A novel mutation in the C-terminal region of RUNX2/CBFA1 distal to the DNA-binding runt domain in a Japanese patient with cleidocranial dysplasia

Abstract

Cleidocranial dysplasia (CCD) is an autosomal dominant inherited skeletal disease with high penetrance and variable expressivity. Although many mutations in RUNX2/CBFA1 , an osteoblast-specific transcription factor, have been identified as causes of CCD, it is unclear whether these mutation genotypes relate to various symptoms. Heterogeneous mutations of RUNX2/CBFA1 result in disease characterized by abnormal skeletal genesis and dental disorders. There are few reports describing the relation between detailed orofacial pathology and the RUNX2/CBFA1 genotype. The case of a Japanese patient with severe orofacial dysplasia who was clinically thought to have CCD is described here. The authors performed mutation analysis on the RUNX2/CBFA1 gene and identified a novel frameshift mutation (722delT), which produces a mutant RUNX2/CBFA1 with a truncating C-terminus distal to the runt domain.

Cleidocranial dysplasia (CCD; OMIM#119600 ) is an autosomal dominant inherited skeletal disease with high penetrance and variable expressivity, characterized by short stature, hypoplastic (or absent) clavicles, large fontanelles, and dental anomalies. Since CCD was first described by Meckle (cited in Siggers) and Martin in the mid-18th century, over 700 cases have been reported . The disease has now been associated with 48 distinct phenotypic features, including axial and appendicular skeletal defects, craniofacial and dental malformations, central nervous system anomalies, and hearing loss. CCD is caused by heterozygous mutations in the osteoblast-specific transcription factor RUNX2 . Mice with a heterozygous mutation in Runx2 (alias Cbfa1 , Pebp2A and Aml3 ) show a CCD phenotype, whilst those with a homozygous mutation die, showing a complete absence of osteoblasts, resulting in total agenesis of bone . Various mutations in the RUNX2 gene have been identified in CCD families . Although many mutations in RUNX2 have been identified as causes of CCD with various orofacial symptoms , no clear genotype–phenotype correlation has been established . Despite it being one of the main features, a detailed description of dental anomaly in the disease has not been published. The authors describe detailed clinical observations on a CCD patient with genetic information, and discuss the implication for the syndrome.

Clinical report

A 28-year-old man diagnosed with CCD was referred to the Department of Maxillofacial Surgery to undergo an operation for occlusal improvement. The characteristic oral findings at the initial medical visit are shown in Fig. 1 a . The patient had short stature (height 154 cm, body weight 51 kg), abnormal facility in opposable shoulders ( Fig. 1 b), brachydactyly ( Fig. 1 c), small maxilla, and malocclusion of the teeth.

Fig. 1
Photographs showing (a) malocclusion, (b) opposable shoulders, and (c) brachydactyly.

The family history showed that only the mother was of short stature, but further information was not available. Chest radiography revealed a cone-shaped chest, high scapular bones, aplasia of the clavicle, and a curved spine ( Fig. 2 a and b ). Plain radiographs of the pelvis did not reveal the clear osteodystrophy that is characteristic of CCD ( Fig. 2 c). A lateral/posteroanterior cephalogram showed clefting of the suture frontozygomatica and zygomatic bone, infraorbital marginal notch, and small maxilla ( Fig. 2 d). Lateral cephalographic analysis demonstrated that he had maxillary retrognathism (Cephalometric A to Z; Yasunaga Labs, Fukui, Japan); measurements are shown in Fig. 3 a . A panoramic radiograph showed multiple supernumerary teeth in the maxilla (one between the left incisors, and two between molars), failure of secondary dentition eruption, and delayed maturation of permanent teeth ( Fig. 3 b).

Fig. 2
Radiological findings. Chest radiograph demonstrates (a) a cone-shaped chest, high scapular bones, curved vertebral, and (b) aplasia of the clavicle. (c) Abnormal pelvis with hypoplastic iliac wings. (d) Lateral posteroanterior cephalogram showing clefting of the suture frontozygomatica and zygomatic bone, infraorbital marginal notch, and small maxilla.

Feb 7, 2018 | Posted by in Oral and Maxillofacial Surgery | Comments Off on A novel mutation in the C-terminal region of RUNX2/CBFA1 distal to the DNA-binding runt domain in a Japanese patient with cleidocranial dysplasia
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