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with normative data, silicone implants are associated with
resonance imaging surveillance was under 5%. Compared
PERFECTOR
silicone for primary augmentation. Long-term magnetic
data included 99,993 patients, 56% of implants were
and operative indication in the short and long terms. LPAS
related complications were analyzed by implant composition
outcomes were compared with normative data. Implant-
reconstruction. Systemic harms, self-harm, and reproductive
and Mentor) placed for primary/revision augmentation/
silicone/saline implants from two manufacturers (Allergan
long-term implant-related outcomes and systemic harms for
postapproval studies (LPAS) prospectively have monitored
efficacy outcomes of patients with breast implants. Long
Coroneos and co-authors analyzed the long-term safety and
long-term outcomes of silicone breast implants
Capsule
pancreatic tumors sampled. Ablating DKK3, either by genetic
stellate cells. This protein was present in the majority of human
therapeutic target called DKK3, which is produced by pancreatic
themselves rather than the stroma. zhou et al. identified a
as for its dense stroma. Most therapies target the tumor cells
Pancreatic cancer is infamous for its bad prognosis as well
Killing tumors by targeting their neighbors
Capsule
Nature 2009; 461: 199-205.
16. Visel A, Rubin EM, Pennacchio LA. Genomic views of distant-acting enhancers.
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15. Hassan AQ, Koh JT. A functionally orthogonal ligand-receptor pair created by
release and negative transcriptional regulation. Mol Endocrinol 1998; 12: 609-21.
in resistance to thyroid hormone syndrome predominantly impairs corepressor
14. Clifton-Bligh RJ, de Zegher F, Wagner RL, et al. A novel TR beta mutation (R383H)
of thyroid hormone treatment. Eur J Endocrinol 2011; 165: 823-30.
deletion in the monocarboxylate transporter 8 gene: 7-year follow-up and effects
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13. Zung A, Visser TJ, Uitterlinden AG, Rivadeneira F, Friesema EC. A child with a
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hormone receptor gene in an Israeli child. Thyroid 2003; 13: 409-12.
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12. Ishay A, Dumitrescu A, Luboshitzky R, Rakover Y, Refetoff S. A new case of
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KEY WORDS:
inappropriate thyrotropin secretion successfully treated with triiodothyronine.
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separate subtypes of resistance. J Clin Endocrinol Metab 1995; 80: 3613-6.
hormone: two mutations of the same codon (H435L and H435Q) produce
hormone receptor beta gene in unrelated patients with resistance to thyroid
9. Tsukaguchi H, Yoshimasa Y, Fujimoto K, et al. Three novel mutations of thyroid
in the live-born population in Israel. IMAJ 2005; 7: 311-4.
8. Dollberg S, Haklai Z, Mimouni FB, Gorfein I, Gordon ES. Birth weight standards
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EDITORIALS
Case CommuniCations The list cannot be completed without In the early 1980s, four young pedia- The third prominent physician in the mentioning two other pediatricians who, cyte adhesion deficiency syndromes [11]. focus was mainly on new forms of leuko- for PID in Israel was created. His research Jeffery Modell Foundation (JMF) center Healthcare Campus in Haifa, where the first group is Prof. Amos Etzioni from Rambam disorders there [10]. The
the pregnancy. The patient began propyl- according to their ligand binding capacity, on interventions during gestation [1]. Clinical and Molecular Characteristics of Eight Israeli
thiouracil treatment while waiting for the but the clinical severity of the syndrome is The appropriate management of pregnant
results from the amniocentesis. The patient’s not necessarily correlated with the degree women with RTH is ideally based on the families with Thyroid Hormone Receptor Beta Mutations
thyroid function tests during the pregnancy of functional impairment of the receptors. prenatal identification of the fetal genotype
and data on propylthiouracil treatment are Moreover, significant differences in clinical and on maternal thyroid function tests. Eliyahu Zaig MD *, Odile Cohen-Ouaknine MD , Anat Tsur MD , Sheila Nagar MD , Gherta Bril MD , Lior Tolkin MD ,
2
2
2
4
3
1
shown in Table 1. symptoms are observed in patients harbor- Several situations may be encountered Avivit Cahn MD , Mozhgan Heyman and Benjamin Glaser MD 1
1
1
The fetus was found to be unaffected. ing the same mutation [2]. in pregnant women with RTH. In a first
Fetal development and well-being was A characteristic feature of the syndrome scenario, both the mother and the fetus 1 2 Departments of Endocrinology and Metabolism and of Internal Medicine, Hebrew University–Hadassah Medical School, Jerusalem, Israel
assessed by prenatal ultrasound per- is the preservation of the TSH response harbor the same mutation. In this case, the 3 Endocrinology Unit, Clalit Health Services, Jerusalem, Israel
Clalit Health Services, Tel Aviv, Israel
formed at weeks 15, 23, 30, and 37. to TRH despite elevated TH levels. In fetus is resistant to TH and tolerates the 4 Department of Internal Medicine and Endocrine Unit, Shaare Zedek Medical Center, Jerusalem, Israel
Cardiotocography for fetal heart rate this respect, it is notable that our patient high maternal TH levels. No treatment is
assessment, performed at weeks 32 and 37, underwent a TRH test twice. The first test recommended during pregnancy.
revealed normal heart rate with moderate was under propylthiouracil treatment and In a second scenario, a normal mother
variability. Fetal thyroid ultrasound was per- the results showed an exaggerated response is carrying an affected fetus. Surprisingly,
formed at week 34 and revealed a normal of TSH, whereas the second time was with- in this situation no increased rates of mis- educed sensitivity to thyroid hormone (RSTH) syndrome is
thyroid size according to the pregnancy age. out propylthiouracil treatment and the carriage or birth complications have been ABSTRACT: Background: Reduced sensitivity to thyroid hormone (RSTH) R a heterogeneous group of defects characterized by impaired
A healthy male infant was born at term. results showed a very flat TSH slope with observed. Such neonates, born to normal syndrome describes a group of rare heterogeneous genetic biological activity of intact thyroid hormones (THs). To date,
His birth weight was 2930 g. Physical maximum TSH 6 mIU/L after 15 minutes. mothers and affected fathers, do not show disorders. Precise diagnosis is essential to avoid unnecessary three distinct clinical syndromes have been identified, each
examination revealed a normal size ante- In healthy euthyroid subjects, the mini- symptoms of TH deprivation or elevations treatment. associated with defects in a different molecular process. The
rior fontanelle, a symmetric head, normal mum peak TSH following a TRH test is 5 of TSH. Objectives: To identify and characterize patients previously most common syndrome is resistance to thyroid hormone
skin color, and normal heart examination. mIU/L, whereas the maximum peak ranges In a third scenario, the RTH mother undiagnosed with RSTH in Israel. (RTH), which is attributed to mutations in the thyroid receptor-
Cord blood TSH concentration was 4.65 between 17.2 and 19.5 mIU/L. has undergone previous ablative therapy Methods: Patients with suspected RSTH throughout Israel were beta (RTH-β) gene. The syndrome is characterized by decreased
IU/ml (normal for reference range). The We speculate that the results of the TRH (radioiodine, surgery) or is affected by referred for study. After clinical evaluation, genomic DNA was sensitivity of target tissues to TH action, leading to elevated TH
neonate did well without jaundice and was test in our patient were probably related to Hashimoto’s thyroiditis. In this situation, obtained and all coding exons of the thyroid hormone receptor levels, accompanied by normal or high thyroid-stimulating
discharged on postpartum day 3. a recent propylthiouracil treatment that she the outcomes (birth weight, TSH at birth) beta (THRB) gene were sequenced. If mutations were found, hormone (TSH) values, with variable clinical manifestations [1].
had received, which caused some degree of are normal, whether the fetus harbors the all available blood relatives were evaluated. The common The molecular mechanism responsible for the clinical het-
polymorphism rs2596623, a putative intronic regulatory
hypothyroidism. mutation or not. In this case, it is suggested erogeneity seen in RTH-β is unknown, but genetic or yet-to-
COMMEnT Due to a lack of prospective studies on to maintain FT4 levels within a maximum variant, was also genotyped. Genotype/phenotype correlations be-discovered environmental factors modifying the mutant/
RTH is a rare disorder characterized by pregnant subjects with RTH, there are no of 20% above the upper limit of normal were sought, and the effect of mutation status on pregnancy normal allele expression ratio in various target tissues may be
outcome was determined.
reduced end-organ responsiveness to definite recommendations for the man- (ULN) [3]. Results: Eight mutations (one novel, two de-novo, six dominant) responsible. One possible mechanism could be related to the
TSH. The prevalence of the condition is agement of pregnancy in women with this A fourth scenario is illustrated by the were identified in eight probands and 13 family members. general observation that genes that are specifically expressed
1:40,000 live births and is equal in both condition. It is also unlikely that such stud- case we report here. In this situation, a Clinical and genetic features were similar to those reported in different tissues may use alternative regulatory regions to
genders [1]. The inheritance is autosomal ies would be performed because this con- normal fetus is carried by a woman with in other populations. Previous suggestions that rs2596623 fine-tune tissue-specific expression. Cis-regulatory non-coding
dominant. Autosomal recessive transmis- dition is very uncommon and is often not RTH. Consequently, the fetus is exposed predicts clinical features were not confirmed. There was no variants can reduce or increase allele-specific transcription in
sion has been found in approximately 10% diagnosed before pregnancy, as the patients to incongruent high maternal TH levels, evidence of increased risk of miscarriage or fetal viability. a particular cell type, modifying disease risk or phenotype and
of families; 15% of subjects with RTH have are usually clinically euthyroid with normal while the mother remains clinically euthy- Mothers carrying a THRB mutation tended to have increased thus contributing to the diversity in human genetic diseases.
no detectable mutation in the TRβ gene [2]. TSH levels. There are sparse published data roid. gestational hypertension and low weight gain during The thyroid hormone receptor beta (THRB) gene has two iso-
Different mutations in the TRβ gene have on the course and outcome of pregnancy in A study of a large Azorean family har- pregnancy. Their affected offspring had increased risk of small- forms, THRB1, which is widely distributed, and THRB2, which
varying effects on the receptor function women with RTH and even fewer reports boring the R243Q TRβ gene mutation found for-gestational age and poor postnatal weight gain. is limited to the cochlea, retina, and pituitary gland. These two
that affected pregnant women carrying unaf- Conclusions: Clinical heterogeneity due to THRB mutations splice variants differ in their amino-terminal ends, but both
Table 1. Thyroid function tests and treatment during pregnancy fected fetuses had a threefold to fourfold cannot be explained by the variant rs2596623. Mothers and include the same functional ligand-binding domain in the
Date weeks of pregnancy TSH (Iu/ml) fT4 (pmol/l) fT3 (pmol/l) pTu treatment higher miscarriage rate [1]. In addition, the newborns with THRB mutations seem to be at increased risk carboxyl-terminal region, where most of the disease-causing
20/10/2014 0 0.58 43.3 – None unaffected infants born to RTH mothers for certain complications, such as gestational hypertension mutations that have been identified to date are located [1].
26/02/2015 13 0.03 54 19 None had significantly lower birth weight com- and poor intrauterine and postnatal growth. However, these Previous in vitro studies using pituitary cell lines defined a basal
25/03/2015 17 0.2 29.9 – 150 mg pared to infants with RTH. Their postnatal issues are usually mild, suggesting that routine intervention promoter region in the THRB2 isoform. While assessing the
TSH level was suppressed in all cases. This to regulate thyroid hormone levels may not be warranted in promoter’s function in vivo, Jones and co-workers [2] identified
21/04/2015 20 0.17 36.2 9.2 450 mg these patients.
situation indicates that the normal fetuses a conserved 600 base-pair intronic region that appears to act
20/05/2015 25 0.26 31.5 8.8 450 mg
were exposed to high maternal TH levels, IMAJ 2018; 20: 679–686 as an enhancer, modifying expression of the THRB2 isoform in
25/06/2015 30 0.7 28.9 9.1 450 mg inappropriate to their genotype, and devel- KEY WORDS: genetic disease of the thyroid, monogenic thyroid disease, pituitary and retinal cells. Alberobello and colleagues [3] pro-
23/07/2015 34 1.01 32 – 450 mg thyroid hormone receptor, thyroid hormone receptor beta
oped fetal hyperthyroidism. Moreover, in a
16/08/2015 37 1.36 28.5 7.8 450 mg recent study, intrauterine exposure to high (THRB) mutations, thyroid hormone resistance *The study was performed in fulfillment of the research requirements
FT3 = free triiodothyronine, FT4 = free thyroxine, PTU = propylthyouracil, TSH = thyroid stimulating hormone TH levels was shown to cause persistent toward an MD degree at the Hebrew University–Hadassah School of
Medicine, Jerusalem, Israel
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