Chronic Mucocutaneous Candidiasis due to Signal Transducer and Activator of Transcription 1 (STAT 1) Mutation in an Indian Patient – A Case Report

Abstract

Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency due to defect in various genes leading to an increase in susceptibility to skin and mucosal infection. Mutation in signal transducer and activator of transcription 1 (STAT 1) gene being the most common cause of CMC can lead to increased risk of infections, multisystem abnormalities, and malignancy. We describe a 27 year old Indian woman with clinical features of CMC including esophageal stenosis, gangrene of the finger, endocrinological and immunological abnormalities and STAT1 mutation (p.Leu407Val). She was treated with antifungals which led to symptomatic improvement.

Introduction

Chronic mucocutaneous candidiasis (CMC) is a rare primary immunodeficiency, characterized by persistent or recurrent infections of the skin, nail, or mucosae with candida species.[1] The autosomal dominant mutation in signal transducer and activator of transcription 1 (STAT 1) gene is the most common genetic cause of CMC.[2] STAT 1 mutation increases the risk of developing CMC, dermatophytosis, invasive fungal, bacterial, viral, and mycobacterial infections, autoimmune disorders, gastrointestinal symptoms and pulmonary symptoms. There is also an increased lifetime risk of developing life-threatening cerebral, extracerebral aneurysms, oral, and esophageal squamous cell carcinoma in these patients.[1]

Herein, we describe the clinical features and management of a patient with an underlying STAT 1 mutation.

Case Report

A 27-year-old lady born at 7 months of gestation to nonconsanguineous parents presented with a history of recurrent oral candidiasis since early childhood. She also noticed discoloration and thickening of finger and toenails associated with recurrent paronychia from 14 years of age. The left index finger became gangrenous and was amputated. She complained of progressive dysphagia. There was a history suggestive of recurrent herpetic stomatitis (three episodes in the past 1 year), recurrent redness of eyes with blurring of vision, and pustular lesions on the trunk. Her medical history included hypothyroidism diagnosed at 8 years of age and was on levothyroxine 100 mcg since then. None of her family members suffered from CMC.

On examination, she had a diffuse adherent whitish plaque with deep fissures over the tongue [Figure 1]. All toenails and bilateral thumbnails were discolored with distal onycholysis and crumbling. The right index finger showed a hyperkeratotic plaque destroying the nail plate, extending to the proximal nail fold [Figure 2a]. Great toenails are onychogryphotic [Figure 2b].

Figure 1.

Deep fissuring of the tongue

Figure 2.

(a) Hyperkeratotic plaque over the right index finger. (b) Onychomycosis of toe nails

Laboratory investigations revealed microcytic hypochromic anemia, hypothyroidism, hyperparathyroidism, hypovitaminosis-D, and low ferritin. As per lymphocyte subset analysis, the levels of lymphocytes (CD4, CD19 and CD56) were within the lower range of the normal limit or below the normal range [Table 1].

Table 1.

Results of the laboratory investigations

Hematological assay
Parameter	Patient	Normal range
Hemoglobin	6.1 g/dL	12-15 g/dL
Total leucocyte count and differential count	5700/mm3 (neutrophils - 58, eosinophils - 3, lymphocytes -30, monocytes - 9)	4000-1200/mm3
Platelet count	291,000/mm3	150,000-450,000/mm3
Biochemical assay
TSH	6.987 μIU/mL	0.3-4.5 µIU/mL
T4	12 ug/dL	4.5-12.5 ug/dL
Parathyroid hormone	164.8 pg/mL	8-74 pg/m
Vitamin D	5.8 ng/mL	>30 ng/dL
Ferritin	3.3 ng/mL	10-290 ng/dL
Viral serology
HIV	Negative
HBsAg	Negative
HCV	Negative
Immunoglobulin assay
Immunoglobulin (Ig)	Patient result (mg/dL)	Normal range (mg/dL)
Immunoglobulin G (IgG)	1875	800-1700
Immunoglobulin A (IgA)	242	140-420
Immunoglobulin M (IgM)	55	50-190
Lymphocyte subset analysis
Cluster differentiation molecules (CD)	Absolute count (%)	Absolute count (Normal range)
CD3	1215 (79.4)	1881±407
CD4	358 (23.4)	958±296
CD8	701 (48.8)	707±221
CD19	101 (8)	514±411
CD56	113 (7.4)	358±189

*Abnormal values highlighted in bold

Fungal culture from hard palate grew Candida albicans (C.albicans) and nail plate culture grew Candida parapsilosis (C.parapsilosis) [Figure 3]. Biopsy from the nail plate with bed of left index finger (amputated specimen) showed evidence of candida infection in the stratum corneum.

Figure 3.

Phenotypic appearance of C.albicans and C.parapsilosis on CHROMAgar. C.albicans – green colonies and C.parapsilosis – white colonies

Barium swallow revealed cricoid web. Chest X-ray, CT angiogram of major vessels, and CT brain were normal.

Her clinical features favored a CMC syndrome. Molecular analysis on DNA obtained from peripheral blood using next-generation sequencing identified STAT1 heterozygous mutation c.1219 C>G, p.Leu407Val at DNA-binding domain. This variant has not been reported from India till date to the best of our knowledge.

Fungal infection responded to oral fluconazole. Dysphagia improved with serial dilatations of cricoid web. Calcium correction, iron supplements and thyroxine were continued.

Discussion

The diagnosis of CMC was made in our patient based on clinical features of recurrent mucocutaneous candidiasis, bacterial infections, hypothyroidism, hypovitaminosis D, esophageal stenosis, associated with, CD4, CD19, and CD56 lymphocyte subsets which were either within the lower range of normal limit or low.[1,3,4] In addition, she also had gangrene of the finger and hyperparathyroidism.

The genetic mutations in various genes, e.g., STAT 1, STAT 3, AIRE, IL-17RA, IL-17 F, TRAF3IP2, CARD 9, Dectin, IL-12 Rβ1, ROR γT, TYK2, have been associated with susceptibility to CMC.[5,6] The reported prevalence of mutations is variable in various ethnic groups. STAT 1 mutation has been reported in around 50% of patients with CMC followed by AIRE deficiency.[2]

Autosomal dominant STAT 1 mutation can be familial or sporadic, presenting predominantly with mucocutaneous candidiasis typically associated with C.albicans infection.[7] Our patient had mucosal C.albicans infection and C.parapsilosis associated onychomycosis. Khullar et al.,[8] reported C.orthosilosis (species described under C.paraspilosis) nail infection in a STAT 1-mutated patient.

A range of STAT 1 GOF mutations secondary to defective nuclear dephosphorylation leading to increased production of IFN-alpha/beta, IFN-gamma, and IL-27 resulting in defective Th-17 response have been described till date.[1,3] These mutations are confirmed by functional immunological assay. Our patient had a mutation of p.Leu407Val which has been previously reported in 2020, in a 12-year-old Peruvian boy by Platt CD et al.,[9]

Three cases of STAT 1-mutated CMC (p.L206H, p.T385M, p.R274Q) have been reported from India.[1,8] Also, Bhattad et al.,[10] described a case of CMC with a mutation in TRAF3IP2 in an Indian boy.

In the absence of overt CMC in the family, the occurrence was probably sporadic in our patient.

At present, management is predominantly symptomatic, with long-term systemic and topical antifungals. However, other treatment options available include immunoglobulin infusion, GM-CSF and G-CSF, JAK/STAT inhibitors, and hematopoietic stem cell transplantation.[2]

Conclusion

STAT1 gene mutations cause a broad array of clinical features including life-threatening complications like cerebral aneurysm and malignancies, hence identifying the genetic subset will help in early screening, counseling, and treatment.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.