In this Review, Tsokos et al. describe recent advances in our understanding of systemic lupus erythematosus (SLE) that are driving repurposing of existing drugs as well as development of new treatments. Cytokines, tolerance pathways, local tissue mediators, and epigenetic mechanisms all show promise as novel targeted therapies that could lead to individualized care in SLE.

New insights into the immunopathogenesis of systemic lupus erythematosus

This Review describes the type I interferonopathies — a set of Mendelian disorders associated with the upregulation of type I interferon activity. The authors explain how defects in key components of innate immune signalling pathways can lead to these diseases and discuss the immunological insights that have resulted from their study.

Aicardi–Goutières syndrome and the type I interferonopathies

Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are key sensors of virus infection, mediating the transcriptional induction of type I interferons and other genes that collectively establish an antiviral host response. Recent studies have revealed that both viral and host-derived RNAs can trigger RLR activation; this can lead to an effective antiviral response but also immunopathology if RLR activities are uncontrolled. In this Review, we discuss recent advances in our understanding of the types of RNA sensed by RLRs in the contexts of viral infection, malignancies and autoimmune diseases. We further describe how the activity of RLRs is controlled by host regulatory mechanisms, including RLR-interacting proteins, post-translational modifications and non-coding RNAs. Finally, we discuss key outstanding questions in the RLR field, including how our knowledge of RLR biology could be translated into new therapeutics.

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RIG-I-like receptors: their regulation and roles in RNA sensing

Recognition of Endogenous Nucleic Acids by the Innate Immune System.

Type I interferon is a potent substance. As such, the induction, transmission, and resolution of the type I interferon–mediated immune response are tightly regulated. As defined, the type I interferonopathies represent discrete examples of a disturbance of the homeostatic control of this system caused by Mendelian mutations. Considering the complexity of the interferon response, the identification of further monogenic diseases belonging to this disease grouping seems likely, with the recognition of type I interferonopathies becoming of increasing clinical importance as treatment options are developed based on an understanding of disease pathology and innate immune signaling. Definition of the type I interferonopathies indicates that autoinflammation can be both interferon and noninterferon related, and that a primary disturbance of the innate immune system can “spill over” into autoimmunity in some cases. Indeed, that several non-Mendelian disorders, most particularly systemic lupus erythematosus and dermatomyositis, are also characterized by an up-regulation of type I interferon signaling suggests the possibility that insights derived from this work will have relevance to a broader field of clinical medicine.

https://rupress.org/jem/article-pdf/213/12/2527/1165091/jem_20161596.pdf

Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview.

Singleton-Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, psoriasis, and other conditions. Despite an apparent autosomal-dominant pattern of inheritance, the genetic background of SMS and information about its phenotypic heterogeneity remain unknown. Recently, we found a family affected by glaucoma, aortic calcification, and skeletal abnormalities. Unlike subjects with classic SMS, affected individuals showed normal dentition, suggesting atypical SMS. To identify genetic causes of the disease, we performed exome sequencing in this family and identified a variant (c.1118A>C [p.Glu373Ala]) of DDX58, whose protein product is also known as RIG-I. Further analysis of DDX58 in 100 individuals with congenital glaucoma identified another variant (c.803G>T [p.Cys268Phe]) in a family who harbored neither dental anomalies nor aortic calcification but who suffered from glaucoma and skeletal abnormalities. Cys268 and Glu373 residues of DDX58 belong to ATP-binding motifs I and II, respectively, and these residues are predicted to be located closer to the ADP and RNA molecules than other nonpathogenic missense variants by protein structure analysis. Functional assays revealed that DDX58 alterations confer constitutive activation and thus lead to increased interferon (IFN) activity and IFN-stimulated gene expression. In addition, when we transduced primary human trabecular meshwork cells with c.803G>T (p.Cys268Phe) and c.1118A>C (p.Glu373Ala) mutants, cytopathic effects and a significant decrease in cell number were observed. Taken together, our results demonstrate that DDX58 mutations cause atypical SMS manifesting with variable expression of glaucoma, aortic calcification, and skeletal abnormalities without dental anomalies.

Mutations in DDX58, which Encodes RIG-I, Cause Atypical Singleton-Merten Syndrome

Background A somatic mutation of GNAQ (c.548G>A, p.Arg183Gln) plays a key role in capillary malformation development. The present study aimed to evaluate clinical manifestations of port-win stain (PWS) associated with this genetic mutation. Methods Skin tissue was obtained from 70 patients with capillary malformation who had been treated with excision for lesions. Droplet digital polymerase chain reaction was used to quantify the abundance of cells with the GNAQ mutation. Results The GNAQ mutation was found in 50 patients. Patients with lesions involving upper facial region, which included forehead, eyebrow, and upper eyelid, showed a significantly higher rate of positive GNAQ mutation than those not involving it. Cases with facial PWS involving all three facial regions (upper, middle, and lower) showed significantly higher positive rate of GNAQ mutation compared to those involving one or two. Conclusions Presence of the somatic mutation GNAQ p.Arg183Gln might be associated with clinical manifestations of PWS.

Phenotypic association of presence of a somatic GNAQ mutation with port-wine stain distribution in capillary malformation.

BACKGROUND We evaluated the preoperative natural growth pattern of craniofacial fibrous dysplasia and postoperative volume changes in patients undergoing shaving procedures. METHODS Thirty-three patients who underwent serial computed tomography (CT) preoperatively and/or postoperatively were identified. The natural tumor growth rate was assessed using preoperative CT scans. The postoperative tumor regrowth rates and relevant variables were analyzed. RESULTS The preoperative tumor growth rates were significantly lower in patients aged ≥ 16 years than in those aged < 16 years (P < .001). The postoperative tumor regrowth rates were significantly greater when a shaving operation was performed at age < 16 years than at age ≥ 16 years (P = .04). In patients with clinical recurrence, the postoperative remnant tumor volume was inversely correlated with the tumor regrowth rate. CONCLUSIONS The tumor growth rate of craniofacial fibrous dysplasia significantly decreased after age 16. This should be considered when conducting functional and aesthetic assessments in planning for the shaving of craniofacial fibrous dysplasia.

Evaluation of natural growth rate and recommended age for shaving procedure by volumetric analysis of craniofacial fibrous dysplasia

Leiomyoma is a benign proliferation of smooth muscle cells that may be found in various anatomical locations. Leiomyoma of the uterus is the most common, and there have been a few case reports of extra-uterine leiomyomas including on the hand, foot, esophagus, trachea, heart, and even in vessels. However, there have been no reports of leiomyoma of the frontalis muscle. We present a case of leiomyoma of the frontalis muscle that was excised using an endoscopic method.

A 5-year-old boy was referred to our hospital with a palpable mass on his left forehead. It was first observed when he was 4-year-old (Fig. 1). Computed tomography revealed a nonspecific soft tissue lesion on his left forehead. Except for the lesion, there were no other abnormalities on his skull, ventricle, or brain parenchyma. The patient revisited the hospital 1 year after the first visit because the size of the mass had increased.



Fig. 1

Preoperative photograph showing bulging of the left forehead due to the mass.



The mass was 1 cm in diameter and non-tender, and the patient did not experience any discomfort. The mass was somewhat firm and movable. There were no clinical signs suggesting an inflammatory lesion such as an epidermal cyst. We initially suspected a lipoma.

The mass was excised using an endoscopic approach under general anesthesia. Anesthesia and hydrodissection were performed by injecting an excessive amount of lidocaine mixed with epinephrine between the galea and the periosteum, to ease the performance of the dissection. Two incisions of 1.5 cm in length were made 1 cm behind the hairline for less visible scarring and to create the shortest distance and easiest approach to the lesion. The endoscope with a retractor and other surgical instruments were inserted through these incisions. We dissected the muscle using a Freer elevator with palpation (Fig. 2). The mass was identified intramuscularly, and was completely excised without any remnant lesion. It was solid with a fibrous capsule (Fig. 3).



Fig. 2

Intraoperative endoscopic image showing the mass (black arrow) in the frontalis muscle.





Fig. 3

Excised specimen showing a solid mass with a fibrous capsule.



Pathologically, the mass showed the characteristics of a leiomyoma, and a definite diagnosis was confirmed based on the immunohistochemistry showing desmin positivity (Fig. 4), because desmin is a specific protein that is expressed in smooth and skeletal muscle myocytes and is also expressed in neoplasms with smooth or skeletal muscle differentiation.



Fig. 4

Desmin stained histology of the patient, showing that the origin of this mass was the smooth muscle (×100).



Usually, leiomyomas originate from the muscle of the uterus and alimentary tract, but it is rare for a neoplasm to originate from the soft tissue of the head or neck. Benign smooth muscle tumors that arise from the forehead are rare, and this is the first case of leiomyoma in the forehead [1-3]. Among the soft tissue tumors in the head and neck area, 96% are known to be benign [4], and leiomyomas comprise only 1.3% of them; no cases of forehead leiomyoma have been published.

A relationship between leiomyoma and trauma has been discussed in a previous study [1]. In our case, however, there was no history of trauma in the years just before the tumor was recognized.

A precise pathological examination is required before surgery in forehead leiomyoma cases, even if the tumor is believed to be benign, because the examination can precisely represent the character of the lesion. A specimen is assumed to be malignant if an average of one or more mitoses in every five high-power fields is identified. Moreover, if mitoses are found in every high-power field, the specimen is considered to be definitely malignant [3]. The pathologic study of this case demonstrated an average of less than one mitosis in every five high-power fields; therefore, the specimen had a high likelihood of being a benign leiomyoma.

The definitive treatment for subcutaneous leiomyomas of the forehead and other body parts is complete excision of the lesion. However, the choice of surgical method, approach, and extent may vary according to the site in which the tumor is involved. In our case, total excision of the mass was achieved via an endoscopic approach. Because the procedure is minimally invasive, the patient was discharged on postoperative day 1 with a mild compressive dressing to minimize the swelling, and the wound healed uneventfully; the scars were almost unidentifiable (Fig. 5).



Fig. 5

Follow-up photograph at 10 days postoperatively.



Leiomyoma is a benign proliferation of smooth muscle cells that may be found in various anatomical locations. The disease is not rare, but most cases are focused on the uterus. An extra-uterine leiomyoma typically presents as a small, painless mass. This article is meaningful in that it shows leiomyoma can occur on the frontalis muscle. Magnetic resonance imaging may be helpful for diagnosis, but a definite diagnosis is confirmed by pathology [5]. Simple excision yields excellent results, but to minimize scarring, an endoscopic approach should be used. In addition, because cases of multiple metastasizing leiomyoma have been reported, regular follow-up should be considered.

/pdf/leiomyoma-of-the-forehead-3abbiqi62d.pdf

Leiomyoma of the Forehead

Extranodal natural killer (NK)/T-cell lymphoma is a very rare and aggressive form of non-Hodgkin's lymphoma, derived from NK cells [1]. The primary site of extranodal NK/T-cell lymphoma is the nose; however, it often extends to adjacent tissues, including the nasopharynx, paranasal sinuses, and oral cavity. Progression of this disease leads to erosion of the palate, accompanied by destruction of the palatal structure, which is an extremely rare condition, and the prognosis is usually poor. A palate defect is difficult to repair conservatively. It causes speech disorders and oronasal regurgitation, significantly impacting patients' quality of life. To our knowledge, a case of reconstruction of a palate defect originating from extranodal NK/T-cell lymphoma has only been reported once in the literature worldwide, but not yet in Korea [2]. In the present study, we report a rare palate defect originating from extranodal NK/T-cell lymphoma that was treated with radial forearm free flap (RFFF) surgery with favorable results.

A 26-year-old male patient had symptoms of chronic sinusitis, night sweating, and a 5-kg weight loss over 5 months. Nasopharyngoscopy showed that the majority of the hard palate was notably absent and ulcerative, and an ill-defined mucosal lesion was detected. Neck computerized tomography showed a heterogeneously enhancing mass lesion on the right nasoethmoidal area (Fig. 1). A biopsy of the palatal and nasal mucosa showed diffuse infiltration of medium-sized lymphoma cells with irregular nuclear contours. Extranodal NK/T-cell lymphoma positive for CD56 was diagnosed by immunohistochemistry (Fig. 2). The patient was started on adjuvant chemotherapy with four cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) cycles and radiation therapy. In follow-up two years later, the patient was in complete clinical remission. The result of palatal and nasal mucosal biopsy showed no evidence of malignancy. Neck computerized tomography showed no evidence of recurrent tumor in the sinonasal cavity and neck (Fig. 3). The patient was transferred to our hospital for reconstruction due to a 5 cm×5 cm defect in his hard palate (Fig. 4). He complained of oronasal regurgitation, dysphagia, and hypernasal voice resonance. In the perceptual speech evaluation performed by a speech-language pathologist, the patient was noted to have severe hypernasality and audible nasal emission. The palate defect was repaired surgically with a RFFF under general anesthesia. With the patient in the supine position and a tourniquet inflated, an incision was made on the ulnar flap margin in order to include the deep fascia of the forearm. The 6 cm×8 cm rectangularly shape flap was designed to fit the size of the palatal defect. After the full dissection, the total length of the pedicle harvested was 11 cm. At the same time, a 5 cm×15 cm, 8/1,000 inch in thickness, split-thickness skin graft was harvested from the right thigh. Then, the harvested split thickness skin graft was sutured to the RFFF on the fascial side. The defect on the oral lining was covered with the RFFF skin paddle, and the nasal lining was covered with the RFFF fascia, with the split thickness skin graft. The pedicles were anastomosed with the left facial artery and concomitant vein in an end-to-end fashion. The postoperative course was uneventful, and no complications were observed. Two years after surgery, the patient remains in good health, without recurrence, and shows good aesthetic results (Fig. 5). In follow up perceptual speech evaluations, the patient was noted to have significantly decreased hypernasality, with greatly improved speech intelligibility. Nasalance scores were 59%, which was measured with a nasometer (Model 6450, KayPENTAX, Lincoln Park, NJ, USA). A cutoff value of 63% was used; that is, nasalance scores higher than 63% were considered to indicate hypernasality.



Fig. 1

Neck computed tomography image at diagnosis: heterogeneously enhancing mass lesion on the right nasoethmoidal area.





Fig. 2

Immunohistochemical findings of the extranodal natural killer/T-cell lymphoma marker: ×400. That CD56 shows that atypical lymphoid cells react positively with the marker and appear brown.





Fig. 3

Neck computed tomography image after complete remission of extranodal natural killer/T-cell lymphoma: no evidence of recurrent tumor.





Fig. 4

Preoperative view: a 26-year-old man with a palatal defect originating from extranodal natural killer/T-cell lymphoma.





Fig. 5

Postoperative 2 years view.



Extranodal NK/T-cell lymphoma is known as a rare form of non-Hodgkin's lymphoma. Patients' subjective symptoms are non-specific, such as nasal obstruction or purulent nasal discharge. These findings are easy to misdiagnose as chronic sinusitis, or they result in a delayed diagnosis. Diagnosis of extranodal NK/T-cell lymphoma is confirmed by histologic and immunohistochemistry analysis. Immunohistochemical staining demonstrates positive reactions to NK cell marker CD56 and a negative reaction to CD3, which meet the description of markers positive for extranodal NK/T-cell lymphoma [3]. Extranodal NK/T-cell lymphoma is an aggressive malignancy with rapid progression. The 5-year overall survival rate in early stage disease is more than twice that of the advanced stage at diagnosis: 54% versus 20% [4]. Highly aggressive types involve anatomical destruction, such as septal perforation and palatal perforation. The treatment for this, combined with radiation therapy and chemotherapy, could prolong long-term survival and achieve greater local control. One month following the completion of planned therapy, the response to treatment should be documented by history, physical examination, flexible nasal endoscopic examination, and an imaging study [5]. In highly aggressive cases, it is difficult for palatal perforation to heal conservatively, and its symptoms, such as speech disorder and oronasal regurgitation, can significantly impact patients' quality of life. Following the completion of treatment, patients should be evaluated for damage to the neighboring bony structures to assess whether reconstructive surgery is needed [5]. Surgical reconstruction must take into account the complicated anatomy, postoperative speech, and swallowing function. As many studies have reported, methods of palate reconstruction include palatal local flap, folded free flap, and free flap combined with pharyngeal flap. RFFF is the most common flap used to reconstruct the oropharynx and oral cavity. The main advantage of RFFF is that the forearm skin is thin and pliable enough to adapt easily to the shapes of defects and is suitable for obliterating dead space in defects.

In conclusion, extranodal NK/T-cell lymphoma is a rare type of lymphoma. Because of its aggressive behavior and the high incidence of tumor recurrence, annual follow-up with detailed imaging studies and histologic and immunohistochemistry analysis are recommended. Furthermore, considering the poor quality of a patient's life due to speech disorders and oronasal regurgitation caused by palate defects, the RFFF is a valuable option for restructuring composite and three-dimensional palatal defects.

/pdf/reconstruction-of-a-rare-palate-defect-originating-from-2b4gdqxog7.pdf

So Young Lim

Papers

Mutations in DDX58, which Encodes RIG-I, Cause Atypical Singleton-Merten Syndrome

Phenotypic association of presence of a somatic GNAQ mutation with port-wine stain distribution in capillary malformation.

Evaluation of natural growth rate and recommended age for shaving procedure by volumetric analysis of craniofacial fibrous dysplasia

Leiomyoma of the Forehead

Reconstruction of a rare palate defect originating from extranodal natural killer/t-cell lymphoma.