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N/A = not available, TSH = thyroid-stimulating hormone
TSH values were determined by a different laboratory; reference range 0.4–7 mU/L
^^
Currently under treatment with T3, 80 mcg/day
^^
distribution of the Israeli population and/or weight < 5th percentile for weight distribution of the Israeli population
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
^
retardation (IQ < 70) [24]
Emotional disturbances (or relevant medical treatment), hyperkinetic behavior, attention deficit hyperactivity disorder, learning disability and/or mental
###
greater than age-adjusted normal range, adapted from Fleming et al. [25].
For adults, resting pulse > 100 beats per minute or current related medical treatment (beta-blockade or calcium-channel blockade). For children, resting heart-rate
##
Physician examination, post-thyroidectomy status, or imaging
#
***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)
designated generation I, individual 1 (I-1). For family 7, generations and individuals are indicated as shown in Figure 1B
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
**Generations are labeled with Roman numerals. Arabic numbers indicate the individual in each generation. For all families except for family 7, the proband
*Mutation names are listed in order of coding sequence
Key clinical categories were adapted from Refetoff S, Dumitrescu AM [24]
Reported Prevalence (1)
Study Prevalence
Pro453Thr
Pro453Ser
p.Arg438His
(Novel)
(p.His435Arg)
p.Arg338Trp
p.Leu328Ser
p.Arg320Leu
p.Arg320Cys
Mutation*
Table 2. Clinical presentation of THRB gene mutation carriers
THRB mutation carriers and 25 non-carrier family mem-
Further evaluation of all eight families identified 13 additional
ClInICAl pRESEnTATIOn Of THRB MuTATIOn CARRIERS
KEY WORDS:
suggest that p.His435Arg is causal and results in RTH-β syndrome.
characteristics [Table 2]. Taken together, these findings strongly
and non-suppressed TSH, as well as typical and variable clinical
regated with classic laboratory phenotype, including elevated THs
found to be mutation carriers [Figure 1B]. The mutation co-seg-
to participate and six of these, one adult and five children, were
Additional family members were recruited. Fifteen agreed
RTH-β (p.His435Leu, p.His435Gln, and p.His435Tyr) [9,10].
patients with clinical and biochemical evidence supporting
missense mutations were previously reported in this codon in
found in any of the relevant databases, although three different
EDITORIALS EDITORIALS Dis 2016; 63: 1-60. Infectious Diseases Society of America. Clin Infect management of aspergillosis: 2016 update by the et al. Practice guidelines for the diagnosis and It should be noted that in some cases, This case provides additional evidence 1. Patterson TF, Thompson GR 3rd, Denning DW , References email: orashovman@walla.co.il Center, Tel Hashomer 5265601, Israel Dept. of Internal Medicine B, Sheba Medical
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References 7. Passwell J, Spirer Z. New vaccines – new dilemmas. In Etzioni, Ochs, eds. Primary Immunodeficiency whom the ICR variant rs2596623 coding mutation haplotype
IMAJ 2005; 7: 397-9. Disease. Elsevier, 2014: 83-96. Table 3. Pregnancy outcomes in THRB mutation carriers
1. Picard C, Bobby Gaspar H, Al-Herz W, et al. could be determined. We identified six individuals with the
International Union of Immunological Societies: 8. Garty BZ, Douglas SD, Danon YL. Immune 15. Shiloh Y, Ziv Y. The ATM protein: the importance of variant on the mutant THRB allele (in-Cis) and three individu- Affected mother (n=7) Unaffected mother (n=4)
2017 Primary Immunodeficiency Diseases Com- deficiency in glycogen storage disease type 1B. Isr J being active. J Cell Biol 2012; 198: 273-5.
mittee Report on Inborn Errors of Immunity. J Clin Med Sci 1996: 32: 1276-81. 16. Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia als with the variant on the wild type allele (in-Trans). Patients Affected Unaffected Affected Unaffected
Immunol 2018; 38: 96-128. telangiectasia gene with a product similar to PI-3 in whom both alleles had the same ICR genotype were defined child child Total child child Total
9. Levy J, Espanol-Boren T, Thomas C, et al. The n (%) (n=8) (n=11) (n=19) (n=6) (n=3) (n=9)
2. Levin S, Perlov S. Ataxia telangectasia in Israel: with clinical spectrum of X linked hyper IgM syndrome. kinase. Science 1995; 268: 1749-53. as concordant and served as controls (12 patients). These three
observation on its relationship to malignant disease. J Pediatr 1997; 131: 47-54. 17. Frydman M, Etzioni A, Eidlitz-Markus T, et al. Total abortions / 6/37 (16) 8/22 (36)
Isr J Med Sci 1971; 7; 1534-41. 10. Schlesinger M, Fishelson Z. Hereditary complement Rambam–Hasharon syndrome of psychomotor small subgroups lacked statistical power to identify anything total pregnancies*
3. Levin S, Schliesinger M, Handzel Z, et al. Thymic deficiencies in Israel. Isr J Med Sci 1992; 28: 302-6. retardation, short stature, defective neutrophil but a very major effect. However, review of the data did not Gestational hypertension 4/8 (50) 4/10 (40) 8/18 (44) 0/6 (0) 1/3 (33) 1/9 (11)
deficiency in Down syndrome. Pediatrics 1979; 63; motility and Bombay phenotype. Amer J Med Gen reveal any suggestion of association between specific clinical Low maternal weight 1/5 (20) 1/7 (14) 2/12 (16) 0/4 (0) 0/3 (0) 0/7 (0)
80-7. 11. Etzioni A. Generic etiologies of leukocyte adhesion 1992; 44: 297-302. symptoms and this variant (data not shown). gain (< 8 kg)
4. Handzel ZT, Dolfin Z, Levin S, et al. Effect of defects. Curr Opinion Immunol 2009; 21: 481-6. 18. Etzioni A, Frydman M, Pollack S, et al. Brief report:
thymic humoral factor on cellular immune factors 12. Wolach b, Gavrieli R, de Boer M, et al. Chronic recurrent severe infections caused by a novel Vaginal delivery 8/8 (100) 7/10 (70) 15/18 (83) 6/6 (100) 2/3 (67) 8/9 (89)
of normal children and of pediatric patients with granulomatous disease: clinical, functional, leukocyte adhesion deficiency. N Eng J Med 1992; EffECT Of THRB MuTATIOnS On pREgnAnCy OuTCOME Term birth 6/8 (75) 9/10 (90) 14/18 (77) 4/6 (67) 2/3 (67) 6/9 (67)
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ataxia telangiectasia and Down’s syndrome. Pediatr molecular and genetic studies. The Israeli experience 327: 1789-92. Abnormal thyroid hormone function is known to have del-
Res 1979; 13, 803-6. with 84 patients. Am J Hematol 2017; 92: 28-36. 19. Vilboux X, Lev A, Malicdan MC, et al. A congenital Small for gestational age 4/8 (50) 1/11 (9) 5/19 (26) 1/4 (25) 1/3 (33) 2/7 (29)
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131118-COHANIM - 131118-COHANIM | 3 - A | 18-11-13 | 11:24:13 | SR:-- | Cyan
5. Spirer Z, Zakuth V, Orda R, et al. Acquired tuffsin 13. Rechavi E, Lev A, Simon AJ, et al. First year of neutrophil defect syndrome associated with eterious effects on pregnancy outcome when present in either Phototherapy 2/8 (25) 3/11 (27) 5/19 (26) 2/6 (33) 0/3 (0) 2/9 (22)
deficiency. Ann N Y Acad Sci 419; 220-6, 1983. Israeli newborn screening for severe combined mutations in VSP45. N Eng J Med 2013; 369: 54-65. the mother or fetus [4]. To evaluate the effect of maternal
immunodeficiency – clinical achievements and Infant, poor weight gain 5/8 (63) 2/10 (20) 7/18 (39) 2/6 (33) 0/3 (0) 2/9 (22)
6. Passwell J, Screiner GF, Nynaka M, Colten HR. Local 20. Picard C, McCarl CA, Papolos A, et al. STIM1 mutation status on miscarriage rate, we included 14 mothers
intrahepatic expression of complement genes C3, insights. Front Immunol 2017; 8: 1448. mutations associated with a syndrome of im- with known mutation status and sufficient clinical data, even *Miscarriage rate calculated in 10 affected and 4 unaffected mothers, subsequent analyses were
factor B, C2 and C4 is increased in murine lupus 14. Etzioni A, Ochs HD, McCurdy D, Gatti RA. Dunall munodeficiency and autoimmunity. N Eng J Med performed on 7 affected and 4 unaffected mothers as indicated
nephritis. J Clin Invest 1988; 82:1676-84. found: Ataxia Telangiectasia gene and function. 2009; 360: 1971-80. if the offspring mutation status was unknown. One additional
mother could not be reached to respond to the questionnaire. Interestingly, affected infants of affected mothers appeared
Capsule Miscarriage rate, defined as spontaneous abortion occurring more likely to be born SGA (50%) and have weight gain
at any stage of pregnancy, was calculated for each mother and problems during infancy (63%) than any of the other groups
was found to be independent of maternal mutation status (9–33%). Moreover, all four affected SGA offspring born to
fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration (P = 0.16 by unpaired t-test) [Table 3]. affected mothers had birth weights below the 5th percentile
Activation of innate immunity and deposition of blood- adenine dinucleotide phosphate (NADPH) oxidase activation Of the 15 mothers with known THRB genotype, four were for gestational age; whereas, the weight of the unaffected SGA
derived fibrin in the central nervous system (CNS) occur in and the expression of proinflammatory genes. In animal excluded from subsequent analyses, two refused to allow off- infant of the affected mother was in the 10th percentile. One
autoimmune and neurodegenerative diseases, including models of MS and AD, 5B8 entered the CNS and bound to spring THRB genotyping, one was lost to follow-up, and one normal infant of an unaffected mother was severely SGA (< 1st
multiple sclerosis (MS) and Alzheimer’s disease (AD). However, parenchymal fibrin, and its therapeutic administration reduced had difficulties recalling pregnancy details and her medical percentile), possibly related to maternal hypertension, which
the mechanisms that link disruption of the blood–brain barrier the activation of innate immunity and neurodegeneration. records were not available. was diagnosed during the first month of gestation. One of two
(BBB) to neurodegeneration are poorly understood, and Thus, fibrin-targeting immunotherapy inhibited autoimmunity- We first determined whether maternal/fetal genotype de-novo affected offspring had intrauterine growth restriction,
exploration of fibrin as a therapeutic target has been limited and amyloid-driven neurotoxicity and might have clinical affected fetal survival. The two families with de-novo mutations which was diagnosed during the second trimester, and was
by its beneficial clotting functions. Ryu et al. studied the benefit without globally suppressing innate immunity or were excluded from this analysis, as were four families in which born SGA (~3rd percentile).
generation of monoclonal antibody 5B8, targeted against the interfering with coagulation in diverse neurological diseases. one or more of the offspring were not genotyped, since missing Only one mother received thyroid-related treatment during
cryptic fibrin epitope γ377–395, to selectively inhibit fibrin- data could skew this particular analysis. Mutations were found pregnancy. This mother (family 4), previously thought to have
induced inflammation and oxidative stress without interfering Nature Immunol 2018; 19: 1212 in four offspring (57%) tested from two unaffected mothers, pituitary T4-monodeiodinase deficiency [11], was treated with
with clotting. 5B8 suppressed fibrin-induced nicotinamide Eitan Israeli
and five offspring (42%) tested from five affected mothers. T3 throughout two pregnancies. She gave birth to two offspring:
Thus, maternal mutation status is independent of mutation a male carrying her mutation, born SGA (2.4 kg at term) and
Capsule transmission (P = 0.75 by chi-square test). his unaffected sister, who was born appropriate to gestational
We then compared the pregnancy and perinatal compli-
age (2.8 kg at term), albeit on the lower end of the birth weight
Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial cations in all four possible combinations of maternal/fetal distribution in Israel.
tumors mutation status. The results are summarized in Table 3 and
are presented as percentages as well as absolute numbers,
T cell dysfunction contributes to tumor immune escape T cell sequestration is accompanied by tumor-imposed loss DISCUSSION
in patients with cancer and is particularly severe amidst of S1P1 from the T cell surface and is reversible upon precluding to account for missing data. Although the numbers are too
glioblastoma (GBM). Among other defects, T cell lymphopenia is S1P1 internalization. In murine models of GBM, hindering S1P1 small to allow statistical analysis, our findings suggest pos- We identified and recruited as many Israeli patients as we
characteristic, yet often attributed to treatment. Chongsathidkiet internalization and reversing sequestration licenses T sible increased risk of gestational complications when the could who presented with evidence supporting the diagnosis
et al. revealed that even treatment-naïve subjects and mice cell–activating therapies that were previously ineffective. mother carried a THRB mutation regardless of fetal geno- of RSTH. During the 20 month recruitment period, 19 poten-
with GBM can harbor AIDS-level CD4 counts, as well as Sequestration of T cells in bone marrow is therefore a tumor- type. Specifically, affected mothers may have a higher rate of tial RSTH patients were recruited; however, only eight of those
contracted, T cell–deficient lymphoid organs. Missing naïve adaptive mode of T cell dysfunction, whose reversal may gestational hypertension (44%) and an increased incidence of were subsequently shown to have clinical and biochemical find-
T cells are instead found sequestered in large numbers in constitute a promising immunotherapeutic adjunct. inadequate weight gain during pregnancy, defined as less than ings fully consistent with RSTH. One novel (p.His435Arg) and
seven previously reported THRB mutations were identified in
8 kg weight gain throughout the duration of the pregnancy
the bone marrow. This phenomenon characterizes not only
PERFECTOR GBM but also a variety of other cancers, although only when Nature Med 2018; 24; 1459 (16%), when compared to unaffected mothers (both 0%). eight probands. After expanding these families to include all
Despite this, the majority of all groups had normal, vaginal,
available relatives, a total of 21 heterozygous THRB mutation
tumors are introduced into the intracranial compartment.
Eitan Israeli
carriers were identified. In addition to the patients reported
full-term deliveries.
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