Hyperimmunoglobulinemia D Syndrome Masquerading as Familial Mediterranean Fever, Hidradenitis Suppurativa, and Crohn’s Disease: A Case Report

Abstract

We report a rare case of hyperimmunoglobulinemia D syndrome (HIDS) in a young man who was initially diagnosed with familial Mediterranean fever, hidradenitis suppurativa, and, eventually, with Crohn’s disease. The final diagnosis of HIDS was based on whole-exome sequencing. The unique concurrence of these three conditions has not been reported previously. The multiple diagnoses and overlapping presentations of these conditions should raise awareness about alternative diagnoses that mimic inflammatory and autoimmune conditions, including HIDS, a rare but clinically relevant condition. Exploring patients’ family histories to understand the genetic contribution to HIDS is also important. This is evidenced by the fact that whole-exome sequencing for our patient was performed because the patient’s brother was diagnosed with HIDS, and the sequencing led to the final diagnosis.

INTRODUCTION

Hyperimmunoglobulinemia D syndrome (HIDS) is a rare autosomal recessive inflammatory disorder that is characterized by recurring fever, chills, and systemic inflammation involving synovial fluids and serosal surfaces. HIDS is caused by a mevalonate kinase (MVK) enzyme deficiency.[1] We present the case of a young patient with pre-existing Crohn’s disease (CD) and concurrent hidradenitis suppurativa (HS) who was subsequently diagnosed with HIDS. HS and HIDS share similar pathophysiology, and their concurrent occurrence has been reported in literature.[2] To the best of our knowledge, the unique combination of these three conditions, CD, HS, and HIDS, has not been reported in the literature.

CASE REPORT

A 25-year-old Saudi male was referred to a gastroenterology service in 2015 for chronic and intermittent abdominal pain, bloody diarrhea, painful oral ulcers, and fever. The patient had been experiencing these symptoms over the past 10 years. The patient was a non-smoker and non-alcoholic, and his family history was unremarkable. In 2008, the patient’s symptoms were evaluated by infectious diseases and allergy/immunology services and he was diagnosed with familial Mediterranean fever (FMF) due to his complaints of recurrent abdominal pain, bouts of diarrhea, joint pain, and continuous fever, in which his symptoms fit the Tel Hashomer criteria of FMF, yet there was no positive family history of first-degree relative with FMF. Colchicine 0.6 mg t.i.d. was initiated at that time, and follow-up revealed minimal symptom improvements. In 2015, DNA analysis for the FMF gene (MEFV) became available; however, the test was negative. The patient was diagnosed with FMF-like disease and colchicine was continued at a lower dose of 0.6 mg b.i.d.

In 2011, the patient developed perianal abscesses and fistulas, and the pelvis magnetic resonance imaging (MRI) revealed a left intersphincteric fistula and abscess requiring fistulotomy and abscess drainage. In 2014, the patient developed recurrent abscesses in the axillae and inguinal areas requiring treatment with antibiotics and excision and drainage of the abscesses. The histopathology of both axillae showed fibrosis and inflammation compatible with HS.

In 2015, the patient presented at the emergency room with diffuse dull aching abdominal pain, bloody diarrhea, and fever with chills and multiple joint pain in the elbows, knees, and ankles. On physical examination, the patient was febrile (38°C) and had oral ulcers. His body mass index was 25 kg/m². No clinically significant lymph nodes were detected. Abdominal examination revealed a scar from a previous appendectomy and mild tenderness all over his abdomen without rebound tenderness. A digital rectal examination revealed scars from a previous perianal abscess drainage and fistulotomy. The patient’s knees and ankles were tender with minimal swelling. The patient was admitted to the gastroenterology service for further management.

Laboratory tests indicated the following: white blood cell count, 13 × 10⁹/L (normal range: 4–11 × 10⁹/L); hemoglobin, 134 g/L (14–16.5 g/dL); platelets, 248 × 10⁹/L (150–450 10⁹/L); mean corpuscular volume, 68 fL (75–95 fL); ferritin, 790 μg/L (30–400 μg/L); serum iron, 6 μmol/L (6–27 μmol/L); erythrocyte sedimentation rate (ESR), 62 mm/hr (2–15 mm/hr), and C-reactive protein (CRP), 265 mg/L (<3 mg/L). Stool examination was negative for ova, parasites, and culture; however, fecal calprotectin was elevated to 283 μg/g (<30). Purified protein derivative skin test and Quantiferon test for tuberculosis were also negative. Abdominal computed tomography revealed diffuse circumferential wall thickening associated with wall edema in the whole colon. No abdominal collection, free air, or lymphadenopathy was observed. A colonoscopy up to the terminal ileum showed patchy erythema and ulcerations in the terminal ileum, rectum, and sigmoid colon. Histopathological analysis revealed active chronic colitis with crypt abscesses. At this stage, the patient was diagnosed with CD due to the mucosal involvement pattern and history of the perianal fistula. He was treated with tapering doses of oral prednisone and maintained on azathioprine (100 mg daily) monotherapy. The patient was also started on mesalamine 1.6 g PO b.i.d. However, colchicine at this point was discontinued after 8 years of maintenance, as it aggravated the diarrhea.

During follow-up, the CD was in clinical and biochemical remission on azathioprine. A colonoscopy in 2016 revealed improved mucosal disease, and histopathology showed mild chronic inactive colitis involving the rectum and sigmoid colon. The patient was followed up every 6 months, wherein he exhibited minimal symptoms of non-bloody diarrhea, abdominal pain, fever, and joint pain. In 2018, abdominal MRI revealed improved diffuse colonic wall thickening with residual featureless proximal sigmoid and descending colonic transmural enhancement, which were likely sequelae of the chronic inflammation. There was no evidence of small bowel disease.

In 2022, the patient mentioned that his brother had recurrent fever and abdominal symptoms for many years and was recently diagnosed with HIDs at another institution following genetic testing and was receiving biological treatment. Previous serum immunoglobulin levels of our patient were requested and were shared as follows: IgA, 5.66 g/L (normal range: 0.7–4 g/L); IgG, 19.3 g/L (7–16 g/L); IgM, 0.52 g/L (0.4–2.3 g/L); IgE, 98 ku/L (5–500 ku/L); and IgD, 789 mg/dL (<150 mg/dL). Whole-exome sequencing revealed that our patient was heterozygous for the MVK gene. Accordingly, he was started on the interleukin-1 receptor antagonist anakinra (100 mg subcutaneously twice a day) and responded well to the treatment. He was later switched to the interleukin-1β blocker canakinumab (150 mg subcutaneously every 8 weeks) and continued on azathioprine. The patient, who was last followed up in February 2024, was asymptomatic with normal complete blood count, ESR, CRP, ferritin, serum iron, and fecal calprotectin. The patient’s last colonoscopy in September 2023 was normal.

DISCUSSION

The MVK gene, located on chromosome 12, is responsible for the synthesis of MVK, which is required for cholesterol synthesis. It also helps in the production of other substances necessary for cell growth, cell differentiation, formation of the cell’s structural framework, gene expression, and protein production. MVK deficiency, possibly caused by gene mutation, causes mevalonic aciduria, a disease characterized by psychomotor retardation, hepatosplenomegaly, anemia, failure to thrive, and recurrent febrile crises. MVK deficiency is broadly divided into HIDS with an enzyme activity of 1.8%–28% and complete enzyme deficiency with enzyme activity <1%. HIDS is an autosomal recessive disorder involving a dysregulated immune system. The most common symptoms of HIDS include painful lymphadenopathy, maculopapular rash, aphthous ulcers, arthralgia, and gastrointestinal symptoms such as vomiting, diarrhea, and abdominal pain.[3]

Behçet disease can present as an overlap of autoimmune conditions. However, this differential was ruled out in the absence of hallmark features such as recurrent oral and genital ulcers, and uveitis. Furthermore, it does not present with elevated IgD levels, as seen in our patient. Whole-exome sequencing further supports HIDS by identifying genetic mutations specific to it, while no such genetic markers exist for Behçet disease.

HS, CD, and HIDS are all autoinflammatory conditions that share common pathophysiological and immunological traits. HS presents with inflamed nodules, abscesses, and tunnels that discharge pus in intertriginous areas and involves the production of pro-inflammatory cytokines such as tumor necrosis factor, IL-1β, and IL-17.[4] Similar to our patient, previous studies showed patients with undiagnosed HIDS undergoing extensive gastroenterological investigations due to suspected inflammatory bowel disease (IBD).[5] In these studies, ultrasound revealed mesenteric lymph node enlargement, diffuse signals on abdominal leukocyte scintigraphy, and elevated serum IgD and IgA levels, similar to our patient. This study delineates how HIDS can be easily mistaken for CD.[5] HIDS often manifests after a period of physical or emotional stress, such as post-vaccination, infections, trauma, or surgery.[6]

Treatments of syndromes that occur secondary to dysregulation of the immune system focus on inhibiting cytokine pathways. Anakinra is a non-selective blocker of the IL-1 receptor, including IL-1α and IL-1β, that prevents inflammation. Anakinra should be prescribed as needed for patients experiencing fewer attacks.[6] Anakinra administration requires daily injections because of its short half-life. Canakinumab is a selective monoclonal antibody targeting IL-1β to prevent flare-ups.[6,7] Canakinumab has a long half-life and can be administered monthly or bimonthly.[8] The switch from anakinra to canakinumab kept our patient in clinical, biochemical, radiological, and endoscopic remission.

The primary lesson from this case is to recognize the challenges of diagnosing overlapping symptoms of autoimmune conditions. This case should raise awareness among the gastroenterology community about IBD mimickers. This case also emphasizes the necessity of a comprehensive diagnostic approach and collaborative care in addressing the intricate clinical presentations of rare diseases, particularly in cases with persistent symptoms. This case also highlights the importance of taking a comprehensive history, including family history, when managing patients with overlapping autoimmune disorders. Timely recognition and a collaborative multidisciplinary approach are essential for the accurate diagnosis and effective management of these complex cases. When a patient presents with a constellation of symptoms that involve the gastrointestinal system accompanied by episodic fever of unknown origin and lymphadenopathy, the treating physician should consider all differential diagnoses, including HIDS, to reach the correct diagnosis, initiate the appropriate therapy, and avoid extensive investigative procedures.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Ethical considerations

The Institutional Review Board of King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, provided ethical approval for reporting this case (Ref. no.: 2245150).

Peer review

This case report was peer-reviewed by two independent and anonymous reviewers.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.