Expanding the Phenotypic Spectrum of Anauxetic Dysplasia Type 3: Reporting an Iranian Family With Unique Systemic...

The cartilage hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum represents a group of rare autosomal recessive skeletal dysplasias with significant phenotypic heterogeneity. These disorders are classified based on pathogenic variants in the RMRP, POP1, and NEPRO genes. Among these, anauxetic dysplasia type 3 (ANXD3), associated with NEPRO variants, manifests as severe skeletal dysplasia characterized by short stature, brachydactyly, skin laxity, and joint hypermobility, with distinct radiographic findings such as ovoid vertebrae, hypoplastic ilia, narrow acetabular angles, and irregular metaphyses. Unlike other CHH-AD subtypes, ANXD3 lacks immunological or gastrointestinal involvement. This study reports three new ANXD3 cases from a consanguineous Iranian family, carrying the homozygous pathogenic variant Chr3:113014014G>A; exon3; c.280C>T; p.Arg94Cys in the NEPRO gene. The clinical phenotypes expand the known spectrum of ANXD3, including unique features such as microcephaly, clubfoot, cataracts, urolithiasis, and hearing impairments, whi12-18ch suggest systemic involvement beyond skeletal abnormalities. Diagnostic whole-exome sequencing, supported by Sanger validation, confirmed the autosomal recessive inheritance pattern. A comparative analysis with previously reported ANXD3 cases revealed shared characteristics, including short stature, brachydactyly, and thoracolumbar kyphoscoliosis, while highlighting variability in head size, scalp hair, and systemic features. Microcephaly was observed in our patients, same as previously reported cases, underscoring the phenotypic variability of ANXD3. This study also emphasizes the importance of genetic counseling and early interventions for associated complications, such as orthopedic, renal, and ophthalmological management.