At Monroe Carell Jr. Children’s Hospital at Vanderbilt, pediatric endocrinologist Jennifer Kelley, M.D., and pediatric nephrologist Tracy (Tray) Hunley, M.D., encountered a novel case which evolved to phenotypical congenital nephrotic syndrome.
In their 10-month-old pediatric patient, hypercalcemia and elevated parathyroid hormone-related peptide (PTHrP) were the sole precursors to congenital nephrotic syndrome and kidney transplant.
There are well-documented cases of children with hypercalcemia that leads physicians to look for endocrinopathies as the cause, say the researchers. Finding even barely detectable PTHrP in infants and children is extraordinarily rare, but when found, the presumption is that it is being secreted by a tumor –or, on rare occasions, congenital anomalies of the renal system, Kelley said. All roads in this case initially appeared to lead to one of these diagnoses but testing supported neither.
“After doing a literature search, we believe this is the first report of a patient who had very clearly demonstrated hypercalcemia, due to elevated PTHrP, without any detectable kidney abnormalities or cancer,” Kelley said. “We haven’t seen this before, at least in the pediatric world, where PTHrP-related hypercalcemia without a clear cause shows up months before the nephrotic syndrome develops.”
Kelley and Hunley submitted this case study, published in JCEM Case Reports in May 2024. Vanderbilt medical student Alex F. Gimeno was first author.
“We haven’t seen this before, at least in the pediatric world.”
PTHrP a Red Flag
PTHrP is structurally homologous to parathyroid hormone (PTH) and both help regulate calcium. PTH is secreted continually, while PTHrP is not secreted by the parathyroid but may be liberated by some tumors. In healthy adults, PTHrP is normally at a low or undetectable level in the blood, and is normally undetectable in children. Associations with nephropathy/nephrotic syndrome have not been verified in humans.
“Experimental models have shown that there is some mechanism in the pathology of nephropathy that results in increased PTHrP production,” Hunley said. “But we’ve really only seen clear associations in animals and cell models.”
Imaging Negative
This is what made the findings in the Monroe Carell case so unusual.
The 10-month-old female was referred to Hunley in 2020 with growth hovering at the first percentile. Her calcium levels were a high 14.3 mg/dL, prompting him to order a blood panel.
“It is well known that elevated PTHrP could cause hypercalcemia, so PTHrP is one of the labs values evaluated when we have hypercalcemia of unclear etiology,” Kelley said.
The elevated PTHrP led to CTs of the abdomen and chest, the most likely place to find a solid tumor in children of this age, Hunley explained. When the scan was negative, the clinicians looked for renal dysplasia or other anatomical abnormalities in the kidneys and collection system, but still no anomalies were found other than the bilateral nephrocalcinosis.
Further, there were no genetic associations that could explain her symptoms.
“While the patient had some mutations, these had not been previously reported as associated with congenital nephrotic syndrome,” Kelley said. “That doesn’t mean the cause wasn’t genetic; it just means we don’t know as much about those particular genes at this time.”
Kidney Disease Develops
Six months later, however, the patient had developed clear symptoms of nephrotic syndrome.
“Initially, her kidneys were intact but at follow-up we found protein in her urine at a very high level,” Hunley said. “Where the PTHrP was coming from is still not entirely clear, but it looks probable that it was related to a functional congenital nephrotic syndrome developing in this patient, one of the things that makes this a novel case.”
Her nephrotic syndrome progressed to end-stage kidney disease two years after initial presentation. Fortunately, the little girl underwent transplantation, receiving a kidney from a healthy family member.
“She began growing well, and is now thriving. The abnormalities that manifest in low protein levels in the blood have all resolved,” Hunley said.
Call for Close Monitoring
Kelley says this case sends a cautionary message to neonatal and pediatrics specialists. While nephrotic syndrome was not clinically initially detectable in this child, it was likely already developing.
“This suggests that if an infant or child has PTHrP-related hypercalcemia without a clear etiology for the detected PTHrP, it might be worth starting to monitor their renal health closely for evidence of nephrotic syndrome,” she said.
“If an infant or child has PTHrP-related hypercalcemia without a clear etiology for the detected PTHrP, it might be worth starting to monitor their renal health closely.”
While no early intervention is available to prevent the disease from progressing, an early diagnosis can enable actions to mitigate damage to other organ systems caused by high blood pressure or protein loss.
“And, of course, anything you can do to improve the overall health of the child sets them up for a better transplant outcome as well,” Hunley said.
