Orphan disease: Cherubism, optic atrophy, and short stature

Article published online: 2021-07-26 PaedIatrIc ImaGInG Orphan disease: Cherubism, optic atrophy, and short stature Balaji Jeevanandham, Rajoo Ramachandran, Vignesh Dhanapal, Ilanchezhian Subramanian, Venkata Sai Department of Radiology, Sri Ramachandra University, Porur, Chennai, Tamil Nadu, India Correspondence: Dr. Balaji Jeevanandham, Department of Radiology, Sri Ramachandra University, Porur, Chennai - 600 116, Tamil Nadu, India. E-mail: bjradiologist@gmail.com Abstract A 12‑year‑old female presented with complaints of progressive visual impairment in both her eyes. On clinical examination, she was short for her age and her ophthalmoscopic examination revealed bilateral optic atrophy. Computed tomography of the patient revealed multiple expansile lytic lesions of mandible suggesting cherubism. The optic atrophy was confirmed on magnetic resonance imaging, which additionally revealed bilateral retrocerebellar arachnoid cysts. This association of cherubism with optic atrophy and short stature was grouped as orphan disease by National Institutes of Health and only one case was reported in the literature so far. Key words: Cherubism; fibrous dysplasia; optic atrophy; short stature Introduction Jones[1] first described this disorder as “familial multilocular cystic disease of the jaws,” in 1933. The term “cherubism” was coined later describing the rounded facial appearance that was reminiscent of cherubs depicted in Renaissance art. Cherubism was considered as a variant and part of fibrous dysplasia in the 19th and early 20th centuries. However, with the advent of genomic research and gene sequencing methods, cherubism had proven to be a distinct form of skeletal dysplasia. Mangion et al.[2] and Tiziani et al.[3] later discovered that cherubism was due to dominant mutations in SH3BP2 gene on chromosome 4p16.3. Cherubism was thought to be self‑limiting and most of the patients will become normal by adulthood. But persistence of the fibrocystic lesions and dysmorphic facial features was not so uncommon. Case Report A 12‑year‑old girl presented with complaints of progressive visual impairment in both her eyes for the past 1 year. On Access this article online Quick Response Code: Website: www.ijri.org DOI: 10.4103/ijri.IJRI_203_17 clinical evaluation, she was found to be short for her age with her height measuring 135.2 cm corresponding to 0.16 percentile. Fundoscopic evaluation revealed bilateral pale chalky white disc pallor, which was more on the left side, suggestive of optic atrophy [Figure 1]. The patient was further imaged for evaluation of bilateral optic nerve atrophy. On magnetic resonance imaging (MRI), optic nerves were thinned out (left > right). However, no altered signal intensity within the nerves was seen [Figures 2 and 3]. Incidentally, bilateral retrocerebellar arachnoid cysts were also seen. The globes, optic chiasm, rest of the neuroparenchyma along with sellar region were unremarkable. The patient also complained of fullness in the cheek with dysmorphic facial features. On evaluation with computed tomography (CT), the patient showed bilateral almost symmetrical expansile lesions involving body, rami, This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: reprints@medknow.com Cite this article as: Jeevanandham B, Ramachandran R, Dhanapal V, Subramanian I, Sai V. Orphan disease: Cherubism, optic atrophy, and short stature. Indian J Radiol Imaging 2018;28:111‑4. © 2018 Indian Journal of Radiology and Imaging | Published by Wolters Kluwer ‑ Medknow 111 Jeevanandham, et al.: Orphan Disease – Rare association and coronoid processes of the mandible. The lesions predominantly showed lytic areas [Figures 4 and 5] with sparing of condyloid processes [Figure 5]. There were no lesions in the maxilla, optic canals, or in the skull. lesions may persist or undergo partial resolution, which may result in dysmorphic features. In 1992, Marck and Kudryk[8] proposed grading system for cherubism based on lesion locations [Table 1]. Biochemical and hormonal evaluation of the patient for short stature was unremarkable. She also had normal secondary sexual characters and the examination of her genitourinary system was within normal limits [Figure 6]. Histological examination of these lesions shows abundant multinucleated giant cells scattered in a stroma of vascularized fibrous connective tissue, which can be seen in other conditions such as giant cell tumor, brown tumor, and giant cell granuloma. Hence histopathological examination had limited value in the diagnosis of cherubism. Discussion Cherubism had been first described as a subtype of fibrous dysplasia, termed as hereditary craniofacial fibrous dysplasia by Cornelius and Bianchi.[4,5] It was considered as the same group of disorder because it shows radiographic similarities with fibrous dysplasia. Ueki et al.[6] discovered a series of point mutations resulting in amino acid substitutions in the SH‑3 binding protein SH3BP2 on chromosome 4p16.3 in patients of cherubism accounting for the disease. Affected children appear normal at birth and usually develop bilateral painless jaw swellings. These lesions begin in first several years of life, with a range of 14 months to 12 years.[7] The disease usually undergoes gradual resolution of the lesions with partial or complete remineralization. On resolution these may appear isodense or sclerotic to the adjacent normal bone. Some of the Cherubism can cause optic atrophy, which is usually due to the mass effect in the optic chiasm or optic nerve by Figure 2: Axial T2 weighted images showing thinned out bilateral optic nerves (arrows) Figure 1: Axial T2 MR image showing bilateral thinned out optic nerves with prominent optic nerve sheath fluid Figure 3: Fundoscopic image showing bilateral optic disc pallor suggestive of optic atrophy predominantly on the left globe 112 Figure 4: Volume rendered images showing bilateral symmetrical expansile lesions giving rise to “Soap bubble” appearance Indian Journal of Radiology and Imaging / Volume 28 / Issue 1 / January ‑ March 2018 Jeevanandham, et al.: Orphan Disease – Rare association Figure 5: Axial, Coronal and Sagittal CT images showing bilateral symmetrical expansile predominantly lytic lesions involving the body, rami and coronoid processes of bilateral mandible (arrows). Typical sparing of condyloid process of mandible (arrow heads) seen Table 1: Marck and Kudryk grading of cherubism Grades Lesion characteristics Grade I Bilateral involvement of mandibular rami Grade 2 Involvement of both mandibular rami and maxillary tuberosities Grade 3 Involvement of the entire maxilla and mandible except for the condyles Grade 4 Involvement of the orbits with ocular disturbances as well as the grade 3 lesions the lesions extending into skull base. Most of these optic atrophies are unilateral and asymmetrical in the reported literature.Cherubism may be associated with genetic diseases such as Ramon’s syndrome, Jafe Campanacci syndrome, Fragile X syndrome, Neurofibromatosis, and Noonan’s syndrome. [9‑14] Only one case of cherubism associated with bilateral optic atrophy and short stature had been reported in the literature.[15] Cherubism associated with optic atrophy and short stature is listed as rare disease by the Office of Rare Diseases of the National Institutes of Health. In our case, incidentally, bilateral retrocerebellar arachnoid cysts were also detected. No syndromic association had been found comprising cherubism, optic atrophy, and short stature, and even in our case we did not have any features to suggest a syndromic association of these findings. Conclusion Cherubism alone is a rare disease and its association with optic atrophy and short stature had been reported by only one case in the literature so far. The association of bilateral retrocerebellar arachnoid cysts in our case may be incidental. Hence cherubism, optic atrophy, and short stature is an orphan disease and we are reporting one of its kind. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have Figure 6: Axial sections of posterior fossa showing Retrocerebellar arachnoid cyst with classical CSF appearance on all images (Hyper in T2, Hypo in T1 and no DWI restriction) with mass effect over both cerebellar hemispheres 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. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Jones WA. Familial multilocular cystic disease of the jaws. Am J Cancer 1933;17:946‑50. 2. Mangion J, Rahman N, Edkins S, Barfoot R, Nguyen T, Sigurdsson A, et al. The gene for cherubism maps to chromosome 4p16.3. Am J Hum Genet 1999;65:151‑7. 3. Tiziani V, Reichenberger E, Buzzo CL, Niazi S, Fukai N, Stiller M, et al. The gene for cherubism maps to chromosome 4p16. Am J Hum Genet 1999;65:158‑66. 4. Cornelius EA, McClendon JL. Cherubism: Hereditary fibrous dysplasia of the jaws. Roentgenographic features. Am JRoentgenol 1969;106:136‑43. 5. Bianchi SD, Boccardi A, Mela F, Romagnoli R. The computed tomographic appearances of cherubism. Skeletal Radiol 1987;16:6‑10. Indian Journal of Radiology and Imaging / Volume 28 / Issue 1 / January ‑ March 2018 113 Jeevanandham, et al.: Orphan Disease – Rare association 6. Ueki Y, Tiziani V, Santanna C, Fukai N, Maulik C, Garfinkle J, et al. Mutations in the gene encoding c‑Abl‑binding protein SH3BP2 cause cherubism. Nat Genet 2001;28:125‑6. 7. WagelJ,ŁuczakK, HendrichB, Guzinski M Sasiadek M. Clinical and radiological features of nonfamilial cherubism. Pol J Radiol 2012;77:53‑7. 8. Marck PA, Kudryk WH. Cherubism. J Otolaryngol. 1992;21:84‑7. 9. Ozkan Y, Varol A, Turker N, Aksakalli N, Basa S. Clinical and radiological evaluation of cherubism: A sporadic case report and review of the literature. Int J PediatrOtorhinolaryngol 2003;67:1005‑12. 10. Carvalho Silva E, Carvalho Silva GC, Vieira TC. Cherubism: Clinicoradiographic features, treatment, and long‑term follow‑up of 8 cases. J Oral Maxillofac Surg 2007;65:517‑22. 11. Roginsky VV, Ivanov AL, Ovtchinnikov IA, Khonsari RH. Familial cherubism: The experience of the Moscow Central Institute for Stomatology and Maxillo‑Facial Surgery. Int J Oral Maxillofac 114 Surg 2009;38:218‑23. 12. Martínez‑Tello FJ, Manjón‑Luengo P, Martin‑Pérez M, Montes‑Moreno S. Cherubism associated with neurofibromatosis type 1 and multiple osteolytic lesions of both femurs; a previously undescribed association of findings. Skeletal Radiol 2005;34:793‑8. 13. Neumann TE, Allanson JE, Kavamura I, Kerr B, Neri G, Noonan J, et al. Multiple giant cell lesions in patients with Noonan syndrome and cardio‑facio‑cutaneous syndrome. Eur J Hum Genet 2009;17:420‑5. 14. S l e z a k R , L u c z a k K , K a l s c h e u e r V, N e u m a n n T E , Sasiadek MM. Noonan‑like/multiple giant cell lesion syndrome in two adult patients with SOS1 gene mutations. ClinDysmorphol2010;19:157‑60. 15. Al‑Gazali LI, Khidr A, PremChandran JS.Cherubism, optic atrophy and short stature.ClinDysmorphol 1993;2:140‑1. Indian Journal of Radiology and Imaging / Volume 28 / Issue 1 / January ‑ March 2018