[Steroid 21-hydroxylase deficiency, the most frequent cause of congenital adrenal hyperplasia]. / Szteroid-21-hidroxiláz-deficientia, a congenitalis adrenalis hyperplasia leggyakoribb oka.

Congenital adrenal hyperplasia is a group of genetic diseases due to the disablement of 7 genes; one of them is steroid 21-hydroxylase deficiency. The genes of congenital adrenal hyperplasia encode enzymes taking part in the steroidogenesis of adrenal gland. Steroid 21-hydroxylase deficiency is an autosomal recessive disorder caused by mutations of the steroid 21-hydroxylase gene. The mutations of steroid 21-hydroxylase gene cause 95% of the congenital adrenal hyperplasia cases. Although the non-classic steroid 21-hydroxylase deficiency with mild symptoms is seldom diagnosed, the classic steroid 21-hydroxylase deficiency may lead to life-threatening salt-wasting and adrenal crises due to the insufficient aldosterone and cortisol serum levels. The classic type requires life-long steroid replacement which may result in cushingoid side effects, and typical comorbidities may be also developed. The patients' quality of life is decreased, and their mortality is much higher than that of the population without steroid 21-hydroxylase deficiency. The diagnosis, consequences and the patients' life-long clinical care require a multidisciplinary approach: the specialists in pediatrics, internal medicine, endocrinology, laboratory medicine, genetic diagnostics, surgery, obstetrics-gynecology and psychology need to work together. Orv Hetil. 2018; 159(7): 269-277.

Loss of Function of the Nuclear Receptor NR2F2, Encoding COUP-TF2, Causes Testis Development and Cardiac Defects in 46,XX Children.

Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks that canalize development down one pathway while actively repressing the other. However, in contrast to testis formation, the gene regulatory pathways governing mammalian ovary development have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization or with testicular/ovotesticular disorders/differences of sex development (TDSD/OTDSD). We identified heterozygous frameshift mutations in NR2F2, encoding COUP-TF2, in three children. One carried a c.103_109delGGCGCCC (p.Gly35Argfs∗75) mutation, while two others carried a c.97_103delCCGCCCG (p.Pro33Alafs∗77) mutation. In two of three children the mutation was de novo. All three children presented with congenital heart disease (CHD), one child with congenital diaphragmatic hernia (CDH), and two children with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). The three children had androgen production, virilization of external genitalia, and biochemical or histological evidence of testicular tissue. We demonstrate a highly significant association between the NR2F2 loss-of-function mutations and this syndromic form of DSD (p = 2.44 × 10-8). We show that COUP-TF2 is highly abundant in a FOXL2-negative stromal cell population of the fetal human ovary. In contrast to the mouse, these data establish COUP-TF2 as a human "pro-ovary" and "anti-testis" sex-determining factor in female gonads. Furthermore, the data presented here provide additional evidence of the emerging importance of nuclear receptors in establishing human ovarian identity and indicate that nuclear receptors may have divergent functions in mouse and human biology.

Implant-Related Complications and Mortality After Use of Short or Long Gamma Nail for Intertrochanteric and Subtrochanteric Fractures: A Prospective Study with Minimum 13-Year Follow-up.

BACKGROUND: The purpose of this study was to evaluate the rates of implant-related complications and mortality after treatment of an intertrochanteric or subtrochanteric fracture with a short or long Gamma nail. METHODS: Between September 1998 and August 2003, 644 patients at 2 centers treated with a long or short Gamma nail for a hip fracture were prospectively enrolled in this study. These patients were followed until they reached 1 of the study end points, which included death, a reoperation directly related to the Gamma nail, or the end date of the study. RESULTS: The average age (and standard deviation) of the patients included in the study was 81.3 ± 8.6 years at the time of the operation, and 28.3% of the patients were male. The rate of implant-related complications was 9.9%. The most common complications included peri-implant fracture (4.2%), proximal lateral thigh discomfort requiring extraction of the implant (2.0%), and lag-screw cutout (1.1%). Interestingly, more than half (56%) of the 27 peri-implant fractures occurred >1.5 years after the index operation. The median time from the operation to death was 2.9 years (range, 0 to 17.1 years). The 30-day mortality rate after treatment was 9.5%. Patients with American Society of Anesthesiologists (ASA) class-3 or 4 physical status had a significantly higher risk of mortality than ASA class-1 patients. CONCLUSIONS: Gamma nails are effective in the treatment of intertrochanteric and subtrochanteric fractures. However, 9.8% of patients had complications requiring additional surgery. The most common serious complications include peri-implant fracture and lag-screw cutout. Several peri-implant fractures occurred long after the index procedure. Patients had a high rate of mortality (27%) after 1 year, and higher preoperative ASA class was found to be a predictor of increased risk of mortality. Therefore, clinicians must carefully consider patients' preoperative comorbidities when counselling patients on the risks of surgery. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Hyperthyroidism caused by a germline activating mutation of the thyrotropin receptor gene: difficulties in diagnosis and therapy.

BACKGROUND: Germline activating mutations of the thyrotropin receptor (TSHR) gene have been considered as the only known cause of sporadic nonautoimmune hyperthyroidism in the pediatric population. Here we describe the long-term follow-up and evaluation of a patient with sporadic nonautoimmune primary hyperthyroidism who was found to have a de novo germline activating mutation of the TSHR gene. SUMMARY: The patient was an infant who presented at the age of 10 months in an unconscious state with exsiccation, wet skin, fever, and tachycardia. Nonautoimmune primary hyperthyroidism was diagnosed, and brain magnetic resonance imaging and computed tomography showed also Arnold-Chiari malformation type I. Continuous propylthiouracil treatment resulted in a prolonged clinical cure lasting for 10 years. At the age of 11 years and 5 months the patient underwent subtotal thyroidectomy because of symptoms of trachea compression caused by a progressive multinodular goiter. However, 2 months after surgery, hormonal evaluation indicated recurrent hyperthyroidism and the patient was treated with propylthiouracil during the next 4 years. At the age of 15 years the patient again developed symptoms of trachea compression. Radioiodine treatment resulted in a regression of the recurrent goiter and a permanent cure of hyperthyroidism without relapse during the last 3 years of his follow-up. Sequencing of exon 10 of the TSHR gene showed a de novo heterozygous germline I630L mutation, which has been previously described as activating mutation at somatic level in toxic thyroid nodules. CONCLUSIONS: The I630L mutation of the TSHR gene occurs not only at somatic level in toxic thyroid nodules, but also its presence in germline is associated with nonautoimmune primary hyperthyroidism. Our case report demonstrates that in this disorder a continuous growth of the thyroid occurs without any evidence of elevated TSH due to antithyroid drug overdosing. This may justify previous recommendations for early treatment of affected patients with removal of as much thyroid tissue as possible.

[Incomplete androgen insensitivity]. / Inkomplett androgéninszenzitivitás szindróma.

In the androgen insensitivity syndrome (AIS) the androgen effect is decreased in the fetus and the youth despite the adequate testosterone production. Usually the mutation of the androgen receptor is responsible for the disease. In the presented case the external genitalia were similar to female genitalia but masses were palpable in the labioscrotal fold. The karyotype was 46,XY. There was no increase in the testosterone level during the first three months of life. The stimulation test by stanazolol and the androgen receptor gene analysis verified the androgen insensitivity. The mutation was absent in the mother's leukocytes. This fact makes the genetic advising difficult in this family.

[Nucleotide sequence variants of the glucocorticoid receptor gene and their significance in determining glucocorticoid sensitivity]. / A glükokortikoidreceptor gén szekvenciavariánsai és jelentoségük a glükokortikoidok iráinti érzékenység meghatározásában.

Nucleotide sequence variants of the glucocorticoid receptor gene and their significance in determining glucocorticoid sensitivity. The physiologic response and sensitivity to glucocorticoids may significantly differ among species, individuals, tissues and cell types. The variability of the effect of endogenous and exogenous glucocorticoids is largely determined by genetic components, of which the authors review the knowledge on the glucocorticoid receptor gene. The authors describe the genomic and non-genomic pathways of receptor function, the significance of isoforms produced during receptor protein formation, the pathomechanism of glucocorticoid resistance syndrome and the results of clinical investigations related to receptor gene polymorphisms. Through subtle alteration of receptor function, the gene polymorphisms may increase or diminish sensitivity to glucocorticoids and may play a role in the pathogenesis of metabolic disorders. In their own studies the authors found, that the N363S polymorphism, which increases glucocorticoid sensitivity, may play a role in the pathogenesis of bilateral adrenal adenomas, it may modify the clinical phenotype of patients with congenital adrenal hyperplasia, and may have an impact on steroid-induced ocular hypertension. It is presumed that further research in other diseases will continue to complete our knowledge on the pathophysiology of glucocorticoid receptor gene polymorphisms.

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.

Estimation of the false-negative rate in newborn screening for congenital adrenal hyperplasia.

OBJECTIVE: Newborn screening based on measurement of 17alpha-hydroxyprogesterone (17-OHP) in a dried blood spot on filter paper is an effective tool for early diagnosis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Its most important rationale is prevention of a life-threatening salt-wasting (SW) crisis; in moderate forms of CAH, early diagnosis and treatment may prevent permanent negative effects of androgen overproduction. Our target was to analyse if all CAH patients who had been identified clinically before puberty would have been detected by the newborn screening. METHODS: Newborn screening cards of 110 CAH patients born between 1988 and 2000 in five Middle-European countries and diagnosed prior to puberty (77 SW and 33 moderate) and cards from 920 random, healthy newborn controls were analysed. CAH screening had not yet been introduced during this time. The diagnosis was based on clinical and laboratory signs and, in most cases, on CYP21 gene mutation analysis. All 17-OHP measurements in dried blood spots were carried out using a time-resolved fluoroimmunoassay kit. RESULTS: In the newborn screening blood spots, the median of 17-OHP levels was 561 nmol/l (range 91-1404 nmol/l) in subjects with the SW form and 40 nmol/l (4-247 nmol/l) in the moderate form. All 77 SW patients would have been detected by newborn screening using the recommended cut-off limits (30 nmol/l). However, 10 of 33 patients with moderate CAH would have been missed. 17-OHP levels of all controls were below the cut-off. CONCLUSION: Newborn screening is efficient for diagnosing the SW form of CAH, but is inappropriate for identifying all patients with a moderate form of CAH. It appears that the false-negative rate is at least one-third in children with the moderate form of CAH.

[Identification of congenital adrenal hyperplasia by measurement of blood-spot 17-hydroxyprogesterone]. / Congenitalis adrenalis hyperplasia azonosítása vérfolt-17-hidroxiprogeszteron mérésével

UNLABELLED: Identification of congenital adrenal hyperplasia by measurement of blood-spot 17-hydroxyprogesterone. INTRODUCTION: 21-hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia (CAH). The simplest way to diagnose the disease is the measurement of 17-hydroxyprogesterone level in the serum. AIMS: The aim of the study was to analyze the clinical advantages of a centralized diagnostic strategy in Hungary using measurement of 17-hydroxyprogesterone in dried blood spots. METHODS: During a 20 years period blood-spot samples of 1837 patients suspected to have CAH have been investigated. RESULTS: 185 patients proved to have CAH (classic 21-OHD 155; NCAH 27; 11beta-OHD 3 patients). A national database for CAH was set up by collecting further information about CAH patients in the country. Based on the frequency of the disease in girls during the nineties, the incidence of classical 21-OHD was calculated to be 1:11,147 in Hungary. CONCLUSIONS: Early diagnosis, optimal medical and surgical treatment, and attention to compliance may lead to further decrease in morbidity and mortality of CAH patients.

Twenty years experience in rapid identification of congenital adrenal hyperplasia in Hungary.

UNLABELLED: The aim of this study was to assess the effectivity of the identification of patients with congenital adrenal hyperplasia (CAH) in Hungary in the absence of systematic neonatal screening and to estimate the incidence. Dried blood-spot samples of patients clinically suspected at any age to have CAH were collected between 1978 and 1998 throughout the whole country. 17-Hydroxyprogesterone (17-OHP) was measured by radioimmunoassay. Age-specific cut-offs were used. The effectivity of the system was retrospectively assessed. Additional cases were sought to assess the overall incidence of CAH in Hungary. Among the 1,837 patients investigated, 185 cases of CAH were identified. The overall effectivity was 94.7%. The sensitivity and the specificity were 98.9% and 94.2%, respectively. Salt-wasting (SW) boys were, on average, diagnosed 2 weeks later than SW girls, while both boys and girls with the simple virilising (SV) form were diagnosed at similar ages (2 versus 2.5 years). An additional 19 cases were diagnosed during the study period using other methods (plasma and urinary steroid profiles without blood-spot 17-OHP measurements). The incidence of classical CAH in Hungary was 1:14,300 (CI 95% between 1:12,450 and 1:16,795). Presuming that the incidence of CAH is the same among boys and girls, one can calculate that the diagnosis was missed in 24 boys (2 SW, 22 SV). CONCLUSION: it is possible to identify the vast majority of classical cases of congenital adrenal hyperplasia without a neonatal mass screening programme. However, a significant number of boys with the simple virilising form missed whereas both salt-wasting boys and girls are diagnosed safely.

Mutational analysis of Hungarian patients with androgen insensitivity syndrome.

OBJECTIVE: To support the clinical diagnosis of androgen insensitivity syndrome (AIS), we performed mutational analysis of the androgen receptor gene. DESIGN: Clinical, hormonal and molecular genetic data of ten undervirilized genetic male patients living in Hungary were recorded. METHODS: PCR-based single strand conformation polymorphism (SSCP) analysis was used to study the whole coding region of the androgen receptor gene. Direct fluorescent sequencing was applied when aberrant migration was detected by SSCP. RESULTS: Five different mutations were identified in five unrelated genetic male patients with abnormal sexual differentiation. One of these mutations was novel, while the other four mutations have been described previously in the literature. One of the mutations identified earlier in individuals with sporadic AIS showed a familial inheritance pattern in our study group. No abnormality of the androgen receptor gene was identified in three patients clinically suspected to have partial AIS. CONCLUSION: Application of molecular techniques helped to clarify the diagnosis in patients with disorders of male sexual differentiation.