Nonlethal presentations of CYP26B1‐related skeletal anomalies and multiple synostoses syndrome

• Published in: American journal of medical genetics. Part A Vol. 185; no. 9; pp. 2766 - 2775
• Main Authors: Grand, Katheryn, Skraban, Cara M., Cohen, Jennifer L., Dowsett, Leah, Mazzola, Sarah, Tarpinian, Jennifer, Bedoukian, Emma, Nesbitt, Addie, Denenberg, Beth, Lulis, Lauren, Santani, Avni, Zackai, Elaine H., Deardorff, Matthew A.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.09.2021; Wiley Subscription Services, Inc
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Birth defects; Child; Cranial sutures; Craniosynostosis; CYP26B1; Dysostosis; Family; Female; Fetuses; Hearing loss; Homozygote; Humans; Infant; Intellectual disabilities; Lethality; Male; Mutation, Missense; Phenotype; radiohumeral synostosis; Radius - abnormalities; Radius - pathology; Retinoic acid; Retinoic Acid 4-Hydroxylase - genetics; skeletal anomalies; Skeleton; Synostosis - genetics; Synostosis - pathology; Teratogenicity; Ulna - abnormalities; Ulna - pathology; skeletal anomalies; CYP26B1; craniosynostosis; retinoic acid; radiohumeral synostosis
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.62387

Retinoic acid exposures as well as defects in the retinoic acid‐degrading enzyme CYP26B1 have teratogenic effects on both limb and craniofacial skeleton. An initial report of four individuals described a syndrome of fetal and infantile lethality with craniosynostosis and skeletal anomalies caused by homozygous pathogenic missense variants in CYP26B1. In contrast, a 22‐year‐old female was reported with a homozygous missense pathogenic variant in CYP26B1 with complex multisuture craniosynostosis and intellectual disability, suggesting that in some cases, biallelic pathogenic variants of CYP26B1 may be compatible with life. Here we describe four additional living individuals from two families with compound heterozygous pathogenic missense variants in CYP26B1. Structural assessment of these additional missense variants places them further from the catalytic site and supports a model consistent with milder nonlethal disease. In addition to previously reported findings of multisuture craniosynostosis, conductive hearing loss, joint contractures, long slender fingers, camptodactly, broad fingertips, and developmental delay/intellectual disability, skeletal imaging in our cases also revealed gracile long bones, gracile ribs, radioulnar synostosis, and carpal and/or tarsal fusions. These individuals broaden the phenotypic range of biallelic pathogenic variants in CYPB26B1 and most significantly clarify that mortality can range from perinatal lethality to survival into adulthood.