Metabolic and Autoimmune Syndromes

Metabolic and Autoimmune Syndromes Victor Nannini, DDS a,b,* KEYWORDS  Fabry disease  Williams syndrome  Hurler syndrome  Hunter syndrome  Heerfordt syndrome  Sjo ¨gren syndrome KEY POINTS  Genetic alterations can cause physiologic responses resulting in systemic and metabolic complications.  These complications can cause significant deficits, as in Hurler and Williams syndromes, which can lead to debilitating disease and early death.  These alterations may also lead to abnormal immune responses that affect significant organs and organ systems.

Fabry disease Key points  Fabry disease, also known as Anderson-Fabry disease, is an inherited X-linked recessive disorder of lysosomal storage.1e3  Fabry disease is the second most prevalent lipid storage disease after Gaucher disease and occurs from a deficient activity of lysosome hydrolase, alpha-galactosidase A.1e4

Genetics The alpha-galactosidase A gene has been mapped to the region q22.1 of the X chromosome.5e8 When mutated, a progressive accumulation of a glycolipid called globotriaosylceramide (Gb3) affects mainly endothelial and vascular smooth muscle cells and causes damage to many major organs1 including renal and cardiac insufficiency,2 and central nervous system disorders including cerebral infarction and skin and pulmonary symptoms.1e4,9e11 It is mostly a male disease with the reported incidence varying from 1 in 17,000 to 1 in 117,000 men in white populations.12e14 However, this disease is probably unreported because many of the manifestations are nonspecific, the disease is rare, and often the initial diagnosis is not accurate.4 Women can have the disease but usually have milder symptoms that occur later in life.15e17 There are rare reports of women being asymptomatic early in life, but then showing symptoms as severe as those of men with the classic phenotype.15,16 The author has nothing to disclose. a Private Practice, Long Island Oral and Maxillofacial Surgery, P.C., 134 Mineola Boulevard, Mineola, New York 11501, USA b Division of Oral and Maxillofacial Surgery, Nassau University Medical Center, 2201 Hempstead Turnpike, East Meadow, New York 11554, USA * Division of Oral and Maxillofacial Surgery, Nassau University Medical Center, 134 Mineola Boulevard, Mineola, NY 11590. E-mail address: [email protected] Atlas Oral Maxillofacial Surg Clin N Am 22 (2014) 123–134 1061-3315/14/$ - see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cxom.2014.05.005

Clinical features Clinical manifestations of the disease often occur early in life, caused by the increase in glycolipids, which causes inflammation and fibrosis.3 Therefore, severe neurologic pain in the limbs, especially during times of stress, begins around the age of 10 years.4 Renal dysfunction with proteinuria and polyuria, often leading to renal failure, is one of the serious complications of the disease.3 Skin lesions are often present, including hypohidrosis and angiokeratomas.4 The labial mucosa is often involved with a maculopapular eruption (Fig. 1). Corneal changes are usually an early sign with a whorl-like keratopathy seen on a slit lamp examination (Fig. 2).11,18,19 As these patients age, central nervous system involvement often leads to increased incidence of stroke.20,21 Cardiovascular effects include hypertension and cardiomyopathy with eventual heart failure.4,22 Oral and maxillofacial findings include increased prevalence of maxillary cysts and maxillary prognathism.23 Thickening of the lips and a bulbous nose have been described in many cases.4 Perioral linear telangiectases24 and cases of granulomatous cheilitis and granulomatous gingivitis25e27 are noted. Tinnitus is reported in approximately 40% of patients with this disorder.4 Because of the severe major organ dysfunction, most of these patients die at an early age secondary to stroke, end-stage renal failure, or cardiovascular complications.

Differential diagnosis Because this disorder is rare, it is often misdiagnosed because of early nonspecific manifestations, including neurologic and skin disorders. These disorders can include rheumatoid arthritis, fibromyalgia, multiple sclerosis, and Meniere disease.4 The disorder is often discovered following more serious complications such as stroke, cardiac insufficiency, and renal failure.20e22,28e30 Because treatment with enzyme replacement therapy has been shown to have positive results, early diagnosis of Fabry disease is important. When suspected, serum assays of leukocyte alpha-galactosidase A activity are effective in men; however, genetic testing in women is recommended because of inclusive serum results.4

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Fig. 1 Fabry disease. Note the pinpoint maculopapular lesions on the lip. (From James WD, Berger TG, Elston DM. Andrew’s diseases of the skin: clinical dermatology. 11th edition. Philadelphia: Saunders, an imprint of Elsevier; 2011; with permission.)

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Fig. 2 Faint but extensive vortex keratopathy seen on retroillumination. (From Kanski J. Clinical diagnosis in ophthalmology. Cornea. 1st edition. Philadelphia: Mosby, an imprint of Elsevier; 2006. Fig. 6.232; with permission; and Courtesy of W. Lisch, MD, Hanau, Germany.)

prevalence of this mutation seems to be in the range of 1 in 7500 to 1 in 25,000 live births.16

Clinical features Oral surgeons should be suspicious that any patient displaying angiokeratomas of the face, cheilitis granulomatosa, or granulomatous gingivitis may have the potential for Fabry disease, especially young men. With late-stage disease and renal, cardiac, and neurologic complications, treatment must be carefully administered with close consultation with the appropriate specialists.

Williams syndrome Key points  Williams syndrome, also known as Williams-Beuren syndrome, is a rare autosomal dominant neurodevelopmental disorder affecting men and women equally.1e3  Williams syndrome was first discovered in 1961 by J.C.P. Williams, who found patients with supravalvar aortic stenosis, facial anomalies, and mental retardation.4  Independently in 1962, A.J. Beuren found similar phenomena in his patients but also certain dental characteristics and pulmonary artery stenosis.5

Genetics Williams syndrome and its manifestations seem to result from a 1.5-Mb deletion on the number 7 chromosome pair at 7q11.23, which includes 26 to 28 genes.6e11 This deletion significantly affects the production of elastin, which leads to supravalvar aortic stenosis and other cardiovascular disorders such as peripheral artery stenosis.6,12e14 The other characteristics of this disease arise because adjacent genes responsible for facial and neural development are located in the deletion.12,15 The

Williams syndrome is characterized by its elfin facial appearance,17,18 growth delays with low body weight,19,20 mental retardation,16,17 cardiovascular disorders,1,4,5,21e28 sleep disorders,29 and transient hypercalcemia, usually as infants. These patients tend to have intelligence quotients in the 50 to 60 range and are overly friendly, extremely talkative, with severe bouts of anxiety.12,16,17 The facial abnormalities (Fig. 3) include periorbital fullness, full upper and lower lips, long philtrum, flat nasal bridge, micrognathia, and abnormal dentition (Fig. 4) including hypocalcification of the enamel, short and narrow primary teeth, and crowded permanent teeth.12,18,19,30e35 Hyperacusis has been noted to be present in most patients.36 Although it is been reported that there is an increase in gingival height and width of these patients, there was no increase in loss of attachment.31,32,37e39 There have been reports in the literature of keratoconus,40 multiple sclerosis,41 Crohn’s disease,42 and Burkitt’s lymphoma,43 but these are rare.

Differential diagnosis Some of the symptoms of Williams syndrome are also found in other disorders. Patients with Noonan syndrome have similar facial appearances, including micrognathia, flat nasal bridge,1,44 and leprechaunism (an endocrine disorder that produces elfin facial features and growth retardation).45 Idiopathic infantile hypercalcemia not related to Williams syndrome has been reported.46 The definitive diagnostic test for Williams syndrome is the fluorescence in-situ hybridization test, which conclusively shows the gene deletion.16,47,48

Treatment considerations for the oral and maxillofacial surgeon Although there is no cure for Williams disease, treatment of the underlying causes becomes paramount. Management of

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Hurler syndrome Key points  Hurler syndrome is a rare autosomal recessive disease that is classified in a group of disorders called mucopolysaccharidosis. It is also known as mucopolysaccharidosis type 1-H.  First described by Dr Gertrud Hurler in 1919, Hurler syndrome was discovered in 2 unrelated boys with similar characteristics including mental impairment, distortion of facial features, respiratory and cardiac disease, hepatosplenomegaly, and corneal opacities.1e4  It is the most severe form of mucopolysaccharidosis and, without treatment, leads to early death before the second decade of life.5

Genetics

Fig. 3 Characteristic facial appearance of Williams syndrome in a 6-year-old boy with nonfamilial supravalvular aortic stenosis and pulmonary artery stenosis. The patient was mentally retarded and shows the typical large mouth with patulous lips, small chin, baggy cheeks, blunt upturned nose, wide-set eyes, and malformed teeth. (From Perloff JK. Clinical recognition of aortic stenosis. The physical signs and differential diagnosis of the various forms of obstruction to left ventricular outflow. Prog Cardiovasc Dis 1968;10:323. Fig. 1; with permission.)

Hurler syndrome occurs when there is a mutation in the alpha 6 L-iduronidase (IDUA) gene. IDUA is required for the degradation of heparan sulfate and dermatan sulfate in the lysosome.6 With the accumulation of these glycosaminoglycans in various organs, multiple systemic effects begin to occur over a short period of time.2,6 It seems that patients with the serious form of the disease have nonsense mutations identified on both alleles.7 The incidence of Hurler syndrome is about 1 in 100,000 live births.2,8

Clinical features these patients can be difficult because of their mental disorders, which often require sedation or general anesthesia for treatment.46 As patients age, cardiovascular concerns along with hypertension require close consultation with the appropriate medical practitioners.

Children with Hurler syndrome initially appear nearly normal at birth but, because of accumulation of glycosaminoglycans, progressive cell and tissue malfunction occurs, leading to mental retardation, hepatosplenomegaly, corneal clouding, with eventual cardiopulmonary failure.5,8,9 Clear cells (Hurler cells) have been identified in infants within the myocardium.10 Affected individuals have short long bones and short and broad digits consistent with dwarfism.5,11 Carpal tunnel syndrome and limited mobility are common.12,13 Facial deformities (Figs. 5 and 6) are prevalent, including an enlarged deformed head with frontal bossing, a flattened nasal bridge, and hypertelorism.11 The patients have thickened patulous lips with a flattened philtrum.11,14e16 They have significant macroglossia that, over time, leads to an anterior open bite11 and, combined with a short neck, leads to sleep apnea and significant complications from anesthesia.17,18 There are dental anomalies, including short conical teeth, widely spaced dentition, and supernumerary teeth in the mandibular rami.19,20 There have been reports of increased dentigerous cyst formation in the mandible.11

Differential diagnosis

Fig. 4 Williams syndrome: typical dental abnormality characterized by small, malformed, widely spaced teeth with malocclusion. (From Perloff JK. Congenital heart disease in adults. 3rd edition. Philadelphia: Saunders, an imprint of Elsevier; 2008. Fig. 20-14; with permission.)

At present 7 different types of mucopolysaccharidosis have been identified.2 Of the mucopolysaccharidosis type 1 (MPS 1) types, the phenotypes of each determines the specific syndrome. As mentioned earlier, Hurler syndrome (MPS 1-H), with the most extensive symptoms, is distinguished from HurlerScheie syndrome (MPS 1-H/S), with intermediate symptoms (no

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Treatment considerations for the oral and maxillofacial surgeon A patient diagnosed with Hurler syndrome before the age of 2 years has shown considerable improvement of symptoms, especially the neurologic defects, with hematopoietic stem cell transplantation.2,5,7,8,17,21,24e27 However, there are significant risks, with increased morbidity and mortality.8 Enzyme replacement therapy (ERT) with laronidase, which is a protein analogous to human alpha iduronidase, is an alternative therapy.2 However, it does not cross the blood-brain barrier and therefore shows no improvement in the neurologic deficits that the syndrome displays. For the oral and maxillofacial surgeon, these patients are extremely difficult to treat because of their neurologic disorders, skeletal deformities, dental anomalies, and anesthetic risks. Close consultation with the appropriate specialists and probable palliative treatment is indicated.

Hunter syndrome Key points Fig. 5 Hurler syndrome. Coarse facial features, macrocephaly, scaphocephalic skull, flattened nasal bridge, hypertelorism, short neck, chest deformity, and protuberant abdomen in a girl with Hurler syndrome (mucopolysaccharidosis I). (From Paller A, Mancini AJ. Hurwitz clinical pediatric dermatology: a textbook of skin disorders of childhood and adolescence. 4th edition. Philadelphia: Saunders, an imprint of Elsevier; 2011. Fig. 24.13; with permission.)

cognitive disturbances), versus the Scheie syndrome (MPS 1-S), with attenuated symptoms that occur later in life and progress slowly.2 Because early diagnosis before the age of 2 years is critical for the long-term survival of a patient with Hurler syndrome, recognition becomes paramount. Early symptoms such as rhinitis and hernia are vague, but radiographic features can aid in the diagnosis.21e23 A decreased level of serum alpha21 L-iduronidase confirms the diagnosis.

 Hunter syndrome, also known as mucopolysaccharidosis II, is a rare X-linked lysosomal storage disorder.1e7  Hunter syndrome was first described by Dr Charles Hunter8 in 1917, who described 2 brothers with significant skeletal deformities, including facial deformities with hearing deficiencies.  The syndrome causes a deficiency in the lysosomal enzyme iduronate-2-sulphatase, which is responsible for cleaving sulfate from the glycol aminoglycosides dermatan sulfate and heparin sulfate.9 As a result, gradual accumulation of these glycosaminoglycans results in multiple organ and systemic disorders.2

Genetics The incidence of mucopolysaccharidosis II (MPS II) ranges from 1 in 110,000 to 1 in 135,500 live births.10 Because it is an X-linked disease, most patients are male. There are some female cases reported, which require either 2 pathologic alleles or a normal inactivated allele.1,6,10 However, the female cases tend to have attenuated symptoms.1,9 The gene that produces iduronate-2sulphatase is located on chromosome Xq28 with the exonic point mutations G374sp comprising half of the mutations.11 Significant variability in the mutations is evident.12 It is thought that this variance explains much of the difference between phenotypes and also the difficulty in treating patients with MPS II.11

Clinical features

Fig. 6 Facial coarseness in Hurler syndrome. (From Kanski J. Clinical diagnosis in ophthalmology. 1st edition. Philadelphia: Mosby, an imprint of Elsevier; 2006. Fig. 6.229; with permission.)

Similar to other patients with mucopolysaccharidosis, patients with MPS II tend to appear normal at birth. Frequent upper respiratory infections, umbilical hernias, and coarse facial features are some of the early signs and symptoms.6,11 As the increase in glycosaminoglycosides accumulate in organs, hepatosplenomegaly, skeletal and joint involvement with decreased mobility, clubbed fingers, cardiac involvement, and obstructive airway disease become prevalent.1,3,9,11,13,14 Facial features (Fig. 7) include frontal bossing, a wide nasal bridge, a large skull, macroglossia often leading to an anterior

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Differential diagnosis Because there are significant differences in the expression of this disorder, it can be difficult to distinguish this from other forms of mucopolysaccharidosis. In the severe expression of MPS II, there are many similar characteristics to Hurler syndrome, except without the corneal clouding.9,11,17 Other lysosomal storage disorders that share similar features include MPS VI (Maroteux-Lamy syndrome) and MPS VII (Sly syndrome).6 A preliminary test to confirm mucopolysaccharidosis is an increase in urinary glycosaminoglycans.6,25 Although this is not specific to Hunter syndrome, further blood testing for deficiency of iduronate-2-sulfatase in leukocytes, serum, or plasma will secure the diagnosis.1,6 A mnemonic screening tool has been developed and has correctly identified 95% of patients with no family history of Hunter syndrome.26

Treatment considerations for the oral and maxillofacial surgeon

Fig. 7 Hunter syndrome. Note frontal bossing, wide nasal bridge, macroglossia. (From Yoskovitch A, Tewfik TL, Brouillette RT, et al. Acute airway obstruction in Hunter syndrome. Int J Pediatr Otorhinolaryngol 1998;44:273e8; with permission.)

open bite, and mandibular immobility.1,6,15e23 Non-tender, irregularly shaped papules may be present on the skin of the upper back (Fig. 8). Dental abnormalities have been reported, including widely spaced teeth, enamel defects, carious teeth, dentigerous cysts, and abscesses.16 In the most severe cases of Hunter disease, central nervous system manifestations begin between the ages of 2 and 4 years and are often expressed as severe mental retardation.24 In these situations, death is usually expected before the third decade of life and usually as a result of cardiac or obstructive respiratory failure.1,6,11 In the milder forms, patients may have normal intellect and nearnormal stature with an increase in life expectancy.1,6,9

With many mucopolysaccharidosis disorders, early diagnosis is critical because estrogen replacement therapy (ERT) with idursulfase has been shown to be effective in delaying and improving many of the symptoms associated with this disorder.4,9,13 However, this drug does not seem to cross the bloodbrain barrier and therefore has little effect on those patients with severe central nervous system involvement.9 Unlike Hurler syndrome (MPS 1-H), hematopoietic stem cell transplantation does not seem to have any significant effect on neurologic improvement.1,9 The oral and maxillofacial surgeon must be cognizant that each individual with Hunter syndrome may present with a variety of symptoms. Anesthetic management and risks associated with individual patients become paramount.

Heerfordt syndrome Key points  Heerfordt syndrome is a rare manifestation of systemic sarcoidosis that includes fever, parotid swelling, uveitis, and facial nerve paralysis.1e5  It was described by Danish ophthalmologist Christian Heerfordt, who reported these traits without the connection to sarcoidosis.6 That direct link was reported in 1937 by Dr Jan Waldenstrom.7  The histology is classic for multiple noncaseating granulomas found in the parotid or salivary glands and lacrimal glands.1  Treatment of Heerfordt syndrome with long-term corticosteroids seems to have a good prognosis.2e4

Genetics

Fig. 8 Ivory-colored papules on the upper back in Hunter syndrome. (From Kliegman RM, Stanton BF, St Geme JW III, et al. Nelson textbook of pediatrics. 19th edition. Philadelphia: Saunders, an imprint of Elsevier; 2011. Fig. 651-13; with permission.)

Sarcoidosis and therefore Heerfordt syndrome seems to be more prevalent in women than in men, and in black Americans versus white with 3 times the rate (36 per 100,000 vs 11 per 100,000) and also with more chronic and fatal disease.8 Most patients show clinical signs between the ages of 20 and 40 years.3,4 Numbers vary around the world but it seems that the frequency of Heerfordt disease is about 0.3% of patients with sarcoidosis.9,10 Because sarcoidosis seems to have a

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genetic and environmental component, it is thought that Heerfordt syndrome has similar findings.9 The human leucocyte antigen (HLA) gene has been implicated in both sarcoidosis and in Heerfordt syndrome but specifically the HLA-DRB1*04 allele seems protective for sarcoidosis, but increases the risk for ocular manifestations.9 Despite significant research the exact cause has remained elusive and further genetic and immunologic studies are required.8,11e13

Clinical features In patients with sarcoidosis, usually fever, followed by uveitis, parotid gland swelling, and then facial nerve palsy are classic for Heerfordt syndrome (Figs. 9 and 10).1e5 The parotid glands usually enlarge bilaterally and are firm to the touch.14e21 Bilateral lacrimal gland enlargement is often seen with either anterior or posterior uveitis, accompanied by blurred vision.9,14,16 Although the facial nerve palsy is usually unilateral, bilateral deficits have been reported.22e24 Neurosensory deficits of other cranial nerves, including the palate,18 have been reported.

Differential diagnosis The differential diagnosis for each of the components for Heerfordt syndrome can be extensive. For example, bilateral ¨gren syndrome, parotid swelling can be attributed to Sjo tuberculosis, mumps, sialadenitis, and Mikulicz disease; however, none of these have uveitis. The definitive diagnosis is made by histologic confirmation of sarcoidosis, which presents as noncaseating granulomas.2,3 In cases in which tissue biopsy is difficult, increased angiotensin converting enzyme levels in combination with a positive 67 gallium scintigraphy have been shown to have 99% accuracy.2

Fig. 10 Seventh nerve palsy may also form part of Heerfordt syndrome. Also note granulomatous infiltration of the nose and tracheostomy. (From Kanski J. Clinical diagnosis in ophthalmology. 1st edition. Philadelphia: Mosby, an imprint of Elsevier; 2006. Fig. 10.76; with permission.)

Treatment considerations for the oral and maxillofacial surgeon Patients presenting with any of the symptoms of Heerfordt syndrome should immediately be referred for the evaluation of sarcoidosis. The treatment of this disorder is usually corticosteroids and occasionally azathioprine.3,4,16,22 Long-term prednisone is often required.25 The long-term prognosis for these patients is usually good, but a small number (less than 5%) die from sarcoidosis, usually as a result of pulmonary fibrosis with respiratory failure.8

Sj¨ ogren syndrome

Key points

Fig. 9 Parotid enlargement typically occurs in Heerfordt syndrome, which also manifests fever and acute anterior uveitis. (From Kanski J. Clinical diagnosis in ophthalmology. 1st edition. Philadelphia: Mosby, an imprint of Elsevier; 2006. Fig. 10.75; with permission.)

¨gren syndrome is a chronic autoimmune inflamma Sjo tory disease that primarily affects the exocrine glands.1,2 It was first described by Swedish ophthal¨gren in 1933.3,4 mologist Henrik Sjo  The syndrome can manifest as a primary disorder usually within the lacrimal and salivary glands or have systemic manifestations (most commonly rheumatoid arthritis or systemic lupus erythematosus), and is ¨gren.2,5 defined therefore as secondary Sjo  Although the exact cause is unknown, it seems that genetic, environmental, and hormonal factors play a significant role.2  Patients with this disorder are at high risk for the development of non-Hodgkin lymphoma.1,2,5  Treatment of this disorder is mainly symptomatic, although immunologic therapies have shown some promise.5

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Fig. 11 (A) Bilateral parotid and submandibular gland hypertrophy in a patient with Sjogren syndrome. (B) Bilateral sublingual gland hypertrophy in a patient with Sjogren syndrome. (Courtesy of D DeLuke, DDS, MBA, Richmond, VA.)

Genetics ¨gren syndrome affects about 0.2% to 3% (200e3000 per Sjo 100,000) of the population and has a significant female/male ratio of 9:1.3,6 The important role of genetics in this disorder is emphasized when siblings and relatives of patients with pri¨gren syndrome have a significantly higher risk of also mary Sjo ¨gren and other autoimmune dishaving the disease.7 With Sjo orders, genetic factors are varied and complex.6 Variations in human leucocyte antigen on chromosome 6 subunit DR (HLA-DR) and human leucocyte anitgen on chromosome 6 subunit DQ (HLA-DQ), which are located within the major histocompatibility complex class II genes, determine basic ¨gren synimmune response and have been implicated in Sjo drome.1,6 Genes that affect production and proliferation of T and B cells have also been studied.6,8,9 Multifactorial genetic and immunologic events are involved in the expression of this disorder.9e14

occurs along with hyaline deposits often described as epimyoepithelial sialoadenitis (Fig. 12).2

Differential diagnosis Sarcoidosis with or without Heerfordt syndrome, multiple sclerosis, and other neurologic disorders has been reported to ¨gren syndrome.25e27 Because exocrine dysfunction is mimic Sjo ¨gren syndrome is often difficult to the primary symptom, Sjo diagnose. The American European consensus group established ¨gren syndrome.28 The patient criteria for the diagnosis of Sjo must have subjective symptoms of dry eyes and dry mouth, objective ocular and salivary gland tests, histopathology

Clinical features ¨gren syndrome is classified primarily by lymphocytic infilSjo tration of multiple exocrine glands, specifically the lacrimal and salivary glands, resulting in keratoconjunctivitis sicca and xerostomia. Because of lack of lacrimal secretions, corneal abrasions, visual discomfort and impairment are possible.5 Xerostomia results in susceptibility to dental caries, periodontal disease, and difficulty in chewing and swallowing.15e19 There is often swelling of the parotid glands bilaterally ¨gren syndrome, extra(Fig. 11A and B).20 In secondary Sjo glandular systemic involvement occurs (most likely rheumatoid arthritis or systemic lupus erythematous).1,2 Other clinical features include fatigue21 and thyroid, liver, and kidney disease.22,23 There are reports of immune-mediated anemia and ¨gren syndrome.24 The most thrombocytopenia secondary to Sjo serious complication related to this disorder is the development of lymphoma; these patients have a 10 to 50 times higher risk than normal individuals.2 On biopsy of the affected glandular tissue, periductal infiltration with lymphocytes

Fig. 12 Photomicrograph of a lip biopsy in a patient with Sjogren syndrome. Note the periductal lymphocytic infiltrate. (Courtesy of J Burns, DDS, Phd, Richmond VA.)

130 usually by minor salivary gland biopsy, and the presence of serum autoantibodies of anti-Ro and/or anti-La specificity.2,28e30

Treatment considerations for the oral and maxillofacial surgeon ¨gren syndrome will have a significant impact on the ability Sjo of the oral and maxillofacial surgeon to treat head and neck issues that might arise. Local secondary effects of the disease may include xerostomia, rampant caries, periodontal disease, and recurrent fungal infection. Systemic effects secondary to treatment with steroids and other immunosuppressive drugs must be considered, and consultation with multiple specialists may be needed prior to surgery.

References Fabry disease 1. Kes VB, Cesarik M, Zavoreo I, et al. Anderson-Fabry disease: developments in diagnosis and treatment. Acta Clin Croat 2012;51(3): 411e7. 2. Kantola I, Penttinen M, Nuutila P, et al. Fabry disease. Duodecim 2012;128(7):729e39 [in Finnish]. 3. Germain DP. Fabry disease. Orphanet J Rare Dis 2010;5:30. 4. Mauer M, Kopp JB. Clinical features and diagnosis of Fabry disease. UpToDate. Massachusetts: Wolters Kluwer Health; 2013. 5. Gal A, Sch¨ afer E, Rohard I. The genetic basis of Fabry disease. In: Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry disease: perspectives from 5 Years of FOS. Oxford (United Kingdom): Oxford PharmaGenesis; 2006. Chapter 33. 6. Mehta A, Hughes DA. Fabry disease [updated March 10, 2011]. In: Pagon RA, Adam MP, Bird TD, et al, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 2002. p. 1993e2013. 7. Mehta A, Beck M, Linhart A, et al. History of lysosomal storage diseases: an overview. In: Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry disease: perspectives from 5 years of FOS. Oxford (United Kingdom): Oxford PharmaGenesis; 2006. Chapter 1. 8. Mitsias P, Levine SR. Cerebrovascular complications of Fabry’s disease. AnnNeurol 1996;40(1):8e17. 9. Mehta A, Ricci R, Widmer U, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest 2004;34:236. 10. Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry disease: perspectives from 5 years of FOS. Oxford (United Kingdom): Oxford PharmaGenesis; 2006. 11. Sivley MD. Fabry disease: a review of ophthalmic and systemic manifestations. Optom Vis Sci 2013;90(2):e63e78. 12. Branton MH, Schiffmann R, Sabnis SG, et al. Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course. Medicine (Baltimore) 2002; 81:122. 13. Meikle PJ, Hopwood JJ, Clague AE, et al. Prevalence of lysosomal storage disorders. JAMA 1999;281:249. 14. Houge G, Skarbøvik AJ. Fabry diseaseea diagnostic and therapeutic challenge. Tidsskr Nor Laegeforen 2005;125:1004e6 [in Norwegian]. 15. Guffon N. Clinical presentation in female patients with Fabry disease. J Med Genet 2003;40(4):e38. 16. Tuttolomondo A, Simonetta I, Miceli S, et al. Anderson-Fabry disease: a multiorgan disease. Curr Pharm Des 2013;19(33): 5974e96. 17. Burton JO, Dormer JP, Binns HE, et al. Sometimes when you hear hoofbeats, it could be a zebra: consider the diagnosis of Fabry disease. BMC Nephrol 2012;13:73.

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Williams syndrome 1. De Rubens Figueroa J, Rodr´ıguez LM, Hach JL, et al. Cardiovascular spectrum in Williams-Beuren syndrome: the Mexican experience in 40 patients. Tex Heart Inst J 2008;35(3):279e85. 2. Sadler LS, Pober BR, Grandinetti A, et al. Differences by sex in cardiovascular disease in Williams syndrome. J Pediatr 2001; 139(6):849e53. 3. Morris CA, Mervis CB. Williams syndrome and related disorders. Annu Rev Genomics Hum Genet 2000;1:461e84. 4. Williams JC, Barratt-Boyes BG, Lowe JB. Supravalvular aortic stenosis. Circulation 1961;24:1311e8. 5. Beuren AJ, Apitz J, Harmjanz D. Supravalvular aortic stenosis in association with mental retardation and a certain facial appearance. Circulation 1962;26:1235e40. 6. Schubert C. The genomic basis of the Williams-Beuren syndrome. Cell Mol Life Sci 2009;66(7):1178e97. 7. Francke U. Williams-Beuren syndrome: genes and mechanisms. Hum Mol Genet 1999;8(10):1947e54. 8. Antonell A, Del Campo M, Flores R, et al. Williams syndrome: its clinical aspects and molecular bases. Rev Neurol 2006;42(Suppl 1): S69e75 [in Spanish]. 9. Alleva E, Cirulli F, Calamandrei G, et al. Williams syndrome. Ann Ist Super Sanita 1999;35(2):211e9 [in Italian]. ´n Z, Kiss E, Ka ´d´ 10. Urba ar K, et al. Genetic diagnosis of Williams syndrome. Orv Hetil 1997;138(27):1749e52 [in Hungarian]. 11. Van Hagen JM, Govaerts LC, de Coo IF, et al. Williams syndrome: new insights into genetic etiology, pathogenesis and clinical aspects. Ned Tijdschr Geneeskd 2001;145(9):396e400 [in Dutch]. 12. Metcalfe K. Williams syndrome: an update on clinical and molecular aspects. Arch Dis Child 1999;81(3):198e200. 13. Lashkari A, Smith AK, Graham JM Jr. Williams-Beuren syndrome: an update and review for the primary physician. Clin Pediatr (Phila) 1999;38(4):189e208.

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Hurler syndrome 1. Dorfman A, Matalon R. The mucopolysaccharidoses (a review). Proc Natl Acad Sci U S A 1976;73(2):630e7. 2. Giugliani R, Federhen A, Rojas MV, et al. Mucopolysaccharidosis I, II, and VI: brief review and guidelines for treatment. Genet Mol Biol 2010;33(4):589e604. 3. Prasad VK, Kurtzberg J. Transplant outcomes in mucopolysaccharidoses. Semin Hematol 2010;47(1):59e69. http://dx.doi.org/10.1053/j.seminhematol.2009.10.008. 4. Kakavanos R, Turner CT, Hopwood JJ, et al. Immune tolerance after long-term enzyme-replacement therapy among patients who have mucopolysaccharidosis I. Lancet 2003;361(9369): 1608e13. 5. van der Linden MH, Kruyt MC, Sakkers RJ, et al. Orthopaedic management of Hurler’s disease after hematopoietic stem cell transplantation: a systematic review. J Inherit Metab Dis 2011; 34(3):657e69. 6. Scott HS, Bunge S, Gal A, et al. Molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological implications. Hum Mutat 1995;6(4):288e302. 7. Terlato NJ, Cox GF. Can mucopolysaccharidosis type I disease severity be predicted based on a patient’s genotype? A comprehensive review of the literature. Genet Med 2003;5(4): 286e94. 8. de Ru MH, Boelens JJ, Das AM, et al. Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure. Orphanet J Rare Dis 2011;6:55. 9. Girard B, Hoang-Xuan T, D’Hermies F, et al. Mucopolysaccharidosis type I, Hurler-Scheie phenotype with ocular involvement. Clinical and ultrastructural study. J Fr Ophtalmol 1994;17(4):286e95 [in French]. 10. Stephan MJ, Stevens EL Jr, Wenstrup RJ, et al. Mucopolysaccharidosis I presenting with endocardial fibroelastosis of infancy. Am J Dis Child 1989;143(7):782e4. 11. Gardner DG. The oral manifestations of Hurler’s syndrome. Oral Surg Oral Med Oral Pathol 1971;32(1):46e57.

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Hunter syndrome ´ssy Z, Beck M, , et alHunter Syndrome European 1. Scarpa M, Alma Expert Council. Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease. Orphanet J Rare Dis 2011;6:72. 2. da Silva EM, Strufaldi MW, Andriolo RB, et al. Enzyme replacement therapy with idursulfase for mucopolysaccharidosis type II (Hunter syndrome). Cochrane Database Syst Rev 2011;(11). CD008185. 3. Muenzer J, Bodamer O, Burton B, et al. The role of enzyme replacement therapy in severe Hunter syndrome-an expert panel consensus. Eur J Pediatr 2012;171(1):181e8. 4. Sohn YB, Cho SY, Park SW, et al. Phase I/II clinical trial of enzyme replacement therapy with idursulfase beta in patients with mucopolysaccharidosis II (Hunter syndrome). Orphanet J Rare Dis 2013;8:42. 5. Kaur J, Swami AC, Kumar A, et al. Anesthetic management of a child with Hunter’s syndrome. J Anaesthesiol Clin Pharmacol 2012; 28(2):255e7.

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Heerfordt syndrome 1. Fischer T, Filimonow S, Petersein J, et al. Diagnosis of Heerfordt’s syndrome by state-of-the-art ultrasound in combination with parotid biopsy: a case report. Eur Radiol 2002;12(1):134e7.

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