Table 3.

Allelic Disorders

GeneDisorderMOIClinical Characteristics
ENPP1 Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) (OMIM 613312) 1AR
  • Short stature, dental caries, & bone deformities
  • Hypophosphatemia, hyperphosphaturia, & ↑ plasma alkaline phosphatase
  • Levy-Litan et al [2010] described affected persons diagnosed between ages 2.5 & 16.8 yrs who at dx showed no evidence of GACI. 2 (Whether these persons had had mild features of GACI that were missed during infancy & resolved after development of hypophosphatemia is unknown.)
Hypophosphatemic rickets / osteomalaciaADFractures, low bone mineral density, hypophosphatemia, hyperphosphaturia, & ↑ FGF23 were reported in persons from 2 unrelated families w/known heterozygous ENPP1 pathogenic variants [Oheim et al 2020], raising the possibility that certain monoallelic variants in ENPP1 can lead to osteomalacia.
Cole disease (OMIM 615522)AD
AR
  • Distinctive hypopigmented macules; punctate keratosis on areas of cornification (specifically the palms & soles)
  • Rare cutaneous calcifications (incl calcinosis cutis & calcific tendinopathy) have been noted. 3
ABCC6

Pseudoxanthoma elasticum

AR
  • Systemic disorder affecting elastic tissue of the skin, eye, & CV & GI systems
  • Commonly presents w/papules in the skin &/or w/angioid streaks of the retina found on routine eye exam or assoc w/retinal hemorrhage
  • Rarely, may present w/vascular signs & symptoms, (e.g., GI bleeding, angina, or intermittent claudication)
  • ↓ vision (from macular hemorrhage & disciform scarring of the macula) is most frequent cause of morbidity & disability.
  • Normal life span in most persons

AD = autosomal dominant; AR = autosomal recessive; CV = cardiovascular; dx = diagnosis; GACI = generalized arterial calcification of infancy; GI = gastrointestinal; MOI = mode of inheritance

1.

Of note, fibroblast growth factor 23 (FGF23), a major regulator of phosphorus homeostasis, leads to decreased renal tubular reabsorption of phosphorus. Intact FGF23 (i.e., the active form of FGF23 prior to cleavage into its inactive C terminal) is either elevated or in the upper range of normal in individuals with ARHR2 [Ferreira et al 2021a].

2.

That is, no vascular or periarticular calcifications on imaging studies.

3.

From: Generalized Arterial Calcification of Infancy

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