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46,XY Disorders of Sexual Development - Endotext - NCBI Bookshelf

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The diagnostic evaluation of DSD includes hormone measurements, imaging, cytogenetic and molecular studies. AMH and inhibin B are useful markers of the Sertoli cells presence and their assessment could help in the diagnosis of testis determination disorders. In boys with bilateral cryptorchidism serum AMH and inhibin B correlate with the presence of testicular tissue and undetectable values are highly suggestive of absence of testicular tissue 9 10 In postpubertal patients with testosterone synthesis defects, the diagnosis is made through basal steroid levels.

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Testosterone levels are low and steroids upstream from the enzymatic blockage are elevated. This pattern can be confirmed by hCG stimulation test, which increases the accumulation of steroids before the enzymatic blockage, with a slight elevation of testosterone. In pre-pubertal individuals, hCG stimulation test is essential for the diagnosis, since basal levels are not altered.

There are several hCG stimulation protocols and normative data have to be established for each of them. Imaging evaluation is indicated in the neonatal period when an atypical genitalia is identified. A family history of DSD and later presentations as abnormal puberty or primary amenorrhea, cyclic hematuria in a male, inguinal hernia in a female also require an imaging evaluation. This exam can also identify associated malformations such as kidney abnormalities Genitography and cystourethrography can display the type of urethra, the presence of vagina, cervix, and urogenital sinus.

Although, the imaging features are non-specific for the cause of DSD, these diagnostic methods are important in gender assignment and specially for surgical planning. Cytogenetic and Molecular Investigation The genetic evaluation includes karyotype, FISH and specific molecular studies to screen for the presence of mutations or gene dosage imbalance. Molecular methodologies have identified already known and also novel causes of DSD, and have led to the adoption of molecular tests into clinical practice for diagnosis and genetic counselling.

Among the genetic tests available, most use a candidate-gene approach, while new high-throughput DNA analysis could enable a genetic diagnosis to be made where the aetiology is unknown or differential diagnosis wide. These new high-throughput DNA approach can reduce the need of hormonal and imaging tests to reach the correct diagnosis. Advances in molecular biological techniques for diagnosing DSD is reviewed Nevertheless, the attainment of molecular diagnosis is related to a properly established clinical and hormonal diagnosis.

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Almost all testosterone synthesis defects can be diagnosed by hormonal evaluation. Careful selection of the genetic test indicated for each condition remains important for good clinical practice. They will be described according to the period of gene expression in gonadal determination.

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Gonadal determination and differentiation The intermediary mesoderm is the primary embrionic tissue at gastrulation that gives rise to the urogenital ridge. This, in turns, is going to derive the primitive gonad from a condensation of the medioventral region of the urogenital ridge.

The primitive gonad separates from the adrenal primordium at about 5 weeks, but remains bipotential until the 6th week after conception. Mammalin sex determination is a complex process, which involves a large number of genes acting in networks. Although mutations or knockout models of these genes produce abnormal gonads in mice, not all these genes have been implicated in gonadal-dysgenesis syndromes in humans. To date, Emx2 null mice have absent kidneys, ureters, gonads and genital tracts and have developmental abnormalities of the brain In humans, mutations in EMX2 have been found in patients with schizencephaly a rare condition in which a person is born with clefts in the brain that are filled with liquor but no gonadal phenotype have been described.

In mice lacking Lhx9 function, germ cells migrate normally, but somatic cells of the genital ridge fail to proliferate and gonads fail to form No human mutation in LHX9 has been identified DAX 1 is also essential for gonadal and adrenal differentiation and when duplicated results in adrenal hypoplasia congenital and hypogonadotropic hypogonadism After the formation of the bipotential gonad, by the 6th week after concepcion, in 46, XY individuals, the expression of the testis-determining gene Sry, which is transcriptionally regulated by the expression of WT1 26 and its co-factor zinc finger protein FOG2 27 and chromobox protein homolog 2 CBX2 28 triggers the gonadal masculinizing fate process In the mammalian male embryo, the first molecular signal of sex determination is the expression of Sry within a subpopulation of somatic cells of the indifferent genital ridge.

The transient expression of Sry drives the initial differentiation of pre-Sertoli cells that would otherwise follow a female pathway becoming granulosa cells. Once Sry expression begins, it initiates the cascade of gene interactions and cellular events that direct to the formation of a testis from the indifferential fetal gonad. So, pre-Sertoli cells proliferate, polarize and aggregate around the germ cells to define the testes cords.

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Migration of cells into the gonad from the mesonephros or the coelomic epithelium is subsequently induced by signals emanating from the pre-Sertoli cells. Peritubular myoid cells surround the testes cords and cooperate with pre-Sertoli cells to deposit the basal lamina and further define the testis cords.

Signalling molecules produced by the pre-Sertoli cells promote the differentiation of somatic cells, found outside the cords, into fetal Leydig cells, thus ultimately allowing the production of testosterone.

Endotelial cells are associated to form the coelomic vessel, which promotes efficient export of testosterone into plasma. The gene Sox9 is up-regulated immediately after Sry expression and is involved in the initiation and maintenance of Sertoli cell differentiation during the early phases of testis differentiation In addition, Sry inhibits b-catenin-mediated Wnt signaling Furthermore, SOX9 directly binds to the promoter of the Ptgds gene which encodes prostaglandin D synthase that mediates the production of PGD2 35 which, in turn, promotes nuclear translocation of SOX9, facilitating Sertoli cell differentiation Antagonism between Dmrt1 and Foxl2 comprises another step for sex-determining decision.

Dmrt1 has been described as essential to maintain mammalian testis determination, preventing female reprogramming in the postnatal mammalian testis However, the role of MAP3K1 in human sex-determination remains unknown as downstream effectors of MAP3K1 in the human developing testis have not been identified, as reviewed by Bashamboo and McElreavey Abnormalities in the expression underexpression or overexpression or timing of expression of genes involved in the cascade of testis determination can cause anomalies of gonadal development and consequently, 46,XY DSD.

Mendonca et al described a pair of siblings, one XY and the other XX, born to a consanguineous marriage, with normal female external and internal genitalia associated to gonadal agenesis The origin of this disorder remains to be determined, but a defect in another gene essential for bipotential gonad development is the most likely cause of this disorder.

The complete form of gonadal dysgenesis was first described by Swyer et al.


Mild clitoromegaly is present in some cases. The partial form of this syndrome is characterized by variable degrees of impaired testicular development and of testicular function. Serum gonadotropin levels are elevated in both the complete and partial forms, mainly FSH levels, which predominate over LH serum levels. Testosterone levels are at prepubertal range in the complete form. Meanwhile, in the partial form, it can range from prepubertal levels to normal adult male levels.

The clinical condition named embryonic testicular regression syndrome ETRS has been considered part of the clinical spectrum of partial 46,XY gonadal dysgenesis In this syndrome, most of the patients present atypical genitalia or micropenis associated with complete regression of testicular tissue in one or both sides.

The variable degree of masculinization of the internal and external genitalia is a consequence of the time of testicular function prior to its loss.

The dysgenetic testes showed disorganized seminiferous tubules and ovarian stroma with occasional primitive sex cords without germ cells Familial cases have been reported with variable degrees of sexual ambiguity, but the nature of the underlying defect is still unknown An interesting study describes a remarkable family pedigree across four generations with multiple affected family members. Phenotypic, with variable degrees of gonadal dysgenesis.

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The phenotypic mode of inheritance was strongly suggestive of X-linkage She gave birth to a 46,XY daughter with complete gonadal dysgenesis. The range of phenotypes observed in this unique family suggests a new mechanism, which predisposes to chromosomal mosaicism Regarding the genetic etiology, 46,XY gonadal dysgenesis is heterogeneous and can results from defects of any gene involved in the process of gonadal formation.

The following review will focus on the main genes causing gonadal dysgenesis in humans, presenting as an isolated or syndromic phenotype. The genes are described in the text accordingly their expression time during gonadal development.

Visitation will be from 9: Pastor Lindsey Burns will officiate. The family has requested donations be made to St. A fellowship luncheon will be served following the interment at the church for family and friends.

Crystal was a devout Christian. She loved to decorate her home and always made sure everyone who entered was always welcome anytime. She was preceded in death by her father, Lee L. Funeral service will be at 2: Jay loved to spend his time hunting and fishing. Those left to cherish his memory are sons, Jay Williamson, Jr.

Visitation will be held on Saturday, January 5, from 5: Funeral service will be at Brother Jim Miers will officiate the service. Her interests included gardening, crochet, and the Bible. She was a member of Pentecostal churches in the various cities where she lived, at times serving as a Sunday School teacher as well as playing piano or the accordion. If desired, donations may be made in her memory to the Rosepine United Pentecostal Church building fund.

Polk and she worked as a legal secretary for many years. She was preceded in death by her brother, husband and two sisters.

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Edna was a loving and devoted wife, mother, and grandmother. She was an avid reader and accumulated a large book collection but loved her Kindle. She enjoyed sewing and made many costumes and outfits for her highly entertaining children. She also enjoyed making her own greeting cards which she shared with family and friends. A graveside service will be held at He loved his family and grandchildren with all of his heart. Lansford was a Navy veteran of the Vietnam Conflict. He was an avid hunter and fisherman who loved being outdoors.

He was preceded in death by his father, Robert C. Visitation will be held on Saturday, January 5, from 6: Brother Lindsey Burns will officiate the service. Reading of obituary and Scriptures by niece, Lyndsay Clark. Visitation was held on Thursday, January 3, from 5: Pallbearers will be family and friends.

John enjoyed the time he had and he always loved to take time out to fish. He was preceded in death by his father, Bobby Cloar; and brother, Thomas Cloar. Visitation will be held on Wednesday, January 2, from 9: No funeral services are scheduled.

Family meant the world to Tom. From all the love of his grandchildren and great grandchildren who enjoyed their PawPaw "Tom", to the friends and people that he met in his lifetime. Tom also spent time gardening, raising cattle, riding horses and playing music. Those left to cherish his memory are his sister, Patsy Davis of DeRidder, LA and a host of nieces, nephews, cousins, family and friends.

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A memorial service will be held Saturday, January 12, at 2: Pastor Jimmy Freeman will officiate. Robin was an avid supporter of the Quilts of Valor Foundation. She retired from the Federal Bureau of Prisons as a lieutenant after over 20 years of service. Those left to cherish her memory are her father, George W. Hauser of Houston, TX; and a host of other family and friends. Graveside Funeral service will be at Garner will officiate the service. Megan Marie Lack A beloved daughter, granddaughter, sister, niece, cousin and friend.

Megan Marie Lack left this world unexpectedly, at 26, on December 27, Megan was a lover of hunting and fishing. She was funny and outgoing, and was loyal to her friends and family. We will always remember her smile and caring personality. Her presence in our lives will be sorely missed. When you think of Megan, celebrate the good memories you have of her. Remember that life is fragile and short and should be lived to the fullest. A celebration of life will begin with visitation on Sunday, December 30,from 5: Funeral service will be held on Monday, December 31,at Visitation will be held on Friday, December 28, from 5: Visitation will continue at 8: Father Jude will officiate the service.

Willis and Daniel Theriot. Those left to cherish her memory are spouse, Jimmy Whiddon, Sr. She was preceded in death by her parents, Reverend C. Visitation will be held on Thursday, December 27, from 5: From there she came to T.

Edith married the love of her life, Bob Winfree, on February 4, and enjoyed 54 years with her beloved husband. Years later, they opened a second agency in DeRidder. They were world renowned travelers, visiting every country in the world at least one time. They shared their knowledge of the world with everyone they came into contact with. Edith was preceded in death by her husband, W. Williams Jarrell Sammie L.

Williams Jarrell was born on December 17,in Broaddus, Texas and passed from this life on December 13,at her home in Merryville, Louisiana surrounded by love.

Sammie or Bo as she was lovingly called touched lives everywhere she went. People who knew her, loved her laugh, giving spirit and heartfelt kindness. She never turned away someone in need. Sammie worked for many years at the Merryville Hospital and Nursing Center where she served in many different positions, everything from an EMT to head of Central Supply to the most rewarding job of taking care of people, families and patients alike.

She continued in this line of caring for people following her departure from the Nursing Center with working for Larry and Carolyn Karr at Sabine Drugs and many, many hours of private duty sitting. She simply loved to do for others, she believed the more she gave the more it enriched her life. She also enjoyed many different creative ventures.

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She was a published poet, loved to draw, paint and color, crochet, embroidery, quilt, and as most know sew. She could take the most common piece of cloth and turn it into a breathtaking masterpiece. Sammie also loved to take road trips. She traveled many miles with her cousin Vergie and then later in life with her daughter Glenda and friend Cheryl. Natchitoches was one of her most favorite places to visit and they made the trip as often as possible.