Hypophosphatemic rickets

Recommended panel testing at Breda Genetics for this condition:

Hypophosphatemic rickets (PHEX, CLCN5, FGF23, DMP1, ENPP1, SLC34A3)

Clinical and genetic variability

Hypophosphatemic rickets is a clinically and genetically heterogenous disorder. Autosomal dominant, receissive and X-linked forms are known.

X-linked forms

There are two forms of X-linked hypophosphatemic rickets: X-linked dominant (PHEX gene mutations) and X-linked recessive (CLCN5 gene mutations).

Autosomal forms

There are also autosomal dominant and autosomal recessive forms of hypophosphatemic rickets.

Autosomal dominant hypophosphatemic rickets is caused by FGF23 gene mutations and, in contrast to X-linked dominant hypophosphatemic rickets, it shows incomplete penetrance, variable age at onset – childhood to adult – and resolution of the phosphate-wasting defect in rare cases.

Autosomal recessive hypophosphatemic rickets 1 (DMP1 gene mutations) has been observed in multiplex families whose clinical manifestations were very similar to those observed in X-linked and autosomal dominant hypophosphatemic rickets.

Autosomal recessive hypophosphatemic rickets 2 is caused by homozygous mutation in the ENPP1 gene.

A form of hypophosphatemic rickets with hypercalciuria is caused by mutation in the SLC34A3 gene, and there is evidence that a form of hypophosphatemic rickets with hyperparathyroidism may be caused by a translocation that results in an increase in alpha-klotho levels.

Recommended testing workflow

Recommended panel testing at Breda Genetics for this condition:

Hypophosphatemic rickets (PHEX, CLCN5, FGF23, DMP1, ENPP1, SLC34A3)

References

X-Linked Hypophosphatemia. Ruppe MD. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2012 Feb 9 [updated 2017 Apr 13]. PMID: 22319799

Phosphate homeostasis disorders. Christov M, Jüppner H. Best Pract Res Clin Endocrinol Metab. 2018 Oct;32(5):685-706. PMID: 30449549

Hypocalcaemic and hypophosphatemic rickets. Lambert AS, Linglart A. Best Pract Res Clin Endocrinol Metab. 2018 Aug;32(4):455-476. PMID: 30086869

Genetic Causes of Rickets. Acar S, Demir K, Shi Y. J Clin Res Pediatr Endocrinol. 2017 Dec 30;9(Suppl 2):88-105. PMID: 29280738

Phosphate homeostasis and genetic mutations of familial hypophosphatemic rickets. Razali NN, Hwu TT, Thilakavathy K. J Pediatr Endocrinol Metab. 2015 Sep;28(9-10):1009-17. PMID: 25894638

OMIM: 193100