Hypophosphatemic rickets, autosomal dominant

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: FGF23 (HGNC:3680)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 11/18/2021
• Curation Status: Released (1.2.3)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
FGF23	autosomal dominant hypophosphatemic rickets (0008660)	193100	Limited Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity of ADHR (rickets, growth, bone/joint pain) / Oral phosphate plus vitamin D analog supplements	1	0C	0C	2	3CC

Severity of Outcome

Prevalence of the Genetic Condition

The population prevalence of autosomal dominant hypophosphatemic rickets (ADHR) is <1 in 1,000,000. Fewer than 100 cases have been described.

Clinical Features (Signs / symptoms)

ADHR is caused by mutations in the FGF23 gene which leads to inappropriately high intact FGF23 levels. ADHR is characterized by isolated renal phosphate wasting, hypophosphatemia, rickets and inappropriately low or normal calcitriol levels. During childhood ADHR presents with short stature and rickets affecting primarily lower extremity deformities. During adulthood clinical findings include bone pain, fatigue, muscle weakness, and repeated fractures.

Natural History (Important subgroups & survival / recovery)

Clinical manifestations depend on the age of onset (childhood, adolescence, adulthood) and on the severity of hypophosphatemia. In contrast to other inherited disorders of FGF23 excess (e.g., X-linked hypophosphatemia), ADHR shows incomplete penetrance and variable time of onset in the clinical phenotype. Two subgroups of patients appear to exist within ADHR. Patients may present in childhood with rickets and hypophosphatemia with some patients normalizing serum phosphate spontaneously as they age. A second group, primarily female, appears to grow normally and do not have hypophosphatemia but present in adolescence or adulthood with phosphatemic osteomalacia. These adults with delayed onset can also spontaneously normalize serum phosphate with a resolution of clinical symptoms. The timing and predisposing factors the waxing and waning of symptoms are largely unknown, recent evidence has indicated that changes in iron status may contribute to the changes in phenotype.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Unknown

No information on prevalence of pathogenic variants causing ADHR was identified. Fewer than 100 cases have been described.

Tier 4

Penetrance (Includes any high-risk racial or ethnic subgroups)

Unknown

ADHR exhibits incomplete penetrance. The onset of the features may be delayed and there is occasional resolution of the phosphate-wasting defect.

Tier 3

Expressivity

Presentation is variable among families even within the same pedigree with patients’ presentations ranging from age 1 to 45 with variable clinical features.

Tier 3

Intervention Effectiveness

Patient Management

Treatment aims at improving growth, bone or joint pain, enhancing mineralization of bones, and preventing skeletal deformities caused by rickets. It consists of daily oral administration of phosphate and calcitriol. Calcitriol is given to prevent secondary hyperparathyroidism that can be caused by phosphate administration.

Tier 4

There have been case reports of individuals with ADHR presenting during childhood and adolescence/adulthood responding to treatment with phosphate and high doses of vitamin D analogs.

Tier 3

However, there is some evidence that current treatment strategies may actually increase the production of FGF23. Thus, some authors have suggested the normalization of FGF23 concentration that occurs in some patients is likely due to an intrinsic physiologic alternation in the patient’s metabolism of FGF23, leading to resolution of ADHR features and observed delayed penetrance.

Tier 5

Surveillance

Individuals should undergo frequent monitoring of height, calcium, alkaline phosphatase, parathyroid hormone, and phosphate serum concentrations, as well as urinary calcium and creatinine.

Tier 4

Nature of Intervention

Nature of Intervention

In general, prescribing phosphate intake in disorders of phosphate wasting is a balance between excessive dosage tending to hyperparathyroidism and insufficient dosage slowing the healing of rickets. Toxicity from vitamin D analog supplementation may result in hypercalciuria, requiring monitoring of urinary calcium and creatinine. As for many chronic diseases, compliance to oral treatment in phosphate wasting is a major issue, even in expert hands. No specific harms of treatment in ADHR were identified.

Context: Pediatric

Chance to Escape Clinical Detection

Patients may have a delayed onset of phenotype and may display features that are not seen in other hereditary phosphaturic disorders, this may lead to difficulties in establishing the presence of the disorder.

Context: Pediatric

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			FGF23			193100	0008660

References List

Autosomal dominant hypophosphatemic rickets. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=89937

Econs MJ, McEnery PT. (1997) Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. The Journal of clinical endocrinology and metabolism. 82(2):674-81.

HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL DOMINANT; ADHR. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 193100, (2010) World Wide Web URL: http://omim.org/

Imel EA, Hui SL, Econs MJ. (2007) FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 22(4):520-6.

Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ. (2011) Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. The Journal of clinical endocrinology and metabolism. 96(11):3541-9.

Kapelari K, Kohle J, Kotzot D, Hogler W. (2015) Iron Supplementation Associated With Loss of Phenotype in Autosomal Dominant Hypophosphatemic Rickets. The Journal of clinical endocrinology and metabolism. 100(9):3388-92.

Linglart A, Biosse-Duplan M, Briot K, Chaussain C, Esterle L, Guillaume-Czitrom S, Kamenicky P, Nevoux J, Prie D, Rothenbuhler A, Wicart P, Harvengt P. (2014) Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocrine connections. 3(1):R13-30.