Overview

Cri du chat syndrome, also known as “cat’s cry syndrome” or “5p- syndrome”, is a rare condition affecting about 1 in 15 000 to 1 in 50 000 babies. The syndrome's name references the particular sound of the newborn’s cry in the first few weeks of its life, which is considered to sound like the high-pitched cry of a cat. The severity of the symptoms is variable, depending on the size of the genetic error causing the syndrome, and the prognosis varies accordingly. 

Besides the characteristic cry, the symptoms of cri du chat syndrome vary widely but may include distinctive facial features, growth and developmental delay, intellectual disability, and a range of other possible problems affecting different systems of the body. A newborn with cri du chat syndrome will have the unique cry, low birth weight, microcephaly (small head circumference), hypotonia (muscle weakness), feeding problems, possible asphyxia and recurrent infections. These factors negatively influence the growth and development of the child.^1,2

The term “growth delay” is used in cases where a child is smaller than his peers of the same age. The growth of a child is an important process for whole body development, so doctors use growth charts to evaluate the height, weight, head circumference and BMI of children. Because growth delay is a characteristic symptom of cri du chat syndrome, specific growth charts have been developed in order to monitor the growth of the affected children.³ 

This article aims to present cri du chat syndrome, covering some general aspects of the syndrome, such as the genetic cause, the clinical features, diagnosis and treatment. We will also focus on the growth delay characteristics and their impact on the course of the disease. 

What is cri du chat syndrome?

Genetic cause

Cri du chat is a genetic condition caused by a variable deletion (missing genetic information) located on the short arm (called “p”) of chromosome 5. The DNA, genes, and chromosomes are the genetic instructions the body needs to function. The deletion of genetic material can be variable in size, and it is a “de novo'' mutation in 85% of cases, which happens “by accident”. In about 10-15% of cases, one of the parents is a carrier of a balanced translocation of the genetic material corresponding to the short arm of chromosome 5, and their child will have an unbalanced translocation, causing a chromosomal anomaly and, therefore, the Cri du chat syndrome.^1,2,4 

Symptoms

The most characteristic symptom is the “high-pitched, cat-like cry”, evident from birth, and manifested during the first few months of life. The newborn also presents with low birth weight, microcephaly (small head circumference), hypotonia (low muscle tone), and particular facial features, such as hypertelorism (widely spaced eyes), epicanthal folds, low-set ears, micrognathia, round face, and a large nasal bridge. Malformations can also be present at birth, involving the heart, kidneys, genito-urinary system, and others.

Affected babies can present with asphyxia, repeated respiratory and intestinal infections, and feeding difficulties, all contributing to failure to thrive. As they grow, affected children also experience growth delays, delays in reaching developmental milestones, speech and language difficulties, and intellectual disability. Most people with cri du chat syndrome have a normal life expectancy, but in some cases, the life-threatening symptoms and complications can be fatal, and about 90% of deaths occur before the age of 12 months.^1,2,4

Diagnosis

The suspicion of cri du chat syndrome is based on the clinical symptoms a newborn presents with, and a genetic test confirms the diagnosis. The standard test is the karyotype, but fluorescence in situ hybridization (FISH) analysis, array comparative genomic hybridization (array CGH), and quantitative polymerase chain reaction (PCR), can also be performed.

A prenatal diagnosis can also be made, through amniocentesis, or chorionic villus sampling. Prenatal ultrasound abnormalities and advanced maternal age can be reasons to perform these tests. Foetal DNA analysis can be made from the maternal blood, using non-invasive prenatal testing (NIPT). Genetic counselling is recommended before and after genetic testing, especially in prenatal settings.^1,2,4

Treatment

Early diagnosis, intervention, and appropriate support therapies, such as physical, occupational, and speech and language therapy, and special education can help children with Cri du Chat syndrome reach their potential and live meaningful lives. This disorder has no specific treatment, and the caring process for these patients is complex, requiring a team of healthcare professionals.^4,5

What does growth delay mean?

The terms “Growth problems”, or “growth delay”, describe the insufficient growth of a child at a certain age. Children with growth delay usually grow for a longer period than their peers and often eventually reach a normal height. They could also be described as “small for their age”. Doctors assess and monitor the growth of children over time, using growth charts as an objective tool to compare the height, weight, head circumference, and BMI, to the expected values for a certain age, from birth to 18 years.

The World Health Organisation's (WHO) child growth standards and The Centers for Disease Control and Prevention (CDC) Growth Charts are international reference tools to monitor and evaluate child growth worldwide. Babies and children in the United Kingdom (UK), are monitored with the UK-WHO growth charts for 0-4 years and with the UK-WHO growth charts for 2-18 years. 

Constitutional growth delay leads to short stature and affects about 15% of children. A child has a short stature if their height is below the 3rd or 5th percentile of a growth chart. This means that a child with short stature is smaller than the shortest 3 to 5% of other children of the same age. To better understand the growth percentiles – if a child is in the 50th percentile for height, it means that their height is exactly average, with 50% of children being taller than them, and 50% shorter than them.

Other data consider short stature to be below the 2.3 percentile, and extremely short stature, below the 1st percentile. The causes of short stature can be constitutional factors, endocrine conditions, growth hormone deficiency, illness, malnutrition, severe stress, genetic disorders, and others, but sometimes no cause can be found.⁶

Cri du chat syndrome and growth delays

Causes of growth delay in cri du chat syndrome

A gene is a segment of the DNA that encodes the “instructions'' for particular functions of the human body. Researchers studied how certain deleted (missing) genes from the short arm of chromosome 5 are linked to the symptoms of cri du chat syndrome.

The deletion of the gene called telomerase reverse transcriptase (hTERT) causes some of the clinical symptoms of the syndrome. The hTERT gene is linked to cell proliferation and is “strictly required” for the normal growth process of the human body. The deletion may affect the normal foetal development, possibly contributing to the growth and intellectual delay of the child affected.^2,7 

The size of the deleted region of the short arm of chromosome 5 appears to be related to microcephaly (small head circumference) in the affected children. Some children have microcephaly at birth, but almost all develop microcephaly later on, with the most severe cases associated with a larger chromosomal deletion.⁸ 

Other causes of growth delay in cri du chat syndrome may be linked to the medical problems that affected babies experience in their first 2 years of life – for example feeding difficulties due to hypotonia and gastroesophageal reflux, breathing problems such as asphyxia, recurrent respiratory infections (pneumonia), and congenital heart defects.^2,4,9

Prenatal and postnatal growth delay in cri du chat syndrome

Prenatal (before birth) and postnatal (after birth) growth delay is a common feature of cri du chat syndrome. On the international standard growth charts for the healthy general population, the median (average) measured values for cri du chat patients regarding weight, height and head circumference, appear to fall below or around the 2nd or 5th percentile. This means that their growth values are smaller than the shortest 2% or 5% individuals of the healthy general population.^2,3,5 

The prenatal growth delay might be difficult to link to cri du chat syndrome if no prenatal genetic test is performed, but the prenatal ultrasound exam can suggest the growth delay by identifying the microcephaly and other abnormalities related to the foetus.

The newborn affected by cri du chat syndrome presents with low birth weight and microcephaly, and adapts to the extrauterine life (life outside of the womb) with difficulty. These aspects could also be indicative of the prenatal growth delay. Some values reported by studies are a mean weight of 2614g, and a mean head circumference of 31.8cm, in newborns affected by cri du chat syndrome.^1,2,4,9,10

Postnatal growth delay can be identified more easily by measuring the weight, height and head circumference of the affected children. A multicentre study published in 2000 analysed cri du chat patient data and developed specific cri du chat growth charts based on the growth charts for the general population. About one-third of the analysed patients had a birth weight of around 2.5kg, interpreted to be “underweight” for the normal population.

The median growth curve regarding weight throughout life was around the 5th percentile of the normal reference. The median head circumference showed microcephaly and was below the 2nd percentile. The median height appeared to be normal for the first 2 years, but then also fell to about the 5th percentile of the normal reference.

Although always under the normal expected values for their age, the growth measurements of the children affected by cri du chat syndrome follow a consistent pattern, and the height and weight seem to be proportional enabling specific growth charts to be developed to guide doctors to care appropriately for their patients, preventing unnecessary interventions related to the growth process.³

Another study published in 2001 analysed the growth measurements of cri du chat patients and suggested that the growth delay might be linked to undernutrition. Microcephaly was more severe in more underweight patients, but most of the patients were rather lean, and their muscle development was “relatively good”. This study concluded with a focus on the need to monitor the nutrition and growth of the affected children.¹¹

The impact of the growth delay 

Early diagnosis and prompt intervention are very important to limit the negative impact the growth delay has on the overall development of children affected by cri du chat syndrome. Newborns should start physical therapy even in the first week after birth, to improve their feeding difficulties and therefore, improve their nutritional intake. Early diagnosis also enables early treatment of the other associated medical problems, improving the physical and overall development of affected children.^1,9

Summary

Cri du chat syndrome is commonly known by this name due to the distinctive cry of the affected newborns, which resembles the cry of a cat. The severity of the symptoms is variable and is related to the specific genes deleted from the short arm of chromosome 5. The growth delay commonly seen in cri du chat patients is caused by genetic factors, such as the deletion of the hTERT gene, and also by other medical problems the affected babies present with in the first two years of life, such as hypotonia, feeding difficulties, recurrent infections and congenital heart problems. 

Prenatal and postnatal growth delay is a common feature of the syndrome, and specific cri du chat growth charts have been developed to help monitor effectively the weight, height, and head circumference of these children, preventing unnecessary treatment or intervention regarding the growth process. 

Cri du chat patients and their families might find support groups helpful:

• The Cri du Chat Support Group 
• Five P Minus Society