Familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are different manifestations of the same disease: novel missense mutations in GALNT3.
OBJECTIVE
To report on the biochemistry and clinical and genetic findings of two siblings, the younger sister presenting with recurrent bone pain of the radius and ulna, and medullary sclerosis, and the older brother with soft tissue calcific deposits (tumoral calcinosis) but who later developed bone pain. Both were found to be hyperphosphaturic.


METHODS
The index family comprised four individuals (father, mother, brother, sister). The affected siblings were the offspring of a non-consanguineous Indian family of Tamil origin. Bidirectional sequencing was performed on the DNA from the index family and on 160 alleles from a population of 80 unrelated unaffected control individuals of Tamil extraction and 72 alleles from individuals of non-Tamil origin.


RESULTS
Two symptomatic siblings were found to harbour previously unreported compound heterozygous missense UDP-N-acetyl-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-transferase; GALNT3) mutations in exon 4 c.842A>G and exon 5 c.1097T>G. This sequence variation was not detected in the control DNA. This is the first report of siblings exhibiting stigmata of familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome with documented evidence of autosomal recessive missense GALNT3 mutations.


CONCLUSIONS
The findings from this family add further evidence to the literature that familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are manifestations of the same disease and highlight the importance of appropriate metabolic and genetic investigations.
Joseph
Leo
L
Department of Orthopaedic Surgery, Vinodhagan Memorial Hospital and Dr. Joseph's Ortho Clinic, Thanjavur, India.
Hing
Sandra N
SN
Presneau
Nadege
N
O'Donnell
Paul
P
Diss
Tim
T
Idowu
Bernadine D
BD
Joseph
Selvanayagam
S
Flanagan
Adrienne Margaret
AM
Delaney
David
D
D000293:Adolescent; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics*; D002114:Calcinosis / Q000000981:diagnostic imaging / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D054559:Hyperphosphatemia / Q000000981:diagnostic imaging / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011859:Radiography; D000097763:Polypeptide N-acetylgalactosaminyltransferase
D017350:N-Acetylgalactosaminyltransferases; D000097763:Polypeptide N-acetylgalactosaminyltransferase