Pallister-Hall Syndrome (PHS) is a rare genetic disorder affecting the development of various body systems. It is characterized by multiple anomalies that can vary greatly among individuals.
Understanding Pallister-Hall Syndrome
PHS is classified as a ciliopathy, a group of genetic disorders that affect cilia, microscopic, hair-like structures found on the surface of many cells. Cilia play a role in cellular processes and signaling pathways during development. The underlying cause of PHS is a mutation in the GLI3 gene, located on chromosome 7 (specifically, 7p13).
The GLI3 gene provides instructions for making a protein that helps control gene expression. This protein is involved in the sonic hedgehog signaling pathway, which is important for the patterning and development of many organs and tissues. Mutations that lead to PHS result in a shortened, abnormal GLI3 protein, which can only turn off (repress) target genes, altering normal development.
Recognizing the Clinical Features
Individuals with PHS can exhibit a wide range of physical and developmental characteristics, with varying symptoms. A common feature is polydactyly, the presence of extra fingers or toes. The skin between some digits may also be fused, known as cutaneous syndactyly.
Many individuals with PHS also have a non-cancerous growth in the brain called a hypothalamic hamartoma. Some can lead to neurological issues such as seizures, including gelastic epilepsy, and may also cause hormone abnormalities. Other features can include a malformation of the airway called a bifid epiglottis, a split opening of the airway, which may lead to respiratory problems. Imperforate anus, where the anal opening is blocked, and kidney abnormalities are also reported. Facial features may include a short nose, a flat nasal bridge, and low-set ears.
Diagnosis and Confirmation
The diagnosis of PHS begins with a clinical evaluation based on observable features. The presence of characteristic signs, such as polydactyly and a hypothalamic hamartoma, prompts consideration of PHS. A brain MRI is frequently used to identify the hypothalamic hamartoma.
To confirm the diagnosis, genetic testing plays a definitive role. Gene sequencing is performed to identify mutations in the GLI3 gene. Early diagnosis allows for better planning and management strategies.
Management and Support Strategies
There is no cure for PHS, so management focuses on addressing individual symptoms. A multidisciplinary team of specialists provides care. Surgical correction may be performed for physical anomalies like polydactyly or imperforate anus.
Hormonal therapies can be used to manage endocrine issues that may arise from hypothalamic hamartomas, such as growth hormone deficiency or precocious puberty. Neurological management, including anti-seizure medications, is provided if the hamartoma causes seizures. Developmental therapies, such as physical, occupational, and speech therapy, support development and address any delays. Ongoing care and access to support networks are components of long-term management.
Genetic Counseling and Family Implications
PHS is inherited in an autosomal dominant pattern, meaning that only one copy of the altered GLI3 gene in each cell is sufficient to cause the disorder. This implies that an affected individual has a 50% chance of passing the condition to each of their children. Genetic counseling is a valuable resource for individuals with PHS and their families.
Genetic counselors can help families understand the inheritance pattern, assess the recurrence risk for future pregnancies, and discuss family planning options. In approximately a quarter of cases, PHS can result from new, or de novo, mutations in the GLI3 gene, meaning the mutation occurred spontaneously. Genetic counseling provides information and support for families navigating these genetic aspects.