Rare diagnosis of Melkersson-Rosenthal syndrome in a paediatric patient

Abstract

Melkersson-Rosenthal syndrome (MRS) is a rare neurocutaneous syndrome characterised by the triad of recurrent orofacial swelling, facial nerve palsy and fissured tongue. This diagnosis is particularly rare in children. We aim to increase awareness of the syndromic association of these clinical features since most patients present with a monosymptomatic form, reiterating the importance of detailed history and thorough physical examination, for the timely identification of these patients. Not only the recurring of symptoms, but also the association of MRS with other medical conditions, make ‘earlier’ diagnosis of the Syndrome beneficial. The average delay in diagnosis is 4–9 years. Although most cases resolve without treatment, when treated, steroids are most commonly used. Variable options have been tried for refractory and frequently recurrent cases. We present a case of MRS in a 12-year-old girl, diagnosed 3 years after onset of symptoms. We reviewed updated literature for MRS and associated clinical conditions as well as published treatment options.

Background

Orofacial granulomatosis is a conglomerate of diseases characterised by non-caseating granulomatous inflammation affecting the soft tissues of the oral and facial areas. Melkersson-Rosenthal syndrome (MRS) and cheilitis granulomatosa of Miescher are conditions that fall under the category of orofacial granulomatosis.¹ These conditions are histologically characterised by non-caseating granulomas, which have also been known to be associated with sarcoidosis, Crohn’s disease and other chronic inflammatory diseases. The hallmark histopathological finding of non-caseating epithelioid cell granulomas confirms the diagnosis of MRS. MRS cannot be excluded in the absence of these granulomas, as they may not be always initially present.

MRS is a rare neurological condition of unknown aetiology. It is most often reported in adults, generally in their third to fourth decade. A triad of symptoms, which include swelling of the lips, facial nerve palsy and a fissured tongue, make up the classical form of the condition. More often patients present with a monosymptomatic form, usually granulomatous cheilitis, which typically, is lip swelling and/or facial oedema.

Bell’s palsy is an acute facial nerve palsy that involves the distal branches of the facial nerve. It is generally idiopathic, develops over hours to days, with a progressive course and maximal weakness is seen within 3 weeks from onset. Most children diagnosed with Bell’s palsy recover without any residual weakness or dysfunction. MRS is often mistaken for Bell’s palsy.

We report a case of MRS in a child which necessitated interdisciplinary approach and collaboration between providers. The patient presented with facial nerve palsy, swelling of the lips and a fissured tongue consistent with MRS. The importance of taking a thorough medical history, a complete head-to-toe physical examination, considering differential diagnoses, appropriate clinical work-up and the use of medical research were integral to achieving a correct diagnosis and treatment of this rare syndrome in paediatrics.

Case presentation

A 12-year-old African American girl presented to the emergency room with sudden onset of left-sided facial and lower lip swelling for 1 day. Swelling occurred acutely over a few hours after the patient reportedly had used the prescribed albuterol inhaler due to her history of wheezing. The patient denied any difficulty breathing or swallowing, pain or discomfort. She was seen at an urgent care 2 days prior for an upper respiratory infection with cough and congestion, without fever, and was sent home with an Albuterol inhaler for mild wheezing. There was no history of trauma, fever, rash, itching or gastrointestinal disturbances. There was no family history of facial palsy, inflammatory or autoimmune conditions reported. The patient had a medical history of being diagnosed with right-sided Bell’s palsy at age 9 that was treated with acyclovir and a short course of steroids as outpatient and fully recovered. On examination in the emergency room, there was left-sided facial swelling and oedema of the lips. She also had sinus tachycardia, without signs of upper or lower airway obstruction, and was haemodynamically stable with normal oxygen saturations. She was treated for suspected angioedema/anaphylaxis and was given epinephrine intramuscular, intravenous steroids and intravenous diphenhydramine. The patient was admitted for further monitoring and management. On admission the patient was awake, alert and oriented. She was well appearing, in no acute respiratory distress, with stable vital signs.

Cardiovascular, respiratory, integumentary and musculoskeletal examinations were normal. Neurological and ‘Face’ examination revealed asymmetry of the face with left-sided facial and lower lip swelling (see figure 1). Facial muscles were noted to be weak, demonstrated by eyebrow sagging and inability to close the left eye and drooping of the corner of the left side of the mouth. With maximal effort, she was able to close her left eye and had asymmetry of the nasolabial fold. The patient reported decreased sense of taste and decreased sensation to the face, but hearing was intact. Along with the findings consistent with left-sided Bell’s palsy, her tongue was noted to have fissures (see figure 2).

Figure 1.

Orofacial swelling.

Figure 2.

Lingua plicata.

Investigations

Work-up included complete blood count, serum electrolytes, renal and liver functions and urinalysis which were normal. Chest radiograph was normal. A rapid antigen detection test for group A streptococcal and rapid influenza A and B antigen were negative. Additional testing for infectious aetiology included mycoplasma antibody IgM, Epstein-Barr virus antibody panel and herpes simplex virus PCR were also negative. Southeastern allergy panel did reveal perennial allergies to dog dander, ragweed and Bermuda grass.

Differential diagnosis

The patient’s clinical presentation was inconsistent with angioedema and anaphylaxis. She lacked any findings of distributive shock. The patient’s medical history of Bell’s palsy and the triad of findings of facial nerve palsy, swelling of the lips and fissured tongue favoured the diagnosis of MRS. The patient did not have any history of medication or food allergies. Associated symptoms of rash, itching, respiratory distress, fever, diarrhoea or vomiting were absent with this episode and the prior episode of Bell’s palsy, making acquired angioedema due to C1 inhibitor deficiency and idiopathic recurrent angioedema unlikely. Lack of any gastrointestinal findings, weight loss, adenopathy, normal chest radiograph made sarcoidosis, Crohn’s disease and lymphoma highly unlikely.

Treatment

The patient was empirically treated with acyclovir and prednisolone 60 mg once daily for 7 days.

Outcome and follow-up

After 36 hours and an uneventful hospital course, the patient was discharged home. At 2-week follow-up appointment with primary care provider, the facial palsy and lip swelling were completely resolved. She was referred to paediatric neurology.

Discussion

MRS is a rare systemic condition characterised by a triad of recurrent orofacial swelling, peripheral facial nerve palsy and furrowing/fissuring of the tongue (lingua plicata). Melkersson, in 1928,² and Rosenthal, in 1931,³ first described the condition. MRS is a rare disease with an estimated total population incidence of 0.02%–0.08%.⁴ Recent reviews report 30 published (paediatric) patients.⁴ Another review published in 2019 analysed that although the first symptoms occurred before the age of 18 years in 116 cases, only 67 patients (57.8%) were diagnosed with MRS before this age. Therefore, this diagnosis is more common in children, than previously known, but probably under diagnosed due to lack of widespread awareness of its occurrence in this younger age group.⁴ Patients with MRS generally present between third to fourth decade (range 1–69 years), with female predominance noted in a small number of reports.⁵ The median age at symptomatic presentation was 35 years, with an average delay in the diagnosis from first presentation of symptoms of 4–9 years (range 1–35).^{4 5} The youngest patient reported was 22 months of age.⁶ The diagnosis is often delayed and difficult because the classic triad of symptoms is only reported in one-third of patients.⁶ In patients with persistent or recurrent orofacial oedema, at least one of the clinical findings, fissured tongue or idiopathic facial palsy, is sufficient to make a definitive diagnosis of MRS. Orofacial swelling is the most common finding of MRS.

The oedema develops abruptly, is non-tender, generalised, firm, non-pitting and mainly confined to the lips. In a small subset of patients, incomplete or non-resolution of oedema may lead to fibrosis and permanent disfiguration of the face.^{4 7} The clinical features of MRS in children are similar to those seen in adults. However, frequency of the episodes and presentation of symptoms reveal specific differences. Facial nerve palsy may occur months to years prior to orofacial oedema.⁸ Facial paralysis can be unilateral or bilateral and is seen in 30%–90% of cases of which recurrent facial paralysis is seen in about 10% of the cases.⁸ In a series by Tang et al, facial paralysis was bilateral in 60% of the cases.⁷ The duration of facial palsy increases with subsequent recurrences. The finding of lingua plicata, defined as grooves on the dorsum of the tongue, occurs in approximately 30% of MRS cases in childhood, whereas in adult patients the rate is much higher at 50%–70%. The furrows typically measure 2 mm deep and up to 15 mm long.⁸ Although genetic, allergic, immunologic and infectious cause has been postulated, the aetiology of this syndrome remains unclear.⁴ The combination of orofacial oedema and peripheral facial nerve palsy in a child should alert the physicians to the diagnosis of MRS. The clinical course is usually progressive. The symptoms can present either synchronously (when all symptoms occur at the same time) or metachronously when recurrent facial nerve palsy, orofacial swelling and/ or fissuring of the tongue happen at different times.⁴ There are different forms of MRS. When only a single clinical feature of MRS is present, the term monosymptomatic is used to describe the disease, whereas the term oligosymptomatic is used when two clinical features are present. These two forms of MRS can pose a diagnostic challenge.⁹ Histopathologic confirmation is necessary in patients presenting with isolated orofacial swelling.¹⁰ Oligosymptomatic or complete forms of MRS do not require biopsy confirmation. Considering that discrete clinical and/or laboratory criteria for the diagnosis of MRS are lacking, this syndrome is probably underestimated and we suggest that clinicians should have a high index of suspicion and increased awareness of this uncommon syndrome. Orofacial granulomatosis, with the subentities of MRS and cheilitis granulomatosa, is an aetiological obscure disease process with varying therapeutic interventions.¹ There are several other clinical conditions that are often associated with MRS, including sarcoidosis, Crohn’s disease as well as autoimmune disorders such as Hashimoto’s thyroiditis, psoriasis and other infectious diseases such as tuberculosis.^11–15 Orofacial granulomatosis has been associated with food allergies, especially to benzoates-related and cinnamon-related compounds.¹⁶

Granulomatous cheilitis may be an initial manifestation of Crohn’s disease in the paediatric population.¹² Thus, in patients with MRS, monitoring for gastrointestinal symptoms and screening is recommended. However, patients without a history of gastrointestinal complaints, like in our patient, should not be exposed to routine investigations of the gastrointestinal tract due to low probability.¹⁷ In paediatric cases, peripheral facial nerve palsy is most likely to recur within the first 2 years from onset, which leads to the reasonable conclusion that follow-up with patients diagnosed with Bell’s palsy should continue for at least 2 years from onset.¹⁸

MRS remains a disease of unknown aetiology and is therefore difficult to treat. Therapeutic options for MRS in childhood are variable and not uniform with lack of uniform guidelines. Many patients are not treated pharmacologically; however, in nearly 40% of cases involving medication administration, steroids were the most common agent of choice.^{8 19} Our patient benefited from a short course of oral steroids and acyclovir.

Some cases described in the literature have either remained steroid refractory or remitted with only partial recovery. In such refractory, partially responsive or frequently recurring cases, other therapeutic options (immune modulators/antibiotics) have shown favourable results. Some of the agents used include dapsone, thalidomide, infliximab, clofazimine, intralesional triamcinolone and Tumour Necrosis Factor-alpha blocker, adalimumab.^{8 19–22} Surgical options such as total facial nerve decompression may be effective to prevent further episodes of facial palsy in MRS patients with frequently recurring facial palsy.²³ Plastic surgical procedures, including ‘reduction cheiloplasty’ and ‘liposuction’ for persistent macrocheilia to improve lip aesthetics, have also been performed.^{24 25}

Learning points.

• The combination of orofacial oedema and peripheral facial nerve palsy in a child should alert physicians to the diagnosis of Melkersson-Rosenthal syndrome (MRS).

• Complete MRS has the triad of recurrent orofacial swelling, peripheral facial nerve palsy and furrowing/fissuring of the tongue.

• All cases of facial nerve palsy should be followed up for at least 2 years for not only monitoring for recurrence but also for new development of orofacial swelling and tongue fissuring. These cases should also be closely monitored for other concomitant diagnoses that have similar pathology such as inflammatory bowel disease.

• Considering that discrete clinical and laboratory criteria for the diagnosis of MRS are lacking, this syndrome is probably underestimated, so we suggest that all clinicians should have a high index of suspicion and increased awareness of this uncommon syndrome.

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