Elsevier

Gene

Volume 641, 30 January 2018, Pages 74-77
Gene

Short communication
Rethinking genotype-phenotype correlations in papillorenal syndrome: a case report on an unusual congenital camptodactyly and skeletal deformity with a heterogeneous PAX2 mutation of hexanucleotide duplication

https://doi.org/10.1016/j.gene.2017.10.050Get rights and content

Highlights

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    A previously unrecognized phenotype of camptodactyly is identified in a case of PRS.

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    The PRS-related camptodactyly is caused by skeletal deformity of bone and joint anomalies.

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    A heterogeneous de novo PAX2 mutation of hexanucleotide duplication is clarified as the molecular pathogenesis.

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    This report provides a new genotype-phenotype correlation in PRS.

Abstract

Papillorenal syndrome (PRS), an autosomal dominant inherited condition, is clinically featured by renal hypoplasia and optic nerve dysplasia. Based on current knowledge of genotype-phenotype correlations in PRS, mutations in the Paired box 2 (PAX2) gene have been recognized as a critical pathogenesis of typical renal and optic disease manifestations. However, little information is currently available on the skeletal abnormalities of PRS and the potential contribution of PAX2 mutations. Here, we present a case of a 10-year-old female PRS patient with the typical features of chronic renal failure and severe myopia, but was unexpectedly discovered camptodactyly of her left middle finger which affects the proximal interphalangeal joint. Pathologically, the camptodactyly was further indicated by radiology as a skeletal deformity, demonstrating a decline of bone mineral density and disappearance of joint space. Molecular diagnostics revealed a heterozygous mutation, 220_225dup, in the exon 3 of her PAX2 gene, which is de novo considering the lack of this mutation in her non-consanguineous parents. This mutation leads to duplication of glutamic acid at position 74 and tyrosine at position 75 in PAX2 protein, which may influence the DNA-binding function. Besides, the absence of Spalt like transcription factor 4 (SALL4) mutation excluded the diagnosis of acro-renal-ocular syndrome (AROS), of which clinical characteristics are similar to our patient's. This case unravels a previously unrecognized phenotype of camptodactyly due to a significant skeletal deformity of PRS with a heterogeneous PAX2 mutation of hexanucleotide duplication. This report challenges against the current belief of genotype-phenotype correlations in PRS.

Introduction

Papillorenal syndrome (PRS, OMIM 120330), also called renal coloboma syndrome (RCS), is an autosomal dominant condition characterized by both renal and ocular anomalies (Schimmenti, 2011). Additionally, a wide range of other lesions have been reported in PRS patients, such as hearing loss, central nervous system anomalies, elevated pancreatic amylase and hyperuricemia (Schimmenti et al., 1999). As to the molecular basis, Paired box 2 (PAX2) mutation is recognized as the critical pathogenesis of PRS, which affects the function of PAX2 protein, a member of the PAX family of transcriptional regulators. Other than its pivotal roles in kidney and eye development, PAX2 regulation is known to be important for homeostasis of the midbrain/hindbrain boundary, the cerebellum, the hypothalamus, the spinal cord, the otic vesicle and the pancreas, establishing the current belief of genotype-phenotype correlations in PRS (Bower et al., 2012). However, function of PAX2 in the skeleton and the associated contribution of its mutation to PRS have not yet been uncovered. In the present study, we report an unexpected case of PRS with congenital camptodactyly, which is further attributed to an unusual skeletal deformity with a heterozygous de novo PAX2 mutation of hexanucleotide duplication.

Section snippets

Patient

A 10-year-old girl was admitted to Department of Pediatrics, Fuzhou Dongfang Hospital, China, for renal failure, which is confirmed by her laboratory findings (Table 1). As shown by the urine dipstick analysis, her urine was + for occult blood and +++ for protein. Furthermore, her urinary α1-microglobulin was 113 mg/L and urinary β2-microglobulin was 30.20 mg/L, both over the normal ranges. Serological analysis additionally demonstrated abnormal levels of urea nitrogen, creatinine and

Results

A heterozygous mutation in PAX2 exon 3, 220_225dup, was identified in the patient. This mutation leads to the duplication of glutamic acid at position 74 and tyrosine at position 75 in PAX2 protein. (Glu74Thr75dup). The identical PAX2 mutation was not detected in her parents (Fig. 1K). Moreover, to further confirm the diagnosis of PRS, Spalt like transcription factor 4 (SALL4) mutation was also examined in this patient, which is recognized as a molecular basis of acro-renal-ocular syndrome

Discussion

PRS, the severe autosomal dominant condition, was first described by Weaver et al. in 1988 (Weaver et al., 1988). Since then, emerging evidence has been raised regarding PRS and its urogenital and ocular manifestations, but PRS with congenital camptodactyly and skeletal deformity caused by an identified PAX2 mutation has not been reported before. In the present study, an unexpected case of a 10-year-old girl is documented, who not only possessed the typical features of PRS including chronic

Acknowledgments

This study was funded by the National Natural Science Foundation of China (81270766); the Major Project of Nanjing Military Command (14ZX27); the Key Project of Social Development of Fujian Province of China (2013Y0072); and the Nature Science Foundation of Fujian Province of China (2015J01407).

Declaration of interest

The authors declare that they have no conflict of interest.

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