Cri Du Chat Syndrome And Thyroid Dysfunction

Overview

Cri du Chat is a genetic condition caused by a partial deletion (missing genetic information) on the short arm of chromosome 5.¹ Depending on the position of the deletion and its length, different symptoms can arise. One of these is various issues with the thyroid. 

The following article will explore this in more detail to help shed light on the secondary thyroid concerns that can arise in patients with Cri du Chat.

What is cri du chat syndrome?

^{Created by Ana Kuznetsova using BioRender}

Cri du Chat is a genetic abnormality that can cause a plethora of issues, caused by a genetic deletion between position 12 and 13 on chromosome 5.¹ Examples of the genetic differences caused by Cri du Chat include:² 

• Extremely wide-set eyes (hypertelorism)
• Down-slanted eyes (antimongoloid palpebral fissures) 
• A smaller-than-average head circumference (microcephaly) 
• Small jaw (micrognathia) 
• Extra skin folds covering the tear ducts (epicanthal folds) 
• One or both eyes facing away from the central line of vision (exotropia) 
• A high-pitched, cat-like cry which gives the syndrome its name 
• Webbing (joining together) of the toes or fingers
• Low-set, or small ears

It can be quite overwhelming to have a child born with this condition, and at times accompanying (secondary) conditions such as the following can also occur:²

• Sleeplessness
• Constipation 
• Speech and language delays
• Cognitive impairment 
• Delays in motor function  
• Problems with the thyroid gland 

But first, we’ll take a closer look at the thyroid gland and its normal function in a healthy body in order to gain a better understanding of what goes wrong in patients with Cri du Chat and what effects it can have on their quality of life.

How does the thyroid typically work?

The thyroid gland is a butterfly-shaped organ that sits in front of the windpipe (organ) at the base of the neck.³ It plays an important role in growth, development and metabolism (chemical reactions in the body). It has two lobes that lie on both sides of the windpipe, connected by a central part called the isthmus. 

The thyroid produces hormones that affect many parts of the body, storing them in small follicle sacs in the thyroid gland until they are released into the bloodstream.³

The thyroid gland is responsible for 3 main hormones³:

• Calcitonin
• Triiodothyronine (T3)
• Tetraiodothyronine (T4)

Our bodies absorb small amounts of iodine from the food that we eat, transporting it to the thyroid gland to produce these hormones. The iodine binds to the tyrosine amino acids, which are then bound to each other to make T3 or T4, depending on how many iodine molecules are involved (3 or 4, respectively).

The amount of these individual hormones required by the body at different points in time can differ due to various factors, so the pituitary gland in the brain guides the thyroid gland on how much hormone to produce.³ 

When they are released into the bloodstream, they are still bound to thyroglobulin or other carrier proteins, and upon separation from this protein by enzymes, they can carry out their functions within the rest of the body. Only 0.2% of T4 is typically unbound and can move freely in the bloodstream.⁴ 

Once they make their way into cells, they can bind to their specific receptors, called alpha or beta, to carry out their respective functions.⁴

These hormones can then be released into the bloodstream to produce various effects, depending on their concentrations and the organs they reach. T3 and T4 can produce many effects including^3,4:

• Increasing heart rate 
• Increasing blood output from the heart (cardiac output) 
• Increasing the amount of blood which is pumped out from the heart (stroke volume) 
• Making the heart pump more strongly with each pump 
• Increased blood flow to the lungs, meaning more oxygen is available for use at any given second
• Increasing type 2 fast muscle fibre expression, therefore permitting faster muscle contractions quickly
• Increasing body temperature

Because of all these effects, oxygen is used more quickly by cells to carry out more respiration, so the body has more energy to carry out its functions. 

The metabolic rate, referring to the below processes, is also increased: 

• Storage of glucose as glycogen 
• Digestion of carbohydrates 
• Making of proteins
• Making or breaking down lipids (fats)

At different concentrations, they can also encourage the body to break down proteins, and again lipid synthesis (formation) or breakdown can occur, depending on the dietary habits of the individual.^4,5

Calcitonin is involved in preventing the natural breakdown of bone, so it keeps calcium locked within the bones and keeps circulating levels of it from rising too high which can also cause adverse effects on health.⁶

In children, T3 and T4 are also involved in growth. They work with another chemical produced in the body called growth hormone to encourage the development of new bone and cells which regulate and interact with bones to keep them healthy and functional.⁴

T3 also plays a key role in the formation of new neurons, both during pregnancy and after birth.⁷ They help new neurons form, help organise the neurons, stimulate growth of the protective myelin sheath that cover motor neurons and help new synapses (connections) between neurons form.⁷ 

Though the way these hormones influence cognition is not entirely understood, diseases with deficiencies in these hormones have resulted in cognitive impairments and it is also thought to influence the onset of dementia in certain cases, so it is important that the hormonal balance is controlled.⁸

Cases of thyroid problems in Cri du Chat syndrome

Case 1

A 4-year-old patient with Cri du Chat syndrome was diagnosed with hypothyroidism (deficiency in thyroid hormones) and treated with L-thyroxine supplementation to correct the extra unwarranted hair growth and delayed cognition and motor skills. 

Although the thyroid problems were corrected with medication, their cognitive and motor skills remained underdeveloped (they could communicate using single words during his early teens) and eventually postural and vision problems also developed. 

As studies have shown that the thyroid hormone T3 influences the formation of new neurons, synaptic connections and maturation of motor neurons, it is entirely possible that controlling and treating the depletion of thyroid hormones seen in the patients allowed them to develop and grow with a better cognitive outlook.⁸ 

Although the thyroid hormones are not related to the genetic regions affected by Cri du Chat deletion, it is entirely possible for new changes (mutations) to occur which can result in this problem co-existing and exacerbating Cri du Chat symptoms.¹ 

Although it is true that few Cri du Chat patients achieve the ability to work and live independently, it is important to also monitor the thyroid function and treat it accordingly to minimise the growth abnormalities that could occur.⁸

Other cases have noted that no thyroid problems existed with Cri du Chat in patients, though ocular issues due to the underdevelopment, or possible death of parts of the optic nerve can typically lead to vision issues in Cri du Chat syndrome.^9,2

Case 2 

Another case demonstrated how a 20-year-old patient was diagnosed with papillary thyroid cancer. Although this is the most common kind of thyroid cancer, it is normally diagnosed between the third and fifth decade of life.¹⁰ 

Earlier incidence may be due to other genetic changes present, and the initiator sequence which permits the formation of proteins (promoter region) called TERT (position 33 on chromosome 5) may be linked with causing thyroid cancer.¹⁰ 

The patient overcame cancer and was cured within 2 years, but it is possible that the genetic changes which caused Cri du Chat syndrome were also responsible for causing this possible mutation that could result in thyroid cancer. 

As such, it is vital to monitor the thyroid function in Cri du Chat patients to ensure that the quality of life of patients with this illness is preserved, especially when many patients may have communication difficulties.^8,10

Summary

Thyroid problems can occur in patients with Cri du Chat syndrome, such as thyroid cancers or insufficient levels of thyroid hormone production which can affect the quality of life of patients. 

These problems can exacerbate the symptoms of the Cri du Chat syndrome, thus causing greater disability during childhood development, or pose the risk of fatality. 

However, thyroid issues aren’t always present in Cri du Chat patients, and the issues may arise due to excessive deletions or other non-related genetic changes during foetal, or adult development. 

It is therefore important to monitor thyroid function to ensure the best quality of life, and to minimise the risk of disability and mental health issues which can result from thyroid issues.