Osteogenesis Imperfecta

Are You Confident of the Diagnosis?

Osteogenesis imperfecta (OI), a heritable disorder of connective tissue, is characterized by brittle bones, blue sclera, dentinogenesis imperfecta, adult onset deafness and short stature. There is marked clinical and genetic heterogeneity which includes dominant or recessive inheritance and mild, severe or lethal phenotypes.

To-date, eight phenotypes have been accepted as clinically diagnostic of OI, which are inherited in an autosomal dominant (AD) or autosomal recessive (AR) manner:

OI Type Bone Involvement Inheritance

Type I mild AD

Type II perinatal lethal AD

Type III severe, progressive AD

Type IV moderate severity AD

Types I – IV involve mutations affecting the type I collagen

pro-alpha-1 or pro-alpha-2 genes.

Type V mild to moderate severity AD

Type VI moderate to severe AD

Type VII moderate severity AR

Type VIII severe to lethal AR

ï,§ Histologic presence of osteomalacia

• OI genotypes: The mutations involving the following genes are associated with OI:

Collagen type I alpha-chain mutations occur in OI Types I-IV

The gene responsible for type V OI has not been defined.

The gene causing type VI OI is SERPINF1 which encodes pigment epithelium -derived factor.

The following genes have recently been associated with OI types VII and VIII which are recessively inherited: (see Pathophysiology)

CRTAP: cartilage associated protein

LEPRE1: leucine proline-enriched proteoglycan (leprecan) 1

PPIB: peptidylprolyl isomerase B (cyclophilin B)

SERPINH1: serpin peptidase inhibitor (heat shock protein 47)

FKBP165: FK506 binding protein 10: these last two genes encode chaparone proteins

Genetic diagnosis is primarily made by DNA sequencing of the full collagen gene or the other genes as listed above using blood samples. Skin biopsies for fibroblast collagen protein analysis are usually not required.

What you should be alert for in the history

Approximately 40 % of OI patients have a family history of the disorder. Prenatal fractures may occur in-utero and be recognized by uterine ultrasound or at birth; however, fractures may not occur for the first decade. Recurrent fractures should alert the physician to the diagnosis. Evaluation of the patient for OI should focus on the frequency of fractures, low bone mineral density on DEXA scan, pulmonary insufficiency, joint involvement secondary to fracture deformity, signs of craniocervical basilar insufficiency (headache, nystgamus and peripheral neuropathy due to cord compression).

Characteristic findings on physical examination

Mildly affected patients (type I OI) may have no skeletal deformity and are ambulatory. Most patients have blue sclera. Height may vary from short to normal. Fractures heal without deformity. Dentinogenesis imperfecta occurs in 10 %. Hearing loss occurs in young adults. More severely affected patients may be wheelchair-bound, using crutches or braces: fractures lead to bone deformities.

Patients may present with: cranial moulding with triangular facies, sclerae that are white or blue, dentinogenesis imperfecta (occuring in 25% of affected patients), short neck or basilar invagination, variable degrees of short stature more marked in type III OI, upper and lower extremity skeletal deformity with restricted joint function, scoliosis, clinical signs of restrictive pulmonary disease, aortic or mitral valve murmurs, and hyperextensible joints (which occur frequently although to a lesser extent than in the Ehlers-Danlos syndromes).

Dermatologic lesions include: (a) easy bruising which is common and probably due to deficient collagen matrix, (b) normal skin laxity in contrast to the Ehlers Danlos syndromes, (c) broad thin surgical scars, (d) elastosis perforans serpiginosa (EPS) and (e) keloids. The incidence of these dermatologic lesions is not documented.

An evaluation of the mechanical characteristics of OI skin have not demonstrated excessive skin elasticity. Scar formation in OI is highly variable. Hypertropic scar formation, as contrasted with atrophic scars, may cluster in specific families, although a genetic relationship has not been defined.

EPS is uncommon in OI. It also occurs in Ehlers-Danlos syndrome, Marfan syndrome, pseudoxanthoma elasticum, Down syndrome and after penicillamine treatment. Although abnormal elastic fibers associated with dermal perforation are found in EPS, elastin is not a primarily affected in OI.

In EPS, large fragmented elastic tissue fibers, other connective tissue elements, and cellular debris are expelled from the papillary dermis via transepithelial elimination. Tunneling lesions may associate with hair follicles. It is characterized by an eruption of small grouped hyperkeratotic papules in a serpiginous arrangement, the papules composed of parakeratotic material expressed through the dermis. These lesions are frequently found on the face, neck and upper truck although other sites may be involved.

Expected results of diagnostic studies

With respect to histopathology, bone biopsies show decreased trabecular and cortical bone volume with a relative increase in bone osteocytes. Skin biopsy is not diagnostic for OI, however, a biopsy may confirm elastosis perforans serpiginosa. Genetic tests (gene DNA sequencing) will confirm a diagnosis in 98 % of OI patients.

Imaging studies including DEXA bone density measurements confirm bone demineralization as well as variable amounts of bone deformity secondary to fractures. In lethal (type II) or severe OI (types III, VIII) “beading” of the ribs signifies healing intrauterine fractures. Bone modeling defects occur with severe disease: thin or broad bone outlines may be seen. Scoliosis and vertebral compression fractures are common in children and adults. Patients may have had surgical long bone rodding or spine fusion with rods. Severely affected patients may show “pop corn” calcifications at the ends of long bones which are whorls of calcified cartilaginous matrix that obliterate the epiphyseal growth plate.

Diagnosis confirmation

Confirmation is by specific DNA gene sequencing (see above list of currently associated genes).

In children, the differential diagnosis includes:

Thanatophoric dwarfism: short-ribs, tubular bones and macrocephaly; lethal due to mutations in FGF receptor 3.

Hypophosphatasia: Perinatal, infantile, childhood and adult forms. osteoporosis, fractures, dental abnormalities. Low tissue-nonspecific alkaline phosphatase levels.

Juvenile idiopathic osteoporosis: onset around puberty, vertebral fractures at onset, low BMD, resolves after puberty

Celiac disease: May or may not have GI symptoms of malabsorption, osteoporosis. Abnormal gliadin and tissue transglutaminase antibodies.

In adults the differential includes:

Endocrine causes of osteoporosis (hyperthyroid, hyperparathyroid, adrenal hormone excess): serum hormone tests, TSH, PTH, Cortisol confirm the diagnosis

Idiopathic female or male osteoporosis in young adults: Low BMD in a young adult, fractures, no skeletal deformities.

Malabsorption syndromes: celiac disease, pancreatitis,

Malignancy (lymphoma,leukemia, multiple myeloma). pathologic fractures, osteolytic bone lesions, hematologic and immune protein abnormalities.

Who is at Risk for Developing this Disease?

Forty percent of OI cases are new mutations. With an affected parent (dominant inheritance, types I-V) 50 % of offspring will be affected. In recessively inherited disease (types VII and VIII) 25 % of offspring will be affected. Recessive OI involves approximately 3 % of patients.

What is the Cause of the Disease?

OI is a result of a variety of different mutations-point substitutions, mis-sense or non-sense mutations, insertions and deletions involving either the synthesis of type I collagen alpha- chains, or mutations affecting proteins (chaperones) that act to modify collagen pro-alpha chains during intracellular processing. The currently defined seven responsible genes are listed above. These seven genes are responsible for approximately 98% of clinically defined OI cases. 85 % are associated with type I collagen mutations; 3% are associated with genes transmitted as recessive traits.


OI is the result of mutations affecting the synthesis and processing of type I collagen, the major protein in bone and connective tissue. In type I OI (mild), mutations associated with the formation of stop-codons affecting one pro-collagen alpha chain allele causes intracellular degradation of that protein: only the protein synthesized by the normal allele is secreted into extracellular matrix. This “null” allele effect leads to production of ½ normal amounts of type I collagen which is incorporated into extracellular matrix (quantitative defect).

In more severe types II-IV, VII and VIII OI, the pro-collagen product of the abnormal allele is processed intracellularly and secreted into extracellular matrix (qualitative defect) leading to more severe bone involvement. CRTAP, LEPRE1 and cytophyllin B genes combine to hydroxylate proline- 986 in alpha-1 or alpha-2 chains. Mutations in chaperone proteins (e.g. HSP-47) are very uncommon and alter intracellular collagen processing. These mutations are inherited as recessive traits, cause severe or lethal OI phenotypes and account for 3 % of OI cases.

Systemic Implications and Complications

OI is a systemic disorder of connective tissue. Skin lesions, although uncommon except for abnormal scar formation and keloids, reflect the underlying connective tissue disorder. Increased risk of fracture and the frequent need for surgical intervention are the major hazards. With age, accidental trauma becomes the major hazard. Hearing loss may be significant in 1/3 of patients.

Type II (lethal) OI is associated with severe neonatal respiratory insufficiency. Infants usually succumb during the first week of life. Because of progressive scoliosis and thoracic deformity in Type III disease, pulmonary insufficiency remains a hazard throughout life. The risk due to heart disease (mitral and aortic valve insufficiency, mitral valve prolapse, aortic expansion and aortic or peripheral vascular dissection) are hazards that may occur in young adults and increase in incidence with age.

Approximately 25 % of patients have dentinogenesis imperfecta. The severily of this lesion is variable but when severe in children may require capping of primary teeth. Permanent teeth are usually less affected.

Treatment Options

Intravenous administration of the bisphosphonate pamidronate has been the mainstay of treatment for children with OI. In general, administered at a dose varying from 9-12mg/kg/year varying with age. Pamidronate has led to a 50% reduction in fracture rate, an increase in vertebral height and a decrease in generalized musculoskeletal pain. Current discussion is focused on effectiveness at different doses, the lower dose range being used by several programs. Oral bisphosphonates appear less effective in decreasing fracture rate. In adults, bisphosphonates, either IV or orally, has proven less effective in reducing fracture rate).

As in other populations, approximately 50% of OI children and adults are vitamin D insufficient with serum 25(OH) vit. D levels less than 32 ng/ml. OI children and adults should have adequate calcium intake for age. However, hypercalcuria may be present in some children, and some adults with OI may have renal calculi so that urine calcium excretion should be monitored if calcium intake is increase to optimal levels for age.

A variety of therapies have been recently proposed for treating EPS: these include liquid nitrogen cryotherapy, imiquimod, tazarotene, allopurinol and flashlamp pulsed dye laser.

Optimal Therapeutic Approach for this Disease

The decision to initiate treatment with bisphosphonates is based on fracture incidence and bone mineral density if this can be obtained in young children. Guidelines suggest treating children with a total of more than three fractures or two long bone fractures or low bone density for age.

Patient Management

In both in children and adults, management of the OI patient is a team effort involving endocrinologists, orthopedic surgeons, physiatrists and the physical therapy group, dentists, and a pain management group. This team manages pharmacologic treatment, fracture repair and rodding, and physical medicine and rehabilitation. Nutritional assessment may be useful. Involvement by this team is particularly important where patients have been immobilized following orthopedic surgery.

High-risk pregnancy management is important when OI patients are pregnant or when OI is diagnosed by prenatal ultrasound. Rehabilitation therapy is essential to full postsurgical functional recovery. School adjustment is critical for OI children. Social service assistance is frequently required to manage school or work-related issues.

Unusual Clinical Scenarios to Consider in Patient Management

Recent concerns related to bisphosphonate treatment in children and adults with osteoporosis include: osteonecrosis of the jaw and spontaneous femur fractures in adults with age-related osteoporosis and long term bisphosphonate exposure. Osteonecrosis of the jaw has not been reported in children or adults with OI. This lesion occurs mainly in elderly subjects or those with malignancy receiving high dose bisophosphonate and adjuvant chemotherapy Femur fractures like those reported in osteoporosis have not been reported in OI because the doses of bisphosphonate are less and the duration of treatment is usually not as prolonged.

What is the Evidence?

Martin, EN, Shapiro, JR. “Osteogenesis Imperfecta: Epidemiology and Pathophysiology”. Current Osteoporosis Reports. vol. 5. 2007. pp. 91-7. (This is a review of current clinical features and underlying mechanisms involved in this bone disorder.)

Cheung, MS, Glorieux, FH. “Osteogenesis Imperfecta: update on presentation and management”. Rev Endocr Metab Disord. vol. 9. 2008. pp. 153-60. (This paper reviews both clinical aspects and treatment considerations in OI.)

Hansen, B, Jemec, GB. “The mechanical properties of skin in osteogenesis imperfecta”. Arch Dermatol . vol. 138. 2002. pp. 909-11. (This study measures mechanical skin elasticity in OI and reports that is it normal which was not the previously defined.)

Scott, D, Stiris, G. “Osteogenesis imperfecta tarda; a study of 3 families with special reference to scar formation”. Acta Med Scand . vol. 145. 1953. pp. 237-57. (This paper describes differences in scar formation in OI as well as focuses on familial differences that may have a genetic origin.)

Pérez-Pérez, L, Allegue, F, Alfonsín, N, Caeiro, JL, Fabeiro, JM, Zulaica, A. “An uncommon association: elastosis perforans serpiginosa and osteogenesis imperfecta”. J Eur Acad Dermatol Venereol . vol. 23. 2009. pp. 172-84. (Presentation of EPS with a review of its occurrence in OI.)

Reed, W, Pidgeon, J. “Elastosis perforans serpiginosa With osteogenesis imperfecta”. Arch Dermatol. vol. 89. 1964. pp. 342-4. (This early paper discusses EPS in OI patients.)

Castillo, H, Samson-Fang, L. “American Academy for Cerebral Palsy and Developmental Medicine Treatment Outcomes Committee Review Panel. Effects of bisphosphonates in children with osteogenesis imperfecta: an AACPDM systematic review”. Dev Med Child Neurol . vol. 51. 2009. pp. 17-29. (This is a critical review of evidence-based studies related to bisphosphonate effectiveness in decreasing fractures in children.)

Shapiro, JR, Thompson, CB, Wu, Y, Nunes, M, Gillen, C. “Bone mineral density and fracture rate in response to intravenous and oral bisphosphonates in adult osteogenesis imperfecta”. Calcif Tissue Int. vol. 87. 2010. pp. 120-9. (This paper presents data showing that bisphosphonates are widely prescribed in adults, they are not uniformly effective in preventing fractures in OI adults.)

Shapiro, JR; Kantipuly, A; Rowe,, D. “Osteogenesis [mperfecta: current and future treatment”. drugs of the future. vol. 35. 2010. pp. 529-34. (This paper reviews the metabolic basis for OI and reviews current treatment as well as possibilities for future genetic and cell-based treatments.)