A familial case of Kikuchi-Fujimoto disease in dizygotic twins

Kikuchi-Fujimoto disease (KFD) or necrotizing histiocytic lymphadenitis, was described separately by both Kikuchi and Fujimoto in Japan in the early 1970’s [1, 2]. Despite its rarity in the pediatric population, it is an important differential in persistent lymphadenopathy. KFD occurs predominantly in young women with associated symptoms of fever, lethargy, arthralgia and rash. Although the current etiology of KFD is unclear, associations have been made with autoimmune disease; with various infectious triggers including several viruses and other non-infective inflammatory conditions suggested. Familial cases of KFD in the literature are rare. Here we describe the first reported case of KFD in non-identical twin sisters.

Kikuchi-Fujimoto disease remains more of a syndrome than a fully characterized disease. Twin 2 had nephrotic syndrome, a disease in which there is HLA linkage and evidence of viral activation similar to KFD [3]. The presence of mycoplasma with positive mycoplasma serology at the time of diagnosis in Twin 2 would be consistent with an infectious trigger for KFD [4].

Although very limited in number, there have been previous case reports documenting familial cases of KFD in siblings and even HLA-identical non-twin sisters [5‐7]. Some of these familial cases have been documented in Japanese literature where related individuals who developed KFD were living in the same environment, were serologically positive for the same infectious trigger and had developed symptoms within a short time period of each other. Exceptions to this include the case report by Amir et al. (2002) in Saudi Arabia where two sisters who were HLA-identical but not twins had presented 10 years apart with no obvious infectious trigger identified and the article by Stasiuk et al. (2011) which reported a similar case in two Aboriginal sisters from Northern Ontario [5, 6]. The shared and common HLA for this disease suggests that like many other HLA-linked diseases, KFD is a two-step disease requiring a predisposing HLA and a secondary trigger such as an infection. Twin 2’s background is particularly interesting as she has two other diseases that are linked to HLA Class II with celiac disease and nephrotic syndrome. This would be consistent with the paradigm that KFD needs an infectious trigger to develop but requires a specific HLA to develop disease. Although multiple offenders have been identified including Epstein Barr Virus, various Human Herpes Viruses, HIV, Torque Teno virus and Toxoplasma Gondii, it remains largely unclear if these pathogens are etiological or more likely inflammatory drivers of disease through TLR or other innate receptors [4, 8‐10].

Of note, the HLA typing of the sets of siblings described in Stasiuk et al. and Amir et al.’s case reports are shown in Table 2 [5, 6]. Interestingly, our twins’ HLA-C type was identical to the siblings reported by Amir et al.⁶. Although the significance of this is unclear, this further supports the hypothesis regarding the etiology of KFD that we have put forward in this report.

There have been many associations with KFD and other diseases in various case reports in the literature including but not exclusive to hemolytic uremic syndrome, Hashimoto’s thyroiditis, hemophagocytic lymphohistiocytosis and more commonly, systemic lupus erythematosus [11‐15]. Twin 2 had a background of nephrotic syndrome and celiac disease as discussed above. Both twins developed mucocutaneous symptoms that led to investigation for SLE but yielded no positive results. Although unclear, these associations with autoimmune conditions should guide clinicians when monitoring patients with prior KFD particularly in the context of disease surveillance or in the presence of new symptoms.

KFD is a rare but self-limiting pathological process of necrotizing histiocytic lymphadenitis. Although further research is needed, there is an increasing amount of evidence which suggests a multifactorial pathological basis of disease. The two cases we document here are the first reported cases of familial KFD in dizygotic HLA-identical twins which reinforces the likely HLA-linkage in the etiology of KFD. Due to its ability to mimic other more sinister illnesses, recognition and appropriate diagnosis of KFD is paramount to ensure that unnecessary investigations and treatment are avoided.