Orthopaedic-Related Syndromes

Heredity and Incidence

Marfan syndrome is transmitted in an autosomal dominant manner. There is great variability in the nature and severity of clinical manifestations, and an unwary physician may not recognize the syndrome in mildly affected patients. Although a family history of Marfan syndrome is an important diagnostic criterion, the incidence of spontaneous mutations is thought to be between 15% and 30%. The lack of a specific laboratory test to confirm the diagnosis of Marfan syndrome and the variable clinical expression of the disorder, including mild manifestations, make it difficult to estimate its incidence with certainty. The prevalence is thought to be approximately 1/5000 population in the United States.

Genetics

Marfan syndrome is caused by a defective gene, FBN1, located on the long arm of chromosome 15. ^{, , ,} This gene encodes for fibrillin-1, a large glycoprotein closely associated with elastin. The biochemistry of fibrillin correlates with the syndromic features of Marfan and Beal syndromes. Fibrillin monomers normally link head to tail in forming microfibrils, which form two- and three-dimensional structures that add elasticity to tissues. Abnormal or absent fibrillin alters tissue elasticity. Fibrillin also alters the bioavailability of transforming growth factor-β (TGF-β). In addition to their presence in the aortic media and suspensory ligaments of the lens, fibrillin microfibrils are found in skin, tendon, cartilage, and periosteum. ^a

a References , , , , , , , , , , , , .

Clinical Features

A person with classic florid Marfan syndrome is easily recognized as an unusually tall, lanky individual with arachnodactyly, disproportionately long arms, chest wall deformity, extreme myopia, and a loud cardiac murmur ( Fig. 37.2 ). ^b

b References , , , , , , , A, , , .

Many patients have much less florid manifestations, however, and the clinician should rely on an awareness of the condition and strict fulfillment of specific criteria to make the diagnosis. Some individuals may have subtle deformities suggestive of the condition, including a taller-than-average appearance, ligamentous laxity, myopia, and minimal cardiac abnormalities, such as mild mitral valve prolapse. In the past, such patients were characterized as having forme fruste Marfan syndrome. ^{, , 60a , , 74a ,}

A number of historical figures are thought to have had Marfan syndrome, the most famous being Abraham Lincoln. Although Lincoln was tall and lanky and had large hands, lending credence to this suggestion, he had no known family history of the disorder and no cardiac anomalies, and he wore glasses for reading only after 50 years of age. More likely to have been affected with Marfan syndrome were violinist Nicolo Paganini ^, and composer Sergei Rachmaninoff. Certain to have had Marfan syndrome was US volleyball player Flo Hyman, whose 1986 death on the volleyball court emphasizes the importance of identifying the presence of the condition and screening for its sequelae.

Other Skeletal Manifestations

Pectus excavatum is common and is caused by excessive longitudinal growth of the ribs. The anteroposterior (AP) diameter of the thoracic cage is reduced. Recurrence after surgical correction is more common than in the general population. ^, Pectus carinatum is also frequently seen in patients with Marfan syndrome.

Joint laxity is another hallmark of the disease. Marked pes planovalgus and genu recurvatum are typical. Dislocations of the hip, either developmental or presenting later, and of other joints can occur. Perilunate dislocations have been reported and are caused by excessive carpal ligamentous laxity. Extreme planovalgus deformity of the feet is a common feature. The combination of joint laxity and long digits results in several clinical signs indicative of, but not pathognomonic for, Marfan syndrome. One of these is the thumb sign ( Fig. 37.3A ), in which the nail of the flexed thumb extends beyond the ulnar border of the clenched fist, often referred to as the Steinberg sign. The wrist sign refers to the patient’s ability to encircle the opposite wrist with the thumb and small finger, with the thumb overlapping the terminal phalanx of the small finger (see Fig. 37.3B ). ^,

The vertebral column is significantly affected in patients with Marfan syndrome. ^e

e References , , , , , .

Radiographs typically show tall vertebral bodies with elongated transverse processes. The position of the sacrum is low in relation to the iliac crests. The spinal canal may appear widened in the lumbar region, with concavity of the posterior borders of the vertebral bodies. Increased localized kyphosis and evidence of ligamentous instability have been noted in the cervical spine. Scoliosis is common, reported in 30% to 100% of patients. ^f

f References , , , , , , , , , , , , , .

The curve pattern in Marfan syndrome is often double or multiple. Pain is frequently associated with these curves. ^{, ,} Spondylolisthesis of L5–S1 is also relatively common in Marfan syndrome. ^{, ,} Several cases of atlantoaxial rotatory instability have been reported in patients with Marfan syndrome, including one case of sudden death. ^,

Diagnosis

Although the defective gene for Marfan syndrome has been identified, the diagnosis remains a clinical one, based on the fulfillment of diagnostic criteria. These criteria were updated by De Paepe and colleagues and are summarized in Box 37.1 . In the past, an increased metacarpal length-to-width ratio (metacarpal index) was thought to aid in the diagnosis of Marfan syndrome. However, there is disagreement regarding the usefulness and specificity of this radiographic assessment, and it should probably not be used as a criterion for the diagnosis of Marfan syndrome. ^{, , ,}

Box 37.1

Diagnostic Criteria for Marfan Syndrome

Skeletal System

For the skeletal system to be considered involved, at least two major criteria or one major criterion plus two minor criteria must be present.

Major Criteria

• Pectus carinatum

• Pectus excavatum requiring surgery

• Reduced upper segment–to–lower segment ratio, or arm span–to-height ratio >1.05

• Wrist and thumb signs

• Scoliosis >20 degrees or spondylolisthesis

• Reduced extension at the elbows (<170 degrees)

• Medial displacement of the medial malleolus, causing pes planus

• Protrusio acetabuli of any degree (ascertained on radiographs)

Minor Criteria

• Pectus excavatum of moderate severity

• Joint hypermobility

• High-arched palate with crowding of teeth

• Facial appearance (dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures)

Ocular System

In addition to the major criterion, at least two minor criteria must be present for the ocular system to be considered involved.

Major Criterion

• Ectopia lentis

Minor Criteria

• Abnormally flat cornea (as measured by keratometry)

• Increased axial length of globe (as measured by ultrasonography)

• Hypoplastic iris or hypoplastic ciliary muscle causing decreased miosis

Cardiovascular System

For the cardiovascular system to be considered involved, one major criterion or one minor criterion must be present.

Major Criteria

• Dilation of the ascending aorta with or without aortic regurgitation and involving at least the sinuses of Valsalva

• Dissection of the ascending aorta

Minor Criteria

• Mitral valve prolapse, with or without mitral valve regurgitation

• Dilation of the main pulmonary artery, in the absence of valvular or peripheral pulmonic stenosis or any other obvious cause, in a patient <40 years

• Calcification of the mitral annulus in a patient <40 years

• Dilation or dissection of the descending thoracic or abdominal aorta in a patient <50 years

Pulmonary System

For the pulmonary system to be considered involved, at least one minor criterion must be present.

Major Criteria

• None

Minor Criteria

• Spontaneous pneumothorax

• Apical blebs (ascertained by chest radiography)

Skin and Integumentary System

For the skin and integument to be considered involved, at least one minor criterion must be present.

Major Criteria

• None

Minor Criteria

• Striae atrophicae (stretch marks)

• Recurrent or incisional hernia

Dura

For the dura to be considered involved, the major criterion must be present.

Major Criterion

• Lumbosacral dural ectasia

Minor Criteria

• None

Family or Genetic History

For the family or genetic history to be considered contributory, one major criterion must be present.

Major Criteria

• Having a parent, child, or sibling who meets these diagnostic criteria independently

• Presence of a mutation of FBN1 known to cause Marfan syndrome

• Presence of a haplotype around FBN1, inherited by descent, known to be associated with unequivocally diagnosed Marfan syndrome in the family

Minor Criteria

• None

Requirements for a Diagnosis of Marfan Syndrome

For the Index Case

• If the family or genetic history is not contributory, major criteria in at least two different organ systems and involvement of a third organ system must be present.

• If a mutation known to cause Marfan syndrome in others is detected, one major criterion in one organ system and involvement of a second organ system must be present.

For a Relative of the Index Case

• Presence of a major criterion in the family history, and one major criterion in one organ system and involvement of a second organ system

Clinicians, particularly primary care physicians and those working in scoliosis clinics, must be alert to the possibility of this condition because the presenting anomaly is usually scoliosis or a heart murmur. The physician should seek a family history of the disorder or its manifestations, especially tall stature, ligament laxity, poor vision, cardiac anomalies, and sudden or premature death. The examiner should check for the typical manifestations, including tall stature, reduced upper body–to–lower body ratio, high-arched palate, spinal deformity, thumb and wrist signs, and cardiac murmur. A survey of patients presenting to a musculoskeletal practice found that craniofacial features, thumb and wrist signs, pectus excavatum, and hindfoot valgus were the physical features with the highest diagnostic yield. Consultation should be sought with an ophthalmologist, who should perform a slit lamp examination to identify the presence of a dislocated lens, and a cardiologist, who should perform echocardiography to assess the diameter of the aortic root and look for evidence of mitral valve prolapse.

As detailed in Box 37.1 , for an individual with a family history of Marfan syndrome (i.e., definite family history of the disease or genetic confirmation in a first-order relative), one major criterion in one organ system and involvement of a second organ system are required to make the diagnosis. For an individual with a noncontributory family history, the presence of major criteria in at least two different organ systems and involvement of a third organ system are required to make the diagnosis of Marfan syndrome.

Differential Diagnosis

A number of conditions have clinical features suggestive of Marfan syndrome and should be considered in the differential diagnosis. The principal considerations for orthopaedic surgeons are homocystinuria, congenital contractural arachnodactyly (Beals syndrome), Loeys-Dietz syndrome, and juvenile ophthalmoarthropathy (Stickler syndrome).

Treatment

Although there is no specific treatment for patients with Marfan syndrome, physicians should be alert to the various manifestations that may be initial evidence of the disorder. Orthopaedic surgeons should assure themselves that patients presenting with flatfeet, joint instability, or scoliosis do not have other manifestations of Marfan syndrome. If the skeletal features are consistent with those of Marfan syndrome, a cardiologist and ophthalmologist should be consulted.

Skeletal System

Scoliosis

Scoliosis is one of the most common and important manifestations of Marfan syndrome from an orthopaedic perspective and is often the presenting complaint. The incidence of scoliosis is 30% to 100% in different series, ⁱ

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with the variation likely related to the heterogenicity of study populations. The treatment of scoliosis in patients with Marfan syndrome parallels that in patients with idiopathic scoliosis. In general, observation is sufficient for curves less than 25 degrees, bracing should be considered for progressive curves greater than 25 to 30 degrees, and spinal fusion and instrumentation should be considered for curves greater than 45 to 50 degrees. However, the results of scoliosis treatment in patients with Marfan syndrome differ from the results in those with idiopathic scoliosis. ^j

j References , , , , , , , , , , , , , .

Specifically, most reports indicate poor patient tolerance of bracing and a relatively high frequency of deformity progression, despite bracing. Vertebral stapling has been reported to have a high failure rate. In younger patients, growing rods may be considered, but again with a fairly high rate of complications. One case is reported of heart failure after rod lengthening, with resolution of the failure with relief of the distraction.

Surgical management is recommended for larger curves, and it is not uncommon for neglected cases to present with extremely severe kyphoscoliosis, in comparison with idiopathic scoliosis. Some authors report success with posterior fusion alone, whereas others recommend combined anterior-posterior fusion. ^, Current reports note comparable clinical outcomes with posterior fusion alone, allowing for shorter operative times and less blood loss. Anterior instrumentation and fusion alone have not been successful. A recent study comparing 34 Marfan patients to a group of idiopathic adolescents found that the Marfan patients had greater kyphosis correction, more fusion levels, more fusions to the pelvis, and greater correction of sagittal imbalance. They also had more CSF leaks, more instrumentation complications, more reoperations, and lower SRS-22 scores. Preoperative halo traction combined with vertebral column resection has been shown to improve outcome in very severe deformities. Marfan patients undergoing spinal fusion and instrumentation may have a higher likelihood of pseudarthrosis, mandating secure instrumentation and careful observation for its development.

In addition to scoliosis, kyphotic deformities and spondylolisthesis occur regularly in patients with Marfan syndrome. These deformities may require treatment, using the same guidelines that apply to patients without Marfan syndrome. Finally, patients with Marfan syndrome have a higher incidence of back pain, with or without spinal deformity, which may require symptomatic care. ^{, , , ,}

Protrusio Acetabuli

Another skeletal manifestation of Marfan syndrome is protrusio acetabuli. ^{, , , ,}

This condition ^{, ,} is characterized clinically by hip joint stiffness and pain and radiographically by collapse of the acetabular teardrop ( Fig. 37.4 ). Steel described surgical closure of the triradiate cartilage in skeletally immature patients who were symptomatic or in whom increasing acetabular deepening was demonstrated radiographically. In his report on 19 hips followed to skeletal maturity, radiographic indices normalized in 12, improved in 4, and were unchanged in 3 (these 3 patients were operated on between 13 and 14 years of age); all hips were asymptomatic. He recommended surgical closure of the triradiate cartilage for patients between 8 and 10 years of age; older patients had symptomatic relief but little improvement in the radiographic appearance of their hips. Others have reported that the incidence of protrusio acetabuli in patients with Marfan syndrome is as high as 31%; however, not all patients are symptomatic, and prophylactic closure of the triradiate cartilage in asymptomatic patients is not recommended. ^{, , ,}

Developmental Dysplasia of the Hip

Patients with Marfan syndrome may present with developmental dysplasia of the hip as newborns or infants. In one report, Pavlik harness treatment was unsuccessful in obtaining reduction of the hip, and closed reduction and spica cast immobilization under anesthesia were required. However, the affected hips stabilized in the usual amount of time, and further treatment was not required.

Generalized Joint Laxity

The generalized joint laxity that characterizes patients with Marfan syndrome may manifest as severe pes planovalgus or joint dislocations, ^, especially of the patellofemoral joint. In general, treatment of these conditions should be as conservative as possible, because obtaining and maintaining joint stability can be difficult in these patients.

Infantile Marfan Syndrome

A rare variant of Marfan syndrome is a relatively severe form presenting in infancy, known as infantile or congenital Marfan syndrome. ^k

k References , , , , , .

The clinical characteristics, as described by Morse and colleagues, include serious cardiac pathology (often present at birth), congenital contractures (64% of their cases; 47% of cases reported in the literature), arachnodactyly, dolichocephaly, high-arched palate, micrognathia, hyperextensible joints, pes planus, anterior chest deformity, iridodonesis, megalocornea, and dislocated lenses. Cardiac anomalies include mitral valve prolapse, valvular regurgitation, and aortic root dilation. Three of the 22 patients identified by Morse and colleagues died during the first year of life; one-third of the survivors developed severe scoliosis, joint dislocations, or both. Sponseller and associates reported that of 14 patients with infantile scoliosis (onset before age 3 years) and Marfan syndrome, 4 died during treatment. Most cases of infantile Marfan syndrome are likely caused by a sporadic mutation in a single germ cell of one parent, because there was a positive family history in only one patient in each series. ^,

Prognosis

In 1972, the predicted average life span of patients with true Marfan syndrome was 45 years, with premature deaths (almost all a result of cardiac complications) occurring at an average age of 32 years. Beginning with the introduction of aortic root surgery by Bentall and De Bono, the life span of Marfan patients has substantially increased. ^{, , , ,} With periodic echocardiographic screening, treatment with β-blockers, and early elective aortic root surgery, the predicted average life span has increased to 72 years, with premature deaths occurring at an average age of 41 years. These improvements and an appreciation of the potentially dire consequences of not identifying the condition should remind orthopaedists to be alert for this syndrome.

Clinical Features

Clinically, the condition is characterized by mild hereditary spondyloepiphyseal dysplasia, premature degenerative arthritis, hearing loss, and congenital myopia that is compounded over time by chorioretinal degeneration and retinal detachment. ^l

l References , , , , , .

In addition, patients often have micrognathia or cleft palate, somewhat reminiscent of Pierre Robin syndrome. ^, Mandibular lengthening is feasible and may eliminate the need for tracheostomy. Herrmann and associates called attention to Stickler syndrome in the 1970s, believing that it was underdiagnosed and might be confused with Pierre Robin syndrome. ^{, ,} Establishing a correct diagnosis is important because of the genetic implications and the need for periodic ophthalmologic assessment because retinal detachment occurs and is preventable. ^,

Orthopaedic Manifestations

The orthopaedic manifestations consist of a mild spondyloepiphyseal dysplasia. Coxa valga with or without acetabular protrusion, acetabular dysplasia, valgus slipped capital femoral epiphysis, and hip subluxation have been described. ^{, ,} Typically, early degenerative changes occur in the hip because of the dysplasia. The digits may have fusiform enlargement. Vertebral body changes are similar to those of Scheuermann kyphosis. Endplate irregularities are seen, and scoliotic or kyphotic deformities can occur. Reduced bone mass and reduced bone turnover may account for some of the skeletal manifestations.

Treatment includes genetic counseling concerning the autosomal dominant trait and referral to an ophthalmologist for the management of eye complications. Progressive scoliosis or kyphosis may require orthotic treatment or spinal fusion. Total joint arthroplasty may be necessary in midlife because of premature degenerative joint disease.

Clinical Features

In patients with CCA, there is a tendency toward retrognathia and a small mouth. The crumpled appearance of the external ear is a distinctive clinical feature. It is caused by extra and prominent crura in the antihelix, partial obliteration of the concha, and flattening of the helix ( Fig. 37.5 ). There may be mild restriction of range of motion of the temporomandibular joints. Intelligence is generally normal, although some cases of neurodevelopmental delay have been reported. ^,

The initial descriptions of CCA suggested that patients with this condition did not exhibit eye or heart abnormalities. As more cases were described, however, it was observed that these patients can have myopia and cardiac abnormalities that are milder than those seen in Marfan syndrome (typically, mitral valve prolapse with regurgitation). ^{, , ,}

Aortic root enlargement has also been reported in three cases. The extremities often exhibit muscle hypoplasia, exacerbating patients’ asthenic appearance. The joint contractures in CCA are present at birth. Knee flexion contracture is the most severe; it may be as great as 90 degrees ( Fig. 37.6 ) and may delay walking. The hips are normal. The ankles may be in the calcaneus position, with limited plantar flexion and excessive dorsiflexion; alternatively, they may demonstrate vertical talus. In the hands and feet, there are flexion contractures of the metacarpal phalangeal and proximal interphalangeal joints ( Fig. 37.7 ). The elbows do not extend completely, and the forearms are restricted in supination, pronation, or both. The joint contractures tend to improve spontaneously with growth and development. This restoration of joint motion may be almost complete, making the diagnosis of CCA somewhat difficult in adolescents.

The limbs, fingers, and toes are long and gracile (see Figs. 37.6 and 37.7 ). The long narrow foot may show metatarsus varus. Vertical talus and equinovalgus are also common. Progressive scoliosis develops in the spine and may be severe ( Fig. 37.8 ).

Radiographic Findings

Radiographs show the elongated appearance of the diaphysis of the long bones, especially of the digits. Scoliosis is evident, and osteopenia may also be present (see Fig. 37.8 ). Long bone films in infancy may suggest osteogenesis imperfecta because of bowing and the appearance of diaphyseal fragility ( Fig. 37.9 ). Interestingly, birth fractures are rare. Scoliosis is often evident early, with a characteristic wedging or dysplasia of apical vertebrae, reminiscent of neurofibromatosis ( Fig. 37.10 ; see also Fig. 37.8 ).

Differential Diagnosis

CCA should be differentiated from Marfan syndrome, homocystinuria, arthrogryposis multiplex congenita, and Achard syndrome. Homocystinuria is distinguished by the presence of lens dislocation, cardiovascular disease (especially thromboembolism), mental retardation, and characteristic biochemical abnormalities in the urine and tissues. These findings are usually not observed in CCA.

Arthrogryposis is characterized by congenital joint contractures that are usually more rigid than those seen in CCA, have little tendency to resolve, and are often associated with other structural anomalies such as talipes equinovarus, vertical talus, dislocated hips, and dislocated or hyperextended knees.

In Achard syndrome, arachnodactyly is present, but it lacks the dolichostenomelia and contractures that are present in CCA. Achard syndrome is differentiated from Marfan syndrome by the absence of lens dislocation and cardiac abnormalities.

Treatment

A cardiac examination, including echocardiography, should be performed, with periodic reassessment as indicated. Contracted joints are treated by gentle passive stretching exercises and splinting to maintain and increase range of motion. Surgical soft-tissue release, particularly of the knee (where the flexion contracture is most severe), should be delayed until the deformity is clearly impeding normal ambulation. Such releases may not be required at all, however, because the contractures tend to resolve spontaneously.

Joint contractures and finger deformities can resemble those of arthrogryposis and are often treated similarly. The scoliosis, however, may be progressive and severe, and although orthotic management can be attempted, surgery is often required. Significant deformity may result, similar to infantile or neuromuscular scoliosis, requiring aggressive treatment such as growing instrumentation and early anterior and posterior fusion. Like other conditions in which osteopenia coincides with dysplastic bone, fixation is often tenuous in CCA, and there is a tendency toward pseudarthrosis (see Fig. 37.10 ). Because CCA patients are generally thin and asthenic, skin coverage for spinal implants may be problematic, especially in young children (see Fig. 37.10 ).

Biochemical Defect and Pathophysiology

A deficiency in the enzyme cystathionine synthase (or synthetase) blocks the conversion of homocysteine to cystathionine ( Fig. 37.11 ). The abnormally accumulated homocysteine is converted to homocystine, causing an elevated level of homocystine in the tissues and plasma and the excretion of large quantities of homocystine in the urine. The plasma concentration of methionine is also increased. Cystathionine is normally present in brain tissue and is a precursor to cysteine. In a homocystinuric patient, cystathionine cannot be found in the brain, and cystine becomes an essential amino acid for the patient.

There are several other extremely rare causes of homocystinuria, such as vitamin B ₁₂ malabsorption syndrome (Imerslund-Graesbeck syndrome), vitamin B ₆ depletion, 5-methyltetrahydrofolate-homocysteine methyltransferase deficiency caused by defective production of cofactor methylcobalamin, and 5,10-methylene tetrahydrofolate reductase deficiency. The latter two causes of homocystinuria are inheritable metabolic defects. In this chapter, only classic homocystinuria is discussed.

Clinical Features

The clinical features consist of a tendency toward venous and arterial thrombosis, ^, mental retardation, ^{, ,} dislocation of the lens, and skeletal changes resembling those of Marfan syndrome, along with the additional findings of osteoporosis and metaphyseal enlargement (particularly around the knee). ^o

o References , , , , , .

Diagnosis

Several studies indicate that the diagnosis of homocystinuria is frequently delayed, despite the presence of typical clinical features. ^, The authors emphasize that unusual myopia (high, abnormally progressive, or occurring at a very young age), especially when combined with skeletal manifestations, should alert the attending physician to the possibility of homocystinuria.

Homocystinuria is apparently caused by a number of potential genetic or biochemical abnormalities, as suggested by the spectrum of clinical manifestations and the variable response to pyridoxine. Thus confirmation of the diagnosis with laboratory tests is not always simple. ^, The measurement of sulfur amino acid concentrations, especially total homocysteine, in plasma or urine is a good screening tool. In patients whose clinical features and laboratory results suggest the diagnosis of homocystinuria, cystathionine synthase assays can be done using fibroblasts cultured from skin biopsy.

Features distinguishing homocystinuria from Marfan syndrome are presented in Table 37.1 .

Treatment

Patients diagnosed with homocystinuria should have a trial of pyridoxine; approximately 50% of patients respond to such treatment, with reversal of the biochemical abnormalities. ^{, ,} This biochemical reversal may reduce the risk of thromboembolic complications and prevent the progression of osteopenia or mental retardation, but the extent is uncertain. Preservation of good vision is enhanced if the diagnosis is made and treatment initiated within the first 6 weeks of life. In addition, Wilcken and Wilcken demonstrated a significant reduction in thromboembolic events (myocardial infarction and pulmonary edema) in a group of patients treated with a combination of pyridoxine, folic acid, and hydrocobalamin. Approximately 50% of patients do not respond to pyridoxine therapy, presumably because of individual variations in the exact nature of the metabolic disorder. ^,

Progressive scoliosis in skeletally immature patients is initially treated with a thoracolumbar orthosis. However, this treatment often fails to prevent progression of the deformity, and spinal fusion and instrumentation must be considered. Vertebral body osteopenia and the risk of thromboembolic complications must be taken into consideration when advising and proceeding with surgery.

Inheritance and Genetics

Onycho-osteodysplasia is transmitted as an autosomal dominant trait. Despite this type of inheritance, there is a marked degree of intrafamilial and interfamilial variation in the clinical severity of the disease. ^, The gene for nail-patella syndrome is LMX1B, located on chromosome 9. ^, Many different mutations in the gene have been described, which lead to a loss of function of the protein. LMX1B is a transcription factor involved in normal patterning of the dorsoventral axis of the limbs and early morphogenesis of the glomerular basement membrane.

Clinical Features

Dystrophy is greatest in the thumbnails and becomes less severe in the more ulnar digits ( Fig. 37.13 ). The little finger is rarely affected. Abnormalities of the toenails have been noted in some patients. The thumbnail may be absent, bifid, or hemiatrophic; the ulnar side of the nail is usually the part that is absent. The nails may be reduced in length and show numerous longitudinal cracks. Nail deformity is present in 98% of cases.

Bony abnormalities of the digits have not been demonstrated. The mesodermal tissues of the fingers appear to be involved to some extent. The terminal pulp may extend from the volar aspect onto the dorsal surface. The dorsal skin creases over the distal interphalangeal joints may be absent or poorly developed. There may also be laxity of the ligaments of the metacarpophalangeal and interphalangeal joints.

The patella is absent or hypoplastic ( Fig. 37.14 ). The hypoplastic patella may be ovoid, triangular, or irregular in shape and may arise from several ossification centers ( Fig. 37.15 ). It may be located more distally than in the normal knee.

The presenting complaint may be knee pain or recurrent lateral dislocation of the patella caused by hypoplasia of the lateral femoral condyle. Some degree of genu valgum is usually present. The medial femoral condyle is frequently large and prominent, whereas the lateral femoral condyle is underdeveloped. The medial tibial plateau may slip downward and medially or may even be grooved. The medial margin of the proximal tibial metaphysis tends to sweep upward and medially in a characteristic arc. Valgus of the foot and ball-and-socket ankle joint have been reported.

The carrying angle of the elbow joint is increased, with varying degrees of cubitus valgus. There is hypoplasia of the lateral side of the elbow joint involving not only the capitellum and lateral condyle but also the radial head. The radial head may articulate normally with the capitellum, or there may be subluxation or dislocation posteriorly ( Fig. 37.16 ). There may be a pointed exostosis of the lateral aspect of the coronoid process. Range of motion of the elbow joints is usually limited.

Radiographic Findings

Iliac horns and flaring of the iliac crests, with prominence of the anterior superior iliac spines, are the two types of pelvic abnormalities encountered. Iliac horns, one of the most common features of onycho-osteodysplasia, are bilateral, present in 80% of cases, and may be visible, palpable, or impalpable, according to their size. The horns are located at the origin of the gluteus medius and project posterolaterally. Secondary centers of ossification may occur at their tips. They are present early in life. When outflaring of the iliac crests and prominent anterior superior iliac spines is combined with iliac horns, the appearance of the pelvis has been likened to that of an elephant’s ear.

Radiographs of the knee reveal a number of patellar and femoral abnormalities. Patellar aplasia is present in 4% while patellar hypoplasia is found in 86% of patients. Shortening of the lateral femoral condyle is present in 55% and a flat anterior surface of the medial femoral condyle is seen in 92% of patients.

Associated Anomalies

Other anomalies that may be found in association with the foregoing main lesions include clubfoot and other congenital foot abnormalities, ^, developmental dysplasia of the hip, scoliosis, glenoid and acromial dysplasia, and congenital contracture of the little finger. Abnormal pigmentation of the iris occurs in approximately 50% of cases. Plummer-Vinson syndrome (dysphagia, hypochromic anemia, and koilonychia) has also been associated with nail-patella syndrome.

Approximately 40% of individuals with nail-patella syndrome have kidney disease. Most have accelerated age-related loss of filtration function, which is usually asymptomatic. A minority, approximately 5% to 10% of people with nail-patella syndrome, have more severe disease, with nephritic syndrome, in their youth, which progresses to end-stage kidney failure. Later in life, usually during the third or fourth decade, nephropathy and proteinuria develop, with subsequent renal failure. ^p

p References , , , , , , , .

Nephropathy occurs in approximately 40% of affected individuals, is more frequent in female patients, and may be linked to the specific mutation location in the LMX1B gene.

Glaucoma is also seen with increased frequency in patients with nail-patella syndrome. ^, Because of the association with both renal failure and glaucoma, patients with nail-patella syndrome should be screened for these serious associated conditions.

Treatment

There is no specific treatment for the disorder. The iliac horns do not affect gait and should not be resected. Recurrent dislocation of the patella may occur; if this is disabling, it is treated by proximal or distal realignment. ^, In a series reported by Guidera and associates, approximately 50% of children with nail-patella syndrome underwent knee surgery to treat instability. A rare finding of a synovial band blocking the patella from engaging the trochlear groove has been treated arthroscopically. Foot deformities often require posteromedial clubfoot releases.

Clinical Features

An initial evaluation is often requested soon after birth because the orthopaedic manifestations are so dramatic. The lower extremities most frequently exhibit bilateral hyperextension deformities of the knees and fairly rigid clubfeet. The knee deformity spans a spectrum from simple congenital hyperextension deformity to complete (grade 3) anterior dislocation of the tibia on the femur ( Fig. 37.17 ), with the more severe dislocation being common. The hips are often teratologically dislocated, with obvious foreshortening of the thighs, but there is often remarkable mobility, reflecting the characteristic generalized ligamentous laxity. Other obvious skeletal manifestations include deformities of the hands and elbows. The elbows frequently demonstrate radiohumeral dislocation, with lateral prominence of the radial heads, even in infants; there may be more extensive dislocation, with total disruption of the radiocapitellar and humeroulnar joints ( Fig. 37.18 ). In the latter case, the elbow is fixed by webbing in the antecubital space, with a flexion contracture varying from 60 to 90 degrees. The fingers are usually long and cylindric, with a series of shortened metacarpals and a spatulate thumb, where the terminal phalanx is short and wide. Dislocation of the metacarpal joint of the thumb can occur (see Fig. 37.18 ). The appearance of the fingers is distinctly different from classic arthrogryposis, one of the other possible diagnoses to be considered in this setting.

Facial dysmorphia aids in the immediate identification of patients with Larsen syndrome, who characteristically have a flattened nasal bridge, relatively widely spaced eyes, and a prominent forehead (hypertelorism). Depression of the nasal bridge is a universal characteristic that makes the facial findings, in conjunction with the orthopaedic deformities, pathognomonic. Other nonorthopaedic involvement includes elasticity of the thoracic cage, tracheomalacia, and laryngomalacia. Respiratory failure and early respiratory death have been reported as part of the syndrome. ^{, , ,} Acquired lesions of the mitral valve and aorta, similar to those found in Marfan syndrome and other hyperelasticity conditions, can further complicate the surgical management of these children. ^{, ,}

Neurologic Evaluation

The neurologic evaluation of children with suspected Larsen syndrome is critical. These patients are often described as being hypotonic, a condition associated with hyperelasticity syndromes and often implicated in the delayed achievement of certain motor skills, such as the ability to walk. In infants who are floppy or who are late in reaching milestones, it may be a dangerous oversimplification to attribute such delay to the syndrome per se or to the presence of multiple joint dislocations or foot deformities; the possibility of cervical cord compression must always be entertained in any infant with hypotonicity. In patients with a known associated cervical kyphosis, the presence of cord compression must be determined as early as possible to avoid chronic myelopathy and neurologic morbidity. Should cervical cord compression occur before complete myelinization, the classic signs of spasticity or hyperactive deep tendon reflexes indicating spinal cord compression are likely to be absent, and the patient may exhibit a flaccid-type paresis (hypotonicity). Although the tracheomalacia or bronchomalacia observed in patients with Larsen syndrome ^{, ,} can be responsible for pulmonary compromise or death in infancy, patients with cord compression and flaccid paresis also suffer respiratory weakness and failure. ^, Thus the importance of early neurologic evaluation and radiographic identification of cervical kyphosis cannot be overemphasized in this patient population. Furthermore, a review of the literature strongly suggests that cervical kyphosis and cord impingement are underdiagnosed. The cervical spine deformities were not emphasized in the original description of the syndrome and, with the exception of sporadic reports, ^{, , , ,} there has been little emphasis on this critical and potentially catastrophic lesion in patients with Larsen syndrome.

Differential Diagnosis

Other entities that share features with Larsen syndrome must be ruled out. These include other hyperelasticity syndromes, such as Marfan and Ehlers-Danlos syndromes, and, because of the contractures and extremity deformities, arthrogryposis multiplex congenita and Beals syndrome (congenital contractural arachnodactyly). The latter two are usually differentiated by the fact that patients with Larsen syndrome have a relatively normal muscle mass. Patients with Beals syndrome or classic arthrogryposis may suffer birth fractures as a result of rigid joints. Arthrogrypotic patients lack normal flexion creases, and with the exception of chest cage elasticity in patients with Larsen syndrome, which may manifest in newborns as paradoxical motion on inspiration and stridor, infants with Larsen syndrome are generally more robust and actively moving. Patients with hyperelasticity syndromes do not exhibit the multiple joint dislocations typical of Larsen syndrome. A milder form of Larsen syndrome lacking full-blown joint dislocations may be confused with other hyperelasticity syndromes. In this case, the dysmorphic facies of Larsen syndrome is the physical finding that settles the issue.

Larsen syndrome is classically inherited by an autosomal dominant pattern, ^, so a family history of the disorder is an important factor in a patient with an otherwise uncertain diagnosis. Evidence of mutations clustered in the FLNB gene indicate that a molecular diagnostic test may be available to assist in diagnosis and genetic counseling.

Radiographic Findings

An unusual radiographic finding—a separate, additional ossification center for the calcaneus ( Fig. 37.19 )—may aid in the diagnosis. ^, The additional calcaneal apophysis is a fairly consistent finding, and its absence casts doubt on a diagnosis of classic Larsen syndrome. Extra carpal ossification centers have also been observed ( Fig. 37.20 ). ^{, ,} The presence of multiple joint dislocations (hip, knee, elbow), with or without cervical kyphosis and spondylolysis, is an additional confirmatory finding. In the spine, particularly at cervical levels, spondylolysis at multiple levels is common, which may represent unossified fibrocartilage or may be associated with AP dissociation. ^,

Treatment

Because of the multiple deformities presenting simultaneously, the order of treatment should be determined as early as possible. In infants with the full-blown syndrome, we recommend that treatment be prioritized as follows:

• Cervical kyphosis (or other threatened instability)

• Congenital dislocation of the knee

• Congenital dislocation of the hip

• Foot deformities requiring correction to reach plantigrade position

Congenital dislocation of the elbow or radial head rarely requires treatment; scoliosis should be treated as described in Chapter 9 .

Congenital Dislocation of the Knee

The full spectrum of knee dislocation has been observed in Larsen syndrome. It is occasionally amenable to nonoperative treatment in infancy. If the knee is merely hyperextended (grade 1), it may be possible to use serial casting and quadriceps stretching to achieve reduction by flexion. More often than not, however, the quadriceps contracture is more severe, and obliteration of the suprapatellar pouch is complete. In this case, open reduction is necessary to gain concentric femorotibial motion. We have also been successful in obtaining closed reduction by inducing neuromuscular blockade of the quadriceps with botulinum toxin (Botox; Fig. 37.21 ). An early attempt at closed reduction by flexion and serial casting should be made in newborns, and if the reduction is successful, it can be maintained by splinting, which may include the use of a Pavlik harness to maintain the knees in a flexed position ( Fig. 37.22 ). In a relatively mild case, knee hyperextension and hip dislocation can be treated simultaneously by a Pavlik harness in the neonatal period, provided that knee flexion greater than 40 to 45 degrees can be achieved.

Open reduction of congenital dislocation of the knee is probably the second most important operative procedure, after cervical spine stabilization, if the patient is to have a good functional outcome and ambulatory ability as an adult. The best results are obtained when the knees are reduced by age 2 years. ^q

q References , , , , , .

Traditional treatment involves extensive quadriceps mechanism lengthening to achieve flexion, as well as an anterior arthrotomy to release intraarticular and extraarticular adhesions, preventing congruous knee flexion, and to mobilize the patellofemoral joint. However, the common end result of such lengthening is an incompetent quadriceps mechanism, producing extensor weakness and poor ambulatory function. If the knee is also unstable because of ligamentous insufficiency (particularly cruciate), or if extensive intraarticular release is required to achieve reduction, the quadriceps weakness further reduces function, and severe valgus or frank subluxation may result, making the patient brace-dependent. Marked instability at the time of reduction, requiring temporary transarticular fixation, portends the later development of valgus, subluxation, and fixed flexion contracture caused by resubluxation of the tibia. In such a clinical scenario, impaired knee function becomes the most significant disability ( Fig. 37.23 ).

Experience with arthrotomy and primary femoral shortening to gain reduction and flexion of the knee has been more encouraging ( Fig. 37.24 ). The purpose of femoral shortening is to lengthen the quadriceps mechanism without extensive dissection and lengthening of the muscle-tendon unit itself. With shortening of the femur, the extension contracture is decompressed, and with a more limited arthrotomy, intraarticular and extraarticular obstructions to reduction of the knee can be released or excised without damage to the suprapatellar quadriceps mechanism itself. The patellofemoral joint can be realigned by extending the arthrotomy proximally on the lateral side of the knee, freeing the patella from its laterally dislocated position, and realigning it in its appropriate intercondylar groove, again aided by femoral shortening. The bony shortening is stabilized by an appropriately sized small or mini-DCP plate (dynamic compression plate). After bony healing, the knees are splinted in a flexed position and gradually brought to full extension as the child grows and ambulatory status develops. Additional details of this technique are available elsewhere.

Late angular deformity, primarily valgus, is common following knee reduction surgery. If the valgus is associated with marked anterolateral instability, ligamentous reconstruction can be attempted. We have used the iliotibial band transfer to substitute for the anterior cruciate ligament, combined with imbrication of the posteromedial corner to stabilize such knees, with definite short-term improvement. Over the longer term, subluxation may recur because of gradual stretching of the ligamentous replacement. As always, any transphyseal cruciate ligament transfer in an immature knee risks a growth disturbance of the proximal tibial physis (see Fig. 37.24E ). However, the stability obtained by the ligament and capsular reconstruction is invaluable to the ultimate function of the knee and is well worth the risk of physeal growth disturbance, which can be addressed later by appropriate lengthening and angular correction. Bony realignment by varus osteotomy may also be appropriate for valgus alignment. Although it does not directly address the pathologic ligamentous and articular structures, realignment may improve symptomatic valgus by preventing further stretching of the medial and posterior capsules.

Foot Deformities

Foot deformities in Larsen syndrome usually include equinovarus or equinovalgus. Foot deformities are usually addressed after the knee and hip have been stabilized. As with other congenital foot problems involving significant equinus, waiting until the patient is ambulatory and fully weight bearing is beneficial in terms of maintaining correction. Although operative treatment is frequently required for equinovarus deformities, it is not unreasonable to attempt closed correction with casting or other stretching techniques while the hip and knee joints are undergoing treatment. The equinus of Larsen syndrome tends to be resistant, however, and Achilles tendon lengthening and posterior release will likely be required to achieve a plantigrade foot. Because of the overall ligamentous laxity, caution is recommended when releasing other components of the clubfoot, because hyperpronated valgus overcorrection is common. An apparently rigid clubfoot in an infant may later become pathologically flexible. Minimal release of the equinus and hindfoot varus in a 1-year-old who has completed treatment for other joint dislocations may be all that is required.

Equinovalgus deformities may not require treatment at all or may require only Achilles tendon lengthening. Patients with Larsen syndrome also tend to develop serpentine or Z-foot deformities, in which hindfoot valgus is combined with forefoot adductus ( Fig. 37.25 ). Because of the ligamentous laxity, the feet of patients with Larsen syndrome frequently appear to have significant deformity in the weight-bearing position but remain asymptomatic. Surgical intervention is rarely required, and supportive shoes or orthoses are usually sufficient. On occasion, however, it may be necessary to correct the hyperpronated portion of the deformity by hindfoot stabilization.