SLE is a chronic systemic autoimmune disease which leads to inflammation and organ damage caused by immune complex deposition. Classically, cSLE has been considered as a polygenic autoimmune disease; however, monogenic lupus-like phenotypes in children are emerging with the recent recognition of several related novel high-penetrance genetic variants in the last decade (5). This fact associated to the high degree of concordance among monozygotic twins, supports the relevance of genetic background in the childhood lupus pathogenesis (5, 6, 7).
Currently, mutations in more than 50 different genes related to complement (e.g. C1, C2, C4), type I interferon (e.g. DNASE, RNASE, TREX, IFIH1, ADAR), self-tolerance (e.g. PRKCD, TNFSF13B) or RAS pathways (e.g. PTPN11, SOS1, KRAS, SHOC2) have been considered responsible for the development of monogenic lupus (7).
At least 20 genetic variants involved in the RAS/MAPK pathway function, are included in a group of disorders collectively defined as RASopathies. Facial dysmorphism, cardiac disease, growth hormone deficiency, and cognitive defects are the main clinical features of RASopathies (8). Pathogenic variant in SHOC2 gene, a scaffold protein with an up-regulatory function on RAS/MAPK pathway, leads to Noonan-like syndrome with loose anagen hair which is characterized by facial feature and ectodermal abnormalities (hair anomalies and hyperkeratotic skin lesions) as distinguishing aspects (9). In addition to these manifestations, a link between Noonan-like syndrome and autoimmune disorders (such as SLE, thyroiditis or hepatitis) has been postulated due to the role of RAS on T cell maturation. This fact suggests that abnormal activation of the RAS/MAPK pathway may be a risk condition for the development of autoimmune diseases (4).
We report a 13-year-old-boy with a constitutional SHOC2 genetic variant (c.4A > G, p.Ser2Gly) who developed a monogenic lupus. This is similar to what observed in RASopathies and specifically in SHOC2-carrier patients, which have a male prevalence and a median age of SLE onset around their teens (7). These data suggest a distinctive underlying pathway on monogenic lupus pathogenesis compared to the classical SLE.
A total of 12 patients with a Noonan syndrome and an associated SLE diagnosis have been described in the literature to date. Of them, 4 carried a constitutional SHOC2 genetic variant, 2 a KRAS variant, 1 a PTPN11 variant and in the remaining 5 patients no genetic variant was specified. Our patient represents the fifth SHOC2-carrier with a diagnosis of monogenic lupus.
Musculoskeletal disorders (8/11) are the most common manifestations in patients with RASopathies. Moreover, other lupus clinical manifestations have also been reported: pleuro-pericarditis (7/11), autoimmune cytopenia (6/11) and rash (2/11) (7). Specifically, in SHOC2 carriers, serositis was the most frequent clinical manifestation (3/3), followed by cytopenia (2/4), polyarthritis (1/3) and mucocutaneous disorders (1/3). No neuropsychiatric or renal manifestations have been previously reported (10, 11, 12, 13). Our patient onset with thrombocytopenia, lymphopenia, polyarthritis of the large and small joints and serositis (pleural and pericardial effusion), which is similar to those described above. However, a lupus nephritis in SHOC2 carriers has not been previously reported.
Regarding immunologic parameters, 3 patients with a SHOC2 variant were positive for ANA and anti-double stranded-DNA (ds-DNA) antibodies, 1 was positive for anti-Smith antibodies (anti-Sm) and one showed low levels of complement - both C3 and C4 (10, 11, 12, 13). Our patient showed ANA, anti-ds-DNA, anti-SSA/Ro positivity with reduced levels of complement. Demographic characteristics, EULAR/ACR 2019 SLE classification criteria, therapeutic strategy and response to the therapy were shown in detail in Table 1.
Table 1
Demographic characteristics, clinical and immunological parameters, therapeutic strategy, and response to the therapy. aB2GP, anti-B2-glycoprotein antibodies; aCL, anticardiolipin antibodies; ANA, antinuclear antibodies; aPL, antiphospholipid antibodies; ASA, acetylsalicylic acid; GC, glucocorticoids; HCQ, hydroxychloroquine; LA, lupus anticoagulant; LN, lupus nephritis; NA, not available; m, months; MM, mycophenolate mofetil.
| Simsek-Kiper et al, 2012 | Bader-Meunier et al, 2013 | Hanaya et al, 2017 | Uehara et al, 2018 | Currently presented patient |
Gender, age at onset (years) | Male | Male, 13 | Male, 13 | Male, 24 | Male, 13 |
EULAR/ACR 2019 criteria | | | | | |
Fever | NA | NA | NA | NA | YES |
Hematologic | Thrombocytopenia | NO | NO | Leukopenia Thrombocytopenia | Leukopenia Lymphopenia Thrombocytopenia |
Neuropsychiatric | NA | NO | NO | NO | NO |
Mucocutaneous | NA | NO | NO | Malar rash | NO |
Pleuritis | NA | Pericarditis | Pericarditis | Pericarditis | Pleuritis and pericarditis |
Articular | NA | Polyarthritis | NO | NO | Polyarthritis |
Renal | NO | NO | NO | NO | Class III LN Zebra bodies |
ANA | NA | 1:800 | 1:640 | 1:2560 | 1:2560 |
Anti-ds-DNA | NA | 39 IU | 87 IU | > 1:400 | 1:640 |
Anti-Smith | NA | Negative | 149 U | Negative | Negative |
Low complement | NA | NO | YES | C3 42 mg/dL C4 5 mg/dL | C3 73 mg/dL C4 2 mg/dL |
aPL and/or LA | NA | NO | NO | YES | IgG aCL, IgG aB2GP, LA |
Treatment | NA | HCQ, ASA | GC | GC | HCQ, MMF, GC, ASA |
Response | NA | Satisfactory (tapered in 3 m) | Satisfactory (tapered in 20 m) | Satisfactory | Satisfactory |
As far as zebra bodies are concerned, this is the first case to date which identify lamellar bodies in a patient with a Noonan-like syndrome and lupus. This renal finding is the result of a blockade of intralysosomal phospholipid catabolism, which culminates in formation of osmiophilic and lamellar inclusions in the lysosome of podocytes. Generally, this condition appears in Fabry disease, but also as a drug-induced condition related to chloroquine or amiodarone (14, 15). However, our patient was not under any of these conditions. A dysregulation in the RAS/MAPK pathway or SLE have been related with the development of lysosomal storage disorders (16, 17). Therefore, our findings suggest that these intralysosomal inclusions may also be present in the context of a RASopathy condition.
In conclusion, we report a new case of monogenic lupus in a 13-year-old male patient with Noonan-like syndrome with loose anagen hair. A lupus onset in a patient with dismorphic features should prompt genetic analysis. RASopathies appear to be a rather frequent cause of monogenic lupus. Notably, lupus nephritis which have never been described in this context, may be part of the presentation.