RESUMEN
Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of congenital adrenal hyperplasia that can manifest with skeletal malformations, ambiguous genitalia, and menstrual disorders caused by cytochrome P450 oxidoreductase (POR) mutations affecting electron transfer to all microsomal cytochrome P450 and some non-P450 enzymes involved in cholesterol, sterol, and drug metabolism. With the advancement of molecular biology and medical genetics, increasing numbers of PORD cases were reported, and the clinical spectrum of PORD was extended with studies on underlying mechanisms of phenotype-genotype correlations and optimum treatment. However, diagnostic challenges and management dilemma still exists because of unawareness of the condition, the overlapping manifestations with other disorders, and no clear guidelines for treatment. Delayed diagnosis and management may result in improper sex assignment, loss of reproductive capacity because of surgical removal of ruptured ovarian macro-cysts, and life-threatening conditions such as airway obstruction and adrenal crisis. The clinical outcomes and prognosis, which are influenced by specific POR mutations, the presence of additional genetic or environmental factors, and management, include early death due to developmental malformations or adrenal crisis, bilateral oophorectomies after spontaneous rupture of ovarian macro-cysts, genital ambiguity, abnormal pubertal development, and nearly normal phenotype with successful pregnancy outcomes by assisted reproduction. Thus, timely diagnosis including prenatal diagnosis with invasive and non-invasive techniques and appropriate management is essential to improve patients' outcomes. However, even in cases with conclusive diagnosis, comprehensive assessment is needed to avoid severe complications, such as chromosomal test to help sex assignment and evaluation of adrenal function to detect partial adrenal insufficiency. In recent years, it has been noted that proper hormone replacement therapy can lead to decrease or resolve of ovarian macro-cysts, and healthy babies can be delivered by in vitro fertilization and frozen embryo transfer following adequate control of multiple hormonal imbalances. Treatment may be complicated with adverse effects on drug metabolism caused by POR mutations. Unique challenges occur in female PORD patients such as ovarian macro-cysts prone to spontaneous rupture, masculinized genitalia without progression after birth, more frequently affected pubertal development, and impaired fertility. Thus, this review focuses only on 46, XX PORD patients to summarize the potential molecular pathogenesis, differential diagnosis of classic and non-classic PORD, and tailoring therapy to maintain health, avoid severe complications, and promote fertility.
Asunto(s)
Hiperplasia Suprarrenal Congénita , Fenotipo del Síndrome de Antley-Bixler , Quistes , Trastornos del Desarrollo Sexual , Femenino , Embarazo , Humanos , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/terapia , Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Fenotipo del Síndrome de Antley-Bixler/genética , Fenotipo del Síndrome de Antley-Bixler/terapia , Rotura Espontánea , Cariotipo , Trastornos del Desarrollo Sexual/diagnóstico , Trastornos del Desarrollo Sexual/genética , Trastornos del Desarrollo Sexual/terapiaRESUMEN
Objective: To raise awareness of Cytochrome P450 Oxidoreductase Deficiency (PORD, a rare form of congenital adrenal hyperplasia (CAH), through a case of pregnant woman with virilization symptoms. Case description: A 30-year-old Chinese woman was referred to hospital after 7 years of presenting signs of virilization, including voice deepening, acromegaly, hirsutism, clitoromegaly, and acne. These symptoms appeared since her third gestation. Her second birth died 9 hours after birth and had signs of clitoris hypertrophy. Her third born was a son who presented with flat nose, radius and humerus bone malformation, and small penis at birth. Panel of POR-related genetic tests revealed that the patient carried c.1370 G>A (p.R457H), which is a POR heterozygous gene, while her husband carried a POR heterozygous gene as well, c.1379 C>A (p.S460Y). Two heterozygous mutations of the POR were found in her son: c.1370 G>A and c.1379 C>A. In PORD, c.1370 G>A (p.R457H) was reported as a susceptible gene, while c.1379 C>A (p.S460Y) has not been reported as responsible for the disease so far. Discussion and literature review: PORD is a rare form of CAH and caused by POR gene mutations. Most PORD patients are identified and diagnosed in pediatrics department. Internal medicine and obstetrics physicians are unfamiliar with the disease. As clinical manifestations are diverse, PORD could be easy to miss or to be misdiagnosed. Typical clinical manifestation includes adrenal insufficiency-related symptoms, such as bone malformations and sexual development disorders. PORD is diagnosed through genetic testing. Investigations of steroid metabolic products in urine through gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry are also helpful for the diagnosis, but neither of them are widely available in China. In this case, the patient had a history of infertility, and her third child was born with congenital defect and carried a PORD-related gene. In general clinical practice, if a pregnant woman presents with abnormal virilization symptoms, CAH possibilities should be considered, including rare causes such as PORD. Conclusion: PORD is a rare autosomal recessive genetic disease. We summarised the clinical characteristics and genotypes that were previously reported in the Chinese population and identified a novel mutation.
Asunto(s)
Hiperplasia Suprarrenal Congénita , Fenotipo del Síndrome de Antley-Bixler , Trastornos del Desarrollo Sexual , Humanos , Masculino , Niño , Embarazo , Recién Nacido , Femenino , Adulto , Hiperplasia Suprarrenal Congénita/complicaciones , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/genética , Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Fenotipo del Síndrome de Antley-Bixler/genética , Virilismo , OxidorreductasasRESUMEN
INTRODUCTION: P450 oxidoreductase (POR) deficiency is a rare form of congenital adrenal hyperplasia. In both genders, it can lead to ambiguous genitalia, impaired steroidogenesis, and skeletal findings similar to those of Antley-Bixler syndrome. CASES: We describe two cases of POR deficiency. The first case was an 8.5-year-old girl who was admitted to our clinic due to ambiguous genitalia. Karyotype was 46, XX. There were mild dysmorphic facial findings and mild metacarpophalangeal joint deformity. The patient's basal cortisol and ACTH levels were normal, while 17-hydroxyprogesterone (17OHP) levels were high. Peak cortisol response to the ACTH stimulation test was found to be insufficient. Our second case, a sibling of the first case, was admitted for routine checkup at the age of 15 months. As in our first case, there were dysmorphic facial findings and metacarpophalangeal joint deformity. The genital structure was normal. Karyotype was 46, XY. Basal cortisol and ACTH levels were normal, while 17OHP level was slightly high. Peak cortisol response to the ACTH stimulation test was found to be insufficient. Based on our findings, POR deficiency was considered in both of these cases and NM_000941.3:c.929_937delTCTCGGACT(p.Ile310_Ser313delinsThr) (homozygous) mutation was detected in the POR gene that had not previously been described. CONCLUSION: We detected a novel variant in the POR gene in two sibling cases with adrenal insufficiency, dysmorphic face, and mild skeletal findings. While the detected mutation caused ambiguous genitalia in the female case, it did not cause ambiguous genitalia in the male case.
Asunto(s)
Hiperplasia Suprarrenal Congénita , Fenotipo del Síndrome de Antley-Bixler , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/genética , Hormona Adrenocorticotrópica , Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Fenotipo del Síndrome de Antley-Bixler/genética , Niño , Femenino , Humanos , Hidrocortisona , Lactante , Masculino , Mutación , Fenotipo , HermanosRESUMEN
OBJECTIVE: To explore the clinical features and molecular basis of a Chinese pedigree with two siblings affected by cytochrome P450 oxidoreductase deficiency (PORD). METHODS: Clinical features of the patients were reviewed, and their genomic DNA was subjected to next generation sequencing (NGS). RESULTS: The two siblings presented peculiar facies, genital hypoplasia and skeletal deformity. NGS revealed that both have carried compound heterozygous variants of the POR gene, namely c.1370G>A and c.517-19_517-10delGGCCCCTGTGinsC, which were respectively inherited from their parents. CONCLUSION: Both siblings were diagnosed with PORD based on sequencing of the POR gene. The newly discovered POR c.517-19_517-10delGGCCCCTGTGinsC has enriched the spectrum of PORD-related genetic variants.
Asunto(s)
Fenotipo del Síndrome de Antley-Bixler , Sistema Enzimático del Citocromo P-450/genética , Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Fenotipo del Síndrome de Antley-Bixler/genética , Pueblo Asiatico , China , Pruebas Genéticas , Humanos , Mutación , LinajeRESUMEN
OBJECTIVE: To characterize the clinical features of a female with P450 oxidoreductase (POR) deficiency and to investigate the underlying mechanisms of POR inactivation. METHODS: The proband was a 35-year-old woman with primary infertility and menstrual irregularity. The reproductive endocrine profile was evaluated. DNA sequencing was conducted for the identification of POR gene mutation. RT-PCR was performed to confirm the impact of the mutation on POR mRNA. A molecular model was built for the structural analysis of mutant POR protein. RESULTS: The evaluation of reproductive endocrine profile revealed elevation of serum follicle-stimulating hormone (11.48 mIU/ml), progesterone (11.00 ng/ml), 17α-hydroxyprogesterone (24.24 nmol/l), dehydroepiandrosterone (6300 nmol/l), and androstenedione (3.89 nmol/l) and decreased estradiol (36.02 pg/ml). Sequencing of the POR gene showed the female was a compound heterozygote of the paternal P399_E401 deletion and a novel maternal IVS14-1G>C mutation. Functional analysis revealed IVS14-1G>C mutation caused alternative splicing of POR mRNA, with the loss of 12 nucleotides in exon 15 (c.1898_1909delGTCTACGTCCAG). Also, the resulting mutant POR protein had a V603_Q606 deletion, which inactivated the nucleotide-binding domain of NADPH in POR protein (K602_Q606). CONCLUSION: The mutation IVS14-1G>C of the POR gene could cause alternative splicing of POR mRNA and dysfunction of the resulting POR protein. Under proper IVF strategy with glucocorticoid therapy and endometrial preparation, females with mild POR deficiency still have the opportunity to have a live birth.
Asunto(s)
Empalme Alternativo/genética , Fenotipo del Síndrome de Antley-Bixler/genética , Sistema Enzimático del Citocromo P-450/genética , Pruebas Genéticas , Adulto , Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Fenotipo del Síndrome de Antley-Bixler/patología , Secuencia de Bases , Sistema Enzimático del Citocromo P-450/deficiencia , Exones/genética , Femenino , Humanos , Intrones/genética , Mutación/genéticaRESUMEN
Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis that causes various symptoms such as skeletal malformations, disorders of sex development, and adrenal insufficiency. The aim of this study was to elucidate the clinical characteristics, especially age at diagnosis and treatment, of PORD from the perinatal period to adulthood in Japan. The first questionnaire was sent to 183 council members of the Japanese Society for Pediatric Endocrinology on 1 September 2018. The response rate was 65%, and a total of 39 patients with PORD were examined at 20 hospitals. The second questionnaire was sent in November 2018 to the council members examining these 39 patients with PORD. The response rate was 77%, and we received clinical information on 30 of the 39 patients. The two novel clinical findings were the age at diagnosis and the treatment of Japanese patients with PORD. In many cases, PORD can be diagnosed at <3 months of age. Hydrocortisone as the primary treatment during infancy can be used daily or in stressful situations; however, because patients with PORD generally have mild to moderate adrenal insufficiency, some might be able to avoid hydrocortisone treatment. Patients with PORD should be carefully followed up, and treatment should be optimized as for patients with other types of adrenal insufficiency. Other characteristics in the present study were similar to those described in previous reports.
Asunto(s)
Fenotipo del Síndrome de Antley-Bixler/epidemiología , Fenotipo del Síndrome de Antley-Bixler/terapia , Adolescente , Adulto , Edad de Inicio , Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Japón/epidemiología , Masculino , Persona de Mediana Edad , Embarazo , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Antley-Bixler syndrome (ABS) is a rare childhood disorder affecting skeletal development. Some patients may also have genital anomalies and impaired steroidogenesis. Diagnostic criteria for ABS has not been fully established, though craniosynostosis, midface hypoplasia and elbow synostosis are minimum requirements. The etiology of ABS is complex, which included autosomal dominant form caused by FGFR2 gene mutations, autosomal recessive form caused by POR gene mutations, and high oral dose of fluconazole during pregnancy. Patients may die from dyspnea due to upper respiratory tract obstruction. This review summarizes research progress on the clinical features, etiology, differential diagnosis, treatment and prevention of ABS.
Asunto(s)
Fenotipo del Síndrome de Antley-Bixler/genética , Animales , Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Fenotipo del Síndrome de Antley-Bixler/etiología , Fenotipo del Síndrome de Antley-Bixler/terapia , Sistema Enzimático del Citocromo P-450/genética , Diagnóstico Diferencial , Feto/efectos de los fármacos , Fluconazol/efectos adversos , Humanos , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genéticaRESUMEN
Although POR deficiency (PORD) is assumed to be accompanied by excessive placental androgen accumulation and enhanced adrenal and testicular androgen production via the backdoor pathway as well as compromised testicular androgen production via the frontdoor pathway, there is no direct evidence for the flux of excessive placental androgens into the fetal circulation and for the production of dihydrotestosterone (DHT) via the backdoor pathway. We examined longitudinal serum and urine steroid metabolite profiles in a 46,XY infant with PORD who was prenatally identified because of the progressive fetal masculinization and maternal virilization from the mid-gestation and the presence of fetal radio-humeral synostosis and was confirmed to have compound heterozygous mutations of POR (p.Q201X and p.R457H). The results showed (1) markedly and inappropriately elevated serum androstenedione and testosterone (T) values at birth, (2) a markedly increased serum DHT value with a normal DHT/T ratio at birth, (3) transient elevation of serum T and DHT values accompanied by a normal DHT/T ratio and concomitant elevations of intermediate steroid metabolites on both the frontdoor and backdoor pathways at 30â¯days of age, and (4) persistent PORD-compatible urine steroid profiles. Although the data obtained from a single infantile patient are too premature to be generalized, they imply: (1) the transfer of excessive placental androgens into the fetal as well as the maternal circulations from the mid-gestation, (2) lack of a clinically discernible amount of DHT production via the adrenal backdoor pathway around birth, and (3) the activation of both the frontdoor and backdoor pathways in the testis around the mini-puberty, with no production of a clinically discernible amount of DHT via the testicular backdoor pathway.
Asunto(s)
Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Trastorno del Desarrollo Sexual 46,XY/genética , Enfermedades Fetales/diagnóstico , Esteroide 17-alfa-Hidroxilasa/metabolismo , Esteroides/sangre , Esteroides/orina , Fenotipo del Síndrome de Antley-Bixler/sangre , Fenotipo del Síndrome de Antley-Bixler/genética , Fenotipo del Síndrome de Antley-Bixler/orina , Trastorno del Desarrollo Sexual 46,XY/patología , Femenino , Enfermedades Fetales/sangre , Enfermedades Fetales/genética , Enfermedades Fetales/orina , Humanos , Lactante , Estudios Longitudinales , Embarazo , Diagnóstico Prenatal , Pronóstico , Esteroide 17-alfa-Hidroxilasa/genéticaAsunto(s)
Fenotipo del Síndrome de Antley-Bixler/diagnóstico , NADPH-Ferrihemoproteína Reductasa/genética , Fenotipo del Síndrome de Antley-Bixler/genética , Codo/diagnóstico por imagen , Femenino , Pie/diagnóstico por imagen , Mano/diagnóstico por imagen , Heterocigoto , Humanos , Linaje , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
BACKGROUND: Cytochrome P450 oxidoreductase deficiency (PORD) is a rare disease exhibiting a variety of clinical manifestations. It can be difficult to differentiate with other diseases such as 21-hydroxylase deficiency (21-OHD), polycystic ovary syndrome (PCOS) and Antley-Bixler syndrome (ABS). Nearly 100 cases of PORD have been reported worldwide. However, the genetic characters and clinical management are still unclear, especially in China. CASE PRESENTATION: In this study, we report a 27-year-old female Chinese patient who first presented with amenorrhea and recurrence of large ovary cyst. She was misdiagnosed with PCOS and non-classical 21-OHD due to ovary cysts and elevated 17-hydroxy-progesterone. The patient's complaining of a mild difficulty of bending the metacarpophalangeal joints reminded us to consider PORD, which usually presents with skeletal deformities and sexual dysfunction. The diagnosis of PORD was confirmed by genetic analyses, which showed the patient harboring a homozygous missense mutation in the POR gene (R457H) and her parents carrying the heterozygous mutation. The patient was treated with low-dose corticosteroids and estrogen/progesterone sequential therapy, and her ovarian cyst gradually reduced with regular menstruation in the follow-up. Moreover, the clinical and genetic characteristics of 104 previously reported PORD cases were also summarized and analyzed. CONCLUSIONS: PORD is a very rare disease which can be easily misdiagnosed in mild cases. Clinicians should keep in mind of this disease in patients with sexual dysfunction, especially combined with special skeletal deformities. Our data could provide a consciously understanding of this disease for clinic practicers. Low-dose corticosteroids combined with estrogen/progesterone sequential therapy will be effective in PORD patients with recurrence of large ovary cyst. The fact that the reported PORD patients in China carrying an identical variant R457H in POR gene also give us a viewpoint that R457H mutation in POR gene maybe important in causing PORD in Chinese as same as in Japanese.
Asunto(s)
Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Fenotipo del Síndrome de Antley-Bixler/genética , Sistema Enzimático del Citocromo P-450/genética , Mutación , Adulto , Sustitución de Aminoácidos , Fenotipo del Síndrome de Antley-Bixler/terapia , Biomarcadores , Huesos/diagnóstico por imagen , Huesos/patología , Codón , Terapia Combinada , Análisis Mutacional de ADN , Femenino , Humanos , Linaje , Fenotipo , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , UltrasonografíaRESUMEN
CASE PRESENTATION: A 36-year old man, operated on for cryptorchidism at the age of 8 years, was referred to the Outpatient Clinic of Reproductive Endocrinology for investigation of infertility. Clinical examination revealed ambiguous genitalia: penis 4-5 cm, testicular volume 2-3 ml, hypospadias, hypertrophic foreskin and scrotum bifida. Mild hypertension was confirmed. No skeletal malformations were detected. DESIGN: Hormonal and electrolytic determinations as well as semen analysis were conducted. PCR of the coding regions of 17-hydroxylase/17,20 lyase (P450c17) and of P450 oxidoreductase (POR) genes was also performed. RESULTS: Normal levels of electrolytes, low levels of androgens, high levels of gonadotropins and 17-hydroxyprogesterone as well as azoospermia were detected. Karyotype was shown to be 46,XY. Both hCG and ACTH stimulation significantly increased 17-hydroxyprogesterone with no increase in androgens. The diagnosis was congenital adrenal hyperplasia with apparent combined P450c17 and P450c21 deficiency due to mutations in the POR gene. Sequencing of the POR gene revealed: one deletion in exon 12 (Del 1696_1698delGTC >del531Valine) and one missense mutation in exon 7 (A259G) as well as two polymorphisms: rs1057868 (C/T A503V) and rs1057870 (G/A S572S) in exons 12 and 13, respectively. No nucleotide changes were detected in the 8 exons of P450c17. CONCLUSIONS: Molecular findings were consistent with the diagnosis of P450 oxidoreductase deficiency. Despite this severe deficiency, skeletal malformations simulating Antley-Bixler syndrome, which usually characterize the most severe forms, were not confirmed. This discrepancy could be attributed to the differential impact of a POR variant on each one of the P450 enzymes.
Asunto(s)
Fenotipo del Síndrome de Antley-Bixler/genética , Sistema Enzimático del Citocromo P-450/genética , Análisis Mutacional de ADN , Diagnóstico Tardío , Trastorno del Desarrollo Sexual 46,XY/genética , Pruebas Genéticas/métodos , Mutación , Polimorfismo Genético , Adulto , Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Fenotipo del Síndrome de Antley-Bixler/enzimología , Fenotipo del Síndrome de Antley-Bixler/fisiopatología , Azoospermia/diagnóstico , Azoospermia/enzimología , Azoospermia/genética , Criptorquidismo/diagnóstico , Criptorquidismo/enzimología , Criptorquidismo/genética , Sistema Enzimático del Citocromo P-450/deficiencia , Trastorno del Desarrollo Sexual 46,XY/diagnóstico , Trastorno del Desarrollo Sexual 46,XY/enzimología , Trastorno del Desarrollo Sexual 46,XY/fisiopatología , Exones , Predisposición Genética a la Enfermedad , Humanos , Cariotipificación , Masculino , Fenotipo , Valor Predictivo de las Pruebas , Esteroide 17-alfa-Hidroxilasa/genética , Esteroide 21-Hidroxilasa/genética , Factores de TiempoRESUMEN
Recently, a newly identified autosomal recessive skeletal dysplasia was described characterized by calvarial abnormalities (including cranium bifidum, coronal, and lambdoid synostosis), oligodactyly, femoral bowing, narrow thorax, small pelvic bones, and radiohumeral synostosis. In the two families described, a more severe phenotype led to in utero lethality in three siblings while in a single patient in a second family the phenotype was sufficiently mild to allow survival to 5 months of age. The disorder is caused by biallelic missense mutations in CYP26B1, which encodes for a cytochrome P450 enzyme responsible for the catabolism of retinoic acid in a temporally and spatially restricted fashion during embryonic development. Here, we provide the third family affected by the disorder and the first affected individual to survive beyond infancy. This woman homozygous for c.1303G>A; p.(Gly435Ser) in CYP26B1, which was associated with multisutural synostosis, radiohumeral synostosis, normal bone mineral density, and apparent intellectual disability, a phenotype with significant similarities to Antley-Bixler and Pfeiffer syndromes. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Acrocefalosindactilia/diagnóstico , Acrocefalosindactilia/genética , Alelos , Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Fenotipo del Síndrome de Antley-Bixler/genética , Mutación , Ácido Retinoico 4-Hidroxilasa/genética , Sustitución de Aminoácidos , Análisis Mutacional de ADN , Diagnóstico Diferencial , Facies , Femenino , Homocigoto , Humanos , Modelos Moleculares , Fenotipo , Conformación Proteica , Ácido Retinoico 4-Hidroxilasa/química , Cráneo/anomalías , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
BACKGROUND: Prenatal diagnosis of severe bone diseases is challenging and requires complete and precise analysis of fetal anomalies to guide genetic investigation and parental counselling. CASE REPORT: We report a rare case of Antley-Bixler syndrome prenatally diagnosed at 26 weeks' gestation by ultrasound and computed tomography in a 28-year-old woman with a history of early termination of pregnancy for "malposition of the inferior limbs". The prenatal ultrasound scan showed severe femoral bowing and frontal bossing. Taking into account the high probability of a recurrent severe skeletal disorder, a computed tomography (CT) scan was proposed. CT findings revealed bilateral femora deformation, craniosynostosis, severe midface hypoplasia, and radiohumeral synostosis. These anomalies strongly suggested Antley-Bixler syndrome. Sequencing of the POR gene in the fetus and the parents revealed compound heterozygous mutations in exon 9 and intron 7, both inherited from each parent, and this finding allowed genetic counseling. CONCLUSIONS: The first step in the proper prenatal diagnosis of fetal bone disorders is the precise analysis of ultrasonographic images. However, when a severe fetal inherited disorder is strongly suspected in late mid-trimester, CT may be discussed and usefully contribute to diagnosis and prognosis assessment.
Asunto(s)
Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Sistema Enzimático del Citocromo P-450/deficiencia , Enfermedades Fetales/diagnóstico , Adulto , Fenotipo del Síndrome de Antley-Bixler/embriología , Sistema Enzimático del Citocromo P-450/genética , Análisis Mutacional de ADN , Diagnóstico Diferencial , Resultado Fatal , Femenino , Humanos , Imagenología Tridimensional , Mutación , Embarazo , Diagnóstico Prenatal/métodos , Tomografía Computarizada por Rayos X , Ultrasonografía PrenatalRESUMEN
OBJECTIVE: To report a case of type 2 Antley-Bixler syndrome (ABS). SUBJECT AND METHODS: A 3-year-old boy who had been raised male, with facial dimorphism and malformations of both elbows and forearms, was referred to our unit for ambiguous genitalia. Genetic testing confirmed the diagnosis of ABS. A surgical intervention was performed to correct the ambiguous genitalia through a combined perineal and transabdominal approach. RESULTS: The postoperative course was uneventful and the patient was released from the hospital 10 days after the surgery. CONCLUSION: Repair of the ambiguous genitalia in this patient was possible, but definitive inferences on the benefit of this intervention cannot be made without long-term follow-up.
Asunto(s)
Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Trastornos del Desarrollo Sexual/cirugía , Preescolar , Humanos , Masculino , Caracteres SexualesRESUMEN
We report the first known case of p450 oxidoreductase deficiency (PORD) in a Spanish boy who presented ambiguous genitalia at birth as a unique feature. He had palpable gonads in the inguinal canal and a normal 46,XY karyotype. Blood tests showed increased lanosterol and androgen precursors (17-OH-pregnenolone and 17-OH-progesterone) and low adrenal androgens (dehydroepiandrosterone and its sulfate). Blood pressure and serum electrolytes were normal. As he had low-testosterone response to human chorionic gonadotropin stimulation but responded to exogenous testosterone with phallic growth, male sex was assigned. Testosterone/dihydrotestosterone ratio and inhibin B were normal. Adrenal insufficiency was detected by corticotropin test. Hydrocortisone replacement treatment was administered. Congenital adrenal hyperplasia was ruled out and molecular analysis of POR gene showed the missense mutation p.Gly539Arg in compound heterozygosity located at splice acceptor site of intron 2 and the coding variant p.Gly80Arg. Surgery for cryptorchidism and hypospadias was performed.
Asunto(s)
Fenotipo del Síndrome de Antley-Bixler/complicaciones , Trastornos del Desarrollo Sexual/etiología , Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Fenotipo del Síndrome de Antley-Bixler/genética , Diagnóstico Diferencial , Trastornos del Desarrollo Sexual/cirugía , Humanos , Recién Nacido , Cariotipo , Masculino , EspañaRESUMEN
Patients with P450 oxidoreductase (POR) deficiency typically present with adrenal insufficiency, genital anomalies and bony malformations resembling the Antley-Bixler craniosynostosis syndrome. Since our first report in 2004, more than 40 POR mutations have been identified in over 65 patients. POR is the obligate electron donor to all microsomal P450 enzymes, including the steroidogenic enzymes CYP17A1, CYP21A2 and CYP19A1. POR deficiency may cause disordered sexual development manifested as genital undervirilization in 46, XY newborns as well as overvirilization in those who are 46, XX. This may be explained by impaired aromatization of fetal androgens that may cause maternal virilization and low urinary estriol levels during pregnancy. In addition, the alternate 'backdoor' pathway of androgen biosynthesis, which leads to dihydrotestosterone production bypassing androstenedione and testosterone, may also play a role. Functional assays studying the effects of POR mutations on steroidogenesis showed that several POR variants impaired CYP17A1, CYP21A2 and CYP19A1 activities to different degrees, indicating that each POR variant must be studied separately for each potential target P450 enzyme. POR variants may also affect skeletal development and drug metabolism. As most drugs are metabolized by hepatic microsomal P450 enzymes, studies of the impact of POR mutations on drug-metabolizing P450s are particularly important.
Asunto(s)
Fenotipo del Síndrome de Antley-Bixler/complicaciones , Fenotipo del Síndrome de Antley-Bixler/metabolismo , NADPH-Ferrihemoproteína Reductasa/deficiencia , Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Fenotipo del Síndrome de Antley-Bixler/genética , Bioquímica , Desarrollo Óseo/genética , Desarrollo Óseo/fisiología , Transporte de Electrón/fisiología , Femenino , Humanos , Recién Nacido , Modelos Biológicos , Modelos Moleculares , Mutación/fisiología , NADPH-Ferrihemoproteína Reductasa/química , NADPH-Ferrihemoproteína Reductasa/genética , NADPH-Ferrihemoproteína Reductasa/fisiología , EmbarazoRESUMEN
The 46,XX disorders of sex development (DSDs) cause virilisation or masculinisation of the female foetus. The final common pathway of all 46,XX DSDs is excess dihydrotestosterone (DHT) or potent foreign androgen in the genital tissue during the critical period of sexual differentiation. Whereas the foetal testis is source of androgen in the male, it is the foetal adrenal that produces the DHT precursors in the female. By understanding the principles of human steroid biosynthesis, the pathogenesis of each disorder may be logically deduced, and treatment strategies are rationally constructed. In practice, however, therapies for many of these diseases are fraught with complications and caveats, and current approaches leave much room for improvement. This review discusses these diseases, their pathogenesis and approaches to therapy. We emphasise areas where improved treatments are sorely needed.
Asunto(s)
Trastornos del Desarrollo Sexual/etiología , Disgenesia Gonadal 46 XX/etiología , Virilismo/etiología , 17-alfa-Hidroxiprogesterona/metabolismo , Adolescente , Glándulas Suprarrenales/embriología , Glándulas Suprarrenales/metabolismo , Hiperplasia Suprarrenal Congénita/genética , Hiperplasia Suprarrenal Congénita/fisiopatología , Adulto , Fenotipo del Síndrome de Antley-Bixler/diagnóstico , Fenotipo del Síndrome de Antley-Bixler/genética , Fenotipo del Síndrome de Antley-Bixler/fisiopatología , Niño , Cosintropina , Deshidroepiandrosterona/metabolismo , Dihidrotestosterona/metabolismo , Trastornos del Desarrollo Sexual/diagnóstico , Trastornos del Desarrollo Sexual/tratamiento farmacológico , Trastornos del Desarrollo Sexual/genética , Femenino , Disgenesia Gonadal 46 XX/genética , Disgenesia Gonadal 46 XX/metabolismo , Humanos , Recién Nacido , Diferenciación Sexual , Esteroide 11-beta-Hidroxilasa/genética , Esteroide 21-Hidroxilasa/metabolismo , Esteroides/biosíntesis , Virilismo/metabolismoRESUMEN
Multiple joint contractures, including radiohumeral synostosis, are the hallmark of Antley-Bixler syndrome (ABS). The detailed description of the skeletal aberration, however, focused in feet is scarce. We carried out the scrutiny for foot lesion in three ABS patients with POR (nicotinamide adenine dinucleotide phosphate-oxidase-cytochrome P450 oxidoreductase) gene mutations, one of whom had undergone surgical intervention for difficulty in walking. Radiographs in all three patients showed middle cuneiform-second metatarsal synostosis and the fourth brachymetapody, irrespective of the severity of their systemic manifestations. In addition, talocalcaneal synostosis, lateral cuneiform-cuboid synostosis, defects of middle phalanx, and distal phalanx-middle phalanx synostosis were found in at least two patients. In conclusion, we found distinctive constellations of foot abnormalities in the patients of ABS with POR gene mutation, which may be useful in planning the treatment strategy, as well as in the diagnostic process.