinical suspicion of the condition. Sometimes, this can be difficult because the features may not be obvious as patients show a cytogenetic variation leading to phenotypic variation. The clinical features, as well as the severity and prognosis, can be determined by the size and position of the deletion. If clinical suspicion is present, a karyotype analysis is 1 of the first tests to confirm the diagnosis. However, in cases where the clinical suspicion is high in the presence of a normal karyotype, further specific tests can be carried out, such as fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), or quantitative polymerase chain reaction (PCR). FISH has improved the diagnosis of genetic disorders caused by chromosome deletion and provided a phenotypic map and an individual's genome. Newer techniques, such as CGH, have opened new doors by including the whole genome and the associated markers, which can identify genetic alterations. There have been very few studies on the findings of MRI. However, pontine hypoplasia seems to be the most common feature. This presentation is associated with other findings, such as cerebellar hypoplasia, microcephaly, and corpus callosum anomalies. Supratentorial abnormalities also have been observed.[2][7]

Treatment / Management

Due to the early onset of cerebral damage during embryonal development, there is no specific treatment for patients. However, patients benefit from rehabilitation, especially with early intervention. This approach has been demonstrated to improve prognosis and social adaptation. During the neonatal period, physical therapy should be started in the first week of life to help with any difficulty in swallowing and suction. Breastfeeding is still possible, and intensive care is rarely necessary.[8][1][9] Physical therapy, psychomotricity, and speech therapy are suggested interventions for psychomotor and speech retardation. Patients often have sensorineural deafness; therefore, audiometric examinations should occur in all children. Other helpful treatments include surgery, a special diet, and healthy routines. Families should be involved in the patient's care and receive information about the disease and available support groups. Genetic counseling services should be offered for subsequent pregnancies.[3][10](A1)

Differential Diagnosis

The differential diagnosis of cri du chat syndrome includes the following:

• Multiple congenital anomalies
• Other autosomal monosomy or trisomy syndromes
• Mental retardation syndromes
• Patau syndrome
• Wolf-Hirschhorn syndrome

Prognosis

Morbidity and mortality rates decrease after the first few years of life. Reportedly, 75% of deaths occur during the first month of life, and about 90% of deaths occur during the first year. It is important to note that the type, size, and location of the deletion(s) significantly influence the prognosis. An early diagnosis is 1 of the most important factors in the prognosis of the disease. Early diagnosis allows for implementing therapeutic measures early on to improve physical and psychomotor development outcomes and help with social adaptation.[2]

Complications

The complications that can manifest with cri du chat syndrome are as follows:

• Heart or other organ defects
• Scoliosis
• Poor muscle tone
• Hearing or visual difficulties
• Intellectual disabilities