Potocki-Shaffer syndrome is extremely rare. The exact prevalence is unknown, and fewer than 100 cases have been reported in the medical literature. Increased use of chromosomal microarray testing may lead to more diagnoses in the future.

PSS results from a deletion of a segment of the short arm of chromosome 11 (11p11.2), see RareShare guide on chromosomal nomenclature. The syndrome is considered a contiguous gene deletion disorder because multiple adjacent genes are deleted. The size of the deletion varies among affected individuals.

Important genes involved include:

• ALX4 – associated with enlarged parietal foramina (two distinct “holes” in the skull due to incomplete bone formation) and skull abnormalities.

• EXT2 – responsible for multiple exostoses or osteochondromas, cartilage-capped bone tumors.

• PHF21A – contributes to intellectual disability, developmental delay, seizures, and craniofacial abnormalities.

Most cases arise de novo (sporadically during egg, sperm, or embryonic development), although inherited cases have been reported. The condition follows an autosomal dominant (see RareShare guide on genetic inheritance) pattern when inherited.

The clinical presentation of Potocki-Shaffer syndrome can vary from mild to severe, heavily influenced by the size of the chromosome deletion. Common findings include:

• Musculoskeletal: Hereditary multiple non-cancerous bone tumors (exostoses or osteochondromas) which usually appear in childhood and can cause pain or bowing of the limbs, and enlarged parietal foramina.

• Neurological & cognitive: Moderate to severe developmental delay, intellectual disability, early-onset infantile spasms, or other forms of epilepsy.

• Craniofacial features: Prominent forehead, brachycephaly (flattened, short skull), sunken nasal bridge, low-set ears, shortened distance between nose and upper lip, downturned mouth, and strabismus (abnormal eye alignment).

• Behavioral: Autistic behaviors and attention deficits.

• Other systems: Sensorineural hearing loss, visual impairments (myopia, strabismus), hypotonia (low muscle tone), and occasional genitourinary abnormalities.

PSS diagnosis is generally suspected based on clinical features (especially the combination of exostoses and developmental delay), craniofacial characteristics, and is definitively confirmed using chromosomal microarray (CMA) or array comparative genomic hybridization (aCGH), which can detect the precise 11p11.2 microdeletion.

There is no cure for PSS. Management is symptomatic, supportive and multidisciplinary, including:

• Orthopedic Management: Regular monitoring of exostoses and osteochondromas. Surgical excision may be necessary if the bone growths cause pain, restrict joint movement, or compress blood vessels/nerves.

• Neurological Care: Anti-seizure medications (such as valproic acid or vigabatrin) to manage epilepsy and infantile spasms.

• Developmental Support: Early intervention with physical, occupational, and speech therapy to address muscle weakness, motor delays, and communication barriers.

• Routine Screening: Regular vision and hearing assessments, as well as renal ultrasounds, to catch secondary symptoms early.

PSS prognosis varies widely depending on the size of the chromosome deletion and the severity of neurological and medical complications. Many affected individuals survive into adulthood, and life expectancy is generally normal provided there are no severe underlying cardiac or systemic complications. Developmental delays and intellectual disability are typically lifelong, although early therapeutic intervention can significantly improve communication, mobility, and adaptive functioning. Long-term outcomes depend on the severity of neurological involvement, seizure control and management of associated congenital abnormalities. The quality of life may be good with appropriate medical, educational and social support.

1. Trajkova, S., Di Gregorio, E., Ferrero, G. B., Carli, D., Pavinato, L., Delplancq, G., Kuentz, P., & Brusco, A. (2020). “New Insights into Potocki-Shaffer Syndrome: Report of Two Novel Cases and Literature Review.” Brain sciences, 10(11), 788. https://doi.org/10.3390/brainsci10110788.

2. MedlinePlus Genetics:  Potocki-Shaffer syndrome.

3. NIH GARD:  Potocki-Shaffer syndrome.