Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)

(OMIM phenotype number #241530)

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder, caused by homozygous or compound heterozygous mutation in the SLC34A3 gene. SLC34A3 gene encodes the sodium (Na+)-dependent phosphate cotransporter 2c (NaPi-IIc). NaPi-IIc, with NaPi-IIa encoded by SLC34A1, reabsorb most of filtered phosphate in the renal proximal tubule. The expression of these two co-transporters are regulated by two phosphaturic hormones, such as PTH and FGF23. HHRH is characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)2 vitamin D levels, hypercalciuria, rickets/osteomalacia, short stature, bone pain, and muscle weakness. The hypercalciuria can lead to the formations of kidney stones and/or the occurrence of nephrocalcinosis. This disease requires phosphate supplements alone, without calcitriol supplementation as this may increase 1,25(OH)2 vitamin D levels resulting to hyperabsorptive hypercalciuria. HHRH is distinguished from XLH and ADHR by the presence of an appropriately elevated level of serum 1,25(OH)2 vitamin D levels concentration, leading to hypercalciuria and suppression of PTH secretion.

Gene

SLC34A3 (NPTIIc) gene, 9q34.3 (OMIM gene/locus number #609826).

Phenotype

Kidney stone, nephrocalcinosis, rickets/osteomalacia, growth retardation, frontal bossing, increased fractures, bone pain, hypotonia, muscle weakness, difficulty walking, and difficulty standing.

Main biochemical alterations: High Ur P, low Pi, low renal TmP/GFR, normal calcium, high Ur Ca, low/normal PTH, normal 25 OH D, high 1,25(OH)2D, and high bone ALP, normal/high Ca, and normal intact FGF23. 

Images

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)

Fig. Radiographies of a patient affected by HHRH. (A) X-ray of the hip and femur shows bilateral long bone bowing and general osteomalacia. (B) Renal ultrasound shows multiple stones in the right kidney. (C) Bone scan shows multiple areas (ribs, hips, knees, skull) of increased tracer uptake and tracer retention in the renal calices.

Reproduced from Bone, Vol 59, Chi Y, Zhao Z, He X et al. A compound heterozygous mutation in SLC34A3 causes hereditary hypophosphatemic rickets with hypercalciuria in a Chinese patient, Pages 114-21, Copyright 2014, with permission from Elsevier.

References
  1. Dasgupta D, Wee MJ, Reyes M, et al. Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis. J Am Soc Nephrol. 2014 Oct;25(10):2366-75.
  2. Yu Y, Sanderson SR, Reyes M, et al.  Novel NaPi-IIc mutations causing HHRH and idiopathic hypercalciuria in several unrelated families: long-term follow-up in one kindred. Bone. 2012 May;50(5):1100-6.
  3. Bergwitz C, Roslin NM, Tieder M, et al. SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. Am J Hum Genet. 2006 Feb;78(2):179-92.
  4. Ichikawa S, Tuchman S, Padgett LR, et al. Intronic deletions in the SLC34A3 gene: a cautionary tale for mutation analysis of hereditary hypophosphatemic rickets with hypercalciuria. Bone. 2014 Feb;59:53-6.
  5. Tieder M, Modai D, Samuel R et al.  Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med. 1985 Mar 7;312(10):611-7.
  6. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  7. http://www.omim.org