Asrani Mukesh et al: Syndromes associated with aphthous ulcers www.jrmds.

in

Review Article

Syndromes associated with aphthous ulcers

Asrani Mukesh*, Patadiya Hiren*, Suman Sen*

* Sr. Lecturer, Department of Oral Medicine and Radiology, Karnavati School of Dentistry, Uvarsad - 382422, Gandhinagar.
Gujarat, India

ABSTRACT

Recurrent Aphthous Stomatitis (RAS) is a common oral condition which is characterized by formation of
recurrent, multiple, small, round or oval ulcers over the oral mucosa. The etiopathogenesis of RAS is still unclear.
The diagnosis of this condition is very easy but many times, these ulcers are a part of an underlying disease or
syndrome. The main aim of this article is to make the clinicians aware of the underlying syndromes associated
with RAS so that appropriate patient care and further management with proper referrals can be arranged. A brief
review of the syndromes associated with RAS is described.

Key words: Aphthous syndromes, Aphthous ulcers, Stomatitis

INTRODUCTION also been implied in the development of aphthous

ulcers [3, 4, 5]
Recurrent Aphthous Stomatitis (RAS), also known
as canker sores is a common oral condition The diagnosis is mainly based on history and
characterized by formation of recurrent, multiple, clinical examination. However, in some cases, RAS
small, round or oval ulcers over the oral mucosa. is associated with some underlying systemic
These ulcers have circumscribed margins, disease or syndrome which should be considered in
erythematous haloes and yellow or grey floors. differential diagnosis. These include Behcet’s
These ulcers appear first in childhood or syndrome, MAGIC syndrome, cyclic neutropenia,
adolosence [1, 2]. PFAPA syndrome, Sweets syndrome and AIDS [1-
5]. A short review of each of these conditions is
RAS can be described under three clinical variants described.
– Minor aphthae, Major aphthae and Herpetiform
aphthae. Minor aphthae are multiple small round or Behcet’s Syndrome :
ovoid ulcers 2 – 4mm in diameter with yellowish
grey floor and are surrounded by erythematous Behcet’s syndrome (BS) is a chronic multisystem
halo. They are found mainly on the non-keratinized inflammatory disorder of unknown cause. The
mobile mucosa of the lips, cheeks, floor of the characteristic features include recurrent aphthous
mouth, sulci or ventrum of the tongue. They heal stomatitis, genital ulcerations, ocular lesions (uveitis
within 7 to 10 days without any scar formation. The or retinal vasculitis), skin lesions (erethema
major form has large painful ulcers more than 1 cm nodosum, papulopustular lesions or acneiform
in size, which remain for a week to month and nodules) or a positive pathergy test. It was first
generally heal with scar formation. Herpetiform described by Hulusi Behcet in 1937 as a triad of
ulcers are rare and occur as small ulcers usually oral and genital aphthous ulceration and
about 50 to 100 in number which may coalesce to iridocyclitis[6]. It is seen mainly in the
form large ulcers. Their clinical course is similar to Mediterranean basin, Middle East and the Far East.
minor RAS [2, 3] Turkey has the highest prevalence, while the
frequency is lower in western countriesn[7,8]
The etiology is still unclear but many predisposing
factors are suggested. These include genetics, This disease is caused by immunocomplexes that
trauma, stress, tobacco, certain drugs, haematinic lead to vasculitis of small and medium sized blood
deficiency, gluten sensitive enteropathy, vessels and inflammation of epithelium caused by
inflammatory bowel disease, sodium lauryl sulphate immunocompetent T lymphocytes and plasma cells.
containing toothpaste, hormonal changes, bacteria Majority of patients with this syndrome are sporadic,
like oral Streptococci and Helicobacter pylori and a familial aggregation of such patients has been
viruses like Cytomegalo virus and Epstein Barr noted. Studies have supported the direct role of
virus. Tumor necrosis factor alpha (TNF – α) has HLA-B5, and particularly with its split B5 in the
pathogenesis of BS [8, 9].

Journal of Research in Medical and Dental Science | Vol. 1 | Issue 2 | October – December 2013 72
Asrani Mukesh et al: Syndromes associated with aphthous ulcers www.jrmds.in

Two forms of this syndrome are recognized, which damage and tissue destruction. All types of
include child onset which affects children mainly cartilage may be involved such as: the elastic
between the age of 9 and 10 years and adult cartilage of the ears and nose, the hyaline cartilage
onset[6]. Most common site of involvement of of peripheral joints, the fibrocartilage of the axial
Behcet’s syndrome is oral mucosa. In 90% of the skeleton and the cartilage of the tracheobronchial
patients, the ulcers resemble the RAS. The lesions tree. It can progress in a fluctuating manner and
can occur anywhere on the oral mucosa as well as without treatment, can result in permanent
pharyngeal mucosa and mimic the minor or major destruction of the affected body part [12, 13].
variety of RAS. The second most common site is
the genital area which involves ulcers of the Pathogenesis of RP is unknown; it is generally
scrotum and penis in males and ulcers of the labia believed to be an autoimmune disease resulting
in females. The eye lesions consists of uveitis, from circulating antibodies against type II collagen
retinal infiltrates, edema and vascular occlusion, in cartilage. It is also associated with HLA DR4
optic atrophy, conjunctivitis and keratitis [8, 10, 11] suggesting an immune mediated pathology [13].

Arthiritis can occur in more than 50% of patients Clinical features of MAGIC syndrome are similar to
and most frequently affects the knees and ankles. Behcets syndrome along with relapsing
Some patients have central nervous system polychondritis which mainly affects the external ear
involvement which includes brainstem syndrome, causing pain, redness, swelling or tenderness of
involvement of cranial nerves, or neurologic one or both ears. The episodes remain for few days
degeneration resembling multiple sclerosis. Other or weeks and then the patient recovers with or
signs of BS include thrombophlebitis, intestinal without treatment. After recurrent or persistent
ulceration, venous thrombosis and renal and inflammation, there is destruction of cartilaginous
pulmonary disease. Involvement of large vessels is structures and there may be hearing loss. Patients
life threatening because of the risk of aterial generally also suffer from joint pain with or without
occlusion or aneurysm [8, 10] arthritis. This arthritis mimics rheumatoid arthritis
but tests for RA factor are negative. Involvement of
A set of diagnostic criteria for BS has been given by nasal cartilage causes swelling and pain initially but
an International Study group for BS that includes destruction of the cartilage can cause saddle nose
recurrent oral ulceration occurring at least three deformity [13, 14].
times in one 12 month period plus two of the
following four manifestations [10]. Inflammation of the laryngeal, tracheal and
bronchial cartilages causes hoarsness, non
 Recurrent genital ulceration productive cough, dyspnea, wheezing and
 Eye lesions including uveitis or retinal casculitis inspiratory stridor. The skin, ocular and genital
 Skin lesions including erythema nodosum, manifestations are similar to Behcet’s syndrome
pseudofolliculitis, papulopustular lesions, or [13, 14].
acneiform nodules in post-adolescent patients
not receiving cortoicosteroids Laboratory findings during the symptomatic phases
 A positive pathergy test. show increased ESR, C – reactive protein, anemia,
leukocytosis and thrombocytosis. Serum antibodies
The management of BS depends on the severity to collagen II have been found in nearly half of the
and the site of involvement. The drugs used are patients. Biopsy from ear cartilage or other inflamed
corticosteroids, azathioprine, pentoxifylline, sites help to confirm the diagnosis [15, 16].
cyclosporine, colchicine and thalidomide. However
corticosteroids remain the mainstay of treatment Management includes control of inflamm ation using
particularly to control the disease rapidly. non steroidal anti inflammatory drugs and oral
Plasmapheresis is also an emergency treatment prednisolone initially. In severe cases, large doses
modality [11]. of prednisolone (1mg/kg/day) is required until there
is control of symptoms and then tapered. Other
MAGIC SYNDROME drugs like azathioprine, cyclosporine, methotrexate,
dapsone, D – penicillamine, colchicine and
This term was given by Firestein et al in 1985 [12]. cyclophosphamide with or without steroids are used
Mouth and genital ulcers with inflammed cartilage with varying results[15,16].
(MAGIC) syndrome is a very infrequent disease
which includes clinical manifestations of Behçet CYCLIC NEUTROPENIA (CN)
disease and relapsing polychondritis (RP). RP is
characterized by recurrent episodes of inflammation Cyclic Neutropenia is a rare disorder occurs
of the cartilaginous structures, resulting in tissue secondary to a periodic failure of the stem cells in

Journal of Research in Medical and Dental Science | Vol. 1 | Issue 2 | October – December 2013 73
Asrani Mukesh et al: Syndromes associated with aphthous ulcers www.jrmds.in

the bone marrow. It is characterized by transient cervical adenitis. It is not familial and begins before
severe neutropenia that occurs approximately every the age of 5 years. The episodes of PFAPA may
21 days due to oscillations in production of last for years and the patient is well between
neutrophils by bonemarrow [17]. episodes [21].

Cyclic neutropenia is inherited as an autosomal This syndrome is defined clinically and diagnosis is
dominant disorder with full penetrance but varying made by exclusion. One of the diagnostic criteria
severity of clinical manifestations. Gene studies include complete resolution of febrile attacks by
have revealed that the families affected with CN single oral administration of corticosteroids[22].
had mutations in the gene for neutrophil elastase
(ELA2). Cellular studies have demonstrated that The most widely accepted treatment of PFAPA
accelerated apoptosis of neutrophil precursors is syndrome is corticosteroids, oral prednisolone
the proximate cause of the reduced neutrophil (1mg/kg/day, 3 to 5 days). It has been observed
production [17, 18]. that one or two doses of prednisolone dramatically
shorten the duration of fever without reducing the
Clinical features include fever, malaise, aphthous number of attacks. Other proposed treatments
stomatitis, mucus membrane infections and include cimetidine and tonsillectomy. It has been
lymphadenopathy. Manifestations of this disease reported that there is complete resolution of
usually begin in childhood but some patients suffer symptoms in about two thirds of patients after
from the adult onset form. Between these periods of tonsillectomy [23].
recurrent fever, mouth ulcers, and infections,
patients are usually without symptoms and have SWEET SYNDROME
normal physical examination [19].
Sweet syndrome (SS) was first described by Robert
Management of CN includes proper care of patient Sweet in 1964 as acute febrile neutrophilic
during the period of decreased nuetrophil count. dermatosis. It is characterized by a constellation of
Antibiotics and antipyretics are administrated to clinical symptoms, physical features, and pathologic
control the symptoms. Splenectomy, androgens, findings which include fever, neutrophilia, tender
glucocorticosteroids, and lithium were used, but are erythematous skin lesions (papules, nodules, and
not much effective. The availability of recombinant plaques), and a diffuse infiltrate consisting
human G-CSF has greatly changed the predominantly of mature neutrophils that are
management of cyclic neutropenia. G-CSF has typically located in the upper dermis [24, 25].
shown to shorten the period of neutropenia as well
as the length of the neutropenic cycle. This Sweet syndrome is classified in three main types:
treatment is known to be effective at least as Classical, paraneoplastic and drug induced.
early as the age of six months to one year. Classical type is more common in women between
For affected individuals with a well matched the ages of 30 to 50 years, is often preceded by
donor, haematopoietic stem cell transplantation upper respiratory tract infection and may be
may be the preferred treatment option[17,18,19]. associated with inflammatory bowel disease and
pregnancy. The paraneoplastic type is associated
PERIODIC FEVER, APHTHOUS STOMATITIS, commonly with haematogenous malignancy mainly
PHARANGYTIS AND CERVICAL ADENITIS acute myleogenous leukemia. The commonly
(PFAPA) SYNDROME associated solid tumors are those of genitourinary
organs, breast and of gastrointestinal tract. Drug-
Periodic fever, aphthous stomatitis, pharangytis and induced Sweet syndrome most commonly occurs in
cervical adenitis (PFAPA) syndrome was first patients who have been treated with granulocyte-
described by Marshall in 1987[20]. It is a pediatric colony stimulating factor, however, other
periodic disease characterized by recurrent febrile medications may also be associated [25, 26].
episodes associated with head and neck symptoms.
The etiology of this syndrome is unknown but The exact pathogenesis of Sweet Syndrome is not
infectious and immunological mechanisms have known. However, altered immunological reactivity
been implicated [20]. may be in the form of hypersensitivity to
bacterial, viral, and tumour antigens, or circulating
The clinical characteristic features of PFAPA auto anti body and immunecomplex reaction or
syndrome is high fevers (usually 40.0°C to 40.6°C) cytokine deregulation are proposed factors
recurring at fixed intervals every 2 to 8 weeks. The [25,26].
fevers last for about 4 days then resolve
spontaneously. Other symptoms associated with Fever is the most common symptom which may be
fever are aphthous stomatitis, pharyngitis and accompanied by general malaise, myalgia and

Journal of Research in Medical and Dental Science | Vol. 1 | Issue 2 | October – December 2013 74
Asrani Mukesh et al: Syndromes associated with aphthous ulcers www.jrmds.in

arthralgia. Cutaneous manifestations consist of 5. Porter SR, Scully C., Pedersen A. Recurrent
erythematous papules, nodules with pseudo aphthous stomatitis. Crit Rev Oral Biol Med
vesicular appearance, sometimes coalescing to 1998; 9:306-321.
6. Mutlu S, Scully C. The person behind the
form plaques which can be studded with
eponym: HulusiBehcet (1889-1948). J Oral
pastules, or giving targetoid appearance. Face, Pathol Med. 1994; 23: 289- 290.
neck, upper limb and trunk are the commonly 7. Gulbay B., Acıcan T., Diken OE, Önen ZP.
involved sites. Oral manifestations include Familial Behçet’s Disease of Adult Age: A
recurrent aphthous stomatitis and their presence Report of 4 Cases from a Behçet Family. Intern
should alarm the association with haematological Med. 2012; 51:1609-11.
disorders [25, 26]. 8. Jaber L., Milo G., Halpern GJ., Krause I.,
Weinberger A. Prevalence of Behçet’s disease
Management includes topical and intralesional in an Arab community in Israel. Ann Rheum Dis.
2002; 61:365–66.
corticosteroids initially however systemic
9. Krause I., Molad Y., Weinberger A. Association
corticosteroids remain the mainstay of treatment.
of HLA-B5 with clinical association of HLA-B51
Other first line systemic drugs include potassium with clinical expression and severity of Behçet’s
iodide and colchicines. Second line treatment disease in Israel. J Clin Rheumatol. 1999;
includes indomethacin, clofazimine, cyclosporin, 5:137–40.
and dapsone. In malignancy associated type, the 10. Anonymous. International Study Group for
treatment of the underlying malignancy has showed Behçet’s Disease. Criteria for diagnosis of
resolution and in drug associated type, stoppage of Behçet’s disease. Lancet. 1990; 335:1078-1080.
11. Seyahi E., Fresko I., Melikoglu M., Yazici H. The
the suspected medication has showed good results
management of Behçet’s syndrome. Acta
[26,27].
Reumatol Port. 2006; 31: 125-31.
12. Firestein GS et al. Mouth and genital ulcers
HIV / AIDS with inflamed cartilage: MAGIC syndrome: Five
patients with features of relapsing polychondritis
Recurrent aphthous stomatitis (RAS) is one of the and Behcet’s disease. Am J Med 1985; 79:65-
common oral manifestations of HIV / AIDS. In this 72.
condition, the ulcers are similar to those of non – 13. Orme RL et al. The MAGIC syndrome (mouth
infected group but are long lasting and are less and genital ulcers with inflamed cartilage). Arch
responsive to routine medications. In many patients, Dermatol 1990;126:940-4.
major aphthae are found and are associated with 14. Valestini G, Priori R, Conti F. Saddle nose in
+ relapsing polychondritis: a problem of differential
advanced HIV infection (CD4 counts less than 50 /
3 diagnosis. N Engl J Med 1995; 333: 525.
mm ) which suggests that immune compromise is a
15. Imai H et al. Mouth and genital ulcers with
factor predisposing to aphthous stomatitis [28,29]. inflamed cartilage (MAGIC syndrome): a case
report and literature review. Am J Med Sci
Topical and systemic steroids are the treatment of 1997; 314:330-2.
choice according to severity of ulceration. Immune 16. Kent PD, Michet CJ Jr, Luthra HS. Relapsing
suppressants and immune modulatory drugs have polychondritis. Curr Opin Rheumatol 2004; 16:
shown to be effective in majority of cases but they 56-61.
do not prevent recurrence and their use is limited by 17. Dale DC, Bolyard AA, Aprikyan A. Cyclic
its toxicity. At present the treatment of choice Neutropenia. Semin Hematol 2002; 39:89-94.
18. Loughran TP Jr, Clark EA, Price TH, Hammond
remains anti retroviral therapy as immune recovery
WP. Adult-onset cyclic neutropenia is
is a determining factor in resolution of ulcers associated with increased large granular
[29,30]. lymphocytes. Blood 1986; 5:1082-87
19. Haurie C, Dale DC, Mackey MC: Cyclical
REFERENCES neutropenia and other periodic hematological
disorders: A review of mecha- nisms and
1. Scully C., Felix DH. Oral medicine - Updates for mathematical models. Blood 1998; 8:2629-
the dental practitioner. Aphthous and other 2640,
common ulcers. Br Dent J. 2005; 199:259–64. 20. Marshall GS, Edwards KM, Butler J, Lawton AR.
2. Jurge S., Kuffer R., Scully C., Porter SR. Syndrome of periodic fever, pharyngitis, and
Recurrent aphthous stomatitis. Oral Dis. 2006; aphthous stomatitis. J Pediatr 1987;110:43-46.
12:1-21. 21. Lee WI, Yang MH, Lee KF, Chen LC, Lin SJ,
3. Scully C., Gorsky M., Lozada-Nur F. The Yeh KW, Huang LJ. PFAPA syndrome (periodic
diagnosis and management of recurrent fever, aphthous stomatitis, pharyngitis,
aphthous stomatitis, a consensus approach. J adenitis). Clin Rheumatol 1999; 18:207-213.
Am Dent Assoc. 2003; 134:200-07. 22. Padeh S, Brezniak N, Zemer D, Pras E, Livneb
4. Boras VV, Savage NW. Recurrent aphthous A, Langevitz P, Migdal A, Pras M, Passwell JH.
ulcerative disease: presentation and Periodic fever, aphthous stomatitis, pharyngitis,
management. Aust Dent J. 2007; 52:10-15. and adenopathy syndrome: clinical

Journal of Research in Medical and Dental Science | Vol. 1 | Issue 2 | October – December 2013 75
Asrani Mukesh et al: Syndromes associated with aphthous ulcers www.jrmds.in

characteristics and outcome. J Pediatr 1999; 30. Phelan JA, Eisig S, Freedman PD, et al. Major
135:98-101. aphthous-like ulcers in patients with AIDS. Oral
23. Wong KK, Finlay, Moxham J P. Role of Surg Oral Med Oral Pathol 1991; 71:68-72
tonsillectomy in PFAPA syndrome. Arch
Otolaryngol Head Neck Surg. 2008; 134:16-9.
24. Astudillo L, Sailler L, Launay F, Josse AG,
Lamant L, Couret B, Arlet-Suau E. Pulmonary Corresponding Author:
involvement in Sweet's syndrome: a case report
and review of the literature. Int J Dermatol 2006; Dr Mukesh Asrani (MDS)
45: 677-680 Sr. Lecturer
Department of Oral Medicine and Radiology
25. Cohen PR. Sweet's syndrome – a
Karnavati School of Dentistry
comprehensive review of an acute febrile Uvarsad - 382422, Gandhinagar.
neutrophilic dermatosis. Orphanet Journal of Gujarat.
Rare Diseases 2007; 2:34.
26. Sitjas D, Cuatrecasas M, De Moragas JM. Acute Date of Submission: 05/10/2013
febrile neutrophilic dermatosis (Sweet's Date of Acceptance: 18/10/2013
syndrome). Int J Dermatol 1993; 32: 261-268.
27. Maillard H, Leclech C, Peria P, Avenel-Audran
M, Verret JL. Colchicine for Sweet's syndrome.
A study of 20 cases. Br J Dermatol 1999; 140:
565-566. How to cite this article: Asrani M, Patadiya H,
28. Santos-Juanes J, Trapiella-Martínez L, Caminal- Suman S. Syndromes associated with
Monterob L. Mouth and Esophageal Ulcers in an aphthous ulcer. J Res Med Den Sci
HIV-infected Patient. Actas Dermosifiliogr. 2013;1(2):72-76
2008;99:653-4
29. Glick M, Muzyka BC, Lurie D, Salkin LM. Oral Source of Support: None
Conflict of Interest: None Declared
manifestations associated with HIV disease as
markers for immune suppression and AIDS.
Oral Surg Oral Med Oral Pathol 1994; 77:344-
49

Journal of Research in Medical and Dental Science | Vol. 1 | Issue 2 | October – December 2013 76