Cleidocranial dysplasia syndrome with epilepsy: a case report
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Cleidocranial dysplasia is a rare autosomal dominant disorder resulting in skeletal and dental abnormalities due to the disturbance in ossification of the bones. The prevalence of CCD is one in a million of live births, and epileptic seizures are rarer in this disease.
Herein, we present a case of a 10-year-old girl, who not only suffered with cleidocranial dysplasia, but experienced frequent seizures. We initiated an anti-epileptic treatment for this patient with dose adjustments to her weight of levetiracetam (10 mg/kg, bid) for 3 months. The epileptic seizures were controlled, but the intelligence level and control of epilepsy need to be followed up for a longer duration.
In clinical practice, if a patient has unusual facies, typical clavicle defect, skull bone enlargement, and unclosed anterior fontanelle, we should consider the possibility of cleidocranial dysplasia, genetic detection are helpful to make a confirmed diagnosis. In such cases, early diagnosis and treatment is important to correct deformities and improve the quality of life of patients.
KeywordsCleidocranial dysplasia RUNX2
Cleidocranial dysplasia is a rare autosomal dominant hereditary skeletal disease (MIM number is 600211). A few of these cases were familial and most were sporadic. There was no significant difference in the incidence between males and females, and the clinical incidence was 1:1000000 . The main manifestations of CCD are systemic skeletal and teeth dysplasia. The typical symptoms include: incomplete or absent development of one or both clavicles, the formation of pseudo joints, shoulders drooping, shoulder joint hypermobility; delayed closure or unclosed anterior fontanelle, widening of cranial sutures, cranial ectasia; retention of deciduous teeth, delayed sprouting of permanent teeth, malformation of roots and tooth cysts with supernumerary teeth . Systemic manifestations include: pigeon chest or conical shape of chest, smaller scapula, widened pubic symphysis gap, Short stature, repeated infection of respiratory tract and ear canal [3, 4]. The incidence of the disease is very low, and combined with seizures are rarer. In this paper, the clinical data of a patient with CCD accompanied by epileptic seizure were reported. Laboratory, imaging studies and related literature were reviewed to discuss the clinical manifestations and genetic characteristics of the disease to improve the clinician’s understanding and knowledge in regard to this specific congenital disorder.
Discussion and conclusions
CCD is also known as Marie and Sainton ‘s disease, Schlotzhauer-Marie-Sainton syndrome, osteogenesis imperfecta, which was first described by Pierre Marie and Paul Sainton in 1898 . RUNX2 gene is a CCD gene that is located on chromosome 6p21 and is a 130 kb length protein. It encodes the transcription factors required for chondrocyte proteins and dentin, influences the differentiation and maturation of osteoblasts, and affects intramembranous and endochondral ossification [4, 6, 7, 8]. In our case, the sequencing of the RUNX2 gene indicate c.947delA p. (His316fs) mutation in patient while her parents’ are normal. This mutation is a frameshift mutation (the RUNX2 translation protein has a disorder in the coding of the amino acid residue His at position 316). This mutation is expected to cause the encoded protein to be truncated and lose its normal function. In addition to the typical dystrophy of the cranial clavicle and various vertebral and dental abnormalities, recurrent ear infections and hearing loss are common in CCD due to maxillofacial hypoplasia and osteogenic deficiencies ; most patients have chest malformations, some severe cases can lead to an early respiratory distress in infants ; some case also indicate that CCD patient are more likely to suffer from hematological disease [9, 10, 11]. Osteopenia is present in most patients due to osteogenesis and ossification ; CCD patients are often of short stature, their birth length is usually normal, but their height is below the two percentiles between 4 and 8 years old. The final average height of the male is 165 cm (±8 cm) and the female is 156 cm (±10 cm) . The motor development may be of slightly delayed onset (age of walking), but in most cases, mental development is normal .
This patient had a typical clavicle defect, skull bone enlargement, and unclosed anterior fontanelle, with funnel chest which conforms to the typical CCD performance and the results of genetic sequencing, confirmed this diagnosis. Several neurological disorders associated with CCD have been reported such as mental retardation, spastic paresis etc. . Seizures associated with this disease are very rare. The patient was diagnosed with epilepsy at 5 years of age but was not on regular treatment. Most of the CCD patients had normal intelligence, but the mental development of this patient was significantly backward compared with children of the same age. As a student of the third grade of elementary school, she cannot read and cannot perform simple addition and subtraction in less than 10. Her cranial magnetic resonance imaging (MRI) showed bilateral parietooccipital atrophy and periventricular leukomalacia. According to her medical history, the mental development delay may be related to the brain damage and poor control of epilepsy. Analysis of the Literature on CCD patients with epilepsy, we found that there were few related literatures. Most of the articles were case reports which had been published over 10 years ago. B. M. Tress’s research found that among the patients with epilepsy, there were 3 cases in which this was secondary to an abscess, 2 with cerebral angiomas and 2 with telangiectasia . Oyer, CE reported a 15-day-old female neonate with CCD. Her postnatal course was characterized by seizures and recognition of hydrocephalus during the first day of life .
This patient had no family history of epilepsy, but cranial MRI suggested sequela of brain injury. So the etiology of epilepsy maybe brain damage. Consistent with the literature, the occurrence of epilepsy may be related to brain structural abnormalities and damage. But the number of cases are limited, further research is necessary in the future. After the patient was admitted to the hospital, oral levetiracetam (10 mg/kg, bid) was used to control seizure and she received supportive treatment [17, 18]. The intelligence level and control of epilepsy need to be followed up for a longer period of time [19, 20, 21].
In clinical practice, if one patient has unusual facies, typical clavicle defect, skull bone enlargement, and unclosed anterior fontanelle, we should consider the possibility of cleidocranial dysplasia, in such cases, early diagnosis and treatment is important to correct deformities and improve the quality of life of patients.
The authors thank the patient’s parents for providing permission to use the information of their children, and also thank Dr. Mowshica Rajah for the English revise.
YMM, DY and FMZ analyzed and interpreted the patient data. YMM wrote the draft of this article, and DY and FMZ revised this article. All authors read and approved the final manuscript.
The study was supported by the Science and Technology Department of Sichuan Province (NO. 2018SZ0123) for data collection and language polish.
Each author declares that they have no competing interests, and certifies that he has no commercial association (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement, etc.) that might pose a conflict of interest in connection with the submitted article.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of the West China Second University Hospital and written informed consent was obtained from parents of the child.
Consent for publication
The study obtained informed written consent from the parents of the study participants in order to publish their clinical details and clinical images.
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