Long‐term clinicopathologic observation in a case of steroid‐resistant nephrotic syndrome caused by a novel Crumbs homolog 2 mutation

Abstract

Recent advances in high-throughput sequencing for clinical genetic testing have revealed novel disease-causing genes, such as Crumbs homolog 2 (CRB2) for early-onset steroid-resistant nephrotic syndrome (SRNS). We report the long-term clinicopathologic observation of a Japanese female patient with SRNS caused by a newly identified compound heterozygous mutation of CRB2 (p.Arg628Cys and p.Gly839Trp located in the 10th and 11th epidermal growth factor-like domains, respectively). She was initially examined during a mass urinary screening for 3.5-year-old children in Japan. Although she developed long-standing SRNS without any extrarenal clinical signs thereafter, her renal function was well-preserved over the next 17 years. In total, six sequential renal biopsy specimens revealed histologic alterations ranging from minor glomerular abnormalities to advanced focal segmental glomerulosclerosis (FSGS). A genetic analysis for SRNS performed at 19 years of age revealed a newly identified compound heterozygous mutation in CRB2. Glomerular CRB2 immunoreactivity in biopsy specimens from the patient was scanty, whereas intense expression was observed in those from patients with idiopathic FSGS or in controls. To our knowledge, this is the first report regarding a long-term outcome in a case of SRNS due to an identified CRB2 mutation. Although the phenotype of CRB2 mutation-related syndrome is now expanding, we believe that this case might provide a novel clinicopathologic aspect of this syndrome.

A case report of CRB2 mutation identified in a Chinese boy with focal segmental glomerulosclerosis

“…These data explore some of the mechanisms and impact of the relationship between CRB2 mutations and phagocytes to some extent. In 2018, Watanabe et al [ 14 ] showed a Japanese patient that her renal biopsy specimens in keeping with FSGS, a newly compound heterozygous mutation of CRB2, p.Arg628Cys and p.Gly839Trp located in the 10th and 11th epidermal growth factor-like domains, respectively. These results demonstrate that CRB2 mutations may also occur in Chinese patients.…”

Bi-allelic variations in CRB2, encoding the crumbs cell polarity complex component 2, lead to non-communicating hydrocephalus due to atresia of the aqueduct of sylvius and central canal of the medulla

“…In human, while there is no known disease associated with CRB3 , both CRB1 and CRB2 bi-allelic pathogenic variations have been reported. CRB1 has been associated with retinal dystrophy including Leber’s congenital amaurosis and retinitis pigmentosa [ 9 ], whereas CRB2 variations are responsible for a wide phenotypic spectrum ranging from a severe prenatal disease with severe renal anomalies variably associated with hydrocephalus to postnatal isolated renal anomalies, with only few cases with retinal involvement [ 10 – 18 ]. To date, 34 cases with CRB2 bi-allelic variations have been reported, including many cases with hydrocephalus, but, partly because this gene was first considered as causal for renal abnormalities, no neuropathological characterization has been performed until now.…”