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J Pediatr. 2016 Jul;174:204-210.e1. doi: 10.1016/j.jpeds.2016.04.007. Epub 2016 May 9.

Dent Disease in Chinese Children and Findings from Heterozygous Mothers: Phenotypic Heterogeneity, Fetal Growth, and 10 Novel Mutations.

Author information

1
Department of Medical Genetics, Genome Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
2
Children's Kidney Disease Center, Department of Pediatrics, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
3
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong Province, China.
4
Center for Reproductive Medicine, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
5
Department of Clinical Laboratory, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
6
Prenatal Diagnosis Center, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong Province, China.
7
Reproductive Center, Changsha Hospital for Maternal & Children Health Care, Changsha, Hunan Province, China.
8
Department of Pediatrics, Boai Hospital, Zhongshan, Guangdong Province, China.
9
Department of Pediatrics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
10
Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong.
11
School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
12
Xinhua College, Sun Yat-sen University, Guangzhou, Guangdong Province, China; Beijing Genomics Institute (BGI) in Shenzhen, Guangdong Province, China. Electronic address: ywzhong@hotmail.com.

Abstract

OBJECTIVE:

To characterize the phenotypes of Dent disease in Chinese children and their heterozygous mothers and to establish genetic diagnoses.

STUDY DESIGN:

Using a modified protocol, we screened 1288 individuals with proteinuria. A diagnosis of Dent disease was established in 19 boys from 16 families by the presence of loss of function/deleterious mutations in CLCN5 or OCRL1. We also analyzed 16 available patients' mothers and examined their pregnancy records.

RESULTS:

We detected 14 loss of function/deleterious mutations of CLCN5 in 15 boys and 2 mutations of OCRL1 in 4 boys. Of the patients, 16 of 19 had been wrongly diagnosed with other diseases and 11 of 19 had incorrect or unnecessary treatment. None of the patients, but 6 of 14 mothers, had nephrocalcinosis or nephrolithiasis at diagnosis. Of the patients, 8 of 14 with Dent disease 1 were large for gestational age (>90th percentile); 8 of 15 (53.3%) had rickets. We also present predicted structural changes for 4 mutant proteins.

CONCLUSIONS:

Pediatric Dent disease often is misdiagnosed; genetic testing achieves a correct diagnosis. Nephrocalcinosis or nephrolithiasis may not be sensitive diagnostic criteria. We identified 10 novel mutations in CLCN5 and OCRL1. The possibility that altered CLCN5 function could affect fetal growth and a possible link between a high rate of rickets and low calcium intake are discussed.

KEYWORDS:

diagnosis; mutations; nephrocalcinosis; nephrolithiasis; structural modeling

PMID:
27174143
DOI:
10.1016/j.jpeds.2016.04.007
[Indexed for MEDLINE]

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