Juvenile cataract morphology in 3 siblings not yet diagnosed with cerebrotendinous xanthomatosis.

PURPOSE: Cerebrotendinous xanthomatosis is a progressive neurodegenerative storage disease caused by recessive CYP27A1 mutations and is characterized by abnormal deposition of cholestanol and cholesterol in multiple tissues, including the lens and brain. Oral chenodeoxycholic acid is preventive and can be therapeutic, but is not used optimally because the condition typically is diagnosed late or not at all. When affected children demonstrate lens opacities, ophthalmologists have the unique potential to facilitate earlier diagnosis and treatment by recognizing the juvenile cataract phenotype. This study highlights the morphology of lens opacities in a family with genetically confirmed disease. DESIGN: Prospective case series. PARTICIPANTS: Four siblings and their 2 parents, who are first cousins. METHODS: Ophthalmic examination, general physical examination, and exome sequencing guided by homozygosity analysis. MAIN OUTCOME MEASURES: Ophthalmic findings, general clinical findings, and results of CYP27A1 candidate gene testing. RESULTS: Two sisters, each visually symptomatic before 10 years of age, had a unique pattern of bilateral fleck deposits throughout the lens with significant posterior capsular cataract. When initially examined at 8 years of age, their then-asymptomatic younger brother had the same bilateral fleck deposits with minimal posterior capsular opacity; 1 year later, he demonstrated anterior capsular opacity and became symptomatic. Both asymptomatic parents had few but distinct similar flecks localized at or near the anterior Y-suture, whereas an asymptomatic sister did not. Genetic analysis revealed homozygosity for a known CYP27A1 mutation (c.1263+1G → A) in the 3 symptomatic siblings, heterozygosity for the mutation in the 2 parents, and no mutation in the asymptomatic sister. When specifically questioned, the 3 affected children had experienced recurrent bouts of diarrhea in early childhood, which is a common feature of the disease. CONCLUSIONS: An unusual pattern of fleck lenticular deposits was seen in affected children. With time, capsular opacities (posterior only or posterior and anterior) developed and caused visual symptoms. Such juvenile lenticular findings should raise suspicion for this treatable metabolic disorder, especially when in the context of recurrent diarrhea during early childhood. Asymptomatic fleck-like opacities at or near the anterior Y-suture may be a carrier sign. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Familial spherophakia with short stature caused by a novel homozygous ADAMTS17 mutation.

PURPOSE: Weill-Marchesani syndrome is characterized by spherophakia, short stature, short hands/feet, joint stiffness, and occasional cardiac abnormalities. The phenotype can be caused by recessive ADAMTS10 mutations or heterozygous fibrillin-1 mutation. In contrast, isolated spherophakia with short stature has been associated with three different homozygous ADAMTS17 mutations in three families from Saudi Arabia. The purpose of this report is to determine the genetic cause of isolated spherophakia with short stature in two siblings from a consanguineous Saudi family. METHODS: Clinical examination, homozygosity screen, and candidate gene analysis. RESULTS: A brother and sister with high myopia were referred for genetic counseling. Ophthalmic examination revealed spherophakia in both and narrow angles in the sister. Axial lengths were not elongated. Although both had short stature, neither had short hands, short feet, joint stiffness, or non-ocular congenital abnormalities. Homozygosity analysis suggested the candidate gene ADAMTS17, which was found to harbor a novel homozygous mutation (p.Asp218ThrfsX41) that segregated with the phenotype. CONCLUSIONS: Recessive ADAMTS17 mutations are a recurrent cause of isolated spherophakia with short stature. In Saudi Arabia this phenotype shows allelic heterogeneity rather than founder effect.