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 Disorders of Sex Development of Adrenal Origin

2021 ◽  
Vol 12 ◽  
Author(s):  
Gabriela P. Finkielstain ◽  
Ana Vieites ◽  
Ignacio Bergadá ◽  
Rodolfo A. Rey
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Special Focus ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Trophic Effect ◽  
Salt Wasting ◽  
Sex Development ◽  
21 Hydroxylase Deficiency

Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.

scholarly journals So, and if it is not congenital adrenal hyperplasia? Addressing an undiagnosed case of genital ambiguity

2021 ◽  
Author(s):  
Reinaldo Luna de Omena Filho ◽  
Reginaldo José Petroli ◽  
Fernanda Caroline Soardi ◽  
Débora de Paula Michelatto ◽  
Taís Nitsch Mazzola ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Treatment Options ◽  
External Genitalia ◽  
Autosomal Recessive Disorder ◽  
Missense Variant ◽  
Ambiguous Genitalia ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Genital Ambiguity ◽  
21 Hydroxylase Deficiency

Abstract The Congenital Adrenal Hyperplasia due to 21 hydroxylase deficiency is the most common cause of genital ambiguity in persons with XX sexual chromosomes. Genital ambiguity among persons with XY sexual chromosomes comprises diverse and rare etiologies. The deficiency of 17-beta-hydroxysteroid dehydrogenase type 3 enzyme (HSD17B3) is a rare autosomal recessive disorder due to functionally altered variants of the HSD17B3 gene. In this disorder/difference of sex development, the conversion of androstenedione into testosterone is impaired. The appearance of external genitalia of 46,XY individuals varies from typically male to almost female. We report on a child presenting severe ambiguous genitalia. Due to access constraints, specialized care did not start until the child was 10 months old. Parents are consanguineous and were born in an area of high isonymy that is a cluster for rare recessive diseases. A new homozygous missense variant c.785G > T was found in exon 10 of the HSD17B3 gene. Researchers-clinicians and researchers-researchers collaborative efforts to elucidate the genetic basis of this disease were critical since this etiologic investigation is not available through the public health system. This case exemplifies the families’ pilgrimage in cases of genital ambiguity due to a rare genetic condition. Recognizing the etiology was the baseline to provide information on prognosis and treatment options, and to shelter family and child doubts and hopes in order to better support their decisions.

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<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.

Congenital adrenal hyperplasia

2010 ◽  
pp. 1891-1900
Author(s):  
I.A. Hughes
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Ambiguous Genitalia ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
Recessive Mutations ◽  
Adrenal Steroidogenesis ◽  
Life Threatening ◽  
Adrenal Rest ◽  
21 Hydroxylase Deficiency

Congenital adrenal hyperplasia (CAH) results from enzymatic defects in the pathways of adrenal steroidogenesis, with over 90% of cases being due to 21-hydroxylase deficiency caused by autosomal recessive mutations in the CYP21 gene. Classical presentation—this is in the neonatal period with ambiguous genitalia/virilization of a female infant, with phenotype traditionally subdivided according to the presence (75%) or absence of salt wasting, which in affected males is the sole manifestation (and can, if unrecognized, be life-threatening). Delayed presentations can occur, manifest in women as hirsutism, oligomenorrhoea, and infertility and in men as infertility or testicular adrenal rest tumours....

Role of Body Weight in the Onset and the Progression of Idiopathic Premature Pubarche

2020 ◽  
pp. 1-10
Author(s):  
Paolo Cavarzere ◽  
Margherita Mauro ◽  
Rossella Gaudino ◽  
Rocco Micciolo ◽  
Giorgio Piacentini ◽  
...  
Keyword(s):  
Birth Weight ◽  
Low Birth Weight ◽  
Late Onset ◽  
Hydroxylase Deficiency ◽  
Predisposing Factor ◽  
Strict Adherence ◽  
Premature Adrenarche ◽  
21 Hydroxylase Deficiency ◽  
Premature Pubarche

<b><i>Background:</i></b> The term premature pubarche (PP) refers to the appearance of pubic hair before age 8 in girls and before age 9 in boys. Although idiopathic PP (often associated with premature adrenarche) is considered an extreme variation from the norm, it may be an initial sign of persistent hyperandrogenism. Factors contributing to PP onset and progression have not been identified to date. <b><i>Aims:</i></b> The objectives of this study are to describe a group of Italian children with PP, to identify potential factors for its onset, and to define its clinical and biochemical progression. <b><i>Methods:</i></b> We retrospectively enrolled all infants born between 2001 and 2014 with PP. Children with advanced bone age (BA) underwent functional tests to determine the cause of PP. Hormonal analysis and BA determination were performed annually during a 4-year follow-up period. <b><i>Results:</i></b> A total of 334 children with PP were identified: idiopathic PP (92.5%, associated with premature adrenarche in some cases); related to precocious puberty (6.6%); late-onset 21-hydroxylase deficiency (0.9%). Low birth weight was associated with premature adrenal activation. Body mass index (BMI) was the only factor that influenced the progression of BA during follow-up. <b><i>Conclusions:</i></b> Low birth weight is a predisposing factor for premature adrenal activation. The increase in BMI in patients with idiopathic PP during the 4-years of follow-up was responsible for BA acceleration. We recommend prevention of excessive weight gain in children with PP and strict adherence to follow-up in order to prevent serious metabolic consequences.

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 Parent-Rated Severity of Illness and Anxiety among Caregivers of Children Born with a Disorder of Sex Development Including Ambiguous Genitalia

2018 ◽  
Vol 90 (5) ◽  
pp. 308-313 ◽  
Author(s):  
Christina M. Sharkey ◽  
Dana M. Bakula ◽  
Cortney Wolfe-Christensen ◽  
Paul Austin ◽  
Laurence Baskin ◽  
...  
Keyword(s):  
Strong Predictor ◽  
Disorders Of Sex Development ◽  
Severity Of Illness ◽  
Ambiguous Genitalia ◽  
Parental Anxiety ◽  
Hydroxylase Deficiency ◽  
Sex Development ◽  
Time Interaction ◽  
21 Hydroxylase Deficiency ◽  
Over Time

Background/Aims: Parents of children born with disorders of sex development (DSD) often experience anxiety, but risk factors, including parental perception of the severity of their child’s DSD, have not been examined. We hypothesized that severity of illness (SOI) ratings would relate to parental anxiety, and would be higher for parents of children with a potentially life-threatening DSD (e.g., 21-hydroxylase deficiency). Methods: Eighty-nine parents (Mage = 33.0, 56.2% mothers) of 51 children (Mage in months = 8.7) with a DSD including ambiguous genitalia were recruited from 12 specialized DSD clinics. Parents completed questionnaires prior to genitoplasty, 6 months post-genitoplasty, and 12 months post-genitoplasty (if completed). Data were analyzed with linear mixed modeling. Results: Parental anxiety decreased over time, χ2(1) = 10.14, p < 0.01. A positive relationship between SOI and anxiety was found, with SOI being a strong predictor of anxiety (b = 0.53, p < 0.01; χ2[1] = 5.33, p < 0.05). An SOI by time interaction indicated SOI had an increasing effect on anxiety over time, b = 0.06, p < 0.05; χ2(1) = 6.30, p < 0.05. There was no diagnosis by SOI interaction. Conclusion: Parental anxiety decreased over time, but those with higher SOI ratings reported greater initial anxiety followed by slower resolution over time. Underlying etiology of DSD had no effect on the relationship between SOI and anxiety.

Vaginal bleeding and a giant ovarian cyst in an infant with 21-hydroxylase deficiency

2018 ◽  
Vol 31 (2) ◽  
pp. 229-233 ◽  
Author(s):  
Nursel Muratoğlu Şahin ◽  
Elvan Bayramoğlu ◽  
Semra Çetinkaya ◽  
Şenay Şavaş Erdeve ◽  
Ayşe Karaman ◽  
...  
Keyword(s):  
Vaginal Bleeding ◽  
Ambiguous Genitalia ◽  
Ovarian Cysts ◽  
Homozygous Mutation ◽  
Adrenal Androgen ◽  
Hydroxylase Deficiency ◽  
Glucocorticoid Treatment ◽  
Salt Wasting ◽  
Laboratory Test Results ◽  
21 Hydroxylase Deficiency

Abstract Background: Increased adrenal androgen hormones in congenital adrenal hyperplasia (CAH) can rarely cause giant ovarian cysts in the neonatal period. Although the exact mechanism of the development of ovarian cysts is unknown, it is thought that increased androgen levels stimulate folicle development by increasing follicle stimulating hormone (FSH) levels. Case presentation: A 16-day-old newborn with ambiguous genitalia was presented to our clinic. Laboratory test results were as follows: sodium: 126 mEq/L, potassium: 5.4 mEq/L, renin: 132 pg/mL, adrenocorticotropic hormone (ACTH): 207 pg/mL, cortisole: 7.8 μg/dL, basal 17OH progesterone: 21 ng/mL, androstenedione: 5.1 ng/mL, testosterone: 1188 ng/dL and dehydroepiandrosterone sulfate (DHEAS)>1500 μg/dL. Karyotype analysis resulted in 46,XX. A homozygous mutation of R356W was detected in the CYP21A2 gene. The classical severe form of salt wasting 21 hydroxylase deficiency was diagnosed and treatment was started with hydrocortisone and fludrocortisone. Good metabolic control was ensured by monthly visits but the baby presented with vaginal bleeding as soiling at 4 months. The cystic lesion which extended to the epigastric area from the pelvis in the midline abdomen, had a size of 90×80×60 mm and medially, thin ovarian parenchyma was detected in ultrasonography. Conclusions: The findings in our patient suggest that a decline in adrenal androgens after glucocorticoid treatment resulted in an increase in gonadotropin levels and the giant cyst is developed by activation of gonadotropin cascade and increased gonadotropin receptors, instead of androgens.

scholarly journals POR polymorphisms are associated with 21 hydroxylase deficiency

2021 ◽  
Author(s):  
F. Pecori Giraldi ◽  
S. Einaudi ◽  
A. Sesta ◽  
F. Verna ◽  
M. Messina ◽  
...  
Keyword(s):  
Clinical Features ◽  
Modifier Genes ◽  
Age At Diagnosis ◽  
Adrenal Hyperplasia ◽  
Phenotype Correlation ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
Control Subjects ◽  
Younger Age ◽  
21 Hydroxylase Deficiency

Abstract Purpose Genotype–phenotype correlation in congenital 21 hydroxylase deficiency is strong but by no means absolute. Indeed, clinical and hormonal features may vary among patients carrying similar CYP21A2 mutations, suggesting that modifier genes may contribute to the phenotype. Aim of the present study was to evaluate whether polymorphisms in the p450  oxidoreductase (POR) gene may affect clinical features in patients with 21 hydroxylase deficiency Methods Sequencing of the POR gene was performed in 96 patients with 21 hydroxylase deficiency (49 classic, 47 non-classic) and 43 control subjects. Results Prevalence of POR polymorphisms in patients with 21 hydroxylase was comparable to controls and known databases. The rs2228104 polymorphism was more frequently associated with non-classic vs classic 21 hydroxylase deficiency (allelic risk 7.09; 95% C.I. 1.4–29.5, p < 0.05). Classic 21 hydroxylase-deficient carriers of the minor allele in the rs2286822/rs2286823 haplotype presented more frequently the salt-wasting form (allelic risk 1.375; 95% C.I. 1.138–1.137), more severe Prader stage at birth (allelic risk 3.85; 95% C.I. 3.78–3.92), higher ACTH levels, and younger age at diagnosis. Conclusions Polymorphisms in the POR gene are associated with clinical features of 21 hydroxylase deficiency both as regards predisposition to classic vs non-classic forms and severity of classic adrenal hyperplasia.

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