Nail-Patella Syndrome: clinical and molecular data in 55 families raising the hypothesis of a genetic heterogeneity

Abstract

Nail-Patella Syndrome (NPS) is a rare autosomal dominant condition comprising nail and skeletal anomalies. Skeletal features include dysplastic patellae and iliac horns, as well as scapula and elbow dysplasia. Nephropathy and glaucoma or intra-ocular hypertension can sometimes be present. NPS is due to variants affecting function in LMX1B, which encodes a LIM-homeodomain protein critical for limb, kidney and eye development. We describe the phenotype and the molecular data of 55 index patients and their 39 relatives presenting with typical NPS. We identified 38 different LMX1B anomalies, 19 of which were not reported before. In our series, 9% of families are not carriers of a LMX1B genomic alteration after extensive study of the coding and non-coding regions of the gene. One of the families showed no linkage to the LMX1B locus, raising the hypothesis of a genetic heterogeneity.

Figure 1

Schematic representation of LMX1B variants. LMX1B is composed of eight exons. The LIM-A and LIM-B domains are encoded by exons 2 and 3, respectively, and the HD is encoded by exons 4 to 6. Variants are clustered in these functional domains. Truncating variants are represented above the gene whereas missense variants are represented under the gene. Splicing variants are represented by stars.

Figure 2

Clinical features in NPS patients. (a) Nail dysplasia. (1) Family 12, nails show more severe dysplasia on the ulnar side. (2, 3) Family 45, thumbnail dysplasia and koilonychia of the second digit in the same patient. (4) Family 48, nail dysplasia of the first and second digits. Typical triangular lunula of the third digit. (b) Elbow dysplasia. (1, 2) Family 43, limitation of the elbow extension. (3) Elbow X-ray showing dysplastic dislocated radial head and hypoplasia of the capitellum. (c) Patellar dysplasia. (1, 2) Family 43, subluxed patella on knee flexion. (3) Family 43, knee X-ray showing superior displacement of hypoplastic patella. (d) Family 43, pelvis X-ray showing typical iliac horns (arrow).