Cri Du Chat Syndrome

Etiology

Cri du Chat results from either a partial or complete deletion of the short arm of chromosome 5. Most deletions occur de novo. Deletions usually arise as spontaneous chromosomal events during gametogenesis or early embryogenesis. Around 80% to 90% are paternal in origin, which can arise from 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% result from interstitial deletions. Mosaicism, inversions, and ring chromosomes are less common mechanisms.[2]

Epidemiology

Although Cri du Chat is considered rare, this syndrome is one 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 worldwide incidence and prevalence, and those among races, have not been established. Similarly, specific risk factors associated with prenatal events or parental age are unclear. However, occasional reports of parental exposure to radiation, hyperemesis, anorexia, and toxemia are documented.[4]

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, leading to the 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 identified 2 regions: 5p15.3, responsible for the characteristic cry, and 5p15.2, responsible for other significant clinical findings, eg, developmental and craniofacial manifestations. Similarly, other areas have been identified for additional features, eg, 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 the following:

• 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.[4][5]

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 and is also seen in 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.[4]

General Characteristics of Cri Du Chat Syndrome

Craniofacial malformations

Characteristic craniofacial malformations include:

• 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 seen clinical features include:

• 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

Other anomalies

Other anomalies that may also be present include:

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

Orofacial abnormalities

Characteristic orofacial abnormalities include:

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

Developmental and behavioral manifestations

Common developmental and behavioral manifestations that may be present include:

• 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

Prenatal Screening and Diagnostic Evaluation

As most cases occur de novo in the absence of specific risk factors, prenatal diagnosis is often limited. Nevertheless, advances in prenatal genetic testing have improved opportunities for earlier detection.

Noninvasive testing

Expanded cell-free DNA screening (noninvasive prenatal testing, NIPT) may detect selected chromosomal copy-number abnormalities, including 5p deletions associated with Cri du Chat syndrome. Sensitivity and positive predictive value vary across studies and population prevalence; still, 2 studies have reported a positive predictive value of 50% for Cri du Chat. Therefore, positive screening results require confirmatory invasive testing.

Conversely, a negative test may yield a more definitive result, with a negative predictive value of 100% reported. In any case, this figure may vary depending on the specific population's genetic pool. In addition to conventional cytogenetics and comparative genomic hybridization, analysis of fetal DNA in maternal blood is a recent method for identifying deletions.

Ultrasound imaging

Studies report that structural abnormalities may be seen on anatomical scans, often involving multiple systems. At least 1 abnormal finding has been reported in around 87% of cases, while 13% show no abnormal features. The most common ultrasound findings noted are cerebellar hypoplasia, cardiac abnormalities (commonly ventricular septal defects), hydrops fetalis, ventriculomegaly, chorioid plexus cyst, and nasal bone hypoplasia. An increase in the nuchal translucency is also seen. A combination of these features should warrant chromosomal studies. Additionally, fetuses who show mosaicism may display fetoplacental and feto-amniotic chromosomal abnormalities along with microcephaly and cerebellar hypoplasia.

Invasive testing

Cri du chat is diagnosable via amniocentesis during the antenatal period, in which a deletion of chromosome 5 is visible. In addition to conventional cytogenetics, chromosomal microarray analysis is widely used because it more precisely defines deletion size and breakpoint regions and detects additional copy-number abnormalities. FISH or conventional cytogenetics identifies parental chromosomal abnormalities in approximately 10% of cases.[4][6][7][8][9][10][11]

Postnatal Diagnostic Evaluation

A diagnosis can be made based on clinical findings. The combined presence of specific characteristic findings, eg, microcephaly, low birth weight, moon facies, muscle hypotonia, and a cat-like cry, should raise clinical suspicion for the condition. Sometimes, this can be difficult because the features may not be obvious, as patients exhibit cytogenetic variation that leads to phenotypic variation. The size and position of the deletion can determine the clinical features, severity, and prognosis.

If clinical suspicion is present, a karyotype analysis is one of the first tests to confirm the diagnosis. However, in cases with high clinical suspicion but a normal karyotype, additional specific tests can be performed, eg, fluorescence in situ hybridization (FISH), comparative genomic hybridization, or quantitative polymerase chain reaction (PCR). FISH has improved the diagnosis of genetic disorders caused by chromosome deletions and provides a genotype–phenotype map by analyzing each affected individual’s genome.

Newer techniques, eg, comparative genomic hybridization, have opened new doors by enabling analysis of the whole genome and associated markers to identify genetic alterations. Very few studies have examined MRI findings; however, pontine hypoplasia appears to be the most common feature. This presentation is associated with other findings, eg, cerebellar hypoplasia, microcephaly, and corpus callosum anomalies. Supratentorial abnormalities have also been observed.[2][12]

Treatment / Management

Cri du Chat syndrome has no disease-specific curative therapy; management is supportive, interprofessional, and tailored to the individual's clinical manifestations. Early intervention is strongly recommended, as timely rehabilitation has been associated with improved developmental progress, functional ability, and social adaptation.[7]

Neonatal and Infant Care

During the neonatal period, assessment for feeding difficulties, poor suck, impaired swallowing, and hypotonia is important. Infants may benefit from early physiotherapy and speech-language input to support feeding, while intensive neonatal care is only occasionally required. Breastfeeding may still be possible with appropriate support.[7][13][1][14](A1)

Rehabilitation and Developmental Support

Ongoing rehabilitation commonly includes physiotherapy, occupational therapy, psychomotor therapy, and speech and language therapy to address motor delay, communication difficulties, and functional independence. Because expressive language impairment may be significant, augmentative and alternative communication methods, eg, gesture systems, sign-supported communication, or visual aids, should be considered when appropriate to improve nonverbal communication.[7][15] 

Speech and language therapy has been shown to improve speech clarity and articulation in children with Cri du Chat.[15] The reported benefits of physiotherapy include earlier or more reliable achievement of motor developmental milestones, improved postural control and gait stability, and better social participation and performance of activities of daily living; however, most of this evidence comes from case reports or small cohorts, which limits the strength of recommendations.[16][4][17](B3)

Medical Surveillance and Associated Conditions

Regular surveillance for associated comorbidities is advised. Audiological assessment should be undertaken in all children because sensorineural hearing loss may occur. Additional review may include ophthalmology, cardiology, orthopedics, dental care, and nutritional assessment, depending on symptoms. Surgical intervention may be required for congenital cardiac defects, strabismus, scoliosis, or other correctable anomalies.[7]

Behavioral and Psychological Support

Behavioral and psychological support may be beneficial for patients with hyperactivity, anxiety, sleep disturbance, or repetitive behaviors. Educational support, including individualized learning plans and structured environments, can help maximize developmental potential.[7]

Family Support and Genetic Counseling

Families should be actively involved in care planning and offered information regarding the condition, available community resources, and patient support organizations. Genetic counseling is recommended, particularly when a parental chromosomal rearrangement is suspected or for future pregnancy planning.[7][4][18](B3)

Differential Diagnosis

The differential diagnosis of Cri du Chat syndrome includes the following:

• Wolf-Hirschhorn syndrome: A close chromosomal mimic, as Wolf-Hirschhorn syndrome is caused by the deletion of the short arm of chromosome 4. This condition overlaps with features seen in Cri du Chat, including growth delay, hypotonia, feeding issues, microcephaly, and distinctive facial dysmorphisms.[19]

• 1p36 deletion syndrome: This disorder should be considered a differential when features, eg, hypotonia, facial dysmorphism, severe developmental delay, and microcephaly are present. This syndrome is characterized by deep-set eyes, hearing loss, straight eyebrows, and structural brain abnormalities.[20]

• Distal 9p deletion syndrome/monosomy 9p: This disorder has overlapping features with Cri du Chat syndrome, namely microcephaly, hypotonia, intellectual delay; however, distal 9p deletion syndrome/monosomy 9p can be distinguished from Cri du Chat syndrome by the presence of a long philtrum, trigonocephaly, and higher incidences of genital anomalies.[21]

• Cornelia de Lange syndrome (CdLs): This syndrome has features similar to Cri du Chat, including microcephaly, feeding difficulties, facial dysmorphism, and severe speech and developmental impairment; however, unlike Cri du Chat, CdLs can be distinguished by hypertrichosis, digital anomalies, or upper limb reduction defects, and severe reflux.[22]

• Bohring-Opitz syndrome: This syndrome is rare but can mimic Cri du Chat as they present with microcephaly, feeding difficulties, and severe developmental delay. However, characteristic features of flexed elbows and wrists with ulnar deviation, recurrent vomiting, facial naevus, and early infections are noted, which are inconsistent with the diagnosis of Cri du Chat.[23]

• Smith-Lemli-Opitz syndrome: This disorder is an important metabolic/genetic exclusion as it overlaps with growth restriction, microcephaly, moderate-to-severe intellectual disability, hypotonia, and facial dysmorphism. Smith-Lemli-Opitz syndrome is characterized by 2- to 3-toe syndactyly, postaxial polydactyly, genital anomalies in males, and abnormal sterol biochemistry.[24]

Prognosis

Morbidity and mortality rates tend to decrease after the first few years of life. Historically, studies report that 75% of deaths occur during the first month of life, and about 90% of deaths occur during the first year. Notably, the type, size, and location of the deletions significantly influence the prognosis. An early diagnosis is one of the most important factors in the prognosis of the disease. Early diagnosis enables the implementation of therapeutic measures to improve physical and psychomotor development outcomes and support social adaptation.[2]

Complications

Individuals with Cri du Chat may experience multisystem complications that vary depending on the size and location of the deletion. Early recognition and interprofessional intervention can reduce functional complications and improve quality of life. Complications can include:

• Neurodevelopmental: Hypotonia in infancy can contribute to delayed motor milestones.
• Growth and feeding: Failure to thrive, poor weight gain, and dehydration can result from feeding difficulties secondary to hypotonia and poor suck/swallow functions.
• Infections: Recurrent respiratory infections can result from hypotonia, ineffective airway clearance, and structural abnormalities. These remain an important cause for morbidity in infancy.
• Cardiovascular: Congenital abnormalities, eg, ventricular septal defects, may increase morbidity and mortality if not identified early.
• Musculoskeletal: Hypotonia can affect mobility, gait, and posture. 

Mortality is highest in early childhood and is usually associated with severe congenital malformations, particularly cardiac disease, or serious respiratory complications. Many individuals survive into adulthood with appropriate supportive care.[2]