A male infant was born at 33 weeks and 4 days gestation via caesarian section, due to fetal tachycardia, following spontaneous premature rupture of membranes. APGAR scores were 9 at one minute and 9 at five minutes. Birth weight was 2920g (90th percentile), head circumference 34.5cm (>97th percentile), length of 44cm (40th percentile). There were no dysmorphic features. Within the first 24 hours of life, blue discoloration was noted to the distal left second finger which progressed to multiple fingers and toes in all four limbs. The infant was transferred to a tertiary care neonatal intensive care unit for evaluation.
The mother was a 28-year-old Caucasian woman who developed new onset symmetrical polyarthritis during her first trimester of pregnancy. Past history was significant for a previous miscarriage at 5 weeks gestation and a cholecystectomy. Family history was negative. There was no smoking, alcohol or drug use during pregnancy. Prenatal screening showed rubella titre indeterminant (7.4IU/ml) as well as hepatitis B, human immunodeficiency virus (HIV), syphilis negative. Parvovirus B19 immunoglobulin G (IgG) reactive, cytomegalovirus IgG non-reactive, toxoplasmosis IgG negative.
At 6 weeks’ gestation, the mother underwent dental work complicated by an oral abscess requiring seven days of amoxicillin. Two days after initiation of amoxicillin, she developed severe myalgias, episodes of nausea, vomiting and diarrhea which resolved in a few days. No fever, rash, or urinary symptoms. At 8 weeks gestation she presented with severe polyarthritis affecting large and small joints with significant functional impairment. She was prescribed oral prednisone at 10 weeks’ gestation for a presumed reactive arthritis. Blood work prior to treatment showed elevated inflammatory markers including C-reactive protein (CRP) of 210 mg/L (normal <3mg/L) and erythrocyte sedimentation rate (ESR) of 60mm/hr (0-20mm/hr normal). She was steroid dependent for the remainder of the pregnancy requiring high dose prednisone (25 mg orally twice daily) with failure to taper below this dose.
Additional infectious work up including Epstein Barr virus and Lyme serology were negative. Anti-nuclear antibody (ANA), extractable nuclear antigen antibodies (ENA), antiphospholipid antibodies (APLA), antineutrophilic cytoplasmic antibodies (ANCA), rheumatoid factor (RF), complement levels (C3, C4) were negative or within normal range. Fetal anatomy scan at 19 weeks was normal.
The neonate was transferred to a tertiary care neonatal intensive care unit (NICU) on day of life 3 and had a negative full septic work up including blood, urine and cerebrospinal fluid cultures. Despite treatment with antibiotics, fresh frozen plasma and topical vasodilators, the discoloration remained, particularly in the left hand (Figure 1). Stress dosing of hydrocortisone for possible adrenal insufficiency was given due to the long in-utero exposure to steroids in the mother. Heparin was given for potential inherited thrombophilia. On day of life 11, he was transferred to a second NICU. He was noted to have erythema of his hands and feet, which prompted initial consideration for neonatal Kawasaki disease (no other clinical criteria for Kawasaki disease). After two doses of intravenous immunoglobulin (IVIG) (2g/kg) short lived improvement was noted. An echocardiogram showed enlarged coronary arteries (maximum in left anterior descending artery (LAD), z-score 3.93). Two days after the second dose of IVIG he continued to have fever (up to 38.2 degrees Celsius), tachycardia and elevated CRP (maximum CRP of 172mg/L, normal <3mg/L) and intravenous methylprednisolone (2mg/kg) was initiated. Inflammatory markers, skin discoloration and tachycardia improved with steroid treatment. Repeat echocardiogram 1 week later demonstrated normal coronaries.
Full body magnetic resonance angiography (MRA) was significant for abnormalities in the upper limbs with tortuosity and gadolinium enhancement of the brachial as well as the distal axillary arteries. In the lower limbs, tortuosities and gadolinium enhancement involving distal femoral, popliteal, posterior and anterior tibialis arteries suggestive of vasculitis or vasculopathy (Figure 3). Aortic, pulmonary, renal and celiac trunk vessels were normal. Given the clinical syndrome, imaging findings and response to corticosteroid administration, vasculitis was favored.
The neonate’s autoimmune work included a negative ANA, ENA, APLA, ANCA, RF, and anti-smooth muscle antibody (ASMA). Complement levels (C3, C4, CH50) and immunoglobulins (IgG, IgA, IgM) were normal. Thrombophilia workup including INR, PTT, fibrinogen, protein C, protein S, antithrombin, homocysteine level, Factor VIII level, lupus anticoagulant, prothrombin mutation were within normal limits or negative. Ophthalmology exam was normal, with no signs of retinal vasculitis. Newborn screen (Appendix 1) was negative and his metabolic work up including ammonia level, plasma amino acids, urine organic acids, total and free carnitine, acylcarnitine profile, methylmalonic acid level were normal. His DNA was screened with targeted sequencing for known hereditary autoinflammatory diseases however, we were not able to identify a causative mutation. Whole exome sequencing was conducted as a trio (both parents and the affected child sequenced simultaneously), which did not identify a pathogenic variant.
Oral prednisolone (2 mg/kg divided twice daily) was continued with improvement of the discoloration in the infant’s hands and feet, however the left index finger discoloration persisted with progression to necrosis. A diagnostic biopsy was considered but was deferred due to the necrosis and likely low diagnostic yield. The male infant was effectively weaned off steroids by 5 months of age and is now 4 years old with normal growth and development. A follow up image of the hand at 21 months old is shown in Figure 2. Repeat MRA at 17 months of age showed residual mild tortuosity of the upper extremity abnormalities with no gadolinium enhancement and the lower limbs arteries normal in appearance with normalization of prior tortuosities (Figure 4).
The mother was seen by an adult rheumatologist post-partum. She was weaned off prednisone with a slow taper of approximately 3 months and was treated with hydroxychloroquine for a total of 8 months. She remains in remission off therapy and has had no further pregnancies.