Cleidocranial dysplasia with decreased bone density and biochemical findings of hypophosphatasia.
Cleidocranial dysplasia (CCD; MIM 119600) is an autosomal dominant skeletal dysplasia characterised by hypoplastic clavicles, patent fontanelles, short stature, tooth anomalies and other variable skeletal changes. Different mutations of the RUNX2/CBFA1 gene (MIM 600211) have been detected in patients with CCD. We investigated a mother and daughter with features of CCD presenting with reduced plasma alkaline phosphatase activity, increased urinary phosphoethanolamine excretion and decreased bone density. The latter findings were suggestive of hypophophatasia but mutation analysis showed no mutation in the tissue-nonspecific alkaline phosphatase gene (TNSALP; MIM 171760). However, a heterozygous mutation (Arg169Pro caused by nucleotide change 506G > C) was detected in the RUNX2 gene. Metabolic alterations gradually improved in both mother and daughter but bone-specific alkaline phosphatase remained low (less than 30% of normal) and mild phosphoethanolaminuria persisted. Recent studies in the Cbfa1 knock-out mouse showed decreased expression of alkaline phosphatase in differentiating bone.


CONCLUSIONS
we suggest that the observed metabolic alterations are secondary to the RUNX2 gene mutation affecting early bone maturation and turnover. This is the first description of biochemical findings of hypophosphatasia in patients with cleidocranial dysplasia.
Morava
Eva
E
Department of Medical Genetics and Child Development, Medical Faculty, University of Pécs, Józesf A u 7, 7623 Pécs, Hungary. emorava@yahoo.com
Kárteszi
Judit
J
Weisenbach
János
J
Caliebe
Almuth
A
Mundlos
Stefan
S
Méhes
Károly
K
D000469:Alkaline Phosphatase / Q000097:blood; D015519:Bone Density; D002648:Child; D002973:Cleidocranial Dysplasia / Q000201:enzymology* / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D050659:Core Binding Factor Alpha 1 Subunit; D004252:DNA Mutational Analysis; D005260:Female; D006579:Heterozygote; D006801:Humans; D007014:Hypophosphatasia / Q000150:complications*; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins; D014157:Transcription Factors / Q000235:genetics*
D050659:Core Binding Factor Alpha 1 Subunit; D009363:Neoplasm Proteins; D014157:Transcription Factors; D000469:Alkaline Phosphatase