Osteogenesis Imperfecta and Bone Marrow Transplant

Pathophysiology of OI

Approximately 90% of cases of OI are caused by dominant mutations in genes COL1A located on chromosome 7q and COL1A2 located on chromosome 17q (Alman & Howard, 2006). More than 200 mutations in these genes exist (Antoniazzi et al., 2000; Monti, 2010; Rauch & Glorieux, 2004). Normally, COL1A and COL1A2 genes code for type I collagen, a major factor in the structure of bones. Type I collagen is also present in ligaments, tendons, dentin, sclera, and skin (Phillipi, Remmington, & Steiner, 2008). Mutations in these 2 genes can be quantitative, meaning a decrease in the amount of type I collagen, or qualitative, signifying an abnormal structure of type I collagen (Alman & Howard, 2006).

In type I OI, the collagen produced is of normal structure; however, the amount of type I collagen produced is significantly less than normal. These cases most often occur when a premature stop codon exists, resulting in half the amount of COL1A1 mRNA (Alman & Howard, 2006; Rauch & Glorieux, 2004). This ultimately leads to decreased collagen production and phenotypically brittle bones. In OI types II, III, and IV, there is usually abnormal collagen resulting from a glycine substitution, which prevents the precursors of collagen from assembling properly, once again leading to weakened bones (Alman & Howard, 2006; Rauch & Glorieux, 2004).

In recent literature, 2 other genes have been noted. One in CRTAP and the second in LEPRE1. Closer examination of these 2 genes suggests that mutations in these genes are associated with more severe and lethal types of OI (Glorieux, 2007; Shapiro & Sponsellor, 2009).

Clinical Features/Classification

Bones that fracture easily is the hallmark clinical feature of OI. Radiographic imaging of the lower extremities often reveals bowed legs. This radiographic finding is characteristic in a person with OI. Other common clinical features include blue sclerae that ranges in intensity; dentinogenesis imperfecta—defined as teeth that are transparent, discolored, fragile, and fracture easily; bone malformations; short stature; and in more severe cases triangular facies (Antoniazzi et al., 2000; Glorieux, 2007). Patients with OI might also develop hearing loss, but this is more common once adulthood is reached (Antoniazzi et al., 2000; Glorieux, 2008). Despite these clinical features, individuals with OI possess a normal intellect (Gloriuex, 2007).

In 1979, David Sillence, MD, developed a classification system for OI that was based on the inheritance pattern, the clinical picture, and the radiologic appearance. He identified 4 different types of OI (Antoniazzi et al., 2000; Glorieux, 2007, 2008; Sillence, Senn, & Danks, 1979). Recent advances in technology, however, have discovered a new inheritance pattern that allows OI to be broken down into even more types (Cabral, 2007; Rauch & Glorieux, 2005). Table 1 summarizes the different types of OI, their clinical features, and the inheritance pattern of each.

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Table 1.

Classification of Osteogenesis Imperfecta

Type	Genetic Mutation	Inheritance	Clinical Findings
I	COLA1—premature stop codon	Autosomal dominant	Bone fragility, little to no limb deformity, shoulder and elbow dislocations frequent, blue sclerae, hearing loss, average or slightly short stature, dentiogenesis imperfecta rare
II	COLA1 or COLA2—glycine substitution	Autosomal dominant	Lethal in perinatal period, most severe form, short limbs, small chest, soft skulls, sclerae dark blue to gray, underdeveloped lungs
III	COLA1 or COLA2—glycine substitution	Autosomal dominant (rarely autosomal recessive)	Most severe in children who survive neonatal period; progressive deforming; frequent fractures; sclerae blue, purple, or gray; hearing loss frequent; stature severely reduced; dentiogenesis imperfecta common
IV	COLA1 or COLA2—glycine substitution	Autosomal dominant	Moderate limb deformity with fracture, sclerae blue in infancy then white, hearing loss less common, moderate to severe short stature, dentiogenesis imperfecta in some
V	Unknown	Autosomal dominant	Moderate severity, similar to OI type IV, radial head dislocation, large hypertrophic calluses on large bones
VI	Unknown	Unknown	Rare, similar to OI type IV with more fractures, characteristic mineralization defect in biopsied bone
VII	Partial expression of CRTAP	Autosomal recessive	Resembles OI type IV or II except that infants have white sclera, moderately short stature
VIII	Mutation in LEPRE1	Autosomal recessive	Severe bone deformity, severe fractures, sclera white, severe short stature

Source: Adapted from Glorieux (2007), Phillipi et al. (2008), and Starr et al. (2010).

Diagnosis

The diagnosis of OI is most often based on medical history, clinical examination, and radiologic findings (Glorieux, 2007; Rauch & Glorieux, 2004; Shapiro & Sponsellor, 2009). Other causes for pathological fractures, including malnutrition, juvenile Paget’s disease, and idiopathic juvenile osteoporosis, must be ruled out (Glorieux, 2008). Furthermore, it is essential that OI be distinguished from child abuse, as often parents of children with OI face charges of abuse (Alman & Howard, 2006; Glorieux, 2008; Mahony, 2000). One clinical distinction to consider is that children with OI lack the bruising with which the victims of child abuse often present.

Diagnosis can also be confirmed by dermal biopsy (Shapiro & Sponsellor, 2009). This test involves culturing the cells of the skin in a medium. The quantity and quality of the collagen is analyzed. Results of this test usually take 6 weeks to 3 months. Although this test may be simple, if used alone, it would miss 13% of individuals with known OI (Hartman, 2005).

DNA sequencing is also used to diagnose OI; however, its main purpose is to identify specifically the genetic mutation in the individual. A blood or skin sample can be used for this test, and it can take as many as 3 months to obtain results (Hartman, 2005).

Prognosis

The lifespan of an individual with OI depends largely on the type of OI he or she has, as well as the number of fractures and degree of deformities (Antoniazzi et al., 2000; Monti et al., 2010). OI does not affect the life expectancy of individuals with mild to moderate manifestations. However, the progressively degenerative type of OI, type III, may decrease life expectancy because these individuals are susceptible to respiratory infection and cardiovascular compromise, in addition to having spinal and thoracic cage deformities (Glorieux, 2007). Today, most individuals with type III OI survive into their late-middle or retirement years. Conversely, type II OI, the most severe form, as well as recessively inherited OI, significantly shorten life expectancy, often causing patients to die within the neonatal period (Glorieux, 2007).

Nonsurgical Management

The goals of nonsurgical management in patients with OI are to enhance motor development, improve muscle strength, increase joint range of motion, and prevent and treat fractures (Engelbert, van der Graaf, van Empelen, Beemer, & Helders, 1997; Glorieux, 2008). Physical therapy should be initiated as soon as an infant exhibits muscle weakness or a delay in motor skills when compared with other children of its age. After fractures or surgeries, the physical therapy often has to be intensified so that the individuals can relearn tasks and regain strength (Glorieux, 2007).

Surgery

Surgery for children with OI is indicated in the management of fractures, as well as in the correction of bone deformities. The more severe the OI, the more likely that surgical intervention will be necessary. Most often, surgery involves the use of rods to correct the bowing of the lower extremities (Antoniazzi et al., 2000; Monti et al., 2010). Rods can be telescopic, which lengthen during growth, or nontelescopic, which do not lengthen during growth. These rods allow for increased weight-bearing ability and ultimately result in greater independence (Antoniazzi et al., 2000; Glorieux, 2007). If a patient does have rods surgically implanted, the individual should undergo physical therapy in an effort to prevent contractures (Engelbert et al., 1997).

Bisphosphonates

Bisphosphonates are the standard pharmacologic treatment for OI. The goal of bisphosphonate therapy is to increase bone mineral density and thereby decrease the incidence of fractures and improve the function of people with OI (Glorieux, 2008; Phillipi et al., 2008). It is theorized that bisphosphonates inactivate osteoclasts either by disrupting osteoclast formation or by causing apoptosis of osteoclasts. Inactivating osteoclasts, in turn, prevents bones from breaking down. There are multiple types of bisphosphonates, including pamidronate. These medications can be taken orally or administered intravenously (IV). A recent Cochrane review examined bisphosphonate therapy in individuals with OI and concluded that there is a “significant improvement in BMD in individuals affected with OI when treated with either oral or IV bisphosphonate” (Phillipi et al., 2008). Questions that remain in the use of bisphosphonate therapy include the following: Are bisphosphates as safe in children as they are in adults? What is the optimal dose, administration method, and length of therapy? (Phillipi et al., 2008)

Parental Interaction

The family of a child with OI has been facing this chronic disease since the birth of the child. In a study that examined the psychosocial aspects of having a child with OI, parents verbalized their frustration that health care professionals ‘limited experience with the disease led to misunderstandings. Parents often felt that they were ignored and that no one “took them seriously” (Claesson & Brodin, 2002).

It is essential that nurses be patient and listen to the parents about handling their child safely as they are already experts in the child’s care (Silverwood, 2001). For example, daily weights are often key in the clinical assessment of a patient receiving a bone marrow transplant. Placing a child with OI on the scale each morning may require more time and a more careful transfer to the scale. Parents play an essential role in obtaining the weight without causing harm to the patient.

Physical Assessment

Children with OI are usually short in stature and appear to be younger than they are. It is important to remember that although their stature is affected, individuals with OI have normal intelligence and should not be spoken to as if they are younger (Silverwood, 2001). In addition, these children may also have many physical deformities requiring sensitivity and care.

Children with OI also might have metabolic issues, particularly increased serum thyroxine levels, which translates into hyperthyroidism. He or she may have increased sweating, heat intolerance, increased baseline body temperature, and increased resting tachycardia and tachypnea (Carroll, 2010). A nurse must become familiar with the baseline of each patient.

As mentioned earlier, often children with OI have surgical rods implanted in their long bones. The nurse must be aware of where these rods are implanted and should always assess the areas for signs and symptoms of infection. Furthermore, because these rods are often made of metal, they can interfere with magnetic resonance imaging, computerized tomography scans, or other radiologic procedures (Hartman, 2005).

Handling

The child, at any age, must be handled with care. Movements should be slow and gentle (Hartman, 2005; Silverwood, 2001). In addition, the nurse should avoid pushing, pulling, twisting, or lifting an infant or child by any extremity (Starr et al., 2010). During transplant, diapered children must be changed frequently to prevent skin breakdown. At the time of these diaper changes, nurses should lift the infant from underneath the buttocks and not from the legs or ankles (Hartman, 2005; Starr et al., 2010). Babies with OI are at increased risk for head flattening, so the use of soft rolled sheets to support them in different positions is necessary (Hartman, 2005; Silverwood, 2001). When the infant or baby is being bathed, the tub should be padded with towels to prevent injury (Werner et al., 1981). Their toys should be soft and easy to handle (Silverwood, 2001). Older children are often very independent in their mobility, and the nurse must find a balance between helping individuals and not completely taking away their independence.

Blood Pressure

Most of the blood pressure cuffs in hospitals today are automatic. Blood pressure in a patient with OI should be taken with a manual cuff (Hartman, 2005). Automatic cuffs have the potential to hyperinflate and could cause a fracture in a patient with OI. If a child has had multiple fractures in one arm, the blood pressure should be taken in the opposite arm. The appropriate cuff size should be used in view of their small stature (Hartman, 2005).

Respiratory Infections

Children with OI are prone to respiratory infections due to scoliosis, chest malformations, and short stature (Hartman, 2005). It is essential that the nurse closely monitor the respiratory status, including oxygen saturation (Antoniazzi et al., 2000). Giving abalative therapy makes these individuals immunocompromised in addition to their preexisting risk of infection. Nurses must identify the early stages of respiratory illness/failure and report the findings to the medical team.

Dental Hygiene

When a patient undergoes a bone marrow transplant, good mouth care is required on a routine basis to reduce the risk of mucositis and infection. Good dental care is imperative is children with OI (Werner et al., 1981). However, in these individuals, it must be done with care as teeth are fragile.

Pain

The pain in a child with OI is often undertreated (Hartman, 2005; Starr et al., 2010). Children with OI do not have less pain than children without OI. Their pain should be assessed often, and appropriate pain medication should be prescribed and administered.

Intravenous Insertion, Cardiopulmonary Resuscitation, and Intubation

The skin of an individual with OI is soft and fragile due to the abnormal collagen production. Veins can also be small and fragile, and children can bruise more easily. Nurses should ask the patient or parents what techniques for intravenous insertion have worked best in the past. A tourniquet should only be used if necessary; if used, nurses should minimize the amount of time that it is on (Hartman, 2005).

Cardiopulmonary resuscitation (CPR) and intubation can be performed on a patient with OI. Their OI should not prevent these emergency interventions if they are medically necessary. Most likely the CPR will lead to the fracture of ribs; however, the depth and force of compressions should be whatever is needed to be effective. Despite their short stature, their age should be used to determine the compression-to-breath ratio (Hartman, 2005).

Intubation can be challenging in patients with OI because of the coexistence of scoliosis, teeth that break easily, neck malformation, and joint laxity. The endotracheal tube should coordinate with the head size of the individual, and care should be taken not to hyperextend the neck when intubating (Hartman, 2005).

Patient/Family Education

Not only do nurses have to educate themselves on emerging transplant populations, but must also educate patients and their families about bone marrow transplant. The family has already been dealing with a child’s chronic disease throughout his or her lifetime, and although they are experts in the child’s care, they are unfamiliar with what a bone marrow transplant entails. Nurses will have to educate the parents on the various chemotherapy agents and their side effects. They will have to teach the families about bone marrow suppression and the need for possible transfusions. Furthermore, a parent will be unfamiliar with a central line and the daily rules that exist in the transplant setting, including diet restrictions, daily bathing, and hand washing.

The amount of new information will be taxing and can potentially create even more stress as another dimension is added to their child’s already complex care. It is essential that the nurses provide the family with support and identify resources that may help the family cope (Claesson & Brodin, 2002).