Introduction

Humans inherit their genes from their parents, half from the father and half from the mother. Normally, humans inherit 23 pairs of chromosomes, with one chromosome in each pair inherited from each parent. These chromosomes are made up of DNA. DNA carries information that tells our body how to grow and develop.¹ Our genes have been studied widely by many scientists to understand how they normally work and how changes in genes can change the body's structure and function. Some gene changes cause mutations, which in turn affect how genes work and hence could lead to diseases.

GLI3 gene

Every gene in the body plays an important role in the development and function of the body. Some gene mutations and changes do not cause a huge abnormality in the function or structure of the body. However, the GLI3 gene mutation can impact the normal development of the body, therefore, causing many abnormalities and discomfort to an individual. 

The GLI3 gene is involved in the early growth and development of the brain and lung during early growth of an embryo and throughout infancy.^2,3 It is known to play a significant role in the Hedgehog signalling pathway. The Hedgehog signalling pathway is involved in foetal development and growth.^3,4 The gene GLI3 acts as a switch in the system, turning it on and off to initiate foetal development.⁵

Pallister-Hall Syndrome Characteristics

Pallister-Hall Syndrome (PHS) is an uncommon congenital disease (a disease present from birth). It is known to be an autosomal dominant disease.⁶ Autosomal dominant disease means that only a single copy of the mutated gene needs to be present to cause the condition. It indicates you are still at risk of developing the disease even if one of your parents is carrying the genetic abnormality. There is a 50% chance (1 in 2 chance) that the child will inherit the disease from their parents. Not many cases have been reported regarding PHS because they are so rare. The exact prevalence is not known.¹²

PHS is characterised by a genetic disorder that is involved in the developmental features during early growth. It is caused by a change (mutation) of the GLI3 gene. About 95% of PHS cases include the change happening in chromosome 7.⁷ This change of structure in the gene plays a significant role in the growth and development of an individual, given that the disorder is present and develops from birth and through the foetus’s development. 

This will lead to many features associated and linked to PHS, including hypothalamic hamartomas, polydactyly, bifid epiglottis, hypopituitarism and a number of anomalies. 

Main Clinical features

• Hypothalamic hamartomas (lesions in the brain)
• Polydactyly (Extra toe or finger)
• Bifid Epiglottis (breathing, swallowing problems)
• Imperforate anus (congenital defect)

Less common features

• Hypopituitarism (hormonal problems)
• Renal anomalies (kidney problems)

Hypothalamic hamartomas (HH)

Hypothalamic hamartomas are characterised by a small, slowly growing formation of a grey lesion located at the base of the brain.⁸ The growth of the abnormal non-cancerous lesion is known to cause seizures and visual impairment due to its very eloquent and sensitive place in the brain.⁹

Polydactyly

Typically, patients with PHS are also characterised by polydactyly, which is when patients have an additional finger or toe.^{10, 11} When a newborn baby has an extra finger or toe, it is advised that the baby be evaluated, as it could be a sign of a condition. The appearance of the extra finger or toe can cause problems in walking and using their hands. 

Bifid Epiglottis

The epiglottis is located at the back of the throat; it plays a role in protecting our airways. It prevents food and liquid from entering our lungs. Bifid epiglottis is when the structure of the epiglottis is distorted, leading to it being divided into two parts.¹² This will cause trouble as unwanted liquid and food will enter the airways, causing difficulty in breathing. Bifid epiglottis is mostly associated with PHS and is rarely seen in other diseases. It is a very useful clinical diagnosis.¹² 

Imperforate anus 

An imperforate anus is when the anal opening is blocked or absent at birth (a congenital defect). This prevents the stool from passing out. Normally, newborn babies fail to have a bowel movement within the first 24 hours after birth.¹³

Hypopituitarism

This will include problems in producing certain hormones in the body. Hormones are chemical messages that are passed down the body to inform it of what to do and how to grow. The underproduction of hormones will lead to delayed puberty and growth problems.¹⁰

Renal anomalies

In PHS, renal anomalies are common. This includes function and structure abnormalities. When this GLI3 gene is not formed properly, it can change the structure of the kidneys, and this will lead to them not working properly. A study on mice has shown that the mutation in the protein GLI3 can impair the structure of the kidneys, so that they do not form properly. It explains the complications that can occur and happen to the urinary and kidney system.¹⁴

Diagnosis

A combination of clinical and genetic tests can be performed to help in diagnosing PHS. If a patient is diagnosed with a hypothalamic hamartoma (HH) and polydactyly (An extra finger or toe), then it is most likely that they have PHS. The key diagnostic tool of HH in PHS is a brain MRI. It is a fast and safe diagnosis without the need for an invasive surgery, such as a brain biopsy. Additionally, it will also help in an earlier diagnosis of PHS. The characteristic of HH will help in differentiating them from tumours growing.⁷ An extra finger or toe will be visible and can be evaluated by an X-ray. Further genetic tests could be done to look for the change and mutation of the GLI3 gene. 

Treatment

The syndrome itself cannot be treated, but the symptoms of the disease can be managed. Individuals require care from different specialists to help them improve their quality of life. 

For instance, for polydactyl, they require a surgeon who can aid and remove the extra finger or toe if it is causing them trouble performing day-to-day activities. In addition to helping with breathing and enhancing the patient’s quality of life. Some research has suggested that airway management devices can aid with bifid epiglottis; they can be used and selected according to each individual circumstance to help with breathing.¹⁵

Seizures caused due to hypothalamic hamartomas (HH) could be treated with antiepileptic drugs. In some cases, surgery could improve the quality of life.¹⁶ Research has shown that surgical treatment could possibly prolong and improve the quality of life. About 80% of patients who have undergone the surgery are freed from seizures.⁹ Having regular seizures as a child could have a significant impact on the cognitive development of a child. Being able to avoid them is very crucial and helpful for this rare disease.  

Individuals with PHS also require specialists who can help them manage and control the level of their hormones through hormone replacement therapy to help with their intellectual development. In addition, they may benefit from a therapist who can support their learning and development skills. 

Summary

There are many different pathways that are involved in the development of the body. One of which is the hedgehog signalling pathway. The hedgehog pathway is a fundamental pathway that controls how and what type of cell to become during foetal development. The pathway includes genes that play a vital role in the system. The gene GLI3 is an important factor in the hedgehog signalling pathway. It works as a switch in the pathway by activating and assisting certain developmental instructions which aid in the growth and development of the foetal and infant. A mutation in the gene GLI3 causes the body to receive wrong instructions, which results in PHS. 

PHS is characterised by a number of features, including extra toes or fingers, non-cancerous brain lesions and abnormal hormone levels. These features vary from one patient to another; not all of them will be present in everyone. 

The only way to handle the disease is by managing the symptoms, such as hormone therapy, surgeries to remove the extra toe or nail and surgery to remove the brain lesion.

Awareness of this disease should be raised and expanded to aid with the illness. Further Research is required, studying the GLI3 gene, to determine how to treat and manage it to enhance quality of life. 

Since PHS is an extremely rare disease and minimal research has been conducted. It is very crucial to conduct additional research about the disease to be able to understand it and be able to manage the symptoms better.