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We then compared the pregnancy and perinatal compli-
We first determined whether maternal/fetal genotype
Of the 15 mothers with known THRB genotype, four were
6. Passwell J, Screiner GF, Nynaka M, Colten HR. Local
0/3 (0)
2/6 (33)
2/9 (22)
2/9 (22)
2/6 (33)
0/3 (0)
5. Spirer Z, Zakuth V, Orda R, et al. Acquired tuffsin
131118-COHANIM - 131118-COHANIM | 3 - A | 18-11-13 | 11:24:13 | SR:-- | Cyan
#131118-COHANIM - 131118-COHANIM | 3 - A | 18-11-13 | 11:24:13 | SR:-- | Black
131118-COHANIM - 131118-COHANIM | 3 - A | 18-11-13 | 11:24:13 | SR:-- | Yellow
1/3 (33)
2/7 (29)
1/4 (25)
131118-COHANIM - 131118-COHANIM | 3 - A | 18-11-13 | 11:24:13 | SR:-- | Magenta
6/9 (67)
4/6 (67)
2/3 (67)
6/6 (100)
8/9 (89)
2/3 (67)
4. Handzel ZT, Dolfin Z, Levin S, et al. Effect of
0/3 (0)
0/7 (0)
0/4 (0)
1/3 (33)
1/9 (11)
0/6 (0)
3. Levin S, Schliesinger M, Handzel Z, et al. Thymic
8/22 (36)
2. Levin S, Perlov S. Ataxia telangectasia in Israel: with
(n=6)
(n=3)
(n=9)
child
child
Total
Affected
Unaffected
Unaffected mother (n=4)
1. Picard C, Bobby Gaspar H, Al-Herz W, et al.
References
#
Original articles Original articles 7/18 (39) 5/19 (26) 5/19 (26) 14/18 (77) 15/18 (83) 2/12 (16) 8/18 (44) (n=19) Total 6/37 (16) 2/10 (20) 3/11 (27) 1/11 (9) 9/10 (90) 7/10 (70) 1/7 (14) 4/10 (40) (n=11) child Unaffected Affected mother (n=7) 5/8 (63) 2/8 (25) 4/8 (50) 6/8 (75) 8/8 (100) 1/5 (20) 4/8 (50) (n=8) child Affected Only one mother received thyroid-related treatment during Interestingly, affected infants of affected
found in any of the relevant databases, although three different bers. Thus, a total of 21 mutation carriers – 13 affected adults The use of fDg pET/CT in the Diagnosis and Monitoring
missense mutations were previously reported in this codon in (3 males, 10 females) and 8 affected children (5 males, 3 females)
patients with clinical and biochemical evidence supporting – were evaluated. of Disseminated Aspergillosis
RTH-β (p.His435Leu, p.His435Gln, and p.His435Tyr) [9,10]. In general, the clinical characteristics of our patients were
Additional family members were recruited. Fifteen agreed similar to those reported in the literature and included goiter Ora Shovman MD 1,2
to participate and six of these, one adult and five children, were (48%), growth disorder (43%), and sinus tachycardia (40%)
found to be mutation carriers [Figure 1B]. The mutation co-seg- [Table 2]. There was no discernable genotype/phenotype 1 Zabludowitz Center for Autoimmune Diseases, Department of Internal Medicine ‘B’ and Rheumatology Unit, Sheba Medical Center, Tel Hashomer, Israel
regated with classic laboratory phenotype, including elevated THs relationship and marked clinical diversity was noted between 2 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
and non-suppressed TSH, as well as typical and variable clinical individuals, even within the same family.
characteristics [Table 2]. Taken together, these findings strongly
suggest that p.His435Arg is causal and results in RTH-β syndrome. EffECT Of InTROn COnTROl REgIOn VARIAnT RS2596623 On
ClInICAl RTH-β pHEnOTypE Currently, computed tomography (CT) This case provides additional evidence
ClInICAl pRESEnTATIOn Of THRB MuTATIOn CARRIERS To test the hypothesis that variants in the putative intron con- KEY WORDS: aspergillosis, fluorodeoxyglucose and magnetic resonance imaging (MRI) regarding the potential role of FDG-PET/
Further evaluation of all eight families identified 13 additional trol region (ICR) could explain phenotypic variability [3], we positron-emission tomography/ may provide excellent structural resolution CT in the diagnosing, monitoring of dis-
THRB mutation carriers and 25 non-carrier family mem- evaluated the clinical characteristics of double heterozygotes in computed tomography for visualizing advanced diseases but they ease activity, guiding of biopsy, and mak-
(FDG PET/CT), invasive fungal generally have limited value in detecting ing of clinical decisions in patients with
infection (IFI), leukemia early disease. 18 F-fluorodeoxyglucose invasive aspergillosis. A different study
Table 2. Clinical presentation of THRB gene mutation carriers
IMAJ 2018; 20: 707–708 positron-emission tomography/com- investigated additional applications of
Family Individual Thyroid function tests Neurologic Growth puted tomography ( 18 F-FDG PET/CT) is FDG PET/CT in patients with aspergil-
Mutation* code code** Age Gender TSH / FT4 / TT3 / FT3*** Goiter # Tachycardia ## disorder ### disorder^ a metabolic imaging technique that may losis and reported that FDG PET/CT may
p.Arg320Cys 8 II-1 61 years Male 2.2 / 33.9 / 2.6 Yes Yes None No
II-2 36 years Female 2.3 / 25.1 / 2.7 No No None No be used to identify lesions associated with help in differentiating between invasive
II-3 33 years Female 2.2 / 26.7 / 3.1 No No Mild-to-Moderate No he prevalence of life-threatening fungal early fungal infection, reveal the extent of and non-invasive aspergillosis [5]. While
p.Arg320Leu 4 II-1 ^^ 33 years Female 4.6 / 7.9 / 11.3 Yes No Mild-to-Moderate No T infections in immunocompromised the infection, and monitor the treatment invasive aspergillosis usually presents with
p.Leu328Ser 5 II-1 2 years Male 6.1 ^^^ / 55.4 / (15.3) No N/A (11) N/A Yes patients has been gradually increasing in response to antifungal therapy [2,3]. multiple hypermetabolic nodules, non-
p.Arg338Trp 2 I-1 44 years Female 2.07 / 39.6 / (11) Yes No None Yes the last decades. This high-risk population In this issue of the Israel Medical invasive aspergillosis presents with solitary
II-1 24 years Female 2.43 / 76 / (16.8) No Yes Severe Yes includes patients with prolonged neutro- Association Journal (IMAJ), an interest- isometabolic nodules with a halo pattern.
II-2 23 years Female 2.66 / 32.7 / 3.9 Yes No None Yes
II-6 8 years, 2 months Male 2.52 / 45.2 / 3.4 Yes Yes Moderate No penia, allogeneic hematopoietic stem cell ing case report by Hod and colleagues [4] It should be noted that in some cases,
(p.His435Arg) 7 III-3 30 years Female 2.1 / 28.4 / (7.2) Yes Yes Mild Yes transplant, solid organ transplant, inher- illustrates the application of FDG-PET/CT pulmonary aspergillosis can mimic a lung
(Novel) IV-7 5 years, 7 months Male 4.6 / 31 / 3.9 Yes Yes N/A Yes ited or acquired immunodeficiencies, in an immunocompromised patient with malignancy with regard to clinical mani-
IV-8 1 year, 7 months Female 4.5 / 25.7 / 4.1 No No N/A No corticosteroid use, and other conditions. acute lymphoblastic leukemia who devel- festations and radiological signs on FDG
IV-9 5 months Male N/A No No N/A Yes
III-2 38 years Male 2.5 / 27.9 / 2.5 Yes No Mild No Aspergillosis is one of the most common oped invasive disseminated aspergillosis. PET/CT [6,7]. Therefore, histopathologic
IV-1 14 years Female 2.3 / 40.5 / 3.6 Yes Yes None No fungal infections, and may involve the Following chemotherapy treatment, the evaluation is necessary for definitive diag-
IV-4 9 years Male 2.0 / 24.7 / 4.4 No No None No
p.Arg438His 6 II-1 38 years Female 2.7 / 24.1 / 2.1 Yes Yes Moderate Yes eyes, ears, larynx, lungs, and sinuses in its patient presented with fever and neutro- nosis before deciding about further treat-
II-2 43 years Female N/A No Yes None Yes localized form [1]. Immunocompromised penia and underwent a CT that revealed ment strategy.
Pro453Ser 1 II-1 26 years Male 2.8 / 31 / (9.3) No Yes Moderate No patients are prone to develop disseminated only liver lesions. In contrast, a FDG-PET/
Pro453Thr 3 II-1 36 years Female 3.3 / 40.4 / (9) No No Mild No multisite disease, with the lung being the CT that was performed shortly afterward COnCluSIOnS
II-2 10.5 years Female 4.2 / 25.9 / 3.9 No No None No most common site of invasive aspergil- demonstrated widespread disease involv- FDG PET/CT may be used for the diag-
Study Prevalence 10/21 (48%) 8/20 (40%) 9/17 (53%) 9/21 (43%) losis, reflecting the usual portal of entry. ing the liver, spleen, kidneys, lungs, and nosis and management of aspergillosis in
The dissemination to other organ systems, muscles. Moreover, FDG-PET/CT was use- immunocompromised patients. However,
Reported Prevalence (1) 66-95% 33-75% 4-60% ~30%
including the central nervous system, ful in guiding an open liver biopsy from the only limited research results exist regard-
Key clinical categories were adapted from Refetoff S, Dumitrescu AM [24]
*Mutation names are listed in order of coding sequence heart, kidney, and liver, usually occurs by most prominent hypermetabolic lesions ing this application of FDG PET/CT, and
**Generations are labeled with Roman numerals. Arabic numbers indicate the individual in each generation. For all families except for family 7, the proband a hematogenous dissemination. Culture that revealed a fungal infection, whereas additional studies are required.
generation is arbitrarily designated as II and the proband designated individual 1. Siblings of the proband are designated II-2, II-3, etc. The proband’s mother is
designated generation I, individual 1 (I-1). For family 7, generations and individuals are indicated as shown in Figure 1B of Aspergillus species in combination with a previous percutaneous biopsy from the
***Results for free T3 (FT3) are given in parenthesis. Reference ranges TSH (0.35–5.5 mU/L), FT4 (10–20 pmol/L), total T3 (1.2–3 nmol/L), FT3 (3.1–6.8 pmol/L) the histopathologic demonstration of tis- liver was inconclusive. FDG-PET/CT was Correspondence
# Physician examination, post-thyroidectomy status, or imaging sue invasion by hyphae provides ultimate also used to monitor the progression of the Dr. O. Shovman
## For adults, resting pulse > 100 beats per minute or current related medical treatment (beta-blockade or calcium-channel blockade). For children, resting heart-rate Dept. of Internal Medicine B, Sheba Medical
greater than age-adjusted normal range, adapted from Fleming et al. [25]. evidence of invasive aspergillosis. disease and the appearance of new lesions Center, Tel Hashomer 5265601, Israel
### Emotional disturbances (or relevant medical treatment), hyperkinetic behavior, attention deficit hyperactivity disorder, learning disability and/or mental In such cases, early diagnosis and evalu- despite different antifungal therapies. email: orashovman@walla.co.il
retardation (IQ < 70) [24] ation of response to antifungal treatments The scan revealed that the treatment was
^ For adults, height < 5th percentile for height distribution of the Israeli population [24], or body mass index < 18 kg/m. For children, height < 5th percentile for height References
distribution of the Israeli population and/or weight < 5th percentile for weight distribution of the Israeli population is of high importance. Although defini- unsatisfactory. Due to these findings, it was 1. Patterson TF, Thompson GR 3rd, Denning DW,
^^ Currently under treatment with T3, 80 mcg/day tive diagnosis is made by histopathologic decided that bone marrow transplantation et al. Practice guidelines for the diagnosis and
^^ TSH values were determined by a different laboratory; reference range 0.4–7 mU/L analysis, several technologies may raise is necessary, despite hematological remis- management of aspergillosis: 2016 update by the
N/A = not available, TSH = thyroid-stimulating hormone Infectious Diseases Society of America. Clin Infect
the suspicion of an aspergillosis infection. sion in bone marrow biopsy [4]. Dis 2016; 63: 1-60.
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