Yao Syndrome in a Child with C2 Deficiency

Clinical Implications Summary

Co-occurrence of rare conditions is uncommon, but should be considered when evaluating patients with complex phenotypes related to inborn errors of immunity. In a child with C2 deficiency, additional focused genetic testing and multidisciplinary collaboration revealed co-occurring Yao syndrome and provided guidance for treatment.

Complement component 2 deficiency (C2D) is an autosomal recessive disorder resulting from mutations in C2. C2D increases susceptibility to severe bacterial infections early in life and confers increased risk of autoimmune diseases including systemic lupus erythematosus (SLE).¹

Yao syndrome (YAOS, #OMIM 617321) is an autoinflammatory disease characterized by episodic fever, dermatitis, polyarthritis, distal extremity swelling, gastrointestinal manifestations, sicca-like symptoms, and eyelid swelling without high autoantibody titers or antigen-specific T-cells.² Diagnosis requires the presence of specific NOD2 variants: IVS8+158 (c.2717+158C>T) and R702W (c.2104C>T, p.Arg702Trp) or other variants. Exclusion criteria include other autoimmune and monogenic autoinflammatory diseases.³

To our knowledge, co-occurring C2D and YAOS has not been previously reported. Herein, we report a child diagnosed with YAOS with known C2D.

A 3-year-old girl with C2D (homozygous variant in C2, [c.237_240del, p.Ser80Argfs*33]⁴, presented with a one year history of recurrent nightly fevers (Figure 1). She also experienced recurrent pain and swelling of her elbows, knees, and ankles, chronic watery diarrhea (up to 10 episodes per day), and a photosensitive, raised erythematous rash on her face and extremities. Her infectious history was significant for group B Streptococcus (GBS) meningitis at 11 weeks of age, multiple urinary tract infections, one episode of lobar pneumonia, and one episode of enteropathogenic E. coli and adenovirus gastroenteritis. Infections subsided at around age 2 years with prophylactic amoxicillin 10mg/kg daily. Her parents are both carriers for C2D and are asymptomatic. There is no history of consanguinity. The remaining family history is unremarkable for infectious, autoimmune, or autoinflammatory conditions.

Figure 1:

Timeline of relevant clinical events.

Basic laboratory testing was unremarkable, including: a complete blood count, inflammatory markers, comprehensive metabolic profile, and urinalysis with a normal urine protein to creatinine ratio. Evaluation by pediatric infectious disease and rheumatology for fever of unknown origin and autoimmune disease was unremarkable except for a transiently positive beta-2 glycoprotein (B2GP) antibody and a positive speckled ANA 1:40 (Table 1). There was no cogent evidence of SLE or other systemic autoimmune disease. A commercially available autoinflammatory and autoimmunity syndrome genetic panel showed a heterozygous “risk allele” in NOD2 c.2014C>T, p.Arg702Trp (a.k.a R702W), a variant of uncertain significance in NOD2 c.2332G>A, p.Glu778Lys, and a heterozygous pathogenic variant in TRNT1 (c.1010del, p.Thr337Lysfs*7) indicating she is a carrier for sideroblastic anemia, an autosomal recessive disease. Given the constellation of symptoms and clinical suspicion for YAOS, targeted NOD2 sequencing was pursued and revealed the intronic IVS8 + 158 variant. The combination of IVS8 + 158 and R702W in NOD2 was consistent with a diagnosis of YAOS.

Table 1:

Results of laboratory evaluation performed.

Serum Test	Result at Initial Presentation	Result at Recent flare	Reference range and units
White Blood Cell Count	5.0	5.5	3.8 – 14.0 x109/L
C-Reactive Protein	< 0.02	0.12	</= 0.85 mg/dL
Erythrocyte Sedimentation Rate	< 1	63	0 – 13 mm/hr
Total Complement - Ch50	< 14		42 – 95 U/mL
C2 Complement, functional	<10		25 – 47 U/mL
C3 Complement	115	223	82 – 173 mg/dL
C4 Complement	15	29	13 – 46 mg/dL
IgG	719		498 – 1,332 mg/dL
IgM	150		31 – 126 mg/dL
IgA	91		21 – 129 mg/dL
IgE	22		1 – 219 IU/mL
Diphtheria toxoid IgG	> 3.00		>/= 0.1 IU/mL
Tetanus toxoid IgG	1.15		> 0.16 IU/mL
EBV VCA IgG/IgM, EBNA IgG, EA IgG	Negative	Negative	Negative
CMV IgG/IgM	Negative	Negative	Negative
Brucella IgG/IgM	Negative		Negative
Quantiferon TB Gold Plus	Negative		Negative
Bartonellla Henselae IgG/IgM	Negative		Negative
Bartonella Quintana IgG/IgM	Negative		Negative
HIV-1&2 Antibody/Antigen	Nonreactive		Nonreactive
Anti-double strand DNA Antibody		< 1	</= 4 IU/mL
Anti-nuclear Antibody titer	Negative	1:40 Speckled	Negative
Direct Antiglobulin Polyspecific	Negative	Negative	Negative
Anti-Cardiolipin IgG	9	< 1.6	1–15 units
Anti-Cardiolipin IgM	5	< 1.5	1–14 units
Anti-Cardiolipin IgA	2	< 2.0	1–14 units
Anti-SM Antibodies	10		< 100 AU/mL
Anti-RNP Antibodies	39		< 100 AU/mL
Anti-RO Antibodies	22		< 100 AU/mL
Anti-LA Antibodies	12		< 100 AU/mL
Anti-Chromatin Antibodies		< 0.2	< 1 AI
Anti-Ribosomal P Antibodies		< 0.2	< 1 AI
Anti-SS-A Antibodies		< 0.2	< 1 AI
Anti-SS-B Antibodies		< 0.2	< 1 AI
Anti-Centromere B Antibodies		< 0.2	< 1 AI
Anti-SM Antibodies		< 0.2	< 1 AI
Anti-SM/RNP Antibodies		0.2	< 1 AI
Anti-RNP Antibodies		0.4	< 1 AI
Anti-Scl-70 Antibodies		< 0.2	< 1 AI
Anti-Jo-1 Antibodies		< 0.2	< 1 AI
Lupus anticoagulant panel	Not detected	Not detected	Not detected
Anti-Beta 2 Glycoprotein 1 IgG	20	< 1.4	</= 20 units
Anti-Beta 2 Glycoprotein 1 IgM	2	< 1.5	</= 20 units
Anti-Beta 2 Glycoprotein 1 IgA	10	< 2.0	</= 20 units

Following diagnosis, she was started on sulfasalazine 10 mg/kg three times daily with improvement in diarrhea. A trial of IL-1 receptor antagonist anakinra was initiated but was poorly tolerated due to painful daily injections. Canakinumab, anti-IL-1β monoclonal antibody, was initiated at a dose of 4 mg/kg of every 4 weeks with resolution of her symptoms. She remained well for 4 months, but recently acquired an Influenza infection triggering a flare in symptoms characterized by 2 months of fevers, fatigue, fussiness, facial flushing, extremity swelling, and myalgias with associated elevated inflammatory markers (Table 1), requiring initiation of prednisolone.

This case highlights the co-occurrence of 2 rare disorders in a single pediatric patient: YAOS and C2D. Since first described by Dr. Yao in 2011 as a separate entity from Crohn’s disease and Blau syndrome, adult cases have been increasingly reported.^3,5,6 This trend likely reflects improved recognition of autoinflammatory conditions, as well as increased accessibility to genetic sequencing. The dearth of recognized pediatric cases of YAOS may reflect undiagnosed early onset disease that is later diagnosed as YAOS.

The exclusion criteria for YAOS includes autoimmune disorders or other autoinflammatory conditions. While C2D increases the risk for developing autoimmune disease, this patient did not have classic features for a characterized connective tissue disease. Additionally, extensive evaluation did not reveal an alternative diagnosis. YAOS is considered as a genetically transitional disease (GTD), where mutations are necessary but not sufficient to cause disease, highlighting the impact of genetic background together with environmental factors.⁷ It is plausible that the C2D and associated infections might contribute to earlier onset of NOD2-related disease. Expanding on the GTD concept, a two-hit like theory has been proposed to describe the disease presentation⁷ and potentially explain the clinical scenario in this patient, who carries three NOD2 variants on a background diagnosis of C2D.

In addition to severe infectious complications, patients with C2D have an increased risk of autoimmune diseases such as SLE.¹ These coinciding manifestations of immunodeficiency and autoimmunity/autoinflammation among inborn errors of immunity have more recently been subcategorized as primary immune regulatory disorders (PIRDs).⁸ A unique challenge for the immunologist is selecting targeted immunosuppressive therapies to “calm” down autoreactive pathways while limiting further suppression of an underlying compromised immune system. This patient experienced significant benefit from anti-IL-1β therapy.

This report reinforces the necessity of clinicians to maintain broad differentials when complex patient phenotypes, or evolving phenotypes, do not align with a single unifying diagnosis. Furthermore, it illustrates that genetic sequencing modalities are not equivalent, and targeted sequencing to include intronic variants should be pursued when specific disorders are being considered. Additionally, interpretation by clinical labs can be conflicting and inconsistent with updated literature. In this case, one lab interpreted the well-established R702W variant as a risk allele and did not report the intronic variant. Due to a high level of clinical suspicion for YAOS, a sample was sent to another lab for targeted analysis for the intronic variant, but the intronic variant was reported as benign when the literature has established that the combination of R702W and IVS8+158 is pathogenic (disease-causing). Multidisciplinary collaborations are often needed to ensure comprehensive evaluations, improve diagnostic accuracy, and develop targeted management plans for patients with PIRDs.

Finally, this case underscores the need for continued case reporting to advance our collective knowledge regarding long-term management and outcomes among patients with inborn errors of immunity and immune dysregulation. YAOS is uncommon and co-occurrence of rare conditions is even rarer. However, the presence of more than one condition should be considered when evaluating patients with complex phenotypes related to inborn errors of immunity.