Hypercalciuria and nephrolithiasis: expanding the renal phenotype of Donnai-Barrow syndrome

Graphical abstract

Whole Exome Sequencing detected novel likely pathogenic variants in LRP2 gene in two patients presenting with hearing and vision loss, and the Dent Disease (DD) classical renal phenotype, i.e. LMWP, hypercalciuria and nephrocalcinosis/nephrolithiasis.

We propose that a subset of patients presenting as DD may represent unrecognized cases or mild forms of Donnai-Barrow syndrome (DB/FOAR) or be on the phenotypic continuum between the two conditions.

Low-molecular-weight proteinuria (LMWP) is a defining feature of two rare genetic conditions, namely Donnai-Barrow/Facio-oculo-acustico-renal (DB/FOAR) syndrome and Dent disease (DD).

DB/FOAR syndrome (MIM #222448) is an autosomal recessive disorder caused by mutations in the LRP2 gene and characterized by typical craniofacial features, agenesis/hypogenesis of the corpus callosum, high-grade myopia, sensorineural hearing loss, and LMWP. Congenital diaphragmatic hernia and omphalocele are frequent additional findings¹. Hypercalciuria, nephrocalcinosis/nephrolithiasis, and rickets have not been reported in DB/FOAR², but they are, in association with LMWP, classical findings in DD, a group of X-linked renal tubulopathies caused by defects in the CLCN5 gene encoding the Cl-/H+ antiporter ClC-5 (DD 1; MIM #300009) or in the OCRL gene (DD 2; MIM#300555)³. Whereas DD 1 only affects the kidney, the spectrum of symptoms in DD 2 can range from apparent exclusive kidney manifestations to the involvement of other organs, notably brain, muscle, and eyes.

We report novel LRP2 likely pathogenic variants in two patients presenting with LMWP, hearing and vision loss, and the DD classical renal phenotype.

Case 1 is a 69 years old male presented with chronic kidney disease (CKD), incomplete Fanconi syndrome, and nephrolithiasis. At 14, he showed progressive bilateral hearing loss and left eye blindness and at age 40 glaucoma of his right eye. At 25, he developed acute kidney injury (AKI) with microhematuria, glomerular proteinuria and LMWP. AKI remitted completely after tonsillectomy but mixed proteinuria persisted with incomplete Fanconi syndrome. A kidney biopsy showed hyaline glomeruli, PAS-positive mesangial hyperplasia, focal sclerosis of Bowman capsule, tubular cells with granular cytoplasm and few hyaline intraluminal casts. A bone biopsy showed osteomalacia, consistent with a diagnosis of renal rickets. He then developed calcium-oxalate kidney stones, hypertension and slow progressive CKD with mixed proteinuria, and hypercalciuria with renal glycosuria.

Case 2 is a teenager of Senegalese origin with LMWP, hypercalciuria and nephrocalcinosis. Omphalocele repair surgery was performed at 6 months. As a child, he showed marked growth failure, hypertelorism, flat and wide nasal bridge, broad forehead and prominent parietal bossing, and mild psychomotor retardation. Hypophosphatemia and hypovitaminoses D and A were noted. He manifested retinal detachment and cataract in his left eye, and severe myopia with peripapillary atrophy in his right eye.

Both patients had received a provisional diagnosis of DD because their renal phenotypes were consistent with the classical DD symptoms³.

Sanger sequencing excluded CLCN5 and OCRL mutations in both cases. Whole Exome Sequencing discovered the c.[242T>A];[6727C>T] variants in LRP2 (NM_004525.2) in case 1. One change was predicted to cause the non-conservative p.(Ile81Asn) substitution, the other to introduce a premature stop codon leading to p.(Arg2243Ter). Parental DNA was not available for testing. The homozygous c.7624C>T variant was identified in case 2, resulting in the p.(Arg2542Cys) missense change. Both parents were unaffected carriers. These variants are not present in dbSNP, 1000 Genome, EVS, or ExAC.

The LRP2 gene encodes Megalin, a large single-spanning transmembrane multiligand receptor, expressed in absorptive epithelia including adult kidney proximal tubules. Together with ClC-5, Megalin forms the endocytic macromolecular complex dedicated to albumin and LMW protein reabsorption (Fig. 1 A)⁴. Case 1 is a compound heterozygote for a likely null variant and a missense variant at the N-terminus of the protein. The other missense variants previously reported in DB/FOAR patients are instead localized to the C-terminal half of Megalin (Fig. 1 B). We speculate that the p.(Ile81Asn) could act as a hypomorph, thus explaining the milder phenotype in case 1.

Fig. 1.

A Comparison of proximal tubular dysfunction in DD and DB/FOAR diseases due to ClC-5 and Megalin impairment, respectively.

B Sequence variants in the probands and DB/FOAR patients. p.(Ile81Asn) (case 1) and p.(Arg2542Cys) (case 2) are in a LDL-receptor class A and B, respectively.

We propose that a subset of patients presenting as DD may represent unrecognized cases or mild forms of DB/FOAR, or be on the phenotypic continuum between the two conditions.

Institutional review boards of Padua University-Hospital and Massachusetts General Hospital approved the study. Informed consent was obtained from all the participants.