Page 208 - 2019_03-Haematologica-web

T. Shahin et al.
during an operation for left hip dislocation at the age of 4 years. He subsequently developed right ankle edema, fol- lowed by progressive difficulty in walking and, finally, knee edema. He did not experience pain, erythema, or any increase in acute-phase reactants. The degeneration of the joints was classified as destructive arthropathy. In addi- tion, the patient had neurodevelopmental delay of 1-2
years at the age of 4 years. PP498L showed consistently ele- vated serum IgE levels (>2000 IU/mL) and eosinophilia (Table 1). Progressive decline in absolute B-cell counts and low central memory T cells were observed (Table 1 and Figure 1C). These findings indicated a high National Institute of Health Hyper IgE syndromes (NIH HIES) score of 57 (Online Supplementary Table S2), raising suspicion of
Table 2. Comparative analysis of clinical features presenting in patients with IL6ST variants compared to other patient cohorts with defined gene defects.
GP130 defect (n=2)
IL6ST
STAT3 ZNF341 DOCK8 CARD11 PGM3 Loeys-Dietz
ERBIN (n=3)56
Wiskott Aldrich syndrome (incidence: 1/250000)57
WAS
ARPC1b defect (n=6)58–60
ARPC1B
HIES (n=140)47,48
STAT3
deficiency deficiency DNdefect deficiency syndrome
(n=19)24,25
ZNF341
(n=64)49
DOCK8
(n=12)50,51
CARD11
(n=29)52–54 (n=8)55
Gene defecta,b
Inheritance
c IgE
Eosinophilia Eczema
NIH HIES score (typical)d
Infections
Abscess
Pneumonia
Sinusitis/otitis + + + ++ Keratitis/ conjunctivitis ++ + - + Candidiasis - ++ ++ + Viralinfections - + - +++
Parenchymal lung abnormalities
PGM3 TGFBR1/TGFBR2 ERBIN
AR AD AR AR AD AR AD AD X-linked AR
↑ ↑↑ ↑↑ ↑ ↑ ↑↑ ↑↑ ↑ ↑ ↑ + + +/- + + + + + + +
+ + + ++ ++ +
40-57 >40 11-62 20-40 ND 27-55
++ + + +
-/+ ++ + + + ++ ++ +++ + + ++ ++
ND ND ND
++ - + ++ ++ +
ND
+ + + - - +
+ +
++
+ +
- -
+ + - + ++ -
+ + - - - + + +/- - ++ + +- - - + - - - -
- - - + - +
- + - -
- - - - - - - - - -
Immunological features
-
Bronchiectasis
Pneumatocele
++ ++ + +
++ ++ ++ ++
+ + +
+
Dysmorphia
Prominentforehead
Cathedralpalate - ++
- - - - -
- - + - -
Decidual teeth retention Abnormal bone fractures Craniosynostosis/ abnormal skull shape Scoliosis
++ ++ ++ ++ ++ +
+ + + +
- - - + + -
-
++ ++ +/- + +/- + +
+ + + +++ +++ + +++ + +
++ -
Allergies
Autoimmunity - + - ++ + ++ - - ++ CNSinvolvement ++ + + ++ - ++ - - -
Neoplasia - + +/- ++ - + -
- ++
Immunoglobulins Normal Normal Normal Normal Normal Normal Normal
(excluding IgE) / high IgG / low / low
Lymphopenia - - +/- +/- - + - - +/- -
Normal
Variable / high IgA
Normal / high IgA
+-- Normal Normal Normal Normal/ Normal Normal
low
Normal/ Normal Normal
Bcells low low low
CD4 lymphopenia Th17 cells
CD19+ B cells
- -
+/- Low Normal
+/- - Low Normal Normal/ Normal/
+/- -/+ Normal ND Normal/ Normal
low
Normal/ Normal
low
Low Low Normal/ Normal/ low low
low low Switched-memory Normal/ Low Low Low Normal/
aApart from STAT3 HIES, DOCK8 deficiency and WAS, the phenotypical comparisons have been made based on a limited number of published cases. Future studies and larger
e.g. immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome due to FOXP3 defects. ↑↑ refers to IgE levels >5000 IU/mL; ↑ refers to IgE levels 1000- 5000 IU/mL.dThe National Institute of Health Hyper-IgE syndromes (NIH HIES) score18 may be highly variable amongst individuals.The numbers indicated here represent ranges of values which are typically seen in the respective diseases; however, these should be taken with caution, in particular for those disease entities for which so far only a few indi- viduals have been identified and described in the scientific literature. DN: dominant negative; ND: not determined; CNS: central nervous system.
cohorts of patients will be needed to describe the full phenotypic spectrum of the individual disease entities.bThere are additional gene defects that can present with high IgE, 61 c
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haematologica | 2019; 104(3)