Association of palmoplantar keratoderma, cutaneous squamous cell carcinoma, dental anomalies, and hypogenitalism in four siblings with 46,XX karyotype: A new syndrome

Micali, Giuseppe; Nasca, Maria Rita; Innocenzi, D.; Frasin, L.A.; Radi, Orietta; Parma, P.; Camerino, Giovanna; Schwartz, Robert A.

doi:10.1016/j.jaad.2005.02.033

Cited by 33 publications

(21 citation statements)

References 28 publications

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“…These mutations are thought to be loss-of-function alleles. In addition to male or ambiguous external genitalia and hypogenitalism, gonadal biopsies revealed the presence of testicular structures and ovotesticular morphology (strictly 46,XX ovotesticular DSD) in affected XX individuals 134,135. These data establish RSPO1 as a human ovary-determining gene with antitestis functions, in line with the ‘Z’ hypothesis discussed above.…”

Section: Disorders Of Sex Development (Dsd) In Humanssupporting

confidence: 78%

The molecular and cellular basis of gonadal sex reversal in mice and humans

Warr

Greenfield

2012

WIREs Developmental Biology

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The mammalian gonad is adapted for the production of germ cells and is an endocrine gland that controls sexual maturation and fertility. Gonadal sex reversal, namely, the development of ovaries in an XY individual or testes in an XX, has fascinated biologists for decades. The phenomenon suggests the existence of genetic suppressors of the male and female developmental pathways and molecular genetic studies, particularly in the mouse, have revealed controlled antagonism at the core of mammalian sex determination. Both testis and ovary determination represent design solutions to a number of problems: how to generate cells with the right properties to populate the organ primordium; how to produce distinct organs from an initially bipotential primordium; how to pattern an organ when the expression of key cell fate determinants is initiated only in a discrete region of the primordium and extends to other regions asynchronously; how to coordinate the interaction between distinct cell types in time and space and stabilize the resulting morphology; and how to maintain the differentiated state of the organ throughout the adult period. Some of these, and related problems, are common to organogenesis in general; some are distinctive to gonad development. In this review, we discuss recent studies of the molecular and cellular events underlying testis and ovary development, with an emphasis on the phenomenon of gonadal sex reversal and its causes in mice and humans. Finally, we discuss sex-determining loci and disorders of sex development in humans and the future of research in this important area. WIREs Dev Biol 2012, 1:559–577. doi: 10.1002/wdev.42

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Section: Disorders Of Sex Development (Dsd) In Humanssupporting

confidence: 78%

The molecular and cellular basis of gonadal sex reversal in mice and humans

Warr

Greenfield

2012

WIREs Developmental Biology

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“…On the gonadal level, patients with RSPO1 mutations have male external genitalia with hypospadias, severe hypogenitalism, or severe ambiguity of external genitalia. Gonadal biopsies showed the presence of testicular structures with Leydig cell nodular hyperplasia in the propositus and others of ovotestis with reminiscence of ovarian tissue [Micali et al, 2005;Radi et al, 2005;Tomaselli et al, 2008]. The variable phenotype and the presence of hypogenitalism, however, may point towards an insufficiency of male steroidogenic hormones.…”

Section: Molecular Basis Of Ovarian Differentiationmentioning

confidence: 97%

Genetics of Ovarian Differentiation: <i>Rspo1</i>, a Major Player

Chassot

Gregoire

Magliano

et al. 2008

Sex Dev

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In mammals, the sex of the embryo is determined during development by its commitment either to the male or female genetic program regulating testicular or ovarian organogenesis. Major steps towards unraveling sex determination in mammals are achieved by the identification of key genes involved in human pathologies and the application of mouse genetics to analyze their function. While the expression of Sry and Sox9 is sufficient to induce the male devel- opmental program, the molecular pathways that specify ovarian differentiation were unclear before the recent demonstration that mutations in the RSPO1 gene induce female-to-male sex reversal in XX patients. By generating the corresponding mouse model, we have shown that Rspo1 is so far the earliest known gene controlling the female genetic developmental program. Rspo1 activates the canonical β-catenin signaling pathway required for female somatic cell differentiation and germ cell commitment into meiosis. The aim of this review is to describe the roles of R-spondins (Rspo)in developmental processes and disorders and the current knowledge obtained from murine models. A particular focus will be on Rspo1 and its crucial function in sex determination.

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“…Loss-of-function mutations of RSPO1 in humans are responsible for palmoplantar keratoderma associated with ambiguous external genitalia development and XX maleness [Micali et al, 2005]. In XX mice, Rspo1 invalidation leads to partial Sox9 up-regulation at around 18.5 dpc, leading to ovotestis formation [Chassot et al, 2008a].…”

Section: Early Determining Factors In the Ovarymentioning

confidence: 99%

Telling the Story of XX Sex Reversal in the Goat: Highlighting the Sex-Crossroad in Domestic Mammals

Pannetier¹,

Elzaïat²,

Thépot³

et al. 2011

Sex Dev

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The conditions for sex reversal in vertebrate species have been studied extensively and have highlighted numerous key factors involved in sex differentiation. We review here the history of the development of knowledge, referring to one example of complete female-to-male XX sex reversal associated with a polled phenotype in the goat. The results and hypotheses concerning this polled intersex syndrome (PIS) are then presented, firstly with respect to the transcriptional regulatory effects of the PIS mutation, and secondly regarding the role of the main ovarian-differentiating factor in this PIS locus, the FOXL2 gene.

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Association of palmoplantar keratoderma, cutaneous squamous cell carcinoma, dental anomalies, and hypogenitalism in four siblings with 46,XX karyotype: A new syndrome

Cited by 33 publications

References 28 publications

The molecular and cellular basis of gonadal sex reversal in mice and humans

The molecular and cellular basis of gonadal sex reversal in mice and humans

Genetics of Ovarian Differentiation: <i>Rspo1</i>, a Major Player

Telling the Story of XX Sex Reversal in the Goat: Highlighting the Sex-Crossroad in Domestic Mammals

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