Cenani-Lenz syndrome: a case of De Novo dual LRP4 mutations

Abstract

Background: Cenani-Lenz syndrome (CLS) is a rare autosomal recessive disorder that causes malformation in limb development most commonly affecting the hands and feet, along with variable craniofacial and renal anomalies. This condition results from mutations in the LRP4 gene, disrupting a critical signaling pathway essential for limb and organ development. CLS has been reported in families from the Middle East and South Asia, with our case adding to its occurrence in Africa.

Case presentation: We report a case of a 5-year-old Sudanese male, the first-born child of consanguineous parents, presenting with severe bilateral hand and foot deformities, including complex syndactyly, oligodactyly, absent thumbs, and facial dysmorphism. The radiographs revealed bilateral complex deformities of the hands and feet, including shortened and disorganized metacarpals and phalanges, with features of syndactyly and ectrodactyly. The left hand showed only three abnormally shaped phalanges, while both feet exhibited reduced metatarsal counts and dysplastic, fused toe bones. He had no delay in developmental milestones or renal involvement. Whole-exome sequencing identified compound heterozygous variants in LRP4 which were a frameshift mutation (c.3813del; p.Thr1272Leufs*18) classified as likely pathogenic, and a missense mutation (c.4910G > A; p.Cys1637Tyr) of uncertain significance. The patient underwent multiple surgical interventions to his hands, however, significant functional limitations persist.

Conclusions: This case expands on the clinical spectrum of CLS and highlights its presence in African populations, reinforcing the importance of considering CLS as a differential diagnosis of complex limb malformations in regions with high consanguinity by supporting the integration of genetic testing into early diagnostic pathways for limb malformations. Given its significant impact on daily function, early genetic diagnosis and a multidisciplinary management approach are crucial for optimizing outcomes, particularly in families with a history of limb malformations.

Our findings: Enabling more accurate classification and timely intervention. Distinguishing CLS from other limb malfunction syndromes through genetic testing is essential.