Cleidocranial dysplasia – A case report discussing the clinical and radiological manifestations
Vikram Singh Shekhawat1, Yoginder Singh Gulati2
1 Department of Endocrinology, Command Hospital (NC), Udhampur, Jammu and Kashmir, India
2 Department of Radiology, Command Hospital (NC), Udhampur, Jammu and Kashmir, India
Lt Col Vikram Singh Shekhawat
Department of Endocrinology, Command Hospital (NC), Udhampur, Jammu and Kashmir
Source of Support: None, Conflict of Interest: NoneCheck
Cleidocranial dysplasia (CCD) is a generalized skeletal disorder characterized by typical clinical and radiological abnormalities which include open cranial sutures and fontanelle, presence of Wormian bones, characteristic abnormalities of the clavicle and pelvic bones, and dentition. We report a teenage boy who presented for the evaluation of short stature. He was detected to have CCD based on his clinical examination and radiographic findings. An early diagnosis and treatment directed at correcting the dental and orthopedic abnormalities are imperative to obtain an optimal cosmetic and functional outcome in these patients.
Keywords: Cleidocranial dysplasia, RUNX2, Chromosome 6p21, generalised skeletal dysplasia
Cleidocranial dysplasia (CCD) is an autosomal dominant, generalized skeletal dysplasia. It is characterized by a myriad of typical clinical and skeletal abnormalities. Skeletal abnormalities typical of CCD include patent cranial sutures and fontanelles, brachydactyly, dental anomalies, clavicular aplasia/hypoplasia, pelvic hypoplasia, and short stature. The prevalence of the disorder is 0.5/100,000 live births, and both males and females are affected equally. They usually present in the age group of 10–15 years with skeletal and dental abnormalities and short stature. Although CCD is transmitted in an autosomal dominant pattern, nearly a third of the affected individuals have sporadic mutations. The disease is characterized by an early developmental disorder of mesenchyme or connective tissue leading to delayed or even failure of ossification of the affected endochondral and intramembranous bones. The culprit gene (RUNX2 – runt-related transcription factor 2) is located on chromosome 6p21.,Case Report
A 13-year-old boy presented for the evaluation of short stature. He was a product of nonconsanguineous marriage and was born at term. His birth weight was 2.8 kg, and there was no history of birth asphyxia. His developmental milestones were normal, and he was good in studies. There was no family history of short stature or any skeletal abnormalities. He had one younger sister who had normal stature. His father had a history of constitutional delay of growth and puberty (CDGP).
On examination, his height was 137 cm (<3rd percentile, −2.53 SDS, height age 10.0 years, target height 166 cm, and upper/lower segment ratio – 1.1) and weight was 31 kg (<3rd percentile, weight age 10.0 years). He had a broad forehead with frontal bossing, wide spaced eyes, depressed nasal bridge, mid facial hypoplasia, and mandibular prognathism. His anterior fontanelle was not closed, and he could approximate his shoulders in the midline [Figure 1]a. The chest was narrow with sloping shoulders. His Tanner staging was A1 P1 G1. Systemic examination was unremarkable. His hematological and biochemical parameters were essentially normal. Hormonal evaluation revealed prolactin 12.06 ng/ml (3.99–15.1 ng/ml), cortisol 16.5 μg/dl (3–18 μg/dl), LH < 0.1 mIU/ml (1.71–8.65 mIU/ml), FSH 0.48 mIU/ml (1.55–12.45 mIU/ml), and testosterone < 0.08 nmol/L (9.89–27.85 nmol/L). His thyroid function test and IgA tTg were normal. His bone age was 11 years.Figure 1: (a) Clinical photograph showing the affected child being able to approximate his shoulders in midline. (b) X-ray of the chest showing obliquely placed ribs resulting in a small and bell-shaped thorax
Skeletal X-rays showed bell- shaped thorax [Figure 1]b, hypoplastic facial bones, wide coronal suture, open anterior fontanelle, Wormian bones in parieto-occipital region, and multiple impacted teeth [Figure 2]a. The outer ends of both the clavicles were absent [Figure 2]b, both scapulae were small with hypoplastic acromian process, and there was incomplete ossification of the pelvic bones [Figure 3]a. The clinical and radiological features were consistent with the diagnosis of CCD. His short stature was attributed to CDGP, and he was advised calcium and Vitamin D supplements with advice to follow-up regularly in endocrine OPD. The patient was also advised periodontal and orthodontic evaluation for his dental anomalies, and he is under their follow-up for planned prosthodontic rehabilitation. The parents were counseled that the children of the index case had a 50% chance of inheriting the same illness.Figure 2: (a) X-ray skull lateral view showing calvarial thickening, hypoplastic maxilla, Wormian bones in parieto-occipital region and impaction of permanent teeth. (b) X-ray chest with shoulder postero-anterior view showing absent outer ends of both clavicles, midline defects in cervical and upper thoracic vertebrae Discussion
CCD is a generalized skeletal dysplasia. This autosomal dominant disorder is caused by the mutation of the RUNX2 gene located on chromosome 6p21. The RUNX2 gene encodes various transcription factors essential for osteoblast differentiation. The mutated RUNX2 gene results in abnormal ossification of the affected endochondral and intramembranous bones. Although the disorder can affect any bone in the body, the triad of cranio-facial, clavicular and pelvic anomalies form the most saliently recognizable features. The disorder is characterized by several typical clinical and radiological findings. Although CCD is a congenital disorder, the spectrum of the clinical and radiological manifestations in the affected patients may vary considerably.
The skeletal changes in CCD result in characteristic facial features., The patients of CCD usually have a large, brachycephalic skull having frontal and occipital bossing, small maxilla, mid facial hypoplasia, prognathic mandible, contracted high-arched palate, and hyperteloriosm. Failure of the nasal bone to ossify results in a depressed nasal bridge. The closure of the anterior fontanelle and the cranial sutures is delayed. Wormanian bones are commonly seen [Figure 2]a. Paranasal sinuses are often hypoplastic and may even be absent. All the above features were present in our patient. Cleft abnormalities of the palate are also common. Conduction hearing abnormalities, platybasia, and basilar invagination have also been described in the patients of CCD. The cognitive abilities of the affected individual as in our patient are not affected.
Thoracic abnormalities include the characteristic clavicular abnormalities, which are present in almost all patients of CCD. A complete clavicle develops from three different ossification centres. One or more of these ossification centers may be affected, resulting in clavicular hypoplasia/aplasia or discontinuous clavicles., All the three ossification centers are affected in only about 10% of cases and may result in complete clavicular agenesis. Partial or complete absence of the clavicle allows an exaggerated abnormal mobility at shoulders, enabling these individuals to approximate shoulders in the midline [Figure 1]a. Although the clavicular abnormalities are typically bilateral, very rarely clavicle may be affected only on one side. Occasionally, the patient may have normal clavicles. In our patient, the outer end of the clavicle was absent on both sides [Figure 2]b. His both scapulae and the associated musculature were hypoplastic. The scapulae on both sides were small, winged, and elevated. The ribs are often short and obliquely placed [Figure 1]b in these patients resulting in a small and bell-shaped thorax predisposing the affected children to recurrent respiratory infections particularly during infancy.
Like the clavicles, the pelvis is almost always involved. Our patient had incomplete ossification of the pelvic bones. The pelvic X-ray also showed wide symphysis pubis and sacroiliac joints, hypoplastic iliac wings, and coxa vara [Figure 3]a. These pelvic and femoral deformities may result in gait abnormality. The underdeveloped pubic and anterior ischial rami result in a narrow pelvis and usually warrant a cesarean section in the affected pregnant female. X-ray of the spine in our patient showed spina bifida occulta in the cervical and upper thoracic vertebrae [Figure 2]b. Ossification defects of the embryonic vertebral bodies may also result in hemivertebrae and neural arch defects.
Abnormalities of the small bones of hand manifest as characteristic physical and radiological abnormalities. The second metacarpal and metatarsal are long due to their excessive growth resulting from the existence of both proximal and distal epiphysis. Early closure of the epiphyseal growth plates leads to shortening of other bones. The middle and distal phalanges of the 2nd and 5th fingers are unusually short [Figure 3]b. Clinodactly of the fifth finger is common. The finger and toe nails can also be affected leading to hypoplasia/dysplasia of the affected nails. Radius may be shortened leading to abnormal wrist articulation.
Dental abnormalities are frequent and very characteristic of CCD. These abnormalities involve both the primary and secondary teeth. The affected patients, like our patient, have multiple retained primary, supernumerary, and impacted teeth. The eruption of the permanent teeth is usually delayed, and root and crown malformations are also common. This may result in poor cosmetic appearance, impaired teeth articulation, and mastication. Management of the dental abnormalities is guided by the dental and chronological age of the affected individual. Appropriate management of dental abnormalities require a dedicated multidisciplinary team involving an orthodontist, an oro-maxillary surgeon, and a prosthodontist.
The patients invariably have a short stature.,, The birth length of children with CCD is normal. The height gain lags behind during the 4th and 8th year of life, and their final height is considerably less than their target height. The short stature in these patients is mildly disproportionate with limbs being shorter in comparison to trunk.
The patients of CCD can be diagnosed by their characteristic clinical and radiological abnormalities. They have an overall good prognosis and can be expected to have a normal life expectancy. However, they are at increased risk of developing complications such as dental caries, osteomyelitis of mandible and maxilla, frequent respiratory infections, conduction hearing loss, dislocation of shoulders and hip, scoliosis and neurological deficits due to platybasia, and basilar invagination. They are usually short, some might have a marginally delayed motor skill development, though intelligence is unaffected. Treatment is directed at correcting the dental and orthopedic abnormalities associated with the disease to obtain optimal cosmetic and functional outcome.
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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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