Case report of an adult female with neglected Congenital Adrenal hyperplasia (CAh) / Journal of the ASEAN Federation of Endocrine Societies

@#An apparently well 27-year-old phenotypically male adult was seen at the endocrine clinic for gender assignment. Patient had been raised as a male and identifies as such. Abdominal CT scan showed a unilateral left adrenal mass and karyotyping revealed 46 XX female karyotype. She was diagnosed to have simple virilizing CAH and needed thorough counselling with subsequent management by a multidisciplinary team

Phenotypic variation of 46,XX Late IdentifiedCongenital Adrenal Hyperplasia among Indonesians / Journal of the ASEAN Federation of Endocrine Societies

Objectives@#To describe the phenotype variation in Indonesian 46,XX late-identified congenital adrenal hyperplasia(CAH) and the correlation between 17-hydroxyprogesterone (17-OHP) and genital virilization.@*Methodology@#Retrospective study of 39 cases with five salt-wasting (SW) and 34 simple virilizing (SV) types.@*Results@#The median age of the patients was 9.83 years (range, 0.58 to 44 years) with Prader score 2 to 5. Clitoromegaly (100%) and skin hyperpigmentation (87%) were the most common features. Lack of breast development(Tanner 1 to 2) and menstrual disorders occurred in 9 patients (teenagers and adults). Short stature (6), low voice (14),prominentAdam’s apple (9) and hirsutism (4) were found only in SV types Rapid growth (7) and precocious puberty (8)were identified in children. Male gender on admission was found in 13 patients. The mean of 17-OHP level was 304.23nmol/L [standard deviation (SD) 125.03 nmol/L]. There was no correlation between 17-OHP levels and virilization(r=0.19, p>0.05).@*Conclusion@#Late-identified CAH showed severe virilization and irreversible sequelae, with clitoromegaly and skinhyperpigmentation as the most commonly seen features. Masculinization of CAH females created uncertainty withregard to sex assignment at birth, resulting in female, male and undecided genders. There is no significant correlationbetween 17-OHP levels with the degree of virilization in CAH females

Management framework paradigms for disorders of sex development

Until 2005, questions regarding medical treatment and diagnostic information on Disorders of Sex Development (DSD) were not systematically discussed with both the patients and their families; however, the way these patients are currently treated have been changing with time. Interventional changes in the clinical-psychotherapeutic-surgical areas of DSD determine not only different medical recommendations but also help to place the patient and the family into the decisional process of therapy. We must consider two paradigmatic periods that have influenced and transformed the clinical management framework of patients with DSD: a) The "Money era" (1955), which emphasized the role of the gonads as the diagnostic criterion, having the environment as determinant of the sex identity; and b) The Chicago Consensus (2005) phase, in which the role of genetics and molecular biology was critical for an early identification, as well as in building a proper sex identity, emphasizing ethical questions and the "stigma culture". In addition, recent data have focused on the importance of interdisciplinarity and statements on questions concerning Human Rights as key factors in treatment decision making. Despite each of these management models being able to determine specific directions and recommendations regarding the clinical handling of these patients, we verify that a composite of these several models is the clinical routine nowadays. In the present paper, we discuss these several paradigms, and pinpoint clinical differences and their unfolding regarding management of DSD patients and their families.

Valores elevados de leptina e LDL-colesterol em pacientes com hiperplasia adrenal congênita bem controlados / Elevated levels of leptin and LDL-cholesterol in patients with well controlled congenital adrenal hyperplasia

OBJETIVO: O objetivo deste estudo foi avaliar pacientes com HAC clássica antes e após tratamento com glicocorticoides e/ou mineralocorticoides e comparar o perfil metabólico entre o grupo bem controlado (BC) e mal controlado (MC). SUJEITOS E MÉTODOS: Foram selecionados pacientes recém-diagnosticados e pacientes em acompanhamento por HAC, forma clássica, em uso regular ou não de glicocorticoides/mineralocorticoides do Serviço de Genética do Hupes-UFBA, atendidos de março/2004 a maio/2006. Todos os pacientes foram submetidos a avaliação clínica detalhada e exames laboratoriais (glicemia, sódio e potássio, colesterol total, HDL, LDL, triglicerídeos, ácido úrico, leptina, 17-hidroxiprogesterona, testosterona total, peptídeo C e insulina). Os pacientes com valores normais de andrógenos foram classificados como bem controlados (BC) e os com valores elevados de andrógenos em uso ou não de glicocorticoides/mineralocorticoides foram classificados como mal controlados (MC). RESULTADOS: Foram estudados 41 pacientes com HAC: 11 no grupo BC e 30 no grupo MC. Leptina e LDL colesterol estavam mais elevados no grupo BC que no MC (p < 0,05). Valores de ácido úrico eram menores no grupo BC quando comparados com MC (p < 0,05). CONCLUSÃO: O controle adequado da HAC com glicocorticoides parece seguro, pois está associado a alterações discretas no perfil lipídico e da leptina. Não observamos outras alterações metabólicas associadas ao uso de glicocorticoides. O motivo para o menor valor de ácido úrico encontrado nos pacientes com HAC bem controlada não é conhecido e deve ser mais bem estudado.

OBJECTIVE: The objective of this study was to evaluate patients with classic CAH before and after treatment with glucocorticoids/mineralocorticoid and compare the metabolic profile of the well controlled (WC) and poorly controlled (PC) group. SUBJECTS AND METHODS: We selected newly diagnosed patients and patients monitored for CAH, classical form, regularly using or not glucocorticoids/mineralocorticoid in the Genetics Service Hupes-UFBA, seen from March/2004 to May/2006. All patients underwent detailed clinical evaluation and laboratory tests (glucose, sodium and potassium; total cholesterol, HDL, LDL, triglycerides and uric acid; leptin, 17-hydroxyprogesterone, total testosterone, C peptide, and insulin). Patients with normal androgens were classified as well controlled (WC), and those with high levels of androgens either using or not glucocorticoids/mineralocorticoids were classified as poorly controlled (PC). RESULTS: We studied 41 patients with CAH: 11 in the WC group and 30 in PC group. Leptin and LDL cholesterol levels were higher in WC than in the PC group (p < 0.05). Uric acid values ​​were lower in WC compared with the PC group (p < 0.05). CONCLUSION: Adequate control of CAH with steroids seems safe, as it is associated with only mild changes in lipid profile and leptin values. No other metabolic abnormality was associated with glucocorticoid use. The reason for lower uric acid levels found in WC CAH patients is unknown and should be further studied.

A Case of Xp21 Contiguous Gene Deletion Syndrome with Hyperglycerolemia, Congenital Adrenal Hypoplasia and Duchenne Muscular Dystrophy

On Xp21 region several genes such as adrenal hypoplasia congenita(AHC) gene, glycerol kinase (GK) gene and Duchenne muscular dystrophy(DMD) gene are located contiguously. If there is a long deletion in that region, various combination of genetic defect can be occurred from one kind of genetic defect to all three kinds of genetic defect simultaneously. In case of more than two genetic defects simultaneously, we call it contiguous gene deletion syndrome. The major clinical manifestations of the Xp21 contiguous gene deletion syndrome are sum of each diseases, electrolyte imbalance and hyperpigmentation for adrenal hypoplasia congenita, psychomotor retardation, letharginess and convulsion for glycerol kinase deficiency and muscle weakness and hypotonia for Duchenne muscular dystrophy. Goals of the treatment are control of each disorders, glucocorticoid and mineralocorticoid for adrenal hypoplasia congenita, low fat diet and prevention of fasting and hypercatabolic status for glycerol kinase deficiency and physiotherapy for Duchenne muscular dystrophy. In case of hyponatremia and hyperkalemia combined with hyperpigmentation, adrenal hypoplasia congenita could be suspected. In glycerol kinase deficiency, markedly elevated glycerol excretion can be detected on urine organic acid analysis by gaschromatography with mass spectrometry. On Duchenne muscular dystrophy, creatinine kinase is markedly elevated on chemistry. We report here first Korean case of Xp21 contiguous gene deletion syndrome of adrenal hypoplasia congenita, glycerol kinase deficiency and Duchenne muscular dystrophy.

Variables Influencing 17-Hydroxyprogesterone Values in Newborn Screening for Congenital Adrenal Hyperplasia

PURPOSE: Congenital adrenal hyperplasia(CAH), which is classified into salt-wasting, simple virilization and non-classic type according to clinical features, is difficult to detect in early stages. Failure to diagnose it in the initial state may lead to life-threatening adrenal crisis, inappropriate male sex assignment in the genetic female, acceleration of skeletal maturation and subsequent short stature. Therefore, we studied the variables increasing the 17-hydroxyprogesterone(OHP) values for more specific and sensitive diagnosis of CAH. METHODS: We classified 3,532 newborns into variable factors; gestational age, birth weight, gender, delivery type, sampling date and stress. Then, we analysed the relationships between 17-OHP values and variable factors. RESULTS: The mean value of 17-OHP was 4.21+/-0.03ng/ml. There were significant differences among the variable factors except gender. The mean value of male was 4.26ng/ml, and that of female was 4.15ng/ml(P=0.10). The mean value of 17-OHP in vaginal delivered newborn was higher than C-section delivered ones(4.71ng/ml, 3.34ng/ml, P=0.0001). It was also higher in low birth weight(P=0.0001), in prematurity(P=0.001), those sampled within 4 days(P=0.0001), stressful condition and ventilator care-assisted(P=0.004). CONCLUSION: 17-OHP value in neonatal screening is influenced by several variables such as vaginal delivery, ventilator management, low birth weight, sampling date and prematurity. If the 17-OHP value is increased, we have to consider the variables influencing the increase in value and follow up with time interval or analysis of genetic mutations.

Variables Influencing 17-Hydroxyprogesterone Values in Newborn Screening for Congenital Adrenal Hyperplasia

PURPOSE: Congenital adrenal hyperplasia(CAH), which is classified into salt-wasting, simple virilization and non-classic type according to clinical features, is difficult to detect in early stages. Failure to diagnose it in the initial state may lead to life-threatening adrenal crisis, inappropriate male sex assignment in the genetic female, acceleration of skeletal maturation and subsequent short stature. Therefore, we studied the variables increasing the 17-hydroxyprogesterone(OHP) values for more specific and sensitive diagnosis of CAH. METHODS: We classified 3,532 newborns into variable factors; gestational age, birth weight, gender, delivery type, sampling date and stress. Then, we analysed the relationships between 17-OHP values and variable factors. RESULTS: The mean value of 17-OHP was 4.21+/-0.03ng/ml. There were significant differences among the variable factors except gender. The mean value of male was 4.26ng/ml, and that of female was 4.15ng/ml(P=0.10). The mean value of 17-OHP in vaginal delivered newborn was higher than C-section delivered ones(4.71ng/ml, 3.34ng/ml, P=0.0001). It was also higher in low birth weight(P=0.0001), in prematurity(P=0.001), those sampled within 4 days(P=0.0001), stressful condition and ventilator care-assisted(P=0.004). CONCLUSION: 17-OHP value in neonatal screening is influenced by several variables such as vaginal delivery, ventilator management, low birth weight, sampling date and prematurity. If the 17-OHP value is increased, we have to consider the variables influencing the increase in value and follow up with time interval or analysis of genetic mutations.

Molecular Characterisation Of Mutations In Congenital Adrenal Hyperplasia In Indian Subjects.

Congenital adrenal hyperplasia (CAH) is one of the most common outosomal recessive condition causing ambiguous genitalia in females. Often, it's a life threatening condition occurring with 1 in 5000 to 15000 live births and caused due to mutations in CYP21 gene encoding the enzyme 21-hydroxylase. 25 cases of CAH reporting at All India Institute of Medical Sciences, New Delhi, were analysed for mutations in the gene CYP21 and the results are discussed.

Serum 17-Hydroxyprogesterone Levels in Term and Preterm Infants / 대한소아내분비학회지

PURPOSE:The incidence of congenital adrenal hyperplasia(CAH) is 1/5,000- 1/20,000 births and thus the importance of the neonatal screening test is being emphasized. However, the reference value for the term and preterm infants has not yet been established and false positive values are frequent due the immature hypothalamic-adrenal axis of the preterm infants or the stress-induced adrenal dysfunction. Therefore, we analyzed the 17-hydroxyprogesterone(17-OHP) concentration in terms of gestational age, birth weight, and postnatal state to establish the reference range for the Korean term and preterm infants. METHODS:We analyzed the results of the CAH screening test retrospectively, which was performed on 737 neonates(624 fullterm neonates, 113 premature neonates) born between January 1998 through July 1998 in Inje University College of Medicine Sanggye Paik Hospital. Mean gestational age and birth weight of infants were 38.2+/-2.6 weeks and 3,116+/-674kg respectively. 17-OHP screening test was performed on 4.9+/-3.8days after birth by obtaining blood samples from the heelstick of neonates. 17-OHP concentration was measured by the ELISA kit(ICN Co.) and repeated the procedure if the result was higher than 35ng/ml. RESULTS: 1) 17-OHP concentration of the preterm infants was significantly higher than that of the fullterm infants(19.1+/-12.3ng/ml vs 11.7+/-7.8ng/ml, P=0.001). 17-OHP concentration was inversely proportional to gestational age. 2)17-OHP concentration was inversely proportional to birth weight(r=0.22, P>0.01). 17-OHP concentration according to birth weight was as follows.:below 1,500g was 26.7+/-11.7ng/ml, 1,500 to 2,000g was 18.0+/-13.9ng/ml, 2,001 to 2,500g was 17.9+/-10.5ng/ml, 2,501 to 3,000g was 12.1+/-7.9ng/ml, 3,001 to 3,500g was 11.5+/-8.1ng/ml, above 3,500g was 11.4+/-7.5ng/ml. There was a significant decline in the 17-OHP concentration as the birth weight increased. 3) 17-OHP concentration was gradually decreased as sampling date increased. 4) The gender of the infants did not influence the 17-OHP concentration(male 13.0+/-9.1 vs female 12.7+/-9.0). 5)17-OHP concentration were significantly higher in sick preterm infants than healthy preterm infants. 6)Six cases, whose 17-OHP concentration were greater than 35ng/ml, were all preterm and low birth weight infants. Reexamination after one week showed the value within normal range. No CAH cases were diagnosed in the study. CONCLUSION: 17-OHP concentration was inversely proportional to gestational age and birth weight. Therefore, reference ranges of 17-OHP concentration should be subdivided according to gestational age and birth weight. Further research about perinatal risk factors affecting the 17-OHP concentration will be required.

Duplication and deletion of 21 hydroxylase gene among the normal Korean subjects and in adrenogenital syndrome patients

Steroid 21 hydroxylase deficiency is a major cause of congenital adrenal hyperplasia(CAH) and is caused by genetic impairment (CYP21B) of this enzyme. In the human genome, CYP21B is located within MHC class III region on the short arm of chromosome 6. Most of the genes in this region are highly polymorphic and crowded. Also the CYP21B gene is accompanied by its pseudogene (CYP21A) and tandemly arranged with two genes of fourth component of complement. This highly complex gene arrangement in this area may predispose genetic unstability of CYP21 genes,i.e. mutations. In the current study, we tried to investigate the frequency of duplication and deletion of CYP21 genes and pattern of the genetic alteration of these genes by RFLPs. We also compared the genetic alteration of CYP21 in normal subjects with those of the CAH patients. According to our study, 15% of the normal Korean population have duplication or deletion of CYP21. There was one normal subject with heterozygous deletion of CYP21B gene. Of the 5 CAH patients examined, we found abnormal patterns in 2 patients. One was a large scale gene conversion and the other was a deletion of CYP21B and C4 locus II genes with gene conversion. These results suggest that high frequency of duplication and deletion of CYP21 and C4 in the general population may provide the genetic pool of instable CYP21 genes and these duplicated or deleted genes may result in gene conversions between CYP21A(pseudogene) and CYP21B(true gene) by preventing the normal recombination event.

Hepatic Piecemeal Necrosis under Electron Microscope / 昆明医科大学学报

It was observed under an electron microscope that in the hepatic piecemeal necrotic area of CAH patients,there were T lymphocytes,plasma cells,monocytes,fatstoring cells and proliferating Hering's tubules.The more severe the patient's condition was,the much more the sorts and numbers of these cells were.We consider that the above observations by electron microscopy afford valuable morphological information about the severity of CAH.

Prenatal diagnosis of a heterozygote of salt wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency by genetic linkage analysis

For the purpose of prenatal diagnosis of CAH, genetic linkage analysis by HLA genotyping with lymphocytes and cultured amniotic cells were performed in a family at risk in which two consecutive children had been affected with SW CAH. In addition, the response of serum 17-OHP to intravenous ACTH was determined in obligate carrier parents, and 17-OHP concentration of amniotic fluid was also measured at 16 weeks of gestation. As might be expected, the baseline levels of 17-OHP in obligate parents were significantly higher than that of normal control. Although the post stimulation response of 17-OHP to ACTH in the mother (I-2) was significantly higher than that of normal control, the post stimulation levels of 17-OHP were in normal range in the father (I-1). The 17-OHP level (5.7 ng/ml) in the amniotic fluid showed intermediate value compared to Pang's report (normal less than 30 ng/ml, CAH greater than 12.0 ng/ml) suggesting heterozygote of the fetus. Genetic linkage analysis by HLA genotyping with cultured amniotic cells revealed heterozygote in their fetus (II-3) who has received one chromosome No,6 containing HLA haplotype A24, B40, Cw3 (normal allele for 21-OH) from the father and the other chromosome No,6 containing HLA haplotype A2, Bw62, Cw4 (mutant allele for 21-OH D) from the mother. In conclusion, attempts to detect heterozygote for 21-OH deficiency by ACTH stimulation test were partially successful and prenatal diagnosis of CAH by the hormone studies in ammiotic fluid requires reliable values in normal, heterozygotes and patients group, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The Clinical Significance of Anti-LSP Antibodies in the Sera of Patients with Viral Hepatitis: An Evaluation with SPA-RIA & ELISA / 第三军医大学学报

Antibodies against LSP in the sera of 168 patients with various types of viral hepatitis were determined with SPA-RIA. The sera of another group of 178 patients (109 of them were from the first group) with viral hepatitis were studied with ELISA for the same antibodies, which were further divided into three categories, that is, IgG, IgM and IgA classes. The results of 109 patients examined with both of the two methods, indicated that anti-LSP antibodies measured by SPA-RIA might mainly represent anti-LSP IgG class. It was found that circu-lating anti-LSP antibodies could easily be detected in most patients with either acute or chronic hepatitis. After analyzing the-results, the authors suggest that the humoral immune response against LSP might not be the sole initiating factor in the pathogenesis of viral hepatitis, they are more likely the result of the antigen variation of the injured liver cells.