Rare Genetic Rickets Case Reveals Early Warning Signs Hidden in Routine Blood Tests

When a two-year-old girl in China stopped walking and her legs began to bow, doctors at Shanghai Children’s Hospital suspected something far more unusual than ordinary nutritional deficiency. A new study published in BMC Pediatrics now documents her case in extraordinary detail, following her for 28 months from diagnosis through treatment, recovery, and an unexpected complication that offers fresh lessons for anyone managing this rare metabolic bone disease. The girl suffered from vitamin D-dependent rickets type 1A, a rare autosomal recessive disorder caused by mutations in a gene called CYP27B1, which disrupts calcium and phosphate homeostasis and leads to skeletal deformities and growth retardation.

The biology behind the condition is elegant in its simplicity. CYP27B1 encodes the enzyme responsible for the final activation step of vitamin D, converting inactive precursor molecules into calcitriol, the hormonally active form that the body relies on to absorb calcium from the gut and maintain the delicate balance between calcium and phosphate in the blood. When both copies of this gene carry damaging mutations, the enzyme’s output collapses, calcium absorption fails, and the parathyroid glands compensate by pumping out parathyroid hormone, which strips calcium from bone. The result is the classic triad the girl presented with: growth retardation, skeletal deformities, and hypocalcemia, or abnormally low blood calcium.

To identify the precise genetic culprit, the team performed whole-exome sequencing, a technique that reads all the protein-coding regions of the genome at once, and then validated the findings using Sanger sequencing, the gold-standard method for confirming individual variants. The analysis revealed a compound heterozygous variant combination in CYP27B1, meaning the girl inherited one damaged copy from each parent, with two different mutations: c.580G>T and c.1442delA. The researchers report that this specific pairing had not been described before, adding a previously unreported genotype to the growing catalogue of CYP27B1 mutations responsible for VDDR1A worldwide.

Treatment began promptly with calcitriol supplementation, which bypasses the broken activation step entirely by delivering the active hormone directly, combined with calcium supplementation to restore the mineral deficit. The response was dramatic. Within months, the girl’s symptoms resolved rapidly, she regained the ability to walk independently, her skeletal deformities corrected, and she entered a phase of catch-up growth that lifted her height from minus 4 standard deviations to minus 2.3 standard deviations relative to her peers. Biochemical abnormalities normalized within one year, and radiographic improvement was visible by month 10 of follow-up, confirming that the bone architecture was healing alongside the clinical recovery.

But the story took an unexpected turn at month 19, when hypercalcemia, or abnormally high blood calcium, first emerged. The team responded by stepwise reduction of both calcium supplementation and calcitriol, yet the calcium levels continued to climb. By month 23, imaging identified nephrocalcinosis, the deposition of calcium salts within the kidney tissue, alongside hypercalciuria, or excess calcium in the urine. These findings prompted temporary withdrawal of calcitriol and treatment of the hypercalcemia itself, a decision that would soon reveal something remarkable about the underlying disease dynamics.

Five months after calcitriol withdrawal, the girl developed recurrent bone pain, the first symptom suggesting the disease was reasserting itself. What makes this observation scientifically significant is the sequence of events that preceded it. As early as two months after withdrawal, alkaline phosphatase, or ALP, and parathyroid hormone, or PTH, had already increased by 185.1 percent and 297.2 percent respectively, despite serum calcium and phosphate remaining within their normal reference ranges. By five months, these increases had become far more pronounced, with ALP rising 274 percent and PTH surging 1885 percent, while calcium and phosphate showed only modest declines of 35.0 percent and 23.2 percent.

This pattern suggests that ALP and PTH function as sensitive early-warning indicators of disease reactivation, increasing earlier and more prominently than the traditional markers clinicians typically monitor. The researchers propose that these two biochemical parameters could serve as complementary indicators during longitudinal monitoring of VDDR1A, potentially allowing clinicians to detect disease recurrence before symptoms appear and before calcium and phosphate levels shift enough to trigger conventional alarm. The finding carries practical weight because the traditional markers, serum calcium and phosphate, remained deceptively normal throughout the early phase of reactivation.

The case also highlights the therapeutic tightrope that VDDR1A management demands. Calcitriol is essential for correcting the fundamental enzymatic deficit, yet the active hormone also drives calcium absorption so powerfully that excess supplementation can push calcium levels into dangerous territory, producing hypercalcemia, nephrocalcinosis, and hypercalciuria. The researchers emphasize that long-term follow-up reveals both the therapeutic benefit of calcitriol and the need for careful monitoring of treatment-related complications, a balance that requires individualized dosing and vigilant biochemical surveillance rather than a one-size-fits-all protocol.

Evidence regarding long-term disease outcomes and optimal monitoring strategies in VDDR1A remains limited, and this study contributes detailed 28-month longitudinal treatment data to a field where such granular case documentation is rare. The researchers suggest that their findings could inform how clinicians structure follow-up schedules, potentially prioritizing ALP and PTH measurements alongside traditional calcium and phosphate monitoring to catch disease reactivation earlier. For a condition so rare that individual cases shape clinical practice, the identification of a previously unreported CYP27B1 genotype combined with granular biochemical dynamics offers both diagnostic and therapeutic guidance.

The study, conducted by Chunjie Liu, Mingyu Jiang, Yan Gong, Pin Li, Sheng Guo, and Fei Wang at Shanghai Children’s Hospital, School of Medicine, Shanghai Jiao Tong University, was approved by the ethics committee of Shanghai Children’s Hospital, and written informed consent was obtained from the patient’s parents. The work was supported by the Clinical Research Data Sharing and Simulated RCT Project of Shanghai Municipal Three-Year Action Plan, the China University-Industry-Research Innovation Fund, the National Natural Science Foundation of China Cultivation Project of Shanghai Children’s Hospital, and the Key Project of the Youth Work Research Program at Shanghai Jiao Tong University School of Medicine. The funding organizations had no role in study design, data collection, analysis, or the decision to submit the article for publication.

Subject of Research: Genetics

Article Title: Clinical and genetic characterization of a patient with vitamin D-dependent rickets type 1A: results from long-term follow-up

Article References: Liu, C., Jiang, M., Gong, Y., Li, P., Guo, S., & Wang, F. (2026). Clinical and genetic characterization of a patient with vitamin D-dependent rickets type 1A: results from long-term follow-up. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07891-3

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07891-3

Keywords: VDDR1A, CYP27B1, calcitriol, rickets, hypercalcemia, nephrocalcinosis, PTH, ALP, BMC Pediatrics, rare disease, Clinical, genetic