Introduction

Pallister-Hall syndrome (PHS) is a rare genetic disorder resulting from a mutation in the GLI3 gene. PHS has an autosomal dominant inheritance, meaning that only one copy of the mutated gene is required for individuals to present with the disorder. 

PHS characteristically presents with a non-cancerous growth in the hypothalamic region of the brain - hypothalamic hamartoma, as well as additional fingers and toes known as polydactyly. Although these are the main characteristics of PHS, individuals with this condition can also present with a divided epiglottis (bifid epiglottis), imperforate anus, small nails, low pituitary gland hormones (hypopituitarism), growth hormone deficiency, and poorly developed genitalia (genital hypoplasia).¹

PHS’s diagnostic features were first documented in the 1970s. Dr Hall reviewed 6 infants with what was then known as neonatally lethal malformation syndrome. Outside of Dr Hall’s work, further cases were being reported to the National Institute of Health. From all these cases, the diagnostic criteria for PHS were established.²

In this article, we will explore the history and discovery of PHS, including the genetic cause and its clinical presentation.  Additionally, we will review the criteria for its diagnosis and proper management.

Historical background 

As mentioned, the first cases of PHS were reported in the 1970s.  The first few cases piqued Dr Hall's medical interest due to the unusual features observed. These newborns had extra fingers and toes, their anus were unperforated, and they would die shortly after birth. As more of these unusual cases were discovered, Dr Pallister, a paediatrician and geneticist, was also encountering newborns with these physical symptoms. 

Further investigation found the newborns to have hypopituitarism. The pituitary gland produces hormones that regulate the body's essential processes necessary for life. Lack of pituitary gland function leads to death and was thought to be the cause of death in this patient group. As time went on, more of the cases were researched. It was clear that the physical and hormonal characteristics were present in all cases. 

Upon genetic analysis, a mutation to the GLI3 gene was found to be the source of these symptoms. The inheritance pattern and mutation type were further studied to make a clear link between the gene and the presentation. Although the impact of Dr Hall and Dr Pallister's work was vast, their research only focused on a small number of children. This minimal presentation in the general population helped recognise PHS as a rare genetic disorder.^3,4

The research behind PHS established diagnostic techniques for rare syndromes. PHS had only been described in 100 cases worldwide.⁵ As with many rare genetic disorders, the name of the condition is that of its founders. To the rare disease community, many common conditions are named after their founder. Even outside of conditions, procedures bear the name of the person who was the lead inventor. Alzheimer's, Heimlich, and Prader-Willi are household names that endure long after the clinicians who discovered them have passed away.⁶

Characteristic features and complications 

Clinical  features of PHS

• Hypothalamic hamartoma 
• Polydactyly 
• Bifid epiglottis
• Hypopituitarism
• Imperforated anus

Although these symptoms are characteristic of PHS, they can vary greatly. Some individuals present with very severe symptoms, whereas others have very mild symptoms. Differences in presentation severity depend on many things. Generally, age is the most reliable indicator of severity since very severe symptoms are life-limiting.

There are some major complications associated with the clinical features. Hypothalamic hamartoma is a non-cancerous tumour that grows in the hypothalamus, a region deep within the brain, which can cause seizures.⁷ Endocrine abnormalities may also be present.⁸ A bifid epiglottis can significantly disrupt newborn feeding and lead to long-term issues with the airway.⁹ An imperforate anus results in the absence of an opening at the end of the gastrointestinal tract. This can cause a complication of bowel perforation.¹⁰

Typical prognosis is solely dependent on the severity of the clinical features. Some individuals pass at infancy, and others live into later life. 

Diagnosis and management

A diagnosis of PHS is made through clinical assessment, medical imaging, and genetic testing. Clinical assessment involves observing the key clinical features that are visible. Imaging, such as an MRI, can help detect the presence of a hypothalamic hamartoma.  Blood tests can be used to investigate hormone levels and create a clinical picture. The definitive diagnosis, however, is genetic testing; through this test, the GLI3 can be reviewed to confirm a mutation that leads to PHS.

Management of PHS  involves many medical specialities due to the wide range of systems affected by the condition. Individuals will be cared for by a multidisciplinary team, including neurologists, endocrinologists, and surgeons. There is no cure for the condition; however, symptomatic treatment is provided to manage the symptoms. This may include anti-epileptic medication, corrective surgery and hormonal replacements. 

Care should also be provided to the family and the individual in order to educate them on the condition and its inheritance. Genetic counselling can be provided to reduce the risk of further passing down this condition.¹¹

Summary 

PHS  is a rare genetic disorder caused by a mutation in the GLI3 gene. Cases were first described by Dr Hall in the 1970s. The symptoms affect the neurological, skeletal, gastrointestinal, respiratory, and hormonal systems. Though genetic testing is used to form the definitive diagnosis, clinical assessment of the characteristic presentation, medical imaging, and hormonal blood tests may also be used. A review of each medical system ensures an accurate diagnosis is made.  There is no cure for PHS; however, symptoms are managed through medication and input from a medical multidisciplinary team, including neurologists, endocrinologists and surgeons.