DOI 10.1515/jpem-2013-0203 J Pediatr Endocr Met 2014; 27(3-4): 383–387
Short communication Veysel Nijat Baş*, Zehra Aycan, Hakan Cangul, Michaela Kendall, Sebahat Yılmaz Ağladıoğlu, Semra Çetinkaya and Eamonn R. Maher
A common thyroid peroxidase gene mutation (G319R) in Turkish patients with congenital hypothyroidism could be due to a founder effect Abstract: The most common congenital endocrine disor der is congenital hypothyroidism (CH), which can lead to mental retardation if untreated. Majority of the patients have been found to have defects in thyroid development and migration disorders (dysgenesis), and the remain ing ones have thyroid hormone synthesis defects (dys hormonogenesis). One of the most common mechanisms to cause dyshormonogenesis is a defect in the thyroid peroxidase (TPO) enzyme. In familial cases, mutations in the TPO gene are fairly prevalent. To date, more than 80 mutations have been identified, which result in variably decreasing TPO bioactivities. Clinical manifestations of TPO defects are typically permanent CH and with or with out goiter. In this report, we presented two children with CH who were born to consanguineous parents and were homozygous carriers of a missense (G319R) TPO mutation, the mutation segregated with the disease status in the fam ilies confirming its pathogenicity. G319R mutation seemed to be a common cause of CH in Turkish population, which could originate from a common founder ancestor. More over, our results also confirmed the phenotypic variability associated with different TPO mutations. Keywords: congenital hypothyroidism; founder effect; mutation; thyroid peroxidase gene. *Corresponding author: Veysel Nijat Baş, Clinics of Pediatric Endocrinology, Dr. Sami Ulus Research and Training Hospital of Women’s and Children’s Health and Diseases, Ankara, Turkey, Phone: +90 312 305 65 08, Fax: +90 312 317 03 53, E-mail: [email protected] Zehra Aycan: Clinics of Pediatric Endocrinology, Dr. Sami Ulus Research and Training Hospital of Women’s and Children’s Health and Diseases and Yıldırım Beyazıt University Medical School, Ankara, Turkey Hakan Cangul: Department of Medical Genetics, Bahcesehir University School of Medicine, Istanbul, Turkey Michaela Kendall: Division of Clinical and Experimental Sciences, Faculty of Medicine, Department of Child Health, Southampton, UK
Sebahat Yılmaz Ağladıoğlu and Semra Çetinkaya: Clinics of Pediatric Endocrinology, Dr. Sami Ulus Research and Training Hospital of Women’s and Children’s Health and Diseases, Ankara, Turkey Eamonn R. Maher: Academic Department of Medical Genetics, University of Cambridge Clinical School, Cambridge, UK
Introduction Congenital hypothyroidism (CH) is the most common con genital endocrine disorder, and the most important cause of preventable mental retardation. It has a reported inci dence of 1 in 3000 to 4000 live births. Although there are various clinical findings in the neonatal period, there may also be no findings at all in the early period (1–3). CH could be sporadic or familial as well as goitrous or non-goitrous. Previous studies have reported that 85% of patients have defects in thyroid development and migra tion (dysgenesis), and the remaining 15% have thyroid hormone synthesis defects (dyshormonogenesis). Thyroid dysgenesis can result in agenesis, hypoplasia, and ectopia of the gland. Thyroid hormone deficiency is quite serious in most cases, and symptoms can emerge early in life. However, symptoms can also manifest weeks later in those who are mildly affected (1, 2). Various defects in thyroid biosynthesis have been described to date. Causative mutations occur in the genes encoding thyroglobulin (TG), sodium/iodide symporter gene (NIS), pendrin gene (PDS), and thyroid oxidase 2 gene (THOX2) (2–4). It is estimated that 15% of CH cases occur as a consequence of defects in thyroid hormone biosynthesis, in which human thyroid peroxidase (TPO) plays an essential role (4, 5). TPO defects comprise one of the most common mechanisms to cause dyshormonogen esis. Thyroid peroxidase is a key enzyme in the synthesis of thyroid hormones; it catalyzes both iodination and cou pling of iodotyrosine residues in thyroglobulin (2, 4, 5).
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384 Baş et al.: Congenital hypothyroidism in Turkish patients was observed through thyroid scintigraphy. In light of these findings, a diagnosis of goitrous CH was made, and the patient underwent treatment of 12 μg/kg/day of L-thyroxine. The patient underwent follow-up sessions for approx imately 7 years, with check-up visits every 3 to 6 months. The L-thyroxine dosage was adjusted according to the results of the laboratory tests. The patient was occasion ally observed to be hypothyroidic due to treatment incom patibility. In his last check-up, the patient was 7 years old with a bone age of 6 years, height of 126.3 cm [0.9 standard deviation score (SDS)], and body weight of 27.9 kg (1.1 SDS); he also had stage 1a thyroid, and borderline mental capacity (IQ = 74). The oversized thyroid tissue (volume = 7.2 cm3) was still present, as observed in thyroid ultrasonography. The patient was eventually treated with 3 μg/kg/day of L-thyroxine until euthyroidism or anti-Tg autoantibody was no longer detected. Table 1 shows the clinical, laboratory, and L-thyroxine dosage information up until the patient’s final check-up.
In the present study, we report detailed clinical fea tures of two CH cases with a TPO mutation, whose parents were second-degree relatives. Both cases were recruited through our studies on genetic background of CH (6–12), and one was diagnosed later in life without goiter whilst the other diagnosed relatively earlier with goiter.
Case reports Case 1 A 28-day-old boy presented with reduced mobility, rough cries, and prolonged jaundice. A detailed medical history revealed that the patient was born at 40 weeks through spontaneous vaginal delivery with a weight of 4250 g, had no cyanosis at birth, had long been monitored for prolonged jaundice that required no treatment, was not screened for CH, and all the aforementioned complaints were present since the day of his birth. Family history revealed that the parents were second-degree relatives (first cousins), and that there were no serious diseases within the family. The patient’s physical examination results were as follows: body temperature, 36.5°C; pulse, 110/min; respi ration rate, 42/min; height, 49 cm (25th percentile); body weight, 4.4 kg (90th percentile); head circumference, 33.5 cm (3rd–10th percentile); anterior fontanelle, 3 × 3 cm; and posterior fontanelle, 0.5 × 0.5 cm. The patient also had a rough facial appearance. Thyroid function test results were as follows: TSH > 100.0 mIU/mL (0.5–5.6), FT4 75 7.34 21.1 2.1 15.2 2.7
Short communication Veysel Nijat Baş*, Zehra Aycan, Hakan Cangul, Michaela Kendall, Sebahat Yılmaz Ağladıoğlu, Semra Çetinkaya and Eamonn R. Maher
A common thyroid peroxidase gene mutation (G319R) in Turkish patients with congenital hypothyroidism could be due to a founder effect Abstract: The most common congenital endocrine disor der is congenital hypothyroidism (CH), which can lead to mental retardation if untreated. Majority of the patients have been found to have defects in thyroid development and migration disorders (dysgenesis), and the remain ing ones have thyroid hormone synthesis defects (dys hormonogenesis). One of the most common mechanisms to cause dyshormonogenesis is a defect in the thyroid peroxidase (TPO) enzyme. In familial cases, mutations in the TPO gene are fairly prevalent. To date, more than 80 mutations have been identified, which result in variably decreasing TPO bioactivities. Clinical manifestations of TPO defects are typically permanent CH and with or with out goiter. In this report, we presented two children with CH who were born to consanguineous parents and were homozygous carriers of a missense (G319R) TPO mutation, the mutation segregated with the disease status in the fam ilies confirming its pathogenicity. G319R mutation seemed to be a common cause of CH in Turkish population, which could originate from a common founder ancestor. More over, our results also confirmed the phenotypic variability associated with different TPO mutations. Keywords: congenital hypothyroidism; founder effect; mutation; thyroid peroxidase gene. *Corresponding author: Veysel Nijat Baş, Clinics of Pediatric Endocrinology, Dr. Sami Ulus Research and Training Hospital of Women’s and Children’s Health and Diseases, Ankara, Turkey, Phone: +90 312 305 65 08, Fax: +90 312 317 03 53, E-mail: [email protected] Zehra Aycan: Clinics of Pediatric Endocrinology, Dr. Sami Ulus Research and Training Hospital of Women’s and Children’s Health and Diseases and Yıldırım Beyazıt University Medical School, Ankara, Turkey Hakan Cangul: Department of Medical Genetics, Bahcesehir University School of Medicine, Istanbul, Turkey Michaela Kendall: Division of Clinical and Experimental Sciences, Faculty of Medicine, Department of Child Health, Southampton, UK
Sebahat Yılmaz Ağladıoğlu and Semra Çetinkaya: Clinics of Pediatric Endocrinology, Dr. Sami Ulus Research and Training Hospital of Women’s and Children’s Health and Diseases, Ankara, Turkey Eamonn R. Maher: Academic Department of Medical Genetics, University of Cambridge Clinical School, Cambridge, UK
Introduction Congenital hypothyroidism (CH) is the most common con genital endocrine disorder, and the most important cause of preventable mental retardation. It has a reported inci dence of 1 in 3000 to 4000 live births. Although there are various clinical findings in the neonatal period, there may also be no findings at all in the early period (1–3). CH could be sporadic or familial as well as goitrous or non-goitrous. Previous studies have reported that 85% of patients have defects in thyroid development and migra tion (dysgenesis), and the remaining 15% have thyroid hormone synthesis defects (dyshormonogenesis). Thyroid dysgenesis can result in agenesis, hypoplasia, and ectopia of the gland. Thyroid hormone deficiency is quite serious in most cases, and symptoms can emerge early in life. However, symptoms can also manifest weeks later in those who are mildly affected (1, 2). Various defects in thyroid biosynthesis have been described to date. Causative mutations occur in the genes encoding thyroglobulin (TG), sodium/iodide symporter gene (NIS), pendrin gene (PDS), and thyroid oxidase 2 gene (THOX2) (2–4). It is estimated that 15% of CH cases occur as a consequence of defects in thyroid hormone biosynthesis, in which human thyroid peroxidase (TPO) plays an essential role (4, 5). TPO defects comprise one of the most common mechanisms to cause dyshormonogen esis. Thyroid peroxidase is a key enzyme in the synthesis of thyroid hormones; it catalyzes both iodination and cou pling of iodotyrosine residues in thyroglobulin (2, 4, 5).
Brought to you by | University of California - San Francisco Authenticated Download Date | 2/17/15 7:50 PM
384 Baş et al.: Congenital hypothyroidism in Turkish patients was observed through thyroid scintigraphy. In light of these findings, a diagnosis of goitrous CH was made, and the patient underwent treatment of 12 μg/kg/day of L-thyroxine. The patient underwent follow-up sessions for approx imately 7 years, with check-up visits every 3 to 6 months. The L-thyroxine dosage was adjusted according to the results of the laboratory tests. The patient was occasion ally observed to be hypothyroidic due to treatment incom patibility. In his last check-up, the patient was 7 years old with a bone age of 6 years, height of 126.3 cm [0.9 standard deviation score (SDS)], and body weight of 27.9 kg (1.1 SDS); he also had stage 1a thyroid, and borderline mental capacity (IQ = 74). The oversized thyroid tissue (volume = 7.2 cm3) was still present, as observed in thyroid ultrasonography. The patient was eventually treated with 3 μg/kg/day of L-thyroxine until euthyroidism or anti-Tg autoantibody was no longer detected. Table 1 shows the clinical, laboratory, and L-thyroxine dosage information up until the patient’s final check-up.
In the present study, we report detailed clinical fea tures of two CH cases with a TPO mutation, whose parents were second-degree relatives. Both cases were recruited through our studies on genetic background of CH (6–12), and one was diagnosed later in life without goiter whilst the other diagnosed relatively earlier with goiter.
Case reports Case 1 A 28-day-old boy presented with reduced mobility, rough cries, and prolonged jaundice. A detailed medical history revealed that the patient was born at 40 weeks through spontaneous vaginal delivery with a weight of 4250 g, had no cyanosis at birth, had long been monitored for prolonged jaundice that required no treatment, was not screened for CH, and all the aforementioned complaints were present since the day of his birth. Family history revealed that the parents were second-degree relatives (first cousins), and that there were no serious diseases within the family. The patient’s physical examination results were as follows: body temperature, 36.5°C; pulse, 110/min; respi ration rate, 42/min; height, 49 cm (25th percentile); body weight, 4.4 kg (90th percentile); head circumference, 33.5 cm (3rd–10th percentile); anterior fontanelle, 3 × 3 cm; and posterior fontanelle, 0.5 × 0.5 cm. The patient also had a rough facial appearance. Thyroid function test results were as follows: TSH > 100.0 mIU/mL (0.5–5.6), FT4 75 7.34 21.1 2.1 15.2 2.7
