A Rare Case of Cockayne Syndrome

Background: Cockayne syndrome is a rare autosomal recessive congenital disorder characterized by growth failure, impaired development of the nervous system, abnormal sensitivity to sunlight (photosensitivity), and premature aging. Case: In this report we present a 24 year old male with decreased height, weight & reduced head circumference measuring 124 cm, 20 kg and 20 cm respectively. Cachectic dwarfism, ataxic gait, Case Study mental retardation, sunken eyes, hypoplastic maxilla, and parrot beak shaped nose giving “bird like facies” were other key features observed in our patient. Oral examination revealed congenital missing teeth and multiple dental caries teeth are also seen. Magnetic resonance imaging and computed tomography findings were also contributory to our diagnosis. Conclusion: This case report aims to rekindle and emphasis the diagnostic features of Cockayne syndrome & highlights the role of various investigations done by both medical & dental professionals to diagnose and manage the patient.


INTRODUCTION
Cockayne syndrome (CS) is one of the several Progeroid Syndromes (PSs) that has been reported and studied for the past several decades. PSs mimic clinical and molecular features of aging [1]. Based on the several studies reported the pathophysiology of progeroid syndrome can be attributed to the mutations in the genetic coding for DNA repair mechanism or genes involved in biological pathways. Several other human disorders occur due to defect in DNA repair mechanism [2,3].
CS is characterized by retarded growth, cachectic dwarfism, premature aging, mental deficiency, microcephaly, intracranial calcifications, neurologic deficits, retinal pigmentary abnormalities, sensori neural hearing loss, and photosensitivity. Oral manifestations like increased dental caries, missing or impacted permanent teeth are also reported. It manifests defective repair of damage induced in DNA by ultraviolet light [2,3].
As per the reports of David MW et al. [4] Cleaver et al. [5] and Jaarsma et al. [6] in the year 2013 suggested that the pathology of Cockayne syndrome can be attributed to the multiple mechanisms such as the DNA repair deficiency, transcription dysregulation, altered redox balance and mitochondrial dysfunction. Conceivably each of these mechanisms participates during a different stage in life of a Cockayne syndrome patient. Endogenous reactive oxygen is considered as an ultimate cause of DNA damage that contributes to Cockayne syndrome pathology. Mutations of two genes, the CKN1 or ERCC8 (Excision-Repair Cross-Complementing Group 8), and the ERCC6 (Excision-Repair Cross Complementing, Group 6), located on chromosomes 5 and 10q11 respectively can be the cause of CS [2,3,7,8].
As the pathology of Cockayne syndrome lies in the molecular level, the modern molecular diagnostics such as DNA repair assay, Complementation groups (research basis only), DNA sequence analysis, Deletion/duplication analysis, Carrier testing, Prenatal diagnosis & preimplantation genetic diagnosis plays an imperative role in the diagnosis of the same [3,[7][8][9][10]. However the biochemical analysis cannot be ignored as it aids diagnosis. Hyperinsulinemia and hyperlipoproteinemia has been observed in most of the cases reported till date [2,11]. Growth hormone levels and functions of T lymphocytes and mixed lymphocytes are normal. However deficiency of growth hormones also been reported [11]. Whereas thymic hormone levels are significantly reduced or undeductable [2].
The management of Cockayne Syndrome in actual fact is merely supportive care. Treatment of Cockayne syndrome includes symptomatic management, prevention of secondary complications, avoidance of risk factors and periodic follow up. Despite the lack of effective treatment and progressive course of the disease, a correct diagnosis is very important to assist the family with the caretaking of the child and genetic counseling should be done to prevent recurrence of the condition in the family [10,12,].
Since 1936, when Cockayne described the first case of Cockayne syndrome, more than dozen cases have been reported in the world. Most of the cases showed the diagnostic features such as growth disturbances either before birth or after birth, ophthalmic involvement as cataracts or retinal pigmentation, severe neurologic dysfunction from birth, sensorineural hearing loss, cutaneous photosensitivity and dental caries. Over the past several decades some cases were reported and studied but the incidences of CS with oral manifestations are very rare [3,7-21].

PRESENTATION OF THE CASE
A male patient aged 24 years came to the dental hospital with chief complaint of pain in his decayed tooth with stunted growth of face. His family history revealed that his mother had consanguineous marriage. He had low birth weight of about 2 kg and crawled lately at the age of 2 years and walked at the age of 4 years with stammering speech and aversion to light.
General examination revealed ataxic gait, cachectic dwarfism with height and weight measuring 124 cm, 20 kg respectively & head circumference measuring 20 cm. He was mentally retarded with abnormal speech & low pitched voice. Ophthalmological examination revealed photophobia with optic atrophy. Auditory examination revealed sensorineural hearing loss. Multiple cystic lesions were seen over the chest. (Fig. 1).
OPG showed multiple dental caries, multiple root stumps with increased caries activity, relative micro-dontia and slight increase in the density of mandible (Fig. 4). Lateral skull radiograph revealed micro-cephaly, small orbits with increase in the gonial angles and marked density of calvarium. Postero anterior skull views show obliterated paranasal sinuses. Plain X-ray of the chest showed decrease in the total length of spine and thoracic kyphosis (Fig. 5). Computed tomographic examination of head revealed obliterated paranasal sinuses, dilated ventricles, and calcification of falx cerebri (Fig. 6).
Magnetic resonance imaging revealed atrophy of cerebellum and basal ganglion calcification and electro retinogram examination revealed "salt and pepper" retinal hyperpigmentation. MR T2 weighed image showed progressive generalised cerebral and cerebellum atrophy with brainstem thinning (Fig. 7).

DISCUSSION
Similar to the cases reported by Guardiola A et al. [14] in 1999, Maria et al. [3] and Sonmez et al. [7], in 2006 patient presented in this case report also showed all the diagnostic features of the Cockayne syndrome. Our patient reported to the dental hospital for pain in decayed tooth. His cachectic dwarfism, ataxic gait and delayed psychomotor skill development during his growth after birth suggested a striking thought for the diagnosis of Cockayne syndrome. Ataxic gait was characteristic of the cases reported by Maria et al. [3] Firosh K et al. [8] and Raghavendra et al. [19] in 2006, 2008 and 2012 respectively. The growth percentile of patient presented in this case report was also compromised as it was evident from his height and weight. This was a characteristic feature of Cockayne syndrome patients reported till date.
As reported by Arun N et al. [20] in 2005 patient presented in this case report also showed characteristic facial appearances such as, loss of subcutaneous fat, sunken eyes, large ears, parrot beak shaped nose giving classical 'bird like facies'. Further intra oral examination revealing multiple dental caries was similar to Robert AB, [13] case reported in 1991. Photosensitivity was also a characteristic feature found in patient presented in this case report as suggested by most of the cases reported, and this is supported by Jabre P et al. [15] case reported in 1999. Jabre's case also showed retinopathy and mental retardation as reported in our case. Majority of the cases showed thoracic kyphosis stunted bone growth as reported by Sun-Kyu et al. [11] in 1994.
The MRI findings of patient presented in this case report was similar to Praveen M [21] case reported in 2012. Literature search also showed that salt and pepper retinal hyperpigmentation, basal ganglionic calcifications as found in patient presented in this case report was also characteristic of the cases reported by Hamdani et al. [16] in 2000 and Arun N et al. [20] [22] in 2010 computed tomography imaged brain calcifications, cerebral atrophy, and white matter hypoattenuation. Calvarial thickening was observed either with or without association with dilation of facial sinuses Magnetic Resonance imaging studies revealed infra-and supratentorial cerebral atrophy with predominantly white matter loss and abnormal white matter signal intensity [7,8,16,17,19,20]. The search for cases reported with multiple cyst like lesion seen over the chest as seen in patient presented in this case report ends in remote cases.
We considered the Bloom syndrome, Hartnup disease, Xeroderma pigmentosum, Rothmund-Thomson syndrome and Progeria for differential diagnosis [2]. Although dwarfism, photosensitivity and delayed development of psychomotor skills suggest Bloom syndrome and Xeroderma pigmentosum for the differential diagnosis, other characteristic features such as unusual facies, microcephaly, retinal pigmentation, basal ganglionic calcification all adds to the support of the diagnosis of Cockayne syndrome. And also absence of multiple cutaneous malignancies excludes the diagnosis of Xeroderma pigmentosum further [2,10]. Presence of retinal changes excludes Rothmund -Thomson syndrome and Progeria from the list. Further except for the short stature Progeria does not feature photosensitivity [2].
As suggested by Vincent Laugel patient presented in this case report can be diagnosed as classic Cockayne syndrome. Thus correlating the clinical findings of patient presented in this case report with the literature allowed us to arrive at the diagnosis of Cockayne syndrome [23].

CONCLUSION
Cockayne syndrome is an uncommon, distressing autosomal recessive disease akin to progeria. Craniofacial and oral anomalies and dental caries are universal finding in the syndrome. While life expectancy is pretty short for these individuals, the pediatric dentist plays a major role in managing the Cockayne syndrome patient. Early dental assessment and parental counseling have the paramount importance. Precautionary dental regimens must be independently planned and implemented because of reduced mandibular motion. Dietary counseling is very important because of a predisposition for dental caries and low weight. Regular examinations and prevention of the dental disease must be emphasized. Suitable and safe dental care for patients with CS can be rendered after medical consultation.

CONSENT
All authors declare that 'written informed consent was obtained from the patient for publication of this case report and accompanying images.

ETHICAL APPROVAL
It is not applicable.