Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.2.3
• Status (Adult): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: FGF23
• Condition: Hypophosphatemic rickets, autosomal dominant
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• FGF23 ⇔ 0008660 (autosomal dominant hypophosphatemic rickets): Limited Actionability

Actionability Rationale

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

Final Consensus Scores

Gene Condition Pairs: FGF23 ⇔ 0008660 (OMIM:193100)

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

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

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. [1]

Clinical Features

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. [1, 2, 3]

Natural History

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. [1, 2, 4, 5, 6]

2. How effective are interventions for preventing harm?

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) [1]

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) [2]

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) [7]

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) [1]

Circumstances to Avoid

No circumstances-to-avoid recommendations have been provided for the Pediatric context.

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant [1, 2]

Prevalence of Genetic Variants

No information on prevalence of pathogenic variants causing ADHR was identified. Fewer than 100 cases have been described. (Tier 4) [1]

Penetrance

ADHR exhibits incomplete penetrance. The onset of the features may be delayed and there is occasional resolution of the phosphate-wasting defect. (Tier 3) [2]

Relative Risk

Information on relative risk was not available for the Pediatric context.

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) [2]

4. What is the Nature of the 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. [3]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

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. (Tier 3) [4]

Date of Search: 07.11.2018

Reference List

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

2. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL DOMINANT; ADHR. MIM: 193100: 2010 Oct 04. World Wide Web URL: http://omim.org.

3. 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. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect. (2014) 3(1):R13-30.

4. Econs MJ, McEnery PT. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab. (1997) 82(2):674-81.

5. Imel EA, Peacock M, Gray AK, Padgett LR, Hui SL, Econs MJ. Iron modifies plasma FGF23 differently in autosomal dominant hypophosphatemic rickets and healthy humans. J Clin Endocrinol Metab. (2011) 96(11):3541-9.

6. Kapelari K, Kohle J, Kotzot D, Hogler W. Iron Supplementation Associated With Loss of Phenotype in Autosomal Dominant Hypophosphatemic Rickets. J Clin Endocrinol Metab. (2015) 100(9):3388-92.

7. Imel EA, Hui SL, Econs MJ. FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J Bone Miner Res. (2007) 22(4):520-6.