[There are more than a dozen different genes in which mutations can cause osteogenesis imperfecta.]

Four types of osteogenesis imperfecta? How are they genetically transmitted?

The four types of osteogenesis imperfecta are type I (mild), type II (perinatal, lethal), type III (progressive, deforming), and type IV (deforming with normal scleras). All forms of osteogenesis imperfecta are characterized by increased susceptibility to fractures (“brittle bones”), but there is considerable phenotypic heterogeneity, even within individual subtypes.

Approximately one fourth of the cases of type I or type IV osteogenesis imperfecta represent new mutations; in the remainder, the history and examination of other family members reveal findings consistent with autosomal dominant inheritance. Type III is also transmitted as an autosomal dominant trait, although type III can occasionally be transmitted in an autosomal recessive manner. Type II, the most severe form, generally occurs as a result of a sporadic dominant mutation.


C. Further workup results in a diagnosis of type I osteogenesis imperfecta. What clinical features may the boy expect in adult life?

In patients with type I osteogenesis imperfecta, the fracture incidence decreases after puberty and the main features in adult life are mild short stature, conductive hearing loss, and occasionally dentinogenesis imperfecta (defective dentin formation in tooth development).

D. What is the pathogenesis of this patient’s disease?

Advances in the last two decades demonstrate two genetically different groups: the “classical” group, in which more than 90% of cases are caused by a mutation of the COL1A1 or COL1A2 genes, which encode the subunits of type I collagen, proα1(I) and proα2(I), respectively, and a newer group, caused by loss-of-function mutations in proteins required for proper folding, processing, and secretion of collagen. The fundamental defect in most individuals with type I osteogenesis imperfecta is reduced synthesis of type I collagen resulting from loss-of-function mutations in COL1A1. Several potential molecular defects are responsible for COL1A1 mutations in type I osteogenesis imperfecta, including alterations in a regulatory region leading to reduced transcription, splicing abnormalities leading to reduced steady-state levels of RNA, and deletion of the entire COL1A1 gene. However, in many cases, the underlying defect is a single base pair change that creates a premature stop codon (also known as a “nonsense mutation”) in an internal exon. In a process referred to as “nonsense-mediated decay,” partially synthesized mRNA precursors that carry the nonsense codon are recognized and degraded by the cell. Each of these mutations gives rise to greatly reduced (partial loss-of-function) or no (complete loss-of-function) mRNA. Because the nonmutant COL1A1 allele continues to produce mRNA at a normal rate (ie, there is no dosage compensation), heterozygosity for a complete loss-of-function mutation results in a 50% reduction in the total rate of proα1(I) mRNA synthesis, whereas heterozygosity for a partial loss-of-function mutation results in a less severe reduction. A reduced concentration of pro1(I) chains limits the production of type I procollagen, leading to both a reduced amount of structurally normal type I collagen and an excess of unassembled proα2(I) chains, which are degraded inside the cell. This ultimately results in fragile bones.


Osteogenesis imperfecta is a condition inherited in mendelian fashion. It is a heterogeneous and pleiotropic group of disorders characterized by a tendency toward fragility of bone. Advances in the last two decades demonstrate two genetically different groups: the “classical” group, in which more than 90% of cases are caused by a mutation of the COL1A1 or COL1A2genes, which encode the subunits of type I collagen, proα1(I) and proα2(I), respectively, and a newer group, caused by loss-of-function mutations in proteins required for proper folding, processing, and secretion of collagen.

More than 100 different mutant alleles have been described for osteogenesis imperfecta; the relationships between different DNA sequence alterations and the type of disease (genotype-phenotype correlations) illustrate several pathophysiologic principles in human genetics.



Type II osteogenesis imperfecta presents at birth (or even in utero) with multiple fractures and bony deformities, resulting in death in infancy and, therefore, not likely to be seen in a child 4 years of age. Type III presents at birth or in early infancy with multiple fractures—often prenatal—and progressive bony deformities. The absence of prenatal fractures and early deformities in this patient’s history is most suggestive of type I or type IV osteogenesis imperfecta. These individuals generally present in early childhood with one or a few fractures of long bones in response to minimal or no trauma, as seen in this case. Type I and type IV osteogenesis imperfecta are differentiated by their clinical severity and scleral hue. Type I tends to be less severe, with 10–20 fractures during childhood plus short stature but few or no deformities. These patients tend to have blue scleras. Patients with type IV osteogenesis imperfecta tend to have more fractures, resulting in significant short stature and mild to moderate deformities. Their scleras are normal or gray.


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Physical Exam


Laboratory Tests



Essentail Criteria to Establish Diagnosis



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A 19-year-old woman is evaluated by her primary care physician for recurrent long bone fractures. She has fractured her femur twice and her humerus three times. She has not had an abnormal number of falls and reports also having easy bruising. Aside from these repeated orthopedic injuries, she is otherwise healthy. Physical examination shows mildly disfigured bones, small, amber-yellowish teeth, and bluish-colored sclera. Osteogenesis imperfecta is suspected. Which of the following statements is true regarding this condition?

A. A mutation in type 1 procollagen likely is present in this patient.


Bone biopsy is needed for definitive diagnosis.


Bisphosphonates have shown long-term success in preventing long bone fractures in this condition.


Fractures in females tend to increase after puberty.


Increased bone mineral density may be demonstrated on x-ray absorptiometry.



The answer is A. Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue in which there is a severe decrease of bone mass that makes bone brittle and prone to fracture due to a deficiency or abnormality in type I procollagen. The disease is often inherited in an autosomal dominant fashion. There are several subtypes of OI that are currently based on the clinical phenotype of the disease. There is debate about whether the disease should be reclassified based on genetic abnormalities, but at present, the classification based on clinical presentation remains the standard. Type 1 OI has a varied clinical presentation, but generally has the mildest bone disease with minimal or no apparent skeletal deformities. The disease may not present until adulthood in those with type 1 OI. However, type 2 OI produces very brittle bones and typically is lethal in utero or shortly after birth. Other types of OI have variable bone disease that can yield bone deformity with frequent fractures or kyphoscoliosis or result in only mild disease. Another common clinical feature of type 1 OI includes blue sclera, which is thought to be due to the thinness of the collagen fibers of the sclerae, allowing the choroid layers to be seen. Additionally, the teeth may have an amber or yellowish brown color due to a deficiency of dentin that is rich in type I collagen. The deciduous teeth are often smaller than normal, whereas the permanent teeth may be bell-shaped and restricted at the base. Hearing loss is common beginning in the second decade of life and affects >50% of individuals over the age of 30. Fractures tend to decrease after puberty in both sexes but may increase in women at the time of pregnancy and after menopause. Diagnosis of OI is usually based on clinical criteria in an individual with fractures and other typical clinical features. Given the autosomal dominant nature of inheritance, a family history of disease may be present. Decreased bone mineral density is demonstrated in a variety of imaging techniques including x-ray absorptiometry and plain radiographs. Bone biopsy is not required for diagnosis and may cause morbidity. Treatment of the disease is primarily aimed at treating complications. Fractures typically are only slightly displaced with little soft tissue swelling. Minimal support and traction are required. Although bisphosphonates are well tolerated and often used for moderate to severe disease, where they may decrease bony pain and fracture risk, their long-term effects and safety in osteogenesis imperfecta are unknown.

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Question 1 of 1

A severe form of osteogenesis imperfecta (OI) was noted, in which newborn infants have extremely deformed limbs and chest, causing them to die shortly after birth because their chest wall was not adequate for respiration. This “type II” severe form was initially thought to be autosomal recessive, but was later shown to involve mutations in type I collagen like other forms of OI. Collagen is a fibrous protein consisting of three peptide chains entwined in a triple helix, formed by a repeating amino acid motif (where X or Y can be any amino acid). Which of the following shows that the repeating 3-amino acid motif is most compatible with collagen triple helix formation and the mutation most likely to cause severe OI?





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