Inherited Diseases of Connective Tissue

Mucopolysaccharidoses

Definition

Proteoglycans are ubiquitous components of the extracellular matrix and the surfaces of cells, and they are among the largest and most complex of human molecules. Proteoglycans consist of a protein core to which are covalently bound glycosaminoglycans (GAGs; formerly called mucopolysaccharides) of several types: dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate. During normal degradation, these four polymeric molecules are cleaved from their protein core in lysosomes; then they, plus hyaluronan (a GAG lacking a protein core), are catabolized further in lysosomes in a stepwise fashion by more than a dozen enzymes. Genetic defects in any one of these enzymes lead to the accumulation of GAG metabolites in lysosomes, with profound disruption of cellular physiology. The phenotypes resulting from deficiencies of these catabolic enzymes are termed mucopolysaccharidoses and are classified into seven types ( Table 239-1 ). Several additional storage disorders, termed mucolipidoses , are caused by a genetic defect in post-translational modification of lysosomal enzymes and share features with the mucopolysaccharidoses.

TABLE 239-1

MUCOPOLYSACCHARIDOSES AND MUCOLIPIDOSES

TYPE	EPONYM OR COMMON NAME	CLINICAL FEATURES	INHERITANCE	OMIM ∗	ENZYMATIC DEFECT
MPS IH	Hurler syndrome	DM and short stature; MR; corneal clouding; HS; heart disease; death in childhood	AR	252800	α- l -iduronidase
MPS IS	Scheie syndrome	Coarse facies; stiff joints; corneal clouding; aortic valve disease; normal intelligence and lifespan	AR	252800	α- l -iduronidase
MPS II	Hunter syndrome	Severe form: coarse facies, DM and short stature, HS; MR; no corneal clouding; death by late adolescence. Mild form: coarse facies, short stature; normal intelligence; survival to adulthood	XL	309900	Iduronate sulfatase
MPS IIIA	Sanfilippo A	Severe MR and hyperactivity; mild somatic changes	AR	252900	Heparan N -sulfatase
MPS IIIB	Sanfilippo B	Same as MPS IIIA	AR	252920	α- N -acetylglucosaminidase
MPS IIIC	Sanfilippo C	Same as MPS IIIA	AR	252930	Acetyl-coenzyme A: α-glucosaminide acetyltransferase
MPS IIID	Sanfilippo D	Same as MPS IIIA	AR	252940	N -acetylglucosamine 6-sulfatase
MPS IVA	Morquio A	Short stature and distinct skeletal dysplasia with odontoid hypoplasia and myelopathy; corneal clouding; normal intelligence; valvular heart disease	AR	253000	Galactose 6-sulfatase
MPS IVB	Morquio B	Same as MPS IVA	AR	253010	β-Galactosidase
MPS VI	Maroteaux-Lamy	DM and short stature; corneal clouding; normal intelligence; aortic stenosis; leukocyte inclusions; hydrocephalus in severe form	AR	253200	N -acetylgalactosamine
MPS VII	Sly syndrome	DM; HS; widely variable, including MR	AR	253220	β-Glucuronidase
MPS IX	—	Short stature; periarticular soft tissue masses	AR	601492	Hyaluronidase
ML II	I-cell disease	Similar to but more severe than MPS IH but with cellular inclusions; no mucopolysacchariduria	AR	252500	UDP- N -acetylglucosamine: lysosomal enzyme N -acetylglucosaminyl-1-phosphotransferase
ML III	Pseudo-Hurler polydystrophy	Short stature and mild DM; stiff joints; mild MR; survival to adulthood	AR	252500	Same as ML II arthropathy, coarse facies; variable but milder

AR = autosomal recessive; DM = dysostosis multiplex; HS = hepatosplenomegaly; MR = mental retardation; UDP = uridine diphosphate; XL = X-linked.

∗ Entries in Online Mendelian Inheritance in Man, OMIM. McKusick-Nathans Institute of Genetic Medicine. Baltimore: Johns Hopkins University. http://omim.org .

Epidemiology

All mucopolysaccharidosis disorders are rare, each with an incidence of one or fewer cases per 100,000 births, and are without ethnic predilection.

Pathobiology

With the exception of mucopolysaccharidosis II (Hunter syndrome), which is X-linked, each of these disorders is autosomal recessive. All mucopolysaccharidoses are caused by deficiency of a single lysosomal enzyme responsible for a specific step in GAG metabolism (see Chapter 192 ). Catabolism of GAG proceeds normally until the step requiring the defective enzyme, when further normal metabolism halts. Although a minor degree of nonspecific breakdown occurs, resulting in urinary excretion of cleaved GAG that can be useful diagnostically, the accumulation of GAG within lysosomes of cells of mesenchymal origin, endothelium, and, in most cases, neurons causes widespread, progressive cellular dysfunction and clinical effects. Lysosomal enzymes are targeted to lysosomes by post-translational addition of mannose 6-phosphate. Deficiency of the phosphotransferase that catalyzes the first step in this reaction results in an inability to catabolize any GAG molecules. The catabolic enzymes, which normally would be transported into lysosomes, instead are secreted from the cell and are found in unusually high concentrations in plasma, providing one diagnostic test for mucolipidoses.

Pathology

All pathologic manifestations of mucopolysaccharidosis and mucolipidosis disorders worsen with age, and some are present from early developmental stages. Gross anatomic hallmarks are hepatosplenomegaly, marked skeletal alterations (termed dysostosis multiplex ) that result in short stature and thoracic cage deformity, thickening and narrowing of airways and arteries, and coarsening of facial features. Although mental retardation is a prominent feature of some of these conditions, the brain may show only ventriculomegaly secondary to communicating hydrocephalus. On microscopy, mesenchymal cells show a cytoplasm full of apparently empty vacuoles; these are lysosomes from which GAG has been removed by fixation. Cells cultured from patients show greatly enlarged lysosomes filled with granular material. In the severe form of mucolipidosis, dense inclusions are present, which gave rise to the common name, I-cell disease .

Clinical Manifestations

Each of the disorders in Table 239-1 shows a wide spectrum of clinical severity. This wide spectrum has led to a classification that gives the impression of separate disorders within some of the mucopolysaccharidosis and mucolipidosis types, but these represent the apparent ends of the continuum. Some of the disorders without treatment result in death by adolescence (Hurler syndrome, severe Hunter syndrome, mucolipidosis II), but others are commonly compatible with survival to adulthood.

The milder end of the mucopolysaccharidosis I spectrum, Scheie syndrome, may not be diagnosed until adulthood; patients present with stiffened joints, corneal clouding and glaucoma, carpal tunnel syndrome, and aortic valvular disease. Stature and intelligence are not affected. The main health risks are cardiac valvular involvement, thickening of meninges that can produce a myelopathy, and thickening of the upper airways that can produce obstructive symptoms and sleep apnea.

Mucopolysaccharidosis II, Hunter syndrome, is distinctive because it is X-linked (affecting males almost exclusively), and the cornea shows little overt clouding. Cervical myelopathy, obstructive airway disease, and cor pulmonale are important concerns. A combined conductive and neurosensory hearing loss is common.

Neither mucopolysaccharidosis IV (Morquio syndrome) nor mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) affects intelligence. Both syndromes often are associated with severe skeletal changes, which are distinct radiographically but produce similar problems of kyphoscoliosis, pectus carinatum, restrictive lung disease, severe short stature, and joint degeneration. Cervical myelopathy resulting from a thickened dura is common to both disorders and is accentuated by odontoid hypoplasia in mucopolysaccharidosis IV. Thickening of the aortic and mitral valves may produce severe dysfunction necessitating their replacement. General anesthesia is especially hazardous because of the narrow upper and middle airways and cervical instability.

Patients with mucolipidosis III (pseudo-Hurler polydystrophy) resemble patients with mucopolysaccharidosis VI but often have mild to moderate mental retardation. Aortic regurgitation is common.

Diagnosis

Differential Diagnosis

Because clinical diagnosis of these conditions is difficult in young children, before most of the clinical features have progressed, many countries have instituted newborn screening. The diagnosis should be considered in any person with hepatosplenomegaly and coarsening of the facial features. Evaluation requires a pedigree analysis, ophthalmologic examination, skeletal radiographic survey, echocardiography, and analysis of the urine for excretion of GAGs. Often the specific mucopolysaccharidosis is evident from radiographs, the presence or absence of corneal clouding, and the pattern of mucopolysacchariduria. Enzymatic analysis of leukocytes confirms the diagnosis. Patients with mucolipidoses do not show mucopolysacchariduria but have marked elevation of all the GAG catabolic lysosomal enzymes in plasma.

Treatment

Ventriculoperitoneal shunting is necessary if intracranial pressure is elevated. Close attention to hearing and visual problems is essential throughout life. Many adults with mucopolysaccharidosis or mucolipidosis require surgery for carpal tunnel syndrome. Cardiovascular surgery for valvular or coronary disease may be necessary. All use of anesthesia is high risk because of the narrow airways and, in the case of mucopolysaccharidosis IV, atlantoaxial instability. For patients who remain ambulatory, selective joint replacement can be beneficial. Because of the morbidity associated with thoracic cage deformity, consideration should be given to stabilizing the spinal deformity before it becomes severe.

Replacement of the deficient enzyme by intravenous infusion is available or being evaluated for most of the mucopolysaccharidosis disorders. Laronidase (Aldurazyme) has been approved in the United States for treatment of mucopolysaccharidosis I. An infusion every 2 weeks for 1 year in adolescent and adult patients resulted in substantial reduction in hepatosplenomegaly and modest improvement in pulmonary function, sleep apnea, and joint mobility. Whether early institution of therapy in young children modulates mental retardation in the Hurler variant of mucopolysaccharidosis I is uncertain. Galsulfase (Naglazyme) has been approved for the treatment of mucopolysaccharidosis VI, in which somatic rather than neurologic problems predominate. Enzyme replacement should be started in all patients when diagnosed.

Bone marrow transplantation has been attempted in many of the mucopolysaccharidosis disorders, with mixed success. The earlier transplantation occurs, the better the outcome in terms of somatic problems, but prevention of mental retardation has not occurred. Current recommendations based on consensus in Europe calls for hematopoietic stem cell transplantation for patients with Hurler syndrome before the age of 2.5 years.

Marfan Syndrome

Definition

Marfan syndrome is an autosomal dominant, pleiotropic disorder caused by defects in the principal component of the extracellular microfibril, the large glycoprotein fibrillin-1. The disease manifestations occur in multiple systems, especially the eye, skeleton, heart, aorta, lung, and integument. Notable features include dislocation of the ocular lens, tall stature with particularly long limbs and digits, deformity of the thoracic cage by pectus carinatum or excavatum with abnormal curvature of the spine, mitral and tricuspid valve prolapse, dilation of the sinuses of Valsalva and predisposition to aortic dissection, spontaneous pneumothorax, abnormal skin stretch marks, hernias, and dural ectasia. If untreated, patients often die before 30 or 40 years of age from aortic dissection or congestive heart failure.

Epidemiology

Marfan syndrome is a common mendelian disorder, with an estimated incidence of about 1 per 5000 births. Marfan syndrome is found throughout the world, without ethnic or geographic predilection.

Pathobiology

Pathogenesis

Mutations in FBN1 , which maps to human chromosome 15q21.1 and encodes fibrillin-1, cause Marfan syndrome and related connective tissue disorders. Several thousand distinct mutations have been found, and few occur in more than one family. Patients are heterozygous for mutations in FBN1 , leading to autosomal dominant inheritance. Extracellular microfibrils are polymers of many fibrillin-1 molecules and are ubiquitous in the extracellular matrix of most tissues. Latent transforming growth factor-β (TGF-β) binding protein, which keeps the cytokine inactive, bears striking homology to regions of fibrillin. Abnormalities of either the quality or the quantity of microfibrils disrupt normal signaling by TGF-β, especially during embryonic development and postnatal growth. Studies in mice engineered to harbor human mutations in FBN1 showed that excessive TGF-β signaling causes abnormal lung septation (the precursor to pneumothorax), bone overgrowth, mitral valve prolapse, muscular hypoplasia, and aortic dilation. This fundamental shift in understanding of the pathogenesis of Marfan syndrome has suggested novel therapies, such as with small molecules that affect the activity of TGF-β or its downstream signaling.

The features of Marfan syndrome are highly variable, even among relatives who share the same mutation in FBN1 . This variability persists after accounting for the effects of age. Men tend to be affected more severely, for unclear reasons.

Pathology

The features of Marfan syndrome are age dependent. Some severely affected infants have flagrant features and often die of mitral regurgitation and heart failure despite aggressive management. At the other end of the clinical spectrum, Marfan syndrome merges with several related disorders and patients may not come to medical attention, let alone receive a definitive diagnosis, until adulthood.

None of the gross or microscopic pathologic changes is specific for Marfan syndrome. The medial degeneration of the aortic wall, characterized by disarray and fragmentation of the elastic fibers and increased proteoglycan (often inappropriately termed cystic medial necrosis ), also can be seen in hereditary aortopathy syndromes and in older people with hypertension. Aortic dissection ( Chapter 63 ) usually begins just superior to the aortic valve (type A) and often progresses to the bifurcation. Death usually results from retrograde dissection and hemopericardium. About 10% of dissections begin in the descending thoracic aorta (type B).

Clinical Manifestations

The lens tends to be displaced superiorly, and usually the zonules remain intact. The retina is at increased risk for detachment, especially in patients who are highly myopic. Tubular bones overgrow, accounting for the disproportionate tall stature (dolichostenomelia), long digits (arachnodactyly), and sternal deformity. Ligaments may be lax, causing scoliosis and joint hypermobility. Alternatively, congenital contractures are common, especially of the elbows. The palate typically is highly arched, and the dentition can be crowded and maloccluded. Mitral valve prolapse occurs in about 80% of cases, and the valve leaflets become progressively thickened (myxomatous on histopathology). The mitral annulus may dilate and calcify. Aortic root dilation begins in the sinuses of Valsalva and progresses with age, albeit at highly variable rates ( Chapters 55 and 63 ). Most males with Marfan syndrome have an aortic root dimension above the upper limit of normal for their body surface area by adolescence. Some females show a slower progression and may have a root diameter near the upper limit of normal well into adulthood. Aortic dissection classically develops in the ascending aorta (type A; see Chapter 63 ). However, with the increasing use of successful preventive aortic root replacement, type B dissections increasingly are seen. The dilation usually does not involve the distal ascending aorta. Spontaneous pneumothorax, resulting from rupture of apical blebs, occurs in about 5% of patients. Stretch marks (striae atrophicae) occur over areas of flexural stress, such as the shoulders, breasts, and lower back. Some clinical features continue to progress as lifespan has been lengthened owing to successful cardiovascular surgery. The neural canal in the lumbosacral region is enlarged in most people with Marfan syndrome; this may be visible on plain radiographs, especially if the neuroforamina are widened. Imaging by computed tomography or magnetic resonance imaging is diagnostic and should be used in patients with back pain and radicular symptoms. Dural ectasia progresses with age; large anterior meningoceles in the pelvis are a severe manifestation. In addition, sleep apnea and simple cysts in the liver and kidneys are common.

Diagnosis

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