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Osteogenesis Imperfecta Background

Descriptions of osteogenesis imperfecta (OI) date back to Egypt from 1000 BC, when a mummy was characterized as having a wormian skull bone, amber-colored teeth, and bowed legs [1]. Olaus Jakob Ekman provided the first scientific description of OI in 1788; however, the first use of the phrase “osteogenesis imperfecta” to describe the condition was by Willem Vrolik in 1849 [1, 2]. Since then, numerous other names have been used to describe OI: mollities ossium, fragilitas ossium, osteopsathyrosis idiopathica, osteoporosis fetalis, osteomalacia congenital, Lobstein’s disease, Vrolik’s disease, Eddome syndrome, and van der Hoeve syndrome [1, 3].

Genetics

OI is characterized as a heterogeneous group of inherited disorders caused by mutations in genes that code for type I procollagen (COL1A1 and COL1A2) [1]. These genes are found on chromosomes 7 and 17, respectively [4], and 286 mutations of type I collagen have already been described [3]. The mutations of type I procollagen account for approximately 90 % of all cases of OI [2] with the majority of these cases inherited in an autosomal dominant fashion or caused by a sporadic mutation [4]. More recently, research has identified eight other genes associated with a portion of the remaining 10 % of OI cases. These are autosomal recessive in inheritance and all but two affect type I collagen by encoding proteins involved in the biosynthesis of type I procollagen. Cartilage-associated protein (CRTAP), LEPRE, PPIB, SERPINH1, and FKBP10 indirectly alter type I collagen synthesis, while SP7, and SERPINF1 do not [2].

Classification/Characterization

Multiple classification systems have been devised to characterize the varying degrees of phenotypic penetrance displayed by OI. Initially categorized by Looser in 1906 as whether fractures were present at birth (congenital) or after birth (tarda), Seedorff expanded on this in 1949 to include fractures within the first year of life (tarda gravis) or after the first year of life (tarda levis) [3]. In 1985, Frederic Shapiro further divided the congenital and tarda into type A and B depending on the timing of initial fracture and the radiographic appearance of the bones at initial fracture. Congenita A is classified as in utero/at birth with crumpled femurs and ribs and congenita B has normal bone contour. Tarda A is classified as fractures before walking age and tarda B is fractures after walking age [3]. The classification system of Sillence, from 1979, is still the most widely used system and was initially broken up into four types. Type I is the mildest form, is autosomal dominant and is broken up into type A (without dentinogenesis imperfecta) and type B (with dentinogenesis imperfecta). Patients will have blue sclera and a normal life expectancy. Type II is inherited in an autosomal recessive pattern and is lethal (primarily from respiratory failure, intracranial hemorrhage, or brainstem compression). Type III is a severe, autosomal dominant or recessive inheritance, and typically presents with normal sclerae and fractures around birth that can result in progressive deformity. Type IV is of intermediate severity, has an autosomal dominant inheritance, and has significant phenotypic variation [1, 3]. The initial Sillence classification system has since been expanded to include patients who do not have a collagen mutation. Type V is autosomal dominant, has hypertrophic callus development after fracture, and can have calcification of the interosseous membranes that can limit pronation and supination and lead to radial head dislocation. Type VI is autosomal recessive, has moderate to severe skeletal deformity and fractures and does not respond as well to bisphosphonate therapy. Type VII is autosomal recessive and has moderate to severe skeletal deformity that includes coax vara and rhizomelic limb shortening [3, 5].

Management

Operative and non-operative/medical management of OI is for symptomatic treatment only and is not curative and includes a multidisciplinary team effort to improve function, minimize disability, and maximize mobility status and quality of life [1]. Various different systemic medical therapy strategies have been attempted and include calcitonin, sodium fluoride, calcium anabolic steroids, growth hormone, magnesium oxide, vitamin C, and vitamin D, all of which have had mixed results [1]. Bisphosphonates are the only medical management option for OI that has been shown to have a beneficial effect and is now considered the standard of care [4, 5]. The nitrogen-containing bisphosphonates inhibits protein prenylation and guanosine triphosphatase formation, which results in osteoclast apoptosis [3], and this ultimately results in increased cortical thickness and bone mineral density [4]. In addition to this, decreased chronic bone pain, improved ambulation scores, decreased fracture rates, increased vertebral height, and improved grip strength (with pamidronate therapy) have also been seen in the initial 6 weeks after bisphosphonate therapy [3, 4]. Cyclical intravenous pamidronate and zoledronic acid are the bisphosphonates most frequently used in patients with OI and is limited to a few years due to the unknown long-term effects of bisphosphonates [3–5]. Osteonecrosis of the jaw is associated with bisphosphonate therapy, however, no reports of OI patients have been identified and the risk of this in OI patients is currently unknown [3].

Bone marrow transplantation is another treatment option that has so far not proven to be beneficial and requires more research to determine its true efficacy. Gene therapy and stem cell therapy are other areas of research that could be beneficial for OI patients but have yet been thoroughly investigated [3, 5].

Surgical principles and goals are designed to restore the normal bone axis by correcting deformity, minimize the incidence of fracture, avoid bone bowing, and use gentle technique to preserve muscle and minimize soft tissue injury [1, 3, 4]. Plates and screws are rarely indicated for fractures in OI patients, and the standard is use of an intramedullary device. Osteotomies are also used in conjunction with internal fixation to correct significant deformity. Multiple different rod systems have been proposed for use including double Rush rods, Bailey–Dubow and Sheffield rods, and Fassier–Duval telescoping nail with the overlying theme of selecting the largest diameter rod that will pass through the medullary canal at its narrowest point [3, 4]. The Fassier–Duval nail allows a minimally invasive technique to be used, can be used on multiple long bones during the same surgical setting, and thus far has had a lower revision rate [4].

Humeral intramedullary rods with either Rush rods or Fassier–Duval nails require the device to not impinge in the shoulder, and the patient to have full range of motion at the end of the procedure. Forearm deformity can be corrected with ulnar intramedullary wires and radial osteotomy and intramedullary fixation with the latter being much more technically challenging [4].

Marfan Syndrome

Background

Antoine Marfan, a French pediatrician, first described the skeletal characteristics of Marfan syndrome in 1896 in a 5-year-old girl who presented a tall stature and slender digits; however, this was more likely a presentation of congenital contractural arachnodactyly [6]. Marfan further characterized features of Marfan syndrome including ectopia lentis and mitral valve disease. Ultimately, it was Victor McKusick who stated that Marfan syndrome was a connective tissue disorder that encompassed abnormalities of the cardiovascular (including aortic dissections and aortic valve pathology), ocular, and skeletal systems [6].

Genetics

Harry Dietz discovered the genetic cause of Marfan syndrome in 1991 when he reported that a mutation in genes that code for fibrillin-1, an extracellular matrix protein, leads to classic Marfan syndrome, which is characterized as a clinically and phenotypically variable inherited disorder [6, 7]. Approximately 25 % of cases are thought to be from de novo mutations, primarily in genes for fibrillin-1, and the remaining cases are inherited in an autosomal dominant fashion [6]. FBN-1 gene, found on chromosome 15q21.1, is the only gene known to cause classic Marfan syndrome when mutated and is present in over 90 % of Marfan syndrome patients [6, 7].

Fibrillin-1 also interacts with transforming growth factor (TGF)-β, a cytokine that influences cell proliferation, differentiation, extracellular matrix formation, cell-cycle arrest, and apoptosis. Mutations in fibrillin-1 can lead to abnormal signaling pathways via this interaction. Mutations in TGFβR1, on chromosome 9, and TGFβR2, on chromosome 3, also alter the TGF-β signaling pathway. Mutations in TGFβR2 have been identified in patients diagnosed with Marfan syndrome (termed Marfan syndrome type II), yet these patients did not have characteristic findings of Marfan syndrome. Loeys–Dietz syndrome, which has many features similar to and unique from Marfan syndrome, is characterized by mutations in either TGFβR1 or TGFβR2 [6, 7]. Dietz states that patients with mutations in TGFβR1 and TGFβR2 tend to have a more aggressive vascular disease and risk of vessel rupture than patients with classic Marfan syndrome, and due to this Loeys–Dietz syndrome, rather than Marfan syndrome type II, in order to further individualize care, counseling, and management [7].

Multiple related disorders are also caused by mutations in the FBN-1 gene and TGF-β signaling pathway including mitral valve prolapse syndrome, MASS phenotype (Mitral valve prolapse, Aortic enlargement, Skin, and Skeletal features), Familial ectopia lentis, Shprintzen–Goldberg syndrome, Weill–Marchesani syndrome, Stiff skin syndrome (TB4 of FBN-1), geleophysic dysplasia (ADAMTSL2), acromicric dysplasia (TB5 of FBN-1), Loeys–Dietz syndrome (TGFβR1 and 2), Loeys–Dietz like syndrome (SMAD3), Myhre syndrome (SMAD4), and isolated skeletal or cardiovascular features of Marfan syndrome [6–8].

Classification/Diagnosis

The typical description of a patient with Marfan syndrome to make a clinician suspicious is a patient who is thin, tall, has long slender limbs (dolichostenomelia), arachnodactyly (long, thin, hyperextensible fingers), a pectus deformity, and scoliosis [6, 9]. The Ghent nosology, a revision from the Berlin criteria, is a stricter set of diagnostic criteria including family history, personal medical history, physical exam, slit lamp evaluation, and echocardiography, used to assist in the diagnosis and treatment of Marfan syndrome [6–8]. The nosology assesses seven systems (skeletal, ocular, cardiovascular, pulmonary, skin and integument, dura, and family history) and has major (uncommon in other diseases) and minor criteria. To consider the skeletal system involved, a patient must have at least two major criteria or one major criterion and two minor criteria. Major criteria include pectus carinatum, pectus excavatum requiring surgery, scoliosis >20° or spondylolisthesis, medial displacement of the medial malleolus causing pes planus, protrusio acetabuli, reduced upper-to-lower segment ratio or arm span-to-height ratio >1.05, positive wrist and thumb signs, and reduced extension at the elbows (<170°). A minor criterion is joint hypermobility/laxity, which can lead to contractures, particularly of the fingers and elbows [6]. While it has been shown that patients with Marfan syndrome have a decreased bone mineral density, there is no difference in their risk for fracture [6].

The wrist and thumb signs are used to evaluate arachnodactyly. The wrist sign/test (aka Walker–Murdoch) is positive when the patient wraps their fingers around their contralateral wrist and their thumb overlaps the distal phalanx of their small finger. The thumb sign/test is positive when the patient grips their thumb in their palm and the entire nail of the thumb projects beyond the ulnar border of the hand [6–9].

Management

Treatment options for patients with Marfan syndrome require a multidisciplinary team effort including geneticist, cardiologist and cardiothoracic surgeons, ophthalmologist, and an orthopedist [7]. The upper extremity manifestations usually require no treatment unless contractures become symptomatic after which time, conservative management may be initiated [10]. This includes physical therapy and bracing for elbow and finger contractures. The hyperlaxity seen in Marfan patients typically requires no treatment; however, it may predispose them to easier dislocation. In certain circumstances, capsular reconstruction has been required to reduce pain and restore function [11]. Ultimately, it is the responsibility of all providers to ensure that appropriate referrals have been made to the aforementioned specialists if there is any clinical suspicion for Marfan syndrome.

Achondroplasia

Background

Disproportionate short stature, macrocephaly, depressed nasal bridge, foramen magnum stenosis, thoracolumbar kyphosis, spinal stenosis, prominent buttocks, protuberant abdomen, genu varum, possible radial head dislocation, and trident hands characterize achondroplasia. Jules Parrot first used the term achondroplasia, which means “without cartilage formation,” in 1878 to help distinguish patients with achondroplasia (disproportionate short stature) from patients with rickets (proportionate short stature), although it was the art from Egypt, Greece, and Rome that first depicted examples of achondroplastic patients [12–14].

Genetics

Achondroplasia is inherited in an autosomal dominant fashion and is part of a spectrum of disorders caused by different mutations in the genes encoding fibroblast growth factor receptor 3 (FGFR3). This gene is found on chromosome 4p16.3 and this receptor is expressed in articular chondrocytes [15]. Other disorders caused by FGFR3 mutations include hypochondroplasia, severe achondroplasia with developmental delay and acanthosis nigricans, and two types of thanatophoric dysplasia [13]. Approximately 80 % of cases are due to sporadic mutations and increased paternal age has been associated with an increased risk of new mutation [14, 15].

Classification/Characterization

Most features of achondroplasia can be traced back to the effect of increased FGFR3 signaling on endochondral bone growth [13]. These features are quite distinct, can present at different stages of life, and are typically recognized clinically or radiographically rather than via DNA analysis; however, approximately 20 % of patients go unrecognized at birth [12–14]. Third trimester prenatal ultrasound can identify short limbs in the 3rd percentile or less, head circumference greater than the 95th percentile, and a low nasal bridge [12, 14, 15]. At birth, short stature, rhizomelic limb shortening, and characteristic facial features (frontal bossing, midface hypoplasia) are evident. In addition, certain joints may be hypermobile, primarily the knees and hands, yet contractures of the elbows and hips can also be present [12–15]. In infancy, patients have normal mental development, although motor development is typically delayed secondary to muscular hypotonia. Apnea symptoms from foramen magnum stenosis and thoracolumbar kyphosis become more evident as the individual grows [12, 14, 15].

In the upper extremity, the rhizomelic shortening is the result of short humeri with the fingertips only able to reach the top of the greater trochanters and consequently, individuals may be unable to reach the top of their head [14, 15]. An elbow flexion contracture can also develop and is secondary to a flexion deformity of the distal humerus. Elbow deformities may also include radial head subluxation or dislocation [14]. The hands have equal length metacarpals and digits and have extra space between the third and fourth rays. This creates three groups of digits (thumb, index and long, and ring and small) and gives the hand a trident appearance [14, 15].

Management

A multidisciplinary team should be involved in the care of any patient with achondroplasia to improve function and positively affect their quality of life and should include but not be limited to pediatricians, pediatric and adult orthopedic surgeons (including spine surgeons), otolaryngologists, endocrinologists, and dentists. Operative and non-operative/medical management of achondroplasia is used primarily for symptomatic or cosmetic reasons. Human growth hormone has been trialed for achondroplastic children. While there is some improvement in growth rate and height, long-term follow-up results show no real benefit and it is not currently recommended worldwide for treatment of achondroplasia [12–15]. Other medical therapies that are being investigated include the use of parathyroid hormone and C-type natriuretic peptide. These could activate signaling pathways that could counteract the excessive FGFR3 signals in physes [13–15]. Physical therapy has also been suggested to assist with flexion contractures, but in general, elbow contractures and radial head subluxation/dislocations do not require any intervention since there is no functional loss [12–14].

Elective surgical limb lengthening has been used to address the short status of achondroplasia patients who average between 112 and 145 cm in height, which corresponds to 6–7 standard deviations below the average of an unaffected adult [12–15]. This process is extremely time-consuming and is still controversial. While it may have significant social and emotional effects, there is little evidence to support any functional benefit. Most of the discussion surrounding surgical limb lengthening is in reference to lower extremity lengthening. This is partially due to the fact that upper extremity length discrepancies are less common and better tolerated than lower extremity discrepancies [16]. On the other hand, there have been reports of functional limitations from upper extremity length discrepancies and treated with humeral lengthening. More recently, humeral lengthening by distraction osteogenesis with a monolateral frame has shown improved functional results when compared to circular frames [16].

Table 26.1 provides a brief description, the genetics, natural history, and treatment possibilities of these various conditions.

Table 26.1 Dysplasias, syndromes, and certain genetic conditions and their associated upper extremity skeletal anomalies
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