Yunis Varon Syndrome: Characteristic Limb Abnormalities and Refining of the Phenotype.

Abstract

Yunis-Varon syndrome (YVS; MIM: 216340) is a rare autosomal recessive lysosomal storage disorder caused by biallelic mutations in FIG4, characterized by skeletal, neurological, and ectodermal abnormalities. This systematic review analyzes 15 cases with biallelic FIG4 variants and a clinical diagnosis of YVS to refine the clinical phenotype and diagnostic criteria, as well as a further 25 clinical diagnoses without FIG4 variants. Three "hand and feet" criteria were developed, identifying 1: bilateral and symmetrical thumb aphalangia with or without first metacarpal aplasia or hypoplasia, 2: aphalangia of at least one other upper limb digit, and 3: hallux absence or proximal positioning consistent with aplastic or hypoplastic first metatarsal. These limb abnormalities serve as highly characteristic diagnostic features. We also show that a significant proportion of cases without molecular confirmation in the literature are likely to be misdiagnosed. All molecularly confirmed cases with published photographs or radiographs exhibited a characteristic "1-2 digital pattern" with the first digit being most severely affected, followed by the second digit, and the remaining digits being more mildly affected. Additional consistent features included microretrognathia, short philtrum with everted upper lip, sparse hair and brows, wide fontanelles, and variable brain abnormalities including ventriculomegaly and cortical malformations. Clavicular hypoplasia or aplasia was common, but less consistent a finding than the digital abnormalities described. Median age at last follow-up or death was 669 days. This review demonstrates that YVS has a highly characteristic and recognizable phenotype, with digital abnormalities representing the most diagnostically valuable finding warranting FIG4 sequencing.