5p- Syndrome (Cri du Chat Syndrome)

Everything to know about 5p minus Syndrome, from the experts.

Podcast

Author and Contributing Experts to this Guide include:

Brenna Bentley Director, Patient Education at YourDNA.com LinkedIn
Alesha Hicks Genetic Counselor LinkedIn
Melanie Author at The Honest Pirate

What is 5p Minus Syndrome?

In 1963, a French physician, Dr. Lejeune first described 5p- syndrome. He originally named the condition Cri du chat (cry of the cat) after the distinctive cat-like cry that is seen in some of patients 1.

“Cri du chat syndrome, is the original name,” explained Alesha Hicks, a pediatric specialty and cancer genetic counselor at the University of Alabama at Birmingham.

“A lot of things in genetics are named from the way that they're first described. And so clinically, when the doctors in France were describing this group of children that all have similar features, they said that they shared this cat cry and they described the way that newborns cry as this very high pitch, almost like a cat's meow.

“It was only later on that we were able to use some of our more advanced technologies to say that they're all due to a common cause, which is this five p micro-deletion or Five P minus,” she added.

Other names for this condition include:

  • 5p deletion syndrome
  • cat cry syndrome
  • chromosome 5p- syndrome
  • monosomy 5p

5p- syndrome is a genetic condition due to the loss of a section of the small arm of the 5th chromosome. Features are often present at birth with a distinctive high-pitched cry, a small head, distinctive facial features including widely set eyes, low-set ears, a small jaw, and a round face 2.

At birth, you might also notice, a low birth weight, delayed growth, low muscle tone, and potentially difficulty feeding and/or breathing. It is important to note that not all patients will experience all of these symptoms and features 3.

The majority of individuals with 5p- Syndrome will experience some degree of developmental delay, intellectual disability, speech delay, and/or behavioral issues such as hyperactivity, inattentiveness, anxiety, or aggressive or self-injurious behavior 4, 5, 6

While, 5p- syndrome is a rare genetic condition, it is also one of the most common conditions caused by a chromosomal difference 7. Specifically, there is a section of genetic information missing from the short arm (p) of the 5th chromosome.

The severity of the condition is determined by the size and location of the deletion on chromosome 5.

What causes 5p- Syndrome?

Typically, humans have 46 chromosomes arranged into 23 pairs. Half of the chromosomes come from our mother and the other half from our fathers.

The chromosomes are number from largest to smallest, with chromosome 1 being the largest, and chromosome 22 being the smallest. The 23rd pair of chromosomes is special as it pertains to our sex chromosomes.

Each of the chromosomes contains several genes that are important in determining our characteristics such as height, eye color, and our health status.

Each chromosome has two “arm” one that is long (q) and one that is short (p). These designations help us communicate the area of genetic information that is being discussed.

When an individual is missing a section of information from the short arm of the 5th chromosome they are said to have 5p- syndrome. The specific amount of missing information can vary from person to person and influence the severity of the condition.

“When we look at all of the instructions that a person has that makes up who they are, that is our genetic material packaged into our chromosomes. For 5p minus syndrome, we're looking at the fifth chromosome and the smallest section of it, the “p” part of the name.

“What we’re really looking for is a lost segment that can look different from person to person. Some people have an entire section missing. Some only have a smaller piece. And we know that depending on the size and location of that piece that's missing from the overall package of the chromosome, there could be some different features that are associated,” said Hicks.

The majority of 5p- Syndrome cases are going to be brand new in the patient and not passed on from a parent (de novo), this most commonly (80-90%) occurs on the paternal (father’s) chromosome and occurs during sperm formation. 8, 9. In de novo cases, the likelihood of the couple having another child with 5p- syndrome is relatively low.

In a small percentage of cases (10-15%), 5p- syndrome arises from a balanced translocation in a parent 10. This would mean that in one parent, thereis a rearrangement of two or more sections of chromosomes.

The parent would have all of their genetic information, but it might be in the wrong place. When they have a child there would be a chance of passing on an unbalanced transolcatin, indicating missing and/or extra genetic information.

When there is a loss of information on the 5p, the child will have 5p- syndrome. When the syndrome is inherited in this manner there is an increased risk for the couple to have future children with 5p- syndrome.

Therefore after receiving a diagnosis, it would be recommended that parents also undergo genetic testing to see they carry a balanced translocation.

“In about 10 percent of cases it's passed on from a parent, the parent is unaffected. What's occurred in the parent who is otherwise healthy is that that missing piece has moved to a different chromosome. So, it doesn't matter for the parent because they still have all of the information, just in different places. But then when they're passing along that chromosome, the missing piece isn't there and the child doesn't get that missing piece,” added Hicks.

What are the Symptoms of 5p- Syndrome?

The size of the deletion plays a role in the severity and types of symptoms a person will experience with 5p- syndrome 11, 12, 13, 14.

Below is a list of signs and symptoms that may present at different life stages. It is important to note that not every child with 5p- Syndrome will experience all of these features. Each child is unique, and this is a broad overview of possibilities.

At Birth 15, 16, 17

  • high-pitched, “mewing” cry (will become less pronounced with time)
  • Due to structural changes in the larynx and epiglottis 18
  • Low birth weight
  • Small head size
  • Distinct Facial Features: found face, large bridge of their nose, widely spaced eyes, downward slanting eyes, the corners of the ears may point down, ears may be set lower on the head than expected
  • Changes in the structure of the heart, kidneys, and/or brain
  • Skin tag on the ears
  • fusing of fingers
  • Cleft Lip
  • undescended testes and/or a small opening on the tip of the penis

Soon After Birth 19

  • Difficulty breathing
  • Turning blue when crying
  • Difficulty feeding
  • Low muscle tone
  • high palate
  • micrognathia

Features that Develop with Age 20

  • The face will elongate and narrow, the length between the nose and upper lip will be shorter than expected, lower lip will increase in fullness,
  • Small hands and feet
  • Premature graying
  • Mental retardation
  • Cataracts and/or nearsightedness
  • Muscle will have greater tone
  • Scoliosis
  • Seizures

Developmental and Behavioral Features 21

  • Intellectual Disability 22
  • Language delay (individuals tend to understand more than they can express)
  • Most are gentle and affectionate
  • Hyperactivity
  • Hypersenstativity to noise
  • Anxiety
  • Some self-injurious behaviors
  • repetitive movements such as hand flapping, string twirling, and rocking

Although some babies are born with structural differences in one or more organs, such as heart defects, most people born with 5p- syndrome have a normal life expectancy 23.

“Some of the things we see in a clinical setting are in facial features such as a slant of the eyes and just the overall spacing of them. And then, the actual skin around the eyes and the way that they fold, we can look at as well.

“We can also see some other physical differences like just the positioning of their ears, some differences with their skin and their hands. And then, we also just in general, we're thinking about the way that these children present.

“There's the high pitch cry that, although not everyone will be affected with that. We also see a low birth weight, a failure to thrive, a baby with poor muscle tone, maybe a smaller head size. So, we kind of tease it out and try to find what's unique and could lead us in the right direction for a diagnosis,” explained Hicks.

According to Dr. Maria-Elena Liverani, an Italian physician who has seen more than 300 5p- syndrome patients and has published care guidelines for people with the condition, the first few months of life are the worst.

“The parents oscillate between the fear that the child will not survive and the secret hope that this will happen. Over time, the phenotype changes. The face becomes longer. Malocclusion appears, which can interfere with phonation, chewing, and nighttime breathing.

“The hair turns gray early. The voice remains a little higher, especially in males. Sometimes there are manifestations of skin breaking,” she commented.

Prevalence and Risk Factors of 5p- Syndrome

The incidence for cri du chat ranges from 1-15,000 to 50,000 live births 24, 25.

Said Hicks, “We see about 50 to 60 kids that are born each year in the United States with it. And then globally, it's more of a one in 20,000 to potentially as rare as one in 50,000. In fact, it's rare enough that it's hard to get a good number.”

“Also, for some reason, we know that it seems to affect females more than males, but we don't have a good answer as to why that is.”

Based on available data, cri du chat is spread evenly across the board in other regards, such as ethnicity, race, or socioeconomic classes.

Diagnosis of 5p- Syndrome

In most cases, cri du chat syndrome is diagnosed at birth.

It is confirmed through clinical evaluation, identifying characteristic findings such as the cat-like cry, and through chromosomal studies to reveal if there is a deletion on the short arm of chromosome 5.

A physician will likely order a specific test known as fluorescence in situ hybridization (FISH) and a microarray to take a closer look at the chromosomes. These tests together will be able to provide a diagnosis.

After diagnosis, parents should consider testing in order to determine if they carry a balanced translocation.

“The syndrome can be picked up by a variety of tests. One is a karyotype where they take a picture of all of the chromosomes spread out. And if it's a big enough loss on that chromosome 5, we'll be able to see it,” said Hicks.

“Another way that they might go about it is using probes that look for specifically that area of Five P and see if that's missing. Another common test that we might order is the chromosomal microarray. That one is more of a broad test that's looking for extra or missing pieces anywhere in all of the chromosomes. That can pick it up as well, especially if it's a smaller deletion that maybe isn't picked up by karyotype.” added Hicks.

“Post-test counseling is important to provide information about the syndrome and help the family to cope with the diagnosis. If a translocation is present, which is the case in ten to 15 percent of the patients, counseling will include discussion as to reproductive options and extension of genetics test to other family members.” stated Dr. Liverani.

Due to advancements in chromosomal testing, techniques used to determine abnormalities are becoming more sophisticated. Because of this, advancements in diagnostic techniques can now be used in some instances to make a prenatal diagnosis.

“If we saw differences on the ultrasound, we would think about prenatal testing. Or in those rare instances where we know that a parent does have that difference in their chromosomes, we would be looking for future siblings potentially.

“We would just do the same kind of test that we used to identify it in the first place, and just do either an amnio where they take fluid from around the baby or a chorionic villus sample, which is taking a piece of the placenta for genetic testing,” said Hicks.

Can Cri du Chat be cured?

There is no cure for cri du chat syndrome.

“Everything that we can offer is geared towards management and support with things like early intervention, physical therapy, occupational therapy, speech therapy, and to take care of whatever symptoms are specific to that child.

“Management is a tailored approach to whatever their needs are and offering as much support as possible so that they can achieve everything that they're capable of. But I think that it takes a diverse range of different professions. And even just from that front, there are a lot of different people involved who can help,” said Hicks.

Dr. Liverani added, “Up to now, no drug or genetic manipulation seems to be helpful, but research is ongoing.”

Treatment and Care Options for 5p- Syndrome

Because there is no specific treatment available for 5p- syndrome, children born with this condition will most likely require ongoing support from a team made up of the parents, therapists, and medical and educational professionals.

Early and consistent educational intervention, as well as physical and language therapy, give children the best chance of reaching their fullest potential so that they can lead full and meaningful lives.

If present, surgery may be performed to treat congenital heart defects, strabismus, scoliosis, clubfoot, cleft palate, and cleft lip.

“A tailored program is the best way to deal with features. The sooner, the better. In Italy, this child has a pediatrician that follows up from birth to 14 years of age. It's his or her task to guarantee the appropriate management. In Five P minus syndrome, it's advisable to have a professional in rehabilitation involved to begin as soon as possible some training to prevent delays in psychomotor development,” said Dr. Liverani.

“Many years ago, children with Five P minus were not able to work, did not speak, and were not apparently interested in interaction with their parents, siblings, and peers. Treatment has changed quite a bit and now, we have patients who walk, run, ride a bike and even a horse, who can communicate through assisted communication, who watch TV and say which program is their favorite, and who go to school with a special program and a special teacher,” added Dr. Liverani.

Many families have found the use of alternative therapies as a way to complement Occupational, Physical, and Speech therapy. Some therapies children and/or adults with the syndrome have benefited from include:

  • ABA Therapy (Applied Behavior Analysis)
  • Adaptive Physical Education
  • Aromatherapy
  • Aquatic Therapy
  • Behavior Therapy
  • Cranial Sacral Therapy
  • Dolphin Therapy
  • Hippo-therapy (also known as Horse Therapy)
  • Music Therapy
  • Play Therapy
  • Pragmatic Group Therapy
  • Sensory Learning Therapy

The Prognosis of 5p- Syndrome

If a child can get treatment early, and their case of 5p- syndrome is not too severe, there is a good chance they will enjoy a near-normal life expectancy 26.

“In the first year of life, there is a mortality rate of about 10 percent. But beyond that, life expectancy has improved greatly, although it is still is far from normal,” said Dr. Liverani.

“The social costs to help someone with cri du chat are high and families are worried about what will happen when parents or siblings are no longer be able to bear the burden? I think the actual challenge is to guarantee lifelong training and top quality assistance. We’ve seen cri du chat people can achieve skills even when everybody thinks it's too late.”

What to do Next: Living with 5p- Syndrome

Living with a rare disease like 5p- syndrome can have a big impact on patients and their families. Finding support in addition to getting quality care is critical to the long-term aspects of this condition.

From a financial standpoint, the Social Security Administration has included 5p- syndrome in their Compassionate Allowances Initiative. This initiative speeds up the processing of disability claims for applicants with certain medical conditions that cause severe disability.

More information about Compassionate Allowances and applying for Social Security disability is available online.

“Some of the best people that you can talk to are other parents. Because as a parent, you become a caretaker, the most familiar person with your child, and most familiar with their needs. So you become the expert.

“Talking to other parents who are also the expert of their child can be helpful. It provides a supportive community of people who are going through the same thing right now or who have already done it and can pass along advice or things that they found really helpful because every child is different and so, it can be difficult,” said Hicks.

“We say often in genetics that we're not fortune-tellers. We don't really know anything about what the child will or won't achieve. I think speaking with other people who've been down that path can be helpful because it is really difficult to predict, but maybe someone who's been through it as well can provide some insight,” she added. For More Information

5p- Society P.O. Box 268
Lakewood, CA 90714-0268 Toll-free: 1-888-970-0777
Telephone: +1-562-804-4506
E-mail: director@fivepminus.org Website: https://fivepminus.org/

Chromosome Disorder Outreach (CDO) PO Box 724
Boca Raton, FL 33429
Telephone: +1-561-395-4252
E-mail: https://chromodisorder.org/contact/ Website: https://chromodisorder.org/

Unique – Rare Chromosome Disorder Support Group G1, The Stables
Station Road West
Surrey
RH8 9EE
United Kingdom Telephone: +44 (0)1883 723356
E-mail: info@rarechromo.org Website: https://www.rarechromo.org/

Referenced Sources

  1. LEJEUNE J, LAFOURCADE J, BERGER R, VIALATTE J, BOESWILLWALD M, SERINGE P, TURPIN R. TROIS CAS DE D'EL'ETION PARTIELLE DU BRAS COURT D'UN CHROMOSOME 5 [3 CASES OF PARTIAL DELETION OF THE SHORT ARM OF A 5 CHROMOSOME]. C R Hebd Seances Acad Sci. 1963 Nov 18;257:3098-102. French. PMID: 14095841.
  2. Niebuhr E. Cytologic observations in 35 individuals with a 5pkaryotype. Hum Genet. 1978;42:143-56
  3. Niebuhr E. Cytologic observations in 35 individuals with a 5pkaryotype. Hum Genet. 1978;42:143-56
  4. LEJEUNE J, LAFOURCADE J, BERGER R, VIALATTE J, BOESWILLWALD M, SERINGE P, TURPIN R. TROIS CAS DE D'EL'ETION PARTIELLE DU BRAS COURT D'UN CHROMOSOME 5 [3 CASES OF PARTIAL DELETION OF THE SHORT ARM OF A 5 CHROMOSOME]. C R Hebd Seances Acad Sci. 1963 Nov 18;257:3098-102. French. PMID: 14095841.
  5. Rodríguez-Caballero A, Torres-Lagares D, Rodríguez-Pérez A, Serrera-Figallo MA, Hernández-Guisado JM, Machuca-Portillo G. Cri du chat syndrome: a critical review. Med Oral Patol Oral Cir Bucal. 2010 May 1;15(3):e473-8. doi: 10.4317/medoral.15.e473. PMID: 20038906.
  6. Collins MS, Cornish K. A survey of the prevalence of stereotypy, self-injury, and aggression in children and young adults with Cri du Chat syndrome. J Intellect Disabil Res. 2002;46:133-40
  7. Niebuhr E. Cytologic observations in 35 individuals with a 5pkaryotype. Hum Genet. 1978;42:143-56
  8. Church DM, Bengtsson U, Nielsen KV, Wasmuth JJ, Niebuhr E. Molecular definition of deletions of different segments of distal 5p that result in distinct phenotypic features. Am J Hum Genet. 1995 May;56(5):1162-72. PMID: 7726173; PMCID: PMC1801456.
  9. Overhauser J, McMahon J, Oberlender S, et al. Parental origin of chromosome 5 deletions in the cri-du-chat syndrome. Am J Med Genet. 1990;37(1):83-86. doi:10.1002/ajmg.1320370119
  10. Mainardi PC, Perfumo C, Calì A, et al. Clinical and molecular characterization of 80 patients with 5p deletion: genotype-phenotype correlation. J Med Genet. 2001;38(3):151-158. DOI:10.1136/jmg.38.3.151
  11. Niebuhr E. Cytologic observations in 35 individuals with a 5pkaryotype. Hum Genet. 1978;42:143-56
  12. Mainardi PC, Perfumo C, Calì A, et al. Clinical and molecular characterization of 80 patients with 5p deletion: genotype-phenotype correlation. J Med Genet. 2001;38(3):151-158. DOI: 10.1136/jmg.38.3.151
  13. Wilkins LE, Brown JA, Nance WE, Wolf B. Clinical heterogeneity in 80 home-reared children with cri du chat syndrome. J Pediatr. 1983;102(4):528-533. doi: 10.1016/s0022-3476(83)80179-6
  14. Cornish KM, Cross G, Green A, Willatt L, Bradshaw JM. A neuropsychological-genetic profile of atypical cri du chat syndrome: implications for prognosis. J Med Genet. 1999 Jul;36(7):567-70. PMID: 10424821; PMCID: PMC1734412.
  15. LEJEUNE J, LAFOURCADE J, BERGER R, VIALATTE J, BOESWILLWALD M, SERINGE P, TURPIN R. TROIS CAS DE D'EL'ETION PARTIELLE DU BRAS COURT D'UN CHROMOSOME 5 [3 CASES OF PARTIAL DELETION OF THE SHORT ARM OF A 5 CHROMOSOME]. C R Hebd Seances Acad Sci. 1963 Nov 18;257:3098-102. French. PMID: 14095841.
  16. Niebuhr E. Cytologic observations in 35 individuals with a 5pkaryotype. Hum Genet. 1978;42:143-56
  17. Cerruti Mainardi, P. (2006). Orphanet Journal of Rare Diseases, 1(1), 33. doi: 10.1186/1750-1172-1-33
  18. Niebuhr E. Cytologic observations in 35 individuals with a 5pkaryotype. Hum Genet. 1978;42:143-56
  19. Cerruti Mainardi P, Pastore G, Castronovo C, Godi M, Guala A, Tamiazzo S, Provera S, Pierluigi M, Dagna Bricarelli F: The natural history of Cri du Chat Syndrome. A report from the Italian Register. Eur J Med Genet 2006 in press.
  20. Cerruti Mainardi P, Pastore G, Castronovo C, Godi M, Guala A, Tamiazzo S, Provera S, Pierluigi M, Dagna Bricarelli F: The natural history of Cri du Chat Syndrome. A report from the Italian Register. Eur J Med Genet 2006 in press.
  21. Cerruti Mainardi P, Pastore G, Castronovo C, Godi M, Guala A, Tamiazzo S, Provera S, Pierluigi M, Dagna Bricarelli F: The natural history of Cri du Chat Syndrome. A report from the Italian Register. Eur J Med Genet 2006 in press.
  22. Niebuhr E. Cytologic observations in 35 individuals with a 5pkaryotype. Hum Genet. 1978;42:143-56
  23. Cerruti Mainardi P, Pastore G, Castronovo C, Godi M, Guala A, Tamiazzo S, Provera S, Pierluigi M, Dagna Bricarelli F: The natural history of Cri du Chat Syndrome. A report from the Italian Register. Eur J Med Genet 2006 in press.
  24. Niebuhr E. Cytologic observations in 35 individuals with a 5pkaryotype. Hum Genet. 1978;42:143-56
  25. Higurashi M, Oda M, Iijima K, et al. Livebirth prevalence and follow-up of malformation syndromes in 27,472 newborns. Brain Dev. 1990;12(6):770-773. doi: 10.1016/s0387-7604(12)80004-0
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Transcript

Brenna: You're listening to the Rare Disease Connection, a production of Aspect Health and raredisease.com. Brenna: Genetics are complicated. There's not many times when a condition is cut and dry. You will often hear genetic counselors and physicians saying things like most of the time or almost never, and that's because there's so much variability from person to person. The condition that we're going to talk about today is no different. Brenna: When I first learned about Five P minus syndrome, also known as Cri du chat in high school, we were taught that children with this condition have a cry that sounds like a cat. But as I've continued through school and learned more, I realized that that infamous cry that the condition is named after isn't even seen in everyone. It just goes to show that while a diagnosis might provide a road map of what to expect, it's not a binding set of rules. Brenna: Rare Disease Connection and our additional resources on raredisease.com and yourdna.com bring together people whose expertise can explain what you're facing from diagnosis to prognosis, to treatment options, all the way to questions like who do I talk to? And where are the people who've been through this before? You'll find those answers here. From doctors, geneticists, academics, genetic counselors, patient organizations, other patients and their families, they're all within your reach, and we're here to connect you. This is Rare Disease Connection. Brenna: Hey, everyone. This is Brenna, co-host of Rare Disease Connection and director of Patient Education at yourdna.com. Today, I'm going to bring you conversations with three experts on Five P minus syndrome. Before we get started, you should know that this episode is just the beginning. We've taken all of the information from this episode and added additional resources, explanations, links, and references for you in a downloadable guide. You can get your free copy by going to raredisease.com/fivep, that's raredisease.com/fivep. So let's get started. Brenna: Our first guest today is Alesha Hicks, a genetic counselor at the University of Alabama at Birmingham, currently working with pediatric patients. Welcome, Alesha. Hi, Alesha. Thanks so much for joining us today. Alesha Hicks: Thanks for having me on, Brenna. Brenna: Yeah, of course. So I know you, but why don't you take a second to introduce yourself to the listeners. Alesha Hicks: Yeah. So I am Alesha Hicks. I am a pediatric specialty and cancer genetic counselor at UAB. So I went to the training program at UAB with Brenna and I specifically have an interest in pediatric genetics. So I spent three out of my five clinical rotations where I was training in pediatric hospitals. One of them was in Kansas City, Children's Mercy. And then the other one, of course, is here in Birmingham at Children's of Alabama. And so, from there, yeah, I'm just working with kids primarily. Brenna: And I know Alesha and that's definitely where she should be. And so, speaking from your experience as a genetic counselor, what immediately comes to mind when you hear Five P minus syndrome? Alesha Hicks: So I am preparing for boards. So the first thing that comes to mind is Cri du chat syndrome, and that's the kind of original name. And a lot of things in genetics are named from the way that they're first described. And so clinically when the doctors in France, which is why the name is in French, were describing this group of children that all have similar features, they said that they shared this cat cry and they described the way that newborns cry as this very high pitch, almost like a cat's meow. And it's only later on that we were able to use some of our more advanced technologies to say that they're all sort of this common cause, which is this Five P micro-deletion or Five P minus. The way I think of it, I think of the low birth weight, poor muscle tone, maybe a smaller head size, some differences in facial features. And then, as they're growing up, some delays and other medical complications. Brenna: So while we have you here and we have your genetics experience, take a second to walk us through what is occurring genetically to give us the signs and symptoms of Five P minus syndrome. Alesha Hicks: So when we look at all of the instructions that a person has that makes up who they are, that information is, of course, our genetic material and genetic material is packaged into our chromosomes. So specifically, we're looking at the fifth chromosome and the smallest section of it, that's the P part of the name, and really we're looking for a lost segment. And that lost segment can actually look different from person to person. Some people have an entire section missing. Some only have a smaller piece. And we actually know that depending on the size and location of that piece that's missing from the overall package of the chromosome, there could be some different features that are associated. Brenna: So is this a condition that's inherited? Can you inherit a piece of your chromosome that's missing? Alesha Hicks: So the majority of cases are actually going to be brand new and not passed on from a parent. When we do see it in about 10% of cases where it's passed on from a parent, the parent is unaffected and really what's occurred in the parent who is otherwise healthy is that that missing piece has moved to a different chromosome. And so, it doesn't matter for the parent because they still have all of the information, just in different places, but then when they're passing along that chromosome, the missing piece isn't there and the child doesn't get that missing piece. And so, then the chance that they would have other children is actually going to be up to 50%, depending whether they get a full chromosome or one with a missing piece. Brenna: And are there certain people that are more likely to have this condition? What are the chances of having a child with Five P minus syndrome? Alesha Hicks: Yeah, that's a great question. So for some reason, we know that it seems to affect females more than males, but we don't have a good answer as to why that is. We do know that this is a rare condition. So we see about 50 to 60 kids that are born each year in the United States with it. And then globally, it's more of a one in 20,000 to potentially as rare as one in 50,000. It's rare enough that it's hard to get a good number, in fact. Brenna: But I think also from what I was seeing, based on ethnic groups or socioeconomic class or anything like that, this condition doesn't seem to vary in those regards. Alesha Hicks: Nope, not at all. It's spread pretty evenly across the board in those. Brenna: So we know genetic counselors play a huge role in the diagnosis of genetic conditions. And so, if we start to think about how someone actually receives this diagnosis, we know the first thing you guys sometimes see is the child themselves. And so, if we were to look at pictures of someone with this condition, are there certain features that we might see that maybe can stand out? Alesha Hicks: Yeah. So some of the things that we might appreciate in a clinical setting with some of those differences in facial features would be the slant of the eyes and just the overall spacing of them. And then, the actual skin around the eyes and the way that they fold, we can look at as well. And we can also see some other physical differences like just the positioning of their ears, some differences with their skin and their hands. And then, we also just in general, we're thinking about the way that these children present. Again, there's the high pitch cry that they're kind of named for, although not everyone will be affected with that. We also just see this general presentation a lot of times in a pediatric clinic where there's a low birth weight, kind of failure to thrive, a baby with poor muscle tone, maybe a smaller head size. And so, we kind of tease it out and try to find what's unique and could lead us in the right direction for a diagnosis. Brenna: And so then, outside of the physical features that you've mentioned, what are some of the common symptoms that someone with Five P minus syndrome might experience? Alesha Hicks: Great question. And I have met some children actually who are older with this condition so, of course, you think of the cat's cry as being the characteristic feature that it's named for. But we know that these children will also go on to just have language difficulties and they'll have some motor delay, hyperactivity, maybe things like scoliosis, intellectual differences. And they could have some other physical differences as well like hernias, heart defects, kidney differences. And then actually if you meet adults, we know that some of them have premature graying as well. So it can be a whole spectrum of different features really, and it just can depend from person to person. Brenna: So now you've seen the kid, you've looked at physical features, maybe you reviewed some of the medical documents, you've looked at signs and symptoms that might occur. How do we actually go about getting this diagnosis? What are the actual steps? Is there a certain age that people get diagnosed? Are there certain types of tests you have to order? Alesha Hicks: Yeah, that's a great question, too. So typically, these children will come to attention shortly after birth, if there wasn't any of those physical differences that were even picked up prenatally on ultrasound, but the kinds of tests that we order really probably depend on the clinical picture and what we're seeing. It can be picked up by a variety of tests. So one is a karyotype where they really take a picture of all of the chromosomes spread out. And if it's a big enough loss on that chromosome 5, we'll be able to see it. Alesha Hicks: Another way that they might go about it is probes that look for specifically that area of Five P and see if that's missing. And then another common test that we might order is the chromosomal microarray. And that one's more of a broad test that's looking for extra or missing pieces anywhere in all of the chromosomes. And so that can pick it up as well, especially if it's a smaller deletion that maybe isn't picked up by karyotype or isn't specific to the probes that we looked for with [FISH 00:00:11:03]. Brenna: So you mentioned this testing might be sent shortly after birth if it's not detected prenatally. So that makes me wonder are there prenatal tests? Alesha Hicks: So there are prenatal tests. It would be pretty much the exact same kinds of tests. And it would be, as I mentioned, maybe if we saw some differences on the ultrasound, we would think about that. Or in those rare instances where we know that a parent does have that difference in their chromosomes, we would be looking for future siblings potentially. And we would just do the exact same kind of test that we used to identify it in the first place, and really just do either an amnio where they take fluid from around the baby or a CVS, which stands for chorionic villus sample, and that's a really big word that just means that they take a piece of the placenta for genetic testing. Brenna: So to ask a question that I think a lot of parents would probably ask, is there a cure for this condition? Alesha Hicks: Yeah, and that is a really tough question and one that comes up a lot in this setting. And unfortunately, the answer is that we don't really at this time. Everything that we can offer is really geared towards management and support. And so, we're really just providing as much support as possible with things like early intervention, physical therapy, occupational therapy, speech therapy, and it's really more to take care of whatever symptoms are specific to that child. And so, it really is a tailored approach to whatever their needs are and offering as much support as possible so that they can achieve everything that they're capable of. But I think that it takes a diverse range of different professions. And even just from that front, there are a lot of different people involved who can help. Brenna: So thank you again for hanging out with us today, Alesha, and answering our questions. Before you go, I'd like to kind of pick your brain and see what might be your best advice for someone who's diagnosed with Five P minus syndrome or maybe who's just had a loved one who was diagnosed. Alesha Hicks: Absolutely. And I think that everyone will take time to process the information at different speeds and so, that can be a challenge, but I do find that when someone is ready to move forward on this journey, that some of the best people that you can talk to are other parents. Because as a parent, you really become, or caretaker, the most familiar with your child and most familiar with what their needs are and so, you become the expert. And so, talking to other parents who are also the expert of their child can be really helpful. It provides a supportive community of people who are going through the same thing right now or who have already done it and can pass along advice or things that they found really helpful because every child is different and so, it can be difficult. Alesha Hicks: And one thing that we do say often in genetics is that we're not fortune tellers. We don't really know anything about what the child will or won't achieve, same as a child without a genetic diagnosis. And so, I think speaking with other people who've been down that path can be really helpful because it is really difficult to predict, but maybe someone who's been through it as well can provide some insight. Alesha Hicks: And I do think, too, that there are just different communities online that can be really helpful. So I use frequently rarediseases.org, and I know that there's also a Five P Minus Society that has great resources specific to this condition. Brenna: Thank you, Alesha, for joining us today. Whether you've interacted with a genetic counselor yet or not, they play an invaluable role in the journey of anyone diagnosed with a rare genetic disease. If you've got questions about Five P minus syndrome, I recommend looking at nsgc.org to find a genetic counselor near you. Brenna: Our next guest is Dr. Maria-Elena Liverani. She is a physician in Italy with a special interest in Five P minus syndrome. She has seen over 300 patients and has published on care guidelines for individuals of all ages with Cri du chat. Thank you for taking the time to speak with us today. Why don't you start by introducing yourself? Maria-Elena Liverani: Okay. Well, my name is Maria-Elena Liverani. I graduated in medicine and surgery in 1983 in Turin, Italy. And then specialized in pediatrics in Turin and later in hygiene and preventative medicine in Verona, Italy. I worked mainly in hospitals and I [retired 00:15:46] from Sant'Andrea Hospital University La Sapienza in Rome last January. Maria-Elena Liverani: And my involvement in Five P minus syndrome dates back to the early '80s when Professor Paola Cerruti Mainardi began studying the natural history of this thing, and I, as a young student, accompanied her in several institutes in Northern Italy, searching for people that matched with her ideas of an Cri du chat phenotype. We found out quite a number of subjects. Maria-Elena Liverani: She later discovered that some families had founded an association in Italy and began a collaboration with them. I was asked to join, and now the association counts more than 300 Cri du chat patients and I am a member of their scientific community. I meet patients and their families at the scientific meetings that once or twice a year take place in San Casciano, Val di Pesa near Florence and I'm available all the time for phone calls, WhatsApp and emails. We decided to organize the meetings, the scientific seminars and care training courses according to the age of the participants because the problems of a newborn are completely different from those of an adolescent or adult. Brenna: With all of your experience seeing over 300 patients and at different stages in their lives, when you hear Five P minus syndrome, what immediately comes to mind for you? Maria-Elena Liverani: My first thought when I hear Five P minus, you're really [in sorrow 00:00:17:21]. I see a lot of that first to improve the quality of life of children, but much less attention is given to the quality of life of grownups. Pediatricians during their study course receive some sort of training in rare diseases, where the general practitioners don't. But pediatric age ends at 12 or at most at 18 when life is much longer. It's important to guarantee appropriate knowledge and resources to that period of time when parents no longer can carry the whole burden of the disease. The people I met in the '80s were abandoned in psychiatric institutions and nobody thought that they could reach stages of psychomotor development, which we now see achieved in almost all subjects, seat without support, walk alone, eat and drink alone, decide what clothes wear, understand what's being said and sometimes bathe, but they will lose those kids if they don't keep on practicing. Brenna: We've had the opportunity to just hear from Alesha Hicks, the genetic counselor, who talked a lot about the underlying genetic cause for Five P minus syndrome. But with all of your experience, I'd like to take some time to focus on diagnosis and management. When are doctors typically seeing families for a suspected diagnosis? Maria-Elena Liverani: In case prenatal diagnosis is carried out, parents know what they will have to face having decided not to interrupt the pregnancy, but prenatal diagnosis is not routine. It is performed in consideration of maternal age or due to abnormal ultrasound findings. New diagnosis involve instead young, healthy couples and very often, [months 00:19:08] are needed to formulate a [inaudible 00:19:10] and prescribe and genetic tests. Brenna: So are there specific physical features or signs or symptoms that might make a physician suspicious for Five P minus syndrome? Maria-Elena Liverani: Yes. A Five P minus child is often a low birth weight baby with some respiratory distress, difficulties in swallowing, is often hypotonic and has a high pitch cry like a meowing. They have small head conference, low set ears and epicanthus. Sometimes internal malformation can be present. Maria-Elena Liverani: The first few months of life are the worst. The parents oscillate between the fear that the child will not survive and the secret hope that this will happen. Over the time, phenotype changes. Face become longer. Malocclusion appears, which can interfere with phonation, chewing and night time breathing. The hair turns gray early. The voice remains a little higher, especially in males. Sometimes there are manifestation of skin breaking. It is not clear whether due to the altered pain threshold or used to bring undiagnosed pain to attention. For example, gastroesophageal reflux or trigeminal neuralgia or toothache or headache. Nobody is completely autonomous. Brenna: So you mentioned genetic testing. So what are those specific tests that are needed to make a diagnosis? And how long does it normally take for those results to come back? Maria-Elena Liverani: For the diagnosis of Five P minus, a traditional karyotype is no longer sufficient. CGH arrays nowadays both of the child and the parents can spot the deletion and the abnormalities. It takes usually from one to three months to get the results. And a post test counseling is important to provide information about the syndrome and help the family to cope with the diagnosis. Of course, if a translocation is present, which is the case in 10, 15% of the patients, counseling will include discussion as to reproductive options and extension of genetics test to other family members. Brenna: So now that someone has received that diagnosis and gotten the results back, the focus shifts to thinking about management for these patients. And so, who should initially be evaluating the patients once they've received that diagnosis? Maria-Elena Liverani: A tailored program is the best way to deal with the problems. The sooner, the better. In Italy, this child has a pediatrician that followups from birth to 14 years of age. It's his or her task to guarantee the appropriate management. In Five P minus syndrome, it's advisable to have a professional in rehabilitation involved to begin as soon as possible some training to prevent delays in psychomotor [development 00:22:11]. Maria-Elena Liverani: As I already said, years ago, children with Five P minus were not able to work, did not speak, were not apparently interested in interaction with their parents, siblings and peers. Continuous quite challenging exercise has improved their performance. And now, we have fellows who walk and either run or ride a bike and even a horse, who can communicate through [alternative 00:22:37] communication, who watch TV and say which program is their favorite, who go to school with a special program and a special teacher. Brenna: So outside of the individuals who should see them, what are some exact care and management options, and what would they consist of? Maria-Elena Liverani: Well, ABC, the Italian association provides a specific program. They call the pedagogies, the special pedagogies, which interact with families, with the teacher at school, and each child has his own program, yeah, this is right. Brenna: So with your research as well, are there any new drugs or therapies that are on the horizon for Five P minus? Maria-Elena Liverani: For sure up to now, no drug or genetic manipulation seems to be helpful, but research is ongoing. We hope. Brenna: Yes. And I think that's probably what a lot of other weird diseases do, too. There might not be something now, but we're going to keep working and keep researching and hope that things evolve over time. So thinking about the prognosis for individuals, I know you've started seeing patients in the '80s and it seems like a lot of things have changed from the first patients you were seeing to the care that individuals are getting now. But what is the general life expectancy for someone with Five P minus syndrome? And how is the quality of life? Maria-Elena Liverani: Life expectancy, let alone the first years of age, which is stillborn and with a mortality rate of almost 10% is excellent. While the quality of life of patients and their caregivers has improved, but still is far from normal. The social costs of their assistance are high and families are worried like what will happen to Cri du chat subjects when parents or siblings will no longer be able to bear the burden? I think the actual challenge is to guarantee all lifelong training and top quality assistance, considering the Cri du chat people can achieve skills even when everybody thinks it's too late. Let's trust them. Brenna: Yeah. I think knowing if you put faith in the child and give them the skills, they'll do way more than what you think that they can do. So I want to thank you for spending time with us today, but before I let you go, what's one thing that you wish people knew about Five P minus syndrome? Maria-Elena Liverani: I like people to know that this rare disease, like many others as you said, is not a stigma, is not a lost battle, but deserves first research and resources because in 30 years, we have seen incredible improvement and it's worthwhile going on and keep [trying 00:25:16]. Brenna: Thank you, Dr. Liverani, for spending time with us today. If you have a loved one who was recently diagnosed with Five P minus syndrome, it is important that you identify physicians familiar with this condition. Don't be afraid to ask your primary doctor for recommendations. Brenna: Our final guest today is Melanie, a mom in Australia to two amazing kids. Melanie's daughter was born with Five P minus syndrome, and Melanie quickly went to work learning all that she could. Thank you for joining us today and for sharing your story. So why don't you start just by telling us a little bit about yourself? Melanie: Well, I'm Melanie from Australia obviously. I have two perfect children, a two-year-old and a nine-year-old who happened to be born a little bit different. She was born with Five P minus syndrome and yeah. Brenna: Yeah. So I imagine you probably didn't know much about this condition prior to having your daughter diagnosed, but now you've sort of been thrown into this world. You've probably seen doctors and you've gone to visits with this. So from your experience with this condition, when you hear Five P minus syndrome, what comes to mind for you? Melanie: Well, when I first heard it when Ella was diagnosed, I had no idea what it was. They told me it was Cri du Chat so, which is French for cry of the cat. And I think I texted my mom first and just said it's this weird cat thing. I had zero clue what it was. I found the community through Facebook, which was really, really helpful. I got to speak to a lot of other parents with kids that have Five P minus syndrome. And there's also an app now called Able Finder, which you can talk to other parents with kids with disabilities, which has just opened my world up amazingly so ... Brenna: Yeah. So you mentioned your daughter. I think you said her name was Ella. Why don't you tell us a little bit about her? Melanie: Where do I start? She's amazing. She's funny. She's cheeky. She's so clever, bloody stubborn. Her most recent cognitive assessment said she was around about two years old, but she's so much more than that. So when she was first diagnosed, they told me she'd never walk. She'd never make eye contact, basically that she'd never do anything, but she walks, she jumps, she sings. She is nonverbal, but she can make herself known. She does a bit of sign language. She has a communication device and she will get her point across one way or another. So she's just amazing, and she turns nine next week. Brenna: Oh, growing up, another birthday. Melanie: Yeah. Brenna: So from that initial diagnosis, you were hearing all of these can'ts and won'ts. What has it been like for you to see her achieve all of these things? Melanie: Oh, I'm bursting with pride basically. She's, like I said, really, really stubborn. When she wants to do something, she will work and work and work until she does it. So I mean it's been a lot of work, a lot of appointments, but she takes it all in her stride. So she's amazing. Brenna: So, when did you first realize that ... I think as I've had the chance to sort of look through your blog, and I think it was pretty early that she was given this diagnosis. Did you know when she was born that she was different or what sort of led to undergo testing and to get that diagnosis? Melanie: I had zero clue. So when she was first born, everybody commented on her cry, how she sounded like a cat and things like that. Her 48-hour check, the pediatrician actually noted her unusual cry, her small round head. She had an ear tag, the way she was a bit floppy. They noted all that down, but they said everything's fine. So we got sent home the next day and she just cried and cried and cried. And then after about 10 days, they realized she wasn't gaining any weight, even though I was breastfeeding constantly. So that's when they decided to do some tests basically. So Five P minus was one of the tests they did. Brenna: That must've been a shock for you to be thinking that things are going okay, like maybe she wasn't gaining weight right, but you didn't have an idea about something like a chromosome piece was missing was going on. Melanie: No, I had no clue. I just didn't even think of it. I kind of was quite naive when I was pregnant I think. I assumed that most sort of disabilities were picked up during pregnancy. I didn't know that there was things out there that you didn't know about. So yeah, I was shocked. Brenna: Yeah. And so, you've mentioned the support groups that you've found that have sort of been a great chance for you to connect with other families and also maybe get some perspective of how things might look. Has there been other things that have been helpful for you specifically? Melanie: Main, the Able Finder app has been amazing. So it's only been around a little while now, a few months, but I think if I had've had that when Ella was first diagnosed, it would've been just a weight off my shoulders because there really wasn't much around. So when Ella was diagnosed and I Googled Five P minus, in Australia, the website that we had hadn't been updated in years. There was just zero information. So it's really good that now that there's Facebook groups and there's a lot more support than there was back then. Brenna: Yeah. There's instantly a community that can sort of say, "Hey, we know where you've been. Here you are. You're not alone. You've got this," so that's ... and I think we're going to talk about it in just a second, but I think your blog is definitely adding to that community of, "Hey, you're not alone. Here's my story. Let me tell you how it's going to go." So sort of thinking about that, what has ... so you receive the diagnosis, you had a chance to sort of do your own Googling, sort of figure things out, but what has the actual therapy and management looked like for Ella, and how has that been for you and your family managing that? Melanie: So when she was six months old, we started early intervention, which in Australia is amazing. So we had speech pathology, physiotherapy, occupational therapy every single week. We also saw other specialists. So we saw an orthopedic surgeon and we saw a lot of specialists. So it's been really good. Now that she's a bit older, it's settled down a bit. So we just see the speech pathologist, the occupational therapist sort of weekly or fortnightly. And we see physio every few months so ... And she goes to a specialist school and they're really helpful with everything there as well. So I think that's sort of the main reason Ella has managed to come as far as she's come is all of the interventions we've been able to get. Brenna: And for you guys that are listening, Ella's very lovely and she seems to be doing great things. You guys can see pictures of her on Melanie's blog and she's in all of the great things she's doing and her little brother as well. So kind of now getting into your blog, which is the whole reason I was able to find you and it's really great. I can't recommend it enough. What made you decide like I need to start blogging and I need to tell people my story? Melanie: Peer pressure, I guess. So I used to write a little bit just on my personal Facebook page, nothing major. And all of my friends were like, "You should write properly. You should start a blog." So I thought, "Well, why not?" And I did it. And then once I started writing, I actually found it to be quite cathartic so it was really helpful for me and it also got me involved with more people. So a lot of people would message me and tell me how I'm helping them, and I made friends. So it's really been amazing for me. Brenna: And I think that's great, and I'm sure everyone who reads it is just as thankful to have a voice and to have awareness that's brought to such a rare condition. So if people who are listening maybe want to check you out, where can they find your blog? What's it called? Give us the details. Melanie: So you can find me on facebook.com/thehonestpirate or just the honestpirate.com, both of those places. I share a lot more on Facebook than the website. The website, I do my big writing on. So yeah, you can find me on either of those places. Brenna: And so, if you could come up with a few things or one top thing, what would be your best advice for families who maybe are trying to get involved in the community? Melanie: Just find us, find us and talk to us. Basically, because it's so rare, we all know everybody. So it's sort of you find one of us and we can get you in contact with the other groups and the other parents and yeah, just listen. Brenna: Yeah. And so, I want to thank you for spending time today, telling us a little bit about your story and also just shedding light on Five P minus syndrome in general. Before I let you leave and while I have you, as someone who's gone through that shocking diagnosis first hand, if you were to talk to someone who has just been diagnosed or maybe has a loved one who's been diagnosed, what would you want to tell them? Melanie: The diagnosis doesn't actually define who you are. Don't let anyone tell you what you can and can't do or what your kid can and can't do. You decide for yourself. Brenna: Thank you, Melanie, for introducing us to Ella. For most families, the diagnosis of Five P minus syndrome can come as a shock, but don't give up. You're not alone. To read more about Melanie and Ella's story, you can check out their blog at thehonestpirate.com. Brenna: In closing, we've had the chance to talk to three experts today in Five P minus syndrome, but this is just the beginning. We've taken all of today's information and included it in a free downloadable guide. You can get your guide by going to raredisease.com/fivep. We would love to connect with you. If you need someone to talk to, we're standing by. Go to raredisease.com/help. We're waiting for you. Rare Disease Connection is a production of Aspect Health and raredisease.com. Thanks for joining us.

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