Date of Award

January 2022

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)



First Advisor

Clemens Bergwitz


Loss-of-function (LOF) mutations in SLC34A3 cause renal phosphate wasting due to loss of sodium phosphate co-transporter NPT2c, generally presenting in childhood with hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Described here are two individuals with atypical presentations of HHRH due to additional heterozygous mutations in SLC34A1 and NPHP4, genetic causes of idiopathic infantile hypercalcemia type 2 and nephronophthisis, respectively. The first case has a 10-year history of well-controlled ulcerative colitis and atrial fibrillation. He wore braces briefly at age 5 for lower extremity bowing, which resolved spontaneously. He was without fractures until age 41, when he sustained a tibial plateau fracture after falling from his treadmill. He presented at age 44 with several outside emergency department visits for weakness and dizziness before presenting to this institution following an episode of light-headedness and rapid heart rate of 160 beats per minute. His physical exam was notable for the absence of lower extremity bowing, dental malformations, and bone tenderness, and his family history was unremarkable for skeletal disorders. The second case initially presented with asymptomatic pyuria and microscopic hematuria at age 7. Renal ultrasound at this age revealed bilateral nephrocalcinosis, and she was started on potassium citrate. At age 19, she was found to have an elevated creatinine of 1.3 mg/dL and diagnosed with mild hypertension, and she was treated with lisinopril and hydrochlorothiazide. She is of normal stature without pathologic fractures, and physical examination was notable for mild knee knock consistent with a history of mild childhood rickets. Whole exome sequencing of the first patient revealed a novel het.SLC34A1.c.847G>A,p.G292S and a previously reported pathogenic het.SLC34A3c.1402C>T,p.R468W variant. The second patient possesses a known pathogenic hom.SLC34A3.c.575C>T,p.S192L variant, consistent with a diagnosis of HHRH, and a cis-inherited het.NPHP4.c.2579G>A,p.G860E; c.133C>T,p.Q45X variant. The first case is the second report of di-genic heterozygous mutations in SLC34A1 and SLC34A3, and the second case is the first report of di-genic mutations in SLC34A3 and NPHP4. Mild bone phenotypes as a child that resolved spontaneously and an absence of hypercalciuria and renal calcifications in the first case, and presence of nephrocalcinosis with early onset renal failure in the second case illustrate the high degree of phenotypic variability caused by SLC34A3 mutations and suggest a polygenic contribution to disease severity.


This is an Open Access Thesis.

Open Access

This Article is Open Access