CC BY
77
Практична медицина / Practical Medicine
БШЬ.
СуГЛОБИ. JOINTS. I ХРЕБЕТ SPINE I
УДК616.71-003.84 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
Osteopetrosis: classification, pathomorphology, genetic disorders, clinical manifestations (literature review and clinical case report)
For cite: Bol', sustavy, pozvonocnik. 2019;9(2):135-142. doi: 10.22141/2224-1507.9.2.2019.172125_
Abstract. Osteopetrosis is a hereditary disease with an autosomal recessive or autosomal dominant type of inheritance, caused by a disruption in the functional activity of osteoclasts due to gene mutation. The article systematizes 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 bone tissue are presented and features of the state of osteoclasts 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 bone disease. Keywords: osteopetrosis; classification; pathomorphology; osteoclasts; gene disorders; diagnosis; treatment
Introduction
Osteopetrosis was first described by Albers-Schonberg in 1904 [1]. Osteopetrosis (congenital family osteosclerosis, marble bone disease, Albers-Schonberg disease) is an umbrella term for a range of rare isolated inherited disorders characterized by skeletal sclerosis [2, 3, 4, 5, 6, 7]. At this moment, there are at least 11 forms known for their different inheritance and severity types. Autosomal-recessive osteopetrosis afflicts 1 in 250 thousand newborns, while autosomal-dominant one — 1 in 20 thousand newborns [6].
Review's purpose is to systematize data on osteopetrosis' etiology, classification, pathomorphology of genetic disorder, treatment methods and to present our own clinical observation study.
Information search has been made in Google, Google-Scolar, AcademicResourslndex, PubMed, РHНЦ (Russian Science Citation Index) for the following keywords:
osteopetrosis, osteoclasts, etiology, classification, genetic disorders, treatment.
Osteopetrosis' etiology
Osteopetrosis' etiology and pathogenesis require a further study. One of the principal pathogenetic mechanisms involved in this disorder is osteoclasts' developmental and functional breakdowns.
Osteoclasts are highly-specialized cells in charge of bone mineral and organic matrix resorption. This process is pivotal for the bone reconstruction, its biochemical strength and mineral homeostasis. Adult skeleton is completely renewed every 10 years [8].
Osteoclasts are derived from the mononuclear precursor cells of hematopoietic myeloid line, also giving rise to macrophages and monocytes. Having united, the precursor cells form osteoclasts with up to 20 nuclei. Their life 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 кореспонденци: Поворознюк Владислав Володимирович, доктор медичних наук, професор, ДУ «1нститут геронтологи iMeHi Д.Ф. Чеботарьова НАМН УкраТни», вул. Вишгородська, 67, м. КиТв, 04114, УкраТна; 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.
For osteoclasts to get differentiated, both receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) are required. For this purpose, they are produced by osteoblastic cellular differon. Precursor cell and osteoclast activation is initiated by RANKL's interaction with osteoblastic RANK receptors. Osteoprotegerin, a protein synthesized by osteoblastic line cells, is a soluble RANKL-binding receptor which prevents its interaction with osteoblastic RANK receptors, along with osteoclastic activation and bone resorption.
Osteoclast is a polar cell sticking to the bone tissue by a P3 integrin-produced corrugated fringe. Resorptive lacunae occur due to enzymes destroying organic and mineral matrix (Fig. 1). Osteoclastic intracellular pH is maintained by carbonic anhydrase and electric-neutral HC03- / Cl- ion exchange.
Mineral matrix destruction is mediated by hydrochloric acid produced in the resorptive lacunae by chlorine ions penetrating them through the protein-made chlorine-specific ion channel (CLCN7) on the osteoclastic membrane and osteoclast-specific ATP driven proton pump [9]. Organic matrix is destroyed by Cathepsin K. Once genes in charge of osteoclastic differentiation and their functional activity become mutated, osteopetrosis occurs.
This disorder develops with reducing or partial/complete loss of osteoclastic function, which leads to bone resorption disorders. In two thirds of patients osteoclasts are being formed; however, they are incapable of a successful bone resorption. Osteoclastic functional disorder is caused by at least 10 genetic mutations; these are considered osteopetrosis-provoking and are revealed in 70 % of osteopetrosis patients [11]. Osteoclastic formation may also be deranged due to precursor cells' inability to differentiate.
Among the best researched mutations there are those occurring in CLCN7, CAII (carbonic anhydrase II) and TCIRG1 (V-ATPase pump) and OSTM1 (trans-mem-
Fig. 1. Active functional osteoclast [adapted from 10]
brane protein-associated osteopetrosis). Mutations disrupt pH organelle regulation and cellular secretion, affecting osteoclastic bone resorption [6].
Fig. 2 represents a complex regulation of osteoclastic differentiation and functional activity by means of intra-cellular signal molecules, RANKL—RANK receptors, cytokines, enzymes. Mutations of genes in charge of this cell's functioning lead to osteopetrosis.
Disorder is inherited by different pathways: autoso-mal-recessive and autosomal-dominant.
Bone pathomorphology
While studying bones of osteopetrosis patients, researchers find significant bone formation sites on the surface, in the medullary canal and inter-trabecular spaces of trabecular bone. Structural organization of the newly formed bone tissue is irregular, mosaic, characterized by the pronounced pathological modifications. Lamellar bone tissue with irregular cementation lines is interspersed with coarse-fibered bone tissue. Within the medulla, there are bone and cartilage islets, osteoid accumulations [3]. Bone trabeculae seem thickened, their inter-trabecular spaces narrowed [12]. Osteoclastic density may vary under different osteopetrosis types ranging from low to normal; however, bone resorption sites are isolated, reflecting osteoclastic resorptive disorders.
Based on bone biopsy and genetic analysis of osteope-trosis patients, it was found that a significant number of osteoclasts (normal or even elevated rate) in the medulla might signify their disrupted functions, namely due to TCIRG1, CLCN7, SNX10 and OSTM1 gene mutations while presence of isolated osteoclasts or even their absence are connected to a rare osteopetrosis type, caused by RANK and RANKL gene disorders [3].
Osteopetrosis classification
For practical considerations, various osteopetrosis forms might be classified in terms of their clinical characteristics, severity of clinical manifestations, medullar histology and genetic basis [3, 13].
The most severe one is autosomal-recessive heredity pathway as it might be associated with a-subunit of ATPase gene defects, namely TCIRG1 (classical type), osteopetrosis-associated protein gene, i.e. OSTM1 (neuropathic type), and carbonic anhydrase Type II, i.e. CAII (associated with renal tubular acidosis) [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 differentiation and activation of osteoclasts [14]. Medullar biopsy reveals cellular shrinking signifying a hemopoietic reduction.
Autosomal-recessive osteopetrosis may manifest itself at the fetal stage, while the neonates and infants are afflicted with progressive anemia, hepatosplenomegaly, macrocephalia or hydrocephalia, as well as nerve restraint resulting in blindness or deafness. This form is qualified as 'malignant' osteopetrosis. With neonatal osteopetrosis form, survival rate is low, while the life span is no more than 2-10 years. Disorder is characterized by multiple fracture osteosclerosis, may result in osteomyelitis, vision loss and hemopoietic disorders. Among its typical features, there are broadened facial skull, nasal and labial anatomic disorders. Mental retardation and progressive neural degeneration may be caused by CLCN7 and OSTM1 gene mutations [9, 15]. CLCN7 gene has 20 mutations. This osteopetrosis type is characterized by bone dysplasias.
Intermediary osteopetrosis is clinically and genetically irregular; its course being less pronounced but also severe. Its hereditary pathways could be both dominant and recessive. Protein-encoding gene (CLCN7) becomes less active, while its mutation leads to several forms of recessive osteopetrosis and autosomal-dominant osteopetrosis Type II [16, 17]. CLCN7 gene defects also provoke intermediary osteopetrosis; CLCN7 being protein domain gene, the same as Pleckstrin homology domain-containing gene also known as PLEKHM1 [6]. Intermediary recessive form is characterized by medullar calcification, renal tubular acidosis caused by carbonic anhydrase Type II gene (CA-II). These patients often have mental disorders [18].
Osteopetrosis might also be induced by RANK, SNX10 and TCIRG1 gene mutations [6, 9, 19, 20, 21]. Other intermediary forms are characterized by a moderate osteo-sclerosis, low height and fragility fractures.
Moderate autosomal-dominant osteopetrosis is characterized by the irregular and late manifestations referred to as a 'benign' adult form. Light osteopetrosis
may be asymptomatic in half the cases [13], while in others are associated with pathological fractures under minimal trauma; and that is very often the only sign of disorder afflicting adults. Factures' union is delayed. Disorder is associated with aching bones, osteomyelitis complications and cerebral nerve affliction [2, 22]. Bone fragility is aggravated by architectonic disorders and atypical bone formation. The most wide-spread complication is optic nerve atrophy due to the bone tissue accretion in cavities and canals, leading to blindness. Autosomal-dominant osteopetrosis is more frequent among the older children and adults; its main manifestation being pathological fractures. With late osteopetrosis, bone lesions become rarer as usual [23]. Early mortality is infrequent, life span is similar to the statistically relevant; however, the quality of life is compromised [10].
There are two types of adult osteopetrosis. In case of autosomal-dominant osteopetrosis Type I, phenotypic pathological manifestations are caused by missence mutation (point mutation leading to a modified codon starting to encode another aminoacid) in LRP5 [24, 25, 26]. In case of autosomal-dominant osteopetrosis Type II, missence mutation might affect CLCN7 [27].
Osteopetrosis types are genetically determined and may be referred to as osteoclast-autonomous osteopetrosis and osteoclast-nonautonomous osteopetrosis [28, 29]. With nonautonomous osteopetrosis, genetic effect may be associated with cells affecting osteoclast precursor differentiation or mature cell functions. With osteo-clast-autonomous osteopetrosis, molecular defect may be present either in osteoclasts themselves or in their precursors.
Although all osteopetrosis forms are genetically determined, this disorder may be induced in children by the bisphosphonates, as the latter favor osteoclast apoptosis [30, 31]. In this case, bone dysplasias are formed.
Intracellular signal molecules disorders:
c-fos, c-src, NFkB, Pu-1, TRAF6, Atpbi
Receptor disorders:
RANK(m-CSF rec), C-fms
Cellular adhesion disorders:
Beta 3-integrin, E-cadherin
Cytokine disorders:
m-csf,
RANKL osteoprotegerin excess
Enzyme disorders:
carbonic anhydrase Type I Cathepsin K
Genetic disorders:
CLCN7,TCIRG1,0STM1,CA2,SNX10 etc. (about 10 genes)
Fig 2. Causes of differentiation and osteoclastic activation disorders [adapted from 6,9,10,11 with additions]
Diagnostics
Osteopetrosis diagnostics involves clinical and X-ray evaluation by means of bone densitometry. To confirm the diagnosis, it is important to rely on genetic studies as well.
Diagnosis is based on the following X-ray characteristics described by Stark Z. and Savarirayan R. [6]:
- presence of diffuse osteosclerosis in the skull, spine, pelvis and limb bones;
- long cortical metaphysis is widened (Erlenmeyer flask), dense and has linear defects;
- 'bone-in-bone' phenomenon — dual bone contour, especially for vertebrae and finger phalanges;
- focal osteoporosis of skull vault, pelvis and vertebral endplates, i.e. 'vertebral sandwich', 'striped spine';
Based on X-ray data, there are two types of autosomal-dominant osteopetrosis singled out [2]. Type I is characterized by skull vault thickening, while Type II is primarily known for 'striped spine' and fan-like stripes in the iliac bone wings, as well as for cortical densifica-tion. In both types, medullary cavities are narrowed. The disorder affects all skeletal bones; however, most prominent lesions occur in long, skull, spinal, rib and pelvic bones. DEXA reveals BMD values 2-4 times and over as normal.
Hematological study presupposes blood count, namely reticulocyte count in blood sample, and lactic dehydro-genase in blood serum; both are necessary for evaluating the hematological disorder severity. Reduced hemoglobin, reticulocyte and platelet count are associated with medullar disorders.
By contrast, increased white blood cell count, along with immature granulocytes and increased lactic dehy-drogenase usually reveals an extra-medullar hematopoi-esis.
Laboratory tests of adult patients show Calcium (general and ionized), Phosphorus and acid phosphatase levels in blood plasma to be within normal bounds. However, these parameters may also reveal hypercalcemia. Children are more often afflicted by hypophosphatemia and moderate hypocalcemia. Acid phosphatase levels are usually increased in blood plasma.
Treatment
There are no protocols of osteopetrosis treatment. It is symptomatic, assisted by a maintenance therapy. Frequent fractures and secondary complications, namely a delayed fragment consolidation or fracture disunion, require orthopedic observation and a special surgical approach [5, 32].
In the recent years, hemopoietic stem cell transplantation enabled achievement of a 5-year survival rate in 73 % of autosomal-recessive cases [23]. This therapy is used, taking into consideration the hematological os-teoclast origin. Mostly positive (> 50 %) results were
received for autosomal-recessive oteopetrosis treatment; however, certain undesired complications were observed, namely vision impairment right after the transplantation [8, 12, 33]. Similar positive results were received while treating patients with carbonic anhydrase mutations Type II [10]. Nevertheless, in case of RANK and RANKL receptor gene mutations this method is ineffective.
There is little clinical evidence that high calcitriol doses may reduce osteopetrosis symptoms [23], while recombinant parathyroid hormone is effective in case of fractures [34, 35]; however, no evidence base exists for these drugs. There are recent pre-clinical trials of new therapies going on: namely, RANKL and denosumab replacement therapy for osteopetrosis with RANK mutation [6, 7, 36].
Success of the drug development is no doubt restricted by absence of animal models which would replicate human disease course. In was in 2017 only that autosomal-dominant oteopetrosis Type II model was developed and tested on mice. Its advantage lies in the fact that phe-notype severity degree was changed; now it resembles a broad phenotype range typical of human patients [37]. Authors suggest that this model will help to identify mutant genes or factors affecting severity and penetrability of this osteopetrosis type, favoring innovative treatment methods being tried out.
Clinical case
Patient R, female, 1952. Complaints of intense lumbo-sacral, genual and talocrural pain, worsened while walking.
Antecedent anamnesis
Dates the onset since 1972, when while undergoing fluorography, was diagnosed with marble bone disease due to a significant densification of bone tissue. At the diagnosis, the patient had no complaints. First ones (lumbar pain and headaches) started in 1979 (at the age of 27) after the second labor. Patient was monitored at the SI "Institute of orthopedics and traumatology", regularly treated for symptomatic signs. In 2016-2017, pain syndrome's intensity grew, affecting lumbar spine and lower limbs.
Anamnesis vitae
Female patient, 65 y.o., no history of smoking, no alcohol use. Denies any professional harm. Allergic anamnesis is not aggravated. Age of menarche — 14 y.o., age of menopause — 49 y.o., no replacement therapy undertaken. Denies any other co-morbidities or medications.
Objective status
Hypersthenic, 164 cm tall, 96 kg, BMI - 35,7 kg/m2. Skin and visible mucous membranes of normal color.
Peripheral lymphatic nodes are not swollen. Pulse rate — 68 strokes/min, AP — 130/80 mm of mercury column, breathing rate — 14 per min. Heart tones are rhythmic, attenuated, accent of II tone on the aorta. Vesicular lung breathing, no rales. Stomach is soft under palpation, no pain. Lower liver edge next to the end of rib curve. Spleen is not palpable. No peripheral swelling. Diuresis is normal, stool normal as well.
Walking is slowed down; however, with no support. Stature is normal, physiological spine curves are extenuated. Cervical and lumbar movement is greatly reduced, moderately painful; while moving, crackling occurs. Paravertebral muscles are hypertonic, paravertebral pain sites at C4-6, L4-S1. Upper limb joint mobility is completely preserved, but painful. Knee joints are swollen, no inflammation signs. Knee joint mobility is associated with pain, completely preserved, and followed by crackling. At palpation: projection of knee articular cavity is painful. Hand joints are moderately swollen, painful at
movement. Strength and muscular tonus of limbs preserved.
Laboratory results. General clinical examination revealed no clinically significant deviation. Complete blood count (10.07.2017) results: erythrocytes — 4,76 (normal: 3,8-5,8*1012/l), hemoglobin - 140 (120-140 g/l), leukocytes - 5,4 (4-10*109/l), lymphocytes - 37,9 (17,0-48,0%), monocytes - 5,2 (4,0-10,0%), granulocytes - 56,9 (43,0-76,0%), platelets - 2 7 2 (150-4 0 0*109), ESR - 28 (2-18 mm/ hour). Blood chemistry: albumin - 40,6 (32,0-52,0 g/l), alanine aminotransferase - 27 (up to 41 mmol/l), aspartate aminotransferase - 24 (up to 40 mmol/l), blood glucose - 5,9 (3,8-6,1 mmol/l), uric acid -5,0 (2,5-8,3 mmol/l), creatinine - 70,4 (53,0-97,0 mcmol/l). Bone metabolism parameters are normal: total Ca - 2,36 (2,15-2,58 mmol/l), total Vitamin D (25(OH)D) - 34,41 (optimum level - 30,0-50,0 ng/ ml). Bone remodeling marker rates are elevated: pro-
C.F. 1040 1026 1000 CF. 1040 1026 1000
Region Area BMC BMD T- 2- Region Area BMC 8M0 T- Z-
(orf) (9) (Stan1) score score (orf) (9) (g'cnfl scofe sc«e
Neck 5.71 10.15 1.779 8.4 99 Neck 5.33 949 1781 84 99
Troch 1284 22 52 1.753 10.4 11.5 Trodi 13.90 25.11 1.807 10.9 12.0
Inter 2093 55.95 2673 10.1 111 Wer 27.32 7203 2637 9.9 10.9
TOTAL 39 48 88.62 2245 110.7 119 1 TOTAL 46.54 106.64 2291 11.1 123
Ward's 1.14 167 1.462 62 85 Ward's 1.10 144 1300 4.8 7.1
Fig. 3. Lumbar spine (A), proximal hip (B), total body (C) BMD values
c
peptides of Type I Procollagen (P1NP) - 157,4 (16,373,9 ng/ml), ß-terminal telepeptides of Type I Collagen (ß-CTx) - 1,13 (<1,008 ng/ml).
Instrumental test results:
ECG (10.07.2017) — sinoatrial rate, regular with cardiac rate of 71 per minute. Electric heart axis — horizontal. Signs of hypertrophied left ventricle, left atrium.
Ultrasonography of abdominal cavity (18.07.2017) — cysts in hepatic lobes, hepatic lipid dystrophy, chronic cholecystitis signs, diffuse pancreatic alterations.
X-ray of cervical spine (12.07.2017) — osteopetrosis, osteochondrosis of C4-5, C5-6 disks, spondylosis.
Dual-energy X-ray absorptiometry (DXA, 13.07.2017) revealed a significant increase of BMD at all the examined sites: lumbar BMD — T = 11,0, femoral neck — right T = 8,4, left T= 8,4, total body — T = 13,8, forearm — T = 5,9 (Fig. 1). Normal T values are within the range of —1 to +1. Trabecular bone quality index (TBS) — 1,630.
Diagnosis: Osteopetrosis (marble bone disease) with static-dynamic disorders and pronounced irritative-pain syndrome was made according to clinical and X-ray findings rather than genetic testing.
Thus, osteopetrosis is a hereditary disease grounded in osteosclerosis. Pathology is attributed to disordered osteoclast differentiation and activity, reveals itself in structural bone changes, compactization and increased fragility, increased fracture risk. Osteopetrosis is a genetically-bound disorder with autosomal-recessive and autosomal-dominant heredity types, greater severity being associated with autosomal-recessive type.
Conflicts of interests. Authors declare the absence of any conflicts of interests that might be construed to influence the results or interpretation of their manuscript.
References
1. Albers-Schonberg H. Rontgenbilder Einer Seltenen Knockenerkrankung. Munch Med Wochen-schr. 1904;51:365-368.
2. Raynberg SA. Rentgenodiagnostika zabol-evaniy kostey i sustavov [Radiodiagnosis of bones and joints diseases]. Moscow: Meditsina; 1964. 440 p. (in Russian).
3. Kalyagin AN, Belozertseva LV, Shchad-neva SI, Katkova MI, Skatova OV, Parkhomenko YuV. Osteopetrosis (marble bone disease). Sovre-mennaya Revmatologiya. 2014;8(1):23-26. doi: 10.14412/1996-7012-2014-1-23-26. (in Russian).
4. Shroff R, Beringer O, Rao K, Hofbauer LC, Schulz A. Denosumab for post-transplantation hypercalcemia in osteopetrosis. N Engl J Med. 2012 Nov 1;367(18):1766-7. doi: 10.1056/NEJMc1206193.
5. Wu CC, Econs MJ, DiMeglio LA, et al. Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group. J Clin Endocrinol Metab. 2017 Sep 1;102(9):3111-3123. doi: 10.1210/jc.2017-01127.
6. Stark Z, Savarirayan R. Osteopetrosis. Orphanet J Rare Dis. 2009 Feb 20;4:5. doi: 10.1186/1750-1172-4-5.
7. Sobacchi C, Frattini A, Guerrini MM, et al. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding rankl. Nat Genet. 2007 Aug;39(8):960-2. doi:10.1038/ng2076.
8. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000 Apr;21(2): 115-37. doi:10.1210/ edrv.21.2.0395.
9. Palagano E, Blair HC, Pangrazio A, et al. Buried in the Middle, But Guilty: Intronic Mutations in the TCIRG1 Gene Cause Human Autosomal Recessive Osteopetrosis. J Bone Miner Res. 2015 Oct;30(10):1814-21. doi: 10.1002/jbmr.2517.
10. Teitelbaum SL. Osteoclasts: what do they do and how do they do it? Am J Pathol. 2007 Feb;170(2):427-35. doi:10.2353/aj-path.2007.060834.
11. Osreopetroz [Osteopetrosis]. Art OR-PHA2781. Available from: https://www.orpha.net/ data/patho/RU/Osteopetrosis-RUrusAbs3700_.pdf. Accessed 16 Mar 2019 (in Russian).
12. Diniz G, Olukman O, Calkavur S, et al. A histologically Diagnosed Case with Infantile Osteopetrosis Complicated by Hypopituita-rism. Case Rep Pathol. 2015;2015:786836. doi: 10.1155/2015/786836.
13. Dawar H, Mugalakhod V, Wani J, Raina D, Rastogi S, Wani S. Fracture management in osteo-petrosis: an intriguing enigma. A guide for surgeons. Acta Orthop Belg. 2017 Sep;83(3):488-494.
14. Helfrich M, Perdu B, Coxon F. Human recessive osteopetrosis: new understanding of osteoclast function through molecular and functional analysis of a rare genetic bone disease. Osteologie. 2009 Jan;18(4):260-267. doi: 10.1055/s-0037-1619909.
15. Mazzolari E, Forino C, Razza A, et al. A single-center experience in 20 patients with infantile malignant osteopetrosis. Am J Hematol. 2009 Aug;84(8):473-9. doi: 10.1002/ajh.21447.
16. Balemans W, Van Wesenbeeck L, Van Hul W. A clinical and molecular overview of the human osteopetroses. Calcif Tissue Int. 2005 Nov;77(5):263-74. doi: 10.1007/s00223-005-0027-6.
17. Pangrazio A, Pusch M, Caldana E, et al. Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations. Hum Mutat. 2010 Jan;31(1):E1071-80. doi: 10.1002/humu.21167.
18. Cotter M, Connell T, Colhoun E, Smith OP, McMahon C. Carbonic anhydrase II deficiency: a rare autosomal recessive disorder of osteopetrosis, renal tubular acidosis, and cerebral calcification. J Pediatr Hematol Oncol. 2005 Feb;27(2):115-7. doi: 10.1097/01.mph.0000154068.86987.47.
19. Farfan MA, Olarte CM, Pesantez RF, Suarez S, Vallejo L. Recommendations for fracture management in patients with osteopetrosis: case report. Arch Orthop Trauma Surg. 2015 Mar;135(3):351-6. doi: 10.1007/s00402-014-2144-z.
20. Pangrazio A, Fasth A, Sbardellati A, et al. SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity. J Bone Miner Res. 2013 May;28(5):1041-9. doi: 10.1002/jbmr.1849.
21. Shapiro F. Osteopetrosis. Current Clinical Considerations. Clin Orthop Relat Res. 1993 Sep;(294):34-44.
22. Bollerslev J, Henriksen K, Nielsen MF, Brix-en K, Van Hul W. Autosomal dominant osteopetrosis revisited: lessons from recent studies. Eur J Endocrinol. 2013 Jul 13;169(2):R39-57. doi: 10.1530/EJE-13-0136.
23. Spichak II, Bogacheva MV, Toporkov DI. Osteopetrosis - rare inherited disorder (literature review and clinical observations). Pediatricheskiy vestnik Yuzhnogo Urala. 2016;(2):106-114. (in Russian).
24. Benichou OD, Laredo JD, de Vernejoul MC. Type II autosomal dominant osteopetrosis (Albers-Schonberg disease): clinical and radiological manifestations in 42 patients. Bone. 2000 Jan;26(1):87-93. doi: 10.1016/S8756-3282(99)00244-6.
25. Tolar J, Teitelbaum SL, Orchard PJ. Osteo-petrosis. N Engl J Med. 2004 Dec 30;351(27):2839-49. doi:10.1056/NEJMra040952.
26. Van Wesenbeeck L, Cleiren E, Gram J, et al. Sixnovel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet. 2003 Mar;72(3):763-71. doi:10.1086/368277.
27. Frattini A, Pangrazio A, Susani L, et al. Chloride channel CLCN7 mutations are responsible for severe recessive, dominant, and intermediate osteo-petrosis. J Bone Miner Res. 2003 Oct;18(10):1740-7. doi: 10.1359/jbmr.2003.18.10.1740.
28. Steward CG. Hematopoietic stem cell transplantation for osteopetrosis. Pediatr Clin North
Am. 2010 Feb;57(1): 171-80. doi: 10.1016/j. pcl.2009.11.006.
29. Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet. 2003 Aug;4(8):638-49. doi: 10.1038/ nrg1122.
30. Waguespack SG, Hui SL, Dimeglio LA, Econs MJ. Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7gene mutation. J Clin Endocrinol Metab. 2007 Mar;92(3):771-8. doi:10.1210/jc.2006-1986.
31. Whyte MP, Wenkert D, Clements KL, McAl-ister WH, Mumm S. Bisphosphonate-induced osteopetrosis. N Engl J Med. 2003 Jul 31;349(5):457-63. doi:10.1056/NEJMoa023110.
32. Driessen GJ, Gerritsen EJ, Fischer A, et al. Long-term outcome of haematopoieticstem cell transplantation in autosomal recessive osteopetrosis: an EBMT report. Bone Marrow Transplant. 2003 Oct;32(7):657-63. doi:10.1038/sj.bmt.1704194.
33. Steward CG. Neurological aspects of os-teopetrosis. Neuropathol Appl Neurobiol. 2003 Apr;29(2):87-97.
34. AlkhiaryYM, Gerstenfeld LC, Krall E, et al. Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1-34). J Bone Joint Surg Am. 2005 Apr;87(4):731-41. doi: 10.2106/ JBJS.D.02115.
35. Sen RK, Gopinathan NR, Kumar R, Saini UC. Simple reproducible technique in treatment for osteopetrotic fractures. Musculoskelet Surg. 2013 Aug;97(2): 117-21. doi: 10.1007/s12306-012-0222-3.
36. Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH. Osteopetrosis: genetics, treatment and new insights into osteoclast function. Nat Rev Endocrinol. 2013 Sep;9(9):522-36. doi: 10.1038/ nrendo.2013.137.
37. Alam I, McQueen AK, Acton D, et al. Phe-notypic severity of autosomal dominant osteope-trosis type II (ADO2) mice on different genetic backgrounds recapitulates the features of human disease. Bone. 2017 Jan;94:34-41. doi: 10.1016/j. bone.2016.10.016.
Received 19.04.2019 Revised 4.05.2019 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
Поворознюк В.В., Дедух Н.В., Бистрицька М.А., Муаенко А.С.
Державна установа «1нститут геронтологи 'тен'1 Д.Ф. Чеботарьова НАМН Украни», м. Ки)'в, УкраУна
Остеопетроз: класифшащя, патоморфолопя, генетичш порушення, клМчш прояви (огляд лiтератури та власне клМчне спостереження)
Резюме. Остеопетроз — спадкове захворювання з автосом-но-рецесивним чи автосомно-домшантним типом успадку-вання, спричинене порушенням функцюнально! активностi остеокласйв внаслщок мутаци генiв. У статп на основi аналь зу лиературних джерел систематизованi данi про етюлогш, класифiкацiю, патоморфологiю, геннi порушення i висвит-ленi сучаснi пщходи до лшування остеопетрозу. Описано три типи остеопетрозу з рiзним ступенем вираженосп порушень у скелетi та тяжкосп патологи. Поданi основнi патоморфоло-
пчш змiни у структурнш органiзацii кютково'1 тканини, вщ-значеш особливостi стану остеокластш залежно вщ мутаци генш, як1 контролюють ix функцiональну актившсть. Прото-колiв лжування ще! патологи немае, але проводиться розроб-ка методiв лiкування на основi використання гемопоетичних стовбурових клiтин. Наведено клшчний приклад пацiентки з остеопетрозом.
Ключовi слова: остеопетроз; класифшацш; патоморфоло-г1я; остеобласти; гент порушення; дiагностика; лiкування
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-сомно-рецессивным или аутосомно-доминантным типом наследования, вызванное нарушением функциональной активности остеокластов за счет мутации генов. В статье на основе анализа литературных источников систематизированы данные об этиологии, классификации, патоморфологии, генных нарушениях и освещены современные подходы к лечению остеопетроза. Описаны три типа остеопетроза с различной степенью выраженности нарушений в скелете и тяжестью патологии. Представлены основные патоморфологические из-
менения в структурной организации костной ткани, отмечены особенности состояния остеокластов в зависимости от мутации генов, контролирующих их функциональную активность. Протоколов для лечения этой патологии не имеется, но ведется разработка методов лечения на основе использования гемопоэтических стволовых клеток. Представлен клинический пример пациентки с остеопетрозом. Ключевые слова: остеопетроз; классификация; патомор-фология; остеокласты; генные нарушения; диагностика; лечение
