Syndromes of Orthopaedic Importance

Syndromes of Orthopaedic Importance

Benjamin A. Alman

Michael J. Goldberg

The word syndrome is derived from a Greek word that means to run together. When several relatively uncommon anomalies occur in the same individual, it may be nothing more than coincidence. However, if all the anomalies result from the same cause, or occur in the same pattern in other children, that particular combination of birth defects is called a syndrome. A syndrome should be suspected if a characteristic orthopaedic malformation (e.g., radial clubhand) is encountered, if all four extremities are affected, if limb deformities are symmetric, if there are several associated nonorthopaedic anomalies, or if the patient has a familiarly dysmorphic face. Children who have syndromes look more like one another than like their parents (1, 2, 3 and 4).

It is not unusual for an orthopaedist to be the first physician to recognize that a child has characteristics of a syndrome. In such cases, appropriate referrals should be made to a geneticist to assist in syndrome identification, order appropriate confirmatory tests, and arrange for management of the nonorthopaedic manifestations of the syndrome. The evaluation of a child for a syndrome includes a family history, a systems review, and a search for minor dysmorphic features, such as abnormal palm creases or abnormal shape of digits or toes. These evaluation processes may not be of immediate orthopaedic importance, but they are the clues to look further.

During fetal development, cell signaling pathways are activated in a coordinated manner to allow cells to divide, differentiate, move, and die off, ultimately resulting in a normally formed individual. These cell signaling pathways play roles in the development of multiple organs. It is not surprising that dysregulation of such developmentally important pathways can cause the malformation of a number of organs, resulting in several otherwise uncommon abnormalities occurring together, producing a syndrome. Such pathways can be dysregulated by a mutation in a key pathway member, by fetal environmental factors (e.g., a teratogen, such as in fetal alcohol syndrome), or both.

The relation between the clinical (phenotypic) features and the cause of a syndrome is not always as simple as one would wish. Even within a family in which all the members carry the identical causative gene mutation, some individuals are minimally affected, whereas others have all of the findings of the syndrome. This may be due to the presence of modifying genes, which may not be inherited in the same way as the gene mutation that causes the syndrome, or due to fetal environmental factors that modify the manner in which the pathways are activated. In addition, different mutations in the same gene can cause different syndromes, because the products of different mutations have different cellular functions. Such is the case with the dystrophin gene, which causes both Duchenne and Becker muscular dystrophies.

Information about the etiology of a syndrome is important, because it has implications for the parents as to the risk of recurrence in subsequent pregnancies, and may hold the key to the development of novel treatments. The rapid pace of basic research in developmental biology and genetics makes it difficult for a traditional textbook to provide the most upto-date information about syndrome etiology. The Internet is becoming an excellent source for such information. One useful site is the On-line Mendelian Inheritance in Man (OMIM), administered by the National Institutes of Health. This site can be accessed at can be searched by syndrome name, causative gene, or clinical findings (5).

The care of children with syndromes involves multiple specialists (6). Discussions about the risk of subsequent pregnancies are in the realm of the genetic counselor. While parents often assume that if the condition has a name, it is treatable or curable, this sadly, is not the case. The importance of understanding syndromes is in recognizing associated medical abnormalities that may be life threatening, adversely influence orthopaedic outcomes, or may influence surgical timing and management. Importantly, patients can come to significant harm if an orthopaedist misses recognizing a syndrome. For instance, in the case of Marfan syndrome, starting a child on beta-blockers can prevent a catastrophic cardiovascular event.

Even if parents are not planning subsequent pregnancies, and if there are no plans for their child to undergo surgery in the near future, genetic evaluation is still important for proper syndrome diagnosis. Correct diagnoses are essential for research into syndrome etiology and treatment. Patients should be given the opportunity to participate in such research, especially in cases of relatively rare syndromes.

Nomenclature can confuse syndrome identification, because a single syndrome may have several names. Eponyms are not descriptive of the syndrome, nor do they give information about etiology. Many syndromes are caused by a mutation in a gene, and the causative gene has been identified in most such syndromes. Classifying syndromes by the causative gene alone can be problematic because some genes cause more than one syndrome, some syndromes are caused by more than one gene, and some syndromes are not caused by a gene mutation. Furthermore, gene names are frequently unrelated to clinical findings associated with a given syndrome. A numbering system is used by computer databases; the most widely used is that of the OMIM (5), but this is helpful only for database searches. An ideal nomenclature, which would give information about clinical findings and etiology, has yet to be developed.

Knowledge of the genetic cause of syndromes does not supplant the need for the clinician to know the phenotypic features of individual syndromes (7). For many syndromes, molecular genetic tests are not available or are available only at a very high cost. As such, it is impractical to test a given patient for every known genetic condition (8). A thorough study of the patient’s history and a physical examination gives clues as to which supportive tests to order, such as radiographs. This information is used for narrowing down the diagnosis to only a handful of syndromes. In many cases, the ultimate diagnosis can be made on the clinical and radiographic findings alone [e.g., neurofibromatosis (NF) type I]. For syndromes in which molecular genetic tests are available, these are usually performed to confirm a diagnosis rather than to make a diagnosis and should only rarely be ordered by an orthopaedist before consultation with a clinical geneticist or genetic counselor.

It is clinically useful to classify syndromes caused by gene mutations into groups broadly categorized by the function of the causative gene (9, 10). Such syndromes can be broadly classified into those caused by mutation in genes encoding one of the following types of proteins: structural proteins, proteins that regulate developmentally important signaling pathways, proteins implicated in neoplasia, proteins such as enzymes that play a role in processing molecules, and proteins that play a role in nerve or muscle function (7). Syndromes within each broad group share similarities in the mode of inheritance and clinical behavior. For instance, syndromes caused by mutations in genes encoding structural proteins tend to be inherited in an autosomal dominant manner and result in skeletal structures that wear out with time, for which corrective surgery has a high recurrence or failure rate. Most of the disorders in this chapter are grouped using this functional genetic scheme. The one exception is contracture syndromes, which are considered as a separate group. Although the genetic etiology of many of the contracture syndromes has been identified, it is easiest, from a practical standpoint, to consider them as a few subgroups based on clinical and treatment similarities.


A variety of proteins play important roles in the connective tissues, including the bones, articular cartilage, ligaments, and skin. Mutations in such genes disrupt the structural integrity of the connective tissues in which they are expressed. In most cases, the phenotype is absent or there are only minor manifestations present at birth; the phenotype evolves with time, because the abnormal structural components slowly fail or wear out with time as the individual grows. Deformity often recurs after surgery, because the structural components are abnormal and will wear out again. In cases where the structural abnormality involves cartilage, there may be growth abnormality caused by physeal mechanical failure or early degenerative disease of the joints caused by articular cartilage failure. When a protein that is important for ligament or tendon strength is affected, joints often subluxate. There can be substantial heterogeneity in the severity of the phenotype, depending upon the exact way in which the mutation alters the protein function. In patients with mild disease, life expectancy is normal; however, in patients with more severe disease, life expectancy may be shortened because of secondary effects of the structural defects on vital organs. These disorders tend to be inherited in an autosomal dominant manner (9, 10). Many of the disorders caused by mutations in genes that encode structural proteins, including osteogenesis imperfecta and spondyloepiphyseal dysplasia, are covered in other sections of this textbook.

Marfan Syndrome.

Anton Marfan, a French pediatrician, first described this syndrome in 1896, as a condition associated with long limbs and involvement of the cardiovascular, ocular, and skeletal systems (11). Although some authorities believe that Abraham Lincoln had Marfan syndrome, there remains considerable controversy surrounding this, and a decision was made against using DNA from his remains to test for this diagnosis (12). This is one of the few syndromes caused by a mutation in a gene encoding a structural protein that is associated with tall stature. Patients can be recognized by the characteristic tall stature, arachnodactyly (abnormally long and slender digits), dolichostenomelia (long, narrow limbs), pectus deformities, and scoliosis. Stria can be seen in the skin (Fig. 8-1). There are a number of cardiovascular anomalies associated with this condition, including aortic regurgitation, aortic dilatation, aneurysms, and mitral valve prolapse. Ocular findings are myopia and superior displacement of the lens. The lens moves in the opposite direction in homocystinuria, a condition that sometimes is misdiagnosed as Marfan syndrome. Undiagnosed patients with Marfan syndrome not infrequently present to an orthopaedist with a diagnosis of scoliosis. It is
important for an orthopaedist to recognize this condition, since its identification allows for referral for management of the cardiovascular abnormalities, early treatment of which can prevent premature mortality.

FIGURE 8-1. Stria in a boy with Marfan syndrome, who initially presented for evaluation of scoliosis.

Radiographic Findings.

Although there are a variety of radiographic findings that are frequently present in patients with Marfan syndrome, none are pathopneumonic. Spinal morphology suggestive of dural ectasia and pedicle dysplasia are suggestive of this disorder. The use of measurements from spine radiographs in making this diagnosis (an interpedicular distance at L5 ≥ 36.0 mm; a sagittal diameter at L5 ≥ 13.5 mm; a transverse process-to-vertebral width ratio at L3 ≥ 2.25 mm) yields a high sensitivity but a relatively poor specificity (16). A arachnodactyly is defined on radiographs as an increase in the ratio of length to width of the second to the fifth metacarpals (Fig. 8-2). The average ratio of the lengths of the second to the fifth metacarpals, divided by the widths of the respective diaphyses, is >8.8 in male patients and >9.4 in female patients with Marfan syndrome (19). There are no studies, however, that determine the sensitivity and specificity of the use of these measures to make a diagnosis of Marfan syndrome.


Marfan syndrome is inherited in an autosomal dominant manner and is caused by mutations in the fibrillin gene (20). Like many inherited genetic disorders, almost a third of cases are sporadic due to a new mutation at embryogenesis. The expression of the mutant gene product inactivates the function of the normal gene product, an effect that is termed dominant negative. As such, this condition could potentially be treated by the use of therapies that decrease the expression of the mutant gene (21). The fibrillin protein plays a role in maintaining the normal mechanical properties of the soft tissues, especially in resistance to cyclic stress (22). The clinical findings of laxity and subluxation of the joints, and weakening of arterial walls with resultant aortic dilatation, are easy to understand on the basis of the function of fibrillin. The tall stature and arachnodactyly associated with the syndrome are seemingly difficult to attribute to the fibrillin mutation. However, the extracellular matrix also contains growth factors, which are bound to extracellular matrix proteins. Fibrillin mutations cause some of these extracellular growth factors, such as transforming growth factor β, to become more readily accessible to cell receptors (23). The increased growth factor availability likely causes increased cellular growth and rapid longitudinal bone growth; resulting in long, thin fingers and toes and tall stature. This raises the possibility that growth factor activity modulation could be used to treat some of the sequelae of Marfan syndrome (23).

Although molecular diagnosis for a mutation in the fibrillin gene is available, this is usually not required in making the diagnosis, as physical findings and information from radiographic studies are generally sufficient for this purpose.

TABLE 8-1 Diagnostic Criteria for Marfan Syndrome: A Comparison of the Berlin land Ghent Diagnostic Criteria


If the patient has an affected first-degree relative, at least two systems of any class must be involved. In the absence of an affected first-degree relative, involvement of the skeleton as well as one major system and two minor systems are required.

Major Involvement

Minor Involvement

Ocular system

Cardiovascular system

Dural ectasia

Skeletal system

Ocular system

Cardiovascular system

Pulmonary system


Central nervous system


Diagnosis requires two major involvements and one minor involvement

Major Involvement

Minor Involvement

Family history or molecular data

Skeletal system

Cardiovascular system

Ocular system

Dural ectasia

Cardiovascular system

Skeletal system

Pulmonary system

Ocular system


Skeletal system

Presence of at least four of the following manifestations

Major Involvement

Minor Involvement

Pectus carinatum

Pectus excavatum of moderate severity

Pectus excavatum requiring surgery

Joint hypermobility

Reduced upper to lower segment ratio or arm span to height ratio >1.05

Wrist and thumb signs

Scoliosis of >20 degrees or spondylolisthesis

Reduced extension at the elbows (<170 degrees)

Medial displacement of the medial malleolus causing pes planus

Protrusio acetabula of any degree (ascertained on radiographs)

Highly arched palate with crowding of teeth Facial appearance (dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures)

Ocular System

Major Involvement

Ectopia lentis

Minor Involvement

Abnormally flat cornea (as measured by keratometry) Increased axial length of globe (as measured by ultrasound) Hypoplastic iris or hypoplastic ciliary muscle causing decreased miosis

Cardiovascular System

Major Involvement

Minor Involvement

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

Mitral valve prolapse with or without mitral valve regurgitation

Dilatation of the main pulmonary artery, in the absence of valvular or peripheral pulmonic stenosis or any other obvious cause, below the age of 40 yr

Dissection of the ascending aorta

Calcification of the mitral annulus below the age of 40 yr Dilatation or dissection of the descending thoracic abdominal aorta below the age of 50 yr

Pulmonary System

Major Involvement

Minor Involvement


Spontaneous pneumothorax

Apical blebs (ascertained by chest radiographs)

Skin and Integument

Major Involvement

Minor Involvement


Striae atrophicae (stretch marks) not associated with marked weight changes, pregnancy, or repetitive stress

Recurrent or incision hernias


Major Involvement

Minor Involvement

Lumbosacral dural ectasia by CT scan or MRI


Family/Genetic History

Major Involvement

Minor Involvement

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


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

CT, computed tomography; MRI, magnetic resonance imaging.

Orthopaedic Manifestations and Their Management.

Hyperlaxity is responsible for many of the clinical problems in Marfan syndrome, including subluxation of joints, a predisposition to sprains, and scoliosis. Scoliosis is a common reason for which patients are referred to the orthopaedist. Smaller curves can be managed in a manner similar to that for idiopathic scoliosis, with bracing considered for select curves in skeletally immature individuals. Although bracing is often prescribed, it seems to be less effective than in idiopathic scoliosis (24). This has led some to suggest that bracing only delays the need for surgical treatment. There are no well-controlled studies comparing brace treatment with observation or any other type of management in these patients. Although the efficacy of brace treatment remains controversial, we offer brace treatment using the same principles as for idiopathic scoliosis. Curves will often be relatively short and associated with deformity of vertebrae termed dysplastic (Fig. 8-3). The spinal deformity is often associated with kyphosis, especially in the lumbar spine region. Surgery is considered for rapidly progressive curves in skeletally immature individuals, or for large curves in skeletally mature individuals. Patients with Marfan syndrome have higher complication rates when undergoing scoliosis surgery than in idiopathic scoliosis. Infection, instrumentation fixation failure, pseudarthrosis, or coronal and sagittal curve decompensation occur in 10% to 20% of patients. Infection is often associated with a dural tear. Perioperative death from valvular insufficiency has been reported. To avoid such complications, the cardiopulmonary condition of patients with Marfan syndrome should be evaluated preoperatively (25—32). Overcorrection can also cause cardiovascular complications, and

reducing the amount of correction in a patient treated with a growing rod was shown in a case report to reverse cardiac failure (33). Computerized tomography (CT) scan to assess bony anatomy, especially of the pedicles, is quite useful in preoperative planning of hook and screw placement. Other unusual spinal deformities can occur, such as subluxation of vertebrae (25, 34). Traction should be used with caution, especially in cases with underlying kyphosis, as it can worsen and cause subluxation (26).

FIGURE 8-2. Hands showing arachnodactyly. Notice the long, thin metacarpals and phalanges.

FIGURE 8-3. Scoliosis (A,B) and protrusia of the hips (E) in a patient with Marfan syndrome. C, D: Deformity of the apical vertebrae is shown in a three-dimensional reconstruction of a computerized tomographic scan image. (Courtesy of Chris Reily, MD, Vancouver, British Columbia, Canada.)

Dural ectasia is common in individuals with Marfan syndrome and seems to increase in severity with age. Its severity is not related to the severity of other clinical findings; for instance, there is no association between aortic dilatation and dural ectasia (27). Although there is a slightly higher incidence of back pain in patients with dural ectasia than in those without, a 40% incidence of back pain in patients with Marfan syndrome without dural ectasia suggests that dural ectasia itself is not the cause of the pain. One should thus evaluate patients with Marfan syndrome for other causes of back pain even in the presence of dural ectasia.

Mild osteopenia is associated with Marfan syndrome; this may be caused in part by the fibrillin abnormality disrupting the normal extracellular matrix structure of bone, and in some cases it may be related to relative physical inactivity. Susceptibility to fracture does not seem to be a problem, and it is therefore not clear whether intervention for the decreased bone density is warranted (28, 29). Protrusio acetabula is present in about one-third of patients with Marfan syndrome. The radiographic diagnosis can be difficult as there is a deformity of the inner aspect of the pelvis that can distort the normal pelvic landmarks. Protrusion is not related to bone mineral density and is usually asymptomatic (30). Although prophylactic fusion of the triradiate cartilage is reported, for these reasons it is not warranted in the majority of cases.

Nonorthopaedic Manifestations.

Cardiovascular failure can lead to premature death in patients with Marfan syndrome. Indeed, many cases of sudden death during athletic activities in the young are in individuals with Marfan syndrome. Despite this, there are no universally accepted criteria for restricting physical activity in individuals with Marfan syndrome. Early intervention using β-blockers can reduce the development of aortic dilatation. New treatments based on reversing the changes associated with the identified mutation are under investigation and will likely change the course for patients with Marfan syndrome. For instance, the antihypertensive agent, Losartan, has also been found to down-regulate the expression of transforming growth factor beta; animal studies as well as small clinical series suggest that its use can slow the progression of the cardiovascular side effects of this condition (23). However, larger scale clinical trials are required before routine use is recommended. Individuals with aortic dilation may also benefit from earlier cardiac surgical intervention. Lens dislocation requires ophthalmologic intervention. In Marfan syndrome the lens is dislocated in a superior direction, whereas in homocystinuria there is an inferior dislocation.

Homocystinuria shares many clinical features with Marfan syndrome but is also associated with a coagulation disorder. As such, it is crucial that an individual suspected of having Marfan syndrome be evaluated for cardiovascular problems, and that the possibility of homocystinuria be excluded before the patient undergoes surgery.


It is important for the orthopaedist to be able to distinguish patients with homocystinuria from those with Marfan syndrome, as patients with homocystinuria often present to the orthopaedists with a clinical picture suggesting Marfan syndrome. Unlike Marfan syndrome, homocystinuria is associated with a coagulopathy, which can be fatal if unrecognized, especially during surgery. Although homocystinuria is not caused by a mutation in a gene encoding a structural protein, it shares phenotypic similarities with Marfan syndrome, and it is therefore being discussed here. It is caused by a defect in one of the enzymes that is important in the production of cysteine from methionine, thereby resulting in the accumulation of intermediate metabolites in the blood (homocysteine and homocystine) and in the urine (homocystine) (31, 32). There are several subtypes, and patients with type I have a phenotype similar to that of Marfan syndrome (35). Affected individuals are tall with long limbs and may have arachnodactyly and scoliosis. Dislocation of the lens of the eye is common but in contrast to Marfan syndrome the displacement is inferior. Osteoporosis is often more severe in type I homocystinuria than in Marfan syndrome. Vertebral osteoporosis can produce biconcavity and flattening of vertebral bodies, whereas in Marfan syndrome the vertebral bodies are either normal or excessively long. Widening of the epiphyses and metaphyses of long bones is more typically seen in homocystinuria. Mental retardation is not a feature of Marfan syndrome, but occurs in approximately half of all patients with homocystinuria (36). Patients with type I homocystinuria have an abnormality in clotting, which leads to venous and arterial thromboembolic episodes (37). Such episodes can complicate surgery, and as such a hematology consultation should be considered when planning surgery.

Type I homocystinuria is caused by a deficiency of cystathionine synthetase, which normally catalyzes the chemical union of homocysteine and serine to form cystathionine. The enzyme uses pyridoxine (vitamin B6) as a cofactor. Blood levels of methionine are increased, and thus screening of patients with Marfan syndrome for homocystine in the urine (with the cyanide nitroprusside test) can differentiate type I homocystinuria from Marfan syndrome. Type II and III homocystinuria are biochemically distinct. Because the errors cause blocks at other points, blood levels of methionine are normal, and other clinical findings such as skeletal changes and thromboses are absent.

The treatment for homocystinuria depends on the type. In type I, the typical course is methionine restriction and pyridoxine supplementation (37). For types II and III, methionine restriction is harmful. Treatment with cofactors also varies for these other types. Vitamin B12 is suggested in the management of type II, and folic acid for type III.

Ehlers-Danlos Syndrome.

Ehlers-Danlos syndrome (EDS) is a collection of different disorders that are associated with the common phenotypic findings of hyperextensibility of the skin and hypermobility of the joints. Easy bruisability of soft tissue, fragility of bone, calcification of soft tissues, and various degrees of osteopenia are associated with the various subtypes. The hyperlaxity allows affected individuals to have impressively large ranges of motion of the joints. Contortionists are often individuals with this syndrome. Although Tschernogobow first described the syndrome in 1892, the condition derives its name from reports by Edward Ehlers, a Danish dermatologist, in 1901, and Henri-Alexandre Danlos, a French physician, in 1908. These two individuals combined the pertinent features of the condition to provide a detailed description of the phenotype (38).

The main features of classic EDS are loose-jointedness and fragile, bruisable skin that heals with peculiar “cigarettepaper” scars and may show changes resulting from multiple bruises (Fig. 8-4). Children with this condition may be born prematurely because of premature rupture of fetal membranes, because these membranes are derived from the fetus itself. The fragile soft tissues can also cause problems such as “spontaneous” carotid-cavernous fistula, ruptures of large vessels, hiatus hernia, spontaneous rupture of the bowel, diverticula of the bowel, rupture of the colon, aortic dilatation, and retinal detachments (39, 40, 41, 42 and 43).

Classification and Etiology.

The tradition classification of EDS into 11 types (44) has been modified in a way that groups individuals with this disorder into 6 major types (45), based on clinical findings, genetic cause, and inheritance pattern (45) (Table 8-2). There additional subtypes of EDS, but these are very rare, often being reported as a single family. Although an understanding of the genetic cause of the rare types provides important information about how various proteins contribute to the maintenance of the mechanical integrity of the soft tissues, the infrequency of their occurrence makes their incorporation into a general classification scheme less useful to the clinician.

FIGURE 8-4. Patient with Ehlers-Danlos syndrome, type I. The knees and the pretibial regions have been subjected to recurrent injury and have accumulated heme pigmentation. (Courtesy of Michael G. Ehrlich, MD, Providence, Rhode Island.)

EDS is caused by mutations in either a collagen gene or in a gene that produces a protein that processes collagen. The types of EDS that are caused by a mutation in collagen are inherited in an autosomal dominant manner, whereas those caused by a protein processing defect (kyphoscoliotic and dermatosparaxis types) are inherited in an autosomal recessive pattern. Since collagen is the main structural component of a variety of connective tissues, it is easy to understand how these mutations cause the associated changes in soft-tissue mechanics (38, 46, 47).

There are several characteristics that are unique to the individual subtypes (48, 49 and 50). The hypermobility type, which is characterized by multiple dislocations of joints, is also associated with a delay in achieving developmental milestones, perhaps because of the dislocations. Individuals with this type have the greatest functional disability. The vascular type is associated with ruptures of vessels or viscera. Such events are rare in childhood, but by the age of 20, one-fourth of those with the condition will have had some vascular or visceral complication. Teenage boys may be at a higher risk for this during their prepubertal growth spurt (51). Early death occurs, most commonly because of vascular rupture, with the median age of survival being <50 years. Individuals with the kyphoscoliosis type often present as “floppy” infants, and this diagnosis should therefore be considered in such children. Although molecular diagnosis is possible for some of the subtypes, these are usually not needed for making the diagnosis, and referral to clinical geneticists is usually sufficient to confirm a diagnosis. There are no universally accepted criteria for restricting participation in physical activity in patients with EDS, so recommendations to limit activity should be made on an individual basis.

Orthopaedic Manifestations and Management.

Subluxations and recurrent dislocations of joints are common occurrences in the various subtypes. The chronic pain that such individuals complain of is often attributed to these subluxations. The management of the subluxations is problematic, and a multidisciplinary effort, including pharmacologic and
physical therapeutic approaches, is often required. As opposed to individuals with normal joint laxity, patients with this condition have patellar instability in multiple planes (39). Since the matrix components that provide the mechanical properties to the soft tissues are defective, surgical approaches focusing on ligaments and tendons (e.g., soft-tissue procedures around the shoulder) have a low success rate. A variety of such operations are reported, such as osteotomies, which change the direction and location of insertion of tendons or osteotomies or that provide a larger joint area (tibial tubercle transfer operations for patellar dislocations, and femoral and pelvic osteotomies for hip subluxation). Procedures that involve surgery to the bones have a higher success rate than operations on ligaments or tendons. In particularly problematic cases, it may be necessary to place a bone graft to limit motion and prevent dislocation (e.g., a posteriorly placed graft at the elbow). Arthrodesis may be required as a last resort in those cases that remain symptomatic despite other managements (52—54).

TABLE 8-2 A Modified Classification Scheme for Ehlers-Danlos Syndrome



Major Clinical Findings

Minor Clinical Findings

Genetic Etiology


Type I

Type II

Skin hyperextensibility

Wide scars

Joint hyperlaxity

Smooth skin (velvety)

Complications of joint hypermobility

Easy bruisability

Tissue fragility and extensibility resulting in hiatal hernia, anal prolapse, or cervical insufficiency

Family history

COL5A1 mutations


Type III

Skin hyperextensibility

Smooth velvety skin

Generalized joint hypermobility

Recurrent joint dislocations

Chronic joint dislocations

Family history



Type IV

Thin, translucent skin

Arterial, intestinal, or uterine rupture or fragility

Hypermobility of small joints

Tendon or muscle rupture


Varicose veins

COL24 7 tenascin-XFJ

Excessive bleeding

Arteriovenous or carotid-cavernous fistulas



Family history

History of sudden death in family


Type VI

Generalized joint laxity

Hypotonia at birth

Progressive infantile scoliosis

Tissue fragility

Easy bruisability

Arterial rupture

Lyslhydroxlyase deficiency

Marfanoid habitus

Scleral fragility

Rupture of the ocular globe



Family history



Severe generalized hypermobility

Skin hyperextensibility

COL1A1 or COL1A2 mutations

Tissue fragility


Congenital hip dislocation

Easy bruisability

Muscle hypotonia





Severe skin fragility

Sagging, redundant skin

Soft doughy skin texture

Easy bruising

Premature fetal membrane rupture


Procollagen 1 N-terminal peptodase

Scoliosis is common in EDS, and is usually managed using the same principles as those for idiopathic scoliosis, although there is a lack of studies investigating the implications of scoliosis in this population and the efficacy of this management approach. Surgical management can be problematic in the vascular type, as there are a number of complications, and vessel ruptures can occur during surgery (41, 55). It is important not to place undue stretch on vessels during surgery, and it is probably safest to have a vascular surgeon available in case a major disruption is encountered. Spondylolisthesis can occur, and it
may be present at multiple levels, including nonadjacent sites (42). Valve problems can occur in EDS, so patients should have a cardiac evaluation before undergoing surgery. Low bone density is identified in EDS; however, when one corrects for the activity level of these patients, the bone density may not be so abnormal (56). Pharmacologic treatment for low bone density should be considered only in rare instances.


There are a variety of cellular proteins and signaling pathways that are important in regulating cell reproduction or proliferation. A mutation that results in dysregulation of such pathways can increase cell proliferation, resulting in overgrowth of a cell type or an organ. Such pathways are frequently dysregulated in neoplasia. In some inherited conditions, when a single copy (one allele) of a gene that is important in regulating cell proliferation is mutated in the germ line, the result is an overgrowth phenotype, but when the second copy becomes mutated in a somatic manner (in a certain cell type), the result is the development of a tumor. Since these disorders are usually caused by one copy of the defective gene, they tend to be inherited in an autosomal dominant manner. The type of tissue or organ involved depends on the cell type in which the gene is expressed. In many syndromes, such as NF, the tissues of the musculoskeletal system are affected, resulting in obvious bone or soft-tissue abnormality. There is a risk of malignant progression, which develops over time as the cells are subjected to genetic damage (second hit), causing the loss of the normal copy of the causative gene. Recurrence of a deformity after surgery is not unusual, because the underlying genetic defect that causes abnormal cell growth cannot be corrected by any surgical procedure. Many children present with limb-length discrepancy, but most of these conditions will not be related to a syndrome and can be managed as described in Chapter 28 on limb-length inequality. It is important to understand the various associated syndromes so that appropriate referrals can be made for nonorthopaedic problems.


There are several forms of NF, the most common of which are type I and type II (NF1 and NF2). Orthopaedic manifestations are common in NF1, which is also called von Recklinghausen disease, whereas they are rare in NF2, which is also called central neurofibromatosis or familial acoustic neuroma. The clinical findings in NF1 are quite variable, and many of these findings develop over time. Children may exhibit none of the typical findings at birth, but the diagnosis can be made as they grow older and develop the characteristics necessary to confirm a diagnosis of NF1 (48, 57). Although a causative gene for NF1 has been identified, this diagnosis is made by identifying at least two of the clinical findings in Table 8-3.

TABLE 8-3 Neurofibromatosis Type I: Diagnostic Criteria

At least two of the following are necessary for establishing the diagnosis of NF1:

• At least six café-au-lait spots, larger than 5 mm in diameter in children, and larger than 15 mm in adults

• Two neurofibromas, or a single plexiform neurofibroma

• Freckling in the axillae or inguinal region

• An optic glioma

• At least two Lisch nodules (hamartoma of the iris)

• A distinctive osseous lesion, such as vertebral scalloping or cortical thinning

• A first-degree relative with NF1

Cutaneous Markings.

Café-au-lait spots are discrete, tan spots (Fig. 8-5). In patients with NF, these spots often appear after 1 year of age, and then they steadily increase in number and size. The spots have a smooth edge, often described as similar to the coast of California, as opposed to the ragged edge of spots associated with fibrous dysplasia, which are described as
similar to the coast of Maine. The spots vary greatly in number, shape, and size, and six lesions >1 cm in size are required for the diagnostic criteria. Axillary and inguinal freckling are common and serve as good diagnostic markers, because such freckling is exceptionally rare except in people with NF. Hyperpigmented nevi are dark brown areas that are sensitive to the touch; they typically overlie a deeper plexiform neurofibroma.

FIGURE 8-5. Neurofibromatosis in a 6-year-old child. Notice the large café-au-lait spot on the thigh and the anterior bowed tibia typical of pseudarthrosis. (From Goldberg MJ. The dysmorphic child: an orthopedic perspective. New York, NY: Raven Press, 1987, with permission.]

FIGURE 8-6. Neurofibromatosis in a 14-year-old patient. Cutaneous neurofibromas make their appearance with the onset of puberty. (From Goldberg MJ. The dysmorphic child: an orthopedic perspective. New York, NY: Raven Press, 1987, with permission.)


The two types of neurofibroma are different in their anatomic configuration and clinical morbidity. The most common is the cutaneous neurofibroma, composed of benign Schwann cells and fibrous connective tissue (Fig. 8-6). This type of neurofibroma may occur anywhere, but is usually just below the skin. These neurofibromas may not be detectable until 10 years of age, and with puberty there is a rapid increase in their number. When many are grouped together on the skin, it is known as a fibroma molluscum. Plexiform neurofibromas are usually present at birth and are highly infiltrative in the surrounding tissues. The overlying skin is often darkly pigmented. They are highly vascular and lead to limb gigantism, facial disfigurement, and invasion of the neuroaxis (Figs. 8-7 and 8-8).

Osseous Lesions.

There are many skeletal manifestations, but the presence of an unusual scoliosis, overgrowth of a part, or a congenital pseudarthrosis lesion seen on radiographs should alert the physician to consider a diagnosis of NF (58). There are a variety of anomalies of bone observed in radiographic images, ranging from a scalloping of the cortex, to cystic lesions in long bones that look much like nonossifying fibromas, to permeative bone destruction (Fig. 8-9). These radiographic findings may mimic benign or malignant bone lesions (49, 50, 59). Radiographs of the pelvis usually show various degrees of coxa valga, and in nearly 20% of patients there is radiographic evidence of protrusio acetabuli (52, 60).

Lisch Nodules.

Lisch nodules are hamartomas of the iris. These nodules are present in 50% of all 5-year-olds with NF1, and in all adults with NF1. It is unusual for Lisch nodules to be present in individuals who do not have NF1, so the detection of these nodules can aid in making this diagnosis. However, it may be difficult to detect these lesions, and patients should be sent to an experienced ophthalmologist for this diagnosis. The lesions do not cause any visual disturbances. Once the
diagnosis is established, further ophthalmologic evaluation is not necessary (53, 54).

FIGURE 8-7. Neurofibromatosis in a 16-year-old patient. The MRI at the level of L4-L5 demonstrates a large plexiform neurofibroma that invades the neural axis. It extends from the level of L3 to the sacrum.

FIGURE 8-8. Neurofibromatosis in a 10-year-old patient. Hypertrophy affects the arm from the shoulder to the fingertips; the major component is soft tissue. Nodular densities throughout the upper arm are consistent with a plexiform neurofibroma. Notice the lack of skeletal overgrowth and some attenuation of the radius and ulna, caused by external compression by the neurofibroma. (From Goldberg MJ. The dysmorphic child: an orthopedic perspective. New York, NY: Raven Press, 1987, with permission.)


NF is the most common single-gene disorder in humans, affecting 1 in 3000 newborns (61, 62 and 63). NF1 is an autosomal dominant disorder with 100% penetrance, but onehalf of cases are sporadic mutations and are associated with an older-than-average paternal age. The most well-known patient who was presumed to have had NF, Joseph Merrick, also called the Elephant Man, probably did not have this condition; his clinical profile better fits Proteus syndrome (64). The NF1 gene is located on chromosome 17 (65). Its protein product, neurofibromin, acts as a tumor suppressor (66). There are also other potential genes located in introns within the NF1 gene, whose functional significance is unclear.

Neurofibromin plays a role stimulating the conversion of Ras-GTP to Ras-GDP, and as such modulates activation of the Ras signaling system, which is involved in the control of cell growth (67). Mutations in the NF1 gene cause a disruption in its normal regulatory control of Ras signaling, giving affected cells an abnormal growth pattern. Neurofibromin is expressed at higher levels in the neural crest during development. Cells from the neural crest migrate to become pigmented cells of the skin, parts of the brain, spinal cord, peripheral nerves, and adrenals, thus explaining the common sites of abnormalities in the disorder. Disruption of the normal Ras signaling cascade is probably responsible for the malignant potential of this disorder. Only one of the two copies of the NF1 gene is mutated in affected patients; however, tumors from such individuals have been found to have only the mutated gene because of loss of the normal copy (68, 69, 70 and 71). The gene defect also gives a clue to potential novel therapies, because pharmacologic agents that block Ras signaling could be used to treat the disorder. Farnesyl transferase inhibitors block the downstream effects of Ras signaling activation and thus have the potential to be used in the treatment of some of the neoplastic manifestations of NF (72, 73). Another therapeutic approach is the use of statin inhibitors, such as lovastatin, which is thought to regulate Ras signaling by the membrane binding of Ras (52, 53).

FIGURE 8-9. Neurofibromatosis in a 10-year-old patient. The radiograph shows an array of cystic and scalloped skeletal lesions in the tibia and os calcis of the right leg. Some of the lesions are characteristic of neurofibromatosis. Other lesions, occurring in isolation, can mimic benign fibrous tumors. Scalloped cortical erosion at the upper end of the femur, permeative bone destruction in the region of the os calcis, and metaphyseal cystic lesions are other features. (From Goldberg MJ. The dysmorphic child: an orthopedic perspective. New York, NY: Raven Press, 1987, with permission.)

Other Types of Neurofibromatosis.

Although patients with other forms of NF rarely present to an orthopaedist, one should be aware of these types because musculoskeletal malformations are occasionally present. Patients with NF2 present with acoustic neuromas, central nervous system tumors, and rare peripheral manifestations. There are usually fewer than six café-au-lait spots, and no peripheral neurofibromata. These patients are very unlikely to present with an orthopaedic deformity. There are two much less common types of NF, type 3 and type 4 (NF3 and NF4), in which patients are more likely to develop a problem requiring orthopaedic intervention. Individuals with NF3 present with some of the characteristics of NF1 but also have acoustic neuromas, which are characteristic of NF2. These individuals often have spinal deformity, especially in the cervical region. NF4 presents with the same clinical findings as NF1, except that one of the cardinal features of NF1, namely, Lisch nodules of the iris, is absent (48, 57).

Orthopaedic Manifestations.

The orthopaedic manifestations of NF include scoliosis, overgrowth of the limbs, pseudarthrosis, and specific radiographic appearances of bone lesions. Patients with NF often exhibit overgrowth, ranging from a single digit to an entire limb and from mild anisomelia to massive gigantism. As such, the possibility of NF should be considered in a child with focal gigantism, such as macrodactyly. When NF is compared with the more symmetric idiopathic hemihypertrophy, there is disproportional overgrowth involving the skin and the subcutaneous tissue more than the bone (Fig. 8-8)

FIGURE 8-10. Neurofibromatosis in a 5-year-old patient. A dystrophic curve is shown in the left panel. There is a shortsegment scoliosis, with ribboned ribs show cystic irregularities. There was a delay in the recommendation for surgery, and the middle two panels show the rapid progression in the dystrophic curve over the next 12 months. The right panel shows the curve after undergoing surgery including anterior and posterior fusions of the dystrophic segments.

Scoliosis is common, and curves fall into two categories: a dystrophic curve and an idiopathic curve. Most curves in NF resemble idiopathic scoliosis curves and can be managed like any other idiopathic curve.

The dystrophic scoliotic curve is a short, sharp, single thoracic curve typically involving four to six segments (Fig. 8-10) (60, 74, 75, 76, 77, 78, 79, 80, 81). It is associated with deformity of the ribs and vertebrae. The onset is early in childhood, and it is relentlessly progressive. Curves that initially appear to be idiopathic in children under age 7 have almost a 70% chance of becoming dystrophic over time, although there may be subtle clues, for example, mild rib penciling (thinning of the ribs in a shape similar to a pencil point near the vertebrae), suggesting that the curve is actually dystrophic. The most important risk factors for progression are an early age of onset, a high Cobb angle, and an apical vertebra that is severely rotated, scalloped (concave loss of bone), and located in the middle-to-lower thoracic area (78). The combination of curve progression and vertebral malformation mimics congenital scoliosis in appearance and behavior. Dystrophic curves are refractive to brace treatment. Sagittal plane deformities may occur, including an angular kyphosis (i.e., gibbus) and a scoliosis that has so much rotation that curve progression is more obvious on the lateral than on the anteroposterior radiograph (78). In those with angular kyphosis, there is a risk of paraplegia. Dystrophic curves are difficult to stabilize, and it is best to intervene with early surgery involving both anterior and posterior fusion (78, 82, 83 and 84). Kyphotic deformities are often the most difficult to manage surgically, and strut grafts across the kyphosis anteriorly may be necessary. In rare
severe cases, the spine can even seem to be “dislocated” because of the kyphosis and scoliosis. In cases with extremely severe deformity, halofemoral or halogravity traction may be necessary to safely straighten the spine to a more acceptable deformity without producing neurologic sequelae. Other reported techniques include inserting a bone graft without instrumentation and then gradually straightening the curve using a cast postoperatively (85). In rare severe cases in which there is a vertebral “dislocation,” one can use instrumentation to achieve an overall alignment of the back, while leaving the vertebrae “dislocated” (86). Unusual complications have been reported in the management of such dystrophic curves, such as a rib head migrating into the neural canal resulting in spinal cord compromise (87).

There can be several vertebral abnormalities evident on radiographs. These include scalloping of the posterior body, enlargement of the neural foramina, and defective pedicles, occasionally with a completely dislocated vertebral body (88, 89, 90, 91 and 92). Such findings may mean that there is a dumbbell-shaped neurofibroma in the spinal canal, extending out through a neural foramina. The dura in NF patients behaves like the dura in patients with a connective tissue disorder, and dural ectasia is common, with pseudomeningoceles protruding through the neural foramina. Unlike neurofibroma, dural ectasia is an outpouching of the dura, without an underlying tumor or overgrowth of spinal elements (Fig. 8-11) (93, 94, 95 and 96). The incidence of anterolateral meningoceles was underestimated until asymptomatic patients were screened with MRI (58, 97). The erosion of the pedicles may lead to spinal instability, especially in the cervical spine. In rare cases, this can even lead to dislocation of the spine (98, 99). MRI and CT scans are helpful preoperatively in delineating the presence of defective vertebrae or dural abnormalities, and may assist in choosing the levels on which to place instrumentation.

Pseudarthrosis of a long bone is typically associated with NF (76). It usually affects the tibia, with a characteristic antero-lateral bow that is obvious in infancy (Fig. 8-12) (100, 101). Fracture usually follows, with spontaneous union being rare and surgical union presenting a challenge. An anterolateral bowed tibia is routinely managed with a total-contact orthosis to prevent fracture, although there are no well-designed studies showing that this is indeed effective. Intramedullary rod fixation seems to offer the best results for the initial management of a pseudarthrosis. Recent studies have shown the importance of achieving neutral tibial alignment in the healing of a tibial pseudarthrosis. The presence of an intact fibula is associated with a lower healing rate, perhaps because of associated tibial malalignment (102). There is a hamartoma of undifferentiated mesenchymal cells at the pseudarthrosis site (75), and in some cases, this is associated with loss of the normal allele of the NF1 gene (76). Neurofibromas have not been identified at the pseudarthrosis site. The pseudarthrosis process may affect the ulna, radius, femur, or clavicle (77, 103, 104, 105, 106, 107, 108 and 109). In each of these locations, there is a course similar to that in the tibia, with bone loss and difficulty in achieving union (Fig. 8-13). Not all pseudarthroses of the forearm require treatment (110), but if they are symptomatic, the available options include proximal
and distal synostosis to produce a single-bone forearm, the use of a vascularized fibula graft, or resection of the pseudarthrosis with shortening of the forearm and internal fixation (111). Pharmacologic approaches to the pseudarthrosis in NF are reported. A mouse model suggests the use of lovastatin, but the mouse does not develop pseudarthroses, only bowing of the bones, and as such human studies of this approach are needed (53). Direct installation of BMP to the pseudarthrosis site may help in the achievement of union, but variable results are reported, and it is not known if the use of BMP in patients with an inherited premalignant condition has long-term harmful consequences (80).

FIGURE 8-11. MRI of the spine of the patient shown in Figure 8-10, showing dural ectasia

FIGURE 8-12. Neurofibromatosis in a 1-year-old patient. The anterolateral bow of the tibia and the fibula warrant concern about impending fracture and pseudarthrosis. (From Goldberg MJ. The dysmorphic child: an orthopedic perspective. New York, NY: Raven Press, 1987, with permission.]

FIGURE 8-13. Neurofibromatosis in a 3-year-old patient. The radiograph shows progressive pseudarthrosis of the radius and ulna after a pathologic fracture. A: Fracture through the cystic lesion of the radius and thinning of the midulna. B: After 10 months of cast immobilization, pseudarthrosis affects the radius and ulna. (From Goldberg MJ. The dysmorphic child: an orthopedic perspective. New York, NY: Raven Press, 1987, with permission.)

There are a variety of benign and malignant neoplastic lesions that affect individuals with NF1. Most neurofibromas do not require treatment, but symptomatic lesions may require excision. Plexiform neurofibromas that become symptomatic are very difficult to manage. Their vascularity and infiltrative nature make complete excision almost impossible, with a substantial risk of uncontrollable hemorrhage and neurologic deficit. Although speculative, the use of angiogenesis inhibitors, such as interferon, or experimental agents that modulate the effect of the causative gene mutation, such as farnesyl transferase inhibitors or statin inhibitors, may be beneficial (88, 89).

The incidence of malignancy in NF is reported at rates ranging from under 1% to over 20% (90, 91 and 92, 112, 113). The most common tumor location is in the central nervous system, with lesions such as optic nerve glioma, acoustic neuroma, and astrocytoma (114). There is a risk of malignant degeneration of a neurofibroma to a neurofibrosarcoma. This process can occur in a central or peripheral neurofibroma (115, 116, 117 and 118). It can be quite difficult to distinguish a malignant lesion from a benign one. CT scans show areas of low-enhancing density in neurofibrosarcomas (119), but there are no studies confirming the sensitivity and specificity of this finding. Similar patterns can also be visualized using MRI. Routine surveillance for sarcomatous change is impossible because of the large number of neurofibromas. Lesions that increase in size or develop new characteristics should be investigated. There is a propensity for children with neurofibroma to develop other malignancies, such as Wilms tumors or rhabdomyosarcomas.

Hypertension as a result of renal artery stenosis or pheochromocytoma is reported regularly, as is a curious type of metabolic bone disease similar to hypophosphatemic osteomalacia (120, 121). Hypertension is a major risk factor for early death (113). Precocious puberty may occur because of an intracranial lesion (103). Affected children are short, but tend to have large heads. Approximately 50% have an intellectual handicap. Although the mean IQ is low, the range of IQ is quite wide (104). More than the low IQ, it is the difficulty in concentrating (which is common in this condition) that may interfere with the learning process (105). Although it was hoped that lovastatin might help with concentration problems, a recent randomized trial suggests that this is not the case (106).

Beckwith-Wiedemann Syndrome. Beckwith

Wiedemann syndrome is a triad of organomegaly, omphalocele, and a large tongue (107). The incidence is 1 in 14,000, and it is probably an autosomal dominant trait of variable expression. Patients are large, although this feature is not always noticed at birth (108). The child is in the 97th percentile for size by 1 year of age. The tongue is gigantic at birth, and although it tends to regress, hemiglossectomy is sometimes needed. Omphalocele is common, and 15% of the babies born with omphaloceles have Beckwith-Wiedemann syndrome. The abdominal viscera are enlarged, and a single-cell hypertrophy
accounts for the large organs: in the adrenals, giant cortical cells; in the gonads, an increased number of interstitial cells; and in the pancreas, islet cell hyperplasia. This underlies the 10% risk of developing benign or malignant tumors. Wilms tumor is the most common.

Beckwith-Wiedemann syndrome is linked to chromosome 11p15, which is near the Wilms tumor gene (11p13) and the insulin-like growth factor gene (11p15.5) (109). There may be some paternal genomic imprinting (122, 123). The closeness of the Beckwith-Wiedemann gene locus and these embryonal tumor gene loci accounts for the dysregulation of the tumor-related genes and the associated overgrowth and higher incidence of tumors seen in this syndrome.

Pancreatic islet cell hyperplasia causes hypoglycemia. It is crucial that the neonatologist diagnose this syndrome early so as to prevent the consequences of hypoglycemia. If it is not managed properly, seizures occur at day 2 or 3. Central nervous system damage from the hypoglycemia leads to a cerebral palsy—like picture. The cerebral palsy—like findings confuse the diagnosis of this syndrome and make the management of these patients more complex. The diagnosis can occasionally be made prenatally by ultrasound (124, 125).

The clinical feature that makes the orthopaedist suspect the presence of this disorder is the unusual combination of two otherwise common problems: spastic cerebral palsy and hemihypertrophy (Fig. 8-14). The spasticity is thought to be a result of the neonatal hypoglycemic episodes, especially if accompanied by neonatal seizures, but spastic hemiplegia is most commonly seen. In general, children with cerebral palsy tend to be small; Beckwith-Wiedemann syndrome should be suspected if a large child has spastic cerebral palsy. Asymmetric growth affects about 20% of the patients. It is usually true hemihypertrophy, but it can be significant if the spastic hemiplegia affects the smaller side.

Children with Beckwith-Wiedemann syndrome are predisposed to a variety of neoplasms, most notably Wilms tumor. Abdominal ultrasounds at regular intervals until the age of 6, to screen for Wilms tumor, are advocated. A series comparing a screened population (ultrasounds every 4 months) with a population that was not screened showed that none of the children in the screened group presented with late-stage Wilms tumor, whereas one-half of the children who developed Wilms tumor in the nonscreened group presented with late-stage disease. This study suggests that screening every 4 months will identify early disease. However, a larger study is needed to determine whether screening improves patient survival (125, 126). Other tumors types, such as alveolar rhabdomyosarcoma, can present in a new born (100).

Scoliosis is common and usually behaves like an idiopathic spinal deformity, but there may be insignificant morphogenic variations, such as 13 ribs. It is managed in the same way as any idiopathic curve. Other orthopaedic findings include cavus feet, dislocated radial heads, and occasional cases of polydactyly (127, 128). All of these can be managed the same as in sporadic deformities.

FIGURE 8-14. Beckwith-Wiedemann syndrome in an 8-year-old patient. Hemihypertrophy on the right, a part of this syndrome, is combined with hemiatrophy on the left, caused by acquired encephalopathy secondary to hypoglycemic seizures as a newborn, leading to a significant leg-length discrepancy of 4.6 cm. Abdominal scars are a consequence of omphalocele repair. (From Goldberg MJ. The dysmorphic child: an orthopedic perspective. New York, NY: Raven Press, 1987, with permission.)

Russell-Silver Syndrome.

The patient with Russell-Silver syndrome is defined clinically as a short child with body asymmetry and a characteristic facial shape (129—131) (Fig. 8-15). The diagnostic characteristics include (i) a birth weight ≤2 standard deviations below the mean, (ii) poor postnatal growth ≤2 standard deviations from the mean at diagnosis, (iii) preservation of occipitofrontal head circumference, (iv) classic facial features, and (v) asymmetric growth (132). Poor feeding is also a common occurrence. The cause of the disorder is unclear; although some cases are associated with uniparental disomy, there is a suggestion of autosomal dominant inheritance, and there is some evidence implicating an abnormal intrauterine environment (130, 131). The associated genitourinary malformations and the variation in the pattern of sexual maturation chemically (increased gonadotropin secretion) or clinically (precocious sexual development) suggest that hypothalamic or other endocrine disturbances may contribute to the pathogenesis. Affected children are small at birth and remain below the 3rd percentile throughout growth, with a marked delay in skeletal maturation. Body asymmetry with hemihypertrophy affects 80% of them. The asymmetry
averages approximately 2 cm at maturity, but can be as much as 6 cm. Regardless of the magnitude of the discrepancy, it is clinically more apparent because the child is small. The face is characteristically triangular and seemingly too small for the cranial vault. There have been several reports of variations in sexual maturation pattern and malformations of the genitourinary system.

FIGURE 8-15. Russell-Silver syndrome. The triangular face is seemingly small for the size of the skull.

Radiologic analysis discloses a remarkable array of orthopaedic findings, but it is not clear which form part of the syndrome and which are coincidental (133—137). Scoliosis is usually idiopathic. Hand and foot abnormalities include clinodactyly, polydactyly, and hallux varus. Developmental hip dysplasia, avascular necrosis of the femoral head, and slipped capital femoral epiphysis (SCFE) may be present. Many radiographic changes, such as the minor hand abnormalities, suggest a disturbed morphogenesis.

Treatment consists of managing leg-length equality. This can be difficult because individual growth curves may vary, the skeletal age is very retarded, and puberty may be very abnormal. It is easy to miss the appropriate timing for epiphysiodesis. Growth hormone has been administered in an attempt to improve stature. Although the use of growth hormone will increase growth velocity, it is not yet known whether the ultimate height is increased (138).

Cytogenetic studies found anomalies on chromosomes 1, 7, and 17, but most patients have anomalies involving chromosome 7. However, no single causative gene has yet been identified. It is not known whether screening for Wilms tumor, as is performed in other forms of hemihypertrophy, is necessary. Despite early evidence that the insulinlike growth factor receptor, which plays a causative role in Wilms tumor, is involved in this syndrome, more comprehensive molecular genetic investigations have not found any abnormalities in this gene. However, there is a case report of Wilms tumor developing in an affected patient (139), leading some to recommend screening for Wilms tumor in these patients as one would in any other hemihypertrophy.

Proteus Syndrome.

Proteus syndrome is an overgrowth condition in which there is a bizarre array of abnormalities that include hemihypertrophy, macrodactyly, and partial gigantism of the hands or feet, or both. The key to this diagnosis is worsening of existing symptoms and the appearance of new ones over time. There is a characteristic appearance to the plantar surface of the feet, often described as similar to the surface of the brain. Unlike in other overgrowth syndromes, an increased incidence of malignancy has not been reported in Proteus syndrome (140, 141, 142, 143 and 144).

The cause of this syndrome is not known. Although there are case reports of familial occurrence, the vast majority of cases are sporadic (145—147). It is most likely due to a gene that is mutated in a mosaic manner (mutated in the affected tissues but not in the normal tissues), similar to McCune-Albright syndrome (polyostotic fibrous dysplasia). Such a mutation can occur very early in development in a single cell, which will divide to ultimately form various structures throughout the body.

The Proteus syndrome is named after the ancient Greek demigod who could change appearance and assume different shapes. The progressive nature of the deformities seen in this syndrome can lead to grotesque overgrowth, facial disfigurement, angular malformation, and severe scoliosis (148). Joseph Merrick, called the Elephant Man, is now believed to have had this syndrome rather than NF (149).

The signs of Proteus syndrome overlap other hamartomatous overgrowth conditions, such as idiopathic hemihypertrophy, Klippel-Trenaunay syndrome, Maffucci syndrome, and NF. However, unlike these other syndromes, the features here are more grotesque and involve multiple tissue types and sites. Proteus can be differentiated from NF1 by the lack of caféau-lait spots and Lisch nodules (150). A rating scale, which assigns points on the basis of clinical findings (macrodactyly, hemihypertrophy, thickening of the skin, lipomas, subcutaneous tumors, verrucae, epidermal nevus, and macrocephaly), may be used to assist in diagnosis (151). However, the finding of worsening overgrowth features over time is usually sufficient to make this diagnosis.

Most children who present with macrodactyly do not have it as part of Proteus syndrome. In these sporadic cases, an isolated digit is involved or, when multiple digits are involved, these are located adjacent to each other. Macrodactyly affecting nonadjacent toes or fingers or opposite extremities is almost always due to Proteus syndrome. There is a characteristic thickening and deep furrowing of the skin on the palms of the hands and soles of the feet. The array of cutaneous manifestations includes hemangiomas and pigmented nevi of various intensities, and subcutaneous lipomas (Fig. 8-16). Varicosities are present, although true arteriovenous malformations are rare. There are cranial hyperostoses and occasionally exostosis of the hands and feet.

Macrodactyly seems to correspond to overgrowth along the terminal branches of a peripheral sensory nerve. Digital involvement in the hand favors the sensory distribution of the median nerve (1). The index is the most frequently affected
finger, followed by the long finger and the thumb. It is the second toe that is most commonly macrodactylous. The regional sensory nerve is greatly increased in size, taking a tortuous route through the fatty tissue.

FIGURE 8-16. Proteus syndrome. Notice the cutaneous markings, large hemangioma of the shoulder, and lightly pigmented area on the back. There is some atrophy of the shoulder and arm muscles and a fixed contracture of the elbow.

There is a wide range of orthopaedic deformities, including focal and regional gigantism, scoliosis, and kyphosis (152, 153). Rather large vertebral bodies, known as megaspondylodysplasia, are present (154). Angular malformations of the lower extremities, especially genu valgum, are common. Because the genu valgum is often associated with restricted range of motion, flexion contractures, and pain in the joints, it is postulated that an intra-articular growth disturbance contributes to the angular malformation. Hip abnormalities that show up in roentgenographic tests, acetabular dysplasia for example, are frequently discovered in asymptomatic patients. Deformities in the hindfoot are frequent and are usually heel valgus, but congenital equinovarus and “Z-foot” deformities have also been described (150, 153, 155).

Recurrences after various surgical intervention are very common. This is probably due to an underlying growth advantage in affected tissues that cannot be corrected operatively. Thus, musculoskeletal deformities caused by Proteus syndrome can be very difficult to manage. When the foot becomes difficult to fit into a shoe because of macrodactyly, it is best managed by ablation rather than debulking (156). Anisomelia is best managed with epiphysiodesis. Osteotomies can correct angular malformations, but the decision to undertake surgical correction must take into account the possibility of a rapid recurrence of the deformity after corrective surgery (152, 153). The use of growth modulation (e.g., 8-plate) to manage limb angular deformity is a rather promising approach (120), but publications on the results of this approach are lacking. In some cases, a sudden overgrowth of the operative limb has been reported. There are anecdotal reports of soft-tissue procedures to “debulk” overgrown lesions; however, there are no series in the literature reporting results of these procedures, and our experience with them is that the results are only temporary. In rare cases, nerve or spinal cord impingement can occur. Nerve compression can be managed using decompression, but spinal cord compression is difficult, if not impossible, to successfully treat operatively (157, 158). Scoliosis can occur and seems to be caused by overgrowth of one side of the spine (159). Since mixed results are obtained from surgical treatment in this disorder, operative treatment should be reserved for individuals who have exhausted nonsurgical management. Sometimes, the operative procedures can be used as a temporizing measure, and patients may need to have repeat procedures performed throughout life.

Functional ability depends on the severity of the limb deformity and the presence of intracranial abnormalities (143, 160). The life expectancy is unknown, but many adult patients have been reported. Intubations can be difficult because of overgrowth of structures surrounding the trachea.


During embryonic development, cell signaling systems are activated in a coordinated manner to cause cells to proliferate, move, and undergo programmed cell death, so as to allow the organism to pattern normally and develop into an adult. Normal patterning is altered by mutations in the genes that encode proteins that play roles in these pathways. Environmental events such as exposure to a teratogen can also dysregulate these same pathways, resulting in a phenotype similar to that of a gene mutation. Such events occurring in a pathway that is important for skeletal development can result
in a musculoskeletal malformation. These disorders can be identified at birth, because the problem is present at the start of development. Despite this, sometimes, the abnormalities do not become obvious to parents or physicians until the child is older. Because these are generally patterning problems, surgery to correct malalignment is usually quite successful. There are frequently manifestations in other organ systems, because the same developmental signaling pathways play important roles in the development of multiple organs. These disorders are not associated with an increased rate of neoplasia. Symptoms from the malformations often increase with age because the abnormally shaped structures cannot sustain the stresses of normal activity. This results in the early development of degenerative problems. These disorders are usually inherited in an autosomal dominant manner, although the inheritance pattern is more variable than in disorders caused by genes encoding for structural proteins or for proteins implicated in neoplasia.

Nail-Patella Syndrome.

Children with nail-patella syn drome have a quartet of findings that include nail dysplasia, patellar hypoplasia, elbow dysplasia, and iliac horns (161). The most prominent feature is dystrophic nails (Fig. 8-17A). The nail may be completely absent, hypoplastic, or have grooves and distortions in its surface (162). The thumb is more involved than the small finger, and the ulnar border more involved than the radial. The hands are often very symmetric, and fingernails are more involved than toenails.

The second cardinal feature is hypoplastic patellae (163). They are quite small, or may be entirely absent (Fig. 8-17B). Where present, they are unstable, and may be found in a position of fixed dislocation. The patellar abnormality highlights the total knee dysplasia, with an abnormal femoral condyle and a peculiar septum running from the patella to the intercondylar groove (septum interarticularis), dividing the knee into two compartments. Abnormalities in varus and valgus alignment occur, with valgus more common because of the small, flat lateral femoral condyle (163).

A third feature is a dislocated radial head (163, 164) (Fig. 8-17C). The elbow joint is dysplastic, with abnormalities in the lateral humeral condyle, in many ways mimicking the dysplasia of the knee. The trochlea is large and the capitellum is hypoplastic, creating an asymmetric shape that may predispose the radial head to dislocation.

The fourth and pathognomonic feature is iliac horns: bony exostoses on the posterior surface of the ilium (165) (Fig. 8-17D). They usually cannot be found on physical examination, are asymptomatic, and require no treatment.

Nail-patella syndrome is caused by a mutation in the LMX1B gene. This gene is a homeodomain protein, which plays a role regulating transcription in limb patterning during fetal development. Mutation in the gene will disrupt normal limb patterning and alter kidney formation, resulting in deformities in the extremities and an associated nephropathy (166).

Children with the syndrome have short stature, the height being between the 3rd and 10th percentiles. There may be a shoulder girdle dysplasia, and a variety of abnormalities of the glenoid and the humeral head are possible. These, however, merely represent curious radiographic features and not any significant functional disability (167). There is a foot deformity that is sometimes the chief presenting complaint of children with nail-patella syndrome (163, 168). The foot deformities include variations of stiff calcaneal valgus, metatarsus adductus, and clubfeet.

There is a restricted range of motion, and contractures affect several large joints; these include knee-flexion deformities and external rotation contracture of the hip. When these contractures are severe and accompanied by stiff clubfeet, the condition may be misdiagnosed as arthrogryposis multiplex congenita. Madelung deformity, spondylolysis, and in some adults, inflammatory arthropathy may be present (161, 169, 170).

Knee disability is variable and related to the magnitude of quadriceps dysfunction and the dislocated patella. At longterm follow-up, knee pain is the main musculoskeletal complaint in patients with nail-patella syndrome (171). Small femoral condyles make it difficult to achieve patellar stability. As a rule, limited soft-tissue or capsular releases are ineffective, but combined proximal and distal patella realignments have an overall favorable outcome (163, 172). A contracted and fibrotic quadriceps may result in a knee extension contracture, and in such cases quadricepsplasty is indicated along with the patella realignment. More commonly, an associated kneeflexion deformity may require hamstring release and posterior capsulotomy, although results have been inconsistent (163). Residual deformity, which is usually related to flexion or rotation, is managed by femoral osteotomy toward the end of the first decade of life. Osteochondritis dissecans of the femoral condyle is relatively common (Fig. 8-17B). An intra-articular septum makes arthroscopic management difficult, but the septum can be removed arthroscopically.

The radial head dislocation is asymptomatic in young children, but may become symptomatic with time. In symptomatic individuals, excision of the radial head will improve symptoms arising from the prominent lateral bump, but the range of motion is rarely improved. Although traditional teaching advocates performing radial head excision after skeletal maturity, earlier excision in symptomatic children does not seem to be associated with significant problems (163). Dislocated hips (173) and clubfeet can occur, and can be managed using techniques similar to those in idiopathic cases.

The most important nonorthopaedic condition is kidney failure. The nephropathy of nail-patella syndrome causes significant morbidity, affecting the patient’s longevity. There is great variability in the age at onset and severity of the nephropathy (174). All patients should be referred for a nephrology evaluation when this diagnosis is made. Patients may go on to chronic renal failure, requiring long-term nephrology management.

Goldenhar Syndrome.

The association of anomalies in the eye, ear, and vertebrae are termed ocular—auricular—vertebral dysplasia or Goldenhar syndrome (175). There is variability in the

severity of the anomalies and they are frequently associated with other malformations (176, 177). It has an estimated incidence of 1 in 5600 births (178), and roughly 2% of individuals with congenital spinal abnormalities will have another manifestations of ocular—auricular—vertebral dysplasia (138).

FIGURE 8-17. Nail-patella syndrome. The classic quartet of features consists of dystrophic nails (A), absent patellae (notice the region of osteochondritis dissecans on the lateral film) (B), posterior dislocation of the radial head (C), and iliac horns (D).

The typical eye defect is an epibulbar dermoid on the conjunctiva (Fig. 8-18A). Preauricular fleshy skin tags are found in front of the ear, and pits extend from the tragus to the corner of the mouth (Fig. 8-18B). In some patients, the ear may be hypoplastic or absent. The eye and ear anomalies are unilateral in 85% of these children, and facial asymmetry is the result of a hypoplastic mandibular ramus, invariably on the same side as the ear anomalies (Fig. 8-18C).

Vertebral anomalies may occur anywhere along the spine, although the lower cervical and the upper thoracic locations predominate (Fig. 8-18C). Hemivertebrae are the most common defect, with an occasional block fusion. Neural tube defect occurs more often than in the general population, and it may involve any portion of the spine, or even the skull (an encephalocele). Half of the patients have clinically detectable scoliosis (179).

FIGURE 8-18. Goldenhar syndrome. A: Facial asymmetry and epibulbar dermoid of the right eye. B: Malformed ears with preauricular tags and sinuses. C: X-ray film demonstrates the congenital anomalies of the lower cervical and the upper thoracic spine. Hypoplasia of the ascending ramus of the mandible accounts for the facial asymmetry. The clavicle is absent on the same side as the deformation of the face. (From Goldberg MJ. The dysmorphic child: an orthopedic perspective. New York, NY: Raven Press, 1987, with permission.)

The congenital curve can cause cosmetic concerns, but these need to be considered in the context of the other abnormalities, which may outweigh the cosmetic implications of the spinal deformity. In addition, Sprengel deformity and rib anomalies may be present in association with the congenital curves in the cervical—thoracic region, and these contribute to the cosmetic implications of the condition. The congenital curves should be managed like congenital scoliosis of other etiologies, although management based on cosmetic concerns needs to be made in the context of the other deformities. Early surgery should be considered when there is progression of the congenital curve. Preoperative CT scan and MRI are recommended to delineate the anatomy of the congenital curve and determine whether there is any intraspinal pathology or occult posterior element defects.

There is frequently a compensatory curve below the congenital curve that can behave like idiopathic scoliosis. The compensatory curve can cause as much, if not more of a problem for the patient as the congenital curve. This curve is managed the same as idiopathic scoliosis. Brace treatment has no effect on the congenital curve, and although orthotic management has been used for the compensatory curve, its success rate seems lower than for idiopathic scoliosis although high-quality comparative studies of its efficacy are lacking.

Intubation for anesthesia may be difficult because of the small jaw, stiff neck, and upper airway dysmorphology (180). Other anomalies include congenital heart disease (e.g., ventricular septal defect) (176), cleft lip, and cleft palate (181). Mental retardation, reported to affect between 10% and 39% of patients, is more common in cases involving microphthalmia or an encephalocele (143, 182).

Cornelia de Lange Syndrome.

Cornelia de Lange syndrome is associated with a characteristic face, and growth retardation, which makes the clinical diagnosis of Cornelia de Lange syndrome reasonably reliable (183). The face has immediately recognizable downturned corners of the mouth, eyebrows meeting in the midline (synophrys), elongated philtrum, and long eyelashes (184, 185) (Fig. 8-19).

Mutations in a number of genes, which all regulate the same signaling pathway, are identified in Cornelia de Lange syndrome. About half of affected individuals have a mutation in the N1PBL gene, which encodes a protein that is a component of a multiprotein complex, called the cohesin complex. The mutation alters the activity of a developmentally important signaling pathway called Notch (186, 187). Notch plays a major role in central nervous system development, hence the associated mental retardation. An X-linked form of the disorder can be caused by mutation in the SMC1L1 gene, which also encodes a component of the cohesin complex. A mild variant of Cornelia de Lange syndrome is related to mutation in the SMC3 gene, which encodes yet another component of the cohesin complex. Duplication or deletion of the chromosome band 3q25-29 produces a phenotype similar to Cornelia de Lange syndrome (188, 189). In these instances, the mother is always the transmitting parent, suggesting genomic imprinting. The syndrome is relatively common, occurring in 1 in 10,000 live births, and it is possible to make a prenatal diagnosis by ultrasound (135, 136, 190, 191).

FIGURE 8-19. Cornelia de Lange syndrome. Notice the classic facial features of heavy eyebrows meeting in the midline, upturned nose, downturned corners of the mouth, and long eyelashes in a 13-year-old boy (A) and a 7-year-old girl (B). (From Goldberg MJ. The dysmorphic child: an orthopedic perspective. New York, NY: Raven Press, 1987, with permission.)

Most have mild orthopaedic deformities of the upper extremities (191, 192, 193, 194, 195, 196 and 197) (Fig. 8-20). They form a curious constellation of a small hand, a proximally placed thumb, clinodactyly of the small finger, and decreased elbow motion, usually caused by a dislocated radial head. This combination rarely causes any disability. Some patients, however, have severe deformities of the upper extremity in the form of an absent ulna and a monodigital hand, a condition that can be unilateral or bilateral (Fig. 8-20).

The lower extremities are less often affected. Tight heel cords and other cerebral palsy—like contractures can be seen. These can be managed similarly to cerebral palsy, but there seems to be a higher rate of recurrence (198). Syndactyly of the toes is fairly constant. Aplasia of the tibia has been reported rarely. There is possibly a higher incidence of Legg-Perthes disease, approaching about 10%. Scoliosis can occur and should be managed similarly to scoliosis in cerebral palsy. Most of the skeletal deformities in Cornelia de Lange syndrome are asymptomatic and probably do not benefit from surgical intervention (198).

The small size begins with intrauterine growth retardation. Children remain small, with a delayed skeletal age. The mortality rate in the first year of life is high because of defective swallowing mechanisms (199), gastroesophageal reflux (200), aspiration, and respiratory infections. If the children survive their first year, they usually do well, but the long-term outcome is unclear.
Almost all of them walk, but their milestones are delayed. There is retarded mentation, but the added features of no speech and no interactions cause major disability (201). Self-mutilating behavior can be an obstacle to orthopaedic care (202, 203).

FIGURE 8-20. Cornelia de Lange syndrome: a child with a severely affected upper extremity on her right side (i.e., absent ulna and fingers) and a mildly affected arm on her left (i.e., short thumb and dysplasia of proximal radius). (From Goldberg MJ. The dysmorphic child: an orthopedic perspective. New York, NY: Raven Press, 1987, with permission.)

Orthopaedic interventions need to be considered in the overall functional context of the individual. Braces, physical therapy, and surgery for tight heel cords, using similar indications as in cerebral palsy are justifiable. Upper extremity surgery is not indicated unless improved performance capacity is ensured. Patients with Cornelia de Lange syndrome rarely if ever use upper extremity prostheses. Lower extremity prostheses, however, should be prescribed for the rare case with tibial deficiency. Because the gastroesophageal reflux and swallowing disorders may persist well past the first year, there is a higher risk of anesthesia complications (204).


Syndromes caused by problems in the fetal environment can share similarities with conditions caused by genes that encode proteins that are important in normal development. Many teratogenic agents modulate the same pathways that are dysregulated by the mutations that cause such syndromes. A good example of this is holoprosencephaly, a midbrain patterning disorder. This can be caused by mutations in a gene called sonic hedgehog, and can also be caused by teratogenic agents that block the hedgehog signaling pathway, such as derivatives found in the plant Veraculum californium (205, 206).

Fetal Alcohol Syndrome.

Fetal alcohol syndrome is a pattern of malformations found in children of alcoholic mothers. There is a great deal of variability in the findings associated with fetal alcohol exposure and the full-blown syndrome is usually seen only in children of chronic alcoholics who drink throughout pregnancy. Multiple terms are used to describe the effects that result from prenatal exposure to alcohol, including fetal alcohol effects, alcohol-related birth defects, alcoholrelated neurodevelopment disorder, and, most recently, fetal alcohol spectrum disorder (207). Although the risk to alcoholic mothers is known, there is substantial difference of opinion about the effects of moderate alcohol use during pregnancy (208—210). This is in part because fetal exposure to alcohol may be relatively common. Indeed, it is estimated that about 12% of U.S. women who are sexually active, do not use contraception effectively, and drink alcohol frequently or binge drink, thereby putting them at risk for an alcohol-exposed pregnancy. As such, alcohol is the most likely teratogen for a mother to encounter (211). Because no safe threshold of alcohol use during pregnancy has been established, the Centers for Disease Control recommend that women who are pregnant, planning a pregnancy, or at risk for pregnancy should not drink alcohol. The overall incidence of full-blown fetal alcohol syndrome is reported to be between 0.5 and 2.0 per 1000 live births (212, 213), making this condition as common as Down syndrome. For an alcoholic mother, there is a 30% risk for fetal alcohol syndrome in her child.

A cardinal clinical feature is disturbed growth; the children have intrauterine growth retardation, small weight, and small length at birth, and these limitations remain despite good nutrition during childhood (214, 215) (Fig. 8-21). Their smallness and a loss of fat suggest a search for endocrine dysfunction; the patients often look similar to those who are deficient in growth hormone. The second cardinal feature is disturbed central nervous system development. Children with fetal alcohol syndrome present with a diagnosis of cerebral palsy clinics. The typical child has a small head, a small brain, and delayed motor milestones. Accomplishing fine motor skills is also delayed. Hypotonia is present early, but many develop spasticity later. The typical face has three characteristic features: short palpebral fissures (i.e., the eyes appear small), a flat philtrum (i.e., no groove below the nose), and a thin upper lip (216, 217) (Fig. 8-21). Because of the variety of clinical features, a joint consensus conference sponsored by the Centers for Disease Control suggested that a diagnosis of fetal alcohol spectrum disorder requires all three of the characteristic dysmorphic facial features (smooth philtrum, thin vermillion border, and small palpebral fissures), prenatal or postnatal growth deficit in height or weight, and a central nervous system abnormality.

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Jul 21, 2016 | Posted by in ORTHOPEDIC | Comments Off on Syndromes of Orthopaedic Importance
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