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Osteopetrosis Clinical Presentation

  • Author: Robert Blank, MD, PhD; Chief Editor: George T Griffing, MD  more...
 
Updated: Dec 17, 2014
 

History and Physical Examination

Infantile osteopetrosis

Infantile osteopetrosis (also called malignant osteopetrosis) is diagnosed early in life. Failure to thrive and growth retardation are symptoms.

Bony defects and associated symptoms occur, including the following:

  • Nasal stuffiness due to mastoid and paranasal sinus malformation is often the presenting feature of infantile osteopetrosis
  • Neuropathies related to cranial nerve entrapment occur due to failure of the foramina in the skull to widen completely
  • Manifestations include deafness, proptosis, and hydrocephalus.
  • Dentition may be delayed
  • Osteomyelitis of the mandible is common due to an abnormal blood supply
  • Bones are fragile and can fracture easily
  • Defective osseous tissue tends to replace bone marrow, which can cause bone marrow failure with resultant pancytopenia
  • Patients suffer from anemia, easy bruising and bleeding (due to thrombocytopenia), and recurrent infections (due to inherent defects in the immune system)
  • Extramedullary hematopoiesis may occur, with resultant hepatosplenomegaly, hypersplenism, and hemolysis
  • Other manifestations include sleep apnea and blindness due to retinal degeneration

Adult osteopetrosis

Adult osteopetrosis (also called benign osteopetrosis) is diagnosed in late adolescence or adulthood. Two distinct types have been described, type I and type II, on the basis of radiographic, biochemical, and clinical features. (See Table 3, below.)[15]

Table 3. Types of Adult Osteopetrosis (Open Table in a new window)

Characteristic Type I Type II
Skull sclerosis Marked sclerosis mainly of the vault Sclerosis mainly of the base
Spine Does not show much sclerosis Shows the rugger-jersey appearance
Pelvis No endobones Shows endobones in the pelvis
Transverse banding of metaphysis Absent May or may not be present
Risk of fracture Low High
Serum acid phosphatase Normal Very high

Approximately one half of patients are asymptomatic, and the diagnosis is made incidentally; the diagnosis often made in late adolescence, because radiologic abnormalities start appearing only in childhood. In other patients, the diagnosis is based on family history. Still other patients might present with osteomyelitis or fractures.

Many patients have bone pains. Bony defects are common and include neuropathies due to cranial nerve entrapment (eg, with deafness, with facial palsy), carpal tunnel syndrome, and osteoarthritis. Bones are fragile and may fracture easily. Approximately 40% of patients have recurrent fractures. Osteomyelitis of the mandible occurs in 10% of patients.

Other manifestations include visual impairment due to retinal degeneration and psychomotor retardation. Bone marrow function is not compromised.

Physical examination

Physical findings are related to bony defects and include short stature, frontal bossing, a large head, nystagmus, hepatosplenomegaly, and genu valgum in infantile osteopetrosis.

 
 
Contributor Information and Disclosures
Author

Robert Blank, MD, PhD Professor of Medicine, Cell Biology, and Physiology, Chief, Division of Endocrinology, Metabolism, and Clinical Nutrition, Director, TOPS Obesity Center, Medical College of Wisconsin; Staff Physician, Clement J Zablocki Veterans Affairs Medical Center

Robert Blank, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Society of Human Genetics, Central Society for Clinical and Translational Research, International Bone and Mineral Society, International Society for Clinical Densitometry, American College of Physicians, American Society for Bone and Mineral Research, Endocrine Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Bristol-Myers Squibb.

Coauthor(s)

Anuj Bhargava, MD, MBA Adjunct Assistant Professor, Drake College of Pharmacy; Co-Director, Diabetes Institute, Mercy Medical Center; President, Iowa Diabetes and Endocrinology Research Center; President, My Diabetes Home, LLC

Anuj Bhargava, MD, MBA is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association

Disclosure: Received honoraria from Merck for speaking, research trials; Received honoraria from Novo Nordisk for speaking and teaching; Received honoraria from Sanofi for speaking and teaching; Received honoraria from takeda for speaking and teaching; Received honoraria from Abbott for speaking and teaching; Received grant/research funds from Lilly for research trials; Received grant/research funds from Gilead for research trials; Received grant/research funds from Novartis for research trials; Received gr.

Chief Editor

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Acknowledgements

Romesh Khardori, MD, PhD, FACP Former Professor, Department of Medicine, Former Chief, Division of Endocrinology, Metabolism, and Molecular Medicine, Southern Illinois University School of Medicine

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, and Endocrine Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Stanley Wallach, MD Executive Director, American College of Nutrition; Clinical Professor, Department of Medicine, New York University School of Medicine

Stanley Wallach, MD is a member of the following medical societies: American College of Nutrition, American Society for Bone and Mineral Research, American Society for Clinical Investigation, American Society for Clinical Nutrition, American Society for Nutritional Sciences, Association of American Physicians, and Endocrine Society

Disclosure: Nothing to disclose.

References
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Table 1. Clinical Classification of Human Osteopetrosis
Characteristic Adult onset Infantile Intermediate
Inheritance Autosomal dominant[3] Autosomal recessive Autosomal recessive
Bone marrow failure None Severe None
Prognosis Good Poor Poor
Diagnosis Often diagnosed incidentally Usually diagnosed before age 1y Not applicable
Table 2. Molecular Lesions Leading to Osteopetrosis in the Mouse
Gene Protein Lesion Phenotype Human Equivalent Key References
Csf1 M-CSF Naturally occurring op allele (frame shift) Reduced size, short limbs, domed skull, absence of teeth, poor hearing, poor fertility, extramedullary hematopoiesis, rescued by administration of M-CSF None known Yoshida et al, 1990
Csf1r M-CSF receptor Targeted disruption in exon 3 Reduced size, short limbs, domed skull, absence of teeth, poor fertility, extramedullary hematopoiesis, slightly more severe than Csf1opphenotype None known Dai et al, 2002
Tnfsf11 RANKL Targeted disruptions Osteopetrosis, failure of lymph nodes to develop None known Kong et al, 1999; Kim et al, 2000
Tnfrsf11a RANK Targeted disruptions Osteopetrosis, failure of lymph nodes to develop Duplications in exon 1 found in Paget disease and in familial expansile osteolysis Li et al, 2000
Ostm1 Osteopetrosis-associated transmembrane protein 1 Naturally occurring deletion Abnormal coat color, short lifespan, chondrodysplasia, failure of tooth eruption, osteopetrosis Infantile malignant osteopetrosis Chalhoub et al, 2003
Acp5 Tartrate resistant acid phosphatase (acid phosphatase 5) Targeted disruption Chondrodysplasia, osteopetrosis None known Hayman et al, 1996
Car2 Carbonic anhydrase II N -ethyl-N -nitrosourea (ENU) mutagenesis No skeletal phenotype in mouse, renal tubular acidosis, growth retardation Osteopetrosis with renal tubular acidosis Lewis et al, 1988
Clcn7 Chloride channel 7 Targeted disruptions Chondrodysplasia, osteopetrosis, failure of tooth eruption, optic atrophy, retinal degeneration, premature death Autosomal dominant type 2 osteopetrosis, autosomal recessive osteopetrosis Kornak et al, 2001; Cleiren et al, 2001
Ctsk Cathepsin K Targeted disruption Osteopetrosis with increased osteoclast surface Pycnodysostosis Saftig et al, 1998; Kiviranta et al, 2005
Gab2 Grb2 -associated binder 2 Targeted disruption Osteopetrosis, defective osteoclast maturation None known Wada et al, 2005
Mitf Micro-ophthalmia–associated transcription factor Spontaneous mutations, ENU mutagenesis, radiation mutagenesis, targeted disruption, untargeted insertional mutagenesis Pigmentation failure, failure of tooth eruption, osteopetrosis, microphthalmia, infertility in both sexes Waardenburg syndrome, type 2a; Tietz syndrome, ocular albinism with sensorineural deafness Hodgkinson et al, 1993; Steingrimsson et al, 1994
Src c-SRC Targeted disruption Osteopetrosis, failure of tooth eruption, premature death, reduced body size, female infertility, poor nursing None known Soriano et al, 1991
Tcirg1 116-kD subunit of vacuolar proton pump Spontaneous deletion, targeted disruption Osteopetrosis, failure of tooth eruption, chondrodysplasia, small size, premature death Autosomal recessive osteopetrosis Li et al, 1999; Scimeca et al, 2000; Frattini et al, 2000
Traf6 Tumor necrosis factor (TNF)-receptor–associated factor 6 Targeted disruptions Osteopetrosis, failure of tooth eruption, decreased body size, premature death, impaired maturation of dendritic cells None known Naito et al, 1999; Lomaga et al, 1999; Kobayashi et al, 2003
Table 3. Types of Adult Osteopetrosis
Characteristic Type I Type II
Skull sclerosis Marked sclerosis mainly of the vault Sclerosis mainly of the base
Spine Does not show much sclerosis Shows the rugger-jersey appearance
Pelvis No endobones Shows endobones in the pelvis
Transverse banding of metaphysis Absent May or may not be present
Risk of fracture Low High
Serum acid phosphatase Normal Very high
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