CINCA/NOMID syndrome is the most severe form of CAPS, which is characterized by neonatal onset and presents with recurrent fever and urticarial rash. Without appropriate treatments, chronic inflammation continues, causing neurological manifestations, arthritis, arthropathy, and uveitis [9, 10]. In Japan, only canakinumab has been approved since 2011 for the treatment of all three forms of CAPS [11]. The definite diagnosis for CINCA/NOMID relies mainly on genetic analysis of NLRP3, which has more than 210 reported variants [8]. Further, approximately 28 ~ 35% of all the CINCA/NOMID patients carry an NLRP3 mutation in somatic mosaicism state [12, 13], which causes patients to present with milder neurologic symptoms compared to those with germline mutation of the same variant. However, no additional differences in symptoms was observed in age at disease onset, skin symptoms and joint involvement, whereas, the p.Phe566Leu variant was previously reported as a CAPS disease-causing mutation within somatic mosaicism cohort [14]. Our patient was found to have p.Phe566Leu variant as a heterozygous germline mutation, which might explain the most severe phenotype including continuous inflammatory biological markers and atypical symptoms.
Furthermore, hepatosplenomegaly with normal liver functions was occasionally described in CINCA/NOMID patients, and liver biopsy demonstrated non-specific presentation for chronic inflammation in the parenchyma and subcapsular area in such a case [7]. However, the patients with cholestasis were only reported by Paccaud et al [14]. Their patient was identified as heterozygous for the p.Glu567Lys mutation and had many similar characteristics to our case. First, both cases were born at preterm 33 weeks of gestation, complicated with polyhydramnios. Second, hepatosplenomegaly with cholestasis was initially severe and gradually improved in parallel to decreasing inflammatory reaction. Following detailed examination, our patient did not have any other disease associated with cholestasis, and her symptoms gradually improved as CRP decreased. The observed chronic inflammation caused the liver damage in preterm neonate, resulting in hepatosplenomegaly and cholestasis. It is of great interest whether the treatment with canakinumab is able to subside the occurrence of complications on hepatobiliary system.
In addition, p.Glu567Lys mutation is the most frequently identified mutation among the somatic mosaicism cohort [15]. The coincidence might indicate that the cholestasis might occur in very severe inflammatory conditions due to gene dosages effect of germline mutations which can cause CINCA/NOMID even in the somatic mosaicism. This hypothesis remains to be evaluated by further accumulating the CINCA/NOMID neonatal cases, especially focusing on their neonatal manifestations.
The preterm, intrauterine growth retardation, polyhydramnios, and placental and umbilical abnormalities were often presented in CINCA/NOMID syndrome. It has been reported that histological examination of the placenta from CINCA/NOMID syndrome has revealed vascular thrombosis, microcalcification and polymorphonuclear cell infiltrates [7, 14]. Table 1 describes intrauterine manifestation of CINCA/NOMID syndrome patients in previous reports. Though two polyhydramnios have been reported, making our case the third, it was not possible to perform the detailed search for polyhydramnios due to an emergency cesarean section.
Table 1
Intrauterine manifestation of CINCA/NOMID patients in previous reports.
Intrauterine manifestation | Reference | The number of cases | Mutation | Commentary |
Abnormal amount of amniotic fluid | Sandra G, et al (1983) [16] | 1 | N.D. | Polyhydramnios |
Prieur AM, et al (1987) [7] | 2 | N.D. | Oligohydramnios |
Caroli F, et al (2006) [17] | 1 | M406I | Oligohydramnios |
Paccaud Y, et al (2014) [14] | 1 | E567K | Polyhydramnios |
Our case | 1 | F566L | Polyhydramnios |
Histological findings of placenta and umbilical cord | Prieur AM, et al (1987) [7] | 1 | N.D. | Placenta with thrombosis and calcification Small villi and umbilical cord with polymorphonuclear infiltration |
Paccaud Y, et al (2014) [14] | 1 | E567K | Umbilical cord infection |
Madison E, et al (2019) [22] | 1 | N.D. | Necrotizing funisitis |
Our case | 1 | F566L | Neutrophilic and lymphocytic villitis Necrotizing umbilical arteritis |
N.D.: not described |
Necrotizing funisitis, which is often associated with increased rates of stillbirth, perinatal infection, and preterm delivery, is sometimes accompanied with congenital syphilis [18]. In our case, the possibility of congenital syphilis was excluded because of the absence of the specific IgM antibodies. Acute chorioamnionitis provides evidence of a maternal host response, whereas funisitis represents a foetal inflammatory response [19]. These inflammatory responses are characterized by the infiltration of neutrophils and release of cytokines [19, 20]. Moreover, funisitis is often associated with inflammation of the chorioamnion due to ascending infection. The inflammation of the umbilical vessels typically begins in the vein (phlebitis) and is followed by involvement of the arteries (arteritis) and the Wharton’s jelly [21]. Since our case was not complicated with severe chorioamnionitis, it is likely that the necrotizing funisitis that only involved the artery, was not secondary to chorioamnionitis, but due to foetal origin inflammation. These evidences suggest that foetal inflammation, probably due to overproduction of IL-1β by CINCA/NOMID, might cause necrotizing funisitis in utero. According to previous reports, all histopathological findings revealed funisitis or inflammation of umbilical cords, which might be quite usual manifestation in CINCA/NOMID syndrome (Table 1).
Moreover, our patient was complicated with villitis, namely inflammation of chorioamniotic villi. Some villitis is caused by an infectious agent, however, most chronic inflammatory lesions are of unknown aetiology [23] [24]. Excessive foetal IL-1β might have injured the villi to induce a maternal inflammatory response, causing the elevated maternal CRP before the emergency caesarean section.