Judit Tőke

Diagnostic performance of salivary cortisol and serum osteocalcin measurements in patients with overt and subclinical Cushing's syndrome

OBJECTIVE The cut-off value for salivary cortisol measurement for the diagnosis of Cushings syndrome (CS) may depend both on the severity of the disease and the composition of control group. Therefore, we examined the utility of midnight salivary cortisol measurements in patients who were evaluated for signs and symptoms of CS or because they had adrenal incidentalomas. Because serum osteocalcin (OC) is considered as a sensitive marker of hypercortisolism, we also investigated whether OC could have a role in the diagnosis of CS. PATIENTS AND METHODS Each of the 151 patients was included into one of the following groups: (A) overt CS (n=23), (B) subclinical CS (n=18), (C) inactive adrenal adenomas (n=40), (D) patients without HPA disturbances (n=70). Patients (C+D) were used as controls. Serum, salivary and urinary cortisol, and OC were measured by electrochemiluminescence immunoassay. RESULTS Group A had suppressed OC as compared to both group B and group (C+D). Serum and salivary cortisol concentrations showed strong negative correlations with OC in patients with overt CS. The areas under the curves of salivary and serum cortisol at 24:00 h (0.9790 and 0.9940, respectively) serum cortisol after low dose dexamethasone test (0.9930) and OC (0.9220) obtained from ROC analysis for the diagnosis of overt CS were not statistically different. CONCLUSION This study confirms the usefulness of midnight salivary cortisol measurements in the diagnosis of overt CS in the everyday endocrinological praxis. Our results suggest that OC may have a role in the diagnosis of overt CS.

High prevalence of PROP1 gene mutations in hungarian patients with childhood-onset combined anterior pituitary hormone deficiency

Combined pituitary hormone deficiency is characterized by the impaired production of pituitary hormones, commonly including growth hormone. The pathomechanism of the childhood-onset form of this disorder may involve germline mutations of genes encoding pituitary transcription factors, of which PROP1 gene mutations have been studied most extensively. However, controversy exists about the significance of PROP1 gene mutations, as both low and high frequencies have been reported in these patients. Because the different results may be related to differences in patient populations and/or the variability of clinical phenotypes, we performed the present study to examine the prevalence and spectrum of PROP1 gene mutations in 35 patients with non-acquired childhood-onset growth hormone deficiency combined with at least one other anterior pituitary hormone deficiency. Genetic testing indicated the presence of disease-causing mutations in exons 2 and 3 of the PROP1 gene in 15 patients (43% of all patients; homozygous mutations in 10 patients and compound heterozygous mutations in 5 patients). Comparison of clinical data of patients with and without PROP1 gene mutations failed to show significant differences, except an earlier growth retardation detected in patients with PROP1 gene mutations. In one patient with PROP1 gene mutation, radiologic imaging showed an enlargement of the anterior lobe of the pituitary, whereas the other patients had hypoplastic or normal pituitary gland. All patients with PROP1 gene mutations had normal posterior pituitary lobe by radiologic imaging. These results indicate that using our inclusion criteria for genetic testing, PROP1 gene mutations can be detected in a high proportion of Hungarian patients with non-acquired childhood-onset growth hormone deficiency combined with at least one other anterior pituitary hormone defect.

Laterality disturbance and hypopituitarism. A case report of co-existing situs inversus totalis and combined pituitary hormone deficiency

The authors present the case history of a 52-yr-old male patient with a unique association of combined pituitary hormone deficiency (CPHD) and situs inversus totalis. Except for signs and symptoms of pituitary hormone deficiency, the patient had no dysmorphic features, and hearing impairment, primary mental or neurologicaldefects were also absent. Pituitary magnetic resonance imaging (MRI) scan showed hypoplasia of the anterior lobe of the pituitary gland and an ectopic posterior pituitary lobe. Despite the presence of situs inversus totalis, thepatient was right-handed and functional MRI demonstrated left-hemisphere activation during language tests. Kartagener syndrome was considered, but immunofluorescence analysis showed normal localization of the outer dynein arm protein in respiratory epithelial cells obtained from the nasal mucosa. Direct DNA sequencing of all coding exons of the pituitary transcription factor 1 (PIT1) and prophet of PIT1 (PROP1) genes failed to detect disease-causing mutations, suggesting that these genes were not involved in the development of CPHD in our patient. More interestingly, the potential role of the paired like homeodomain transcription factor 2 (PITX2) gene, which has been implicated not only in CPHD, but also in left-right patterning in animal models, was also excluded, as sequencing showed the absence of mutations in coding exons of this gene. To our knowledge, PITX2 gene mutations have not been investigated in CPHD patients who had situs inversus totalis. We conclude that in contrast to animal models, the PITX2 gene is not involved in the development of situs inversus totalis, at least not in our CPHD patient.

Gradual Development of Brachydactyly in Pseudohypoparathyroidism

Our patient, a 20-year-old female, presented with slightly delayed motor development and increasing obesity from age 9 months. Macrocephaly, facial dysmorphism, and mild mental retardation were noted at age 12 months. Despite a series of investigations and extensive workup for various suspected disorders, the final diagnosis of pseudohypoparathyroidism type Ia (PHP) was not established until age 15 years. At that time, she presented with perioral and upper/lower extremity numbness and tingling. Her labs showed serum calcium, 1.60 mmol/L (reference range, 2.2–2.6); serum phosphate, 2.16 mmol/L (0.8–1.45); serum PTH, 398 pg/mL (10–55); and 25-hydroxyvitamin D3, 16.7 ng/mL (30–73). Subsequently, typical features of Albright’s hereditary osteodystrophy (AHO) were recognized with short stature, obesity, and brachydactyly. Extensive calcifications in the basal ganglia, as well as the subcortical and deep white matter, were observed on her brain computed tomography scan. Her PTH remained elevated despite normalized serum vitamin D. The patient had hypothyroidism and hypergonadotropic primary amenorrhea, as well as insulin resistance. She had no family history of AHO or PHP. Genetic analysis revealed a new GNAS mutation. We present a series of 14 chronological photographs from our patient with typical AHO phenotype to document the gradual development of brachydactyly from age 6 weeks to 20 years. The images indicate that short fingers became evident in our patient only after the age of 5 years (Figure 1). Brachydactyly is one of the most specific phenotypic signs of AHO and PHP (1, 2). Although its presence may facilitate the correct diagnosis, it is very important to be aware that brachydactyly may not be present in early childhood.

Parathyroid hormone-dependent hypercalcemia

ZusammenfassungIn den vergangenen 15 Jahren wurden große Fortschritte im Verständnis der Pathogenese und der Pathophysiologie sowohl der sporadisch als auch der familiär auftretenden hyperkalzämischen Erkrankungen erzielt. Die vorliegende Arbeit gibt einen kurzen Überblick über die wichtigsten neuen Erkenntnisse bezüglich der sporadischen und der vererbbaren Formen der von der Nebenschilddrüse abhängigen hyperkalzämischen Erkrankungen, wobei der Schwerpunkt der Besprechung bei den familiären Syndromen, wie der MEN Typ I und der MEN Typ II A, dem Hyperparathyreoidismus-Kiefertumor- Syndrom, dem isolierten familiären Hyperparathyreoidismus, der familiären hypokalziurischen Hyperkalzämie und schließlich dem schweren neonatalen primären Hyperparathyreoidismus liegt. Zusätzlich werden die wichtigsten klinischen Charakteristika von 141 an einem ungarischen endokrinologischen Zentrum zwischen 1997 und 2007 diagnostizierten Patienten mit Parathormon-abhängiger Hyperkalzämie vorgestellt, wobei die Index-Patienten von 18 Familien mit vererbbaren Erkrankungen inkludiert sind.SummaryThe past fifteen years have resulted in great progress in our understanding of the pathogenesis and pathophysiology of hypercalcemic disorders occurring either sporadically or in a familial setting. This paper briefly reviews the clinically most important new knowledge on sporadic and hereditary forms of parathyroid hormone-dependent hypercalcemic disorders, with special emphasis on familial syndromes such as multiple endocrine neoplasia type 1 and type 2A, hyperparathyroidism-jaw tumor syndrome, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia and neonatal severe primary hyperparathyroidism. In addition, the authors briefly present the most important clinical characteristics of 141 patients with parathyroid hormone-dependent hypercalcemia, including index patients of 18 families with hereditary disorders, diagnosed in a Hungarian endocrine center between 1997 and 2007.

Parathyroid hormone-dependent hypercalcemia@@@Parathormon-abhängige Hyperkalzämie

ZusammenfassungIn den vergangenen 15 Jahren wurden große Fortschritte im Verständnis der Pathogenese und der Pathophysiologie sowohl der sporadisch als auch der familiär auftretenden hyperkalzämischen Erkrankungen erzielt. Die vorliegende Arbeit gibt einen kurzen Überblick über die wichtigsten neuen Erkenntnisse bezüglich der sporadischen und der vererbbaren Formen der von der Nebenschilddrüse abhängigen hyperkalzämischen Erkrankungen, wobei der Schwerpunkt der Besprechung bei den familiären Syndromen, wie der MEN Typ I und der MEN Typ II A, dem Hyperparathyreoidismus-Kiefertumor- Syndrom, dem isolierten familiären Hyperparathyreoidismus, der familiären hypokalziurischen Hyperkalzämie und schließlich dem schweren neonatalen primären Hyperparathyreoidismus liegt. Zusätzlich werden die wichtigsten klinischen Charakteristika von 141 an einem ungarischen endokrinologischen Zentrum zwischen 1997 und 2007 diagnostizierten Patienten mit Parathormon-abhängiger Hyperkalzämie vorgestellt, wobei die Index-Patienten von 18 Familien mit vererbbaren Erkrankungen inkludiert sind.SummaryThe past fifteen years have resulted in great progress in our understanding of the pathogenesis and pathophysiology of hypercalcemic disorders occurring either sporadically or in a familial setting. This paper briefly reviews the clinically most important new knowledge on sporadic and hereditary forms of parathyroid hormone-dependent hypercalcemic disorders, with special emphasis on familial syndromes such as multiple endocrine neoplasia type 1 and type 2A, hyperparathyroidism-jaw tumor syndrome, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia and neonatal severe primary hyperparathyroidism. In addition, the authors briefly present the most important clinical characteristics of 141 patients with parathyroid hormone-dependent hypercalcemia, including index patients of 18 families with hereditary disorders, diagnosed in a Hungarian endocrine center between 1997 and 2007.

Analysis of laboratory data of 155 patients with pheochromocytoma-paraganglioma syndrome diagnosed during the past 20 years

Bevezetés: A phaeochromocytoma-paraganglioma szindróma laboratóriumi kórismézése jelentős fejlődésen ment keresztül az utóbbi két évtizedben. Célkitűzés: Jelen vizsgálat célja, hogy retrospektív elemzéssel bemutassa és értékelje a Semmelweis Egyetem, II. Belgyógyászati Klinikán 1993–2013 között diagnosztizált phaeochromocytomás/paragangliomás betegek klinikai és laboratóriumi adatait. Módszer: A vizeletkatecholaminokat és metabolitjaikat nagy felbontású folyadékkromatográfiát követő elektrokémiai detektálással mérték 155 phaeochromocytoma-paraganglioma szindrómás (28,4%-uk örökletes hátterű) betegben és 170 nem phaeochromocytomás egyénben. A szérum-chromogranin-A-t immunradiometriás módszerrel vizsgálták. Eredmények: A 24 órás gyűjtött vizeletben a frakcionált metanephrinek szenzitivitása (93,2%) és specificitása (87,0%) meghaladta a katecholaminok (90,9% és 85,7%) és a szérum-chromogranin-A-meghatározás (88,7%, illetve 77,5%) hasonló értékeit. A vizeletnormetanephrin, illetve a szérum-chromogranin-A pozitív összefüggést mutatott a daganatátmérővel (r = 0,552, p<0,0001, illetve r = 0,618, p<0,0001). Következtetések: Az eredmények a vizelettel ürülő katecholaminmetabolitok meghatározásának jelentőségét igazolják a phaeochromocytoma-paraganglioma diagnosztikájában. A vizeletnormetanephrin és a szérum-chromogranin-A segíthet a tumortömeg és a progresszió megítélésében. Orv. Hetil., 2015, 156(16), 626–635.INTRODUCTION Laboratory diagnosis of pheochromocytoma-paraganglioma syndrome has been markedly improved during the past two decades. AIM Retrospective assessment of diagnostic utility of urinary catecholamines and their metabolites as well as serum chromogranin A in 155 patients diagnosed at the 2nd Department of Medicine, Semmelweis University. METHOD Urinary catecholamines and metabolites were measured using high-performance liquid chromatography with electrochemical detection in 155 patients with pheochromocytoma-paraganglioma (of whom 28.4% had hereditary background) and in 170 non-pheochromocytoma patients used as controls. Serum chromogranin A was measured by immunoradiometry. RESULTS Sensitivity (93.2%) and specificity (87.0%) of urinary fractionated metanephrines were higher than those of urinary catecholamines (90.9% vs. 85.7%, respectively) and serum chromogranin A (88.7% and 77.5%, respectively). Urinary normetanephrine and serum chromogranin A correlated positively with tumor size (r = 0.552, p<0.0001 and r = 0.618, p<0.0001, respectively). CONCLUSIONS These data confirm the diagnostic utility of urinary catecholamines and their metabolites. Urinary normetanephrine and serum chromogranin A may help to estimate tumour mass and probably tumour progression.

Genetikai tényezők a hypopituitarismus kialakulásában. A transzkripciós faktorok szerepe az agyalapimirigy-elégtelenség hátterében

Developmental disorders affecting the hypothalamic-pituitary system can result in pituitary hormone deficiency showing a diverse clinical presentation. A significant majority of these disorders are closely linked to defects in transcription factor genes which play a major role in pituitary development. Those affecting the early phase of organogenesis typically lead to complex conditions affecting the pituitary as well as structures in the central nervous system. Transcription factors involved in the late phase can result in combined but rarely isolated pituitary hormone deficiency without extra-pituitary manifestation. Identifying the defects in these pituitary transcription factor genes may provide a useful tool in predicting disease progression as well as screening family members. Several pituitary transcription factors can be detected in the adult gland as well which is strongly emphasized in the World Health Organizations most recent guideline for pituitary tumor classification. Our review summarizes the current essential knowledge relevant for clinical endocrinologists. Orv Hetil. 2018; 159(7): 278-284.Developmental disorders affecting the hypothalamic-pituitary system can result in pituitary hormone deficiency showing a diverse clinical presentation. A significant majority of these disorders are closely linked to defects in transcription factor genes which play a major role in pituitary development. Those affecting the early phase of organogenesis typically lead to complex conditions affecting the pituitary as well as structures in the central nervous system. Transcription factors involved in the late phase can result in combined but rarely isolated pituitary hormone deficiency without extra-pituitary manifestation. Identifying the defects in these pituitary transcription factor genes may provide a useful tool in predicting disease progression as well as screening family members. Several pituitary transcription factors can be detected in the adult gland as well which is strongly emphasized in the World Health Organizations most recent guideline for pituitary tumor classification. Our review summarizes the current essential knowledge relevant for clinical endocrinologists. Orv Hetil. 2018; 159(7): 278-284.

A laboratóriumi diagnosztika eredményei az elmúlt 20 évben kórismézett 155 phaeochromocytoma/paraganglioma szindrómás beteg adatainak elemzése alapján@@@Analysis of laboratory data of 155 patients with pheochromocytoma-paraganglioma syndrome diagnosed during the past 20 years

Bevezetés: A phaeochromocytoma-paraganglioma szindróma laboratóriumi kórismézése jelentős fejlődésen ment keresztül az utóbbi két évtizedben. Célkitűzés: Jelen vizsgálat célja, hogy retrospektív elemzéssel bemutassa és értékelje a Semmelweis Egyetem, II. Belgyógyászati Klinikán 1993–2013 között diagnosztizált phaeochromocytomás/paragangliomás betegek klinikai és laboratóriumi adatait. Módszer: A vizeletkatecholaminokat és metabolitjaikat nagy felbontású folyadékkromatográfiát követő elektrokémiai detektálással mérték 155 phaeochromocytoma-paraganglioma szindrómás (28,4%-uk örökletes hátterű) betegben és 170 nem phaeochromocytomás egyénben. A szérum-chromogranin-A-t immunradiometriás módszerrel vizsgálták. Eredmények: A 24 órás gyűjtött vizeletben a frakcionált metanephrinek szenzitivitása (93,2%) és specificitása (87,0%) meghaladta a katecholaminok (90,9% és 85,7%) és a szérum-chromogranin-A-meghatározás (88,7%, illetve 77,5%) hasonló értékeit. A vizeletnormetanephrin, illetve a szérum-chromogranin-A pozitív összefüggést mutatott a daganatátmérővel (r = 0,552, p<0,0001, illetve r = 0,618, p<0,0001). Következtetések: Az eredmények a vizelettel ürülő katecholaminmetabolitok meghatározásának jelentőségét igazolják a phaeochromocytoma-paraganglioma diagnosztikájában. A vizeletnormetanephrin és a szérum-chromogranin-A segíthet a tumortömeg és a progresszió megítélésében. Orv. Hetil., 2015, 156(16), 626–635.INTRODUCTION Laboratory diagnosis of pheochromocytoma-paraganglioma syndrome has been markedly improved during the past two decades. AIM Retrospective assessment of diagnostic utility of urinary catecholamines and their metabolites as well as serum chromogranin A in 155 patients diagnosed at the 2nd Department of Medicine, Semmelweis University. METHOD Urinary catecholamines and metabolites were measured using high-performance liquid chromatography with electrochemical detection in 155 patients with pheochromocytoma-paraganglioma (of whom 28.4% had hereditary background) and in 170 non-pheochromocytoma patients used as controls. Serum chromogranin A was measured by immunoradiometry. RESULTS Sensitivity (93.2%) and specificity (87.0%) of urinary fractionated metanephrines were higher than those of urinary catecholamines (90.9% vs. 85.7%, respectively) and serum chromogranin A (88.7% and 77.5%, respectively). Urinary normetanephrine and serum chromogranin A correlated positively with tumor size (r = 0.552, p<0.0001 and r = 0.618, p<0.0001, respectively). CONCLUSIONS These data confirm the diagnostic utility of urinary catecholamines and their metabolites. Urinary normetanephrine and serum chromogranin A may help to estimate tumour mass and probably tumour progression.

Az ösztradiol hatásai és jelentősége férfiakban@@@Effects and significance of estradiol in men

The most important estrogen is estradiol in both men and women. In men elevated estradiol levels and associated metabolic disorders have been implicated in the development of common diseases including cardiovascular disorders, insulin resistance and type 2 diabetes mellitus, as increased estradiol associated with decreased testosterone levels increases the risk of these diseases. In this review the authors summarize the causes and consequences of androgen deficiency and estradiol excess, and they review recent studies on potential therapeutic strategies to correct increased estradiol levels in men.