Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Heritable connective tissue disorders
Key Points
- ■
Heritable disorders of the skeleton and connective tissues are individually rare but collectively constitute an important source of morbidity and mortality.
- ■
Improved diagnostic classification criteria allow more accurate prognostication for disorders such as Marfan syndrome, Ehlers-Danlos syndrome, and osteopetrosis.
- ■
Over the past 40 years, the individual genes causing most of these disorders have been identified, paving the way for accurate molecular diagnosis and improved genetic counseling.
- ■
Whole-exome and whole-genome sequencing is now a practicable method for identifying the underlying cause in individual cases where the diagnosis is not clear clinically.
- ■
Knowledge of the underlying mutations in a few rare genetic disorders has resulted in the development of highly effective treatments.
- ■
Understanding the mechanisms behind rare genetic skeletal disorders has also yielded crucial insights for the treatment of common conditions, such as osteoporosis.
Introduction to Genetic Disorders of the Skeleton and Associated Soft Tissues
Several hundred discrete monogenic skeletal disorders are recognized. Individually, these conditions are generally rare (birth incidence <1 : 10,000), but together they constitute an important source of mortality, morbidity, and social disability. Many of these disorders have profound lifelong consequences on the bones, joints, and associated soft tissues, and it is important that all clinicians should have at least some understanding of them. Although it is impossible for most practitioners to have an intimate knowledge of all the conditions included in this section, it is nevertheless important that they should have the basic skills required for their recognition, investigation, and management. The following account provides an outline of some of the more important rare monogenic skeletal disorders and related conditions. For more detailed reviews, interested readers are referred to more comprehensive texts and the online compendium “Mendelian Inheritance in Man.”
Some well-defined but extremely rare monogenic disorders have revealed the mechanisms underlying normal bone physiology and actually led to novel strategies for treating bone diseases such as osteoporosis. These include several phenotypes affecting bone density. Healthy bone relies on the normally closely regulated balance between bone formation (osteoblasts) and its breakdown (osteoclasts). Reduced bone mass or density can result either from impaired synthesis or increased catabolism of bone; the reverse is true for conditions of excessive bone density. Further, impaired bone synthesis itself is multifactorial; causes include (1) deleterious mutations in extracellular matrix (ECM) proteins; (2) abnormalities in enzymes that modify matrix components; (3) abnormalities in growth factors; or (4) loss of function in modifiers of these factors, such as antagonists of bone morphogenetic protein (BMP). Thus the causes of heritable bone fragility are numerous; for example, various conditions associated with osteoporosis, including the brittle bone syndrome osteogenesis imperfecta (OI), hypophosphatasia, and osteoporosis pseudoglioma syndrome are superficially similar in many ways (phenocopies), but careful examination reveals that they actually have quite distinct phenotypes, and each has its own underlying genetic cause (genotype).
Disorders of Bone Density
Hyperostosis and sclerosis of bone can be caused by activating mutations in bone morphogenetic factors (BMPs—members of the transforming growth factor-β [TGF-β] superfamily that also includes TGF-β itself) or inactivating mutations in their natural inhibitors (e.g., sclerostin and noggin). Thus Camurati-Engelmann syndrome (MIM131300), in which there is characteristic cortical enlargement of the diaphyses of the long bones, reflects underlying activating mutations in TGFB1 , a potent bone mitogen. In contrast, another hyperostostic phenotype, sclerosteosis (MIM269500, an extremely rare recessive cause of massive hyperostosis typically occurring in a few population isolates due to a founder population effect) results from inactivating mutations in SOST (sclerostin), an inhibitor of bone formation that acts by sequestering BMPs.
In certain rare monogenic disorders mimicking Paget disease, the normally tight regulation of bone formation and resorption breaks down because of abnormal activation of osteoclasts; this results in osteolysis and dramatically altered skeletal architecture. The reasons for this became clear when the underlying causal mutations in the RANK (receptor activator of nuclear factor-κB [NF-κB])–RANKL (RANK ligand) pathway were identified. The resulting insights into bone physiology have now been harnessed for the treatment of osteoporosis. Thus in familial expansile osteolysis (MIM174810), activating mutations in RANK also known as TNFRSF11A —tumor necrosis factor receptor superfamily member 11A—cause abnormal unbalanced osteoclast activation and excessive resorption of bone. RANK is a cell surface receptor on osteoclast precursors that stimulates their differentiation toward active, mature, multinucleate bone-resorbing osteoclasts. It is normally activated by RANKL, which is produced by activated osteoblasts, thereby revealing one of the means by which osteoclast activity in health is coupled to that of osteoblasts. In the related disorder, juvenile-onset familial Paget disease (MIM239000), mutations in the same pathway, but in this case recessive inactivating mutations in osteoprotegerin (OPG, also known as TNFRSF11B —a decoy receptor for RANKL) also result in excessive RANKL/RANK-mediated activation of osteoclasts, leading to the osteolytic bone disease characteristic of both disorders. The crucial role of RANKL in regulating the fine balance in bone turnover has now been exploited in the treatment of osteoporosis. The therapeutic monoclonal antibody denosumab targets RANKL to reduce RANK-mediated osteoclast activation, which tips the balance in favor of bone formation, increased bone density, and reduced fracture risk. Adding to the complexity of this system it has also recently been shown that soluble RANK from activated osteoclasts forms part of a feedback loop by reverse signaling through membrane-bound RANKL on activated osteoblasts.
Skeletal Dysplasias
The skeletal dysplasias are also included here; these include a range of conditions in which there are skeletal abnormalities typically associated with short stature. In this section we have included the chondrodysplasias, dysostoses, and craniosynostoses. The chondrodysplasias are generalized disorders of bone in which the bony abnormalities are caused by abnormal endochondral ossification secondary to abnormal cartilage growth in the developing skeleton. In contrast, the dysostoses affect a restricted set of bones usually at a specific stage in their development. The craniosynostoses most obviously involve the skull but often affect other parts of the skeleton too. The underlying mechanisms operating in the chondrodysplasias are broadly similar to those in OI and the other brittle bone syndromes: for example, abnormalities in the structural genes for cartilage matrix components, such as type 2 collagen (COL2A1) , cartilage oligomeric matrix protein (COMP) , or type 9 collagen (COL9A1, 2, or 3), give rise to different types of epiphyseal dysplasias; abnormalities in processing enzymes (e.g., the sulfate transporter SLC26A2 , which is important in the sulfation of proteoglycans in the cartilage matrix ground substance) cause type 4 multiple epiphyseal dysplasia (MIM226900) and the more severe diastrophic dysplasia (MIM222600); and inactivating mutations in growth factor receptors are involved in some disorders (e.g., PTHR1 , parathyroid hormone receptor 1 in Jansen-type metaphyseal dysplasia), but in others, there are activating mutations (e.g., FGFR3 , fibroblast growth factor receptor 3 [FGFR3] in achondroplasia; PTHR1 in Blomstrand metaphyseal dysplasia). Many of these conditions can be recognized from their clinical or radiographic appearances ( Table 216.1 ), but with the development of rapid DNA sequencing methods, genetic diagnosis is increasingly practicable, potentially even in those with unique syndromes. The clinical phenotypes of a selection of these disorders are presented in the following sections.
Table 216.1
Main Clinical and Radiographic Features of Selected Skeletal Dysplasias
Modified from Smith R, Wordsworth P: Clinical and biochemical disorders of the skeleton, 2nd ed. Oxford: Oxford University Press; 2016.
| Disorder | Main Clinical Features | Relevant Radiographic Changes | Form of Inheritance |
|---|---|---|---|
| Osteogenesis imperfect | Varies with type (see Table 216.10 ) | Variable multiple fractures; Wormian bones | Mostly AD |
| Type 2 achondrogenesis | Perinatal lethal; striking micromelia | Poorly ossified pelvis; unossified vertebral bodies; short ribs; short, broad femora with cupped metaphyses | AD |
| Spondyloepiphyseal dysplasia congenital | Variable severity, severe short-limbed short stature with short spine, myopia and retinal detachment, extensive secondary arthritis | Short bones; delayed ossification; proximal femora mainly affected; platyspondyly develops with age; odontoid, often hypoplastic; sometimes metaphyseal involvement (Strudwick form) | AD |
| Kniest dysplasia | Short trunk and extremities, joints enlarged, progressive contractures, myopia, hearing loss | Flattened wedged vertebrae, dumbbell long bones, capital femoral epiphyses fuse late | AD |
| Stickler syndrome (at least three forms) | Typical flat face, cleft palate, eye problems (in type 1), hearing loss, mild dysplasia | Degenerative joint changes, mild irregularities of the epiphyses and spine | AD |
| Multiple epiphyseal dysplasia (EDM, numerous forms; see text) | Mild generalized arthritis, painful joints, waddling gait | Mild abnormalities of epiphyses, especially hips | Almost all AD |
| Metaphyseal chondrodysplasia (type Schmid) | Short stature, bow legs, coxa vara | Growth plate widened; metaphysis cupped and ragged; similar to rickets | AD |
| Pseudoachondroplasia | Short stature, short limbs, lax ligaments, severe hip disease, normal face | Vertebrae flat and beaked, deformed femoral heads | AD |
| Diastrophic dysplasia | “Hitchhiker” thumb, “cauliflower” ears, progressive joint contractures, scoliosis, severe short stature | Phalangeal, metacarpal, and metatarsal abnormalities; kyphoscoliosis; epiphyseal dysplasia | AR |
| Type 2 atelosteogenesis | Features of severe diastrophic dysplasia, perinatal lethal | Similar to diastrophic dysplasia | AR |
| Type 1B achondrogenesis | Invariably lethal; severe micromelia | Severe shortening of limbs, rudimentary ossification of vertebrae and pelvis | AR |
| EDM 4 | Moderately severe joint disease | Double-layered patellae, irregular epiphyses | AR |
| Metaphyseal dysplasia (Jansen type) | Very rare; short stature, enlarged joints, hypercalcemia | Short tubular bones, irregular mineralization of expanded metaphyses | AD |
| Campomelic dysplasia | Most neonatal lethal with sex reversal of XY males | Bowed femurs and tibias; hypoplasia of the scapula, pelvis, and ribs | AD |
| Chondrodysplasia punctata (Conradi syndrome): many forms; see text | Heterogeneous group; severe rhizomelic form, short stature, multiple contractures, skin lesions | Stippled epiphyses in all forms | Variable; X-linked form (lethal in males) |
| Achondroplasia | Rhizomelic short limbs, trident hand, short fingers, midface hypoplasia, large head, spinal stenosis | Tubular bones, short and wide with flared metaphyses; lumbar interpedicular distance narrows L1 to L5 | AD |
| Hypochondroplasia | Moderately short stature; near normal appearance | Mild changes only | AD |
| Thanatophoric dysplasia | Perinatal lethal, large head, narrow thorax, very short limbs | Short femora, H-shaped vertebrae, short ribs, “clover-leaf” skull | AD |
| Crouzon syndrome | Craniosynostosis | Craniosynostosis | AD |
| Apert syndrome | Craniosynostosis, digital abnormalities | Craniosynostosis | AD (but nearly all sporadic) |
| Cleidocranial dysplasia | Absent or hypoplastic clavicles, open fontanelles, supernumerary teeth | Wormian bones, absent or underdeveloped clavicles | AD |
| Multiple hereditary exostoses | Progressive exostoses near metaphyses | Multiple exostoses | AD |
| SED tarda | Short spine from adolescence, short stature, males only | “Heaped-up” appearance of posterior vertebral body | X-linked recessive |
| Cartilage-hair hypoplasia (metaphyseal chondrodysplasia, McKusick type) | Severe short stature, thin blond hair, cellular immune deficiency | Short tubular bones, cupped metaphyses, abnormal hands | AR |
| Chondroectodermal dysplasia (Ellis-van Creveld syndrome) | Short limbs at birth, polydactyly, ASDs in many, abnormal teeth | Spur above medial acetabulum, tubular bones short with club-shaped ends | AR |
| SED tarda with progressive arthropathy | Joint contractures, expansion ends of phalanges, short stature | Flattened vertebral bodies, progressive deformity femoral heads, expanded ends tubular bones | AR |
| Spondyloepimetaphyseal dysplasia (short limb, abnormal calcification type) | Short limbs and short narrow trunk, hypertelorism, broad nose, atlantoaxial instability | Platyspondyly and odontoid hypoplasia, calcific stippling of the bones, short tubular bones and ribs | AR |
AD , Autosomal dominant; AR , autosomal recessive; ASD , atrial septal defect; EDM , multiple epiphyseal dysplasia; SED , spondyloepiphyseal dysplasia; SEDC , spondyloepiphyseal dysplasia congenita.
Only a brief outline of these disorders and their classification into related subgroups is given here. Included are selected examples of the clinical, biochemical, genetic, and radiographic parameters that facilitate diagnosis along with some guidelines for their management. The complex nature of many of these disorders requires the involvement of multidisciplinary specialist teams (including rheumatology, pediatrics, orthopedics, endocrinology, radiology, genetics, psychology, physiotherapy, nursing).
Marfan Syndrome (MIM154700) and Related Conditions
Marfan syndrome (MFS) is a dominantly inherited connective tissue disorder with an estimated birth incidence of between 1 in 5,000 to 15,000. It is probably best known for its extraskeletal features, including ocular lens dislocation, thoracic aneurysms, and aortic dissection, but there are also many musculoskeletal signs ( Table 216.2 ). The pathology of the vascular consequences of MFS is well described. There may be massive dilatation of the aortic root with “cystic medial necrosis” (fragmentation and disarray of the elastic fibers, reduction in smooth muscle cells, and separation of the smooth muscle fibers by collagen and mucopolysaccharide).
Table 216.2
Systemic Features Found in Marfan Syndrome With Corresponding Scoring
From Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476–85.
| Feature | Score |
|---|---|
| Wrist and thumb sign | 3 |
| Wrist or thumb sign alone | 1 |
| Pectus carinatum | 2 |
| Pectus excavatum or chest asymmetry | 1 |
| Hindfoot valgus deformity | 2 |
| Flat thin foot alone | 1 |
| Spontaneous pneumothorax | 2 |
| Dural ectasia on MRI | 2 |
| Protrusio acetabuli on pelvic x-ray | 2 |
| Reduced upper segment or lower body segment ration and increased arm-to-height ratio (in absence of severe scoliosis) | 1 |
| Scoliosis (≥20 degrees) or thoracolumbar kyphosis | 1 |
| Elbow contracture (≥15 degrees) | 1 |
| Facial features (dolichocephaly, enophthalmos, downward-slanting palpebral fissures, malar hypoplasia, retrognathia: 3/5) | 1 |
| Skin striae | 1 |
| Myopia >3 diopters | 1 |
| Mitral valve prolapse (all types) | 1 |
| Maximum total 20 points; score ≥7 indicates systemic involvement | |
MRI , Magnetic resonance imaging.
Most cases are caused by mutations in FBN1 , the gene encoding fibrillin 1, but there is some genetic heterogeneity with about 10% of cases caused by mutations in other genes (see later). FBN1 is the major component of the 10-nm microfibrils that are distributed widely through the tissues. They are highly conserved from jellyfish to humans, but their organization and biology are still incompletely understood. They constitute the scaffold for the deposition of tropoelastin in elastic tissues, but they can also form independent structures, such as the suspensory ligament of the ocular lens. This probably accounts for most (but not all) of the clinical manifestations of MFS. Some features probably reflect rather more complex mechanisms than simple mechanical failure of the elastic tissues. The pathophysiology of Marfan syndrome also involves abnormal interactions between fibrillin and other components of the ECM and growth factors sequestered therein, such as TGF-β. Fibrillins are cysteine-rich glycoproteins belonging to the TGF-β–binding family of proteins, which includes FBN1, 2, and 3 and four latent TGF-β–binding proteins (LTBPs), each of which shares an 8-cysteine domain that is unique to these proteins. Fibrillins also contain multiple repeats homologous to the calcium binding epidermal growth factor module. These domains both play key roles in determining the secondary structure of the fibrillin by influencing its folding. The N-terminus of FBN1 interacts with the C-terminus of LTBP1, which in turn is bound to inactive TGF-β (noncovalently bound to its latency associated peptide) in a large latent complex. FBN1 interacts with many other components of the ECM, including proteoglycans and integrins. In this way, TGF-β is sequestered in the ECM, where it is normally maintained in the inactive state. FBN1 mutations seem to interfere with the interactions between LTBP1 and the FBN1 microfibrils, thereby reducing the sequestration of latent TGF-β complexes and increasing the amounts of locally active TGF-β. Some of the potential consequences of this imbalance are shown in Fig. 216.1 . Phenotypes related to Marfan syndrome, such as Loeys-Dietz syndrome (MIM609192), have their origins in another part of the TGF-β pathway as a result of mutations in the TGF-β receptor that increase signaling. A family of distinct but related conditions known as the fibrillinopathies is now recognized ( Table 216.3 ).
Table 216.3
The Fibrillinopathies
| FBN1 | Marfan syndrome (MIM 154700) |
| Familial ectopia lentis (MIM 129600) | |
| Isolated Marfan-like body habitus | |
| Familial isolated aortic disease (aneurysm, dissection) | |
| Other MFS-related disorders (e.g., “MASS” phenotype; see text) | |
| Shprintzen-Goldberg craniosynostosis syndrome (MIM 182212) | |
| Weill-Marchesani syndrome (autosomal dominant types) (MIM 608328) | |
| Geleophysic dysplasia (type 2) (MIM 614185) | |
| FBN2 | Congenital contractural arachnodactyly (Beal syndrome) (MIM 121050) |
MASS , Mitral valve prolapse, aorta in the upper end of the range but not progressively dilating, skin striae, and limited skeletal features; MFS , Marfan syndrome; MIM , Mendelian Inheritance in Man.
Clinical Features of Marfan Syndrome
The diagnosis of Marfan syndrome is made from a combination of clinical, imaging, and genetic criteria coupled with a well-taken personal and family history. However, the diagnosis is often made incorrectly, simply on the basis of rather soft features, such as long fingers (arachnodactyly), tall stature, or a high arched palate. Without extensive corroborating evidence, such features alone are quite insufficient for diagnosis because they are common in the general population. The 2010 Brussels revision of the Ghent nosology ( Box 216.1 ) provides a robust framework for the diagnosis of Marfan syndrome but still requires judicious application in borderline cases in which longer-term follow-up may be required before a final decision can be reached. Ideally, evaluation of the individual suspected of having Marfan syndrome should in all cases involve expert cardiac assessment (including echocardiography), careful ophthalmic assessment (including slit lamp examination), expert musculoskeletal evaluation, and expert clinical and molecular genetic advice. Some of the “systemic features” that potentially contribute to the diagnosis of Marfan syndrome (see Table 216.2 ) have a subjective element to them that requires a degree of musculoskeletal expertise for correct interpretation.
Box 216.1
Brussels Revision Of Ghent Nosology For Marfan Syndrome
From Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476-85.
In the absence of family history a
a A family member independently diagnosed using these criteria.
- 1.
Aortic root (Z score ≥2) + EL = MFS
- 2.
Aortic root (Z score ≥2) + FBN1 mutation = MFS
- 3.
Aortic root (Z score ≥2) + Systemic score (≥7 points) = MFS
- 4.
EL + FBN1 with known Ao FBN1 = MFS
EL +/− Systemic score without Ao +/− FBN1 not known with Ao = ELS
In the presence of family history a
- 5.
EL + FH of MFS (as defined above) = MFS
- 6.
Systemic score (≥7 pts) + FH of MFS (as defined above) = MFS
- 7.
Aortic root (Z score ≥2) + FH of MFS (as defined above) = MFS
Ao , Aortic diameter at sinuses of Valsalva above indicated Z-score or aortic dissection; EL , ectopia lentis; ELS , ectopia lentis syndrome; FBN1 not known with Ao, FBN1 mutation not previously with associated aortic root disease; FBN1 with known Ao, FBN1 mutation identified in an individual with aortic aneurysm; MFS , Marfan syndrome.
Cardiovascular disease
The most serious manifestations of the condition reflect pathology in the proximal aorta; aortic aneurysm and dissection represent its most catastrophic complications. Cardiovascular disease, mainly in the proximal aorta, significantly reduces life expectancy. Previous estimates of life span in the 1970s suggested that it was reduced to as little as 32 years (with 80% of deaths caused by cardiovascular disease), but this is certainly unduly pessimistic and distorted by case ascertainment bias. Many less severe cases are now recognized, so the prognosis overall is better than formerly believed; improvements in medical and surgical care have also undoubtedly contributed to improved outcomes even in the more severely affected cases. Nevertheless, cardiovascular involvement is still the major source of morbidity and mortality in Marfan syndrome. Aortic dissection can occur without preceding dilatation of the proximal aorta, but in general the risk is markedly increased when the aortic root diameter at the sinus of Valsalva exceeds 5 cm. This risk is further increased where there is a family history of aortic dissection. Echocardiography usually provides a reliable estimate of the dimensions of the proximal aorta, but it can be complicated by distorted anatomy of the chest wall (severe pectus excavatum). Sometimes additional magnetic resonance imaging is required for accurate assessment. Results should be interpreted according to body surface area and age using appropriate nomograms. In adults, aortic regurgitation and associated heart failure are common, but in children, severe mitral valve disease is more common than that caused by the aorta. Eventually, two thirds of affected individuals show at least some evidence of mitral valve involvement; mitral regurgitation and conduction disturbances contribute significantly to mortality. The distal aorta should not be forgotten because the risk of abdominal aortic aneurysm is also significantly increased. Occasional monitoring of the abdominal aorta by ultrasonography should therefore also be performed, particularly in those who have already shown significant dilatation of the aortic root.
Ocular disease
Dislocation of the lens, which affects up to 55% of those with classic MFS, is its most important ocular complication. It is caused by weakness of the suspensory ligament and is specifically associated with mutations in the cysteine-rich domains of FBN1, which reduce the intra-chain disulfide bonding crucial for the secondary structure of the protein. Lens abnormalities may be present at birth and are almost invariably detectable by the second decade of life in those with the predisposition. In contrast to much previous teaching, the dislocation may be in any direction (rather than invariably “upward and outward”), but this does contrast with that seen in homocystinuria (in which it is invariably downward). Subtle degrees of subluxation may only be detectable by slit lamp examination, but these may subsequently progress. Closed-head injury is a potential risk factor for progression, which is one reason why participation in contact sports should be very carefully evaluated. Myopia (caused by excessive length of the globe) is relatively common, there is an increased risk of retinal detachment, the cornea may be unusually flat (by keratometry), and the iris may exhibit abnormal wobbling (“iridodonesis”) caused by hypoplasia of the ciliary muscle or suspensory ligament.
Skeletal involvement
Among the “systemic” features that should be assessed in considering the diagnosis of MFS are many that involve the skeleton. These include disproportionate tall stature, scoliosis, chest wall abnormalities, foot and ankle deformities, facial features, protrusio acetabuli, contractures of the elbow, and the wrist and thumb signs ( Fig. 216.2 ). In assessing skeletal disproportion, it is important to remember that the normal approximately 1 : 1 ratio between the upper and lower body segments is not attained until the age of 10 years and that assessments of this and the span-to-height ratio may be spuriously increased by the presence of scoliosis due to any cause. Scoliosis is a particularly important orthopedic complication of MFS, which may deteriorate rapidly through the adolescent growth spurt ( Fig. 216.3 ). Careful monitoring is essential in children because spinal instrumentation may be necessary to prevent rapid progression of the curve in the adolescent growth spurt ( Fig. 216.4 ). Spondylolisthesis is another cause of back pain found in about 6% of people with MFS. Severe planovalgus deformities of the feet are common, typically requiring specialist supportive footwear and occasionally corrective orthopedic surgery to realign the hindfoot ( Fig. 216.5 ). Surgery may sometimes be considered to correct severe chest wall deformities (typically pectus excavatum) either for cosmetic reasons or to improve respiratory function. However, any potential benefits from surgery should be weighed against the possible problems that would be created for the surgical field if cardiac surgery were to be required later in life ( Fig. 216.6 ). Protrusio acetabuli may be pronounced but rarely causes significant functional impairment or secondary degenerative arthritis (see Fig. 216.4 ). Likewise, although dural ectasia affects 60% of individuals with classic MFS and may present an extreme appearance on lumbosacral imaging, it is only occasionally associated with significant neurologic symptoms or signs ( Fig. 216.7 ). However, care should be exerted with spinal anesthesia because dural tears may occur and be slow to heal. Joint hypermobility (usually mild) is reported in up to a quarter of affected individuals but rarely causes major problems; along with hernias and high-arched palate it is no longer considered one of the relevant “systemic features” that contribute to the diagnosis of MFS.
Respiratory system
Pneumothorax is relatively common due to rupture of apical pleural blebs that result from abnormal alveolar septation during lung development. Recurrent pneumothoraces may sometimes be associated with FBN1 mutations in the absence of any other major features of MFS. There is a high prevalence of obstructive sleep apnea, which can exacerbate the fatigue that is commonly associated with the condition. It is also a potential cause of hypertension, which may explain the strong association between sleep apnea and aortic root dilatation in these individuals.
Diagnosis of Marfan Syndrome
In classic cases, the diagnosis of MFS is fairly straightforward as long as the guidelines outlined in Table 216.3 are followed. However, at the milder end of the spectrum, the phenotype merges with the normal range, and additional special investigations may be required to confirm or refute the diagnosis with confidence. This is important because thoracic aneurysms sometimes develop only later in life. Individuals at risk should be accurately identified as soon as possible and have the proximal aorta monitored periodically. MFS should be diagnosed in sporadic cases by the combination of significant aortic root involvement plus either ectopia lentis or significant systemic features; it may also be diagnosed in individuals with ectopia lentis or systemic features if they carry an FBN1 mutation of a type known to be associated with thoracic aortic dissection or aneurysm or have an unequivocally affected first-degree relative. Closely related phenotypes include familial ectopia lentis, isolated Marfan-like body habitus, and isolated thoracic aneurysm syndromes, in which there is prominent involvement of one organ system without evidence of involvement of other systems. FBN1 mutations may be found in some of these cases. Clusters of “minor” features of a type associated with MFS but insufficient to justify the formal diagnosis are found in the “MASS phenotype” ( M itral valve prolapse, A orta in the upper end of the range but not progressively dilating, skin S triae, and limited S keletal features). This carries a benign prognosis and breeds true in families.
More than 2000 FBN1 mutations are described in MFS, but about 10% of cases are associated with mutations in other genes, including TGFBR1 and TGFBR2 (encoding components of the heterodimeric TGF-β receptor). These are more typically associated with the related Loeys-Dietz phenotype, in which vascular tortuosity and dilatation are prominent but ocular lens abnormalities do not occur. Thoracic aneurysm or dissection syndromes are also associated with mutations in ACTA2 (smooth muscle actin alpha 2), MYH11 (smooth muscle myosin heavy chain 11), TGFB2 (TGF-β2), SMAD3 , and SLC2A10 (solute carrier family 2 member 10). The differential diagnosis of MFS is shown in Table 216.4 .
Table 216.4
Differential Diagnosis of Marfan Syndrome
Modified from Smith R, Wordsworth P. Clinical and biochemical disorders of the skeleton. 2nd ed. Oxford: Oxford University Press; 2016.
| Causes of scoliosis | Idiopathic adolescent scoliosis |
| Homocystinuria | |
| Kyphoscoliotic Ehlers-Danlos syndrome (type 6) | |
| Causes of tall stature | Familial tall stature |
| Familial Marfan-like body habitus | |
| Klinefelter syndrome | |
| Hyperpituitary gigantism | |
| Cerebral gigantism (Soto syndrome) | |
| Causes of aortic disease | Familial thoracic aortic aneurysm or Loeys-Dietz syndrome |
| Causes of mitral valve prolapse | Familial |
| Causes of dislocated lenses | Homocystinuria |
| Familial isolated ectopia lentis | |
| Weill-Marchesani syndrome | |
| Causes of contracture | Congenital contractural arachnodactyly |
| Hypermobility or vascular fragility | Ehlers-Danlos syndrome (particularly types 4 and 6) |
| Causes of cutaneous striae | Rapid weight gain |
| Pregnancy | |
| Cushing syndrome |
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here