Cri du chat is a rare genetic disorder that results in specific anatomical features as well as severe delays in cognitive and motor development. In addition, Cri du chat can affect how the body produces and responds to growth hormones, thus stunting bone growth and potentially leading to neonatal failure to thrive and life-long small stature.

Introduction

Cri du chat syndrome (CdCS) is a genetic disorder which affects 1 in 50,000 children. It is characterised by the deletion of the short arm on chromosome 5. Symptoms include characteristic facial features – such as round faces and wide-spaced eyes - malformation of the larynx, hormonal imbalances, and varying levels of intellectual, emotional and motor impairments. The condition derives its name from the French meaning “cry of the cat”, which alludes to a typical vocalisation found in affected babies, which resembles the “meowing” of a cat due to abnormalities in the larynx.¹

Hormonal deficiencies often accompany Cri du chat syndrome. The short arm of chromosome 5 contains the genetic information to generate the receptors that growth hormone and prolactin bind to. As such, its deletion can reduce the functions of these hormones, most notably growth hormone dysfunction can lead to short stature and failure to thrive.² In addition, CdCS is also characterised by craniofacial malformations associated with atrophy of the pituitary gland, which is responsible for stimulating secondary endocrine activity.³

Unlike other genetic disorders, CdCS has a normal life expectancy, and many patients live a normal life with the required adjustments. Understanding all aspects of the disease is fundamental to maintaining long-term health across adult life. Low birth weight, particularly, is associated with poor growth hormone function and is a common complication and predictor of poor health in Cri du chat syndrome.⁴

Cri du chat syndrome

Cri du chat syndrome was first described in 1963 by Jérome Lejéune, a pioneer researcher in chromosomal disorders who had previously discovered Trisomy 21 (Down´s Syndrome).⁵ It results from a partial or complete deletion of the short arm of chromosome, which is usually de novo; in 20% of cases, the mutation is inherited from heterozygote parents.⁶ CdCS affects 1 in 50,000 live births and is slightly more prevalent in people assigned female at birth (AFAB). Common features found in affected babies include:

Craniofacial features

• High-pitched cat-like cry
• Round face
• Low-set ears
• Down-turned mouth
• Broad nasal bridge
• Microcephaly
• Epicanthic folds
• Micrognathia (Small mandible)
• Dental malocclusions            

Neurodevelopmental and behavioural features

• Moderate-to-severe intellectual disability can occasionally be mild
• Characteristic behavioural features such as hyperactivity
• Gentle personality
• Obsessive interest in specific persons and objects
• Speech and language delays
• Poor motor control characterised by hypotonia or hypertonia and late onset of walking

Other symptoms

• Low birth weight and low weight throughout life
• Growth retardation and short stature
• Cardiac abnormalities such as patent ductus arteriosus, and atrial and ventricular septum defects (ASD/VSDs), often require surgery
• Ocular abnormalities such as myopia and cataracts 
• Gastrointestinal problems, especially gastroesophageal reflux
• Excessive drooling
• Hearing loss
• Recurrent infections^1,5

CdCS is usually diagnosed through Genomic Comparative Hybridisation (GCH), undertaken in infants with typical vocalisations and facial features at birth. Doctors will often carry out a mandatory counselling session with the parents before genetic testing.¹

There is no treatment for CdCS. However, some investigations are recommended to recognise life-threatening cardiac abnormalities that can be treated with surgery. In addition, children affected have to be monitored for short stature and hearing/visual defects, which can be corrected with aids. Supporting patients and families with CdCS requires a special needs care team to address developmental and health concerns and promote quality of life from infancy through adulthood.¹

The endocrine system and growth

The endocrine system consists of a set of organs and their respective signalling chemicals, which function together to maintain homeostasis in the human body. Hormones are chemicals that can activate receptors in cells to change their behaviour and alter certain biochemical pathways. Hormones are released into the blood circulation by organs and glands to signal homeostatic changes and the necessary tissue response.

The pituitary gland, “the master gland”, communicates with the nervous system and releases hormones. These hormones coordinate the activity of other endocrine structures – e.g. pituitary thyroid-stimulating hormone (TSH) stimulates the thyroid to produce Thyroxine (T4), which then accelerates nutrient and fat breakdown by the liver.⁷

10-15% of all pituitary cells secrete Growth Hormone (GH) into the hypophyseal portal vessels. This chemical travels along the bloodstream, activating its receptors to modulate several cells and tissues across the body, serving as a pivotal regulator.⁸

Some of its effects include:

• Facilitates growth during childhood and adolescence by stimulating the activity of bone-forming cells called osteoblasts
• Regulates metabolism by promoting fat breakdown and controlling blood sugar levels.
• Fosters muscle growth and repair
• Promotes a healthy body composition by reducing fat deposition
• Enhances bone density indirectly through insulin-like growth factor 1 (IGF-1) production.
• Aids immune function
• Contributes to emotional well-being through interactions with neurochemistry⁹

Growth hormone abnormalities in cri du chat syndrome

One significant aspect of CdCS is its association with hormonal deficiencies. The short arm of chromosome 5 contains the genetic information necessary for producing receptors that growth hormone and prolactin (a hormone involved in lactation and other functions) bind to. When this genetic material is deleted or altered, it can lead to reduced functionality of these hormones.²

Moreover, CdCS is associated with atrophy (shrinkage or degeneration) of the pituitary gland, a small gland located at the base of the brain. The pituitary gland plays a vital role in regulating various hormonal functions by producing and releasing hormones that stimulate other glands to produce their hormones. The atrophy of the pituitary gland in CdCS can affect its ability to stimulate secondary endocrine activity, contributing to the hormonal imbalances observed in individuals with this syndrome.³

The dysfunction of growth hormone is particularly notable in CdCS. Growth hormones play a crucial role in stimulating growth and development throughout childhood and adolescence. When its receptor function is impaired due to the genetic deletion associated with CdCS, individuals may experience short stature and failure to thrive; most patients remain below the 5th percentile in height and weight for their respective age.^4,10

Management of endocrine problems in cri du chat syndrome

For infants with Cri du chat, clinical guidelines recommend supportive interventions and growth monitoring to promote weight gain and bone development. In severe cases of low birth weight, neonatals should be incubated to ensure survival.¹ Feeding difficulties can further exacerbate stunted growth. Therefore, doctors may recommend using the nasogastric tubes in some cases. Dysphagia is a common feature of CdS; research shows these babies can benefit from oral stimulation training through non-nutritive sucking.¹⁰ Height, weight and head circumference should also be regularly monitored by care providers, allowing for comparison with average values.¹¹

Some drugs that mimic the structure of growth hormones are also approved for the management of GH deficiency associated with chromosomal syndromes. This treatment can only, however, be initiated if deemed appropriate by a paediatric endocrinologist.¹²

Summary

Cri du chat is a genetic disorder caused by a deletion in chromosome 5. It affects 1 in 50,000 births, causing several health problems and affecting the quality of life. In addition to potentially severe intellectual and motor retardation, patients also often fail to grow to age-appropriate height and weight standards. Low birth weight is a predicting factor of poor health across infancy and adult life.

The endocrine system regulates all metabolic processes in the human body. The pituitary gland releases hormones or stimulates the secondary endocrine glands to release hormones. One such is growth hormone, which upon activating its receptor, stimulates osteoblast deposition.

In CdCS, there is often a deficiency in growth hormone signalling, which researchers hypothesise may underlie the failure to thrive observed in many children with the condition. Supporting growth through feeding, milestone monitoring, and potentially pharmacotherapy is, thus, fundamental to counteracting this biochemical abnormality.