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Osteopetrosis: Classification, Pathomorphology, Genetic Disorders, Clinical Manifestations (Literature Review and Clinical Case Report)

Osteopetrosis: Classification, Pathomorphology, Genetic Disorders, Clinical Manifestations (Literature Review and Clinical Case Report)

Практична медицина / Practical Medicine

УДК 616.71-003.84 DOI: 10.22141/2224-1507.9.2.2019.172125

V.V. Povoroznyuk, N.V. Dedukh, M.A. Bystrytska, A.S. Musiienko State Institution “D.F. Chebotarev Institute of Gerontology of NAMS of Ukraine”, Kyiv, Ukraine : classification, pathomorphology, genetic disorders, clinical manifestations (literature review and clinical case report)

For cite: Bol', sustavy, pozvonočnik. 2019;9(2):135-142. doi: 10.22141/2224-1507.9.2.2019.172125

Abstract. Osteopetrosis is a hereditary with an autosomal recessive or autosomal dominant type of in- heritance, caused by a disruption in the functional activity of due to gene mutation. The article sys- tematizes data on etiology, classification, pathomorphology, gene disorders based on the analysis of 38 sources of literature, and deals with the modern approa­ches to the treatment of osteopetrosis. Three types of osteopetrosis with different severity degrees of skeletal disorders and pathological severity are described. The main pathomor- phological changes in the structural organization of tissue are presented and features of the state of osteo- clasts are shown depending on the mutation of genes controlling their functional activity. There are no protocols for the treatment of this pathology, but treatment me­thods based on the use of hematopoietic stem cells are under development. The paper presents with clinical case report of a patient with marble . Keywords: osteopetrosis; classification; pathomorphology; osteoclasts; gene disorders; diagnosis; treatment

Introduction osteopetrosis, osteoclasts, etiology, classification, genetic Osteopetrosis was first described by Albers-Schönberg disorders, treatment. in 1904 [1]. Osteopetrosis (congenital family osteoscle- rosis, marble bone disease, Albers-Schönberg disease) Osteopetrosis’ etiology is an umbrella term for a range of rare isolated inherited Osteopetrosis’ etiology and pathogenesis require a fur- disorders characterized by skeletal sclerosis [2, 3, 4, 5, 6, ther study. One of the principal pathogenetic mechanisms 7]. At this moment, there are at least 11 forms known for involved in this disorder is osteoclasts’ developmental and their different inheritance and severity types. Autosomal- functional breakdowns. recessive osteopetrosis afflicts 1 in 250 thousand new - Osteoclasts are highly-specialized cells in charge of borns, while autosomal-dominant one – 1 in 20 thousand bone mineral and organic matrix resorption. This process newborns [6]. is pivotal for the bone reconstruction, its biochemical Review’s purpose is to systematize data on osteope- strength and mineral homeostasis. Adult skeleton is com - trosis’ etiology, classification, pathomorphology of ge- pletely renewed every 10 years [8]. netic disorder, treatment methods and to present our own Osteoclasts are derived from the mononuclear precur- clinical observation study. sor cells of hematopoietic myeloid line, also giving rise to Information search has been made in Google, Google - macrophages and monocytes. Having united, the precur- Scolar, AcademicResoursIndex, PubMed, РИНЦ (Rus- sor cells form osteoclasts with up to 20 nuclei. Their life sian Science Citation Index) for the following keywords: cycle takes only up to 14 days.

© 2019. The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 International License, CC BY, which allows others to freely distribute the published article, with the obligatory reference to the authors of original works and original publication in this journal. Для кореспонденції: Поворознюк Владислав Володимирович, доктор медичних наук, професор, ДУ «Інститут геронтології імені Д.Ф. Чеботарьова НАМН України», вул. Вишгородська, 67, м. Київ, 04114, Україна; e-mail: [email protected] For correspondence: Vladislav Povoroznyuk, MD, PhD, Professor, State Institution “D.F. Chebotarev Institute of Gerontology of the NAMS of Ukraine”, Vyshgorodska st., 67, Kyiv, 04114, Ukraine; e-mail: [email protected] Full list of author information is available at the end of the article.

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For osteoclasts to get differentiated, both receptor ac - brane protein-associated osteopetrosis). Mutations dis- tivator of nuclear factor kappa-Β ligand (RANKL) and rupt pH organelle regulation and cellular secretion, af - macrophage colony-stimulating factor (M-CSF) are re- fecting osteoclastic bone resorption [6]. quired. For this purpose, they are produced by osteoblas - Fig. 2 represents a complex regulation of osteoclastic tic cellular differon. Precursor cell and activa - differentiation and functional activity by means of intra - tion is initiated by RANKL’s interaction with osteoblastic cellular signal molecules, RANKL–RANK receptors, RANK receptors. Osteoprotegerin, a protein synthesized , enzymes. Mutations of genes in charge of this by osteoblastic line cells, is a soluble RANKL-binding cell’s functioning lead to osteopetrosis. receptor which prevents its interaction with osteoblastic Disorder is inherited by different pathways: autoso- RANK receptors, along with osteoclastic activation and mal-recessive and autosomal-dominant. bone resorption. Osteoclast is a polar cell sticking to the bone tissue Bone pathomorphology by a β3 -produced corrugated fringe. Resorptive While studying of osteopetrosis patients, re - lacunae occur due to enzymes destroying organic and searchers find significant bone formation sites on the mineral matrix (Fig. 1). Osteoclastic intracellular pH is surface, in the medullary canal and inter-trabecular maintained by carbonic anhydrase and electric-neutral spaces of trabecular bone. Structural organization of the - - newly formed bone tissue is irregular, mosaic, charac - НСО3 / Сl ion exchange. Mineral matrix destruction is mediated by hydrochlo- terized by the pronounced pathological modifications. ric acid produced in the resorptive lacunae by chlorine Lamellar bone tissue with irregular cementation lines is ions penetrating them through the protein-made chlo- interspersed with coarse-fibered bone tissue. Within the rine-specific ion channel (CLCN7) on the osteoclastic medulla, there are bone and cartilage islets, osteoid ac - membrane and osteoclast-specific ATP driven proton cumulations [3]. Bone trabeculae seem thickened, their pump [9]. Organic matrix is destroyed by Cathepsin K. inter-trabecular spaces narrowed [12]. Osteoclastic den- Once genes in charge of osteoclastic differentiation and sity may vary under different osteopetrosis types ranging their functional activity become mutated, osteopetrosis from low to normal; however, bone resorption sites are occurs. isolated, reflecting osteoclastic resorptive disorders. This disorder develops with reducing or partial/com- Based on bone biopsy and genetic analysis of osteope - plete loss of osteoclastic function, which leads to bone trosis patients, it was found that a significant number of resorption disorders. In two thirds of patients osteoclasts osteoclasts (normal or even elevated rate) in the medulla are being formed; however, they are incapable of a suc - might signify their disrupted functions, namely due to cessful bone resorption. Osteoclastic functional disorder TCIRG1, CLCN7, SNX10 and OSTM1 gene mutations is caused by at least 10 genetic mutations; these are con - while presence of isolated osteoclasts or even their ab - sidered osteopetrosis-provoking and are revealed in 70 % sence are connected to a rare osteopetrosis type, caused of osteopetrosis patients [11]. Osteoclastic formation may by RANK and RANKL gene disorders [3]. also be deranged due to precursor cells’ inability to dif - ferentiate. Osteopetrosis classification Among the best researched mutations there are those For practical considerations, various osteopetrosis occurring in CLCN7, CAІІ (carbonic anhydrase ІІ) and forms might be classified in terms of their clinical char - TCIRG1 (V-ATPase pump) and OSTM1 (trans-mem- acteristics, severity of clinical manifestations, medullar histology and genetic basis [3, 13]. The most severe one is autosomal-recessive hered- ity pathway as it might be associated with α-subunit of ATPase gene defects, namely TCIRG1 (classical type), osteopetrosis-associated protein gene, i.e. OSTM1 (neu- ropathic type), and carbonic anhydrase Type ІІ, i.e. CA- II (associated with ) [3]. Autoso - mal-recessive osteopetrosis is also provoked by CLCN7 mutations, more rarely by SNX10, RANK and RANKL mutations. It was revealed that RANK-RANKL-OPG signal pathway disorders result in autosomal-recessive os- teopetrosis due to the osteoclasts’ reduced number and functional capacities, as this pathway regulates differen- tiation and activation of osteoclasts [14]. Medullar biopsy reveals cellular shrinking signifying a hemopoietic reduc- Fig. 1. Active functional osteoclast [adapted from 10] tion.

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Autosomal-recessive osteopetrosis may manifest itself may be asymptomatic in half the cases [13], while in at the fetal stage, while the neonates and infants are af - others are associated with pathological fractures under flicted with progressive , , minimal trauma; and that is very often the only sign of macrocephalia or hydrocephalia, as well as nerve restraint disorder afflicting adults. Factures’ union is delayed. resulting in blindness or deafness. This form is qualified Disorder is associated with aching bones, osteomyeli - as ‘malignant’ osteopetrosis. With neonatal osteopetrosis tis complications and cerebral nerve affliction [2, 22]. form, survival rate is low, while the life span is no more Bone fragility is aggravated by architectonic disorders than 2-10 years. Disorder is characterized by multiple and atypical bone formation. The most wide-spread fracture , may result in , vi- complication is optic nerve atrophy due to the bone tis - sion loss and hemopoietic disorders. Among its typical sue accretion in cavities and canals, leading to blind - features, there are broadened facial skull, nasal and la - ness. Autosomal-dominant osteopetrosis is more fre - bial anatomic disorders. Mental retardation and progres- quent among the older children and adults; its main sive neural degeneration may be caused by CLCN7 and manifestation being pathological fractures. With late OSTM1 gene mutations [9, 15]. CLCN7 gene has 20 mu - osteopetrosis, bone lesions become rarer as usual [23]. tations. This osteopetrosis type is characterized by bone Early mortality is infrequent, life span is similar to the dysplasias. statistically relevant; however, the quality of life is com - Intermediary osteopetrosis is clinically and genetical- promised [10]. ly irregular; its course being less pronounced but also se - There are two types of adult osteopetrosis. In case of vere. Its hereditary pathways could be both dominant and autosomal-dominant osteopetrosis Type I, phenotypic recessive. Protein-encoding gene (CLCN7) becomes less pathological manifestations are caused by missence mu- active, while its mutation leads to several forms of reces - tation (point mutation leading to a modified codon start - sive osteopetrosis and autosomal-dominant osteopetrosis ing to encode another aminoacid) in LRP5 [24, 25, 26]. Type II [16, 17]. CLCN7 gene defects also provoke in - In case of autosomal-dominant osteopetrosis Type II, termediary osteopetrosis; CLCN7 being protein domain missence mutation might affect CLCN7 [27]. gene, the same as Pleckstrin homology domain-contain- Osteopetrosis types are genetically determined and ing gene also known as PLEKHM1 [6]. Intermediary re - may be referred to as osteoclast-autonomous osteope - cessive form is characterized by medullar calcification, trosis and osteoclast-nonautonomous osteopetrosis [28, renal tubular acidosis caused by carbonic anhydrase Type 29]. With nonautonomous osteopetrosis, genetic effect ІІ gene (CA-II). These patients often have mental disor - may be associated with cells affecting osteoclast precur - ders [18]. sor differentiation or mature cell functions. With osteo - Osteopetrosis might also be induced by RANK, SNX10 clast-autonomous osteopetrosis, molecular defect may and TCIRG1 gene mutations [6, 9, 19, 20, 21]. Other in - be present either in osteoclasts themselves or in their termediary forms are characterized by a moderate osteo - precursors. sclerosis, low height and fragility fractures. Although all osteopetrosis forms are genetically deter- Moderate autosomal-dominant osteopetrosis is mined, this disorder may be induced in children by the characterized by the irregular and late manifestations bisphosphonates, as the latter favor osteoclast apoptosis referred to as a ‘ benign’ adult form. Light osteopetrosis [30, 31]. In this case, bone dysplasias are formed.

Monocytes, disorders: Intracellular signal macrophages m-csf, molecules disorders: RANKL osteoprotegerin excess c-fos, c-src, NFkB, Pu-1, TRAF6, Atpbi

Enzyme disorders: carbonic anhydrase Type ІІ, Receptor disorders: Cathepsin K RANK(m-CSF rec), C-fms

Genetic disorders: Cellular adhesion disorders: CLCN7,TCIRG1,OSTM1,CA2,SNX10 Beta 3-integrin, E-cadherin etc. (about 10 genes)

Fig 2. Causes of differentiation and osteoclastic activation disorders [adapted from 6, 9, 10, 11 with additions]

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Diagnostics received for autosomal-recessive oteopetrosis treat- Osteopetrosis diagnostics involves clinical and X-ray ment; however, certain undesired complications were evaluation by means of bone densitometry. To confirm observed, namely vision impairment right after the the diagnosis, it is important to rely on genetic studies transplantation [8, 12, 33]. Similar positive results were as well. received while treating patients with carbonic anhydrase Diagnosis is based on the following X-ray characteris - mutations Type II [10]. Nevertheless, in case of RANK tics described by Stark Z. and Savarirayan R. [6]: and RANKL receptor gene mutations this method is in - - presence of diffuse osteosclerosis in the skull, spine, effective. and limb bones; There is little clinical evidence that high - long cortical is widened (Erlenmeyer doses may reduce osteopetrosis symptoms [23], while flask), dense and has linear defects; recombinant is effective in case of - ‘bone-in-bone’ phenomenon – dual bone contour, fractures [34, 35]; however, no evidence base exists for especially for vertebrae and finger phalanges; these drugs. There are recent pre-clinical trials of new - focal of skull vault, pelvis and vertebral therapies going on: namely, RANKL and denosumab re - endplates, i.e. ‘vertebral sandwich’, ‘striped spine’; placement therapy for osteopetrosis with RANK muta- Based on X-ray data, there are two types of autoso - tion [6, 7, 36]. mal-dominant osteopetrosis singled out [2]. Type I is Success of the drug development is no doubt restricted characterized by skull vault thickening, while Type II is by absence of animal models which would replicate hu - primarily known for ‘striped spine’ and fan-like stripes man disease course. In was in 2017 only that autosomal- in the iliac bone wings, as well as for cortical densifica - dominant oteopetrosis Type II model was developed and tion. In both types, medullary cavities are narrowed. The tested on mice. Its advantage lies in the fact that phe - disorder affects all skeletal bones; however, most promi - notype severity degree was changed; now it resembles a nent lesions occur in long, skull, spinal, rib and pelvic broad phenotype range typical of human patients [37]. bones. DEXA reveals BMD values 2-4 times and over as Authors suggest that this model will help to identify mu - normal. tant genes or factors affecting severity and penetrability Hematological study presupposes blood count, namely of this osteopetrosis type, favoring innovative treatment reticulocyte count in blood sample, and lactic dehydro - methods being tried out. genase in blood serum; both are necessary for evaluating the hematological disorder severity. Reduced hemoglo- Clinical case bin, reticulocyte and platelet count are associated with Patient R, female, 1952. Complaints of intense lumbo - medullar disorders. sacral, genual and talocrural pain, worsened while walk - By contrast, increased count, along ing. with immature granulocytes and increased lactic dehy- drogenase usually reveals an extra-medullar hematopoi- Antecedent anamnesis esis. Dates the onset since 1972, when while undergo - Laboratory tests of adult patients show (gen - ing fluorography, was diagnosed with marble bone dis - eral and ionized), Phosphorus and acid phosphatase lev - ease due to a significant densification of bone tissue. At els in blood plasma to be within normal bounds. How - the diagnosis, the patient had no complaints. First ones ever, these parameters may also reveal hypercalcemia. (lumbar pain and headaches) started in 1979 (at the age Children are more often afflicted by hypophosphatemia of 27) after the second labor. Patient was monitored at the and moderate . Acid phosphatase levels are SI “Institute of orthopedics and traumatology”, regularly usually increased in blood plasma. treated for symptomatic signs. In 2016-2017, pain syn - drome’s intensity grew, affecting lumbar spine and lower Treatment limbs. There are no protocols of osteopetrosis treatment. It is symptomatic, assisted by a maintenance therapy. Fre - Anamnesis vitae quent fractures and secondary complications, namely a Female patient, 65 y.o., no history of smoking, no al - delayed fragment consolidation or fracture disunion, re- cohol use. Denies any professional harm. Allergic anam - quire orthopedic observation and a special surgical ap - nesis is not aggravated. Age of menarche – 14 y.o., age proach [5, 32]. of menopause – 49 y.o., no replacement therapy under - In the recent years, hemopoietic stem cell transplan - taken. Denies any other co-morbidities or medications. tation enabled achievement of a 5-year survival rate in 73 % of autosomal-recessive cases [23]. This therapy is Objective status used, taking into consideration the hematological os - Hypersthenic, 164 cm tall, 96 kg, BMI – 35,7 kg/m 2. teoclast origin. Mostly positive (> 50 %) results were Skin and visible mucous membranes of normal color.

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Peripheral lymphatic nodes are not swollen. Pulse rate – movement. Strength and muscular tonus of limbs pre - 68 strokes/min, AP – 130/80 mm of mercury column, served. breathing rate – 14 per min. Heart tones are rhythmic, Laboratory results. General clinical examination attenuated, accent of II tone on the aorta. Vesicular lung revealed no clinically significant deviation. Com - breathing, no rales. Stomach is soft under palpation, no plete blood count (10.07.2017) results: erythro - pain. Lower liver edge next to the end of rib curve. Spleen cytes – 4,76 (normal: 3,8-5,8*10 12/l), hemoglobin is not palpable. No peripheral swelling. Diuresis is nor - – 140 (120-140 g/l), leukocytes – 5,4 (4-10*10 9/l), mal, stool normal as well. lymphocytes – 37,9 (17,0-48,0%), monocytes – 5,2 Walking is slowed down; however, with no support. (4,0-10,0%), granulocytes – 56,9 (43,0-76,0%), Stature is normal, physiological spine curves are extenu - platelets – 272 (150-400*10 9), ESR - 28 (2-18 mm/ ated. Cervical and lumbar movement is greatly reduced, hour). Blood chemistry: albumin – 40,6 (32,0-52,0 moderately painful; while moving, crackling occurs. g/l), alanine aminotransferase – 27 (up to 41 mmol/l), Paravertebral muscles are hypertonic, paravertebral pain aspartate aminotransferase – 24 (up to 40 mmol/l), sites at С4-6, L4-S1. Upper limb joint mobility is com- blood glucose – 5,9 (3,8-6,1 mmol/l), uric acid – pletely preserved, but painful. Knee joints are swollen, 5,0 (2,5-8,3 mmol/l), creatinine – 70,4 (53,0-97,0 no inflammation signs. Knee joint mobility is associated mcmol/l). Bone metabolism parameters are normal: with pain, completely preserved, and followed by crack - total Ca – 2,36 (2,15-2,58 mmol/l), total ling. At palpation: projection of knee articular cavity is (25(ОН)D) – 34,41 (optimum level – 30,0-50,0 ng/ painful. Hand joints are moderately swollen, painful at ml). Bone remodeling marker rates are elevated: pro -

a

b

Fig. 3. Lumbar spine (А), proximal hip (B), c total body (C) BMD values

Vol. 9, No. 2, 2019 http://pjs.zaslavsky.com.ua 139 Практична медицина / Practical Medicine peptides of Type I Procollagen (P1NP) – 157,4 (16,3- 5. Wu CC, Econs MJ, DiMeglio LA, et al. Diag- 73,9 ng/ml), β-terminal telepeptides of Type I Colla - nosis and Management of Osteopetrosis: Consensus gen (β-СТх) – 1,13 (<1,008 ng/ml). Guidelines From the Osteopetrosis Working Group. Instrumental test results: J Clin Endocrinol Metab. 2017 Sep 1;102(9):3111- ECG (10.07.2017) – sinoatrial rate, regular with 3123. doi: 10.1210/jc.2017-01127. cardiac rate of 71 per minute. Electric heart axis – 6. Stark Z, Savarirayan R. Osteopetro- horizontal. Signs of hypertrophied left ventricle, left sis. Orphanet J Rare Dis. 2009 Feb 20;4:5. doi: atrium. 10.1186/1750-1172-4-5. Ultrasonography of abdominal cavity (18.07.2017) – 7. Sobacchi C, Frattini A, Guerrini MM, et al. cysts in hepatic lobes, hepatic lipid dystrophy, chronic Osteoclast-poor human osteopetrosis due to muta- tions in the gene encoding RANKL. Nat Genet. 2007 cholecystitis signs, diffuse pancreatic alterations. Aug;39(8):960-2. doi:10.1038/ng2076. X-ray of cervical spine (12.07.2017) – osteopetrosis, 8. Manolagas SC. Birth and death of bone cells: osteochondrosis of С , С disks, spondylosis. 4-5 5-6 basic regulatory mechanisms and implications for Dual-energy X-ray absorptiometry (DXA, the pathogenesis and treatment of osteoporosis. 13.07.2017) revealed a significant increase of BMD at Endocr Rev. 2000 Apr;21(2):115-37. doi:10.1210/ all the examined sites: lumbar BMD – Т = 11,0, femoral edrv.21.2.0395. neck – right Т = 8,4, left T= 8,4, total body – Т = 13,8, 9. Palagano E, Blair HC, Pangrazio A, et al. forearm – Т = 5,9 (Fig. 1). Normal T values are with - Buried in the Middle, But Guilty: Intronic Muta- in the range of –1 to +1. 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18. Cotter M, Connell T, Colhoun E, Smith OP, Am. 2010 Feb;57(1):171-80. doi: 10.1016/j. McMahon C. Carbonic anhydrase II deficiency: a pcl.2009.11.006. rare autosomal recessive disorder of osteopetrosis, 29. Teitelbaum SL, Ross FP. Genetic regula- renal tubular acidosis, and cerebral calcification. J tion of osteoclast development and function. Nat Pediatr Hematol Oncol. 2005 Feb;27(2):115-7. doi: Rev Genet. 2003 Aug;4(8):638-49. doi:10.1038/ 10.1097/01.mph.0000154068.86987.47. nrg1122. 19. Farfán MA, Olarte CM, Pesantez RF, Suárez 30. Waguespack SG, Hui SL, Dimeglio LA, S, Vallejo L. Recommendations for fracture man- Econs MJ. Autosomal dominant osteopetrosis: clini- agement in patients with osteopetrosis: case report. cal severity and natural history of 94 subjects with a Arch Orthop Trauma Surg. 2015 Mar;135(3):351-6. 7gene mutation. J Clin Endocrinol doi: 10.1007/s00402-014-2144-z. Metab. 2007 Mar;92(3):771-8. doi:10.1210/jc.2006- 20. Pangrazio A, Fasth A, Sbardellati A, et al. 1986. SNX10 mutations define a subgroup of human auto- 31. Whyte MP, Wenkert D, Clements KL, McAl- somal recessive osteopetrosis with variable clinical ister WH, Mumm S. Bisphosphonate-induced osteo- severity. J Bone Miner Res. 2013 May;28(5):1041- petrosis. N Engl J Med. 2003 Jul 31;349(5):457-63. 9. doi: 10.1002/jbmr.1849. doi:10.1056/NEJMoa023110. 21. Shapiro F. Osteopetrosis. Current Clini- 32. Driessen GJ, Gerritsen EJ, Fischer A, et al. cal Considerations. Clin Orthop Relat Res. 1993 Long-term outcome of haematopoieticstem cell Sep;(294):34-44. transplantation in autosomal recessive osteopetrosis: 22. Bollerslev J, Henriksen K, Nielsen MF, Brix- an EBMT report. Transplant. 2003 en K, Van Hul W. Autosomal dominant osteopetrosis Oct;32(7):657-63. doi:10.1038/sj.bmt.1704194. revisited: lessons from recent studies. Eur J Endocri- 33. Steward CG. Neurological aspects of os- nol. 2013 Jul 13;169(2):R39-57. doi: 10.1530/EJE- teopetrosis. Neuropathol Appl Neurobiol. 2003 13-0136. Apr;29(2):87-97. 23. Spichak II, Bogacheva MV, Toporkov DI. 34. AlkhiaryYM, Gerstenfeld LC, Krall E, et Osteopetrosis - rare inherited disorder (literature al. Enhancement of experimental fracture-healing review and clinical observations). Pediatricheskiy by systemic administration of recombinant human vestnik Yuzhnogo Urala. 2016;(2):106-114. (in Rus- parathyroid hormone (PTH 1-34). J Bone Joint sian). Surg Am. 2005 Apr;87(4):731-41. doi: 10.2106/ 24. Benichou OD, Laredo JD, de Vernejoul MC. JBJS.D.02115. Type II autosomal dominant osteopetrosis (Albers- 35. Sen RK, Gopinathan NR, Kumar R, Saini Schonberg disease): clinical and radiological mani- UC. Simple reproducible technique in treatment for festations in 42 patients. Bone. 2000 Jan;26(1):87- osteopetrotic fractures. Musculoskelet Surg. 2013 93. doi: 10.1016/S8756-3282(99)00244-6. Aug;97(2):117-21. doi: 10.1007/s12306-012-0222- 25. Tolar J, Teitelbaum SL, Orchard PJ. Osteo- 3. petrosis. N Engl J Med. 2004 Dec 30;351(27):2839- 36. Sobacchi C, Schulz A, Coxon FP, Villa A, 49. doi:10.1056/NEJMra040952. Helfrich MH. Osteopetrosis: genetics, treatment 26. Van Wesenbeeck L, Cleiren E, Gram J, et al. and new insights into osteoclast function. Nat Rev Sixnovel missense mutations in the LDL receptor- Endocrinol. 2013 Sep;9(9):522-36. doi: 10.1038/ related protein 5 (LRP5) gene in different conditions nrendo.2013.137. with an increased bone density. Am J Hum Genet. 37. Alam I, McQueen AK, Acton D, et al. Phe- 2003 Mar;72(3):763-71. doi:10.1086/368277. notypic severity of autosomal dominant osteope- 27. Frattini A, Pangrazio A, Susani L, et al. Chlo- trosis type II (ADO2) mice on different genetic ride channel CLCN7 mutations are responsible for backgrounds recapitulates the features of human severe recessive, dominant, and intermediate osteo- disease. Bone. 2017 Jan;94:34-41. doi: 10.1016/j. petrosis. J Bone Miner Res. 2003 Oct;18(10):1740- bone.2016.10.016. 7. doi: 10.1359/jbmr.2003.18.10.1740. Received 19.04.2019 28. Steward CG. Hematopoietic stem cell trans- Revised 4.05.2019 plantation for osteopetrosis. Pediatr Clin North Accepted 19.05.2019

Information about authors Povoroznyuk V.V., MD, PhD, Professor, Head of the Department of clinical physiology and pathology of locomotor apparatus, State Institution “D.F. Chebotarev Institute of Gerontology of the NAMS of Ukraine”, Kyiv, Ukraine, e-mail: [email protected], ORCID iD: http://orcid.org/0000-0002-9770-4113 Dedukh N.V., MD, PhD, Professor, Department of clinical physiology and pathology of locomotor apparatus, State Institution “D.F. Chebotarev Institute of Gerontology of the NAMS of Ukraine”, Kyiv, Ukraine Bystrytska M.A., PhD, Department of clinical physiology and pathology of locomotor apparatus, State Institution “D.F. Chebotarev Institute of Gerontology of the NAMS of Ukraine”, Kyiv, Ukraine Musiienko A.S., PhD, Department of clinical physiology and pathology of locomotor apparatus, State Institution “D.F. Chebotarev Institute of Gerontology of the NAMS of Ukraine”, Kyiv, Ukraine

Vol. 9, No. 2, 2019 http://pjs.zaslavsky.com.ua 141 Практична медицина / Practical Medicine

Поворознюк В.В., Дєдух Н.В., Бистрицька М.А., Мусієнко А.С. Державна установа «Інститут геронтології імені Д.Ф. Чеботарьова НАМН України», м. Київ, Україна Остеопетроз: класифікація, патоморфологія, генетичні порушення, клінічні прояви (огляд літератури та власне клінічне спостереження)

Резюме. Остеопетроз — спадкове захворювання з автосом- гічні зміни у структурній організації кісткової тканини, від- но-рецесивним чи автосомно-домінантним типом успадку- значені особливості стану остеокластів залежно від мутації вання, спричинене порушенням функціональної активності генів, які контролюють їх функціональну активність. Прото- остеокластів внаслідок мутації генів. У статті на основі аналі- колів лікування цієї патології немає, але проводиться розроб- зу літературних джерел систематизовані дані про етіологію, ка методів лікування на основі використання гемопоетичних класифікацію, патоморфологію, генні порушення і висвіт- стовбурових клітин. Наведено клінічний приклад пацієнтки лені сучасні підходи до лікування остеопетрозу. Описано три з остеопетрозом. типи остеопетрозу з різним ступенем вираженості порушень Ключові слова: остеопетроз; класифікація; патоморфоло- у скелеті та тяжкості патології. Подані основні патоморфоло- гія; остеобласти; генні порушення; діагностика; лікування

Поворознюк В.В., Дедух Н.В., Быстрицкая М.А., Мусиенко А.С. Государственное учреждение «Институт геронтологии имени Д.Ф. Чеботарева НАМН Украины», г. Киев, Украина Остеопетроз: классификация, патоморфология, генетические нарушения, клинические проявления (обзор литературы и собственное клиническое наблюдение) Резюме. Остеопетроз — наследственное заболевание с ауто- менения в структурной организации костной ткани, отме- сомно-рецессивным или аутосомно-доминантным типом на- чены особенности состояния остеокластов в зависимости от следования, вызванное нарушением функциональной актив- мутации генов, контролирующих их функциональную актив- ности остеокластов за счет мутации генов. В статье на основе ность. Протоколов для лечения этой патологии не имеется, анализа литературных источников систематизированы дан- но ведется разработка методов лечения на основе использо- ные об этиологии, классификации, патоморфологии, генных вания гемопоэтических стволовых клеток. Представлен кли- нарушениях и освещены современные подходы к лечению нический пример пациентки с остеопетрозом. остеопетроза. Описаны три типа остеопетроза с различной Ключевые слова: остеопетроз; классификация; патомор- степенью выраженности нарушений в скелете и тяжестью па- фология; остеокласты; генные нарушения; диагностика; ле- тологии. Представлены основные патоморфологические из- чение

142 Bol', sustavy, pozvonočnik, ISSN 2224-1507 (print), ISSN 2307-1133 (online) Vol. 9, No. 2, 2019

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