A case of familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features.
CONCLUSIONS
A new case of familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) due to a novel compound heterozygous mutation in N-acetylgalactosaminyltransferase 3 (GALNT3) and with new phenotypic findings is presented. The response in serum phosphate and fibroblast growth factor 23 (FGF23) to medical treatment is detailed. This case expands the genotype and phenotype of FTC/HHS and gives insight into its treatment and pathophysiology.


BACKGROUND
FTC and HHS are caused by mutations in FGF23, GALNT3, or KLOTHO. They are characterized by hyperphosphatemia, increased phosphate reabsorption, and elevated or inappropriately normal serum 1,25-dihydroxyvitamin D(3) (1,25-D(3)); FTC is associated with calcific masses, and HHS with diaphyseal hyperostosis.


METHODS
A 36-year-old woman presented with abnormal dental X-rays at age 12 and was hyperphosphatemic at 22. She underwent radiographic, biochemical and genetic testing, and medical treatment.


RESULTS
Serum phosphorus was 7.3 mg/dL (2.5-4.8), TmP/GFR 6.99 mg/100 mL (2.97-4.45), 1,25-D(3) 35 pg/mL (22-67). Radiographs revealed tooth anomalies, thyroid cartilage calcification, calcific masses in vertebral spaces, calcification of the interstitial septa of the soft tissue in the lower extremities, and cortical thickening of the long bones. Her total hip Z score was 1.9. C-terminus serum FGF23 was 1,210 RU/mL (20-108), but intact FGF23 was 7.4 pg/mL (10-50). DNA sequencing determined she was a compound heterozygote for mutations in GALNT3. Treatment with niacinamide and acetazolamide decreased TmP/GFR and serum phosphate, which was paralleled by a decrease in serum C-terminus FGF23.


CONCLUSIONS
This case broadens the spectrum of phenotypic and genotypic features of FTC/HHS and suggests treatments to decrease renal phosphate reabsorption in the setting of a low intact FGF23.
Dumitrescu
C E
CE
Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, NIDCR, NIH, Bethesda, MD 20892-4320, USA.
Kelly
M H
MH
Khosravi
A
A
Hart
T C
TC
Brahim
J
J
White
K E
KE
Farrow
E G
EG
Nathan
M H
MH
Murphey
M D
MD
Collins
M T
MT
D000086:Acetazolamide / Q000627:therapeutic use; D000328:Adult; D002114:Calcinosis / Q000188:drug therapy / Q000235:genetics*; D002648:Child; D004232:Diuretics / Q000627:therapeutic use; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood; D006579:Heterozygote; D006621:Hip Joint / Q000000981:diagnostic imaging; D006801:Humans; D015576:Hyperostosis / Q000188:drug therapy / Q000235:genetics*; D054559:Hyperphosphatemia / Q000188:drug therapy / Q000235:genetics*; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D009536:Niacinamide / Q000627:therapeutic use; D010710:Phosphates / Q000097:blood; D011859:Radiography; D014803:Vitamin B Complex / Q000627:therapeutic use; D055815:Young Adult
D004232:Diuretics; C000717427:FGF23 protein, human; D010710:Phosphates; D014803:Vitamin B Complex; D009536:Niacinamide; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D017350:N-Acetylgalactosaminyltransferases; D000086:Acetazolamide