Cleidocranial dysplasia in a Polish population: high frequency of the R193X mutation

To the Editor: Cleidocranial dysplasia (CCD; MIM119600) is an autosomal dominant disease characterized by multiple skeletal abnormalities, dental anomalies and hearing impairment (HI) (1, 2). CCD is caused by mutations in the CBFA1 gene (corebinding factor a1) (2, 3) encoding a transcription factor that activates osteoblast differentiation (4). CBFA1 contains three major domains: Q/A domain, runt domain and PST domain (3, 5–7). A majority of the mutations detected in patients with CCD affect the runt domain or the Q/A domain (8–13). The aim of our study was to assess the clinical features and genetic background of Polish patients with CCD. A total of 12 patients with a clinical diagnosis of CCD (2) were studied (3 from a single family – Fig. 1 – and 9 sporadic cases). The studied cohort included six boys and six girls; the average age was 8.2 years (range 4–13 years). The molecular analysis was performed on seven patients (one familial and six sporadic cases, whereas three remaining patients refused to participate). Exons 1–3 of CBFA1 (encoding Q/A and runt domains) were amplified by PCR and sequenced. Primers were designed by Primer 3 software (14). Sequence positions are according to the GenBank entries AF001443 to AF001450, with the A in the start codon ATG and the initiator Methionine numbered as the first base pair and amino acid residue, respectively. For the statistical analysis, Fisher’s exact test was used. All patients displayed delayed closure of fontanels and sutures and hypoplastic/aplastic clavicles. Supernumerary teeth were found in six out of eight examined subjects. Other relatively constant abnormalities were short stature (less than fifth percentile) in 11/12 (92%), facial dysmorphism (midfacial hypoplasia and hypertelorism) in 10/12 (83%), highly arched palate in 9/12 (75%), Wormian bones in 10/12 (83%), pelvis anomalies (hypoplastic iliac wings and/or hypoplastic/aplastic pubic bones) in 10/12 (83%), and coxa vara/valga in 5/12 (42%). In seven patients, audiological examination was performed revealing HI in four cases (conductive HI in three patients and mixed HI in one). In summary, we found in our patients the typical clinical features of CCD as described previously (1, 15). An interesting observation is that all patients with HI had also chronic otitis media. This finding emphasizes the role of chronic otitis media in the pathogenesis of HI in CCD (16). Another interesting observation is a history of laryngotracheomalacia in one patient. To our knowledge, this complication has not yet been reported in CCD. However, since CBFA1 is involved not only in bone formation but also in regulation of chondrocyte differentiation (2), it is possible that this manifestation was also related to CCD. Mutations in the sequenced region of CBFA1 were found in four subjects: the p.R193X (c.577C.T) mutation (10) in three sporadic cases and the p.R190W (c.568C.T) mutation (17) in one sporadic case. The patient with the p.R190W