Kury-Isidor syndrome

Kury-Isidor syndrome is a neurodevelopmental disorder with a highly variable phenotype. It is primarily characterized by a mild global developmental delay that occurs in infancy or early childhood, with a delay in walking ability of several years and a speech delay, often with language deficits. Intellectual development may be mildly delayed, borderline or even normal; most patients have behavioral problems, including autism. Additional variable systemic features may include poor overall growth, hypotonia, distal skeletal abnormalities, seizures, and nonspecific dysmorphic facial features.

Caused by mutations in the BAP1 gene. >10 mutations are known to date (West EC et al. 2024).

The tumor suppressor gene BAP1 encodes a deubiquitinase enzyme that is involved in various cellular activities, including DNA repair and apoptosis. The nuclear deubiquitinase BAP1 (BRCA1-associated protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor whose germline variants predispose to cancer with loss of function. Remarkably, there are very rare examples of different germline variants of the same gene causing either a neurodevelopmental disorder (NDD) or a tumor predisposition syndrome (Küry S et al. 2022).

Any cutaneous papulonodular lesion found to be growing should be excised. If a Wiesner nevus is diagnosed histopathologically and is associated with multiple cutaneous (fibroma-like) melanocytic tumors, the patient should be tested for a genetic tumor predisposition syndrome.

1. Küry S et al. (2022) Rare germline heterozygous missense variants in BRCA1-associated protein 1, BAP1, cause a syndromic neurodevelopmental disorder. Am J Hum Genet 109:361-372.
2. Rai K et al. (2016) Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases. Clin Genet 89:285-294.
3. West EC et al. (2024) BRCA1-associated protein 1: Tumor predisposition syndrome and Kury-Isidor syndrome, from genotype-phenotype correlation to clinical management. Clin Genet. 2024 Jun;105(6):589-595.