Case Report Osteopetrosis complicated by schizophrenia results from mutations on Chromosome 16

Size: px

Start display at page:

Download "Case Report Osteopetrosis complicated by schizophrenia results from mutations on Chromosome 16"

Nigel Sullivan
5 years ago
Views:

1 Int J Clin Exp Med 2016;9(9): /ISSN: /IJCEM Case Report Osteopetrosis complicated by schizophrenia results from mutations on Chromosome 16 Yuwei Zhang, Decai Chen, Fang Zhang, Qingguo Lv, Lizhi Tang, Nanwei Tong Division of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, China Received September 25, 2015; Accepted December 8, 2015; Epub September 15, 2016; Published September 30, 2016 Abstract: Objective: To investigate the genetic pathogenesis and diagnosis of osteopetrosis, and its relationship with schizophrenia. Methods: Conducting extensive review of literature related to osteopetrosis patients with schizophrenia, summing common disease genes and diagnosis of osteopetrosis in association with schizophrenia. Results and Conclusion: Osteopetrosis is a rare inherited metabolic bone disease, with 12 kinds of common disease genes. In particular, mutations at 16p13.3 are closely related to schizophrenia. In recent years, molecular studies have identified three genes on chromosome 16 closely associated with schizophrenia, located at 16p13.3, 16p11.2, 16p Thus osteopetrosis and schizophrenia may not be two independent diseases, and understanding their relationship may help to identify schizophrenia at an earlier stage in osteopetrosis patients with mutations of chromosome 16. Conversely, patients with a family history of schizophrenia may be at increased risk for developing osteopetrosis. Keywords: Osteopetrosis, schizophrenia, pathogenic gene, diagnosis Introduction Osteopetrosis is an extremely rare hereditary metabolic bone disease characterized by a decrease in number or functionality of osteoclasts, resulting in defective bone resorption. Typical clinical manifestations include increased bone density, skeletal deformities, and various associated complications. Osteopetrosis is also known as marble bone disease or Albers-Schönberg disease. Schizophrenia is a group of diseases with a complex etiology comprising hereditary, neurodevelopmental, neurochemical and socio-environmental factors. The clinical syndrome of schizophrenia is characterized by dysfunction of reasoning, emotions, insight and other aspects of thought and behavior. Patients generally have intact consciousness, acceptable intellectual capacity, although during the course of their disease they may have episodes of disturbed cognitive function. At first glance, there seems to be no discernable connection between osteopetrosis and schizophrenia, the former being a metabolic bone disease, and the latter being a neuropsychiatric disorder. However, we seek to explore the possibility of such an association in the present case study of a patient diagnosed with both disorders and possessing common identified genetic mutations. In this study, the patient was given a written informed consent. Case report and results The patient is a 25 year old female, presenting with a 2 year history of continuous, low-intensity lower back pain that initiated as a result of an accidental fall (landing on her lower back). She experienced no limitations of activities and thus did not seek medical attention. 3 months ago, following the pass away of her brother, she reports an increase in intensity of her pain, with a sensation of rigidity located in her lumbar spine, and activity limitation. The symptoms improved with rest and were exacerbated with emotional stress. During this time, she also reports oligomenorrhea (once per 2-3 months, low flow volume), as well as gradual onset of depressed mood, auditory hallucinations, thoughts of self-harm and suicide. She was subsequently admitted to our hospital for evaluation of lower back pain and psychiatric symp-

2 Table 1. Auxiliary examinations: bone density of lumbar vertebrae toms. A preliminary diagnosis of schizophrenia was made based on positive family history, as well as the suicide-death of her brother 3 months prior. Physical examination The patient had stable vital signs on admission, clear consciousness, psychomotor excitement, normal cardiopulmonary and abdominal examination, and without notable trunk and limb deformities. Biochemical markers of bone turnover Serum calcium (Ca) 2.19 mmol/l, serum inorganic phosphorus (P) 1.49 mmol/l, bone alkaline phosphatase (B-ALP) µg/l, C-terminal telopeptide of type I collagen (CTX-1) ng/ml, N-MID osteocalcin (NMID) 31.3 ng/ml, parathyroid hormone (PTH) 6.51 pmol/l, thyroid hormone (TSH) 6.14 mu/l, thyroid peroxidase antibody (TPOAb) IU/mL. Her bone mass density was detected as below (Table 1). Serology Immunoglobulin G (IgG) 20.1 g/l, Immunoglobulin A (IgA) < 66.7 mg/l, Immunoglobulin M (IgM) 2350 mg/l, antinuclear antibody (ANA) weakly positive, anti-neutrophil cytoplasmic antibody (ANCA) negative, erythrocyte sedimentation rate (ESR) 20 mm/h, C-reactive protein (CRP) 4.24 mg/l, urinary light chains normal, rheumatoid factor (RF) < IU/mL Radiography L1 L2 L3 L4 Average L1-4 T-score Z-score The three images displayed as bellow. Figure 1A shows normal appearance of heart and lungs, increased density of superior and inferior aspects of vertebral bodies, with sandwich sign. Figure 1B presents sandwich-like change of vertebral bodies, increased bone density. From Figure 1C, we can see heterogeneous increase in density of bilateral femoral head, acetabulum and right sacroiliac joint, growth rings appearance. Genetic analysis CLCN7 mutation, locus 16p13.3. Discussion Osteopetrosis is a generic disease composed of a group of rare bone disorders characterized by increase of bone mass due to defective osteoclast function. It is divided into ARO (autosomal recessive osteopetrosis) and ADO (autosomal dominant osteopetrosis) types. Further divisions are as follows [1-4]: Autosomal Recessive Osteopetrosis (ARO): 1. Intermediate subtype: thickening of calvarium, stunted growth, osteomyelitis, mild anemia; 2. Severe subtype: earlier age of onset, including within postnatal months. Sick children can have recurrent infections and frequent bleeding secondary to medullar hyperplasia. They can also have blindness and deafness caused by compressions of cranial nerves. Autosomal Dominant Osteopetrosis (ADO): 1. ADO subtype I: mild diffuse generalized osteosclerosis; 2. ADO subtype II: thickening of superior and inferior aspects of vertebral bodies, high rate of long bone fractures, classic sandwich-like change of vertebral bodies (rugger-jersey sign), growth rings appearance, significant increase in serum ALP and creatine kinase BB (CK-BB); 3. ADO subtype III: eccentric osteopetrosis with osteosclerosis mainly involving distal extremities and skull. Our patient s radiographic findings of sandwich-like change of vertebral bodies, increased bone density and heterogeneous increase in density of bilateral femoral head, acetabulum and right sacroiliac joint conform to manifestations of ADO subtype II, which is also called benign osteoptrosis. Current research lists 12 common genetic mutations for osteopetrosis, as follows (Table 2) [3, 5-14]: Our patient has an identified mutation of CLCN7 at 16p13.3, which allows for a genetic diagnosis of chromosome 16 (CLCN7) mutation induced ADO subtype II. Concurrent diagnosis of schizophrenia with positive family history as well as exacerbation of her back pain with emotional stress leads us to speculate on a connection between osteopetrosis and schizophrenia. After searching our nationwide and international database, mutations in 3 etiologic genes for schizophrenia are identified on chromosome 16, specifically at 16p11.2, 16p13.11, 16p13.3 [15-24], note the proximity of the 3 loci. Our Int J Clin Exp Med 2016;9(9):

Figure 1. Radiography Imagines. A. Increased density of superior and inferior aspects of vertebral bodies, with sandwich sign; B. Sandwich-like change of vertebral bodies, increased bone density; C.

3 Figure 1. Radiography Imagines. A. Increased density of superior and inferior aspects of vertebral bodies, with sandwich sign; B. Sandwich-like change of vertebral bodies, increased bone density; C. Heterogeneous increase in density of bilateral femoral head, acetabulum and right sacroiliac joint, growth rings appearance. Table 2. Twelve genetic mutations for osteopetrosis Gene CAII Locus 8q22 TCIRG1 11q13.2 CLCN7 16p13.3 OSTM1 RANKL 6q21 13q17 PLEKHM1 17q21.3 Kindlin-3 11q13.1 RANK 18q22.1 CalDAG-GEFI 11q13.1 NEMO Xq28 LRP5 11q13.4 SNX10 7p15.2 patient has an identified mutation at 16p13.3. Therefore, we boldly speculate that this mutation on chromosome 16 may be responsible for the pathogenesis of both osteopetrosis and schizophrenia, and that the 2 diseases may not be entirely independent, but rather share a common genetic basis. Furthermore, we propose to increase screening of schizophrenia in osteopetrosis patients with identified mutations of chromosome 16, as well as performing related prevention for osteopetrosis in applicable schizophrenic patients, all in the effort to decrease co-morbidity with a second disease. Disclosure of conflict of interest None. Address correspondence to: Dr. Nanwei Tong, Division of Endocrinology and Metabolism, West China Hospital, Sichuan University, 37 Guoxuexiang, Chengdu , Sichuan, China. Tel: ; Fax: ; buddyjun@hotmail.com References [1] Del Fattore A, Cappariello A, Teti A. Genetics, pathogenesis and complications of osteopetrosis. Bone 2008; 42: Int J Clin Exp Med 2016;9(9):

4 [2] Aggarwal S. Skeletal dysplasias with increased bone density: Evolution of molecular pathogenesis in the last century. Gene 2013; 528: [3] Cleiren E, Bénichou O, Van Hul E, Gram J, Bollerslev J, Singer FR, Beaverson K, Aledo A, Whyte MP, Yoneyama T, devernejoul MC, Van Hul W. Albers-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet 2001; 10: [4] Driessen GJ, Gerritsen EJ, Fischer A, Fasth A, Hop WC, Veys P, Porta F, Cant A, Steward CG, Vossen JM, Uckan D, Friedrich W. Long-term outcome of haematopoietic stem celltransplantation in autosomal recessive osteopetrosis: an EBMT relsort. Bone Marrow Transplant 2003; 32: 657. [5] Roberts CM, Angus JE, Leach IH, McDermott EM, Walker DA, Ravenscroft JC. A novel NEMO gene mutation causing osteopetrosis, lymphoedema, hypohidrotic ectodermal dysplasia and immunodeficiency (OL-HED-ID). Eur J Pediatr 2010; 169: [6] Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, Keeling DJ, Andersson AK, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet 2000; 25: [7] Wada K, Harada D, Michigami T, Tachikawa K, Nakano Y, Kashiwagi H, Yamashita S, Sano T, Seino Y. A case of autosomal dominant osteopetrosis type II with a novel TCIRG1 gene mutation. J Pediatr Endocrinol Metab 2013; 26: [8] Sobacchi C, Frattini A, Guerrini MM, Abinun M, Pangrazio A, Susani L, Bredius R, Mancini G, Cant A, Bishop N, Grabowski P, Del Fattore A, Messina C, Errigo G, Coxon FP, Scott DI, Teti A, Rogers MJ, Vezzoni P, Villa A, Helfrich MH. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet 2007; 39: [9] Mory A, Feigelson SW, Yarali N, Kilic SS, Bayhan GI, Gershoni-Baruch R, Etzioni A, Alon R. Kindlin-3: a new gene involved in the pathogenesis of LAD-III. Blood 2008; 112: [10] Malinin NL, Zhang L, Choi J, Ciocea A, Razorenova O, Ma YQ, Podrez EA, Tosi M, Lennon DP, Caplan AI, Shurin SB, Plow EF, Byzova TV. A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nat Med 2009; 15: [11] Guerrini MM, Sobacchi C, Cassani B, Abinun M, Kilic SS, Pangrazio A, Moratto D, Mazzolari E, Clayton-Smith J, Orchard P, Coxon FP, Helfrich MH, Crockett JC, Mellis D, Vellodi A, Tezcan I, Notarangelo LD, Rogers MJ, Vezzoni P, Villa A, Frattini A. Human Osteoclast-Poor Osteopetrosis with Hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet 2008; 83: [12] Kilic SS, Etzioni A. The clinical spectrum of leukocyte adhesion deficiency (LAD) III due to defective CalDAG-GEF1. J Clin Immuno 2009; 29: [13] Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP. High bone density due to a mutation in LDL-receptorrelated protein 5. N Engl J Med 2002; 346: [14] Aker M, Rouvinski A, Hashavia S, Ta-Shma A, Shaag A, Zenvirt S, Israel S, Weintraub M, Taraboulos A, Bar-Shavit Z, Elpeleg O. An SNX10 mutation causes malignant osteopetrosis of infancy. J Med Genet 2012; 49: [15] Stewart LR, Hall AL, Kang SH, Shaw CA, Beaudet AL. High frequency of known copy number abnormalities and maternal duplication 15q11-q13 in patients with combined schizophrenia and epilepsy. BMC Med Genet 2011; 12: 154. [16] Bassett AS, Chow EW, Husted J, Weksberg R, Caluseriu O, Webb GD, Gatzoulis MA. Clinical features of 78 adults with 22q11 Deletion Syndrome. Am J Med Genet A 2005; 138: [17] Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, Hansen T, Jakobsen KD, Muglia P, Francks C, Matthews PM, Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Sigurdsson A, Jonasdottir A, Jonasdottir A, Bjornsson A, Mattiasdottir S, Blondal T, Haraldsson M, Magnusdottir BB, Giegling I, Möller HJ, Hartmann A, Shianna KV, Ge D, Need AC, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Paunio T, Toulopoulou T, Bramon E, Di Forti M, Murray R, Ruggeri M, Vassos E, Tosato S, Walshe M, Li T, Vasilescu C, Mühleisen TW, Wang AG, Ullum H, Djurovic S, Melle I, Olesen J, Kiemeney LA, Franke B; GROUP, Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nöthen MM, Peltonen L, Collier DA, St Clair D, Stefansson K. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455: [18] International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008; 455: Int J Clin Exp Med 2016;9(9):

5 [19] Helbig I, Mefford HC, Sharp AJ, Guipponi M, Fichera M, Franke A, Muhle H, de Kovel C, Baker C, von Spiczak S, Kron KL, Steinich I, Kleefuss-Lie AA, Leu C, Gaus V, Schmitz B, Klein KM, Reif PS, Rosenow F, Weber Y, Lerche H, Zimprich F, Urak L, Fuchs K, Feucht M, Genton P, Thomas P, Visscher F, de Haan GJ, Møller RS, Hjalgrim H, Luciano D, Wittig M, Nothnagel M, Elger CE, Nürnberg P, Romano C, Malafosse A, Koeleman BP, Lindhout D, Stephani U, Schreiber S, Eichler EE, Sander T. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet 2009; 41: [20] Rodríguez-Santiago B, Brunet A, Sobrino B, Serra-Juhé C, Flores R, Armengol L, Vilella E, Gabau E, Guitart M, Guillamat R, Martorell L, Valero J, Gutiérrez-Zotes A, Labad A, Carracedo A, Estivill X, Pérez-Jurado LA. Association of common copy number variants at the glutathione S-transferase genes and rare novel genomic changes with schizophrenia. Mol Psychiatry 2010; 15: [21] McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, Perkins DO, Dickel DE, Kusenda M, Krastoshevsky O, Krause V, Kumar RA, Grozeva D, Malhotra D, Walsh T, Zackai EH, Kaplan P, Ganesh J, Krantz ID, Spinner NB, Roccanova P, Bhandari A, Pavon K, Lakshmi B, Leotta A, Kendall J, Lee YH, Vacic V, Gary S, Iakoucheva LM, Crow TJ, Christian SL, Lieberman JA, Stroup TS, Lehtimäki T, Puura K, Haldeman-Englert C, Pearl J, Goodell M, Willour VL, Derosse P, Steele J, Kassem L, Wolff J, Chitkara N, McMahon FJ, Malhotra AK, Potash JB, Schulze TG, Nöthen MM, Cichon S, Rietschel M, Leibenluft E, Kustanovich V, Lajonchere CM, Sutcliffe JS, Skuse D, Gill M, Gallagher L, Mendell NR; Wellcome Trust Case Control Consortium, Craddock N, Owen MJ, O Donovan MC, Shaikh TH, Susser E, Delisi LE, Sullivan PF, Deutsch CK, Rapoport J, Levy DL, King MC, Sebat J. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 2009; 41: [22] Vassos E, Collier DA, Holden S, Patch C, Rujescu D, St Clair D, Lewis CM. Penetrance for copy number variants associated with schizophrenia. Hum Mol Genet 2010; 19: [23] Mulle JG, Dodd AF, McGrath JA, Wolyniec PS, Mitchell AA, Shetty AC, Sobreira NL, Valle D, Rudd MK, Satten G, Cutler DJ, Pulver AE, Warren ST. Microdeletions of 3q29 confer high risk for schizophrenia. Am J Hum Genet 2010; 87: [24] Ingason A, Kirov G, Giegling I, Hansen T, Isles AR, Jakobsen KD, Kristinsson KT, le Roux L, Gustafsson O, Craddock N, Möller HJ, McQuillin A, Muglia P, Cichon S, Rietschel M, Ophoff RA, Djurovic S, Andreassen OA, Pietiläinen OP, Peltonen L, Dempster E, Collier DA, St Clair D, Rasmussen HB, Glenthøj BY, Kiemeney LA, Franke B, Tosato S, Bonetto C, Saemundsen E, Hreidarsson SJ; GROUP Investigators, Nöthen MM, Gurling H, O Donovan MC, Owen MJ, Sigurdsson E, Petursson H, Stefansson H, Rujescu D, Stefansson K, Werge T. Maternally derived microduplications at 15q11-q13: implication of imprinted genes in psychotic illness. Am J Psychiatry 2011; 168: Int J Clin Exp Med 2016;9(9):

Absence seizures with intellectual disability as a phenotype of the 15q13.3 microdeletion syndrome

BRIEF COMMUNICATION Absence seizures with intellectual disability as a phenotype of the 15q13.3 microdeletion syndrome *Hiltrud Muhle, yheather C. Mefford, *Tanja Obermeier, *Sarah von Spiczak, zevan E.