Complex MEFV and MVK Variations in a Syrian Child: Implications for Clinical Phenotypes and Treatment Response—A Case Report

Abstract

This case report presents a 10-year-old Syrian boy with concurrent mutations in the Mediterranean fever (MEFV) and mevalonate kinase (MVK) genes, resulting in overlapping symptoms of Familial Mediterranean Fever (FMF) and Hyperimmunoglobulinemia D syndrome (HIDS), both classified as Periodic Fever Syndromes (PFSs). The co-occurrence of these mutations within a single individual is highly unusual. He presented with pallor, intermittent fever, and recurrent respiratory infections from an early age, along with anemia, splenomegaly, hepatomegaly, cervical lymphadenopathy, and growth failure noted in initial investigations. Still’s disease was initially considered as the most likely differential diagnosis, leading to the initiation of treatment with methylprednisolone; however, the parents did not follow-up with the treatment. The child returned at 5 years old with appendicitis, which was surgically removed, and parents reported recurrent episodes of arthralgia and joint swelling accompanied by nearly daily fever. Although the child experienced delayed motor development, his cognitive abilities were normal. Genetic analysis identified a homozygous likely pathogenic variant in the MVK gene and a heterozygous likely pathogenic variant in the MEFV gene. The child remains reliant on corticosteroids, with limited response to colchicine and improvement noted after transitioning from tocilizumab to infliximab. The latest follow-up demonstrated significant improvement with no fever, joint swelling, or lymphadenopathy; however, signs of growth failure persist. The atypical manifestations observed in this case may indicate a synergistic effect between the 2 mutations, contributing to the overall clinical picture. Therefore, although HIDS may dominate the clinical presentation, we cannot entirely dismiss the possibility that the FMF mutation plays a role in modulating these symptoms.

Background

Periodic fever syndromes (PFSs), also known as autoinflammatory diseases (AIDs), constitute a spectrum of disorders characterized by recurrent and sudden episodes of inflammation lacking significant levels of autoantibodies or antigen-specific T cells. ¹ Familial Mediterranean fever (FMF) arises from recessive mutations in the Mediterranean fever (MEFV) gene, presenting with recurrent brief febrile episodes and serositis leading to abdominal, chest, joint, and muscle pain.^2,3 Hyperimmunoglobulinemia D syndrome (HIDS), a rare autoinflammatory disorder caused by recessive mutations in mevalonate kinase (MVK), is characterized by recurring febrile episodes lasting 3 to 7 days, accompanied by symptoms such as abdominal pain, diarrhea, headaches, arthralgia, rash, aphthous ulcers, and cervical lymphadenopathy. ⁴

The onset of HIDS typically occurs within the first year of life, whereas FMF often manifests in childhood.^2,3,5 The FMF predominantly affects individuals of Middle Eastern and Mediterranean descent, with HIDS being infrequent.^4,5 Remarkably, the co-occurrence of MEFV and MVK mutations within a single family member is highly unusual. ⁶ The diagnosis of AIDs presents challenges due to atypical or subtle initial clinical presentations, symptom overlap with other pathologies, and the absence of definitive diagnostic criteria for AIDs. ³ This case report describes a 10-year-old Syrian boy with a rare condition who harbors both mutations in both the MEFV and MVK genes.

Case Presentation

A 10-year-old male Syrian child born to non-consanguineous parents, with no family history of PFSs, presented to the hematology department at the age of 1 year and 4 months with complaints of pallor and recurrent respiratory infections specifically bronchitis since the age of 2 months. He had undergone blood transfusions twice due to low hemoglobin levels (Hb = 5.5). Physical examination revealed splenomegaly measuring 5 cm, hepatomegaly of 2 cm, cervical lymphadenopathy, and growth failure (weight 7 kg, head circumference 43 cm, height 77 cm) in addition to intermittent fever without abdominal pain or skin rash. Initial laboratory investigations were conducted to rule out hematological abnormalities, infections, and parasites (Table 1).

Table 1.

Laboratory evaluation.

Investigation	Result	Units	Reference range
Hemoglobin	7	g/dL	15.0-11.9
MCV	53.3	fL	100-75
Iron	10	mcg/dL	120-50
TIBC	281	mcg/dL	450-240
White blood cells	8.4	×10.e3/µL	10-3.5
Lymphocytes	33.3	%	50-15
Granulocytes	60	%	80-35
Platelet	266	×10.e3/µL	400-100
Sodium	139	mEq/L	135-145
Potassium	4.46	mEq/L	3.4-4.7
ALT/GPT	13.6	U/L	10-50
AST/GOT	20	U/L	33-8
ALP	125	U/L	<187
Total protein	6.3	g/dL	8.3-6
Albumin	3.3	g/dL	5.4-3.6
LDH	614.7	mg/dL	105-333
CRP	67.5	mg/dL	1-0.3
ESR	83	mm/first hour	20-0
Ferritin	556	ng/mL	336-24
Fibrinogen	812	mg/dL	400-200
D-dimer	687	ng/mL	<500
Urea	11	mg/dL	20-5
Creatinine	0.4	mg/dL	0.7-0.3
Uric acid	4.6	mg/dL	5.5-2.5
C3 complement	136	mg/dL	175-75
Rheumatoid factor	9	IU/mL	24-0
ANA	Negative	–	Negative
Coombs (direct, indirect)	Negative	–	Negative
Anti-CCP	13	IU/mL	<20
Immunoglobulin A, IgA	3.27	IU/mL	0.27-1.95
Immunoglobulin M, IgM	2.6	IU/mL	0.5-2
Immunoglobulin G, IgG	8.3	IU/mL	5-14
Immunoglobulin D, IgD	Not done	–	–
CMV antibody	Negative	–	Negative
EBV antibody	Negative	–	Negative
Leishmaniasis antibodies	Negative	–	Negative
FT4	1.5	ng/dL	1.9-0.7
TSH	3.7	mIU/L	4.0-0.4
Lyme borreliosis, IgM	Negative	–	Negative
Lyme borreliosis, IgG	Negative	–	Negative
IgA-EMA	Negative	–	Negative

Abbreviations: µL, microliter; g/dL, gram/deciliter; MCV, mean corpuscular volume; fL, femtoliter; pg, picograms; mEq/L, mill equivalents per liter; ALT/GPT, alanine aminotransferase/glutamic-pyruvic transaminase; U/L, units per liter; AST/GOT, aspartate aminotransferase/glutamic-oxalacetat transaminase; LDH, lactate dehydrogenase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; ANA, anti-nuclear antibody; ALP, alkaline phosphatase; FT4, free thyroxin; TSH, thyroid-stimulating hormone; Anti-ccp, anti-cyclic citrullinated peptide; TIBC, total iron-binding capacity; EMA-IgA, IgA anti-endomysial antibodies, CMV, cytomegalovirus; EVB, Epstein-Barr Virus.

Peripheral blood smear showed features consistent with anemia. Further diagnostic tests including bone marrow aspiration, biopsy, osmotic fragility test, and hemoglobin electrophoresis yielded negative results. Imaging studies such as chest X-ray, abdominal ultrasound, bone scintigraphy, and computed tomography (CT) scan were unremarkable except for splenic and lymph node enlargements. Echocardiography demonstrated mild left ventricular dilation attributed to anemia. Although joint manifestations were absent initially, Still’s disease was considered in the differential diagnosis. Treatment with methylprednisolone (30 mg/kg) was initiated; however, the parents did not adhere to the prescribed regimen.

The child presented again at the age of 5 years with clinical and laboratory signs suggestive of appendicitis, which was surgically removed and histopathologically confirmed to have nonspecific follicular hyperplasia. Upon reassessment, the parents reported that despite initial improvement in fever with glucocorticoids prescribed by an external physician, the fever recurred daily (38-40°C) once the medication’s effect waned, without abdominal pain except during the episode of appendicitis and without diarrhea, vomiting, aphthous ulcers, or rash. They also noted recurrent episodes of arthralgia and joint swelling with restricted movement involving multiple joints such as wrists, knees, elbows, and ankles. An episode of extra-articular swelling in the forearm with localized heat was identified by ultrasound as an abscess. The hepatomegaly, splenomegaly, and cervical lymphadenopathy are still present.

In terms of motor and cognitive development, the child experienced delayed crawling at one and a half years of age and delayed walking at two and a half years of age with no delays in speech or other cognitive skills. Subsequent laboratory tests were repeated to establish a definitive diagnosis, including flow cytometry to exclude autoimmune lymphoproliferative syndrome (ALPS); however, all inflammatory markers remained elevated without providing a conclusive diagnosis. Despite treatment with methylprednisolone, methotrexate, cyclosporine, and tocilizumab, the child did not exhibit a significant clinical response. Owing to the recurrent symptoms and the limited efficacy of corticosteroids, genetic analysis was pursued.

Exome sequencing conducted on a blood sample at CENTOGENE GmbH in Germany revealed 2 distinct gene variants: a homozygous likely pathogenic variant in the MVK gene, c.60T>A p. (His20Gln), consistent with an autosomal recessive MVK-related disorder, and a heterozygous likely pathogenic variant in the MEFV gene, c.1958G>A p. (Arg653His), consistent with an autosomal dominant FMF.

The child continues to rely on corticosteroids, with a partial response to colchicine and improvement noted following the transition from tocilizumab to infliximab (5 mg/kg). At the most recent follow-up at 9 years and 8 months of age, the child demonstrated significant improvement with the absence of fever, joint swelling, and lymphadenopathy; however, growth failure indicators persist (weight 20 kg, height 116.5 cm). Inflammatory markers showed significant elevation during disease episodes while displaying mild positivity in between. The child’s overall health is stable, and his cognitive abilities remain excellent.

Discussion

We describe a detailed diagnostic journey of a 10-year-old male Syrian child who carries 2 distinct variants in the MEFV and MVK genes. Although FMF is typically inherited in an autosomal recessive manner, certain mutations can lead to autosomal dominant transmission, ⁷ as evidenced in this case.

Mevalonate kinase deficiency (MKD) encompasses a spectrum of clinical presentations, with HIDS and mevalonic aciduria (MVA) being the primary types. The HIDS, characterized by recurrent febrile episodes and symptoms like abdominal pain and vomiting, is milder, whereas MVA is associated with severe neurological manifestations such as psychomotor retardation, ataxia, and seizures. ⁴ Despite exhibiting delays in acquiring gross motor skills like walking, the child’s cognitive abilities remain intact, and he has not displayed any of the aforementioned neurological symptoms. Notably, he has shown signs of growth failure, a feature uncommon in milder forms of MVD. ⁸

Furthermore, this symptom is not typically observed in pediatric patients diagnosed with FMF. ⁹ Treatment options for FMF and HIDS vary, with colchicine being the cornerstone for FMF but demonstrated limited effectiveness in HIDS. ¹⁰ Canakinumab is an evidence-based therapy for MKD; however, its high cost and unavailability in Syria restrict its utilization. Glucocorticoids, anakinra, etanercept, and tocilizumab are alternative treatments with limited supporting evidence. ¹¹

In this case, glucocorticoid provided partial relief during attacks, aligning with previous findings on their use in HIDS. ¹² Prior research has indicated the potential benefits of anti-tumor necrosis factor (TNF) therapy in improving the frequency and severity of attacks in HIDS. ¹¹ In FMF, the use of anti-TNF agents, particularly in cases involving joint complications, is backed by level 3 evidence, although specific recommendation grades are lacking. ¹³ Transitioning from tocilizumab to infliximab resulted in substantial clinical and laboratory improvement, underscoring the potential efficacy of anti-TNF therapy in instances of overlapping genetic mutations and intricate clinical manifestations. These findings may offer valuable insights for future investigations exploring therapeutic strategies in similar complex cases.

Conclusion

The notable overlap between FMF and HIDS warrants attention. The atypical manifestations observed in this case may indicate a synergistic effect between the 2 mutations, contributing to the overall clinical picture. Therefore, although HIDS may dominate the clinical presentation, we cannot entirely dismiss the possibility that the FMF mutation plays a role in modulating these symptoms. To comprehensively delineate the clinical spectrum of these disorders and formulate guidelines for optimal treatment strategies, a larger cohort of individuals should be investigated. Although clinical manifestations can assist in diagnosis, genetic testing is imperative for cases exhibiting atypical phenotypes.