Cri-du-chat Syndrome Clinical Presentation

The following may be noted in the history of patients with cri-du-chat syndrome:

• Characteristic cry

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

  • Many infants with cri-du-chat syndrome have this distinctive cry, but it is not associated with other aneuploidies.

  • About one third of children no longer exhibit the catlike cry by age 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 affected individuals 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 due to 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.

  • Cornish and Pigram consider an auditory behavioral phenotype, hyperacusis, as a characteristic trait. ^[12] Hyperacusis is a condition characterized by a hypersensitivity to sound, which causes auditory discomfort, and is reported to be one of the main characteristics of the syndrome.

  • Auditory neuropathy or neural dys-synchrony may be another phenotype of the condition possibly related to abnormal expression of the protein β -catenin mapped to 5p. ^[13]

Neonatal period

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• Newborns have a 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 the following:

  • Low birth weight

  • Hypotonia

  • Microcephaly

  • Growth retardation

  • 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

  • Cardiac defects (eg, ventricular septal defect, atrial septal defect, patent ductus arteriosus, tetralogy of Fallot)

• Less common findings include the following:

  • 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

  • Hyperextensible joints

Childhood

See the list below:

• Findings include the following:

  • Severe mental retardation

  • Developmental delay

  • Microcephaly

  • Hypertonicity

  • Premature graying of the hair

  • Small, narrow, and often asymmetrical face

  • Dropped-jaw, open-mouth expression secondary to facial laxity

  • Short philtrum

  • Malocclusion of the teeth

  • Scoliosis

  • Short third-fifth metacarpals

• Children with cri-du-chat syndrome also have chronic medical problems such as upper respiratory tract infections, otitis media, severe constipation, and hyperactivity.

Late childhood and adolescence

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• 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, the testes are often small, but spermatogenesis is thought to be normal.

Dermatoglyphics

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• Transverse flexion creases

• Distal axial triradius

• Increased whorls and arches on digits

See the list below:

• Niebuhr, from a review of 331 published cases, estimated that most cri-du-chat syndrome cases are the result of de novo deletions (about 80%), some derive from a familial rearrangement (12%), and only a few show other rare cytogenetic aberrations, such as mosaicism (3%), rings (2.4%), and de novo translocations (3%). ^[14]

• Most cases (80-85%) are due to sporadic de novo deletion of 5p (15.3 → 15.2). ^[15]

• Approximately 10-15% of cases result from the unequal segregation of a parental balanced translocation in which 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 patients have other rare cytogenetic aberrations (eg, interstitial deletions, mosaicisms, rings and de novo translocations).

• Approximately 1-2% of cases have recombinations that involve a pericentric inversion in one of the parents.

• The occurrence of mosaicism is a very rare finding, with frequency estimated at about 3% of patients. Chromosomal mosaicism has been described and involves a cell line with a 5p deletion and a cell line with a normal karyotype ^[16] or a 5p deletion with rearranged cell lines. ^[17]

  G-banded karyotype [46,XX,del(5)(p13)].

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  G-banded karyotype of a carrier father [46,XY,t(5;17)(p13.3;p13)].

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• A mechanism that involves dicentric chromosome formation with subsequent breakage and telomere healing during meiosis was recently proposed to explain the rare cases in which a parental paracentric inversion likely results in a viable terminal deletion.

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

• Loss of a small region in band 5p15.2 (cri-du-chat critical region) correlates with all clinical features of the syndrome except for 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) has provided the following findings:

  • The region associated with the cry was localized to 1.5 Mb in distal band 5p15.31, between bacterial artificial chromosomes (BACs) that contain markers D5S2054 and D5S676.

  • The region associated with the speech delay was localized to 3.2 Mb in band 5p15.32-15.33, between BACs that contain markers D5S417 and D5S635.

  • The region associated with the facial dysmorphology was localized to 2.4 Mb in band 5p15.2-15.31, between BACs that contain markers D5S208 and D5S2887.