From variome to phenome: Pathogenesis, diagnosis and management of ectopic mineralization disorders

Table 1 Causes of metastatic/dystrophic calcification and ectopic ossification

	Metastatic calcification	Dystrophic calcification	Ectopic ossification
Primary	Primary hyperparathyroidism Pseudo(pseudo)hypoparathyroidism HFTC	PXE PXE-like syndrome GACI Keutel syndrome IBGC ACDC AI	Fibrodysplasia ossificans progressiva
Secondary	Sarcoidosis Vitamin D intoxication Milk-Alkali syndrome Secondary hyperparathyroidism Renal failure Hemodialysis Tumor lysis Therapy with vitamin D and phosphate	Scleroderma Dermatomyositis SLE	Nonhereditary myositis ossificans

ACDC: Arterial calcification due to CD73 deficiency; AI: Amelogenesis imperfecta; GACI: Generalized arterial calcification of infancy; HFTC: Hyperphosphatemic familial tumoral calcinosis; IBGC: Idiopathic basal ganglia calcification; PXE: Pseudoxanthoma elasticum; SLE: Systemic lupus erythematosus.

Table 2 Differential diagnosis of pseudoxanthoma elasticum manifestations[1,19,47,49,53-59]

Disease	Distinct differences with PXE
Beta-thalassemia (PXE phenocopy)	Severe anemia Reduced production of hemoglobin
PXE-like syndrome (AR; GGCX gene)	More severe cutaneous phenotype not restricted to flexural areas Vitamin K-dependent coagulation factor deficiency
GACI (AR; ENPP1 gene)	Onset in infancy or early childhood Arterial stenosis Early-onset severe myocardial ischemia High mortality rate in early childhood
Fibroelastolytic papulosis, Treatment with D-penicillamine	No ophthalmological or CV phenotype
Buschke-Ollendorf syndrome (AD; LEMD3 gene)	Skeletal manifestations (osteopoikilosis, stiff joints, osteosclerosis) No ophthalmological or CV phenotype No mineralization
Solar elastosis	Dermatological features (lentigines, mottled pigmentation, actinic keratoses, telangiectasias, xerotic texture) No ophthalmological or CV phenotype No mineralization
Late-onset focal dermal elastosis	Onset in 7th to 9th life decade No ophthalmological or CV phenotype
Cutis laxa	No ophthalmological or CV phenotype Histopathology: scarce and mottled elastic fibers, no mineralization
A(R)MD (age-related macular degeneration)	No AS No CV or dermatological phenotype Less unique lesions (outer retinal tabulation or Bruch’s membrane undulation)
Presumed ocular histoplasmosis	No AS No CV or dermatological phenotype

AD: Autosomal dominant; AR: Autosomal recessive; A(R)MD: Age-related macular degeneration; AS: Angioid streaks; CV: Cardiovascular; ENPP1: Ectonucleotide pyrophosphatase/phosphodiesterase 1; GACI: Generalized arterial calcification of infancy; GGCX: Gamma-glutamyl carboxylase; LEMD3: Lem domain-containing protein 3; PXE: Pseudoxanthoma elasticum.

Table 3 Differential diagnosis of the pseudoxanthoma elasticum-like syndrome[19,47]

Disease	Distinct differences with PXE-like syndrome
PXE (AR; ABCC6 gene)	More severe CV and ophthalmological manifestations Skin lesions are less severe and restricted to flexural areas No coagulation factor deficiency associated EM: mineralization in the core of the EF
Cutis laxa	No retinopathy No deficiency of coagulation factors Atherosclerosis and cerebral aneurysm are infrequent Histopathology: scarce and mottled elastic fibers, no mineralization

ABCC6: Adenosine triphosphate-binding cassette, subfamily C, member 6; AR: Autosomal recessive; CV: Cardiovascular; EF: Elastic fiber; EM: Electron microscopy; PXE: Pseudoxanthoma elasticum.

Table 4 Differential diagnosis of generalized arterial calcification of infancy[73,78,87-90]

Disease	Distinct differences with GACI
PXE (AR; ABCC6)	GACI-like phenotype possible, however infrequent CV phenotype usually less severe No onset in infancy Dermatological and ophthalmological phenotypes more prominent
Singleton-Merten Calcification (AD; unknown causal gene)	Dental anomalies (delayed eruption and early loss of permanent teeth, alveolar bone erosion) Osteopenia Acroosteolysis
Metastatic calcification due to hypervitaminosis D, hyperparathyroidism or end-stage renal disease	Different distribution of extravascular calcification (renal tubules, bronchial walls and basal mucosa and muscularis mucosae of the stomach) Microscopic vascular changes in media instead of intima
Congenital syphilis	Only calcification of the (ascending) aorta Diagnosed mainly in adults Hutchinson teeth, interstitial keratitis, saber tibiae, saddle-shaped nose Histopathology: endarteritis obliterans of vasa vasorum with perivascular plasma cells, lymphocytic cuffing and adventitial fibrosis
Iliac artery calcification in healthy infants	Only calcification in the common and internal iliac arteries

ABCC6: Adenosine triphosphate-binding cassette, subfamily C, member 6; AD: Autosomal dominant; AR: Autosomal recessive; CV: Cardiovascular; GACI: Generalized arterial calcification of infancy; PXE: Pseudoxanthoma elasticum.

Table 5 Differential diagnosis of Keutel syndrome[98,110-112]

Disease	Distinct differences with Keutel Syndrome
X-linked chondrodysplasia punctata (XL; ARSE gene)	Ichtyosis Cataracts Microcephaly, intellectual disability ASD, VSD, PDA Failure to thrive in infancy Age at diagnosis: usually infancy
Warfarin embryopathy	Pectus carinatum Congenital heart defects different from those seen in Keutel syndrome (ASD, PDA, ventriculomegaly)
Combined Vitamin K-dependent coagulation factor deficiency	Easy bruising, mucocutaneous bleeding Osteoporosis with normal serum markers
Relapsing polychondritis	Age at diagnosis: 40-60 yr Cartilage inflammation, possibly progressing to destruction Aortic or mitral valvular disease Facies: saddle nose deformity, multifocal, tender chondritis, including variably floppy or calcified auricles Cranial neuropathies, hemiplegia

ARSE: Arylsulfatase E; ASD: Atrial septal defect; PDA: Patent ductus arteriosus; VSD: Ventricular septal defect; XL: X-linked.

Table 6 Differential diagnosis of idiopathic basal ganglia calcification[116,140-143]

Disease	Distinct differences with IBGC
Basal ganglia calcification as incidental finding on CT scans/ aging	In 1% of CT scans Usually benign No clear etiology, especially when in older patients Asymptomatic
Hypoparathyroidism	Early onset: childhood/adolescence Hypoparathyroidism, hypocalcemia, hyperphosphatemia Alopecia, dry hair Dental dysplasia, caries Moniliasis Albright osteodystrophy symptoms (short stature, round facies, obesity, short metacarpals/metatarsals)
Pseudohypoparathyroidism (AD/maternal imprinting; GNAS, GNASAS1 and STX1A gene)	Early onset: childhood/adolescence Hyperparathyroidism, hypocalcemia, hyperphosphatemia Baseline cAMP in urine low; after Ellsworth Howard test subnormal Intellectual disability Albright osteodystrophy symptoms
Pseudo- pseudohypoparathyroidism (AD/paternal imprinting; GNAS gene)	Similar phenotype as pseudohypoparathyroidism Normal serum PTH, calcium and phosphorus Intellectual disability (more obvious than in PHP)
Kenny-Caffey syndrome, type 1 (AR; TBCE gene)	Growth delay Cortical thickening of long bones Hypocalcemia, hypoparathyroidism
PKAN (AR; PANK2 gene)	Early onset (10% > 10 yr) Pigmentary retinopathy
DRPLA (AD; CAG expansion in DRPLA gene)	Phenotype similar to IBGC
Neuroferritinopathy (AD; FTL gene)	Dysphagia
PLOSL (AR; TYROBP and TREM2 gene)	Radiography: polycystic osseous lesions Frontal lobe syndrome
Cockayne syndrome; Aicardi- Goutières syndrome	Onset in infancy/early childhood

AD: Autosomal dominant; AR: Autosomal recessive; CAG: Cytosine, adenine, guanine; cAMP: 3’-5’-cyclic adenosine monophosphate; CT: Computed tomography; DRPLA: Dentatorubropallidoluysian atrophy; FTL: Ferritin light chain; GNAS: GNAS complex locus; GNASAS1: GNAS complex locus, antisense transcript 1; IBGC: Idiopathic basal ganglia calcification; PANK2: Panthothenate kinase 2; PHP: Pseudohypoparathyroidism; PKAN: Panthothenate kinase-associated neurodegeneration; PLOSL: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy); PTH: Parathyroid hormone; STX1A: syntaxin 1A; TBCE: Tubulin-specific chaperone E; TREM2: Triggering receptor expressed on myeloid cells 2; TYROBP: Tyro protein tyrosine kinase-binding protein.

Table 7 Differential diagnosis of hyperphosphatemic familial tumoral calcinosis[149,151,158-166]

Disease	Distinct differences with HFTC
Calcinosis universalis	Calcium depositions in tendons and muscle tissues Normophosphatemia High hemosedimentation Microcytic and hypochromic anemia
Calcinosis circumscripta	Adult onset Local calcinosis Fingers symmetrically affected
Calcific tendinitis	Adult onset Calcification limited to tendons
Synovial chondromatosis	Lesions arising from synovial tissue Widespread throughout the body Not all lesions are calcified
Osteosarcoma	Long bone malignant tumor 2nd life decade or late adulthood No subcutaneous/skin lesions
Fibrodysplasia ossificans progressiva (AD; ACVR1 gene)	Hallux valgus, monophalangism and/or malformed first metatarsal Sporadic episodes of painful soft tissue swellings (flare-ups) in 1st life decade
Tophaceous gout	Severe form of gout Severe joint deformity, chronic pain and functional decline More prominent in Asian population (slow metabolizers) and in young men with strong genetic predisposition
Calcific myonecrosis	Post-traumatic (time interval of several years possible) Lower limbs only
NFTC (AR; SAMD9 gene)	Reddish-to-hyperpigmented skin lesions during the first year of life (preceding calcified nodules) Severe conjunctivitis and gingivitis Normophosphatemia
Secondary tumoral calcinosis	Renal insufficiency, hyperparathyroidism, or hypervitaminosis D
Rheumatological diseases	Usually normophosphatemia and - calcemia Possibly positive results in antinuclear, anti-Smith, anti-centromere and anti-scleroderma antibodies, which should all be negative

ACVR1: Activin A receptor, type 1; AD: Autosomal dominant; AR: autosomal recessive; HFTC: Hyperphosphatemic familial tumoral calcinosis; NFTC: Normophosphatemic familial tumoral calcinosis; SAMD9: Sterile alpha motif domain-containing protein 9.