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FT3 = free triiodothyronine, FT4 = free thyroxine, PTU = propylthyouracil, TSH = thyroid stimulating hormone
KEY WORDS:
Table 1. Thyroid function tests and treatment during pregnancy
varying effects on the receptor function
Different mutations in the TRβ gene have
no detectable mutation in the TRβ gene [2].
of families; 15% of subjects with RTH have
sion has been found in approximately 10%
dominant. Autosomal recessive transmis-
genders [1]. The inheritance is autosomal
1:40,000 live births and is equal in both
TSH. The prevalence of the condition is
reduced end-organ responsiveness to
RTH is a rare disorder characterized by
COMMEnT
discharged on postpartum day 3.
neonate did well without jaundice and was
IU/ml (normal for reference range). The
Cord blood TSH concentration was 4.65
skin color, and normal heart examination.
rior fontanelle, a symmetric head, normal
examination revealed a normal size ante-
His birth weight was 2930 g. Physical
thyroid size according to the pregnancy age.
ABSTRACT:
formed at week 34 and revealed a normal
variability. Fetal thyroid ultrasound was per-
revealed normal heart rate with moderate
assessment, performed at weeks 32 and 37,
Cardiotocography for fetal heart rate
formed at weeks 15, 23, 30, and 37.
assessed by prenatal ultrasound per-
Fetal development and well-being was
shown in Table 1.
4
and data on propylthiouracil treatment are
thyroid function tests during the pregnancy
results from the amniocentesis. The patient’s
thiouracil treatment while waiting for the
the pregnancy. The patient began propyl-
Original articles Original articles 3 2 educed sensitivity to thyroid hormone (RSTH) syndrome is Medicine, Jerusalem, Israel toward an MD degree at the Hebrew University–Hadassah School of *The study was performed in fulfillment of the research requirements The thyroid hormone receptor beta (THRB) gene has two iso- The molecular mechanism responsible for the clinical het- pituitary and retinal cells. Alberobello and colleagues [3] pro- as an enhance
#
8. Dollberg S, Haklai Z, Mimouni FB, Gorfein I, Gordon ES. Birth weight standards 17. Ventura SJ, Curtin SC, Abma JC, et al. Estimated pregnancy rates and rates of primary Immunodeficiency: The Israeli Connection
in the live-born population in Israel. IMAJ 2005; 7: 311-4. pregnancy outcomes for the United States, 1990-2008. Natl Vital Stat Rep 2012;
60: 1-21.
9. Tsukaguchi H, Yoshimasa Y, Fujimoto K, et al. Three novel mutations of thyroid Amos Etzioni MD
hormone receptor beta gene in unrelated patients with resistance to thyroid 18. Medici M, Timmermans S, Visser W, et al. Maternal thyroid hormone parameters
hormone: two mutations of the same codon (H435L and H435Q) produce during early pregnancy and birth weight: the Generation R Study. J Clin Endocrinol
separate subtypes of resistance. J Clin Endocrinol Metab 1995; 80: 3613-6. Metab 2013; 98: 59-66. Ruth Children’s Hospital, Rambam Healthcare Campus, affiliated with Rappaport Faculty of Medicine, Technion–Institute of Technology, Haifa, Israel
10. Shin JY, Ki C-S, Kim JK. Identification of a de novo mutation (H435Y) in the 19. Anselmo J, Cao D, Karrison T, et al. Fetal loss associated with excess thyroid
THRB gene in a Korean patient with resistance to thyroid hormone. Korean J hormone exposure. JAMA 2004; 292: 691-5.
Pediatr 2007; 50: 576-9. 20. Sarkissian G, Dace A, Mesmacque A, et al. A novel resistance to thyroid hormone
11. Rosler A, Litvin Y, Hage C, Gross J, Cerasi E. Familial hyperthyroidism due to associated with a new mutation (T329N) in the thyroid hormone receptor beta
inappropriate thyrotropin secretion successfully treated with triiodothyronine. gene. Thyroid 1999; 9: 165-71. After earning a medical degree in South after several weeks the transplant was
J Clin Endocrinol Metab 1982; 54: 76-82. 21. Alonso M, Goodwin C, Liao X, et al. Effects of maternal levels of thyroid hormone KEY WORDS: immunodeficiency, Israel, pediatrics, Africa, he arrived in Israel on the day of the rejected (personal communication).
(TH) on the hypothalamus-pituitary-thyroid set point: studies in TH receptor beta
12. Ishay A, Dumitrescu A, Luboshitzky R, Rakover Y, Refetoff S. A new case of knockout mice. Endocrinology 2007; 148: 5305-12. primary immunodeficiency (PID) declaration of the State of Israel – 14 May The third prominent physician in the
resistance to thyroid hormone caused by a de novo P453T mutation in the thyroid IMAJ 2018; 20: 703–706 1948. He was sent directly to the frontline group is Prof. Jastin Passwell. Like Prof.
hormone receptor gene in an Israeli child. Thyroid 2003; 13: 409-12. 22. Adams M, Matthews C, Collingwood TN, Tone Y, Beck-Peccoz P, Chatterjee KK.
Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid and opened a field hospital in Gedera in the Levine, he finished his medical training
13. Zung A, Visser TJ, Uitterlinden AG, Rivadeneira F, Friesema EC. A child with a hormone. Identification of thirteen novel mutations in the thyroid hormone
deletion in the monocarboxylate transporter 8 gene: 7-year follow-up and effects receptor beta gene. J Clin Invest 1994; 94: 506-15. Negev. After the war, he moved to Tiberius in South Africa and immigrated to Israel
of thyroid hormone treatment. Eur J Endocrinol 2011; 165: 823-30. 23. Grace MB, Buzard GS, Weintraub BD. Allele-specific associated polymorphism and headed the department of pediatrics. during the early 1970s. Later, he attended
14. Clifton-Bligh RJ, de Zegher F, Wagner RL, et al. A novel TR beta mutation (R383H) analysis: novel modification of SSCP for mutation detection in heterozygous alleles he field of primary immunodeficiency In 1956, he was sent to study pediatric Harvard University, USA, and completed a
in resistance to thyroid hormone syndrome predominantly impairs corepressor using the paradigm of resistance to thyroid hormone. Hum Mutat 1995; 6: 232-42. T (PID) is quite young in medicine. Until immunology at Johns Hopkins University fellowship in pediatric immunology under
release and negative transcriptional regulation. Mol Endocrinol 1998; 12: 609-21.
24. Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: the early 1950s there were no treatment in Baltimore, MD, USA. When he returned, the mentorship of Dr. Fred Rosen and Dr.
15. Hassan AQ, Koh JT. A functionally orthogonal ligand-receptor pair created by genetic defects in hormone receptors, cell transporters and deiodination. Best
targeting the allosteric mechanism of the thyroid hormone receptor. J Am Chem Pract Res Clin Endocrinol Metab 2007; 21: 277-305. options for patients with immunodefi- he became the director of pediatrics at Harvey Colten, two well-known research-
Soc 2006; 128: 8868-74. ciency and no laboratory techniques were Kaplan Hospital in Rehovot and started his ers in the field. After returning to Sheba
25. Fleming S, Thompson M, Stevens R, et al. Normal ranges of heart rate and
16. Visel A, Rubin EM, Pennacchio LA. Genomic views of distant-acting enhancers. respiratory rate in children from birth to 18 years of age: a systematic review of in use. With the invention of protein- research on ataxia telangiectasia and Down Medical Center, he established a pediatric
Nature 2009; 461: 199-205. observational studies. Lancet 2011; 377: 1011-8.
electrophoresis technology, the first case syndrome. He was able to show the cellular immunology research laboratory. He was
of agammaglobulinemia was described in immune defects in these two syndromes by interested in complement defects [6] and
Capsule 1952. Since then, the field has increased applying new techniques that he learned in chronic granulomatous disease, and per-
dramatically and the first cases of success- the United States [2,3]. formed the first bone marrow transplanta-
Killing tumors by targeting their neighbors ful bone marrow transplantation, and later Prof. Zeev Hadzel, who replaced Prof. tion for this condition in Israel. He then
Pancreatic cancer is infamous for its bad prognosis as well means or with a monoclonal antibody, provided a potentially gene therapy, were made in patients with Levine at the pediatric immunology unit attempted to develop a new vaccine against
as for its dense stroma. Most therapies target the tumor cells effective treatment. Antibody treatment reduced tumor growth PID. Currently, more than 350 different at Kaplan Hospital, belongs to the second dysentery [7], research he continued until 131118-COHANIM - 131118-COHANIM | 3 - A | 18-11-13 | 11:24:13 | SR:-- | Magenta 131118-COHANIM - 131118-COHANIM | 3 - A | 18-11-13 | 11:24:13 | SR:-- | Yellow
themselves rather than the stroma. zhou et al. identified a and extended survival in mouse models, especially when genes have been found to be defective in generation of pediatric immunologists in his death at the age of 63 years. #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:-- | Cyan
therapeutic target called DKK3, which is produced by pancreatic combined with an immune checkpoint inhibitor. cases of immune deficiency and the list Israel. He continued to research Down In the early 1980s, four young pedia-
stellate cells. This protein was present in the majority of human Sci Transl Med 2018; 10: eaat3487 increases every month [1]. syndrome and studied the effect of thymic tricians (all retired by now) created the
pancreatic tumors sampled. Ablating DKK3, either by genetic Eitan Israeli In Israel, in the first years after its inde- humoral factor in various forms of PID third generation. Prof. Benzi Garti was at
pendence, there was no interest in immuno- [4]. Later, he devoted most of his time to Schneider Children’s Medical Center and
deficiency. The founder of the field in Israel studying the first cases of human immu- devoted his time to the study of PID and
Capsule was the late Prof. Stanley Levine [Figure 1]. nodeficiency virus (HIV) in Israel, together the immune defects in glycogen storage
with Prof. Zvi Bentwitz [5]. disease [8]. Prof. Yacov Levi went to Soroka
long-term outcomes of silicone breast implants Two other prominent researchers con- Medical Center in Beer Sheba and wrote a
figure 1. Prof. Levine and his wife at their
Coroneos and co-authors analyzed the long-term safety and higher rates of Sjögren syndrome (standardized incidence wedding in 1948 cluded the second generation of pediatric seminal paper on hyper IgM syndrome
efficacy outcomes of patients with breast implants. Long ratio [SIR] 8.14), scleroderma (SIR 7.00), rheumatoid arthritis immunologists in Israel. The first, Prof. Zvi [9]. He headed the immunological clinic
postapproval studies (LPAS) prospectively have monitored (SIR 0.96), stillbirth (SIR 4.50), and melanoma (SIR 3.71). Spirer, began his research in the early 1970s. for many years. Prof. Menachem Slezinger
long-term implant-related outcomes and systemic harms for One case of BI-ALCL was reported. There was no association He was interested in studying infectious established the immunology service at
silicone/saline implants from two manufacturers (Allergan with suicide. In the short term, rupture was higher for saline agents. Already in the late 1960s he was tak- Barzilai Medical Center in Ashkelon and
and Mentor) placed for primary/revision augmentation/ (2.5% vs. 0.5%, P < 0.001), and capsular contracture was ing care of patients with severe combined headed the Israeli center for complement
reconstruction. Systemic harms, self-harm, and reproductive higher for silicone (5.0% vs. 2.8%, P < 0.001). At 7 years, immunodeficiency and hypogammaglobu- disorders there [10]. The last one in the
outcomes were compared with normative data. Implant- reoperation rate was 11.7% for primary augmentation, and linemia, and he treated the country’s first group is Prof. Amos Etzioni from Rambam
related complications were analyzed by implant composition 25% for primary/revision reconstruction. Capsular contracture case of bare lymphocyte syndrome. Later Healthcare Campus in Haifa, where the first
and operative indication in the short and long terms. LPAS (III/IV) occurred in 7.2% of primary augmentations and 12.7% he focused his interest on phagocytosis Jeffery Modell Foundation (JMF) center
data included 99,993 patients, 56% of implants were primary reconstructions, and is the most common reason for and chemotaxis and the importance of the for PID in Israel was created. His research
silicone for primary augmentation. Long-term magnetic reoperation among augmentations. spleen, as well as the tuffsin hormone, for focus was mainly on new forms of leuko-
resonance imaging surveillance was under 5%. Compared Ann Surg doi 10.1097/SLA.0000000000002990 the immune system [6]. He also treated a cyte adhesion deficiency syndromes [11].
with normative data, silicone implants are associated with Eitan Israeli patient with combined immunodeficiency The list cannot be completed without
with a thymic transplant but unfortunately mentioning two other pediatricians who, PERFECTOR
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