256 Cri-du-chat syndrome is a chromosome 5p deletion syn- drome first describe by Lejeune et al. in 1963. The incidence is estimated to be approximately 1 in 15,000–50,000 births. The prevalence among mentally retarded individuals is approxi- mately 1.5 in 1000.
GENETICS/BASIC DEFECTS
1. Cause
a. Caused by deletion of short arm of chromosome 5 (5p15.2–15.3)
i. De novo deletion (80%): paternally derived dele- tions in 80% of cases
ii. Familial rearrangement (12%) iii. Mosaicism (3%)
iv. Rings (2.4%)
v. De novo translocation (3%)
b. A high-resolution physical and transcription map generated a 3.5-Mb region of 5p15.2 that is associated with the Cri du chat syndrome region
2. Genotype–phenotype correlation
a. Deletion of 5p15.3 results in a cat-like cry and speech delay
b. Deletion of 5p15.2 results in the distinct facial fea- tures associated with the syndrome as well as the severe mental and developmental delay
3. Hemizygosity of δ-catenin (CTNND2, mapped to 5p15.2), reported to be associated with severe mental retardation in cri-du-chat syndrome
4. Deletion of the telomerase reverse transcriptase (TERT) gene (mapped at 5p15.33) and haploinsufficiency of telomere maintenance is probably a genetic element contributing to the phenotypic changes in cri-du-chat syn- drome
CLINICAL FEATURES
1. Characteristic mewing cry
a. A high-pitched monochromatic cry with subtle dys- morphism and neonatal complications: commonly observed in infants with this syndrome
b. Observed in many infants with Cri-du-chat syndrome c. Not associated with other aneuploidies
d. Usually considered diagnostic
e. Loss of the characteristic cry by age 2 years in one third of children
2. Clinical findings during infancy a. Low birth weight
b. Hypotonia c. Microcephaly
d. Poor sucking/swallowing difficulties e. Need for incubator care
f. Respiratory distress
g. Jaundice h. Pneumonia
i. Dehydration
j. Failure to thrive/growth retardation k. Early ear infections
l. Severe cognitive, speech and motor delays m. Facial features
i. Round face with full cheek ii. Hypertelorism
iii. Epicanthal folds
iv. Down-slanting palpebral fissures v. Strabismus
vi. Flat nasal bridge vii. Down-turned mouth viii. Micrognathia
ix. Low-set ears n. Cardiac defects
i. VSD ii. ASD iii. PDA
iv. Tetralogy of Fallot o. Short fingers
p. Single palmar creases q. Less frequent features
i. Cleft lip and palate
ii. Preauricular tags and fistulas iii. Thymic dysplasia
iv. Gut malrotation v. Megacolon vi. Inguinal hernia vii. Dislocated hips viii. Cryptorchidism
ix. Hypospadias
x. Rare renal malformations a) Horseshoe kidneys b) Renal ectopia or agenesis c) Hydronephrosis
xi. Clinodactyly of the fifth fingers xii. Talipes equinovarus
xiii. Pes planus
xiv. Syndactyly of the second and third fingers and toes xv. Oligosyndactyly
xvi. Hyperextensible joints 3. Clinical findings in childhood
a. Severe mental retardation b. Developmental delay c. Microcephaly d. Hypertonicity
e. Premature graying of the hair
f. Small, narrow and often asymmetric face g. Dropped-jaw
h. Open-mouth expression secondary to facial laxity
i. Short philtrum
j. Malocclusion of the teeth k. Scoliosis
l. Short third-fifth metacarpals m. Chronic medical problems
i. Upper respiratory tract infections ii. Otitis media
iii. Severe constipation iv. Hyperactivity
4. Clinical findings in late childhood and adolescence a. Coarsening of facial features
b. Prominent supraorbital ridges c. Deep-set eyes
d. Hypoplastic nasal bridge
e. Affected females reaching puberty and developing secondary sex characteristics and menstruate at the usual time
f. Small testis and normal spermatogenesis in males 5. Dermatoglyphics
a. Transverse flexion creases b. Distal axial triradius
c. Increased whorls and arches on digits 6. Behavioral profile
a. Hyperactivity b. Aggression c. Tantrums
d. Stereotypic and self-injurious behavior e. Repetitive movements
f. Hypersensitivity to sound g. Clumsiness
h. Obsessive attachments to objects
i. Able to communicate needs and interact socially with others
j. Autistic-like features and social withdrawal: more characteristic of individuals who have a 5p deletion as the result of an unbalanced segregation of a parental translocation
7. Prognosis
a. Ability of many children to develop some language and motor skills
b. Ability of these children to attain developmental and social skills observed in 5- to 6-year-old children, although their linguistic abilities are seldom as advanced
c. Older, home-reared children i. Usually ambulatory
ii. Able to communicate verbally or through gestural sign language
iii. Independent in self-care skills.
DIAGNOSTIC INVESTIGATIONS
1. Conventional cytogenetic studies. The size of the 5p dele- tion may vary from the entire short arm to only 5p15. A small deletion of 5p may be missed by a conventional cytogenetic technique
2. High-resolution cytogenetic studies are required for a smaller 5p deletion
3. Molecular cytogenetic studies using fluorescent in situ hybridization (FISH)
a. Allow the diagnosis to be made in the patients with very small deletions
b. Use genetic markers that have been precisely local- ized to the area of interest
c. The absence of a fluorescent signal from either the maternal or paternal chromosome 5p regions: indica- tive of monosomy for that chromosomal region 4. Skeletal radiographs
a. Microcephaly b. Retromicrognathia
c. Cranial base malformations i. Reduced cranial base angle ii. Malformed sella turcica and clivus
d. Disproportionately short third, fourth, and fifth metacarpals and disproportionately long second, third, fourth, and fifth proximal phalanges (frequent) 5. Echocardiography to rule out structural cardiac malfor-
mations
6. MRI of the brain
a. Atrophic brainstem, middle cerebellar peduncles and cerebellar white matter
b. Possible hypoplasia of cerebellar vermis with enlargement of the cisterna magna and 4th ventricle 7. Swallowing study for feeding difficulty
8. Comprehensive evaluation for receptive and expressive language. Most children have better receptive language than expressive language
9. Developmental testing and referral to early intervention and appropriate school placement
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Recurrence risk for a de novo case is 1% or less ii. Rare recurrences in chromosomally normal par- ents: most likely the result of gonadal mosaicism for the 5p deletion in one of the parents
iii. The risk is substantially high if a parent is a bal- anced carrier of a structural rearrangement. Risk should be assessed based on the type of structural rearrangement and its pattern of segregation b. Patient’s offspring: female patients are fertile and can
deliver viable affected offspring, with an estimated recurrence risk of 50%
2. Prenatal diagnosis by amniocentesis, CVS, and PUBS for chromosome analysis to detect 5p deletion
3. Management
a. Supportive care. No treatment exists for the underly- ing disorder
b. Appropriate treatment for chronic medical problems i. Upper respiratory tract infections
ii. Otitis media iii. Severe constipation
c. Using the relatively good receptive skills to encour- age language and communicative development rather than relying on traditional verbal methods
d. Early intervention programs i. Physical therapy ii. Occupational therapy iii. Speech therapy
e. Introduction to sign language, an effective means of developing communication skills (50% of children are able to use sign language to communicate) f. Behavior modification programs to successfully man-
aging hyperactivity, short attention span, low thresh- old for frustration, and self-stimulatory behaviors (eg, head-banging, hand-waving)
g. Surgical interventions
i. Correction of congenital heart defects if indicated ii. Medical problems involving minor malforma-
tions such as strabismus and clubfoot
iii. Gastrostomy in infancy to protect airway of patients with major feeding difficulties
iv. Orchiopexy for undescended testes v. Issues important to anesthetic plan
a) Anatomical abnormalities of the airway b) Congenital heart disease
c) Hypotonia d) Mental retardation e) Temperature maintenance
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Fig. 1. Two infants with cri-du-chat syndrome. Note a round face with full cheeks, hypertelorism, epicanthal folds, and apparently low-set ears.
Fig. 2. Cri-du-chat syndrome in an older child and a teenager show- ing a long and narrow face.
Fig. 3. G-banded karyotypes with 5p deletion in two children with cri-du-chat syndrome.
Fig. 4. FISH of an interphase cell and a metaphase spread with two orange signals (LSI SpectrumOrange, D5S721) and one green signal (LSI SpectrumGreen, D5S23 chromosome 5p15.2-specific probe) indicating deletion of 5p15.2.
