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Detection of Hereditary 1,25-Hydroxyvitamin D-Resistant Rickets Caused by Uniparental Disomy of Chromosome 12 Using Genome-Wide Single Nucleotide Polymorphism Array.

Tamura M, Isojima T, Kawashima M, Yoshida H, Yamamoto K, Kitaoka T, Namba N, Oka A, Ozono K, Tokunaga K, Kitanaka S - PLoS ONE (2015)

Bottom Line: She was successfully treated with high-dose oral calcium.Comprehensive examination of the homozygous state is essential for accurate genetic counseling of recurrence risk and appropriate monitoring for other chromosome 12 related disorders.Furthermore, oral calcium therapy was effective as an initial treatment for rickets in this instance.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

ABSTRACT

Context: Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is an autosomal recessive disease caused by biallelic mutations in the vitamin D receptor (VDR) gene. No patients have been reported with uniparental disomy (UPD).

Objective: Using genome-wide single nucleotide polymorphism (SNP) array to confirm whether HVDRR was caused by UPD of chromosome 12.

Materials and methods: A 2-year-old girl with alopecia and short stature and without any family history of consanguinity was diagnosed with HVDRR by typical laboratory data findings and clinical features of rickets. Sequence analysis of VDR was performed, and the origin of the homozygous mutation was investigated by target SNP sequencing, short tandem repeat analysis, and genome-wide SNP array.

Results: The patient had a homozygous p.Arg73Ter nonsense mutation. Her mother was heterozygous for the mutation, but her father was negative. We excluded gross deletion of the father's allele or paternal discordance. Genome-wide SNP array of the family (the patient and her parents) showed complete maternal isodisomy of chromosome 12. She was successfully treated with high-dose oral calcium.

Conclusions: This is the first report of HVDRR caused by UPD, and the third case of complete UPD of chromosome 12, in the published literature. Genome-wide SNP array was useful for detecting isodisomy and the parental origin of the allele. Comprehensive examination of the homozygous state is essential for accurate genetic counseling of recurrence risk and appropriate monitoring for other chromosome 12 related disorders. Furthermore, oral calcium therapy was effective as an initial treatment for rickets in this instance.

No MeSH data available.


Related in: MedlinePlus

After Treatment with High-dose Oral Calcium Supplementation.(A) Treatment course and laboratory data are shown. (B) Bone roentgenogram at 3 years and 8 months of age, showing markedly improved signs of rickets.
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pone.0131157.g004: After Treatment with High-dose Oral Calcium Supplementation.(A) Treatment course and laboratory data are shown. (B) Bone roentgenogram at 3 years and 8 months of age, showing markedly improved signs of rickets.

Mentions: Initial treatment with increasing amounts of alfacalcidol up to 5 μgkg/day with oral calcium 60 mg/kg/day failed to improve her symptoms. After detecting the VDR mutation, she was admitted to another hospital for further treatment. After increasing her oral elemental calcium (calcium lactate) dose to 300 mg/kg/day (divided 3 times), her serum calcium and PTH levels improved (Fig 4A). The oral calcium was subsequently reduced to 240 mg/kg/day when high urinary calcium excretion started; the alfacalcidol dose was stopped because it was considered ineffective based on the genetic analysis. After 12 months of therapy, her laboratory data, including alkaline phosphatase levels, had normalized, her height gain improved, she started to run, and a repeat bone roentgenogram showed an improvement in the features of rickets (Fig 4B and 4C). Her most recent 1,25(OH)2D level was 20 pg/mL, whereas her FGF23 was 12 pg/mL, and her urine calcium/creatinine ratio was 0.5. Although her rickets improved, alopecia has remained. Her amblyopia was noticed at age three.


Detection of Hereditary 1,25-Hydroxyvitamin D-Resistant Rickets Caused by Uniparental Disomy of Chromosome 12 Using Genome-Wide Single Nucleotide Polymorphism Array.

Tamura M, Isojima T, Kawashima M, Yoshida H, Yamamoto K, Kitaoka T, Namba N, Oka A, Ozono K, Tokunaga K, Kitanaka S - PLoS ONE (2015)

After Treatment with High-dose Oral Calcium Supplementation.(A) Treatment course and laboratory data are shown. (B) Bone roentgenogram at 3 years and 8 months of age, showing markedly improved signs of rickets.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496068&req=5

pone.0131157.g004: After Treatment with High-dose Oral Calcium Supplementation.(A) Treatment course and laboratory data are shown. (B) Bone roentgenogram at 3 years and 8 months of age, showing markedly improved signs of rickets.
Mentions: Initial treatment with increasing amounts of alfacalcidol up to 5 μgkg/day with oral calcium 60 mg/kg/day failed to improve her symptoms. After detecting the VDR mutation, she was admitted to another hospital for further treatment. After increasing her oral elemental calcium (calcium lactate) dose to 300 mg/kg/day (divided 3 times), her serum calcium and PTH levels improved (Fig 4A). The oral calcium was subsequently reduced to 240 mg/kg/day when high urinary calcium excretion started; the alfacalcidol dose was stopped because it was considered ineffective based on the genetic analysis. After 12 months of therapy, her laboratory data, including alkaline phosphatase levels, had normalized, her height gain improved, she started to run, and a repeat bone roentgenogram showed an improvement in the features of rickets (Fig 4B and 4C). Her most recent 1,25(OH)2D level was 20 pg/mL, whereas her FGF23 was 12 pg/mL, and her urine calcium/creatinine ratio was 0.5. Although her rickets improved, alopecia has remained. Her amblyopia was noticed at age three.

Bottom Line: She was successfully treated with high-dose oral calcium.Comprehensive examination of the homozygous state is essential for accurate genetic counseling of recurrence risk and appropriate monitoring for other chromosome 12 related disorders.Furthermore, oral calcium therapy was effective as an initial treatment for rickets in this instance.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

ABSTRACT

Context: Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is an autosomal recessive disease caused by biallelic mutations in the vitamin D receptor (VDR) gene. No patients have been reported with uniparental disomy (UPD).

Objective: Using genome-wide single nucleotide polymorphism (SNP) array to confirm whether HVDRR was caused by UPD of chromosome 12.

Materials and methods: A 2-year-old girl with alopecia and short stature and without any family history of consanguinity was diagnosed with HVDRR by typical laboratory data findings and clinical features of rickets. Sequence analysis of VDR was performed, and the origin of the homozygous mutation was investigated by target SNP sequencing, short tandem repeat analysis, and genome-wide SNP array.

Results: The patient had a homozygous p.Arg73Ter nonsense mutation. Her mother was heterozygous for the mutation, but her father was negative. We excluded gross deletion of the father's allele or paternal discordance. Genome-wide SNP array of the family (the patient and her parents) showed complete maternal isodisomy of chromosome 12. She was successfully treated with high-dose oral calcium.

Conclusions: This is the first report of HVDRR caused by UPD, and the third case of complete UPD of chromosome 12, in the published literature. Genome-wide SNP array was useful for detecting isodisomy and the parental origin of the allele. Comprehensive examination of the homozygous state is essential for accurate genetic counseling of recurrence risk and appropriate monitoring for other chromosome 12 related disorders. Furthermore, oral calcium therapy was effective as an initial treatment for rickets in this instance.

No MeSH data available.


Related in: MedlinePlus