Persistent Oral Thrush

Dr.Reepa Agrawal

Case Summary
7 yrs old male child
2nd by birth order
Born of nonconsanguinous marriage

chief complaints of :
persistent white lesions
on tongue
since 16 months of age
associated with difficulty in
swallowing

 lesions responded to clotrimazole

mouth paint temporarily
H/o genital lesions present
No h/o hair ,nails involvement

 No h/o any other infections or

prolonged antibiotic and steroids
usage in the past
Immunised till date
Family History- Unremarkable
Birth & Developmental historyNormal

Physical Examination
Vitals stable
Curdy white patches present on gingiva,
buccal mucosa, palate & tongue
Conical Teeth
Dry Skin
Pallor present
Genitals: Phimosis
Hair, Nails: Normal

 BCG scar present

Anthropometry

No Lymphadenopathy

Observed

Expected

Percentile

Weight

15 kg

21 kg

<5th

Height

109.4 cm

117.8 cm

5th- 10th

Bone age : 4 years

Height age : 5 yrs 6 mths
Weight for age : 4 yrs 4 mths
Systemic Examination: Normal

Impression

Persistent oral
thrush with
conical teeth
with failure to
thrive

Oral thrush and immunodeficiency

T- cell immune defects

Combined defects
Mucocutanaeous Candidiasis
Hyper IgE syndrome
APECED (Autoimmune
Polyendocrinopathy Candidiasis
Ectodermal Dystrophy)
HIV infection

Investigations
1.
2.
3.
4.
5.
6.
7.

CBC
Lymphocyte Subset Analysis
Immunoglobulin Levels
HIV
Endocrine evaluation
Markers of Autoimmunity
Genetic Studies

1. CBC
Jan 2015

July 2015

Hb

10.3

11.9

MCV

80.9

75.6

MCH

28.5

25.10

Total WBC
Count

3440

5700

ANC

1410

2907

ALC

1582

2223

AEC

138

228

AMC

310

342

Platelets

16000

365000

Bone Marrow Aspiration : s/o Idiopathic

Thrombocytopenia

2. Lymphocyte Subset
Sr.
No

Lymphocyte
Subpopulation

Result %
Lymphocyt
e

Absolute
Lymphocyt
e
Count/mm
3

Normal
Count/mm
3

Lymphocytes

38

1322

1100-5900

CD19+ B
Lymphocytes

14

487

200-1600

CD3+ T
Lymphocytes

68

2366

700-4200

CD3+/ CD4+ T
Lymphocytes

29

1009

300-2000

CD3+/ CD8+ T
Lymphocytes

26

905

300-1800

CD3-/ CD16+56+
NK Cells

12

418

90-900

3. Immunoglobin Levels
Sr.
No.
IgG Total

1900 mg/dL

350-1620

Ig M Total

72.8 mg/dL

30-265

Ig A Total

323 mg/dL

17-318

Ig E Total

4.3 Ku/L

0-80

4. HIV
Non-Reactive

5. Endocrine Evaluation
T3

39 ng/dL

90-190

T4

2.6ug/dL

4.5-12.5

TSH

66.8 uIU/mL

0.3-5.0

Anti TPO Ab

0.7 (negative)

USG Thyroid : Normal

RBS

89

Ca/ P/ Alk.P

9.4/ 4.0/ 169

25-OH Vit D

39

Na+/ K+

142/ 4.0

GAD-65 Ab

Negative

Islet Cell Ab

Negative

6. Markers for Autoimmunity

1. ANA- Negative
2. DCT- Negative
3. ICT- Negative

Diagnosis
Chronic Mucocutanaeous
Candidiasis with
Hypothyroidism with
Thrombocytopenia

Fungal infections and

Immunity
T(H)17 cells and their specific
cytokines
(IL-17A and IL-17F cytokines and IL22) main players in conferring
antifungal protection.
Sir slides

Genetic Etiologies of fungal

G
infections
CMC:
STAT1 GOF, STAT3 def., APECED, Th17 pathway
defects

Deep Dermatophytosis:
CARD 9 deficiency

Cryptococcosis
Antibody against GM-CSF; or Against IFN

Dimorphic Fungal Infections:

IL12R1 & IFNR1 deficiency, STAT1 GOF mutation.

Pneumocystosis.
SCID, X Linked CD40L deficiency
Fanny Lantenier et al: Curr Opinion in Pediatrics 25(6):736-747.
Bodo Grimbacher JACI 2011

7. Genetic Testing
Heterozygous for Gain of Function
STAT 1 L206H Mutation

Analysis done at INSERM,Paris by

Dr.Anne Puel

STAT1 Exon 8 KACHARE Family

008548 Patient STAT1

L206H

008549 father STAT1 WT

008550 mother STAT1 WT

008551 sister STAT1 WT

Treatment
Fluconazole 150 mg OD
Tapering doses of Prednisolone for
thrombocytopenia
Thyroxine 75 ug OD

Chronic Mucocutaneous Candidiasis

Persistent or Recurrent infection of
mouth, oesophagus, digestive and
genital mucosae, nails and or skin
Mostly with C. albicans
HIV, SCID, CID, ICL, IKB GOF mutation,
DOCK8

Superficial candidiasis

PIDs associated with CMC

CMCD
is CMC in patients with no other
prominent clinical signs and none of
the above genetic defects.

Complete IL17RA deficiency

Partial IL17 F Deficiency
STAT1 GOF Mutation
ACT 1 deficiency

Fanny Lantenier et al: Curr Opinion in Pediatrics 25(6):736-747.

Bodo Grimbacher JACI 2011

APECED

Take Home Message

High suspicion for immunodeficiency
if persistent or recurrent oral thrush
Ongoing evaluation for
endocrinopathies and autoimmunity
with candidiasis

Extracellular Space

Tissue

Epithelium

Antimicrobial
peptide

Yeast

glucan

IL22
Receptor

STA
T3

Dectin 1

IL22

NFB

SYK

MALT1BCL 10
CARD 9

I B

STAT 3

Tissue

Th 17
Cell
membrane

IL17
Receptor

IL17

D ectin -1 C A R D 9 p ath w ay in h an d lin g yeast fu n g ii

Development & Effector function of Th17 cells

Migration of Th17 cells
In to inflamed tissue

Mature DC

CCR4

CCR6

IL21

TNF

Th17 cell
CD

86

Nave T cells
IL6

CD40L
P
ep

28

II

Cd

M
H
C

ti
d

CD28

RORt
ROR

TCR

IL6

STAT 3
STAT 3

IL1

IL26

IL17A
IL17F
IL 22

Induces more Induction of Defensins

Production & activation
Nave T cells
of Epithelial cells
To differentiate
in to Th17 cells
G CSF

CXCL8

IL23

Differentiation in to Th17 cells

GranulopoiesisRecruitment of Neutroph

Discussion
T(H)17 cells and their specific
cytokines (IL-17A and IL-17F
cytokines and IL-22) are the main
players in conferring antifungal
protection.

 Neutralizing autoantibodies against

IL-17A and 1L-22 are involved in
patients with autoimmune
polyendocrinopathy and ectodermal
dystrophy syndrome

 IFN Gamma, IFN Alpha and IL 27 are

potent inhibitors of TH17 cell
development via STAT 1
Therefore gain of function mutation
could be associated with deficient TH
17 cell development

-Takezaki S etal; CMC caused by a Gain of Function Mutation in STAT1

DNA binding domain; journal of immunology june2012

 T(H)17 cells and their specific cytokines (IL-17A and IL-17F cytokines
and IL-22) are the main players in conferring antifungal protection.
Autoimmune polyendocrinopathy and ectodermal dystrophy and hyperIgE syndrome are 2 entities caused by different genetic mutations
affecting distinct immune pathways but eventually share a similar
clinical phenotype of Candida species infection. Impaired T(H)17
responses, although mediated by different mechanisms, seem to
underlie this common feature: neutralizing autoantibodies against IL17A and 1L-22 are involved in patients with autoimmune
polyendocrinopathy and ectodermal dystrophy syndrome, whereas
abnormal T(H)17 proliferation and IL-17 production are observed in the
latter. Although various degrees of T(H)17 dysfunction were also
observed in most cases of isolated chronic mucocutaneous candidiasis,
only in very few families was a distinct mutation detected (caspase
recruitment domain family, member 9 [CARD9]), thus indicating certain
forms of chronic mucocutaneous candidiasis as monogenic with a
Mendelian pattern of inheritance.