Journal of Back and Musculoskeletal Rehabilitation 28 (2015) 197–200 DOI 10.3233/BMR-140486 IOS Press

Case Report

Autosomal Dominant Osteopetrosis Type II Aslihan Kusvuran Ozkana, Pinar Doruka , Mehmet Adama,∗ , Zerrin Yilmaz Celikb and Berrin Leblebicia a


Department of Physical Medicine and Rehabilitation, Baskent University, Adana, Turkey Department of Medical Genetics, Faculty of Medicine, Baskent University, Ankara, Turkey

Abstract. Osteopetrosis is a rare genetic disorder caused by osteoclast failure. Dominant negative mutations of the ClCN7 gene cause the so-called, autosomal dominant osteopetrosis type II, which represents the most frequent and heterogeneous form of osteopetrosis, ranging from asymptomatic to intermediate-severe, thus suggesting additional genetic and environmental determinants affecting penetrance. Here, we present a case a 46 year-old woman complained low back pain for 15 years. The patient lacked any history of direct trauma and her pain was radiating to her left leg, increasing with physical activity, she had no pain at nights. The patient was diagnosed with autosomal dominant osteopetrosis on the basis of the presence of typical radiological appearance. Were present a case report of osteopetrosis type II (an autosomal dominantly inherited disease) as a cause for low back pain without any familial penetrance of the disease. Keywords: Autosomal dominant osteopetrosis, low back pain

1. Introduction Osteopetrosis is a collective term for a range of sclerosing bone diseases resulting from absence or defective function of osteoclasts [1]. It is inherited in three forms with autosomal recessive, autosomal dominant and X-linked, respectively [2]. It is usually an autosomal disease, with no gender preference, however, a few X-linked cases (XLO) have recently been described, associated with ectodermal dysplasia, lymphedema and immunodeficiency (so-called OL-EDAID syndrome) [2]. Osteopetrosis is caused by failure of osteoclast differentiation or function and mutations in at least 10 genes have been identified as causative in humans with osteopetrosis [3]. There are three clinical groups: infantile-malignant autosomal recessive, fatal within the first few years of life; intermediate autosomal recessive, appears during the first decade of life but does not follow a ma∗ Corresponding author: Mehmet Adam, Department of Physical Medicine and Rehabilitation, Baskent University, Adana Training and Research Hospital, Adana, Turkey. Tel.: +90 322 3444444 1095; Fax: +90 322 3444445; E-mail: [email protected].

lignant course; and adult-benign autosomal dominant, with full-life expectancy but many orthopedic problems [4]. In all 3 forms of osteopetrosis, there is a lack of osteoclast function resulting in decreased bone resorption with increased cortical bone and calcified cartilage [5]. Autosomal Dominant Osteopetrosis (ADO) is much more common than its recessive counterparts [6]. The clinical diagnosis of ADO is based on characteristic radiological manifestations [7]. Among families with ADO, two subtypes are generally reported based primarily on radiographic features [6]. Both types have osteosclerosis throughout the skeleton, primarily involving the axial skeleton, but with symmetrical involvement of the long bones [7]. In Type I ADO (ADO I) there is prominent sclerosis and increased thickness of the cranial vault, whereas Type II ADO (ADO II) has end-plate thickening of the vertebrae (Rugger Jersey spine) and endobones in the pelvis [4,7]. ADO II is the most common form with an estimated prevalence of up to 5.5/100 000, originally described by Albers-Schönberg in 1904 as “marble bone disease” due to intense sclerosis of the skeleton [1,2,6, 7]. ADO II presents with an extremely heterogeneous

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A.K. Ozkan et al. / Autosomal dominant osteopetrosis type II

Fig. 1. Rugger-Jersey spine (Sandwich vertebrae). (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/ BMR-140486)

course from asymptomatic to rarely fatal. The patients do not usually present with any symptoms, and in some instances the disease is only detected when radiographs are taken for some other purpose [8]. Bone pain, fractures and osteomyelitis (particularly affecting the mandible) are the most prominent symptoms [1]. Back pain is mentioned in most reports of benign autosomal dominant osteoporosis [4]. This report is intended to remind osteopetrosis type II, which is a rare disorder in differential diagnosis of low back pain, should be taken into consideration and to show a family with no penetrance.

2. Case A 46-year-old farmer woman admitted to the Department of Physical Medicine and Rehabilitation of Baskent University Hospital with complaint of low back pain for fifteen years without history of direct

trauma. Her pain was radiating to her left leg without numbness and neurological deficit, increasing with physical activity, no pain at nights. The patient and family backgrounds showed no peculiarities. On her physical examination; lumbar flexion was limited and painful, no weakness and numbness were examined, she had no hepatosplenomegaly and no other systemic examination finding was obtained. On laboratory investigations; erythrocyte sedimentation rate was 18 mm/h, C-reactive protein was 3 mg/l (0–6 mg/l), the serum level of calcium was 9.3 mg/dl (8.40– 10.20), phosphorus was 4.8 mg/dl (2.70–4.50) and alkaline phosphatase was 49 IU/L (25–100). Thyroidstimulating hormone, parathyroid hormone, complete blood count and other biochemical tests were at normal levels. Her plain radiographs of thoracic and lumbar spine showed a characteristic finding in many adult autosomal dominant patients the Rugger-Jersey spine appearance caused by thick radiodense accumulations at the superior and inferior vertebral body surfaces with relatively radiolucent areas in between (Fig. 1). Her right tibia plain radiograph showed tibia enlargement and sclerosis (Fig. 2). Pelvis radiograph also showed bone within bone appearance (Fig. 3). Lumbar magnetic resonance imaging showed diffuse sclerotic appearance at vertebral end-plates, L4-L5 spinal stenosis and compression to tecal sac. The patient was diagnosed with autosomal dominant osteopetrosis on the basis of the presence of typical radiological appearance on her imaging studies and history. She was informed about her illness and genetic inheritance and asked that her first degree relatives appeal to our clinic. Seven members of her family (2 sons, 2 daughter, and 3 grandchildren) were investigated. Their all routine laboratory tests (complete blood count, erythrocyte sedimentation rate, C-reactive protein, and biochemical tests) were within normal limits and plain radiographs (skull, pelvis, and lumbosacral vertebrae) were normal. The patient’s sister and brothers were refused to participated any screening test for osteopetrosis. The patient’s and her family genetic analyses were made in Baskent University Genetic Laboratory; Cytogenetic analysis was performed on peripheral blood lymphocyte cultures after an informed consent was obtained from the patient and her family members. Karyotype after GTG banding, at the 450–500 band level was revealed as normal constitutional karyotype [9]. They had undergone formal genetic counseling before the chromosome analysis and post diagnostic counseling after the karyotype results. The pretest genetic counseling included pedigree analysis and they were informed about having a genetic risk for adult variant of osteopetrosis.

A.K. Ozkan et al. / Autosomal dominant osteopetrosis type II


Fig. 3. Diffuse pelvic bone osteosclerosis. (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/BMR140486)

Fig. 2. Tibia enlargement end sclerosis. (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/BMR140486)

3. Discussion ADO usually affects adults but it has also been detected in very young people and early childhood [8]. It is a much more benign condition and, in general, patients have a full-life expectancy [4]. Almost half of the patients diagnosed with this condition are asymptomatic [4,7]. However, when the patients systematically investigated, nearly all have manifestations related to the disorder [7]. Patients with ADO II have frequent orthopedic problems, which include frequent fractures, scoliosis, coxa vara, long-bone bowing, osteomyelitis (frequently mandible), osteoarthritis and fracture malunion [11,12]. The major symptom is pathologic fracture in approximately 40% of patients [4]. Bone pain, especially in the lumbar area, is reported in 25% of patients [4]. Manifestations of neurologic involvement are usually depend on the optic, trigeminal, facial, and auditory nerve compression syndromes affecting 5% of individuals [1,3,4].

Biochemical markers of bone and calcium homeostasis in ADO have previously been described as normal or in favor of increased bone formation [7]. There are no specific hematologic problems in patients with the ADO [4]. Radiologically, ADO is characterized by a generalized, uniform osteosclerosis mainly of the skull, the spine and the long bones [8]. The radiographic features of ADO have often described as heterogeneous [7]. However, authors disclosed two different, family- related, radiographic types. Both types had; universal osteosclerosis, primarily involving the axial skeleton, little or no modeling defects were found in the long bones. The most striking finding in Type I was a marked sclerosis and increased thickness of the cranial vault. Moreover a diffuse osteosclerosis was seen in the spine and pelvis. In Type II, the osteosclerosis was most pronounced at the skull base. The spine showed consistent end-plate thickening (Rugger Jersey spine), and subcristal sclerosing bands (endobones) were always seen in the pelvis [7]. In present case the diagnosis was based on the clinical and radiographic appearances – an approach frequently defended [8]. Our patient had low back pain ongoing for fifteen years. She had no history of fracture, osteomyelitis and cranial nerve involvement. She was diagnosed with ADO II on the basis of the presence of typical radiological appearance. The radiographic findings are compatible with those described in the literature which include: the Rugger-Jersey spine appearance of thoracic and lumbar area, “bone within bone” in pelvis, tibia enlargement and sclerosis. Interestingly, her lateral skull plain radiograph was normal. The Rugger Jersey spine sign is said to be almost diagnostic of the osteosclerosis associated with


A.K. Ozkan et al. / Autosomal dominant osteopetrosis type II

secondary hyperparathyroidism of chronic renal failure [10]. Paget disease, osteoporosis, metastatic lesions, osteomalacia, fluorosis and miyelofibrosis are the diseases that have radiographic appearances that are commonly confused with the Rugger Jersey spine [10]. These conditions should be excluded before the diagnosis of ADO II. Our patient’s serum levels of calcium, alkaline phosphatase, parathyroid hormone, complete blood counting and other biochemical tests were at normal levels, but her serum level of phosphorus was increased. High serum level of phosphorus could not identify with any clinical implication. She had no chronic renal failure. Bone mineral density of patient was not measured due to it has no any additional inform. The existing clinical, radiological and laboratory findings indicated ADO II. The penetrance, the ability to transmit the disease from one generation to the next, seems to be higher in ADO I patients compared with ADO II [7]. The penetrance estimated between 60 or 80% in ADO II, whereas a fully penetrance in ADO I [8]. Cytogenetic analyses of this patient’s and her children were revealed and found normal. This is considerable with respect to our diagnosis and a family with no penetrance. In conclusion, ADO II is a rare genetic condition and asymptomatic and uncomplicated ADO II cases diagnose the incidental imaging finding. Our case presents a number of radiological features of potential diagnostic usefulness and provides information on their pattern in symptomatic cases. Ongoing genetic studies will probably allow identification of the mutation responsible for ADO II.

Acknowledgement We wish to thank radiologist Haydar Kaderoglu M.D, and Selim Eryurek M.D. for contributions to manuscript preparation.

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Steward CG. Neurological aspects of osteopetrosis. Neuropathology and Applied Neurobiology. 2003;29:87-97 [2] Del Fattore A, Cappariello A, Teti A. Genetics, pathogenesis and complications of osteopetrosis. Bone 2008;42(1):19-29. [3] Stark Z, Savarirayan R. Osteopetrosis. Orphanet J Rare Dis.2009(4):5. [4] Shapiro F. Osteopetrosis. Current clinical considerations. Clin Orthop Relat Res 1993;294:34-44. [5] Strickland JP, Berry DJ. Total Joint Arthroplasty in Patients with Osteopetrosis: A Report of 5 Cases and Review of the Literature. J Arthroplasty. 2005 Sep;20(6):815-20. [6] 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 Dec 1;10(25):2861-7. [7] Bollerslev J, Mosekilde L. Autosomal Dominant Osteopetrosis. Clin Orthop Relat Res. 1993 Sep;(294):45-51. [8] Filho AM, de Castro Domingos A, de Freitas DQ, Whaites EJ. Osteopetrosis- review and report of two cases. Oral Dis. 2005 Jan;11(1):46-9. [9] Verma RS, Babu A. Banding techniques. In: Verma RS, Babu A (Eds). Human Chromosomes Principles and Techniques.New York: McGraw-Hill Inc, 1995:72-133. [10] Wittenberg A. The Rugger Jersey Spine Sign. Radiology. 2004 Feb;230(2):491-2. [11] Gupta R, Gupta N. Femoral fractures in osteopetrosis: case reports. J Trauma 2001;51(5):997-9. [12] Benichou OD, Laredo JD, de Vernejoul MC. Type II autosomal dominant osteopetrosis (Albers-Schönberg disease): clinical and radiological manifestations in 42 patients. Bone 2000;26(1):87-93.

Autosomal Dominant Osteopetrosis Type II.

Osteopetrosis is a rare genetic disorder caused by osteoclast failure. Dominant negative mutations of the ClCN7 gene cause the so-called, autosomal do...
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