http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2014; 30(10): 694–696 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.929654
TURNER SYNDROME AND PSEUDOHYPOPARATHYROIDISM
Pseudohypoparathyroidism with Hashimoto’s thyroiditis and Turner syndrome: a case report Wen-Heng Zeng, Jiao-Jun Xu, Min-Yue Jia, and Yue-Zhong Ren Department of Endocrinology and Metabolism, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
Abstract
Keywords
Objective: To report the case of an individual with PHP, Turner syndrome and Hashimoto’s thyroiditis. Case: A 16-year-old girl was referred to our hospital with chief complaint of short stature. She presented with round chubby facies, short neck, obesity and short stature. Radiography indicated short metatarsals and metacarpals, which mainly affected the second, third and fourth digits. Biochemistry revealed hyperphosphatemia, increased serum concentrations of parathyroid hormone and thyroid stimulating hormone, elevated levels of follicular-stimulating hormone and prolactin, and increased thyroid peroxidase antibody and thyroglobulin antibody. Radiographic examination revealed delayed bone age and pelvic ultrasonography demonstrated an immature uterus. Karyotype analysis showed 46,X,i(Xq10), while molecular analysis revealed a same sense mutation in exon 5 of GNAS (ATC ! ATT, Ile).The specific diagnosis was made of Turner syndrome in the presence of Hashimoto’s thyroiditis and PHP. She was treated with calcium supplementation, calcitriol and thyroxine. Conclusions: This is the first case report to describe a combination of Turner syndrome with these other clinical entities, and their co-existence should be considered and further investigated.
Hashimoto’s thyroiditis, pseudohypoparathyroidism, Turner syndrome
Introduction The idiopathic and inherited forms of parathyroid hormone (PTH) resistance are termed pseudohypoparathyroidism. Affected patients have hypocalcemia and hyperphosphatemia, and also exhibit a number of features that are characteristic of Albright’s hereditary osteodystrophy (AHO) [1]. These features include short stature, rounded faces, foreshortened metacarpals (particularly the fourth), obesity and subcutaneous calcifications. Turner syndrome is characterized by the absence of all or part of one X chromosome from all or some cell types, which affects 1 in 2500 live births [2]. Features include short stature, gonadal dysgenesis, primary amenorrhea, decreased fertility, and cardiac, renal and endocrine anomalies. The diagnosis of TS is difficult to consider in females with PHP, as both syndromes share common clinical features. Moreover, the combination of Turner syndrome (TS) and classical PHP has never been reported in literature.
Case report A 16-year-old girl was referred to our hospital with chief complaint of short stature. According to the patient history, she was born at term via cesarean section to non-consanguineous parents who had one older female child. Her parents reported
Corresponding Author: Dr. Yue-Zhong Ren, MD, PhD, Department of Endocrinology and Metabolism, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Rd, Hangzhou, Zhejiang 310009, China. E-mail: [email protected]
History Received 16 December 2013 Revised 23 May 2014 Accepted 27 May 2014 Published online 10 June 2014
thickened hands and feet, difficulty feeding, and intestinal polyps that had been treated by an endoscopic polypectomy at the age of 8 years. She presented with round and chubby facies, a short neck and stature, obesity, and brachydactyly, with metacarpal shortening in particular. She had never started menstruation. We examined the entire family and found that her elder sister and her mother had started menstruation at the age of 16 years old. On physical examination, she weighted 52 kg and measured 140 cm in height, and she had a body mass index of 26.53 kg/m2. A further general body examination revealed that the patient had frontal bossing, a depressed nasal bridge, short metatarsals and metacarpals (mainly the second, third and fourth). She had normal mental abilities, and both Chvostek’s and Trousseau’s signs were negative. She was at Grade 3 on the Tanner staging system. According to laboratory evaluations, her blood count, urinalysis, renal and liver function tests were normal. Biochemistry analyses revealed the following: PTH level: 93.66 pg/ml (normal range: 15.00–65.00 pg/ml); serum phosphorous: 1.84 mmol/L (normal range: 0.81–1.45 mmol/L); alkaline phosphatase: 231 U/L (normal range: 47–119 U/L), 25-OH vitamin D: 10.8 mg/L (normal range: 20.0–50.0 mg/L) and serum calcium: 2.51 mmol/L (normal range: 2.08–2.60 mmol/L). Thyroid hormone levels were within the normal ranges (TT3: 2.60 nmol/L; normal range: 0.92–2.79 nmol/L; FT3: 6.09 pmol/L; normal range: 3.5– 6.5 pmol/L; TT4: 117.2 nmol/L; normal range 58.1–140.6 nmol/L; FT4: 15.90 pmol/L; normal range: 11.5–22.7 pmol/L; TSH: 10.76 mIU/L; normal range: 0.55–4.78 mIU/L). Furthermore, thyroid autoantibodies were both raised [TGAb: 1778 IU/ml (normal range: 5115 IU/ml); TPOAb: 60.76 IU/ml (normal range: 534 IU/ml)]. Assays for reproductive hormones showed the
PHP with Hashimoto’s thyroiditis and Turner syndrome
DOI: 10.3109/09513590.2014.929654
following results: prolactin (PRL): 583 mIU/L (normal range: 40.3–530 mIU/L); luteinizing hormone (LH): 9.2 IU/L; follicularstimulating hormone (FSH): 37.7 IU/L; progesterone (PRG): 2.22 nmol/L; estrogen (E2): 116 pmol/L; testosterone (TES): 0.93 nmol/L; endomethal antibody (EMAb): negative; anti-ovary antibody (AOAb): negative. A metoclopramide stimulation test
695
was performed to evaluate the hyperprolactinemia. The result of the test was normal and the pituitary MRI showed no abnormality. A growth hormone (GH) provocation test (insulin tolerance test, ITT) showed a normal response. Radiographic examinations revealed delayed bone age and short metacarpals (Figure 1), while pelvic ultrasonography demonstrated a uterus that measured 4.2 1.8 3.2 cm. Thyroid ultrasonography showed heterogeneous hypoechoic changes that involved both thyroid lobes. Molecular analysis revealed a same sense mutation in GNAS exon 5 (ATC ! ATT, Ile). The short stature, amenorrhea and high level of FSH prompted suspicion of TS. Karyotype analysis showed 46,X,i(Xq10) (Figure 2). She was treated with calcium supplementation, calcitriol and thyroxine.
Discussion
Figure 1. Radiographic examination revealed delayed bone age and short metacarpal.
Pseudohypoparathyroidism (PHP) is a rare genetic disorder caused by a mutation of the GNAS1 gene, which encodes the a-subunit of the stimulatory GTP-binding protein, with a prevalence of 3.4 per million [1]. It is a group of disorders characterized by resistance to PTH, which results in hypocalcemia and hyperphosphatemia. Several types of PHP have been identified: type Ia presents with features of AHO, including short stature, brachydactyly, subcutaneous calcification, obesity, rounded facies, and occasional mental retardation); types 1b and 2 lack the features of AHO [2]. Several patients with AHO and PTH resistance have been found to have normal Gsa activity, and this subgroup of the disorder has been designated PHP type 1c (PHP-1c). The inheritance pattern of PHP appears to be autosomal dominant and displays variable penetrance. The gene locus is very complex and gives rise to Gsa as well as several other splice variants [3,4]. Defects in Gsa, which stimulates adenylyl cyclase, may result in either the loss or gain of endocrine function. Reduced Gsa activity can present with resistance to several hormones, in addition to PTH [5]. Patients with PHP-Ia may develop resistance to other hormones that also act via Gs-coupled receptors, such as TSH, gonadotrophins and GH-releasing hormone [6–10]. PHP-1c manifests as AHO with PTH resistance,
Figure 2. Karyotype analysis showed 46,X,i(Xq10).
696
W.-H. Zeng et al.
and patients have normal Gsa activity. Several studies have found some of the patients with PHP-1c have epigenetic, genetic and functional changes of GNAS [11–14]. However, several patients with the diagnosis of PHP-1c lack either epigenetic or genetic changes in GNAS, which demonstrates that PHP-1c may be caused by other pathogenic mechanisms [11]. In our case, who had features of AHO and resistant to PTH, we discovered a same sense mutation in exon 5 of GNAS. Although we did not test Gsa activity in this patient, we deduce that the patient has PHP-1c from her clinical presentation. The age of presentation and the severity of PTH resistance as part of PHP show a wide range. In most cases, mild hypothyroidism, GH deficiency, delayed puberty, sexual precocity or infertility. In our case, the individual displayed the characteristic features of AHO, as well as resistance to multiple hormones, including TSH, GH and gonadotropins. Congenital hypothyroidism has been reported as the presenting manifestation of PHP-Ia [7,15]. The TSH concentration is typically elevated at birth but may subsequently normalize for 9–20 months before increasing again. The resistance to TSH is generally mild, and this may be explained by partial imprinting in the thyroid with incomplete silencing of the paternal allele [16]. In our case, the patient manifested resistance to TSH. After treated with thyroxine, TSH was decreased to 5.4 mIU/L. Hashimoto’s thyroiditis was partly responsible for the increased TSH levels. It was difficult to distinguish. Although the incidence and the clinical and biochemical characteristics of PTH and TSH resistance have been widely investigated and described, the study of the reproductive dysfunction in AHO is still poorly reported in the literature. Namnoum et al. [8] found that reproductive dysfunction was common in women with AHO and probably represents partial resistance to gonadotropins. The diagnosis of PHP seemed to explain all of manifestations of our case. But some clinical studies showed that serum concentrations of gonadotropins FSH and LH were normal to slightly elevated. In our case, FSH level was high implied ovary failure. This prompted the suspicion of TS. The combination of PHP with Hashimoto’s thyroiditis and TS is very rare. The genetic background of TS is highly variable. The most frequent occurring karyotypes are 45,X, karyotypes with an isochromosome of X [i(Xq) or i(Xp)], the mosaic karyotype of 45,X/46XX, and karyotypes that contain an entire Y chromosome or parts thereof [17]. In our case, karyotype analysis showed 46,X,i(Xq10). TS can be accompanied by diverse problems, such as short stature, amenorrhea, skeletal and lymphatic abnormalities, hearing loss, aortic coarctation or stenosis, thyroiditis, metabolic abnormalities, renal abnormalities, and ovarian insufficiency, among others [18]. Some of these symptoms can also be present in patients with PHP. It was therefore difficult for us to distinguish between PHP and TS, especially for atypical cases, and genetic investigations remain the gold standard treatment. In our case, it is also difficult to tell which disease contributes to the increased gonadotrophins and delayed onset of menstruation. We inferred that TS was the main reason of ovary failure. The mainstay of treatment for this patient involves the administration of oral calcium, 1a-hydroxylated vitamin D metabolites (calcitriol) and thyroxine. Hormonal replacement therapy should begin at a normal pubertal age and be continued until the age of 50 years. GH therapy should generally begin as soon as growth failure occurs, allowing for the rapid normalization of height. Advanced assisted reproductive technology (ART) may help some patients with TS to achieve pregnancies [19,20]. We have described a patient with PHP-1c associated with Hashimoto’s thyroiditis and TS. The endocrine abnormalities observed in the present case are very interesting with combination of PHP and TS and difficulties in getting the suspicion of TS.
Gynecol Endocrinol, 2014; 30(10): 694–696
To the best of our knowledge, no information is available in the literature on this combination of hormonal abnormalities.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. Albright F, Burnett CH, Smith PH. Pseudohypoparathyroidism: an example of ‘‘Seabright-Bantam syndrome’’. Endocrinology 1942; 30:922–32. 2. Stochholm K, Juul S, Juel K, et al. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006;91:3897–902. 3. Bastepe M, Juppner H. GNAS locus and pseudohypoparathyroidism. Horm Res 2005;63:65–74. 4. Bastepe M, Juppner H. Pseudohypoparathyroidism and mechanisms of resistance toward multiple hormones: molecular evidence to clinical presentation. J Clin Endocrinol Metab 2003;88:4055–8. 5. Nakamoto JM, Zimmerman D, Jones EA, et al. Concurrent hormone resistance (pseudohypoparathyroidism type Ia) and hormone independence (testotoxicosis) caused by a unique mutation in the G alpha s gene. Biochem Mol Med 1996;58:18–24. 6. Levine MA, Downs RW, Moses AM, et al. Resistance to multiple hormones in patients with pseudohypoparathyroidism: association with deficient activity of guanine nucleotide regulatory protein. Am J Med 1983;74:545–56. 7. Liu J, Erlichman B, Weinstein LS. The stimulatory G protein alphasubunit Gs alpha is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types 1A and 1B. J Clin Endocrinol Metab 2003;88:4336–41. 8. Namnoum AB, Merriam GR, Moses AM, et al. Reproductive dysfunction in women with Albright’s hereditary osteodystrophy. J Clin Endocrinol Metab 1998;83:824–9. 9. Mantovani G, Maghnie M, Weber G, et al. Growth hormonereleasing hormone resistance in pseudohypoparathyroidism type Ia: new evidence for imprinting of the Gs alpha gene. J Clin Endocrinol Metab 2003;88:4070–4. 10. Mantovani G, Spada A. Resistance to growth hormone releasing hormone and gonadotropins in Albright’s hereditary osteodystrophy. J Pediatr Endocrinol Metab 2006;19:663–70. 11. Thiele S, de Sanctis L, Werner R, et al. Functional characterization of GNAS mutations found in patients with pseudohypoparathyroidism type Ic defines a new subgroup of pseudohypoparathyroidism affecting selectively Gsa-receptor interaction. Hum Mutat 2011;32: 653–60. 12. de Nanclares GP, Ferna´ndez-Rebollo E, Santin I, et al. Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright’s herediatary osteodystrophy. J Clin Endocrinol Metab 2007;92:2370–3. 13. Linglart A, Carel JC, Garabedian M, et al. GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance. J Clin Endocrinol Metab 2002;87:189–97. 14. Mantovani G, de Sanctis L, Barbieri AM, et al. Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of Albright hereditary osteodystrophy and molecular analysis in 40 patients. J Clin Endocrinol Metab 2010;95:651–8. 15. Pinsker J, Rogers W, Mclean S, et al. Pseudohypoparathyroidism type 1a with congenital hypothyroidism. JPEM 2006;19:1049–52. 16. Plagge A, Kelsey G, Germain-Lee EL. Physiological functions of the imprinted GNAS locus and its protein variants G’s and XL’s in human and mouse. J Endocrinol 2008;196:193–214. 17. Davenport ML. Approach to the patient with Turner syndrome. J Clin Endocrinol Metab 2010;95:1487–95. 18. Stochholm K, Juul S, Juel K, et al. Prevalence,incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006;91:3897–902. 19. Sugawara N, Kimura Y, Araki Y. Case report: a successful pregnancy outcome in a patient with non-mosaic Turner syndrome (45, X) via in vitro fertilization. Hum Cell 2013;26:41–3. 20. Nwosu EC, Brockbank A, Walkinshaw SA. A successful pregnancy in a Turner syndrome with oocyte donation. J Obstet Gynaecol 2012; 32:419–21.
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TURNER SYNDROME AND PSEUDOHYPOPARATHYROIDISM
Pseudohypoparathyroidism with Hashimoto’s thyroiditis and Turner syndrome: a case report Wen-Heng Zeng, Jiao-Jun Xu, Min-Yue Jia, and Yue-Zhong Ren Department of Endocrinology and Metabolism, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
Abstract
Keywords
Objective: To report the case of an individual with PHP, Turner syndrome and Hashimoto’s thyroiditis. Case: A 16-year-old girl was referred to our hospital with chief complaint of short stature. She presented with round chubby facies, short neck, obesity and short stature. Radiography indicated short metatarsals and metacarpals, which mainly affected the second, third and fourth digits. Biochemistry revealed hyperphosphatemia, increased serum concentrations of parathyroid hormone and thyroid stimulating hormone, elevated levels of follicular-stimulating hormone and prolactin, and increased thyroid peroxidase antibody and thyroglobulin antibody. Radiographic examination revealed delayed bone age and pelvic ultrasonography demonstrated an immature uterus. Karyotype analysis showed 46,X,i(Xq10), while molecular analysis revealed a same sense mutation in exon 5 of GNAS (ATC ! ATT, Ile).The specific diagnosis was made of Turner syndrome in the presence of Hashimoto’s thyroiditis and PHP. She was treated with calcium supplementation, calcitriol and thyroxine. Conclusions: This is the first case report to describe a combination of Turner syndrome with these other clinical entities, and their co-existence should be considered and further investigated.
Hashimoto’s thyroiditis, pseudohypoparathyroidism, Turner syndrome
Introduction The idiopathic and inherited forms of parathyroid hormone (PTH) resistance are termed pseudohypoparathyroidism. Affected patients have hypocalcemia and hyperphosphatemia, and also exhibit a number of features that are characteristic of Albright’s hereditary osteodystrophy (AHO) [1]. These features include short stature, rounded faces, foreshortened metacarpals (particularly the fourth), obesity and subcutaneous calcifications. Turner syndrome is characterized by the absence of all or part of one X chromosome from all or some cell types, which affects 1 in 2500 live births [2]. Features include short stature, gonadal dysgenesis, primary amenorrhea, decreased fertility, and cardiac, renal and endocrine anomalies. The diagnosis of TS is difficult to consider in females with PHP, as both syndromes share common clinical features. Moreover, the combination of Turner syndrome (TS) and classical PHP has never been reported in literature.
Case report A 16-year-old girl was referred to our hospital with chief complaint of short stature. According to the patient history, she was born at term via cesarean section to non-consanguineous parents who had one older female child. Her parents reported
Corresponding Author: Dr. Yue-Zhong Ren, MD, PhD, Department of Endocrinology and Metabolism, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Rd, Hangzhou, Zhejiang 310009, China. E-mail: [email protected]
History Received 16 December 2013 Revised 23 May 2014 Accepted 27 May 2014 Published online 10 June 2014
thickened hands and feet, difficulty feeding, and intestinal polyps that had been treated by an endoscopic polypectomy at the age of 8 years. She presented with round and chubby facies, a short neck and stature, obesity, and brachydactyly, with metacarpal shortening in particular. She had never started menstruation. We examined the entire family and found that her elder sister and her mother had started menstruation at the age of 16 years old. On physical examination, she weighted 52 kg and measured 140 cm in height, and she had a body mass index of 26.53 kg/m2. A further general body examination revealed that the patient had frontal bossing, a depressed nasal bridge, short metatarsals and metacarpals (mainly the second, third and fourth). She had normal mental abilities, and both Chvostek’s and Trousseau’s signs were negative. She was at Grade 3 on the Tanner staging system. According to laboratory evaluations, her blood count, urinalysis, renal and liver function tests were normal. Biochemistry analyses revealed the following: PTH level: 93.66 pg/ml (normal range: 15.00–65.00 pg/ml); serum phosphorous: 1.84 mmol/L (normal range: 0.81–1.45 mmol/L); alkaline phosphatase: 231 U/L (normal range: 47–119 U/L), 25-OH vitamin D: 10.8 mg/L (normal range: 20.0–50.0 mg/L) and serum calcium: 2.51 mmol/L (normal range: 2.08–2.60 mmol/L). Thyroid hormone levels were within the normal ranges (TT3: 2.60 nmol/L; normal range: 0.92–2.79 nmol/L; FT3: 6.09 pmol/L; normal range: 3.5– 6.5 pmol/L; TT4: 117.2 nmol/L; normal range 58.1–140.6 nmol/L; FT4: 15.90 pmol/L; normal range: 11.5–22.7 pmol/L; TSH: 10.76 mIU/L; normal range: 0.55–4.78 mIU/L). Furthermore, thyroid autoantibodies were both raised [TGAb: 1778 IU/ml (normal range: 5115 IU/ml); TPOAb: 60.76 IU/ml (normal range: 534 IU/ml)]. Assays for reproductive hormones showed the
PHP with Hashimoto’s thyroiditis and Turner syndrome
DOI: 10.3109/09513590.2014.929654
following results: prolactin (PRL): 583 mIU/L (normal range: 40.3–530 mIU/L); luteinizing hormone (LH): 9.2 IU/L; follicularstimulating hormone (FSH): 37.7 IU/L; progesterone (PRG): 2.22 nmol/L; estrogen (E2): 116 pmol/L; testosterone (TES): 0.93 nmol/L; endomethal antibody (EMAb): negative; anti-ovary antibody (AOAb): negative. A metoclopramide stimulation test
695
was performed to evaluate the hyperprolactinemia. The result of the test was normal and the pituitary MRI showed no abnormality. A growth hormone (GH) provocation test (insulin tolerance test, ITT) showed a normal response. Radiographic examinations revealed delayed bone age and short metacarpals (Figure 1), while pelvic ultrasonography demonstrated a uterus that measured 4.2 1.8 3.2 cm. Thyroid ultrasonography showed heterogeneous hypoechoic changes that involved both thyroid lobes. Molecular analysis revealed a same sense mutation in GNAS exon 5 (ATC ! ATT, Ile). The short stature, amenorrhea and high level of FSH prompted suspicion of TS. Karyotype analysis showed 46,X,i(Xq10) (Figure 2). She was treated with calcium supplementation, calcitriol and thyroxine.
Discussion
Figure 1. Radiographic examination revealed delayed bone age and short metacarpal.
Pseudohypoparathyroidism (PHP) is a rare genetic disorder caused by a mutation of the GNAS1 gene, which encodes the a-subunit of the stimulatory GTP-binding protein, with a prevalence of 3.4 per million [1]. It is a group of disorders characterized by resistance to PTH, which results in hypocalcemia and hyperphosphatemia. Several types of PHP have been identified: type Ia presents with features of AHO, including short stature, brachydactyly, subcutaneous calcification, obesity, rounded facies, and occasional mental retardation); types 1b and 2 lack the features of AHO [2]. Several patients with AHO and PTH resistance have been found to have normal Gsa activity, and this subgroup of the disorder has been designated PHP type 1c (PHP-1c). The inheritance pattern of PHP appears to be autosomal dominant and displays variable penetrance. The gene locus is very complex and gives rise to Gsa as well as several other splice variants [3,4]. Defects in Gsa, which stimulates adenylyl cyclase, may result in either the loss or gain of endocrine function. Reduced Gsa activity can present with resistance to several hormones, in addition to PTH [5]. Patients with PHP-Ia may develop resistance to other hormones that also act via Gs-coupled receptors, such as TSH, gonadotrophins and GH-releasing hormone [6–10]. PHP-1c manifests as AHO with PTH resistance,
Figure 2. Karyotype analysis showed 46,X,i(Xq10).
696
W.-H. Zeng et al.
and patients have normal Gsa activity. Several studies have found some of the patients with PHP-1c have epigenetic, genetic and functional changes of GNAS [11–14]. However, several patients with the diagnosis of PHP-1c lack either epigenetic or genetic changes in GNAS, which demonstrates that PHP-1c may be caused by other pathogenic mechanisms [11]. In our case, who had features of AHO and resistant to PTH, we discovered a same sense mutation in exon 5 of GNAS. Although we did not test Gsa activity in this patient, we deduce that the patient has PHP-1c from her clinical presentation. The age of presentation and the severity of PTH resistance as part of PHP show a wide range. In most cases, mild hypothyroidism, GH deficiency, delayed puberty, sexual precocity or infertility. In our case, the individual displayed the characteristic features of AHO, as well as resistance to multiple hormones, including TSH, GH and gonadotropins. Congenital hypothyroidism has been reported as the presenting manifestation of PHP-Ia [7,15]. The TSH concentration is typically elevated at birth but may subsequently normalize for 9–20 months before increasing again. The resistance to TSH is generally mild, and this may be explained by partial imprinting in the thyroid with incomplete silencing of the paternal allele [16]. In our case, the patient manifested resistance to TSH. After treated with thyroxine, TSH was decreased to 5.4 mIU/L. Hashimoto’s thyroiditis was partly responsible for the increased TSH levels. It was difficult to distinguish. Although the incidence and the clinical and biochemical characteristics of PTH and TSH resistance have been widely investigated and described, the study of the reproductive dysfunction in AHO is still poorly reported in the literature. Namnoum et al. [8] found that reproductive dysfunction was common in women with AHO and probably represents partial resistance to gonadotropins. The diagnosis of PHP seemed to explain all of manifestations of our case. But some clinical studies showed that serum concentrations of gonadotropins FSH and LH were normal to slightly elevated. In our case, FSH level was high implied ovary failure. This prompted the suspicion of TS. The combination of PHP with Hashimoto’s thyroiditis and TS is very rare. The genetic background of TS is highly variable. The most frequent occurring karyotypes are 45,X, karyotypes with an isochromosome of X [i(Xq) or i(Xp)], the mosaic karyotype of 45,X/46XX, and karyotypes that contain an entire Y chromosome or parts thereof [17]. In our case, karyotype analysis showed 46,X,i(Xq10). TS can be accompanied by diverse problems, such as short stature, amenorrhea, skeletal and lymphatic abnormalities, hearing loss, aortic coarctation or stenosis, thyroiditis, metabolic abnormalities, renal abnormalities, and ovarian insufficiency, among others [18]. Some of these symptoms can also be present in patients with PHP. It was therefore difficult for us to distinguish between PHP and TS, especially for atypical cases, and genetic investigations remain the gold standard treatment. In our case, it is also difficult to tell which disease contributes to the increased gonadotrophins and delayed onset of menstruation. We inferred that TS was the main reason of ovary failure. The mainstay of treatment for this patient involves the administration of oral calcium, 1a-hydroxylated vitamin D metabolites (calcitriol) and thyroxine. Hormonal replacement therapy should begin at a normal pubertal age and be continued until the age of 50 years. GH therapy should generally begin as soon as growth failure occurs, allowing for the rapid normalization of height. Advanced assisted reproductive technology (ART) may help some patients with TS to achieve pregnancies [19,20]. We have described a patient with PHP-1c associated with Hashimoto’s thyroiditis and TS. The endocrine abnormalities observed in the present case are very interesting with combination of PHP and TS and difficulties in getting the suspicion of TS.
Gynecol Endocrinol, 2014; 30(10): 694–696
To the best of our knowledge, no information is available in the literature on this combination of hormonal abnormalities.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. Albright F, Burnett CH, Smith PH. Pseudohypoparathyroidism: an example of ‘‘Seabright-Bantam syndrome’’. Endocrinology 1942; 30:922–32. 2. Stochholm K, Juul S, Juel K, et al. Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006;91:3897–902. 3. Bastepe M, Juppner H. GNAS locus and pseudohypoparathyroidism. Horm Res 2005;63:65–74. 4. Bastepe M, Juppner H. Pseudohypoparathyroidism and mechanisms of resistance toward multiple hormones: molecular evidence to clinical presentation. J Clin Endocrinol Metab 2003;88:4055–8. 5. Nakamoto JM, Zimmerman D, Jones EA, et al. Concurrent hormone resistance (pseudohypoparathyroidism type Ia) and hormone independence (testotoxicosis) caused by a unique mutation in the G alpha s gene. Biochem Mol Med 1996;58:18–24. 6. Levine MA, Downs RW, Moses AM, et al. Resistance to multiple hormones in patients with pseudohypoparathyroidism: association with deficient activity of guanine nucleotide regulatory protein. Am J Med 1983;74:545–56. 7. Liu J, Erlichman B, Weinstein LS. The stimulatory G protein alphasubunit Gs alpha is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types 1A and 1B. J Clin Endocrinol Metab 2003;88:4336–41. 8. Namnoum AB, Merriam GR, Moses AM, et al. Reproductive dysfunction in women with Albright’s hereditary osteodystrophy. J Clin Endocrinol Metab 1998;83:824–9. 9. Mantovani G, Maghnie M, Weber G, et al. Growth hormonereleasing hormone resistance in pseudohypoparathyroidism type Ia: new evidence for imprinting of the Gs alpha gene. J Clin Endocrinol Metab 2003;88:4070–4. 10. Mantovani G, Spada A. Resistance to growth hormone releasing hormone and gonadotropins in Albright’s hereditary osteodystrophy. J Pediatr Endocrinol Metab 2006;19:663–70. 11. Thiele S, de Sanctis L, Werner R, et al. Functional characterization of GNAS mutations found in patients with pseudohypoparathyroidism type Ic defines a new subgroup of pseudohypoparathyroidism affecting selectively Gsa-receptor interaction. Hum Mutat 2011;32: 653–60. 12. de Nanclares GP, Ferna´ndez-Rebollo E, Santin I, et al. Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright’s herediatary osteodystrophy. J Clin Endocrinol Metab 2007;92:2370–3. 13. Linglart A, Carel JC, Garabedian M, et al. GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance. J Clin Endocrinol Metab 2002;87:189–97. 14. Mantovani G, de Sanctis L, Barbieri AM, et al. Pseudohypoparathyroidism and GNAS epigenetic defects: clinical evaluation of Albright hereditary osteodystrophy and molecular analysis in 40 patients. J Clin Endocrinol Metab 2010;95:651–8. 15. Pinsker J, Rogers W, Mclean S, et al. Pseudohypoparathyroidism type 1a with congenital hypothyroidism. JPEM 2006;19:1049–52. 16. Plagge A, Kelsey G, Germain-Lee EL. Physiological functions of the imprinted GNAS locus and its protein variants G’s and XL’s in human and mouse. J Endocrinol 2008;196:193–214. 17. Davenport ML. Approach to the patient with Turner syndrome. J Clin Endocrinol Metab 2010;95:1487–95. 18. Stochholm K, Juul S, Juel K, et al. Prevalence,incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 2006;91:3897–902. 19. Sugawara N, Kimura Y, Araki Y. Case report: a successful pregnancy outcome in a patient with non-mosaic Turner syndrome (45, X) via in vitro fertilization. Hum Cell 2013;26:41–3. 20. Nwosu EC, Brockbank A, Walkinshaw SA. A successful pregnancy in a Turner syndrome with oocyte donation. J Obstet Gynaecol 2012; 32:419–21.
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