Sanfilippo syndrome (mucopolysaccharidosis III)

Sanfilippo syndrome (mucopolysaccharidosis III) is a rare genetic neurometabolic disorder caused by impaired degradation of heparan sulfate, resulting in progressive neurodevelopmental, neuropsychiatric, and multisystemic manifestations. It comprises four genetically distinct subtypes, MPS IIIA–D. It typically occurs as an inherited autosomal recessive genetic condition; absence of a relevant family history does not exclude the diagnosis because the parents of an affected individual are typically unaffected carriers. A distinctive presentation may include the combination of mild coarse facies, mild joint stiffness, intellectual disability, and behavioural problems.

It can present with psychiatric features such as hyperactivity, impulsivity, aggression, irritability, anxiety, sleep disturbance, behavioural dysregulation, autistic features, and psychosis. Psychiatric manifestations typically emerge during childhood, but psychosis may become clinically significant during adolescence or adulthood and can occasionally be an early or presenting manifestation.

From a morphologic lens perspective, features include (but are not limited to):

• Coarse face

• Synophrys

Other characteristic features include developmental delay, speech and language impairment, intellectual disability followed by progressive cognitive and functional decline, developmental regression, seizures, gait disturbance, spasticity, and other progressive neurologic manifestations. Other characteristic physical findings may include thick hair, hirsutism, macrocephaly, and hepatosplenomegaly. Some individuals with very attenuated disease may present in mid-to-late adulthood with early-onset cognitive decline or dementia, with or without a history of intellectual disability.

From a multisystemic lens perspective, clinical features in other body systems include (but are not limited to):

• Cardiovascular: valvular heart disease, cardiomyopathy, and cardiac conduction abnormalities or arrhythmias may occur.

• Respiratory: recurrent upper-respiratory and sinopulmonary infections, airway obstruction, and sleep apnea may occur; respiratory complications are an important cause of morbidity and mortality.

• Gastrointestinal: chronic diarrhea or constipation, gastrointestinal discomfort, and umbilical or inguinal hernias may occur.

• Hepatobiliary: hepatomegaly and splenomegaly may occur, although visceral organ enlargement is generally less prominent than in several other mucopolysaccharidoses.

• Musculoskeletal: joint stiffness or contractures, scoliosis, hip dysplasia, osteonecrosis of the femoral head, and other manifestations of dysostosis multiplex may occur.

• Dermatologic: thickened or coarse skin, hirsutism, and other connective-tissue or soft-tissue changes may occur.

Early diagnosis is important to recognize progressive neurodevelopmental and psychiatric manifestations, distinguish psychosis and behavioural deterioration from primary psychiatric disorders, identify potentially serious respiratory, cardiac, gastrointestinal, and musculoskeletal complications, provide appropriate developmental and educational support, guide multidisciplinary management and genetic counselling, and enable timely treatment and supportive care to preserve function and quality of life.