Diagnostic delay in monogenic disease: A scoping review.

PURPOSE: Diagnostic delay in monogenic disease is reportedly common. We conducted a scoping review investigating variability in study design, results, and conclusions. METHODS: We searched the academic literature on January 17, 2023, for original peer reviewed journals and conference articles that quantified diagnostic delay in monogenic disease. We abstracted the reported diagnostic delay, relevant study design features, and definitions. RESULTS: Our search identified 259 articles quantifying diagnostic delay in 111 distinct monogenetic diseases. Median reported diagnostic delay for all studies collectively in monogenetic diseases was 5.0 years (IQR 2-10). There was major variation in the reported delay within individual monogenetic diseases. Shorter delay was associated with disorders of childhood metabolism, immunity, and development. The majority (67.6%) of articles that studied delay reported an improvement with calendar time. Study design and definitions of delay were highly heterogenous. Three gaps were identified: (1) no studies were conducted in the least developed countries, (2) delay has not been studied for the majority of known, or (3) most prevalent genetic diseases. CONCLUSION: Heterogenous study design and definitions of diagnostic delay inhibit comparison across studies. Future efforts should focus on standardizing delay measurements, while expanding the research to low-income countries.

Hypercalcemia Secondary to Elevated PTHrP in an Infant Followed by Progression to Nephrotic Syndrome.

In infants, hypercalcemia from elevated parathyroid hormone-related protein (PTHrP) is rare, often signaling neoplasm or renal or urinary anomalies. We report an infant who presented with failure to thrive and hypercalcemia at 10 months old, with initial evaluation showing elevated PTHrP of unclear etiology with imaging negative for neoplasm and no structural anomalies of the kidneys or ureters on ultrasound. Within 6 months of presentation, the patient developed nephrotic syndrome and by 2 years had progressed to end-stage kidney disease, necessitating kidney transplantation. Genetic testing was inconclusive but suggested congenital nephrotic syndrome. While reports of hypercalcemia secondary to elevated PTHrP exist in children with known structural renal anomalies, this is the first to demonstrate hypercalcemia and PTHrP elevation before detection of renal abnormalities. Experimental models have suggested a role for increased PTHrP expression in renal cells following acute kidney injury from nephrotic syndrome, and clinically detectable PTHrP levels may indicate progression of renal injury. We suggest monitoring of renal function for early detection of nephrotic syndrome in infants and children with elevated PTHrP who otherwise lack anatomical renal anomalies or detectable malignancies.