Alan Rope
The connective tissues are a challenging entity to define precisely in isolation, as they are a component of every system of the body. They can be characterized as an ordered array of cells and extracellular matrix (specific protein fibers and amorphous ground substance). From a functional perspective, connective tissues provide structure, support, protection, delineate tissue boundaries, and serve as a medium for cellular transport, nutrient exchange and storage and play an especially significant role in the normal operation of skeletal, dermatologic, cardiovascular, humoral, and sensory systems.
From a histologic perspective, connective tissues are primarily composed of an extracellular, proteinaceous substance or matrix secreted from chief cells that populate the localized region. Connective tissues are usually described by these chief cells and the matrix they manufacture. The chief cells are almost entirely derived from the mesoderm and include fibroblasts, osteocytes, chondrocytes, mast cells, myocytes, lymphoid cells, adipose cells, macrophages, and granulocytes. The many different forms of collagen account for the vast majority of protein fibers that are found within the matrix. Other important proteins include elastin, fibronectins, laminins, and fibrillins. The amorphous ground substance is primarily composed of glycosaminoglycans, proteoglycans, and glycoproteins.
Disorders of connective tissue are segregated by their associated medical complications and comorbid features. It is important to realize that these manifestations (Table 181-1) are nonspecific to an individual diagnosis and may present, to some degree, within the entire community of these disorders. Having a good knowledge base regarding the signs and symptoms of connective tissue disease will enable the identification of individuals with connective tissue disease and those who are potentially at medical risk. The distinctive, recognizable syndromes will tend to have more pronounced and medically important characteristics. In addition to revised treatments of the Marfan and the Ehlers-Danlos syndromes, the Stickler syndromes and the newly characterized Loeys-Dietz syndromes will also be presented in this chapter.
MARFAN SYNDROME
Marfan syndrome is a potentially life-threatening disorder with cardinal features involving cardiovascular, skeletal, and ocular systems as well as the dural coverings. It is caused by mutations in the gene FBN1, that encodes the extracellular matrix glycoprotein fibrillin 1; this gene localizes to chromosome 15q21. The majority of affected individuals inherit an FBN1 mutation from a parent, but roughly 25% of cases are de novo mutations, with a higher incidence associated with advancing paternal age. Mutations of FBN1 disrupt the structure and/or function of fibrillin-1, contributing to the formation of microfibrils, which play a role in the structural integrity of the tissues they support. Histopathology reveals fragmentation and loss of elastic fibers and accumulation of amorphous matrix components in the aortic media. Although corruption of structural integrity has been implicated, there is mounting evidence that the impaired ability of fibrillin-1 to keep the latent transforming growth factor beta (TGFβ) complex in its inactive form may be a major contributor to the pathophysiology of this condition through dysregulation of this growth factor.1 Increased signaling of TGFβ has been observed in the developing lung, the mitral valve, and the ascending aorta in models of this condition. Mutant forms of fibrillin-1 are believed to have a dominant-negative effect, interfering with the function of the wild-type protein. Genotype–phenotype correlations do not have a predictable association in Marfan syndrome, with the exception of neonatal Marfan syndrome (Fig. 181-1). These individuals will more typically have mutations of FBN1 found within exons 24 through 32.2
Table 181-1. Features of Connective Tissue Dysplasias
Many individuals with Marfan syndrome are ascertained by recognition of typically associated skeletal manifestations, but screening individuals based upon their family history is also very important. Marfan syndrome is transmitted in an autosomal-dominant pattern with nearly complete penetrance, but with variable expression. The diagnosis of Marfan syndrome is made by satisfying sufficient clinical criteria (Table 181-2).3 Major manifestations in at least two of the cardinal systems with major or minor involvement of another system must be seen (Fig. 181-1). Evaluation of individuals suspected as having Marfan syndrome typically includes formal ophthalmologic characterization, echocardiography, and formal review and examination by medical genetics. Molecular analysis of FBN1 can serve a purpose in individuals presenting with borderline features, for prenatal/presymptomatic screening for a known familial mutation and to distinguish between conditions with overlapping clinical manifestations. A fatal aortic dissection is the most significant complication associated with Marfan syndrome and monitoring of the aorta is the focus of lifelong evaluation and intervention. The incidence of the Marfan syndrome has been estimated at 1 in 5000 in all populations.
FIGURE 181-1. (A) Arachnodactyly, (B) Walker-Murdoch “wrist”, (C) Steinberg “thumb” sign. Sternal deformities resulting from overgrowth of the ribs include pectus excavatum (D) and pectus carinatum (E). This individual’s foot is disproportionately long and thin with pes planus (F) owing to displacement of the medial malleolus. A typical high, narrow palate (G), and (H) shows lens displacement (ectopia lentis) from distended zonular suspensory fibers (Courtesy of David Dries, MD). Stretch marks or striae of the skin are shown in (I). Significant dilation of the aortic root is demonstrated by 3D reconstruction from MR (J) and angiography (K) (Courtesy of Michael Puchalski, MD), and dural ectasia seen on an MRI of the lower spine (L) (Courtesy of Gary Hedlund, DO).
Cardiovascular manifestations are the most medically important features of Marfan syndrome and include dilation of the aortic root at the level of the sinuses of Valsalva and ascending aorta, possibly leading to dissection and/or rupture. The aortic dilation may be appreciated at birth, but is more typically seen later in childhood or early adolescence and is progressive, with a significantly increased risk for dissection or rupture as the aortic diameter exceeds 5.0 cm. Beta-blockers (β-B) have traditionally been employed to produce negative chronotropic and inotropic effects, with the hypothesis that this would ultimately reduce the rate of dilation and dissection. Research models have suggested that other agents such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor antagonists (ARB) could play a significant role in the pharmaceutical management of the disease by decreasing the amount and suppressing the effect of bioavailable TGFβ. A double-armed multi-center, prospective clinical trial comparing the effect of atenolol (β-B) with losartan (ARB) is currently in progress. Incompetence of the aortic valve can occur as the vessel enlarges and distends the aortic annulus. Anticipatory surgical intervention aims to replace the aortic root before the structure and function of the aortic valve is compromised, as there is a better outcome associated with this management. There are special considerations for the evaluation and treatment of the aorta in pregnancy that are not covered in this chapter.
Mitral valve prolapse with subsequent congestive heart failure can be seen in a younger population and may require surgical intervention. Less common features include triscuspid valve prolapse and enlargement of the proximal pulmonary artery. In addition to medical management including annual evaluation by cardiology, affected individuals are advised to avoid strenuous exercise and activities that have a risk for high-energy contact, such as competitive sports. However, restriction of activity in younger children is rarely necessary.
Skeletal manifestations are usually seen as disorders of growth and joint mobility and contribute to a stereotypic appearance. Although not a major criterion, individuals with Marfan syndrome may have a recognizable constellation of facial features that include a narrow face with downward-slanting palpebral fissues, flatter cheek bones, a high and/or narrow arched palate, and a smaller chin. Dolichostenomeliais the term for extremities that are disproportionately long and lead to an increase in the arm span-to-height and upper-to-lower segment ratios. Rib overgrowth can push the sternum inward (pectus excavatum) or outward (pectus carinatum) and may require surgical correction. Scoliosis is relatively common, can be progressive, and may require surgical intervention as well. Arachnodactyly is a hallmark feature and is determined by the presence of both the wrist and the thumb signs, also known as the Walker-Murdoch and Steinberg signs, respectively (Fig. 181-1). Pes planus is a common characteristic, but is more specific to the diagnosis when there is inward displacement of the medial malleolus. Another characteristic feature is the protrusio acetabuli, an abnormally deep setting of the femoral head in the hip socket, which may become progressively erosive in the joint. Joint laxity is common with Marfan syndrome, especially in the distal extremities, but limited mobility can also be seen, most commonly at the elbows.
Table 181-2. Ghent Criteria for the Diagnosis of Marfan Syndrome
The most common ocular anomaly of Marfan syndrome is myopia, which is often significant enough to require correction in early childhood. Far more specific to the diagnosis is ectopia lentis, or displacement of the lens, which is eventually appreciated in more than 50% of affected individuals. Iridodonesis (cine-iridodonesis), or tremor of the iris, may be an early manifestation of this feature. This phenomenon is attributed to weakness and/or distension of the zonular suspensory fibers, which attach to the lens. Over the course of a lifetime, individuals with Marfan syndrome are at increased risk for retinal detachment, glaucoma, and cataracts, necessitating regular ophthalmologic evaluation and care.
The chronic pulse wave of cerebrospinal fluid may cause progressive erosion of the vertebral bodies and out-pouching dural coverings and is known as dural ectasia, which is seen by MRI or CT of the lower spine. Dural ectasia may be asymptomatic or may cause orthostatic headaches or nerve entrapment with associated pain and dysfunction.
Dermatologic manifestations of Marfan syndrome are nonspecific, but include incisional hernia and striae distensae (stretch marks), usually following rapid growth and most often seen over the lower back, shoulders, axilla, chest, hips, thighs, and knees. Affected individuals typically lack the same proportion of subcutaneous adipose stores and might be said to have an asthenic appearance. Pulmonary manifestations of Marfan syndrome are also non-specific and include an increased risk for spontaneous and traumatic pneumothorax and apical blebs or bullae.
A number of conditions, for example, MASS phenotype (MASS, Mitral valve prolapse, nonprogressive Aortic enlargement, Skin and Skeletal findings), share significant clinical overlap with Marfan syndrome,4 suggesting a commonality in pathways involving fibrillin-1 and TGFβ. The major difference between MASS and Marfan is that the aortic enlargement is nonprogressive, with no risk for dissection or rupture. The condition requires continued cardiac evaluation and is more of a diagnosis of exclusion. Familial ectopia lentis may have skeletal manifestations similar to Marfan syndrome, but is without cardiovascular manifestations. Familial thoracic aneurysm syndrome is caused by mutations of FBN2, and is distinguished by a lack of noncardiovascular manifestations. Beals congenital contractural arachnodactyly syndrome is caused by mutations of FBN2, and shares some of the skeletal manifestations seen in Marfan syndrome. Recent data imply that some individuals with Beals syndrome have an associated, nonprogressive aortic dilatation, but the condition is distinguished by its congenital contractures and crumpling of the ears. Loeys-Dietz syndrome (to be covered in greater detail below) is associated with mutations of TGFβR1 and TGFβR2 and has many skeletal features of Marfan syndrome. It is distinguished by its rapidly progressive aortic involvement and features not typically associated with Marfan syndrome, such as craniosynostosis, cleft palate, and atrial septal defect. Shprintzen-Goldberg syndrome is a condition manifesting with craniosynostosis, dolichostenomelia, arachnodactyly, pectus deformity, and scoliosis, but is more commonly associated with neurocognitive involvement including developmental delays and Chiari malformation. Homocystinuria is an autosomal recessive inborn error of metabolism that typically manifests with Marfan-like skeletal changes, aortic dilation, and ectopia lentis. Neurocognitive impairments may be present, as well as an increased risk for thrombosis and coronary artery disease. Lujan syndrome is an X-linked mental retardation syndrome with skeletal features reminiscent of Marfan syndrome. Klinefelter syndrome is exclusively seen in males and caused by a chromosome imbalance, 47,XXY. The condition is characterized by an increased risk for neurocognitive impairments, gynecomastia, delayed puberty, and infertility, but overlaps with Marfan syndrome by manifesting with occasional mitral valve prolapse, skeletal disproportion, and joint hypermobility.
THE EHLERS-DANLOS SYNDROMES
The Ehlers-Danlos syndromes (EDS) are a diverse community of disorders with similar associated manifestations including hyperextensible of the skin, hypermobile joints, easy bruisability, dystrophic scarring, and variable cardiovascular manifestations. Abnormalities of mature collagen structures are common to all of them and they are subcategorized by their predominating features and molecular characterization. Although other forms exist, the classic, hypermobile, vascular, and kyphoscoliotic subtypes, as defined by the Villefranche nosology, will be specifically covered.5
The EDS classic type is the most common form and is typically associated with mutations of genes encoding for type V (COL5A1, COL5A2) and type I collagen (COL1A1). Dermatologic features predominate in this subtype and include soft, hyperextensible skin—best evaluated in areas not subject to mechanical stress and difficult to appreciate in very young children because of subcutaneous fat stores, molluscoid pseudotumors, subcutaneous spheroids, piezogenic papules (small herniations of subcutaneous fat), easy bruising, abnormal wound healing, atrophic scar tissue, and hernias.
The EDS hypermobility type is distinguished by joint hyperextensibility (Table 181-3; Fig. 181-2)6 with the absence of significant involvement in other organ systems as an important negative finding. A clear etiology for this form has not been identified, but some affected individuals have an associated autosomal dominant mutation of tenascin X (TNXB) and type III collagen. Complications of joint hyperlaxity are common, including subluxation and dislocations occurring with minimal mechanical forces or even spontaneously. Degenerative joint disease and chronic disabling and debilitating pain can long-term complications. The skin may have a soft or velvety texture and mild elasticity is sometimes seen, but atrophic scarring is unusual.
The Ehlers-Danlos syndrome (EDS) vascular type is characterized by arterial aneurysm and rupture, intestinal perforation, translucent skin, easy bruising, polyarthropathies, a characteristic facial appearance (Fig. 181-3), uterine rupture, progeroid features, and is by far the most severe form of EDS, with a risk for a significantly shortened lifespan because of its associated complications. It is estimated that 25% of affected individuals will experience a significant medical complication by age 20. The arterial aneurysms are particularly hard to manage surgically, as the vessels are often described as friable and not amenable to anastomosis.7 The diagnosis of the EDS vascular type is based on clinical findings, and confirmed by analysis of type III procollagen from cultured fibroblasts and/or identification of mutations in COL3A1.
The EDS kyphoscoliotic type is characterized by kyphoscoliosis, joint laxity, hypotonia, and fragility of the optic globe, although vascular involvement has also been associated, including dilation and rupture of arteries. The condition is caused by deficiency of the procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1; lysyl hydroxylase 1), and is distinguished from other forms of EDS as being autosomal recessive, while the other forms described above are inherited in a dominant fashion. The diagnosis of this form is based on clinical findings and detection of an increased ratio of deoxypyridinoline to pyridinoline cross-links in urine,8 which is measured by high performance liquid cheomatography (HPLC). Furthermore, the lysyl hydroxylase activity can be directly measured in cultured skin fibroblasts and supported by mutations found in the associated gene, PLOD1.
Table 181-3. Beighton’s Criteria for Hypermobility
Other forms include the dominant arthrocalasia type, featuring congenital hip dislocation, severe hypermobility, and soft skin; the recessive dermatosporaxis type, featuring extreme skin fragility, sagging, and redundant skin; the recessive valvular type caused by mutations in COL1A2, with joint hypermobility, skin hyperextensibility, and cardiac valvular defects; an X-linked classic type, and others.
There is a long list of nonspecific signs and symptoms associated with the Ehlers-Danlos syndromes, many of which may be unaddressed or stigmatizing for the affected individual. Chronic pain leading to sleep disturbance, fatigue, fibromyalgia, depression, and headaches is a significant comorbid feature for individuals with EDS. Hypotonia may occur and may cause delayed gross motor development and clumsiness. Some individuals also experience frequent muscle cramping. Dental issues include temporomandibular dysfunction, periodontal disease, and a high palate with associated dental crowding. Hematologic issues include easy bruising, and prolonged bleeding may be seen in the absence of typical laboratory anomalies. The gastrointestinal tract can be affected by reflux, sometimes associated with hiatal hernia, but also gastritis that is often refractory to the spectrum of typical treatments. Irritable bowel syndrome, diverticulitis, and rectal prolapse may also occur. Mitral valve prolapse, stable aortic root dlilation, atypical chest pain, palpitations, and orthostatic intolerance are sometimes found. Generalized tissue dysfunction may manifest with an increased risk for inguinal, umbilical, and incisional hernias. Although not usually considered a pediatric issue, maternal complications of Ehlers-Danlos syndrome may include progression of aortic dilation and aneurysm, premature rupture of membranes, cervical incompetence, and uterine rupture.
FIGURE 181-2. Beighton scale montage. Scoring 9 out of 9 on the Beighton scale, this girl demonstrates hyperextension of knees (17°), fifth metacarpal joint, wrist, hips, and elbow (21°).
FIGURE 181-3. Child with Ehlers-Danlos vascular type. Although her features are subtle, she has prominence of the eyes, deeper orbits, smaller alae nasi, a thinner upper lip, and a relatively small chin.
Tailored medical management of individuals with Ehlers-Danlos syndrome comes from the ability to anticipate, recognize, and maintain low threshold to evaluate for potential associated complications. Some manifestations benefit from treatment and may have an improved prognosis with early detection and intervention by subspecialists. Primary prevention of comorbid features can be useful and in most instances treatments are fairly standard. With primary muscular hypotonia and joint laxity, gross motor delays and dysfunction of coordination may benefit from physical therapies and some strength training. Special evaluations are not typically needed. Chronic joint laxity can also lead to degenerative arthritis, subluxation, and dislocation. Preventive measures include muscle group conditioning and avoidance of injurious activities. Radiographs have a role in identifying orthopedic issues that may require bracing, reduction, or surgical intervention. Acute injuries may be amenable to standard pain management, but a more chronic process may benefit from evaluation and intervention from a subspecialty pain clinic and sometime psychiatry. Wound and incision management require special consideration, in that the skin and underlying tissues are closed without tension, with sutures applied to both surface and deeper tissues. Cutaneous sutures are generally left in place for twice the average length of time. Consideration for more careful monitoring of wound closure and healing is also suggested. Management of wounds and abnormal scarring management by plastic surgery may be indicated, but this intervention does not always improve outcomes. Ascorbic acid supplementation has been advocated for improved wound healing and prevention of bruising, although this has not been well studied. Systematic management of cardiovascular features is not regularly employed outside of the vascular and valvular forms, but there is increasing evidence that these features are found in many of the subtypes and conservative management encourages screening affected individuals for mitral valve involvement and aortic dilation, as detection and interventions may significantly impact outcomes. There is no standardized guideline for bone health screening, but screening for osteopenia with dual energy x-ray absorptiometry (DEXA) scans and use of supplementary vitamin D has been recommended in some instances. The vascular subtype of Ehlers-Danlos syndrome demands special considerations because of the risk of catastrophic complications. Affected individuals should seek immediate medical attention for sudden, unexplained deficits of neurologic function, visceral, and cranial pain. Pregnant women affected with the vascular type of Ehlers-Danlos syndrome should unequivocally be followed in a high-risk obstetrical program. Although periodic surveillance of the primary arterial tree with MRI or CT is recommended, arteriography is contraindicated because of the risk of vascular injury with this relatively invasive technique. Almost all forms of contact sports and strenuous exercise are discouraged.
LOEYS-DIETZ SYNDROME
Loeys-Dietz syndrome (LDS) is a recently delineated connective tissue dysplasia characterized by aggressive vascular disease, craniofacial findings, skeletal manifestations, and dermatologic involvement. The diagnosis is split into two subtypes based on the predominance of craniofacial features (type I) seen in approximately 75% of individuals, or cutaneous involvement (type II) found in the remaining 25%9(Fig. 181-4).
Loeys-Dietz syndrome is probably somewhat heterogeneous, but to date, only mutations of TGFβR1 and TGFβR2 have been shown to associate with this condition.10 As in Marfan syndrome, changes to these gene products (TGFβ-receptors) directly impact the regulation and activity of TGFβ signaling and probably accounts for much of their overlapping features. LDS is inherited in an autosomal dominant fashion and it occurs in all populations, though the actual prevalence is unknown. There is no appreciable difference of phenotype in individuals who have LDS due to mutations TGFβR1 or TGFβR2. Furthermore, the same mutation has been known to associate with type I and type II LDS. The vast majority of mutations confer changes to the intracellular portion to the gene product.
Loeys-Dietz syndrome is usually characterized by four major groups of clinical findings: Vascular: Generalized vessel tortuosity (usually of the head and neck) and aneurysms, aortic dilation (which has been reported on prenatal imaging11) and dissection (cases < 12 months of age and at dimensions much smaller than in Marfan have been reported). Skeletal: Cervical subluxation, kyphosis, scoliosis, spondylolisthesis, pectus excavatum or pectus carinatum, joint laxity, camptodactyly, contractures, dolichostenomelia, arachnodactyly, pes planus and talipes equinovarus. Craniofacial: Macrocrania, hypertelorism, malar hypoplasia, bifid uvula/cleft palate, micro-retrognathia, craniosynostosis resulting in dolicho-, brachy-, or trigonencephalies. Cutaneous: Velvety and translucent skin; easy bruising; dystrophic scars. Other important findings include a higher incidence of atrial septal defects, mitral valve prolapse, gastrointestinal perforations and uterine rupture. Less common findings include CNS anomalies such as the Chiari malformation, dural ectasia, and developmental delays.
Due to the rapidly progressive nature of the cardiovascular disease,12 it is necessary to ascertain the diagnosis in a timely manner, as early identification of Loeys-Dietz syndrome (LDS) is necessary to initiate appropriate medical surveillance and interventions. Though non-specific, the newborn with LDS may present with macrocrania, hypotonia, arthrogryposis and palate anomalies13; and in fact, otolaryngology may become an important discipline contributing to the ascertainment of affected children. A substantial clinical overlap is seen between Marfan, forms of Ehlers-Danlos, other related disorders (already covered above), and Loeys-Dietz syndrome, supporting the hypothesis that there are common pathways of gene regulation, signaling and physiology.14 Molecular confirmation of LDS by TGFβR1 or TGFβR2 sequence analysis is available on a clinical basis, but experience is teaching us that the pheno-type can be found in individuals with no identifiable mutations in these associated genes.
FIGURE 181-4. Loeys-Dietz syndrome montage. Subtle facial features of Loeys-Dietz syndrome are seen in these unrelated children, including macrocephaly, prominence of the forehead, hypertelorism, a thinner upper lip, and a relatively small chin. A magnetic resonance angiogram (MRA) of the neck and angiography isolating left-sided vessels in the same individual demonstrate significant tortuosity of the internal carotid arteries and a degree of vessel dilation.
At the time of suspected or confirmed diagnosis, the following evaluations are recommended: echocardiography to determine the relative size of the aortic root, head to pelvic MRI or CT with 3D reconstruction to identify arterial aneurysms, and tortuosity. Tortuosity may require intervention by a cardiothoracic or vascular surgeon, spine radiographs to detect treatable scoliosis, and/or cervical spine instability, which may require intervention by orthopedics, formal ophthalmologic examination by an ophthalmologist to rule out lens involvement (as it has not been associated with LDS to date), and assessment for retinal involvement.
Special management of LDS includes screening for occult, but potentially serious complications of the cardiovascular and skeletal systems. Although early in onset and progressive, the vascular disease is far more amenable to surgical interventions than that in Ehlers-Danlos type IV. Other manifestations are treated based on presenting features. As in Marfan syndrome, pharmaceutical stabilization of the aortic root is attempted with β-adrenergic blockade, angiotensin-coverting enzyme (ACE) inhibitors, and angiotensin receptor antagonists, but evidence of their efficacy has not yet been established in this condition. As with Marfan syndrome, affected individuals are advised to avoid strenuous exercise and activities that have a risk for high-energy contact such as competitive sports.
STICKLER SYNDROME
Stickler syndrome is a heterogeneous, dominant disorder of connective tissue with manifestations of affecting craniofacial development, ocular, auditory, and skeletal systems. No consensus criteria exist for Stickler syndrome, but a diagnosis is generally made on a clinical basis; consideration for the disorder should occur if two of the four systems are affected by typical manifestations. Very high myopia, retinal detachment, profound hearing loss, and Robin sequence are classic features of the condition. Stickler syndrome is further categorized into one of three subtypes based on the predominant features15 (Table 181-4). Variable expressivity of features is common even within the same kindred. Stickler syndrome is relatively common, with a population frequency estimated at 1 in 10,000.
Procollagen genes COL2A1, COL11A1, and COL11A2, which contribute to the formation of type II and type XI collagen, are expressed in the eye and cartilage and are associated with the condition. Haploinsufficiency for the procollagen monomer is thought to be the underlying pathologic mechanism, rather than a dominant-negative effect.
Typical craniofacial features include midface hypoplasia, giving a flat facial profile, a low nasal bridge, anteverted nares, micrognathia, and cleft palate (Fig. 181-5). In fact, Stickler syndrome is the most common identified etiology (approximately 25%) for the Robin sequence16 (micrognathia, cleft palate, glossoptosis) and should be considered as a potential etiology in all newborns with that presentation.
Ocular manifestations include high myopia, more pronounced than –3 diopters in the neonatal period and progressing beyond 5 diopters in childhood. Congenital or early onset of cataracts, especially “fleck cataracts,” glaucoma, vitreous anomaly, chorioretinal atrophy, and retinal detachment, are also associated with Stickler syndrome.
Audiologic manifestations include chronic middle ear disease as a comorbid feature of cleft palate, sensorineural, and conductive hearing impairments. The hearing loss is typically in the higher frequencies and mild for the type 1 syndrome, but may be progressive and profound for type 2 Stickler syndrome.
Skeletal features include manifestations of a mild spondyloepiphyseal dysplasia with delayed ossification of the vertebrae, femoral heads, pubis, and calcanei. The vertebral bodies may be ovoid to flat, with an increased frequency of scoliosis and kyphosis and the coxa vara deformity. Shorter stature is more common, but Marfanoid proportions have been described in some. In either case, relative arachnodactyly is frequently encountered. Joint hypermobility progressing to arthritis and chronic pain are also associated.
Allelic variants of Stickler syndrome often have a significant degree of clinical overlap and are usually classified as skeletal dysplasias. The most well-known of these include Kniest dysplasia, associated with COL2A1 and distinguished by disproportionate short stature, numerous radiographic features, and cleft palate with or without the Robin sequence; Marshall syndrome, associated with COL11A, similar to type 2 Stickler syndrome, and distinguished by a more pronounced facial appearance that persists beyond childhood and dermatologic involvement such as hypotrichosis and hypohidrosis; and Weissenbach-Zweymuller syndrome, a recessive form associated with COL11A2, distinguished by its pattern of inheritance, the presence of rhizomelic shortening, and vertebral clefting.
Table 181-4. Classification of Stickler Syndromes
FIGURE 181-5. Stickler montage. (A, B). Infant with typical features of Stickler syndrome, including a flat face because of midfacial hypoplasia, prominence of the eyes, telecanthus, a low nasal root, an upturned nasal tip, and Robin anomaly, being actively treated with mandibular distraction. A toddler with very similar facial features (C), and visible cleft of the soft palate (D).
Individuals suspected of having Stickler syndrome should have baseline evaluations by ophthalmology and audiology. An osseous survey may be a consideration, but would be more important as a tool to ascertain specific features of the allelic variants. Molecular analysis of the three associated genes is clinically available, but is not utilized in most circumstances.
As with all underlying etiologies, management of the Robin sequence in infancy may require specialized feeding systems and tracheostomy or mandibular advancement to protect the airway from obstruction (see Chapter 371). Myopia can be addressed with prescription lenses, but annual follow up with ophthalmology is important to screen for treatable cataracts, glaucoma, and progressive retinal disease. Owing to associated middle ear involvement, there should be a low threshold to place pressure equalization tubes to protect against conductive losses. Because hearing impairment can be progressive and severe, hearing aids may be necessary and regular follow-up with audiology is recommended. Mild skeletal manifestations may not require special interventions, but evaluation by physical therapy and orthopedics should be considered to identify correctable deformities. Chronic pain may be a significant issue and is an important feature to treat appropriately.