Introduction

Pallister W syndrome is a rare genetic condition that is characterised by distinctive facial features, including clefting of the palate and upper lip, a flattened nose, and broadly spaced slanted eyes. People with this condition may also experience learning difficulties, speech challenges, arm and leg bone abnormalities, and seizures. Further indications can include a broad uvula, missing teeth, hair that is not flat on the head (cowlick), and involuntary muscle movements. Pallister W syndrome currently has no recognised cause.¹

Genetic basis and inheritance patterns

Although the precise cause remains unknown, researchers have suggested the condition can be caused by a change in genetic material (DNA mutations) or be inherited as an X-linked genetic characteristic.² 

Chromosomes are thread-like structures located inside the cell nucleus. Every chromosome consists of protein and a single deoxyribonucleic acid (DNA) molecule. Inherited from parents to offspring, DNA carries instructions that differentiate an organism from another. Humans have 23 pairs of chromosomes, resulting in a total of 46 chromosomes. 

People assigned female at birth (AFAB) typically have two X chromosomes (XX), while people assigned male at birth (AMAB) have one X and one Y chromosome (XY).³ Mutations in a gene on the X chromosome can result in X-linked recessive inheritance, which means a genetic characteristic can be passed down from a parent to a child. In people who are AMAB, only one mutation in the single X chromosome is needed, while people who are AFAB can only be affected if there are mutations in both X chromosomes. 

If a parent carries a mutated X-linked gene, daughters are often unaffected and are instead referred to as “carriers” since one of their X chromosomes has the mutation and the other is normal. Sons, however, will be impacted if they inherit the X-linked gene mutation from their mother. Additionally, X-linked recessive disorders cannot be passed down from fathers to their sons.⁴

Epidemiology

Pallister W syndrome is an extremely rare condition, with less than one in one million cases reported. Over half of the people affected are children who are AMAB; however, the number of cases is too limited to determine if it impacts one sex more than the other. Many cases likely go unreported because of the condition’s rarity, and possibly underdiagnosed due to limited awareness and access to genetic testing.¹

Spectrum of neurological symptoms

Relevance of neurological symptoms

Neurological symptoms are crucial for both diagnosis and prognosis because they are often the first signs and the distinguishing characteristics that can guide specific genetic testing. Doctors may first notice low muscle tone (hypotonia), feeding difficulties, developmental delay, and seizures in infancy. The degree of neurological involvement directly affects day-to-day function and long-term independence. Intellectual difficulties, involuntary movements (epilepsy), and hypotonia signify long-term disability and, as such, long-term support plans.⁵

Neurological symptoms

Developmental delays

A common characteristic of many X-linked genetic disorders is developmental delay; however, the nature and severity of the illness vary depending on the specific genes implicated. Additionally, growth during pregnancy may vary, and children may have shorter stature despite their head circumference staying normal.⁶

Intellectual disability

The percentage of X-linked variants that result in intellectual disability is significant. Several syndromic and non-syndromic X-linked disorders include intellectual impairments as a primary feature.⁷

Hypotonia and muscle weakness

Hypotonia is a broad term used to describe reduced muscle tone in the arms and legs, torso, or facial muscles. It can be identified at birth or later in childhood. In one recorded case, hypotonia in early childhood was followed by seizures and spasticity with increased deep tendon reflexes.⁸

Seizures and epilepsy

In X-linked disorders, seizures and epilepsy are caused by a change in a specific gene in the X chromosome that is crucial for neurological growth and nerve cell interaction. These changes can disrupt the regular signal balance in the brain, resulting in nerve cells becoming hyperactive and increasing the risk of seizures. People who are AMAB are typically more seriously affected because they only have one X chromosome, but females may be carriers while exhibiting less severe signs.⁹

Structural brain abnormalities

In X-linked syndromes, the brain develops irregularly, which can result in seizures and intellectual disabilities. Magnetic resonance imaging (MRI), electroencephalogram (EEG), or computed tomography (CT) scans of the brain can reveal the brain’s abnormal outer patterns, such as smooth or an overly irregular surface, a fragile or absent corpus callosum (the structure that links the two hemispheres of the brain). The genes impacted by these disorders can interfere with normal brain development and wiring, resulting in both intellectual and motor difficulties.¹⁰

Behavioural and cognitive issues

On the X chromosome, several genes either require both copies to function properly or are immune to X-inactivation. Gene expression is reduced if one copy is absent or altered, a concept known as haploinsufficiency, which can be seen in people who are AMAB with certain X-linked mutations or in people who are AFAB with Turner syndrome. Haploinsufficiency can lead to issues with mental agility, impulse control, and concentration.¹¹

Diagnostic evaluation

Clinical assessment 

Early diagnosis and intervention can improve outcomes and help families plan for ongoing care.^12,13 If an X-linked disorder is suspected in newborns or young children, clinicians should observe for certain symptoms and indicators. Family history should also be studied, and some key signs may include: 

• Developmental delays
• Low muscle tone (hypotonia) 
• Seizures 
• Poor attention 

Treatment 

Treatment for Pallister W Syndrome is individualised and may involve:¹

• Surgery to correct cleft lip or palate and bone abnormalities 
• Anti-seizure medication to manage seizures 
• Speech therapy, particularly following surgical repair of the cleft palate 
• Special educational support to assist learning and communication
• Genetic counselling to help families understand inheritance and future planning

Summary

The main characteristics of Pallister W Syndrome include facial deformities, such as clefting of the palate and upper lip, flattened nose, and wide-set eyes. The neurological symptoms may include developmental delay, intellectual difficulties, and seizures, which can typically be seen from infancy or during early childhood.

Early identification allows children to begin physical, occupational, and speech therapies sooner, which can improve developmental outcomes, as well as manage seizures, feeding issues, growth problems, and sensory impairments. It also makes it possible for families to get genetic counselling, arrange care, and get a tailored support system.

The key to improving outcomes for people with X-linked disorders continues to be raising awareness among physicians and families, and providing early, multidisciplinary care.