Article

Cri du Chat Syndrome: Causes, Symptoms, Diagnosis and Treatment
February 05, 201901,289

What is Cri du Chat Syndrome?

Cri du Chat Syndrome is a genetic disorder caused by the deletion of part of the short (p) arm of chromosome 5.1-6

The name of this syndrome is French and means “cry of the cat”. This refers to the characteristic cry of many babies with Cri du Chat. The cry is high-pitched and one-toned, similar to that of a mewling cat.1-7

Since not all babies born with deletions in their 5p chromosomes have this cat-like cry, doctors also refer to the disorder as “5p deletion syndrome” or “5p minus syndrome”.1,7,8

 

How common is Cri du Chat?

Cri du Chat is one of the most common deletion syndromes. Epidemiologists estimate that between 1 in 15,000 and 1 in 50,000 babies born have Cri du Chat.1,2,7,8

 

Where do 5p deletions come from?

There are two different ways that a baby can end up with a 5p deletion.

Inherited 5p deletions

Some children inherit a shortened chromosome 5 from one of their parents.1,2,7

The shortened chromosome can come from either parent and be given to both girls and boys.

If one parent has a shortened chromosome 5, there is a 50 percent chance that a child will inherit it.

Spontaneous 5p deletions

The majority of 5p deletions are not inherited. In most cases of Cri du Chat, neither of the baby’s parents have a 5p deletion to pass on.1

This means that the 5p deletion developed either during the production of the egg or sperm that became the baby, or shortly after fertilization.1

There are several different ways part of a chromosome can be deleted. All of them start with the DNA being broken.9

DNA can be broken by exposure to toxins, radiation, free radicals or a mistake during cell division.10-12

Usually, when DNA gets broken, cells can put it back together. Sometimes, the cell fails to fix it, or fixes it incorrectly, leading to missing pieces or other mutations.9 Some of these failures and mistakes lead to chromosomal abnormalities, such as:

Deletions: one chromosome breaks and the piece (or part of the piece) that

     should be re-attached gets lost before it can be fixed

Translocations: pieces broken off two different chromosomes get switched

Inversions: one chromosome breaks twice and the middle piece gets flipped

around backwards

Ring chromosomes: one chromosome breaks in two places and the broken ends fuse

together to create a circle; the broken piece gets lost

 

Figure 1: Diagram of common chromosome abnormalities.
Includes diagram of a chromosomal deletion, which cause most cases of Cri du Chat (Shutterstock/Meletios)

 

DNA abnormalities in Cri du Chat

Chromosomal Structure Abnormalities

Between 80 and 90 percent of 5p abnormalities in individuals with Cri du Chat are deletions on the end of the short arm of chromosome 5.1,2,7

Around 3 to 5 percent are deletions in the middle of the short arm of chromosome 5.1,2

Less than 1 percent show inversions or ring chromosomes.1

Size of Abnormality

The amount of DNA that is missing differs between individual cases of Cri du Chat.

Some individuals are missing 560 thousand base pairs. Others can be missing up to 33 million. Scientists think that deletions of more than about 33 million base pairs are incompatible with life.1

 

What causes the symptoms of Cri du Chat Syndrome?

The symptoms of Cri du Chat Syndrome come from the missing genes located in the deleted DNA.1

These genes cannot be used to make proteins cells need to function properly. This causes the visible symptoms of the syndrome.1

The symptoms of each person with Cri du Chat depend on how many genes are missing and exactly which genes these are.1

 

Cri du Chat Syndrome Symptoms

Depending on the size and location of the 5p deletion, the symptoms of Cri du Chat Syndrome can range from non-existent to life-threatening.1 Naturally, most cases are somewhere in the middle.

Common symptoms of Cri du Chat include:

  • very low birth weight and size1,2
  • growth deficiency1
  • high-pitched, cat-like cry: caused by changes in development of the vocal  chords/throat and changes in nerve signaling1,2,4,6,7
  • unique facial structure: small head, round face, wide-set eyes, wide nose, down-turned mouth, low set ears, over or under-bite, early grey hair1-4,6,7
  • poor vision: crossed-eyes, cataracts, short-sightedness1,2,7
  • spinal abnormalities: short neck, scoliosis1
  • hearing abnormalities: hearing loss, regular ear infections, or over-sensitivity to sound1,2
  • developmental delays: speech delays, delays in crawling and walking, social delays1,2,4,6-8
  • behavioral abnormalities: attention deficit disorder, autistic behaviors, stubbornness, aggression, overly-friendliness, self-harming  behavior1,2,4,8,13
  • brain abnormalities: changes in brain stem or cortex, changes in nerve cell structure1,2,5
  • organ abnormalities: changes in heart, kidney, lung, muscles, intestinal tract, genitals or bladder1,2,6,7

Many of the symptoms seen in individuals with Cri du Chat may be caused or made worse by one another.1,2

Some examples include:

  • delays in speech may be made worse by hearing loss1
  • sensitivity to sound may cause anger or stress, which may trigger aggressive or self-harming behavior1
  • intestinal abnormalities and muscle weakness may decrease a baby’s ability to eat, increasing delays in growth and development2

The interactions between symptoms are likely part of the reason why early diagnosis and treatment can improve the prognosis of babies born with Cri du Chat.1,14

 

Figure 2: Facial features of a patient with Cri du Chat Syndrome.
Note the wide-set eyes, wide nose, over-bite and down-turned mouth.
Clinical features of a patient with Cri du Chat syndrome at age of 8 months (A), 2 years (B), 4 years (C) and 9 years 6/12 (D)
by Paola Cerruti Mainardi is licensed under CC 2.0.

 

How is Cri du Chat diagnosed?

Usually, the initial diagnosis is made based on doctors’ observation of a baby’s health. The final diagnosis comes from DNA tests.2

If a baby has symptoms of Cri du Chat, a doctor may order genetic testing.2

In most cases, the first test done to see if a baby has Cri du Chat is a karyotype.2

In this test, scientists isolate the baby’s chromosomes and view them under a microscope.15 This allows the scientists to see how many chromosomes the baby has and if any of them are too big or too small.

 

Figure 3: Karyotypes. Left: Normal female karyotype Right: Karyotype showing a translocation from chromosome 22 to chromosome 9. (Shutterstock/Kateryna Kon)

 

If the karyotype shows that one of the two chromosome 5s is shorter than the other, the baby can be diagnosed with Cri du Chat.2

If the karyotype comes back normal, this does not mean that Cri du Chat is impossible. It may mean that the deletion is too small to be seen under the microscope.2

The baby’s doctor may order other DNA tests that allow scientists look more closely at the baby’s genome to see if a smaller deletion exists. This may be done by using special dyes or sequencing sections of the baby’s genome.2,7

Even if the karyotype confirms Cri du Chat, the baby’s doctor may still order further DNA testing. This can tell the doctor exactly which parts of chromosome 5 are missing. This will help the doctor decide on the best treatment options for the baby as he or she grows up.1,7

There is a chance that the baby’s doctor may ask the parents and the baby’s siblings to get DNA testing done, as well. This helps the doctor determine if the baby inherited the 5p deletion, or if it occurred spontaneously. It also allows the doctor to make sure that the baby’s siblings do not need extra medical attention.1

 

Cri du Chat Prognosis and Life expectancy

It is estimated that 94 percent of babies born with Cri du Chat survive to adulthood.1 Of the 6 percent who die in childhood, 75 percent do so within the first few months after birth and 90 percent within the first year.1,2

This means that children with Cri du Chat who survive the first year of life have a good chance of survival into adulthood.

Most early deaths from Cri du Chat are from problems with their heart or lungs, particularly heart failure or pnemonia.1

As far as scientists know, if there are no major organ abnormalities, individuals with Cri du Chat have a normal life expectancy.1

Generally speaking, improved prognosis is associated with1,2:

  • smaller deletions
  • deletions with fewer genes
  • simple deletions, rather than translocations
  • no delay in speech development
  • no cat-like cry
  • early diagnosis1,14

 

Cri du Chat Treatment and Management

The treatment for Cri du Chat depends on the exact symptoms.2

Some individuals show no symptoms and require no treatment.1,2

If an individual has symptoms, they will likely need special care from infancy. Babies with Cri du Chat often have problems feeding. Nutrient deficiencies can add to their growth and developmental delays.2 Feeding therapy, a feeding tube, or IV feeding may help keep their nutritional status up.

As babies age, they may need:

  • continued nutritional support (to aid with gastrointestinal problems)1,2
  • personalized education2,4,6
  • physical therapy1,2,6
  • speech therapy2,6
  • ear tubes to help with ear infections and hearing1
  • hearing aids1
  • glasses2
  • behavioral therapy1,2,6
  • surgery2

Future Treatments

Advancements in biology and genetics are opening up new treatment possibilities. Among the most promising of these are:

Chaperone Proteins

One new strategy that may improve the symptoms of those with Cri du Chat Syndrome is to provide their cells with so-called “chaperone” proteins. These proteins work to help the cells make new proteins from their genes. If they can help the cells make more of the proteins from the one 5p arm they have, it may help balance out the missing genes. This may help improve the symptoms of the syndrome.1

Transcriptional Activators & Histone Deacetylase Inhibitors

Medications are being developed that could increase how often the genes on the remaining p-arm of chromosome 5 are transcribed into proteins. Increasing the amount of protein from these genes may help improve the symptoms of the syndrome.1

Gene Therapy

Gene therapy would allow doctors to put the missing DNA from chromosome 5 back into cells. The DNA for the treatment would be 100 percent individualized. Doctors would add back the exact DNA sequence that is missing.1

Returning all the missing genes to the cells is the closest medicine could offer to a cure.

Gene therapy is still a new treatment, but it has shown promising results in some other syndromes, such as spinal muscular atrophy, amytrophic lateral sclerosis and beta-thalassemia. Scientists and doctors hope that it may eventually be used to treat Cri du Chat as well.1

 

Can Cri du Chat be Prevented?

Yes and no.

There are steps you can take to minimize the risk of having a baby with a 5p deletion. However, because most cases occur randomly, eliminating the risk is impossible.

Inherited 5p Deletions

Since many parents who pass on a 5p deletion do not know they have one1, you can decrease your risk of passing on this chromosomal abnormality by testing your DNA to see if you have it. If a 5p deletion is found, you could visit a fertility specialist to decide the best course of action to prevent passing it on.

This would not eliminate the possibility of a spontaneous 5p deletion in the baby.

Spontaneous Deletions

Preventing spontaneous 5p deletions is trickier. Studies suggest that between 80 and 90 percent of spontaneous 5p deletions come from the sperm.1,2 Since DNA deletions are mostly caused by DNA damage, men may decrease the risk of having a 5p deletion in their sperm by protecting their DNA.10

This may include avoiding:

  • radiation (radiotherapy, UVA from sunlight)10,11
  • chemotherapy10
  • toxins (air pollution, cigarette smoke, heavy metals, benzene)10-12

Men may also protect the integrity of sperm DNA by increasing their intake of foods rich in vitamin E, vitamin C and vitamin A.11

Using the sperm from a second ejaculation to create a baby may also decrease the risk of passing on a 5p deletion. Sperm that has sat in the vas deferens for a while is more likely to have DNA damage. Ejaculating once before trying to conceive may decrease the percentage of sperm in the following ejaculate with DNA abnormalities.10

While egg cells appear to play a smaller role in the development of 5p deletions, women protecting the stability of their DNA through avoiding toxins and increasing antioxidant intake may, theoretically, be of use as well.

 

Other Chromosomal Abnormalities like Cri du Chat

Some other common genetic disorders have similar symptoms to Cri du Chat, but are caused by very different genetic abnormalities.

Down Syndrome

Down Syndrome is much more common than Cri du Chat. It is estimated that 1 in 700 babies are born with Down Syndrome.16

Down Syndrome is caused by too much DNA in the cell, rather than too little. In Down Syndrome, each cell has an entire extra chromosome 21 (trisomy 21).16,17

The symptoms of Down Syndrome can be similar to Cri du Chat and include: small head, unique facial features, hearing loss, vision problems, intestinal problems, heart defects and low IQ.17

Individuals with Down Syndrome often have symptoms that do not occur in people with Cri du Chat.

These can include: changes in 5th fingers and big toes, thyroid problems, hip displacements, extra skin around the neck, disorders of the nervous system and abnormal blood counts.17

Klinefelter Syndrome

Klinefelter Syndrome is caused by an extra X chromosome in girls (trisomy X).18

While this condition can only effect girls, it is still more common than Cri du Chat. It is estimated that 1 in 1000 girls born have Klinefelter Syndrome.18 (That is 1 in approximately 2000 of all births, assuming a 1:1 boy-to-girl ratio.)

Symptoms of Klinefelter Syndrome similar to those of Cri du Chat include: small head at birth, brain abnormalities, hearing problems, delayed motor skills, delayed speech, delayed social skills, heart defects, low IQ and scoliosis.18

Klinefelter Syndrome is associated with symptoms that are different from Cri du Chat, as well. These include: quick growth in childhood, psychological disorders, low self-esteem and infertility.18

Turner Syndrome

Turner Syndrome is caused by a partially or completely missing X chromosome (monosomy X). Similar to Klinefelter Syndrome, Turner Syndrome affects girls. Between 1 in 1,500 and 1 in 2,500 babies born have Turner Syndrome.19

Symptoms of Turner Syndrome that are similar to Cri du Chat include: low birth weight, growth deficiency, short neck, scoliosis and heart defects.19

Symptoms different from Cri du Chat include: lack of period, risk of hip displacement, rounded back, and abnormal bones in the arms, hands and wrists.19

Williams-Beuren Syndrome

Williams Syndrome is caused by a deletion of part of chromosome 7.20

It is estimated that 1 in 10,000 babies born have Williams-Beuren Syndrome.20

Williams-Beuren Syndrome symptoms similar to Cri du Chat include: sensitivity to noise, heart defects, low IQ, growth deficiencies, over or under-bite, problems with digestion, bladder and genital abnormalities, scoliosis, attention deficit disorder, overly-friendly personality, early grey hair and aging skin.20

Symptoms which are different from Cri du Chat include: pixie-like face, high blood pressure, diabetes and overly-bendable joints.20

Luckily, DNA tests provide a fool-proof way to tell these syndromes apart. Doctors may use symptoms to help them decide which chromosomes to look at first, but the DNA tests will decide the diagnosis.

 

Cri du Chat FAQs

  • Is there a cure for Cri du Chat Syndrome?

No. Unfortunately, at the moment there is no cure for Cri du Chat. Scientists hope that in the future they will be able to use gene therapy to put the missing DNA back into the cells.1 This would offer the closest medicine we could get to a true “cure”.

There are, however, many therapy options available to help manage symptoms.1,2

  • Are there any prenatal tests for Cri du Chat?

Yes. There are prenatal tests for Cri du Chat.

There are new, non-invasive tests that are very safe for the baby. Doctors can take a blood sample from the mother and isolate the baby’s DNA from it. Testing the baby’s DNA can tell you if the baby has any deletions on chromosome 5.1,14,21,22

There are also invasive tests that take samples from inside the womb to run genetic tests on. These are associated with a small, but real, risk of miscarriage.21

  • Is Cat Cry Syndrome dominant or recessive?

Cri du Chat is a dominant condition.

If you inherit a 5p deleted chromosome, you have the deletion and can be diagnosed with Cri du Chat, even if you have no symptoms. 1,2

  • Can someone with Cri du Chat reproduce?

Yes. If you have Cri du Chat, you can have children.2

There is a 50 percent chance your children will inherit your shortened chromosome 5 if you do not use in vitro fertilization to screen the embryos before pregnancy.

There is no way to predict the degree of symptoms children who inherit your shortened chromosome might have. It may be the same as your symptoms, much milder, or much worse.1

 

References

  1. Nguyen JM, Qualmann KJ, Okashah R, Reilly A, Alexeyev MF, Campbell DJ. 5p deletions: Current knowledge and future directions. American journal of medical genetics Part C, Seminars in medical genetics. 2015;169(3):224-238.
  2. Rodriguez-Caballero A, Torres-Lagares D, Rodriguez-Perez A, Serrera-Figallo MA, Hernandez-Guisado JM, Machuca-Portillo G. Cri du chat syndrome: a critical review. Medicina oral, patologia oral y cirugia bucal. 2010;15(3):e473-478.
  3. Rodriguez-Caballero A, Torres-Lagares D, Yanez-Vico RM, Gutierrez-Perez JL, Machuca-Portillo G. Assessment of orofacial characteristics and oral pathology associated with cri-du-chat syndrome. Oral diseases. 2012;18(2):191-197.
  4. Pituch KA, Green VA, Didden R, et al. Educational Priorities for Children with Cri-Du-Chat Syndrome. Journal of developmental and physical disabilities. 2010;22(1):65-81.
  5. Uzunhan TA, Sayinbatur B, Caliskan M, Sahin A, Aydin K. A clue in the diagnosis of Cri-du-chat syndrome: Pontine hypoplasia. Annals of Indian Academy of Neurology. 2014;17(2):209-210.
  6. Guala A, Spunton M, Tognon F, et al. Psychomotor Development in Cri du Chat Syndrome: Comparison in Two Italian Cohorts with Different Rehabilitation Methods. TheScientificWorldJournal. 2016;2016:3125283.
  7. Gu H, Jiang JH, Li JY, et al. A familial Cri-du-Chat/5p deletion syndrome resulted from rare maternal complex chromosomal rearrangements (CCRs) and/or possible chromosome 5p chromothripsis. PloS one. 2013;8(10):e76985.
  8. Moss J, Howlin P, Hastings RP, et al. Social behavior and characteristics of autism spectrum disorder in Angelman, Cornelia de Lange, and Cri du Chat syndromes. American journal on intellectual and developmental disabilities. 2013;118(4):262-283.
  9. Chen JM, Cooper DN, Ferec C, Kehrer-Sawatzki H, Patrinos GP. Genomic rearrangements in inherited disease and cancer. Seminars in cancer biology. 2010;20(4):222-233.
  10. Sakkas D, Alvarez JG. Sperm DNA fragmentation: mechanisms of origin, impact on reproductive outcome, and analysis. Fertility and sterility. 2010;93(4):1027-1036.
  11. Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O. Oxidative stress and antioxidant defense. The World Allergy Organization journal. 2012;5(1):9-19.
  12. Marchetti F, Eskenazi B, Weldon RH, et al. Occupational exposure to benzene and chromosomal structural aberrations in the sperm of Chinese men. Environmental health perspectives. 2012;120(2):229-234.
  13. Powis L, Oliver C. The prevalence of aggression in genetic syndromes: a review. Research in developmental disabilities. 2014;35(5):1051-1071.
  14. Helgeson J, Wardrop J, Boomer T, et al. Clinical outcome of subchromosomal events detected by whole-genome noninvasive prenatal testing. Prenatal diagnosis. 2015;35(10):999-1004.
  15. Shemilt L, Verbanis E, Schwenke J, et al. Karyotyping human chromosomes by optical and X-ray ptychography methods. Biophysical journal. 2015;108(3):706-713.
  16. Antonarakis SE. Down syndrome and the complexity of genome dosage imbalance. Nature reviews Genetics. 2017;18(3):147-163.
  17. Bull MJ, Committee on G. Health supervision for children with Down syndrome. Pediatrics. 2011;128(2):393-406.
  18. Otter M, Schrander-Stumpel CT, Curfs LM. Triple X syndrome: a review of the literature. European journal of human genetics : EJHG. 2010;18(3):265-271.
  19. Chacko E, Graber E, Regelmann MO, Wallach E, Costin G, Rapaport R. Update on Turner and Noonan syndromes. Endocrinology and metabolism clinics of North America. 2012;41(4):713-734.
  20. Pober BR. Williams-Beuren syndrome. The New England journal of medicine. 2010;362(3):239-252.
  21. Wapner RJ, Babiarz JE, Levy B, et al. Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes. American journal of obstetrics and gynecology. 2015;212(3):332 e331-339.
  22. Benn P, Cuckle H, Pergament E. Non-invasive prenatal testing for aneuploidy: current status and future prospects. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2013;42(1):15-33.

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