scholarly journals 3?-hydroxysteroid dehydrogenase type II deficiency on newborn screening test

2014 ◽  
Vol 58 (6) ◽  
pp. 650-655 ◽  
Author(s):  
Vitor Guilherme Brito de Araújo ◽  
Renata Santarem de Oliveira ◽  
Kallianna Paula Duarte Gameleira ◽  
Cátia Barbosa Cruz ◽  
Adriana Lofrano-Porto
Keyword(s):  
Newborn Screening ◽  
Screening Test ◽  
Hydroxysteroid Dehydrogenase ◽  
Screening Tests ◽  
Adrenal Crisis ◽  
Type Ii ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
Genital Ambiguity ◽  
21 Hydroxylase Deficiency

3b-hydroxysteroid dehydrogenase II (3β-HSD) deficiency represents a rare CAH variant. Newborns affected with its classic form have salt wasting in early infancy and genital ambiguity in both sexes. High levels of 17-hydroxypregnenolone (Δ517OHP) are characteristic, but extra-adrenal conversion to 17-hydroxyprogesterone (17OHP) may lead to positive results on newborn screening tests. Filter paper 17OHP on newborn screening test was performed by immunofluorometric assay, and serum determinations of 17OHP and Δ517OHP, by radioimmunoassay. A 46,XY infant with genital ambiguity and adrenal crisis at three months of age presented a positive result on newborn screening for CAH. Serum determinations of 17OHP and Δ517OHP were elevated, and a high Δ517OHP/cortisol relation was compatible with the diagnosis of 3β-HSD deficiency. Molecular analysis of the HSD3B2 gene from the affected case revealed the presence of the homozygous p.P222Q mutation, whereas his parents were heterozygous for it. We present the first report of 3β-HSD type II deficiency genotype-proven detected at the Newborn Screening Program in Brazil. The case described herein corroborates the strong genotype-phenotype correlation associated with the HSD3B2 p.P222Q mutation, which leads to a classic salt-wasting 3β-HSD deficiency. Further evaluation of 17OHP assays used in newborn screening tests would aid in determining their reproducibility, as well as the potential significance of moderately elevated 17OHP levels as an early indicator to the diagnosis of other forms of classic CAH, beyond 21-hydroxylase deficiency.

scholarly journals Delayed Diagnosis of Congenital Adrenal Hyperplasia with Salt Wasting Due to Type II 3β-Hydroxysteroid Dehydrogenase Deficiency

2005 ◽  
Vol 90 (4) ◽  
pp. 2076-2080 ◽  
Author(s):  
Trine H. Johannsen ◽  
Delphine Mallet ◽  
Harriet Dige-Petersen ◽  
Jørn Müller ◽  
Katharina M. Main ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Delayed Diagnosis ◽  
Bone Age ◽  
Hydroxysteroid Dehydrogenase ◽  
Type Ii ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
21 Hydroxylase Deficiency ◽  
Premature Pubarche

Abstract Classical 3β-hydroxysteroid dehydrogenase (3β-HSD) deficiency is a rare cause of congenital adrenal hyperplasia. We report two sisters presenting with delayed diagnoses of classical 3β-HSD, despite salt wasting (SW) episodes in infancy. Sibling 1 was referred for premature pubarche, slight growth acceleration, and advanced bone age, whereas sibling 2 had no signs of virilization. At referral, increased 17α-hydroxyprogesterone associated with premature pubarche at first suggested a nonclassical 21-hydroxylase deficiency. Sequencing of the CYP21 gene showed both girls only heterozygotes (V281L mutation). This result, combined with SW in infancy, suggested a 3β-HSD deficiency because of increased dehydroepiandrosterone sulfate levels. Further hormonal studies showed markedly elevated Δ5-steroids, in particular 17α-hydroxypregnenolone greater than 100 nmol/liter (the clue to the diagnosis) and elevated Δ5-/Δ4-steroid ratios. Sequencing of the type II 3β-HSD gene documented that both girls were compound heterozygotes for T181I and 1105delA mutations. Retrospectively, elevated levels of 17α-hydroxyprogesterone were found on blood spots from Guthrie’s test. There is no previous report of the combination of SW and premature pubarche due to mutations in the type II 3β-HSD gene. Because neonatal diagnosis could have prevented life-threatening crises in these girls, this report further supports the benefits for neonatal screening for congenital adrenal hyperplasia whatever the etiology.

scholarly journals 408 Cases of Genital Ambiguity Followed by Single Multidisciplinary Team during 23 Years: Etiologic Diagnosis and Sex of Rearing

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Georgette Beatriz De Paula ◽  
Beatriz Amstalden Barros ◽  
Stela Carpini ◽  
Bruna Jordan Tincani ◽  
Tais Nitsch Mazzola ◽  
...  
Keyword(s):  
Birth Weight ◽  
Low Birth Weight ◽  
Gonadal Dysgenesis ◽  
Disorders Of Sex Development ◽  
Ambiguous Genitalia ◽  
Gonadal Development ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
Genital Ambiguity ◽  
21 Hydroxylase Deficiency

Objective. To evaluate diagnosis, age of referral, karyotype, and sex of rearing of cases with disorders of sex development (DSD) with ambiguous genitalia.Methods. Retrospective study during 23 years at outpatient clinic of a referral center.Results. There were 408 cases; 250 (61.3%) were 46,XY and 124 (30.4%) 46,XX and 34 (8.3%) had sex chromosomes abnormalities. 189 (46.3%) had 46,XY testicular DSD, 105 (25.7%) 46,XX ovarian DSD, 95 (23.3%) disorders of gonadal development (DGD), and 19 (4.7%) complex malformations. The main etiology of 46,XX ovarian DSD was salt-wasting 21-hydroxylase deficiency. In 46,XX and 46,XY groups, other malformations were observed. In the DGD group, 46,XY partial gonadal dysgenesis, mixed gonadal dysgenesis, and ovotesticular DSD were more frequent. Low birth weight was observed in 42 cases of idiopathic 46,XY testicular DSD. The average age at diagnosis was 31.7 months. The final sex of rearing was male in 238 cases and female in 170. Only 6.6% (27 cases) needed sex reassignment.Conclusions. In this large DSD sample with ambiguous genitalia, the 46,XY karyotype was the most frequent; in turn, congenital adrenal hyperplasia was the most frequent etiology. Malformations associated with DSD were common in all groups and low birth weight was associated with idiopathic 46,XY testicular DSD.

scholarly journals Measurement of 17-Hydroxyprogesterone by LCMSMS Improves Newborn Screening for CAH Due to 21-Hydroxylase Deficiency in New Zealand

2020 ◽  
Vol 6 (1) ◽  
pp. 6 ◽  
Author(s):  
Mark R. de Hora ◽  
Natasha L. Heather ◽  
Tejal Patel ◽  
Lauren G. Bresnahan ◽  
Dianne Webster ◽  
...  
Keyword(s):  
New Zealand ◽  
Positive Predictive Value ◽  
Newborn Screening ◽  
Predictive Value ◽  
False Positive ◽  
Screening Tests ◽  
Hydroxylase Deficiency ◽  
Second Tier ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency

The positive predictive value of newborn screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency was <2% in New Zealand. This is despite a bloodspot second-tier immunoassay method for 17-hydroxyprogesterone measurement with an additional solvent extract step to reduce the number of false positive screening tests. We developed a liquid chromatography tandem mass spectrometry (LCMSMS) method to measure 17-hydroxyprogesterone in bloodspots to replace our current second-tier immunoassay method. The method was assessed using reference material and residual samples with a positive newborn screening result. Correlation with the second-tier immunoassay was determined and the method was implemented. Newborn screening performance was assessed by comparing screening metrics 2 years before and 2 years after LCMSMS implementation. Screening data analysis demonstrated the number of false positive screening tests was reduced from 172 to 40 in the 2 years after LCMSMS implementation. The positive predictive value of screening significantly increased from 1.71% to 11.1% (X2 test, p < 0.0001). LCMSMS analysis of 17OHP as a second-tier test significantly improves screening specificity for CAH due to 21-hydroxylase deficiency in New Zealand.

Etiology of primary adrenal insufficiency in children: a 29-year single-center experience

2019 ◽  
Vol 32 (6) ◽  
pp. 615-622 ◽  
Author(s):  
Melati Wijaya ◽  
Ma Huamei ◽  
Zhang Jun ◽  
Minlian Du ◽  
Yanhong Li ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Clinical Characteristics ◽  
Clinical Symptoms ◽  
Wide Spectrum ◽  
Adult Population ◽  
Adrenal Crisis ◽  
Hydroxylase Deficiency ◽  
Primary Adrenal Insufficiency ◽  
Genital Ambiguity ◽  
21 Hydroxylase Deficiency

Abstract Background Primary adrenal insufficiency (PAI) in children is a rare condition and potentially lethal. The clinical characteristics are non-specific. It may be manifested as a chronic condition or crisis. The etiologies of PAI in children are different from the adult population. Therefore, diagnostic investigation becomes challenging. Methods A retrospective study was conducted at The First Affiliated Sun Yat Sen University Pediatric Endocrine unit between September 1989 and July 2016. Results A total of 434 patients (237 males, 197 females) were identified as having PAI. Congenital adrenal hyperplasia (CAH) was the most frequent etiology (83.4%, n = 362, male:female = 174:188), of which 351 (97.2%) were 21-hydroxylase deficiency (21-OH) CAH. Non-CAH etiology accounted for 11.3% (n = 49, male:female = 47:2), of which 46 (93.9%) were of non-autoimmune. The etiologies of the 49 cases were adrenoleukodystrophy (ALD; n = 22), X-linked adrenal hypoplasia congenital (X-AHC; n = 20), autoimmune polyglandular syndrome (APS; n = 3), triple A syndrome (n = 2), steroidogenic factor 1 (SF-1) gene mutation (n = 1) and adrenalectomy (n = 1). The etiology was not identified for 23 patients (5.3%, male:female =16:7). Clinical symptoms were in accordance with the incidence of genital ambiguity (42.6%), digestive symptoms (vomiting and diarrhea) (35.5%), failure to thrive (26.5%), gonadal-associated symptom (premature puberty, sexual infantilism and amenorrhea) (21.2%), hyperpigmentation (9.7%), adrenal crisis (AC; 4.1%), neurological symptoms (3.2%), fatigue (2.5%) and prolonged jaundice (2.1%). Through physical examination, 58.5% were found to have hyperpigmentation. Conclusions This study spanned 29 years at our institution. The etiology of PAI in children was mostly of congenital forms, which exhibits a wide spectrum of clinical characteristics. For etiological diagnosis, chromosomal karyotyping is recommended for female phenotype patients.

Prevention of ambiguous genitalia by prenatal treatment with dexamethasone in pregnancies at risk for congenital adrenal hyperplasia

2003 ◽  
Vol 75 (11-12) ◽  
pp. 2013-2022 ◽  
Author(s):  
M. I. New
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Chorionic Villus ◽  
Chorionic Villus Sampling ◽  
Prenatal Treatment ◽  
Adrenal Hyperplasia ◽  
Inherited Disorders ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
Genital Ambiguity ◽  
21 Hydroxylase Deficiency

Congenital adrenal hyperplasia (CAH) refers to a family of monogenic inherited disorders of adrenal steroidogenesis most often caused by a deficiency of the 21-hydroxylase enzyme. In the classic forms of CAH (simple virilizing and salt-wasting), androgen excess causes external genital ambiguity in newborn females and progressive postnatal virilization in males and females. Prenatal treatment of CAH with dexamethasone has been successfully utilized for over a decade. This article reports on 595 pregnancies prenatally diagnosed using amniocentesis or chorionic villus sampling between 1978 and 2002 at the New York Presbyterian Hospital-Weill Medical College of Cornell University. No significant or enduring side effects were noted in the fetuses, indicating that dexamethasone treatment is safe. Prenatally treated newborns did not differ in weight from untreated, unaffected newborns. Based on our experience, prenatal diagnosis and treatment of 21-hydroxylase deficiency is effective in significantly reducing or eliminating virilization in the newborn female. Prevention of genital virilization in female newborns with classic CAH avoids the risk of sex misassignment and diminishes the need for corrective surgery and the resulting psychological impact that may extend into adulthood.

scholarly journals SUN-LB11 What Is the Value of Clinical Suspicion in Neonatal Screening for Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency (CAH 21OHD)?

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
María Sanz Fernández ◽  
Marina Mora Sitja ◽  
Lucía L Carrascón González-Pinto ◽  
Esther González Ruiz de León ◽  
Dolores Rodríguez Arnao ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Neonatal Screening ◽  
Positive Family History ◽  
Ambiguous Genitalia ◽  
Clinical Suspicion ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
Men 2 ◽  
21 Hydroxylase Deficiency ◽  
At Home

Abstract Aim: The aim of the study was to analyze the clinical suspicion and where patients were when they received the positive result of the neonatal screening for CAH 21OHD.Patients, material and methods: The present data derived from a retrospective analysis of a relatively large group of patients with classical CAH 21OHD patients nosed by newborn screening in Madrid, Spain. Results: During the period from 1990 to 2015 of this study 46 children were diagnosed with classical 21OHD [36 with the salt-wasting (SW) form and 10 with simple virilizing (SV)]. The median age at diagnosis for the patients with SW and SV form were 8,0 (6,0 - 9,0) and 18,0 (14,5 - 37,5) days respectively (P= 0,001). The disease had been suspected before the result of the newborn screening in only 11 (23,9%) patients but had not been suspected before the screening in 35 (76,1%) patients. In 11 of the patients with clinical suspicion of the disease, 8 of them were affected by SW form (1 male with a previous brother affection and 7 females, 2 of them by previous brother affected and 5 of them with ambiguous genitalia). In only 3 patients affected by SV the disease there was clinical suspicion before the result of the screening. One of them was a boy with a previous brother affected and 2 of them were females born with ambiguous genitalia. In 35 patients the disease had not been suspected before the result of the newborn screening. Twenty-eight of them were affected by SW form and 7 by SV form. Twenty five of the 28 patients with SW form were males and 4 were females (in 3 of them had been an incorrect sex assignment at born). Six of the 7 patients affected by SV form without clinical suspicion of the disease were males and 1 was female (with genitalia classificated by degree 2 according to Prader scale). The disease was suspected in 64.3% of women (9/14) and only 6.3% of men (2/32) (p&lt;0.001).The most frequent cause of clinical suspicion of CAH 21OHD were the presence of ambiguous genitalia in women [n = 7 (63.6%), of which 5 were SW and 2 SV form) followed by positive family history [n = 4 (36, 4%), of which 3 were SW form and 1 SV form)]. When the result of Neonatal Screening was obtained 30 positive patients (65.2%) were at home without suspicion of illness, 11 (24.0%) newborns were admitted to the hospital for different reasons before the screening results were available and 5 (10.8%) patients were at home but with hospital follow-up due to clinical suspicion of illness (2 of them due to prenatal diagnosis by a previous relative, 2 women with SW form with incorrect assignment of sex at birth, labels such as men with cryptorchidism at birth and 1 woman with SV form in study by ambiguous genitalia). Conclusions: Clinical suspicion of CAH 21OHD was clearly insufficient to diagnose this severe disorder. In the majority of patients with 21OHD detected by newborn screening, the diagnosis by screening was anticipated to the clinical suspicion of the disease even in female patients with ambiguous genitalia.

scholarly journals Increased Mortality in Patients With Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

2014 ◽  
Vol 99 (12) ◽  
pp. E2715-E2721 ◽  
Author(s):  
Henrik Falhammar ◽  
Louise Frisén ◽  
Christina Norrby ◽  
Angelica Lindén Hirschberg ◽  
Catarina Almqvist ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Neonatal Screening ◽  
Causes Of Death ◽  
Population Based ◽  
Personal Identification ◽  
Adrenal Crisis ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
21 Hydroxylase Deficiency

Context: Reports on mortality in patients with congenital adrenal hyperplasia (CAH) are lacking. Objective: This study sought to study mortality and causes of death in CAH. Design, Setting, and Participants: We studied patients with CAH (21-hydroxylase deficiency, n = 588; CYP21A2 mutations known, &gt;80%), and compared them with controls (n = 58 800). Data were derived through linkage of national population-based registers. Main Outcome Measures: Mortality and causes of death. Results: Mean age of death was 41.2 ± 26.9 years in patients with CAH and 47.7 ± 27.7 years in controls (P &lt; .001). Among patients with CAH, 23 (3.9%) had deceased compared with 942 (1.6%) of controls. The hazard ratio (and 95% confidence interval) of death was 2.3 (1.2–4.3) in CAH males and 3.5 (2.0–6.0) in CAH females. Including only patients born 1952–2009, gave similar total results but only patients with salt wasting (SW) or with unclear phenotype had an increased mortality. The causes of death in patients with CAH were adrenal crisis (42%), cardiovascular (32%), cancer (16%), and suicide (10%). There were seven additional deaths in CAH individuals with incomplete or reused personal identification number that could not be analyzed using linkage of registers. Of the latter, all except one were deceased before the introduction of neonatal screening in 1986, and most of them in the first weeks of life, probably in an adrenal crisis. Conclusions: CAH is a potentially lethal condition and was associated with excess mortality due to adrenal crisis. The SW phenotype also seemed to have worse outcome in children and adults due to adrenal crisis and not only before the introduction of neonatal screening.

scholarly journals Characterization of Two Novel Homozygous Missense Mutations Involving Codon 6 and 259 of Type II 3β-Hydroxysteroid Dehydrogenase (3βHSD) Gene Causing, Respectively, Nonsalt-Wasting and Salt-Wasting 3βHSD Deficiency Disorder1

2000 ◽  
Vol 85 (4) ◽  
pp. 1678-1685
Author(s):  
Li Zhang ◽  
J. Ian Mason ◽  
Yasuhiro Naiki ◽  
Kenneth C. Copeland ◽  
Mariano Castro-Magana ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Clinical Phenotype ◽  
Hydroxysteroid Dehydrogenase ◽  
Missense Mutations ◽  
Type Ii ◽  
Mutant Type ◽  
Salt Wasting ◽  
Genital Ambiguity ◽  
Relative Conversion

We identified two homozygous missense mutations in the human type II 3β-hydroxysteroid dehydrogenase (3βHSD) gene, the first in codon 6 of exon II [CTT (Leu) to TTT (Phe)] in a male infant with hyperpigmented scrotum and hypospadias, raised as a male and no apparent salt-wasting since neonatal age, and the second in codon 259 of exon IV [ACG (Thr) to ATG (Met)] in a male pseudohermaphrodite with labial scrotal folds, microphallus, chordee, and fourth degree hypospadias, raised as a female and with salt-wasting disorder since neonatal age. In vitro transient expression of mutant type II 3βHSD complementary DNAs of L6F, T259M, as well as T259R for comparison was examined by a site-directed mutagenesis and transfection of construct into COS-1 and COS-7 cells. Northern blot analysis revealed expression of similar amounts of type II 3βHSD messenger ribonucleic acid from the COS-1 cells transfected by L6F, T259M, T259R, and wild-type (WT) complementary DNAs. Western immunoblot analysis revealed a similar amount of L6F mutant protein compared to WT enzyme from COS-1 cells, but neither L6F from COS-7 cells nor T259M or T259R mutant protein in COS-1 or COS-7 cells was detectable. Enzyme activity in intact COS-1 cells using 1 μmol/L pregnenolone as substrate in the medium after 6 h revealed relative conversion rates of pregnenolone to progesterone of 46% by WT enzyme, 22% by L6F enzyme, and 8% by T259M enzyme and less than 4% activity by T259R enzyme. Using 1 μmol/L dehydroepiandrosterone as substrate, the relative conversion rate of dehydroepiandrosterone to androstenedione after 6 was 89% by WT enzyme, 35% by L6F enzyme, 5.1% by T259M enzyme and no activity by T259R enzyme. However, the L6F mutant 3βHSD activity, despite its demonstration in the intact cells, was not detected in homogenates of COS-1 cells or in immunoblots of COS-7 cells, suggestive of the relatively unstable nature of this protein in vitro, possibly attributable to the decreased 3βHSD activity. In the case of T259M and T259R mutations, consistently undetectable proteins in both COS cells despite detectable messenger ribonucleic acids indicate severely labile proteins resulting in either no or very little enzyme activity, and these data further substantiate the deleterious effect of a structural change in this predicted putative steroid-binding domain of the gene. In conclusion, the findings of the in vitro study of mutant type II 3βHSD enzyme activities correlated with a less severe clinical phenotype of nonsalt-wasting and a lesser degree of genital ambiguity in the patient with homozygous L6F mutation compared to a more severe clinical phenotype of salt-wasting and severe degree of genital ambiguity in the patient with homozygous T259M mutation in the gene.

Partial 3β-hydroxysteroid dehydrogenase type 2 deficiency: Diagnosis of a novel mutation after positive newborn screening for 21-hydroxylase deficiency

2016 ◽  
Vol 146 (2) ◽  
pp. 92-93
Author(s):  
M. Pilar Bahíllo-Curieses ◽  
Lourdes Loidi Fernández de Trocóniz ◽  
Agustín del Cañizo López ◽  
María José Martínez-Sopena
Keyword(s):  
Newborn Screening ◽  
Novel Mutation ◽  
Hydroxysteroid Dehydrogenase ◽  
Hydroxylase Deficiency ◽  
21 Hydroxylase Deficiency
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