Pseudohypoparathyroidism Type la with Normocalcemia.
Pseudohypoparathyroidism (PHP) is an autosomal dominant disorder, which is related with parathormone target organ resistance resulting from mutations in guanine nucleotide binding protein (G protein) and alpha stimulating activity polypeptide 1 (GNAS1) genes. It is characterized by hypocalcemia, hyperphosphatemia and elevated PTH levels (1). The disorder occurs as a result of maternal transmission of the mutation. As Gs alpha protein activity is necessary for other hormones such as thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and gonadotropin-releasing hormone (GnRH), growth hormone-releasing hormone (GHRH), resistance against these hormones may also exist (2-6). Characteristic phenotypic features such as short stature, obesity, round face, low nasal bridge, shortened metacarpals, shortness and thickness in distal phalanges, subcutaneous calcifications, polyostotic fibrous dysplasia, developmental delay, and besides, mental retardation can be observed in these patients (1,7). This phenotype is named as "Albright hereditary osteodystrophy" (AHO).
Some cases with PHP type Ia are present with heterogeneity in terms of their phenotypical and biochemical characteristics (8-11). In this paper, an eight-year and nine-month-old female with normocalsemic PHP type Ia is reported.
Eight-year and nine-month-old female patient was admitted to the hospital with the complaint of having short stature with a height of 117.2 cm (<3p, -2.5 SDS) and weight of 28.9 kg (50-75p, 0.124 SDS). She was term born, birth weight was 3100 gr (25-50 p) and birth height was 50 cm (50-75 p), respectively. Her parents were third-degree relatives. Her father's and mother's heights were 165 cm (-1.65 SDS), and 135.9 cm (-4.2 SDS), respectively. She had healthy four siblings. Her physical examination at presentation showed a short stature, obesity, round face, low nasal bridge, and shortened metacarpals (picture 1 and 2). Her pubertal stage was in tanner phase 1. She was evaluated as mentally retarded in a mild degree.
Skeletal maturation assessment by direct hand wrist radiography revealed shortened metacarpals and metatarsals (picture 3) and her bone age was consistent with her age. Her thyroid ultrasonography and cranial magnetic resonance imaging were both reported as normal. Hypothyroidism and elevated PTH levels with normocalcemia and normal 25-OH vitamin D levels were detected in her laboratory tests. Laboratory findings including complete blood counts, biochemical parameters, TSH, free T4, calcium, phosphorus, alkaline phosphatase, PTH level, 25-hydroxyvitamin D, insulin like growth factor 1 (IGF-1) were given in Table 1.
As a result of clinic and laboratory tests, the findings were consistent with PHP type Ia with hypotyroidism and normocalcemia, her GNAS gene sequencing analysis was performed; C-308T>C (p1103T) transformation was detected, which was previously reported in PHP type Ia patient. Oral L-thyroxine treatment was initiated to the patient. Her growth velocity and calcium and phosphorus levels are still on follow-up.
Written informed consent was obtained from the patient's parents for publication of this case report.
Pseudohypoparatyroidism Ia is the most prevalent PHP type. Along with typical phenotypic findings, cases showing heterogeneity have also been reported (12-14). Our patient had typical AHO phenotypes.
Transport system which is sensitive to parathormone consists of three sections namely receptor, adenyl cyclase and protein G. The GNAS gene encodes the alpha-stimulatory subunit (Gs) of the intracellular G protein, which stimulates the production of cAMP under certain physiologic conditions (7). Gs alpha protein activity in PHP-Ia is low as a result of GNAS 1 gene mutation therefore, sufficient c-AMP response to PTH cannot occur in receptor level (15-18). Resistance to other hormones which uses protein G as a second messenger, may also be observed. Moreover, the most common resistance is observed against TSH, which affects more than 90% of PHP patients type Ia (19,20). Previous reports have shown hypothyroidism may be the first manifestation of PHP type Ia in absence of hypocalcemia and elevated PTH levels (8-21). In our case, hypothyroidism with elevated TSH and decreased sT4 levels was detected.
The characteristic findings of the disorder are hypocalcemia, hyperphosphatemia and high level of PTH. However, previously normocalcemic cases have also been reported (10,22-24). Tamada et al. (24) reported a case with R358H mutation with normocalcemia. We have detected C-308T >C (p1103T) change in our case. The mechanism behind the fact of normocalcemia cannot be explained completely. It is proposed that normal serum calcium concentrations in these patients may be explained by the presence of normal bone responsiveness to PTH (10,25,26). Further studies are needed on this issue.
In conclusion, we have presented a PHP type Ia patient with normocalcemia and hypothyroidism caused by C-308T >C (p1103T) change in the GNAS gene. In children with hypothyroidism without apparent etiology, GNAS1 gene mutations should be also considered even calcium levels are normal.
Informed Consent: Written informed consent was obtained from the patient's parents for publication of this case report.
Peer Review: Internally peer-reviewed.
Concept: E.K., I.T.O., G.Y., Design: E.K., I.T.O., Y.C., Data Collection or Processing: E.K., I.T.O., G.Y., Analysis or Interpretation: I.T.O., Y.C., G.Y., Literature Search: E.K., G.Y., I.T.O., Writing: E.K., I.T.O.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.
(1.) Albright F, Burnett CH, Smith PH, Parson W. Pseudohypoparathyroidism--an example of 'Seabright-Bantam syndrome': report of three cases. Endocrinology 1942;30:922-32.
(2.) Bastepe M, Juppner H. GNAS locus and pseudohypoparathyroidism. Horm Res 2005;63:5.
(3.) Spiegel AM, Weinstein LS, Shenker A. Abnormalities in G protein-coupled signal transduction pathways in human disease. J Clin Invest 1993;92:1119.
(4.) Ahmed SF, Dixon PH, Bonthron DT, Stirling HF, Barr DG, Kelnar CJ, et al. GNAS1 mutational analysis in pseudohypoparathyroidism. Clin Endocrinol (Oxf) 1998;49:525-31.
(5.) Nakamoto JM, Sandstrom AT, Brickman AS, Christenson RA, Van Dop C. Pseudohypoparathyroidism type Ia from maternal but not paternal transmission of a Gsalpha gene mutation. Am J Med Genet 1998;77:261-7.
(6.) Levine MA, Downs RW Jr, Moses AM, Breslau NA, Marx SJ, Lasker RD, 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.) Carlson HE, Brickman AS. Blunted plasma cyclic adenosine monophosphate response to isoproterenol in pseudohypoparathyroidism. J Clin Endocrinol Metab 1983;56:1323-6.
(8.) Mantovani, G., Spada, A. Mutations in the Gs alpha gene causing hormone resistance. Best Pract. Res. Clin. Endocr. Metab 2006;20:501-13.
(9.) Downs RW Jr, Levine MA, Drezner MK, Burch WM Jr, Spiegel AM. Deficient adenylate cyclase regulatory protein in renal membranes from a patient with pseudohypoparathyroidism. J Clin Invest 1983;71:231-5.
(10.) Levine MA, Jap TS, Hung W. Infantile hypothyroidism in two sibs: an unusual presentation of pseudohypoparathyroidism type Ia. J Pediatr 1985;107:919-22.
(11.) Mantovani G1, Maghnie M, Weber G, De Menis E, Brunelli V, Cappa M, et al. Growth hormone-releasing hormone resistance in pseudohypoparathyroidism type Ia: new evidence for imprinting of the Gs-alpha gene. J Clin Endocrinol Metab 2003;88:4070-4.
(12.) de Nanclares GP, Fernandez-Rebollo E, Santin I, Garcia-Cuartero B, Gaztambide S, Menendez E, et al. Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright's hereditary osteodystrophy. J Clin Endocrinol Metab 2007;92:2370-3.
(13.) Stirling HF, Barr DG, Kelnar CJ. Familial growth hormone releasing factor deficiency in pseudopseudohypoparathyroidism. Arch Dis Child 1991;66:533-5.
(14.) Breslau NA, Notman DD, Canterbury JM, Moses AM. Studies on the attainment of normocalcemia in patients with pseudohypoparathyroidism. Am J Med 1980;68:856-60.
(15.) Ish-Shalom S, Rao LG, Levine MA, Fraser D, Kooh SW, Josse RG, et al. Normal parathyroid hormone responsiveness of bone-derived cells from a patient with pseudohypoparathyroidism. J Bone Miner Res 1996;11:8-14.
(16.) Hewitt M, Chambers TL. Early presentation of pseudohypoparathyroidism. J Roy Soc Med 1988;81:666-7.
(17.) Izraeli S, Metzker A, Horev G, Karmi D, Merlob P, Farfel Z. Albright hereditary osteodystrophy with hypothyroidism, normocalcemia, and normal Gs protein activity: a family presenting with congenital osteoma cutis. Am J Med Genet 1992;43:764-7.
(18.) Zung A, Herzenberg JE, Chalew SA. Radiological case of the month. Arch Pediatr Adolesc Med 1996;150:643-4.
(19.) Germain-Lee EL, Groman J, Crane JL, Jan deBeur SM, Levine MA. Growth hormone deficiency in pseudohypoparathyroidism type 1a: another manifestation of multihormone resistance. J Clin Endocrinol Metab 2003;88:4059-69.
(20.) Mantovani G, Bondioni S, Linglart A, Maghnie M, Cisternino M, Corbetta S, et al. Genetic analysis andevaluation of resistance to thyrotropin andgrowth hormone-releasing hormone in pseudohypoparathyroidismtype Ib. J Clin Endocrinol Metab 2007;92:3738-42.
(21.) Weisman Y, Golander A, Spirer Z, Farfel Z. Pseudohypoparathyroidism type Ia presenting as congenital hypothyroidism. J Pediatr 1985;107:413-5.
(22.) Ozbey N. Pseudohypoparathyroidism with normocalcemia. J Endocrinol Invest 2001;24:642-3.
(23.) Thiele S, Werner R, Ahrens W, Hoppe U, Marschke C, Staedt P, et al. A disruptive mutation in exon 3 of the GNAS gene with Albright hereditary osteodystrophy, normocalcemic pseudohypoparathyroidism, and selective long transcript variant Gsalpha-L deficiency. J Clin Endocrinol Metab 2007;92:1764-8.
(24.) Tamada Y, Kanda S, Suzuki H, Tajima T, Nishiyama T. A Pseudohypoparathyroidism Type Ia Patient with Normocalcemia. Endocrine Journal 2008;55:169-73.
(25.) Zerwekh JE, Breslau NA. Human placental production of 1 alpha,25-dihydroxyvitamin D3: biochemical characterization and production in normal subjects and patients with pseudohypoparathyroidism. J Clin Endocrinol Metab 1986;62:192-6.
(26.) Murray TM, Rao LG, Wong MM, Waddell JP, McBroom R, Tam CS, et al. Pseudohypoparathyroidism with osteitis fibrosa cystica: direct demonstration of skeletal responsiveness to parathyroid hormone in cells cultured from bone. J Bone Miner Res 1993;8:83-91.
[iD] Esra KUTLU (1), [iD] Ilker Tolga OZGEN (1), [iD] Yasar CESUR (2), [iD] Gozde YESIL (3)
(1) Bezmialem Vakif University Faculty of Medicine, Department of Child Endocrinology, Istanbul, Turkey
(2) Bezmialem Vakif University Faculty of Medicine, Department of Child Endocrinology and Metabolism, Istanbul, Turkey
(3) Bezmialem Vakif University Faculty of Medicine, Deparment of Medical Genetics, Istanbul, Turkey
Address for Correspondence: Esra KUTLU, Bezmialem Vakif University Faculty of Medicine, Department of Child Endocrinology, Istanbul, Turkey
Phone: +90 505 520 3411 E-mail: firstname.lastname@example.org ORCID ID: orcid.org/0000-0002-4554-1631
Cite this article as: Kutlu E, Ozgen IT, Cesur Y, Yesil G. Pseudohypoparathyroidism Type la with Normocalcemia. Bezmialem Science 2019;7(2):170-3.
Table 1. Hemoglobin 12.9 (11-13 (**) ALT (U/L) 15 (8.7-39) (g/dL) (*) MCV (fL) 85.6 (75-90) AST (U/L) 192 (100-500) Platelet 227 (142-424) FT4 (pmol/L) 8.71 (11.2-18.6) (10*3 u/L) Leucocyte 7.2 (6-17) TSH (mIU/L) 9.2 (0.51-4.82) (10*3 u/L) Sodium 140 (139-146) Calcium (mg/dL) 9.7 (8.8-10.8) (mmol/L) Potassium 4.4 (4.1-5.3) Phosphorus 5.8 (3.78-6.19) (mmol/L) (mg/dL) Chlorine 105 (98-106) ALP (U/L) 205 (135-537) (mmol/L) BUN (mg/dL) 12.5 (5.1-16.8) PTH (pg/mL) 436.9 (15-68.3) Creatine 0.44 (0.35-0.59) 25 OH vit D 28 (20-70) (mg/dL) (ng/mL) Fasting 80 (50-80) IGF-1 (ng/mL) 197 (51-303) Glucose (mg/dL) MCV: mean cell volume, BUN: blood urea nitrogen, AST: aspartate aminotransferase, ALT: alanine aminotransferase, FT4: free tetraiodothyronine, TSH: thyroid stimulating hormone, ALP: alkaline phosphatase, IGF-1: insuline like growth factor-1, (*) Laboratory measurement units; (**) Reference Values
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|Title Annotation:||Case Report|
|Author:||Kutlu, Esra; Ozgen, Ilker Tolga; Cesur, Yasar; Yesil, Gozde|
|Date:||Apr 1, 2019|
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