Analysis of FGD1 gene variant in a child with Aarskog-Scott syndrome / 中华医学遗传学杂志

OBJECTIVE@#To detect pathogenic variant of the FGD1 gene in a boy with Aarskog-Scott syndrome.@*METHODS@#Genetic variant was detected by high-throughput sequencing. Suspected variant was verified by Sanger sequencing. The nature and impact of the candidate variant were predicted by bioinformatic analysis.@*RESULTS@#The child was found to harbor a novel c.1906C>T hemizygous variant of the FGD1 gene, which has led to conversion of Arginine to Tryptophane at codon 636(p.Arg636Trp). The same variant was found in his mother but not father. Based on the American College of Medical Genetics and Genomics guidelines, the c.1906C>T variant of FGD1 gene was predicted to be likely pathogenic(PM1+PM2+PM5+PP2+PP3+PP4).@*CONCLUSION@#The novel c.1906C>T variant of the FGD1 gene may underlay the Aarskog-Scott syndrome in this child. Above finding has enabled diagnosis for the boy.

Identification of three novel SRD5A2 mutations in Chinese patients with 5α-reductase 2 deficiency / 亚洲男科学杂志(英文版)

In this study, we investigated the genetics, clinical features, and therapeutic approach of 14 patients with 5α-reductase deficiency in China. Genotyping analysis was performed by direct sequencing of PCR products of the steroid 5α-reductase type 2 gene (SRD5A2). The 5α-reductase activities of three novel mutations were investigated by mutagenesis and an in vitro transfection assay. Most patients presented with a microphallus, variable degrees of hypospadias, and cryptorchidism. Eight of 14 patients (57.1%) were initially reared as females and changed their social gender from female to male after puberty. Nine mutations were identified in the 14 patients. p.G203S, p.Q6X, and p.R227Q were the most prevalent mutations. Three mutations (p.K35N, p.H162P, and p.Y136X) have not been reported previously. The nonsense mutation p.Y136X abolished enzymatic activity, whereas p.K35N and p.H162P retained partial enzymatic activity. Topical administration of dihydrotestosterone during infancy or early childhood combined with hypospadia repair surgery had good therapeutic results. In conclusion, we expand the mutation profile of SRD5A2 in the Chinese population. A rational clinical approach to this disorder requires early and accurate diagnosis, especially genetic diagnosis.

Clinical aspects associated with syndromic forms of Orofacial Clefts in a Colombian population / Aspectos Clínicos asociados a Fisuras Orofaciales en una población Colombiana

Objectives: To present descriptive epidemiology of Orofacial Clefts and to determine the association of syndromic forms with antenatal high-risk conditions, preterm birth, and comorbidities among nested-series of cases. Methods: A study of nested-series of cases was conducted. Frequencies of cleft type, associated congenital anomalies, syndromic, non-syndromic and multiple malformation forms, and distribution of Orofacial Clefts according to sex and affected-side were determined. Odds ratios were calculated as measures of association between syndromic forms and antenatal high-risk conditions, preterm birth and comorbidities. A total of three hundred and eleven patients with Orofacial Clefts were assessed in a 12-month period. Results: The most frequent type of Orofacial Clefts was cleft lip and palate, this type of cleft was more frequent in males, whereas cleft palate occurred more often in females. The most common cases occurred as non-syndromic forms. Aarskog-Scott syndrome showed the highest frequency amongst syndromic forms. Hypertensive disorders in pregnancy, developmental dysplasia of the hip, central nervous diseases and respiratory failure showed significant statistical associations (p <0.05) with syndromic forms. Conclusions: These data provide an epidemiological reference of Orofacial Clefts in Colombia. Novel associations between syndromic forms and clinical variables are determined. In order to investigate causality relationships between these variables further studies must be carried out.

Objetivos: Presentar la epidemiología descriptiva en torno a las Fisuras Orofaciales y determinar asociaciones entre Fisuras Orofaciales sindromica y antecedentes antenatales de alto riesgo, parto pretérmino, y comorbilidades en una población Colombiana. Métodos: Se planteó un estudio de serie de casos anidado estratificado. Se calcularon frecuencias en relación al tipo de fisura desde el punto de vista anatómico, anomalías congénitas paralelas, morbilidades y forma clínica. Se analizó la distribución de las Fisuras Orofaciales de acuerdo al género y lateralidad. Se determinaron razones de disparidad entre la forma sindrómica y antecedentes antenatales de alto riesgo, parto pretérmino, y comorbilidades. Se evaluaron trecientos once pacientes que asistieron a la consulta de genética clinica durante un año. Resultados: La Fisura Labio-palatina fue el tipo más frecuente en la muestra evaluada y la más frecuente en hombres. La Fisura Palatina fué la más frecuente en mujeres, la forma clínica más común fue la no sindrómica. En la población sindrómica el Síndrome de Aarskog-Scott mostró la frecuencia más alta. Los trastornos Hipertensivos de Embarazo, la Displasia del Desarrollo de la Cadera, las enfermedades respiratorias y del sistema nervioso central mostraron una asociación estadísticamente significativa con la forma sindrómica. (p <0.05). Conclusiones: Estos datos ofrecen una referencia epidemiológica descriptiva de las Fisuras Orofaciales en Colombia. Las asociaciones encontradas entre los aspectos clínicos estudiados y la forma sindrómica, deben ser investigadas en próximos estudios con el fin de determinar relaciones de causalidad.

Testículos supernumerarios: anomalía infrecuente del sistema genital, reporte de caso / Polyorchidism infrequent anomaly of the genital system: report of a case

Introducción: El testículo supernumerario es una anomalía congénita urológica poco frecuente, que es definido como la presencia de más de dos testículos, ya sea de localización intra o extraescrotal. Los testículos supernumerarios son una rara anomalía a considerar durante el estudio de masas escrotales. La ecografía doppler y la resonancia magnética proveen elementos útiles para diagnosticar la presencia de esta entidad. Objetivo: Conocer la incidencia de testículos supernumerarios, anomalía infrecuente del sistema genital. Se realizó de forma retrospectiva la revisión de los casos operados por el servicio de Urología, según el registro de documentación clínica de nuestro centro entre los años 1970 y 2010, con un promedio anual de 250 casos intervenidos por año, siendo un solo paciente portador de esta anomalía. Se realizó una revisión de la literatura, encontrando solamente tres casos en Cuba y menos de 100 pacientes en el mundo. Se reportó el tercer caso de testículo supernumerario en Cuba.

Introduction: The polyorchidism is a few frequent urologic congenital anomaly defined as the presence of more than two testicles, located inside or outside the scrotum. The polyorchidism is a rare anomaly to be considered when studying scrotal masses. The Doppler echography and the computerized magnetic resonance imaging give useful elements to diagnose the presence of this entity. Objective: Knowing the incidence of the polyorchidism, infrequent anomaly of the genital system. Patients and methods. We retrospectively reviewed the cases operated in the Urology service, according to the Clinic Documentation records of our center in the period from 1970 to 2010, with a year average of 250 cases operated, and only one patient carrying this anomaly. We made a literature review, finding only three cases in our country and less than 100 patients in the world. We report the 3rd case of polyorchidism in Cuba.

Ambiguous genitalia: two decades of experience

Ambiguous genitalia is a complex, medical and social emergency. The aim of this study is to present our experience over two decades, focusing on the pattern and clinical presentation. A retrospective study conducted in the pediatric endocrine clinic at a university hospital in Saudi Arabia during the period 1989-2008. Medical records of children with ambiguous genitalia were reviewed and the genitalia described. Of the 81 children with ambiguous genitalia, 53 [65.4%] patients were genetically females [46XY], with congenital adrenal hyperplasia being the common cause in 51 [96.5%] patients. Hyperpigmentation, variable degrees of salt wasting and a family history of a similar problem helped in diagnosis. Male genetic sex [46XY] was present in only 28 [34.6%] patients with a diversity of causes; multiple congenital anomalies in 9 [32.1%], local anorectal anomalies in 2 [7.1%], congenital adrenal hyperplasia [3-[beta-hydroxysteroid dehydrogenase deficiency] in 2 [7.14%], 5-alpha-reductase deficiency in 4 [14.28%], partial androgen insensitivity in 3 [10.7%], complete androgen insensitivity in 4 [14.28%], and hypogonadotrophin deficiency in 4 [14.3%]. Twenty-five [47.2%] of females were wrongly assigned as males, where only two [7.1%] males were wrongly assigned as females. Ambiguous genitalia, currently termed disorders of sex development [DSD], is not uncommon in our community. Increased awareness, a detailed history, and a careful physical examination, coupled with appropriate laboratory and radiological investigations aid in early diagnosis and avoid serious sequelae

Aarskog syndrome: a familial syndrome of short stature with facial dysmorphism and genital anomalies

Aarskog syndrome, also known as: Aarskog-Scott syndrome, a familial syndrome combining short stature, abnormal facies, genital, hand and foot abnormalities. Characteristic features include a round face with a broad forehead, a broad nasal bridge with a short stubby nose and anteverted nostrils, hypertelorism, and a shawl [saddlebag] scrotum. There are also hand and foot anomalies, and the cornea is usually enlarged. Males are fully affected; but female carriers sometimes exhibit phenotypical manifestations. The affected child has generally good health and developmental landmarks are within normal limits. In some cases, moderately impaired intelligence or early delay in motor performance, or both are recognized

Two cases of ambigious genitalia

The term "Ambiguous genitalia" applies to confusing appearance of the external genitalia. Sex assignment becomes essential for the parent's peace of mind, and in turn depends on anatomy and functional endocrinology rather than karyotype. Two cases with all different genetic sex, gonadal sex and phenotypic sex are described. First case is that of congenital adrenal hyperplasia [CAH] in a month old baby whose genotype was female with laboratory investigations exposing her diagnosis. She is doing well with oral hydrocortisone and fludrocortisone. Second case is that of probable 5-alpha reductase deficiency who would probably need future surgery

Pênis curvo congênito chordee / Congenital penile curvature chordee

O chordee é a causa mais comum de curvatura ventral na hipospadia e também em muitos casos de curvatura ventral sem hipospadia esta última não é muito assinalada. A curvatura ventral sem hipospadia é um defeito congênito decorrente da ação insuficiente dos hormônios produzidos pelos testículos, os quais estimulam o desenvolvimento masculino. Clinicamente, chordee sem hipospadia é uma curvatura ventral entretanto, o meato da uretra está localizado em sua posição normal na glande e o tecido fibroso é o principal responsável pelo encurvamento. Para a correção da angulação do pênis, várias técnicas cirúrgicas têm sido descritas. Todavia, adotando um conceito diferente sobre a curvatura ventral, tenho utilizado o método progressivo para corrigir a deformidade. Acredito que, em princípio, a clássica excisão do tecido fibroso da face ventral até o meato uretral é o procedimento mais apropriado e frequentemente será suficiente para conseguir a adequada retificação do falo.

[External genital anomalies in newborn babies]

External genital anomalies are common congenital anomalies, especially in male newborns. It seems that the incidence of these anomalies is increasing. Although the etiology of these anomalies is obscure in most cases, genetic and environmental factors have important roles. This study aimed to determine the types and frequency of these anomalies in newborn babies and to compare the results with those of a study which was conducted in the same hospital in 1991. In a descriptive analytic and cross-sectional study, all babies born March 2005 to February 2006 in Alzahra Hospital, Tabriz, were recruited. 6800 newborns consisting of 3475 [51.1%] boys and 3325 [48.9%] girls were studied. No anomaly was found in girl newborns, but 6.6% of boys had external genital anomalies. Undescended testis and hypospadias were first and second common anomalies. In comparison with the previous study, the frequency of anomalies was higher in preterm and low birth weight babies, babies of related parents and older mothers. The frequency of external genital anomalies had an ascending trend in the last decade. Low birth weight, preterm delivery, high maternal age, and related parents are risk factors for these anomalies

O pediatra frente a uma criança com ambigüidade genital: [revisão] / The role of the pediatrician in the management of children with genital ambiguities: [review]

OBJETIVO: Apresentar os critérios diagnósticos de ambigüidade genital, a conduta médica inicial e a postura esperada do pediatra. FONTES DOS DADOS: Revisão de literatura científica por meio de artigos publicados no MEDLINE nos idiomas inglês e português, no período de 1990 a 2007 e na faixa etária pediátrica. SÍNTESE DOS DADOS: O pediatra tem papel fundamental na avaliação da ambigüidade genital, cujo objetivo é obter diagnóstico etiológico preciso no menor tempo possível para definição do sexo e estabelecimento dos procedimentos terapêuticos. Há critérios diagnósticos específicos, porém, de modo geral, uma genitália é ambígua sempre que houver dificuldade para se atribuir o sexo à criança. O pediatra deve informar à família que a definição do sexo dependerá de investigação laboratorial minuciosa, feita preferencialmente por equipe interdisciplinar em serviço terciário. O cariótipo 46,XX ou 46,XY não é suficiente para definir o sexo de criação, porém esse exame é fundamental para direcionar a investigação. Quando não houver gônadas palpáveis, a primeira hipótese deve ser hiperplasia adrenal congênita. Entre as outras causas, estão insensibilidade parcial a andrógenos, deficiência da enzima 5alfa-redutase, disgenesia gonadal parcial e hermafroditismo. A família deve receber apoio e informações durante todo o processo de avaliação, e sua participação é fundamental na decisão sobre o sexo de criação. CONCLUSÕES: Embora casos de ambigüidade genital sejam relativamente raros para o pediatra, este deve estar informado sobre o tema e a conduta adequada a tomar, pois freqüentemente será o responsável pela orientação inicial da família e pela ligação entre esta e a equipe interdisciplinar.

OBJECTIVE: To present the diagnostic criteria of genital ambiguity, the initial medical management and the attitude expected of pediatricians. SOURCES: Review of the scientific literature in the form of articles indexed on MEDLINE, in English and Portuguese, published between 1990 and 2007 and dealing with the pediatric age group. SUMMARY OF THE FINDINGS: Pediatricians have a fundamental role to play in the assessment of genital ambiguity, the purpose of which is to arrive at an etiologic diagnosis in the shortest possible time in order to define the patient's sex and plan treatment. There are specific diagnostic criteria, but, in general, genitalia are ambiguous whenever there is difficulty in attributing gender to a child. The pediatrician should inform the patient's family that assignment of their child's sex will depend upon detailed laboratory investigations, preferably carried out by a multidisciplinary team at a tertiary service. The 46,XX or 46,XY karyotypes are not alone sufficient to define the gender of rearing, although the test is fundamental to guide the investigation. When there are no palpable gonads, the first hypothesis should be congenital adrenal hyperplasia. Other causes included partial androgen insensitivity, 5alpha-reductase deficiency, partial gonadal dysgenesis and hermaphroditism. The family should be provided with support and information throughout the assessment process, and their participation is fundamental in the decision of which gender to rear the child in. CONCLUSIONS: Although cases of genital ambiguity are relatively rare for pediatricians, they should be well-informed on the subject and the correct management of these conditions, since they will often be responsible for the initial guidance that families receive and for maintaining contact between them and the multidisciplinary team.

WAGR syndrome--a case report.

The WAGR syndrome is a multiple congenital anomaly-mental retardation syndrome caused by interstitial deletion of the distal portion of chromosome 11p13. It is a contiguous gene deletion syndrome, and WAGR is an acronym for the primary features: W for Wilms tumor, A for aniridia, G for genital anomalies, and R for mental retardation. Wilms tumor and male genital anomalies are caused by deletion of the WT1 tumor-suppressor gene, and aniridia is caused by deletion of PAX6 ocular developmental gene. Mental retardation is presumed to be a consequence of deletion of multiple as yet unidentified genes in the region. Individuals with the WAGR syndrome have a high risk for developing Wilms tumor and late-onset renal failure, and should be monitored for these complications.

Lissencephaly, abnormal genitalia and refractory epilepsy: case report of XLAG syndrome / Lisencefalia, genitália ambígua e epilepsia refratária: relato de caso da síndrome XLAG

INTRODUCTION: X-linked lissencephaly with ambiguous genitalia (XLAG) is a recently described genetic disorder caused by mutation in the aristaless-related homeobox (ARX) gene (Xp22.13). Patients present with lissencephaly, agenesis of the corpus callosum, refractory epilepsy of neonatal onset, acquired microcephaly and male genotype with ambiguous genitalia. CASE REPORT: Second child born to healthy nonconsanguineous parents, presented with seizures within the first hour of life that remained refractory to phenobarbital, phenytoin and midazolam. Examination identified microcephaly, axial hypotonia, pyramidal signs and ambiguous genitalia. EEG showed disorganized background activity and seizures starting at the right midtemporal, central and occipital regions. MRI showed diffuse pachygyria, moderate thickening of the cortex, enlarged ventricles, agenesis of the corpus callosum and septum pellucidum. Karyotype showed a 46,XY genotype. Additional findings were hypercalciuria, vesicoureteral reflux, patent ductus arteriosus and chronic diarrhea.

INTRODUÇÃO: Lisencefalia com genitália ambígua ligada ao X (XLAG) é doença genética recentemente descrita, causada por mutação no gene aristaless-related homeobox (ARX) (Xp22.13). Os pacientes apresentam lisencefalia, agenesia de corpo caloso, epilepsia refratária com início no período neonatal, microcefalia adquirida e genótipo masculino com genitália ambígua. RELATO DE CASO: Segundo filho de pais não-consangüíneos, apresentou crises na primeira hora de vida que permaneceram refratárias a fenobarbital, fenitoína e midazolam. Apresentava microcefalia, hipotonia axial, sinais de liberação piramidal e genitália ambígua. EEG demonstrou atividade de base desorganizada, crises convulsivas com início nas regiões temporal-média, central e occipital direitas. RNM demonstrou paquigiria difusa, moderado espessamento do córtex, ventrículos aumentados, agenesia de corpo caloso e septo pelúcido. Cariótipo evidenciou genótipo 46,XY. Achados adicionais foram: hipercalciúria, refluxo vésico-ureteral, ducto arterioso persistente e diarréia crônica.

Anatomical study on true hermaphroditism in an Indian pig (Sus Scrofa Domesticus)

A pig was confirmed to be a true hermaphrodite on the basis of gross and histomorphological studies of the genital organs. The genitalia was consisted of left ovary, oviduct, two coiled uterine horns, body of uterus alongwith right testis and an epididymis. Vagina and vulva were absent but male urethra with prostate gland was present. Grossly the size of all the genital organs appeared to be normal. Histomorphologically, testis and epididymis were underdeveloped as there was no clearcut spermatogenia and sertoli cells but Leydig cells were normal. The ovary presents normal histological features with some portion of testicular tissue. Degeneration of uterine epithelium was observed along with normal endometrial glands.

Criptorquidia: revisao da diferenciacao sexual e aspectos etiologicos / Cryptorchidism: review of male sexual differentiation and etiologic aspects

A criptorquidia e a mais comum das desordens da diferenciacao sexual masculina, ocorrendo em cerca de 1(por cento) dos meninos com mais de um ano. Suas sequelas...

novel mutation in the androgen receptor gene causing partial androgen insensitivity syndrome

In the present study, a novel mutation in exon 7 of the androgen receptor [AR] gene in an Egyptian patient with partial androgen insensitivity syndrome [PAIS] was described. A male patient aged seven months was presented with ambiguous genitalia; the parents were not consanguineous. The patient had 46, XY karyotype and normal testosterone levels. Both basal and after human chorionic gonadotrophin [HCG] testosterone/dihydrotestosterone ratio was within normal suggesting normal 5-alpha reductase activity. Sequencing analysis of the AR gene revealed a novel mutation [P817A] within the ligand-binding domain [LBD]

Ambiguous genitalia: an overview of 22 years experience and the diagnostic approach in the Pediatric Department, Siriraj Hospital.

The newborn with abnormal genital development presents a difficult diagnostic and treatment challenge for the pediatrician providing care. It is important that a definitive diagnosis be determined as quickly as possible so that the appropriate treatment plan can be established to minimize medical, psychological and social complications. The purpose of this study was to provide an extensive review of the clinical characteristics of a patient cohort with ambiguous genitalia, from 22 years' experience in the Division of Endocrinology and Metabolism, Department of Pediatrics, Siriraj Hospital, and to classify them into diagnostic categories. Moreover, a cascade of diagnostic tools in approaching sexual ambiguity in the authors' institution, starting with history and physical examination and leading to further radiographic and laboratory investigations is demonstrated and can be adopted as a guideline for the clinical management of these disorders. From 1979 to 2001, care was provided to a total of 109 patients with ambiguous genitalia, of whom 104 patients were reviewed. Among these individuals, 52 patients (50.0%) belonged to the diagnosis of female pseudohermaphroditism, 5 patients (4.8%) were in the true hermaphroditism group and the remaining 47 patients (45.2%) were in the male pseudohermaphroditism group. All female pseudohermaphrodites carried a diagnosis of congenital adrenal hyperplasia (CAH) and were reared as girls. 21 hydroxylase deficiency CAH accounted for all except one (98%) in this group. Among the 47 male pseudohermaphrodites, 9 (19.1%) had dysgenetic male pseudohermaphroditism, 7 (14.9%) had either testosterone biosynthetic defects or hCG unresponsiveness, 22 (46.8%) had either androgen insensitivity syndrome or 5 alpha-reductase deficiency, 4 (8.5%) had ambiguous genitalia in a 46,XY male associated with multiple anomalies and 5 (10.6%) had an unidentifiable cause. Sex reassignment occurred, not uncommonly, in 4 cases of female pseudohermaphrodites (7.7%) and at least 2 cases (3.9%) in the combined group of male pseudohermaphrodites and true hermaphrodites. The scope of the ambiguous genitalia problem is definitely not minor. An inappropriate approach to this problem poses an undue risk to the integrity of the physical and psychosexual health in the future for these children.

Estudio del hombre estéril / Study of sterile man

El enfoque en la evaluación del hombre estéril debe ser similar al utilizado para evaluar otros problemas médicos. Debe obtenerse un interrogatorio detallado con particular atención en aquellas áreas que pueden afectar la fertilidad. El interrogatorio debe ser seguido de un examen físico completos y de las pruebas de laboratorio indicadas. Lo ideal es que la evaluación del hombre estéril conduzca a la identificación de la anormalidad específica responsable de la esterilidad. Si bien esto es posible en algunos casos, muchos hombres presentan anormalidades del análisis seminal cuya etiología no puede ser establecida con certeza

Groin hernias and scroto-penile lesions in a defined Jordanian children

To find out the incidence of groin hernias and external genitalia abnormalities in children in the south of Jordan, for referral and for early treatment and to educate the population about the risk and complications of these abnormalities. Male children aged 6-12 years in the city of Tafila were examined at schools. A total of 1748 children underwent careful clinical examination of groin region, penis and scrotum. Out of 1748 examined children, abnormal findings were detected in 320 children [18.30%]. The abnormalities were as follows:- indirect inguinal hernia in 235 children, undescended testes in 37, retractile testes in 22, hypospadias in 13, left varicocele in eight, hydrocele in four, ambiguous genitalia in one. Herniotomy was detected in 56 children with failed herniotomy in two. Orchidopexy was found in four children with failure in two. No child has had surgery for hypospadias or varicocele. Indirect inguinal hernia is common in children. Undescended testes are not uncommon in children, the majority of children are late for treatment. Increased incidence of failure rate of treated children is noted. Education of public and medical staff about these abnormalities is needed to improve the outcome