The clinical presentation of osteopetrosis somewhat varies depending on the subtype, but bone marrow failure that leads to pancytopenia and compensatory hepatosplenomegaly due to extramedullary hematopoiesis is seen in all patients [6]. Developmental delays, cranial nerve palsies, as well as auditory and visual impairment, are some of the most prominent features. Pyknodysostosis is characterized by deformities of the chest, very short stature, a high arched palate and spinal pathologies including kyphosis and/or scoliosis, whereas a large cranium, persistent patency of the anterior fontanel and separated cranial sutures are prominent features as well [4]. Phosphatasia may be suspected as early as during the perinatal period, when polyhydramnios and intrauterine death occurs without an apparent cause, while symptoms in newborn babies and infants comprise failure to thrive, rachitic-like syndrome and premature loss of deciduous teeth (before age 5) [4]. The onset may be mild with teeth changes being the only symptom, but a more severe clinical presentation may be present as well. In progressive diaphyseal dysplasia, the most common symptoms include fatigue, muscle wasting, disturbances of gait and physical examination reveals very thin limbs and little muscle mass [4] [5]. Additional signs include cranial nerve palsies, hypogonadism, and a prominent forehead. In all conditions causing osteosclerosis, a markedly increased risk for fractures exists and pathological fractures may be the only presenting symptom.

• Anemia

  On admission, the patient had anemia and a high serum alkaline phosphatase level. Lumbar and femoral neck T-scores were +10.5 and +9.6, respectively. His radius 33 % T-score was -2.8. [ncbi.nlm.nih.gov]

  Bony overgrowths may narrow the marrow cavity and cause cytopenias ranging from anemia to pancytopenia. Extramedullary hematopoiesis may occur, resulting in hepatosplenomegaly; consequent hypersplenism may worsen anemia. [merckmanuals.com]

  This report is that of a case of a severe progressive anemia with osteosclerosis. The clinical picture as well as the pathological findings we deem to be of sufficient interest for detailed description. [annals.org]

• Splenectomy

  Some patients require transfusion or splenectomy to treat anemia. This type of osteopetrosis is autosomal recessive, malignant, and congenital, manifesting during infancy. [merckmanuals.com]

  Allogeneic HLA-identical bone marrow transplantation, various forms of surgery, transfusions, splenectomy, corticosteroids and symptomatic measures may be necessary for these patients, but symptomatic and supportive treatment is usually the mainstay, [symptoma.com]

• Pallor

  On physical examination no abnormalities were detected except for pallor of the skin and mucous membranes. Laboratory examination revealed a hemoglobin level of 8.7 gm/100 ml, with normal white blood cell and platelet counts. [jamanetwork.com]

• Failure to Thrive

  It causes weakness, stunted stature, and failure to thrive. Bones appear dense on x-rays, and cerebral calcifications are seen; renal tubular acidosis is present, and red blood cell carbonic anhydrase activity is decreased. [merckmanuals.com]

  Some conditions may present in early infancy, such as hypophosphatasia and osteopetrosis, when failure to thrive, an early loss of deciduous teeth and a prominently enlarged skull may be seen. [symptoma.com]

  Calcium metabolism in idiopathic hypercalcaemia of infancy with failure to thrive. Arch Dis Child. 1955 Oct; 30 (153):399–404. [ PMC free article ] [ PubMed ] BUTLER NR. [ncbi.nlm.nih.gov]

• Nausea

  Symptoms of UCD include the following: changes in behavior feeling annoyed difficulty concentrating feeling confused headaches nausea and vomiting trouble sleeping feeling tired 1 Answer A A urea cycle disorder (UCD) is a problem with how the liver handles [sharecare.com]

  I.D. is a 60-year-old retired driver who presented to the accident and emergency department of University of Benin Teaching Hospital with 1-month history of anorexia, vomiting, facial and leg swelling, nausea, inability to walk and low-urine output. [smjonline.org]

  These sorrel formulations may cause nausea or vomiting when taken with the prescription drugs metronidazole (Flagyl®) or disulfiram (Antabuse®). Avoid if pregnant or breastfeeding. [livingnaturally.com]

• Hepatosplenomegaly

  Extramedullary hematopoiesis may occur, resulting in hepatosplenomegaly; consequent hypersplenism may worsen anemia. The skeleton usually is radiologically normal at birth. [merckmanuals.com]

  Patients can have hepatosplenomegaly and compressive optic neuropathySOST-related sclerosing bone dysplasiasTarget site: intramembranous ossification. Van Buchem disease (VBD); inheritance: AR. [ncbi.nlm.nih.gov]

  The clinical presentation of osteopetrosis somewhat varies depending on the subtype, but bone marrow failure that leads to pancytopenia and compensatory hepatosplenomegaly due to extramedullary hematopoiesis is seen in all patients. [symptoma.com]

• Hypotension

  This reaction may result in chills, headache, backache, chest pain, tachycardia, and hypotension. Rarely, blood products can sometimes be contaminated with bacteria, and there is a chance that a virus may be transmitted to the recipient. [thesourcenatural.com]

• Blue Sclera

  Blue sclerae (due to a deficiency in connective tissue allowing the underlying vessels to show through) are usually recognized during infancy. [merckmanuals.com]

• Bone Disorder

  disorders such as osteopetrosis. [ncbi.nlm.nih.gov]

  Localized osteosclerosis may be caused by a severe injury that compresses the bone, osteoarthritis, chronic osteomyelitis, or an osteoma. Osteosclerosis occurs throughout the body in the inherited bone disorder osteopetrosis. [humpath.com]

  It may accompany a variety of bone disorders such as renal osteodystrophy, Paget´s disease, or oxalosis, among others. In uremic patients, osteosclerosis appears more commonly in the axial skeleton, associated with secondary hyperparathyroidism. [senefro.org]

  (OMIM phenotype number #144750 ) Osteosclerosis/endosteal hyperostosis, autosomal dominant, is a sclerosing bone disorder characterized by generalized skeletal densification, particularly of the cranial vault and tubular long bones without an increased [iofbonehealth.org]

• Osteoporosis

  Seventeen (32%) patients had osteopenia/osteoporosis and 30 (57%) had osteosclerosis. Bone resorption was diminished in patients with osteosclerosis and increased in those with osteopenia/osteoporosis. [ncbi.nlm.nih.gov]

• Small Face

  Affected people resemble each other closely; they have a small face, a receding chin, and carious, misplaced teeth. The cranium bulges, and the anterior fontanelle remains patent. Pathologic fractures are a complication of pyknodysostosis. [merckmanuals.com]

• Cerebral Calcification

  Bones appear dense on x-rays, and cerebral calcifications are seen; renal tubular acidosis is present, and red blood cell carbonic anhydrase activity is decreased. [merckmanuals.com]

  May benefit from HSCTClassical radiographic features of osteopetrosis are presentMilder course where RTA and cerebral calcifications are typical. [ncbi.nlm.nih.gov]

  Similar dysmyelination in Cockayne syndrome is more likely to demonstrate cerebral calcifications, particularly in the basal ganglia. 1, 2, 6, 9 Other entities in the differential diagnosis for diffuse dysmyelination in the absence of gray matter abnormalities [ajnr.org]

The diagnostic workup should include measurements of serum calcium, phosphate, ALP, vitamin D and parathyroid hormone, which are main parameters of bone mineralization and metabolism of calcium. Reduced levels of ALP in the setting of increased bone density and normal PTH/vitamin D levels with either normal or elevated calcium is highly specific for hypophosphatasia [4]. X-rays of the affected limbs, however, is necessary for the diagnosis. Thickening of both cortical and trabecular bones, broadening of diaphyses and metaphysis are some of the most prominent signs of osteopetrosis, while pyknodysostosis may be distinguished on radiography studies by normally shaped long bones, which is not seen in osteopetrosis patients [4]. Additionally, hypoplasia of the facial bones and paranasal sinuses is one of the main features of pyknodysostosis [2]. Patchy progressive endosteal and periosteal formation of new bone is observed along the diaphysis of the affected long bones in progressive diaphyseal dysplasia [4]. Once a valid suspicion toward osteosclerosis is made based on radiographic and biochemical findings, genetic studies to determine the underlying condition should be performed.

• Cytopenia

  Osteosclerosis is a type of osteopetrosis that involves abnormal hardening of bone and increased skeletal density with little disturbance of modeling; in some types, bony encroachment on the marrow cavity causes cytopenias. [merckmanuals.com]

A similar approach to many of the diseases that induce osteosclerosis exists, but certain differences must be noted. Firstly, vitamin D and calcium supplementation in hypophosphatasia patients should be strongly avoided, as they may further aggravate hypercalcemia, but a low-calcium diet, calcitonin, and glucocorticoids are recommended in that setting [4]. Glucocorticoids are also vital constituents of therapy in progressive diaphyseal dysplasia, while recent studies have evaluated the roles of bisphosphonates in these patients [4]. Hypophosphatasia often requires the placement of intramedullary rods to facilitate fracture repair and to prevent further bone trauma [4]. Allogeneic hematopoietic stem cell transplantation (HSCT) is performed osteopetrosis patients with variable success, but supportive therapy to cope with frequent fractures and the quality of life are currently the mainstay in these patients [4] [6].

The prognosis of patients solely depends on the underlying disease. Patients suffering from pyknodysostosis are expected to have a normal lifespan, whereas hypophosphatasia carries a mortality rate of about 50% and a severe onset of symptoms in infancy [4]. Autosomal recessive forms of osteopetrosis are usually fatal in early life, while autosomal dominant forms have a normal life expectancy [6]. Having in mind the fact that there is no cure for virtually all of the conditions that induce osteosclerotic changes, the quality of life can be mildly or severely impaired, but it is important to recognize the pathophysiological changes early on so that the burden of the disease can be reduced through supportive therapy as much as possible.

Osteosclerosis appears in a condition of various etiological mechanism [1] [4] [5] [7]:

• Osteopetrosis - Also known as "marble bone disease", this term encompasses a group of rare genetic disorders of the skeletal system including osteosclerosis is a constitutive finding [6] [8]. There are two main forms: Autosomal dominant (known as Albers-Schönberg disease), characterized by mutations in the CLCN7 gene that encodes a chloride channel vital for the function of osteoclasts; and autosomal recessive, further stratified into classic (mutations of genes coding for vacuolar type H+-ATPases that stabilize proton levels) [9], neuropathic (mutations of osteopetrosis associated transmembrane protein 1 gene - OSTM1 and CLCN7) and osteopetrosis with renal tubular acidosis, in which deficiency of carbonic anhydrase II is the principal cause of abnormal bone density [6] [10].
• Pyknodysostosis - The principal mechanism of in this autosomal recessive disease is the loss of function of genes encoding cathepsin K, a lysosomal metalloproteinase expressed in osteoclasts that play an important role in the degradation of the bone and the bone matrix [4].
• Hypophosphatasia - Although very rare, deficiency of tissue-nonspecific alkaline phosphatase (ALP) and formation of deficient ALP forms may induce osteosclerotic changes by allowing accumulation of one of its substrates, inorganic pyrophosphate, a potent inhibitor of hydroxyapatite formation.
• Camurati-Engelmann disease - Commonly known as progressive diaphyseal dysplasia, this syndrome stems from mutations in genes encoding for transforming growth factor beta (TGF-β1), resulting in thickening of endosteal and periosteal diaphyseal surfaces of long bones (most commonly the femur and tibia).
• Osteopathia striata - A rare disorder of osteoblast differentiation is caused by mutations of the Wnt pathway and may also be responsible for osteosclerosis [11].

In addition to congenital sclerosing disorder, a range of other conditions may trigger such changes in the skeleton. Intramedullary osteosclerosis is a recently introduced term for a syndrome characterized by increased tibial shaft bone density in adult patients and the cause remains unknown [12], while other skeletal-related illnesses include melorheostosis, blastic stage of Paget disease and so-called Overlap syndromes, in which two or more skeletal dysplasias can be present [10]. Additional etiologies are poisoning by fluoride, bisphosphonates or heavy metals, endocrine disorders such as primary or secondary HPT, hypothyroidism or acromegaly, inflammatory diseases involving the skeleton (sclerosing myelitis, sarcoidosis and severe osteomyelitis), but also hematopoietic conditions that target the bone marrow and induce profound changes favoring an increase in bone density, with sickle cell disease and lymphomas being documented as potential causes [1] [7]. A number of cases have also described hepatitis-C associated osteosclerosis (HCAO) [13]. Lastly, metastatic cancers, most notably of the breast and prostate, can also trigger osteosclerotic changes [1].

The incidence rates of autosomal dominant osteopetrosis estimate that the disease will develop in 1 every 20,000 live births, whereas autosomal recessive forms have a much lower rate of occurrence - 1 in 250,000 live births [6]. Severe forms of hypophosphatasia develop in about 1 in 100,000 live births, according to studies conducted in Canada and a strong ethnic predilection toward the local tribal populations was observed, while African American ancestry is considered to be a negative risk factor [4]. Prevalence rates of other osteosclerotic bone diseases are yet to be determined, but the vast majority are quite rarely encountered in medical practice.

Under physiological circumstances, bone mineralization is a complex process regulated mainly by calcium, parathyroid hormone (PTH), vitamin D, calcitonin, phosphorus and several other hormones and cytokines [14]. The initial step is secretion of collagen and ground substance by osteoblasts, followed by the formation of an osteoid and differentiation of osteoblasts into osteocytes, the final step being deposition of hydroxyapatite crystals made of calcium [14]. Bone resorption mediated by osteoclasts occurs simultaneously with this process and a range of mutations and disorders are seen along this pathway. In osteopetrosis, the process of bone resorption and osteoclastic activity is impaired as a result of various genetic mechanisms [3], whereas deficiency of cathepsin K, which is necessary for collagen degradation of osteoclasts, causes a similar effect in pyknodysostosis [10]. Across all diseases, the end-result is an overall increase in bone mass, causing reduced elasticity and an increased risk of fracture [10].

Screening of at-risk individuals with a positive family history may be an effective strategy in recognizing the actual number of cases and thus enable appropriate genetic counselling before pregnancy and conception are planned, but preventive steps currently do not exist.

Osteosclerosis is a clinical sign illustrating an abnormal process of bone resorption and formation, leading to an increased bone mass and its subsequent hardening [1]. This skeletal malformation can be seen in more than 45 conditions [2], with the most notable ones being congenital (osteopetrosis, pyknodysostosis, hypophosphatasia, progressive diaphyseal dysplasia, etc.), endocrine (both primary and secondary hyperparathyroidism, as well as hypothyroidism), inflammatory (osteomyelitis, sarcoidosis, radiation-induced) and hematopoietic illnesses, such as sickle cell disease [1]. Metastatic spread of the breast and prostate into the skeleton may also induce such changes [1], but the exact mechanism somewhat depends on the underlying cause. Genetic mutations seen in osteopetrosis and pyknodysostosis impair the normal activity of osteoclasts, thus impeding the normal process of bone resorption, whereas thickening of long bones due to excessive activity of cytokines (mainly transforming growth factor beta) is the pathophysiological model seen in progressive diaphyseal dysplasia [3] [4]. Across all conditions, however, impaired bone mineralization is the end-result, either because of genetic mutations or inflammatory processes that debilitate this process [2] [5]. Epidemiological studies in terms of osteosclerosis are virtually non-existent, and neither gender nor ethnic predilection has been established in conditions that are known to induce this event. The clinical presentation depends on the disease in which it appears. In osteopetrosis, patients may develop deafness, facial palsy and anemia due to bone marrow failure in the delayed type (known as Albers-Schonberg disease), while spontaneous bruising, abnormal bleeding, bone marrow failure and hepatosplenomegaly are seen in infants suffering from the precocious type [2]. Pyknodysostosis is, on the other hand, characterized by a short stature, short extremities and an enlarged skull with misplaced teeth [2]. Regardless of the underlying event, skeletal changes will be always seen in some form on plain radiography [2] [5]. Increased bone density on X-rays may present as transverse or horizontal bands, endo bones ("bone within a bone"), or profound thickening of virtually any skeletal structure, including the skull, the ribs, vertebrae and all bones situated in the extremities [2] [5]. It is necessary to conduct a thorough laboratory workup and determine the underlying cause of osteosclerosis, as treatment principles may somewhat vary. Allogeneic HLA-identical bone marrow transplantation [4], various forms of surgery, transfusions, splenectomy, corticosteroids and symptomatic measures may be necessary for these patients [2], but symptomatic and supportive treatment is usually the mainstay, as curative therapy currently does not exist for the majority of conditions causing osteosclerosis [6].

Osteosclerosis is a term that describes a pathological increase in overall bone mass, which can occur in genetic, endocrine, inflammatory and malignant diseases. Under physiological circumstances, the bones are constantly being remodeled through two processes - mineralization (deposition of calcium under the effects of osteoblasts, cells that synthesize new bone and promote storage of calcium in the form of hydroxyapatite crystals) and resorption (degradation of bone mediated by specialized cells called osteoclasts). The main role of this dynamic process is to rapidly supply the body with calcium when necessary, but also to ensure optimal bone growth and development. In osteosclerosis, various mutations and pathological causes lead to an increased deposition of calcium (mostly through inactivity of osteoclasts), resulting in an increased bone mass. Numerous mutations lead to osteosclerosis include osteopetrosis (which possesses five subtypes, all caused by genetic mutations), pyknodysostosis, hypophosphatasia, Camurati-Engelmann disease (known as progressive diaphyseal dysplasia) and several other, whereas hyperparathyroidism and hypothyroidism are important endocrine diseases that may induce osteosclerotic changes. Although increased bone mass would unexpectedly provide greater stability to the skeletal system, its normal architecture is severely disturbed and a much higher frequency of fracture in this population is seen. Virtually all bones in the body may be affected, including the skull, the ribs and the long bones of both upper and lower extremities. The clinical presentation, in addition to fractures, may include various cranial nerve palsies (due to the narrowing of the openings in the skull through which cranial nerves pass), growth retardation, short stature and a number of deformities - kyphosis, scoliosis, a high arched palate and rib cage abnormalities. Some conditions may present in early infancy, such as hypophosphatasia and osteopetrosis, when failure to thrive, an early loss of deciduous teeth and a prominently enlarged skull may be seen. Muscle wasting may occur as well, as can disturbances of gait. It is important to mention that excessive bone mass disrupts the activity of the bone marrow and the process of hematopoiesis (production of blood cells) must be conducted with the help of liver and spleen, organs that can produce new blood cells if necessary. Consequently, enlarged liver and spleen (termed hepatomegaly and splenomegaly, respectively) will be a frequent finding. To recognize osteosclerosis as a major feature of illness, it is necessary to perform an X-ray, which will show a marked bony proliferation that is often termed "bone within a bone". Laboratory studies must include serum levels of calcium and phosphorus, parathyroid hormone (PTH), vitamin D, calcitonin and genetic studies if a valid clinical suspicion is made. Treatment of conditions that cause osteosclerosis is mainly supportive, as there is no cure for the mutations responsible for this phenomenon, but stem cell transplantation has been attempted in some individuals suffering from osteopetrosis. The prognosis of patients solely depends on the underlying disease. Some forms of osteopetrosis and hypophosphatasia are frequently fatal in infancy, whereas other conditions, apart from day-to-day impairment, have a normal life expectancy. For this reason, early recognition of the underlying disorder is necessary.

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