From pollakiuria to Donnai‐Barrow syndrome diagnosis in pediatric age

We report the case of two siblings with incomplete Donnai-Barrow syndrome (DBS) phenotype carrying three LRP2 variants never associated before with DBS phenotype. Donnai-Barrow syndrome (DBS) (MIM #222448) is an autosomal recessive multisystemic disorder caused by biallelic variants in the LRP2 gene.1 Affected patients have low-molecular-weight proteinuria (LMWP), typical facial dysmorphology, agenesis/hypogenesis of the corpus callosum, high-grade myopia, and sensorineural hearing loss. Congenital diaphragmatic hernia or omphalocele is present in 40% of cases. We report the case of two siblings with incomplete DBS phenotype carrying three LRP2 variants never associated before with DBS phenotype. The proband was an Indian 12-year-old girl born to non-consanguineous parents and referred to our pediatric nephrology service for pollakiuria. Her medical history revealed severe myopia without other eye diseases since the first months of life. No clinically significant diaphragm or body wall defects, hypertelorism or other dysmorphic features were detected. Her development/cognition was normal. Urinalysis showed mild LMWP and hypercalciuria. Laboratory tests evaluating kidney function and renal ultrasound were normal. Audiometry revealed monolateral sensorineural hearing loss. She had a 16-year-old brother who had severe myopia with no other eye disease since his early years. His urine test showed LMWP without hypercalciuria. The renal ultrasound was normal. The audiometry showed no alterations. LMWP associated with severe myopia in both siblings suggested an underlying genetic tubular disease. The genetic analysis of choice was next generation sequencing (NGS) on DNA obtained from proband's blood. Multigene-panel testing was part of the routine diagnostic procedures and identified in the LRP2 gene (NM_004525.2) two novel missense variants (MAF 0) c.3427T>C p.(Cys1143Arg), c.10651C>G p.(Arg3551Gly) and a rare missense variant (gnomAD 0,0019%) c.10703C>T p.(Pro3568Leu) (rs 753477259) in heterozygosity. Each variant was confirmed in the proband using Sanger sequencing. VarSome, a pathogenicity prediction tool, scored and classified the variants as variants of uncertain significance (VUS) in agreement with the interpretation guidelines of the American College of Medical Genetics and Genomics (ACMG).2 The CADD score >20 (c.3427T>C: 28.4; c.10651C>G: 28.5; c.10703C>T 24.9) for each variant identified the variants as potentially pathogenic. Sanger sequencing was used to determine whether LRP2 variants co-segregated with the disease phenotype in the family (Figure 1). The healthy parents were found to be heterozygous for the variants; the father for the complex allele carrying the c.10651C>G and the c.10703C>T variants in cis, and the mother for the c.3427T>C allele. The siblings who inherited the two alleles were both compound heterozygotes. Although variants were classified as VUS, their segregation with the disease in the family allowed us to consider them causative. Which of the two in cis variants is more likely to be pathogenic is difficult to determine based on available information. LMWP with vision and hearing defects without the classical phenotypic features of DBS has been recently reported to be associated with LRP2 pathogenic variants.3, 4 Faridi et al. suggested that one of the two LRP2 variants segregating with the incomplete DBS phenotype could act as a hypomorphic allele, thus enabling some megalin function.3 They identify the hypomorphic allele at the 5′ end of the gene, where no LRP2 missense variants have been found to cause the complete DBS phenotype.3 We could hypothesize that a hypomorphic variant is also present in our two siblings, the p.(Cys1143Arg) variant, located in exon 22. When the clinical trait is mild, genetic testing can help reach the diagnosis. In our case, genetic testing enabled us to recognize DBS, albeit in an incomplete phenotypical presentation. The diagnosis is fundamental for a multidisciplinary follow-up. The association of severe myopia with tubular proteinuria further broadens the phenotypic spectrum associated with DBS. Including the LRP2 gene in many clinical multi-gene panels will likely allow more forms of incomplete DBS phenotype to be detected. MMG and LP designed the work, acquired, and analyzed the data, drafted the initial manuscript, and reviewed the manuscript. FA and MC acquired and analyzed the genetic data, drafted the results related to this aspect and reviewed the manuscript. AP and GP reviewed the manuscript. MB conceptualized, designed the work, analyzed the data, drafted and reviewed the initial manuscript. All authors approved the final version of the manuscript. None. The authors declare no conflicts of interest. The patient's parents signed a written consent to report this case. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/cge.14417. The data that support the findings of this study are available from the corresponding author upon reasonable request.