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Synonyms: CdCS, 5p deletion syndrome, 5p minus syndrome, Lejeune's syndrome, cat cry syndrome
This is a congenital anomaly caused by partial deletion of the short arm of chromosome 5 (5p-) The affected infant makes a characteristic high-pitched mewing cry like a cat, and associated features include growth failure, other congenital abnormalities and general learning disability. Clinical severity appears related to the size of the deletion.
- The incidence is said to be between 1 in 15,000 to 50,000 live births.
- There is a slight female preponderance with a ratio of about 4:3.
- It accounts for between 0.15% and 1% of patients with severe learning difficulties.
- 80% of cases appear to be de novo mutations but approximately 15% have a parent with a balanced rearrangement. The remainder are due to rare cytogenetic aberrations, eg mosaicism.
Because of variation in the size of the deletion, there can be considerable variation in the condition.
The most common presenting signs in infancy are:
- A high-pitched cry like a cat, giving the syndrome its name. Genetic studies have confirmed that this characteristic cry results from the deletion at 5p15. Duration of the cry is controversial but it tends to disappear with time and about a third have lost it by the second birthday. Whilst the cry is very common in cri du chat syndrome, it cannot be said to be pathognomonic because it can be observed in some other neurological disorders and, in rare cri du chat cases, presentation is with a persistent inspiratory stridor instead.
- Low birthweight (<20%) and slow growth
- Feeding difficulties (poor suck, dysphagia, muscle hypotonia, gastro-oesophageal reflux).
Other typical features include:
- Downward slant to the eyes (palpebral fissures).
- Low-set ears that may be malformed.
- Skin tags just in front of the ear.
- Partial webbing or fusing of fingers or toes (syndactyly).
- Simian crease (single palmar crease).
A number of other less distinctive features are also often found:
- Inguinal hernia.
- Diastasis recti (separation of rectus abdominis).
- Prominent epicanthal folds.
- Incompletely or abnormally folded external ears.
- Cardiac abnormalities including ventricular septal defect, atrial septal defect, patent ductus arteriosus and Fallot's tetralogy.
- Thymic dysplasia.
- Malrotation of the gut.
Over childhood and adolescence, emergent features of the syndrome include:
- General learning disability.
- Developmental delay.
- Premature greying of the hair.
- Dropped-jaw, open-mouth expression secondary to facial laxity.
- Malocclusion of the teeth.
- Short metacarpi and metatarsi resulting in small hands and feet.
Children with cri du chat syndrome are generally described as having a gentle and affectionate personality but a number of abnormalities of behaviour have been described which may present in variable amounts:
- Hyperactivity (approximately 50%)
- Stereotypical behaviour and self-injury
- Repetitive movements
- Hypersensitivity to sound
- Obsessive attachments to objects
The single palmar crease is seen more often in Down's syndrome.
Conventional and high-resolution cytogenetics look for a missing portion of the short arm of chromosome 5. Fluorescence in situ hybridisation (FISH) is used where the chromosomes appear normal and can reveal very small deletions, and is used to confirm 5p abnormalities.
Whilst the mewing cry usually prompts chromosome analysis, the diagnosis is sometimes delayed. A large study from Italy found that the diagnosis was made in the first month of life in 42% and within the first year in 82% of cases. The remaining 18% were diagnosed at an age ranging from 13 months to 47 years.
Other investigations will be arranged as appropriate and may include:
- Skeletal X-ray studies looking at facial, cranial base and digit abnormalities.
- MRI scan, looking for brainstem or cerebellar abnormalities.
- Echocardiogram to assess cardiac malformations.
- Speech and language therapy assessment of swallow and expressive and receptive language.
- Comprehensive developmental assessment.
- Good support for the family, from diagnosis. Consider the family's information needs and access to support groups and other families affected by the disorder. As the child grows, families often feel that the most difficult problem is the child's maladaptive behaviour and they may need support managing this.
- Impaired growth is common in cri du chat syndrome from birth, usually related to feeding problems. Breast-feeding is possible but specialist support may be required. Growth and nutrition should be monitored to ensure that growth is not hindered by undernutrition. Sometimes a gastrostomy is performed in infancy to protect the airway where there are major feeding difficulties.
- The routine schedule of childhood immunisation is advised.
- Early rehabilitation (physiotherapy, speech and language therapy, and occupational therapy) in close collaboration with the family, is recommended for psychomotor and speech retardation. As some patients have sensorineural deafness, audiometry should be carried out on all affected children. Receptive language is often better than expressive language, and sign language has been widely used with these children.
- Corrective surgeries may be required, eg for congenital heart defects, strabismus or undescended testes. There are potential anaesthetic risks related to intubation (due to underlying larynx and epiglottis malformations), cardiac malformations and hypotonia but most older patients with cri du chat syndrome undergo general anaesthesia without complications.
A large multidisciplinary team may be involved with a child with cri du chat syndrome, including geneticists, community paediatricians, paediatric cardiologists and neurologists, dentists, paediatric surgeons and anaesthetists, speech and language therapists, physiotherapists, occupational therapists, social workers, psychologists, special education teachers and support workers. The management of transition to adult services is also important.
Pneumonia, including aspiration pneumonia, congenital heart defects, and respiratory distress syndrome are the most common causes of death.
The majority of cases have good survival expectations (in an Italian study, the oldest patient was aged 61 years) although about 10% of cases die in the first year of life. Disability is quite variable but the identification of phenotypic subsets associated with a specific size and type of deletion is being increasingly used to aid prognosis.
Improvements in supporting these children, both educationally and in terms of rehabilitation, have allowed better psychomotor development, social adaption and improved autonomy. Although many cri du chat syndrome children have a range of severe developmental delays, they can achieve many social skills in childhood and continue to learn, with older children usually able to walk, to communicate with words or through gestures and able to be independent in a range of self-care skills.
Most cases are spontaneous mutations, so risk of recurrence is extremely low - 1% or less. Rare recurrences when parents have normal chromosomes are most likely the result of gonadal mosaicism in one of the parents.
If a parent is a balanced carrier of a structural rearrangement, the risk of recurrence is substantial. Risk should be assessed based on the type of structural rearrangement and its pattern of segregation. Where there is a balanced familial translocation, the risk of transmission is 8.7-18.8%.
Female patients are fertile and can deliver viable offspring, with an estimated risk of recurrence of 50%.
Following the birth of an affected child, prenatal diagnosis can be offered for future pregnancies. Prenatal diagnosis of de novo 5p deletions is not common but opportunities for identification prenatally include:
- Ultrasound-detected structural abnormalities, eg bilateral ventriculomegaly, fetal choroid cysts, microcephaly with cerebellar hypoplasia, agenesis of the corpus callosum.
- Abnormal maternal serum test.
- Fetal chromosomal analysis.
It should be noted that not all 5p deletions result in the cri-du-chat phenotype and some may result in a very mildly abnormal or normal phenotype.
Jérome Jean Louis Marie Lejeune was a French paediatrician who was born in 1926 and died in 1994. He confirmed the theory of Petrus Waardenburg, from 1932, that Down's syndrome might be the consequence of a chromosomal aberration. He identified the extra chromosome in 1958. Down's syndrome was the first chromosomal disorder to be identified positively. He described cri du chat syndrome in 1963 although it was later before the chromosomal origin was identified.
Further reading & references
- Chen H; Cri-du-chat Syndrome, eMedicine, May 2009
- Mainardi PC, Perfumo C, Cali A, et al; Clinical and molecular characterisation of 80 patients with 5p deletion: J Med Genet. 2001 Mar;38(3):151-8.
- Rodriguez-Caballero A, Torres-Lagares D, Rodriguez-Perez A, et al; Cri du chat syndrome: a critical review. Med Oral Patol Oral Cir Bucal. 2010 May 1;15(3):e473-8.
- Mainardi PC, Pastore G, Castronovo C, et al; The natural history of Cri du Chat Syndrome. A report from the Italian Register. Eur J Med Genet. 2006 September - October;49(5):363-383. Epub 2006 Jan 13.
- Cri-Du-Chat Syndrome, Online Mendelian Inheritance in Man (OMIM)
- Cerruti Mainardi P; Cri du Chat syndrome. Orphanet J Rare Dis. 2006 Sep 5;1:33.
- Wolf-Hirschorn Syndrome, Online Mendelian Inheritance in Man (OMIM)
- Collins MS, Eaton-Evans J; Growth study of cri du chat syndrome. Arch Dis Child. 2001 Oct;85(4):337-8.
- Kristoffersen KE; Speech and language development in cri du chat syndrome: a critical review. Clin Linguist Phon. 2008 Jun;22(6):443-57.
- Erlenkamp S, Kristoffersen KE; Sign communication in Cri du chat syndrome. J Commun Disord. 2010 May-Jun;43(3):225-51. Epub 2010 Mar 27.
- Martinez JE, Tuck-Muller CM, Superneau D, et al; Fertility and the cri du chat syndrome. Clin Genet. 1993 Apr;43(4):212-4.
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Dr Huw Thomas
Dr Chloe Borton