Case 2: A 14-year-old girl with oral and genital ulcers

A 14-year-old girl of Lebanese descent presented with a one-year history of intermittent, painful vulvar ulcers. The patient denied prodromal symptoms or vaginal discharge, and she had never been sexually active. The history was also remarkable for painless oral ulcers recurring every month, a three-month history of headaches and occasional upper abdominal pain. Before presentation, she was treated for conjunctivitis with antibiotic drops. She gave no history of visual disturbances, ocular pain, rashes or arthritis. The review of systems was otherwise negative, and her history was noncontributory. Initial examination revealed a well-appearing, afebrile, adolescent girl with two minor (<10 mm) oral ulcers on her tongue and two minor, healing, genital ulcers on her left labium majus. Her general physical examination was otherwise normal. She was found to have bilateral papillitis and panuveitis on a screening ophthalmological examination.

Her complete blood counts were normal. Her inflammatory markers were elevated: her erythrocyte sedimentation rate was 54 mm/h (normal 1 mm/h to 10 mm/h) and her C-reactive protein was 190 nmol/L (normal 0 nmol/L to 76 nmol/L). Electrolyte levels, renal function and liver enzyme levels were normal. An infectious work-up was negative, which included testing for herpes simplex virus among other sexually transmitted infections. A screening rheumatological work-up was negative, including antinuclear antibody for systemic lupus erythematosus, antineutrophil cytoplasmic antibody for vasculitis, and serum calcium and angiotensin-converting enzyme for sarcoidosis. A urinalysis was positive for trace ketones and 1+ protein, and negative for blood, nitrites and leukocytes. Magnetic resonance imaging (MRI) of the head and orbits revealed bilateral, nonspecific, scattered small foci of abnormal signal in the bifrontal white matter but no abnormal enhancement of the optic nerves. A cerebral angiogram and lumbar puncture were normal.

CASE 2 DIAGNOSIS: BEHÇET DISEASE

Behçet disease is a relapsing inflammatory disorder with multi-system involvement. Oral and genital ulcers with uveitis were once considered the classical signs, but the disease can involve the neurological, musculoskeletal, gastrointestinal and vascular systems (1,2). The geographical origins of this disease are largely located along the historical route of the Silk Road from Japan to the eastern edge of the Mediterranean Sea. Genetic factors play an important role in the development of Behçet disease, with environmental factors playing a supplemental role. The diagnosis relies on clinical criteria rather than laboratory tests (Table 1) (3), but these have not yet been validated in children.

TABLE 1.

Diagnostic criteria for Behçet disease^*

Finding	Definition
Recurrent oral ulceration	Minor aphthous, major aphthous or herpetiform ulceration recurring at least three times in one 12-month period, observed by physician or patient
Recurrent genital ulceration	Aphthous ulceration or scarring observed by physician or patient
Eye lesions	Anterior uveitis, posterior uveitis, cells in the vitreous on slit-lamp examination or retinal vasculitis detected by an ophthalmologist
Skin lesions	Erythema nodosum observed by physician or patient, pseudofolliculitis, papulopustular lesions or acneiform nodules observed by physician in postadolescent patient not receiving corticosteroids
Pathergy	Skin reaction to a needleprick observed by physician at 24 h to 48 h

^*For the diagnosis to be made, a patient must exhibit recurrent oral ulceration plus at least two of the other findings in the absence of other clinical explanations

In paediatric studies, the most common initial presentation of Behçet disease is oral ulceration. However, the clinical features can be easily misdiagnosed and may not present until the disease evolves over time. Various etiologies must be carefully considered, and important differential diagnoses of orogenital ulceration include immunological, gastrointestinal, dermatological, infectious, hematological and medication-related causes (Table 2) (4). The patient initially presented with nonsexually related oral and genital ulcers, and it was the screening ophthalmological examination that prompted the diagnosis of Behçet disease. Within the framework of orogenital ulceration and panuveitis, the diagnostic possibilities become more limited.

TABLE 2.

Differential diagnosis of orogenital ulceration

System	Diagnosis
Unknown	Complex aphthosis
Multisystem, immune-mediated disease	Behçet disease
	Reactive arthritis (arthritis, conjunctivitis and urethritis)
	Mouth and genital ulcers with inflamed cartilage (MAGIC)
Gastrointestinal	Crohn disease
Dermatological	Sweet syndrome
	Erythema multiforme
	Bullous skin disease
	Erosive lichen planus
	Fixed drug reaction
Infectious	Cytomegalovirus
	Herpes simplex virus
	Salmonellosis
	Epstein-Barr virus
	HIV
	Syphilis
	Toxoplasmosis
HLA-B27-related syndromes	Ankylosing spondylitis
Medication reaction	Nonsteroidal anti-inflammatory drug
Hematological	Cyclical neutropenia
	Lymphoma

HLA Human leukocyte antigen

The clinical features of Behçet disease can be diverse (3,5). Although recurrent oral ulceration is required for diagnosis, up to 3% of patients can experience other features of the disease without having oral ulceration (3). When present, these oral ulcers are small, round, painful and erythematous, and can present anywhere in the mouth. They recur at various intervals and generally heal without scarring. The genital ulcers are also painful, but they are deeper and may leave scarring. They usually occur on the labia in females and on the scrotum in males. The patient presented with a history of painless oral ulcers, which is not typical for the oral ulceration associated with Behçet disease.

Skin lesions tend to occur in more than 90% of children and include erythema nodosum, acneiform lesions, folliculitis and purpura (6). Neither rash nor pathergy (Table 1) were present in our patient. Ocular involvement can occur in up to 61% of cases, is most often bilateral and affects boys more than girls. Panuveitis and posterior uveitis are more common, but isolated anterior uveitis and intermediate uveitis can also occur. Corneal ulceration, cystoid macular degeneration, papillitis, retinal vasculitis, retinal detachment and retrobulbar neuritis are rare events. Central nervous system disease has been reported in 10% to 20% of children with Behçet disease and includes meningoencephalitis, encephalomyelitis, benign intracranial hypertension and organic psychiatric disturbances (5,6). Arthritis is common, affecting 50% to 75% of children and is most often oligoarticular in distribution. Vascular involvement in Behçet disease is unique in that it is the only vasculitis affecting both the arterial and venous systems. In children, vascular disease is rare but also a major cause of morbidity and mortality (2,5). Uncommon manifestations in children include gastrointestinal, renal and cardiac disease.

There is no curative treatment for Behçet disease. The goal is to prevent organ damage and control acute exacerbations. Topical corticosteroids are the first line of treatment for oral and genital ulcers and also ocular inflammation (2). Oral colchicine, dapsone and azathioprine have been used to treat Behçet disease, but a course of systemic steroids is sometimes required during acute flares.

Although bilateral papillitis was detected on initial screening ophthalmological examination, optic nerve involvement and central nervous system inflammation were excluded in the patient with neuroimaging, cerebral angiography and lumbar puncture. She was treated with topical corticosteroid eye drops and oral colchicine with good response. At 18 months follow-up after disease onset, the patient continues to be in disease remission on oral colchicine alone.

CLINICAL PEARLS

• The differential diagnosis of orogenital ulcerations is extensive, including immunological, gastrointestinal, dermatological, infectious, hematological and medication-related etiologies.

• The clinical features of Behçet disease can be easily misdiagnosed and may only be recognized as the disease evolves over time; longitudinal follow-up of patients with orogenital ulceration is essential.

• An ophthalmological examination must be performed in patients presenting with oral and genital ulceration, and consideration must be given to a possible diagnosis of Behçet disease.