Pediatric APS may occur at any age during childhood. There are no validated criteria for the diagnosis and using the adult classification criteria for the diagnosis of pediatric APS may result in missed or delayed diagnoses as non-thrombotic clinical manifestations may precede thrombotic manifestations [6]. The exact prevalence and incidence of APS in children is unknown. According to data from the International Pediatric APS Registry (APS-IPR) including 121 pediatric cases from 14 countries, the female to male ratio was 1:1 and the mean age at onset was 10.7 years [3]. Almost 50% of the patients in the registry had an underlying autoimmune disease. Primary APS was associated with younger age and a higher frequency of arterial thrombotic events, whereas secondary APS accompanied by an underlying autoimmune disease was associated with older age and a higher frequency of venous thrombotic events. Most frequent non-thrombotic clinical manifestations included hematologic, cutaneous, cardiac, and non-thrombotic neurologic manifestations [3]. The most common APL detected in these patients was aCLs (81%), followed by LA (72%), and anti-β2GP1 (67%). Multiple positivity of aPLs was detected in 42 patients who were simultaneously tested for all three subtypes, and only one third of these patients had triple positivity [3]. Both of our patients had high triple APL positivity on multiple occasions. Although the brother eventually fulfilled the updated international classification criteria for adult APS [7], the sister did not meet APS criteria while the diagnosis of non-thrombotic APS fits very well.
Familial APS is extraordinarily rare but has been reported. Among the earliest reports of familial APS was the occurrence of LA in two pairs of siblings with a spectrum of autoimmune manifestations and clear evidence of LA positivity; the pair of brothers aged 18 and 20 years and the pair of sisters aged 46 and 50 years were reported in 1980 (8). In 1990, nine individuals with an age range of 21–64 years, from four different generations in a large kindred, were reported to have aPL antibodies associated with a spectrum of clinical manifestations including stroke, deep venous thrombosis, and recurrent abortions (9). Another report in 1997 describes a family with aPL in whom HLA-DRB gene associations were observed. Patients had a spectrum of manifestations including arthritis, sagittal vein thrombosis, glomerulonephritis, congestive heart failure, and interstitial lung disease. The youngest patient was 33 years old and had symptoms of lupus for ten years [10]. Many of these reported cases predate the publication of APS classification criteria. Subsequent studies have reported that first-degree relatives of patients with SLE or primary APS had a higher incidence of aCL antibodies, suggesting a genetic predisposition to the development of these antibodies. Identification of several kindred with an increased frequency of aPL antibodies and the associated clinical manifestations further supports the presence of familial forms of APS [11].
In 2013, Jelušić et al. [4] reported a case of a 17-year-old girl with primary APS developing subacute signs of hand and leg ischemia caused by radial and popliteal artery occlusions associated with triple APL positivity. The mother of the girl presented just months later with symptoms of superficial thrombophlebitis and blood tests showed triple APL positivity with possible secondary APS related to evolving SLE. In 2016, Islam et al. [5] reported three familial primary APS adult patients from Malaysia. The three patients comprised two sisters and one male cousin with a mean age of 26.3 years. The first diagnosis was made between 2005 and 2009, and all patients demonstrated deep vein thrombosis, high levels of IgM and IgG aCL antibodies, and received warfarin treatment. Follow up in 2014 showed that the patients became seronegative. There were no available genetic studies done for this family. Our reported siblings are among the youngest to present with APS manifestations, at 13 years of age. To our knowledge, there are no cases of familial APS reported in the large pediatric APS cohorts [3, 12 ].
No clear gene association has been identified for APS. Although raised levels of aPL antibodies have been described in a few families, the characterization of the APS, coexisting autoimmune diseases, and clinical complications are more heterogeneous, not well defined, and difficult to study. Not only is there rarity of multiplex families with APS to study, many reported cases have other comorbidities such as an autoimmune disease or some other hereditary prothrombotic feature [11]. Whole exome sequencing (WES) was done for our patients but was inconclusive. To our knowledge, WES was not done for families with familial APS reported in the literature, in part because many cases predate the availability thereof. Multiple human leukocyte antigen (HLA)-DR or -DQ associations with aPL antibodies have been described including HLA-DR4, Drw53, DQw7, and DQB1*0302 [11, 13]. However, these associations are difficult to interpret because of small patient sample size and questions regarding appropriate ethnically matched control populations [11]. Of interest, our two reported siblings with APS had positive HLA-DR4 and DQB1*0302 tests compared to the healthy brother as shown in Table 1.