Page 42 - DIFDUF

709
blood relatives were recruited and evaluated using the same pro-
diagnosis of RTH-β. After a mutation was identified, all available
on patients who presented with THs levels consistent with the
PERFECTOR
samples were taken. THRB mutation analysis was performed
was obtained, physical examination was performed and blood
ment. At the time of recruitment, after written informed consent
levels with non-suppressed TSH) were invited for further assess-
of RSTH (namely, persistent inappropriately elevated free-T4
Only those patients with results consistent with the diagnosis
each candidate was re-evaluated by the study team (EZ, BG).
inclusion in the study, clinical history and medical record of
one each from northern and southern areas of Israel. Prior to
participants: eight from Jerusalem, three from Tel Aviv, and
Thirteen endocrinologists responded and referred potential
out Israel were asked to refer patients suspected of having RSTH.
Between August 2011 and May 2013, endocrinologists through-
pATIEnT RECRuITMEnT
PATIENTS AND METHODS
THRB mutation status on pregnancy outcome.
variant on the RTH-β clinical phenotype and the effects of
novel (p.His435Arg). We discuss the impact of a specific ICR
lies harboring eight different THRB mutations, one of them
Our study comprised 21 patients from eight different fami-
mutations.
evaluate the outcomes of pregnancies in families with THRB
the observed heterogeneity in RTH-β clinical symptoms and to
determine whether a common variant in the ICR could explain
2400 patients identified to date [7]. Secondary goals were to
which is the most common subtype of RSTH, with more than
families with RSTH in Israel, particularly those with RTH-β,
The primary goal of our study was to identify additional
maternal mutation status [5,6].
studies are needed to determine the clinical impact of fetal and
mutations and pregnancy outcome are sparse and further
to TH excess. Data addressing the particular issue of THRB
whereas a normal fetus of an affected mother could be exposed
131118-COHANIM - 131118-COHANIM | 3 - B | 18-11-13 | 11:24:13 | SR:-- | Cyan
mother could be exposed to relatively insufficient TH levels,
#131118-COHANIM - 131118-COHANIM | 3 - B | 18-11-13 | 11:24:13 | SR:-- | Black
131118-COHANIM - 131118-COHANIM | 3 - B | 18-11-13 | 11:24:13 | SR:-- | Yellow
an affected (i.e., THRB mutation carrier) fetus of an unaffected
131118-COHANIM - 131118-COHANIM | 3 - B | 18-11-13 | 11:24:13 | SR:-- | Magenta
negative impact on fetal growth and pregnancy outcome since
KEY WORDS:
mismatch in maternal and fetal mutation status could have a
nervous system. Hence, in a family carrying a THRB mutation,
tant role in normal fetal development, particularly of the central
delivery of maternal thyroid hormones, which play an impor-
early gestation, the fetus is solely dependent on transplacental
effects when present in either the mother or the fetus [4]. In
Abnormal thyroid function is known to have deleterious
presentation.
expression of the mutated THRB allele, thus affecting clinical
in this intronic enhancer region (ICR) could modulate pituitary
vided evidence to support their hypothesis that polymorphisms
#
EDITORIALS Case CommuniCations At the age of 27 the patient married Sequencing analysis of four exons (7–10) by amniocentesis performed at week 16 of her mother. Fetal genotyping was obtained p.F245F, in exon 7, which was also found in in exon 10 as well as a variant, c.735C>T; the already known c.1357C>A; p.P453T revealed two changes in a heterozygote state: (Illumina Inc., San Diego, CA, USA) and by Illumina NeXTSeq 500 technolog
although not trained in immunology, con- in Europe and the United States. A road- In other clinical settings, maternal or fetal hypo- or hyperthy- associated with RSTH and pregnancy and that more data are
tributed significantly to the field of PID in Table 1. Genes that were first found in Israeli map was designed to resolve key molecular roidism has been associated with gestational and postnatal needed before management recommendations can be made. A
Israel. The first was Prof. Baruch Wolach, patients and genetic interactions as it was clear that complications [4], as demonstrated, for example, in a recent subsequent article reiterated this recommendation [6].
who finished his pediatric hematology fel- gene year of discovery A-T is a multisystem condition [14]. large Dutch cohort correlating high maternal TH levels during
lowship under the late Prof. Rina Zaizov and ATM 1995 In the summer of 1977, an Israeli gradu- pregnancy with higher incidence for low birth weights and SGA COnCluSIOnS
continued to study neutrophil function in the FUCTI 2000 ate student, Yosef Shiloh, was exploring newborns [18]. When both mother and fetus have the same We identified eight Israeli families with RTH-β, each with a
laboratory of Dr. Larry Boxer in the United FERMT3 2008 research options for his doctoral thesis. THRB mutation genotype, physiologically appropriate TH levels different THRB mutation. Clinical features were variable, even
States. After his return, he opened a labora- ORAI1 2009 He had just completed his MSc thesis in are predicted, leaving unexplained our observation of increased among affected family members. Our findings do not confirm
tory for leukocyte function at Meir Medical LRBA 2012 human genetics at the Hebrew University– incidence of SGA and poor postnatal growth in affected infants a previous report suggesting that a specific intronic genetic
Center in Kfar Saba and he dedicated his time Hadassah Medical Center. His mentor, of affected mothers. variant affects the clinical phenotype. Although, in general,
to study many neutrophil defects, mainly VPS45 2013 Prof. Maimon Cohen, invited Shiloh to Our findings appear to contradict those reported by Anselmo pregnancy outcomes in our cohort were good and without the
chronic granulomatous disease (CGD) [12]. TPPD 2015 visit an A-T family. Intrigued by the com- and co-authors [19], which described pregnancy outcomes in need for thyroid-related treatment, our findings also suggest
The second was Prof. Gidi Rechavi from STN1 2016 plexity of the syndrome and its devastating a large Azorean family with a known THRB gene mutation that mothers with RSTH may be at risk of gestational hyperten-
Sheba Medical Center, who also was trained LAT 2016 prognosis, Shiloh decided to focus on A-T. (p.Arg243Gln). Affected mothers (n=9) were compared to nor- sion and their infants may be at risk for SGA at birth and later
as a pediatric hemato-oncologist. Under his EFL1 2017 This decision was followed by research that mal mothers married to affected fathers (n=9), and unaffected poor weight gain regardless of fetal genotype.
leadership, the immunological pediatric unit DBR1 2018 Dr. Shiloh has continued to conduct [15]. first-degree relatives (n=18) served as controls. Affected mothers As with all rare diseases, no single study can be large enough
expanded and became a well-known labora- ZNF341 2018 Under the guidance of Prof. Yechiel were noted to have an increased obstetric risk, with threefold to to present conclusive, statistically validated results. More data
tory in the field. He published many articles Becker, Shiloh investigated the cellular fourfold increased chance for miscarriage, an observation sug- are needed to develop clear and well-supported recommenda-
in the field of PID, discovered several new of consanguinity. For example, while in the phenotype of A-T and concluded that cells gested by the authors as being due to relative intrauterine hyper- tions for treatment and follow-up of patients with THRB muta-
entities, and was involved with bone mar- rest of the Western world 70% of patient from A-T patients had a special difficulty thyroidism in unaffected fetuses. In addition, normal infants tions, particularly during pregnancy, which is an issue that is
row transplantation in patients with PID. with CGD have an X-linked inheritance, repairing specific types of DNA double- carried by affected mothers were significantly smaller for ges- addressed in only a small number of reports. This undertaking
Rechavi and his student Prof. Amos Toren in Israel the situation is just the opposite strand breaks (DSBs). The major question tational age and had undetectable serum levels of TSH at birth. could be accomplished by the formation of an international
were among the pioneers in the application and about 70% have an autosomal recessive at that time was identifying the culprit The differences between our findings and those of Anselmo’s consortium aimed at collecting and analyzing data from a large
of preimplantation genetic diagnosis (PGD) inheritance. Furthermore, our newborn gene. Positional cloning was just emerg- group might be explained by the fact that, by studying a single number of cases.
for the treatment of a patient with Fanconi screening for SCID showed that the inci- ing as a way to identify disease genes. The large family, Anselmo was able to better define disease-related
anemia by cord blood transplantation from dence of SCID in Israel is 2.5 times higher ATA locus was mapped to chromosome phenotypes by eliminating variances related to different muta- Acknowledgments
a sibling who was born after detailed single than in the rest of the world [13]. It is not 11q22-23 by Gatti and colleagues in 1988, tions and limiting environmental variation. However, we believe The authors thank Judith Furth-Lavi, Sharona Tornovsky-Babeay, and
cell genetic testing of very early embryos. surprising, therefore, that quite a few of and positional cloning efforts followed in this to be unlikely since our study population also included a Dr. Yaron Suissa for their technical help and advice; Ran Avrahami
for assistance with statistical analysis; and all of the patients and their
The pediatric hemato-oncology unit and the new genes associated with PID were many laboratories. In 1995, Shiloh was the large, extended family (family 7) that enabled comparison families who agreed to participate in this study
bone marrow transplantation department described for the first time in Israel. first to show that a single gene was solely between two nuclear families carrying the same mutation,
at Sheba Medical Center were also among responsible for A-T, and he designated it one maternally and the other paternally inherited [Figure 1B]. Correspondence
the pioneers in transplantation in patients ATAxIA TElAngIECTASIA ATM [16]. He subsequently published a As with our entire study population, no excess obstetric risk was Dr. B. glaser
with advanced CGD and in curing PID by Ataxia telangiectasia was first described in series of studies in the ATM protein, con- observed and only affected infants born to an affected mother Dept. Endocrinology and Metabolism, Hadassah–Hebrew University Medical
using cord blood transplantation without 1926 by two Czech neurologists: Syllaba comitantly with other labs. ATM turned appeared to have more gestational and neonatal complica- Center, Jerusalem 91120, Israel
phone: (972-2) 677-6788, fax: (972-2) 643-7940
conditioning. and Henner. They described three siblings out to be a homeostatic protein kinase tions than the other group (data not shown). The findings in email: ben.glaser@mail.huji.ac.il
The field of PID is flourishing in Israel, who presented with chorea atethosis and responsible for the cellular response to both our study and that of Anselmo must be interpreted with
with many medical centers caring for ocular telangiectasia. Another case was DNA DSBs and many other cellular cir- caution since in both clinical and genetic data is missing for a References
patients with various forms of PID. In the described by a Belgian pediatrician in cuits. The immune deficiency in A-T was relatively large percentage of individuals. Sarkissian et al. [20] 1. Dumitrescu AM, Refetoff S. The syndromes of reduced sensitivity to thyroid
last 10 years, more than 200 research papers 1941. In 1958, two American neurologists subsequently explained by a defect in V(D) also reported multiple miscarriages in a RTH-β affected female. hormone. Biochim Biophys Acta 2013; 1830: 3987-4003.
on PID have been published by pediatric described an extensive series of patients J and class-switch recombination – a result In contrast to the findings in these two reports, our findings 2. Jones I, Ng L, Liu H, Forest D. An intron control region differentially regulates
expression of thyroid hormone receptor β2 in the cochlea, pituitary, and cone
immunologist from Israel, and more than and provided a detailed account of the of the defective handling of DSBs in A-T are more consistent with previous studies that describe benign photoreceptors. Mol Endocrinol 2007; 21: 1108-19.
100 hematopoietic stem cell transplantation disease characteristics, including recur- patients [17]. outcomes of pregnancies involving THRB mutations, albeit 3. Alberobello AT, Congedo V, Liu H, et al. An intronic SNP in the thyroid hormone
have been performed. With the implemen- rent pulmonary infections, and named the frequently associated with some degree of intrauterine growth receptor β gene is associated with pituitary cell-specific over-expression of a
mutant thyroid hormone receptor β2 (R338W) in the index case of pituitary-
tation of newborn screening for all infants in disorder ataxia telangectasia (A-T). lEuKOCyTE ADHESIOn DEfICIEnCy II retardation [5,6]. selective resistance to thyroid hormone. J Transl Med 2011; 9: 144.
Israel, severe combined immunodeficiency Several years later, Dr. Robert Good In the early 1980s, leukocyte adhesion defi- Our findings are more consistent with studies in a mouse 4. Yazbeck CF, Sullivan SD Thyroid disorders during pregnancy. Med Clin North Am
(SCID) patients have had a successful rate of characterized the immunodeficiency ciency (LAD) was described as mutations model of RSTH described by Alonso and colleagues [21], who 2012; 96: 235-56.
transplantation [13]. associated with A-T, mainly low IgA and in the beta subunit of the Integrins, which observed no increased intrauterine mortality in any of the 5. Weiss RE, Dumitrescu A, Refetoff S. Approach to the patient with resistance to
thyroid hormone and pregnancy. J Clin Endocrinol Metab 2010; 95: 3094-102.
IgG with high IgM, absence of antibody leads to increased susceptibility to infec- groups and also demonstrated that pregnancies of mothers with 6. Jonas C, Daumerie C. Conservative management of pregnancy in patients with
gEnE fOunD fOR THE fIRST TIME In response to recall antigens, and impaired T tions, impaired wound healing, and marked THRB gene deletions result in low birth weights regardless of resistance to thyroid hormone associated with Hashimoto’s thyroiditis. Thyroid
ISRAElI pATIEnTS cell response. leukocytosis. Ten years later, a child was fetal genotype. 2014; 24: 1656-61.
Israel is a country with diverse popula- Due to the increased interest in A-T, admitted to our department at Rambam In their recent review of the topic, Weiss and co-authors [5] 7. Refetoff S, Bassett JHD, Beck-Peccoz P, et al. Classification and proposed
nomenclature for inherited defects of thyroid hormone action, cell transport, and
tions, some of which have a very high rate starting in 1980, workshops were conducted Medical Center with recurrent infections, concluded that there are insufficient data to determine the risk metabolism. Euro Thyroid J 2014; 3: 7-9.
704 685