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tions, some of which have a very high rate
Israel is a country with diverse popula-
In their recent review of the topic, Weiss and co-authors [5]
ISRAElI pATIEnTS
gEnE fOunD fOR THE fIRST TIME In
transplantation [13].
(SCID) patients have had a successful rate of
Israel, severe combined immunodeficiency
Our findings are more consistent with studies in a mouse
tation of newborn screening for all infants in
have been performed. With the implemen-
100 hematopoietic stem cell transplantation
immunologist from Israel, and more than
on PID have been published by pediatric
last 10 years, more than 200 research papers
patients with various forms of PID. In the
with many medical centers caring for
The field of PID is flourishing in Israel,
conditioning.
using cord blood transplantation without
with advanced CGD and in curing PID by
the pioneers in transplantation in patients
at Sheba Medical Center were also among
bone marrow transplantation department
The pediatric hemato-oncology unit and
cell genetic testing of very early embryos.
a sibling who was born after detailed single
anemia by cord blood transplantation from
for the treatment of a patient with Fanconi
of preimplantation genetic diagnosis (PGD)
were among the pioneers in the application
Rechavi and his student Prof. Amos Toren
row transplantation in patients with PID.
entities, and was involved with bone mar-
in the field of PID, discovered several new
tory in the field. He published many articles
expanded and became a well-known labora-
leadership, the immunological pediatric unit
as a pediatric hemato-oncologist. Under his
Sheba Medical Center, who also was trained
The second was Prof. Gidi Rechavi from
chronic granulomatous disease (CGD) [12].
Our findings appear to contradict those reported by Anselmo
to study many neutrophil defects, mainly
Center in Kfar Saba and he dedicated his time
tory for leukocyte function at Meir Medical
States. After his return, he opened a labora-
laboratory of Dr. Larry Boxer in the United
continued to study neutrophil function in the
lowship under the late Prof. Rina Zaizov and
who finished his pediatric hematology fel-
Israel. The first was Prof. Baruch Wolach,
tributed significantly to the field of PID in
although not trained in immunology, con-
Original articles Original articles metabolism. Euro Thyroid J 2014; 3: 7-9. nomenclature for inherited defects of thyroid hormone action, cell transport, and 2014; 24: 1656-61. resistance to thyroid hormone associated with Hashimoto’s thyroiditis. Thyroid thyroid hormone and pregnancy. J Clin Endocrinol Metab 2010; 95: 3094-102. 2012; 96: 235-56. selective resistance to thyroid hormone. J Transl Med 2011; 9: 144. mutant thyroid hormone receptor β2 (R338W) in
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vided evidence to support their hypothesis that polymorphisms cedure. The Hadassah Medical Center ethics review committee Treatment of Resistance to Thyroid Hormone in
in this intronic enhancer region (ICR) could modulate pituitary approved the study.
expression of the mutated THRB allele, thus affecting clinical Pregnancy: How to Address the Challenge
presentation. lABORATORy STuDIES
Abnormal thyroid function is known to have deleterious Peripheral blood samples were obtained for DNA extraction Elena Chertok Shacham MD , Elena Chervinsky and Avraham Ishay MD 2
1,2
3
effects when present in either the mother or the fetus [4]. In and hormone determination. At the time of recruitment, hor-
2
3
early gestation, the fetus is solely dependent on transplacental monal data were supplemented by results obtained from patient 1 Department of Internal Medicine E, Endocrinology and Diabetes Unit, and Genetic Institute, Emek Medical Center, Afula, Israel
delivery of maternal thyroid hormones, which play an impor- medical records. In all cases, hormone levels were evaluated
tant role in normal fetal development, particularly of the central by fully certified automated assays. Whenever possible, free T3
nervous system. Hence, in a family carrying a THRB mutation, (FT3), free T4 (FT4), and TSH levels were verified at the clini-
mismatch in maternal and fetal mutation status could have a cal laboratory of Hadassah Medical Center using the ADVIA Clinical data has shown that fetal expo- 80–180), and TSH 0.78 mU/l (normal range,
negative impact on fetal growth and pregnancy outcome since Centaur system (Siemens Healthcare, Bayswater, Australia), KEY WORDS: pituitary thyroid hormone resistance, sure to high maternal TH levels during 0.2–3.8). A radioactive iodine uptake test
an affected (i.e., THRB mutation carrier) fetus of an unaffected catalogue numbers 03154228, 06490106, and 06491080 pregnancy, resistance to thyroid pregnancy may cause fetal thyrotoxicosis, with I131 revealed a high uptake (42% and
mother could be exposed to relatively insufficient TH levels, respectively. If plasma was not available at time of testing, the hormone (RTH), thyroid hormone low birth weight, and fetal loss. It may also 84% at 2 and 24 hours, respectively). Graves’
whereas a normal fetus of an affected mother could be exposed last available values were recorded from the medical records. receptor β gene (TRβ; OMIM 190160) cause transient hypothyroidism in neonates disease was suspected, and she was treated
to TH excess. Data addressing the particular issue of THRB Because of the high prevalence of autoimmune thyroid disease IMAJ 2018; 20: 709–711 due to overtreatment with anti-thyroid with propylthiouracil. Despite the treatment,
mutations and pregnancy outcome are sparse and further in RTH-β, thyroid autoantibodies were not measured and their drugs and fetal TSH suppression during FT4 and FT3 levels remained high and TSH
studies are needed to determine the clinical impact of fetal and presence on previous tests was not an exclusion criteria. pregnancy. Thus, it is important to deter- levels increased. Thyroid stimulating immu-
maternal mutation status [5,6]. Genomic DNA was extracted from peripheral blood leuko- mine the fetal genotype and to treat a preg- noglobulin was normal and thyroperoxidase
The primary goal of our study was to identify additional cytes using the Flexi-Gene DNA Extraction Kit (Qiagen, Germany, esistance to thyroid hormone (RTH) nant woman who has an RTH mutation if and thyroglobulin antibodies were negative.
families with RSTH in Israel, particularly those with RTH-β, catalog number 51206). In infants, buccal swabs were used (DNA R is a syndrome characterized by she is carrying an unaffected fetuses. In the A computed tomography (CT) scan of the
which is the most common subtype of RSTH, with more than Genotek Inc., Canada, catalog number YGT50). All seven THRB reduced target organ responsiveness to same way, prenatal fetal genotyping will pituitary did not reveal any abnormalities.
2400 patients identified to date [7]. Secondary goals were to coding exons (exons 4–10, NG_009159.1, ENST00000356447) thyroid hormones. In a majority of cases, reveal fetuses affected with the mutation. In A thyrotropin releasing hormone (TRH)
determine whether a common variant in the ICR could explain were Sanger sequenced (primer sequences available on request) RTH is caused by mutations in the thy- such circumstances, if the fetus is resistant stimulation test was performed under
the observed heterogeneity in RTH-β clinical symptoms and to in one clinically affected individual per family (proband). Each roid hormone receptor beta gene (TRβ; to TH, no treatment is recommended. propylthiouracil treatment and revealed an
evaluate the outcomes of pregnancies in families with THRB identified variant was evaluated using the NCBI dbSNP, 1000 OMIM 190160). The disorder is char- exaggerated TSH elevation: 36 µIU/ml at 0
mutations. Genomes and Human Gene Mutation Database (HGMD). We acterized by high serum concentrations minutes to 156.8 µIU/ml after 30 minutes.
Our study comprised 21 patients from eight different fami- reviewed the literature to determine the strength of evidence sup- of free thyroxine (FT4) and usually free pATIEnT DESCRIpTIOn Based on the patient’s clinical picture, her 131118-COHANIM - 131118-COHANIM | 3 - B | 18-11-13 | 11:24:13 | SR:-- | Magenta
lies harboring eight different THRB mutations, one of them porting causality for each identified mutation. Family members triiodothyronine (FT3), and is accompa- The proposita was a 28 year old female thyroid test results, and the normal pituitary 131118-COHANIM - 131118-COHANIM | 3 - B | 18-11-13 | 11:24:13 | SR:-- | Yellow #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
novel (p.His435Arg). We discuss the impact of a specific ICR were genotyped by sequencing the relevant exon. nied by normal or slightly elevated serum who was initially seen in the endocrinol- imaging on the CT, a diagnosis of RTH was
variant on the RTH-β clinical phenotype and the effects of In all patients who tested positive for an established THRB thyroid-stimulating hormone (TSH) con- ogy clinic for goiter, tachycardia, and poor suspected.
THRB mutation status on pregnancy outcome. mutation, the 600 base-pair intronic control region (ICR), centrations [1]. Most patients with RTH weight gain when she was 8 years old. At Sequencing analysis of four exons (7–10)
previously reported to regulate allele-specific THRB2 expres- are clinically asymptomatic, but some the first visit, her weight was 20 kg (10th of the TRβ gene identified a heterozygous
sion in the pituitary, was also sequenced [2]. A common single show signs of elevated thyroid hormone percentile) and her height was at the 25th mutation, 10 c.1357C>A; p.P453T, in exon
PATIENTS AND METHODS nucleotide polymorphism (SNP) in this region, rs2596623, (TH) levels, such as goiter and tachycar- percentile. She was a student in first grade 10. There was no evidence for this mutation
pATIEnT RECRuITMEnT has been implicated as a cis-acting, allele-specific modifier of dia. Some patients may exhibit hypo- with fair performance at school. Her physi- in nine other family members. The patient
Between August 2011 and May 2013, endocrinologists through- pituitary expression, thus potentially influencing the clinical thyroid symptoms, such as poor growth cal examination was insignificant except continued to be monitored in our endocri-
out Israel were asked to refer patients suspected of having RSTH. phenotype [3]. In probands who were heterozygous for both and slow weight gain, or have a mixture for congenital nystagmus and bilateral nology clinic without treatment.
Thirteen endocrinologists responded and referred potential a THRB mutation and for this variant, we genotyped parents of hypo- and hyperthyroidism features. sensorineural hearing loss. Mild learning At the age of 27 the patient married
participants: eight from Jerusalem, three from Tel Aviv, and (if available) and children for both. Haplotype was determined Additional symptoms include attention disabilities were reported as well. A prod- and successfully conceived. She underwent
one each from northern and southern areas of Israel. Prior to assuming complete linkage disequilibrium between the muta- deficit, hyperactivity, and learning dis- uct of a consanguineous marriage of first- genetic counseling to estimate the recur-
inclusion in the study, clinical history and medical record of tion and the variant. Clinical characteristics of individuals in abilities. Typically, anti-thyroid treat- degree cousins, she was born at term after rence risk of RTH syndrome and to clarify
each candidate was re-evaluated by the study team (EZ, BG). whom the mutation and the rs2596623 variant co-segregated ment is unnecessary; however, treatment an uneventful pregnancy. Her family was of the genetic status of her fetus. Sequencing
Only those patients with results consistent with the diagnosis on the same allele were compared with those in whom the for RTH in patients during pregnancy Jewish Caucasian descent that had immi- analysis of the TRβ gene was performed
of RSTH (namely, persistent inappropriately elevated free-T4 mutation and the variant were located on different alleles. remains challenging and is based on fetal grated to Israel from Dagestan in 1995. by Illumina NeXTSeq 500 technology
levels with non-suppressed TSH) were invited for further assess- genotype [1]. Her two brothers were healthy. The family (Illumina Inc., San Diego, CA, USA) and
ment. At the time of recruitment, after written informed consent pREgnAnCy, lABOR, AnD THE InfAnT’S fIRST MOnTHS Of lIfE We present the case of a young woman history was otherwise unremarkable. revealed two changes in a heterozygote state:
was obtained, physical examination was performed and blood A telephone questionnaire addressing key issues related to preg- who was diagnosed with RTH in childhood The patient had a diffusely enlarged the already known c.1357C>A; p.P453T
samples were taken. THRB mutation analysis was performed nancy and perinatal outcomes was designed and administered and followed in our clinic. Genetic testing thyroid gland, no tremor, and no exoph- in exon 10 as well as a variant, c.735C>T;
on patients who presented with THs levels consistent with the to all mothers recruited to the project. Given the limitations of amniotic fluid performed while she was thalmos. Her thyroid function tests on the p.F245F, in exon 7, which was also found in
diagnosis of RTH-β. After a mutation was identified, all available associated with retrospective data collection primarily based on pregnant demonstrated that her fetus did first visit were: FT4 4.85 ng/dl (normal her mother. Fetal genotyping was obtained PERFECTOR
blood relatives were recruited and evaluated using the same pro- maternal recall, all questions were designed to maximize reli- not carry the maternal mutant gene. range 0.6–1.8), FT3 343 ng/dl (normal range by amniocentesis performed at week 16 of
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