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

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.

Mineral status of premature infants in early life and linear growth at age 3.

BACKGROUND: Preterm infants are at significant risk of reduced bone mineral content and subsequent bone disease (metabolic bone disease of prematurity, MBDP). MBDP is frequently found in very low-birthweight (VLBW) infants, but long-term height prognosis is not well known. METHODS: VLBW infants from two major neonatal intensive care units were studied. Medical records were reviewed. A total of 143 subjects were analyzed after excluding subjects who died, or who had severe complications that could affect linear growth, Silver-Russell syndrome, severe cholestasis, and/or chromosomal abnormality. The relationship between MBDP and height at age 3 was investigated. RESULTS: Height standard deviation score (SDS) at age 3 negatively correlated with peak serum alkaline phosphatase (ALP) activity in early life (r = -0.30, P = 0.0003) and positively correlated with serum phosphorus (P) at peak ALP (r = 0.33, P = 0.0002). In addition, serum P independently affected height SDS at 3 years of age (ß = 0.19, P = 0.018), and was significantly different between infants with and without catch-up growth in height (difference: 0.23 mmol/L, 95%CI: 0.09-0.36, P = 0.0010). CONCLUSIONS: MBDP, particularly hypophosphatemia in the early period of life, is associated with linear growth until 3 years of age in VLBW infants.

Successful intermittent intravenous calcium treatment via the peripheral route in a patient with hereditary vitamin D-resistant rickets and alopecia.

BACKGROUND: Hereditary vitamin D-resistant rickets (HVDRR) is a rare genetic disorder caused by mutations in the vitamin D receptor (VDR) gene, which result in end-organ resistance to 1,25-(OH)2D3. PATIENTs with HVDRR are mostly treated using i.v. calcium therapy with a central catheter. However, central catheter-related complications have been reported. PATIENT: The patient was a 3-year-old boy presenting with waddling gait and alopecia. He had hypocalcemia [8 mg/dl (2 mmol/l)], hyperparathyroidism (1,232 ng/l), and elevated 1,25-(OH)2D3 levels (>250 pmol/l). DNA sequence analyses of the VDR gene showed a homozygous C-T transition at codon 152, resulting in a non-sense mutation in exon 5. INTERVENTIONS AND OUTCOMES: The patient was initially treated with calcitriol (80 ng/kg/day) and high-dose oral calcium (150 mg/kg/day) for one year. At the end of the first year, intermittent (5 days per month) i.v. calcium therapy without a central catheter was initiated because of insufficient clinical and radiological improvement. After 2 years of intermittent i.v. calcium therapy, there was a clear improvement based on clinical progress and on X-ray and biochemical findings. No peripheral complications were reported either. CONCLUSION: HVDRR with a non-sense mutation in the ligand-binding domain and alopecia was successfully treated with intermittent i.v. calcium without a central catheter.