Publications by authors named "Delphine Mallet"

22 Publications

  • Page 1 of 1

In cases of familial primary ovarian insufficiency and disorders of gonadal development, consider NR5A1/SF-1 sequence variants.

Reprod Biomed Online 2020 Jan 10;40(1):151-159. Epub 2019 Oct 10.

Université de Lille, CHU Lille, INSERM U1172, Lille F-59000, France; Université de Lille, CHU Lille, Department of Reproductive Medicine, Lille F-59000, France. Electronic address:

Research Question: Primary ovarian insufficiency (POI) is defined as the early exhaustion of ovarian function, before the age of 40 years. Its origin is genetic in 20-25% of cases. In rare cases, sequence variants of the NR5A1/SF-1 gene may result in POI, or in various disorders of gonadal development (DGD) or adrenal insufficiency.

Design: This study describes the cases of two families in which the association of DGD and POI enabled a diagnosis of NR5A1 deleterious variations. Their clinical, hormonal, ultrasound and genetic characteristics are reported.

Results: The mothers of the affected children were 21 and 29 years when POI was diagnosed. Each nonetheless had two spontaneous pregnancies. The children have different phenotypes and different forms of DGD. None of the affected family members had adrenal insufficiency. A new sequence variant of the NR5A1 gene was identified in one family: p.Cys283Phe (c.848G>T), and the NR5A1 sequence variant c.86G>C was found in the other family.

Conclusion: Sequence variation of the NR5A1 gene is a possibility that must be considered when a woman with POI or a diminished ovarian reserve has a family member or child with DGD. If a variant is identified, genetic counselling is essential for the patient and his/her family.
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http://dx.doi.org/10.1016/j.rbmo.2019.10.002DOI Listing
January 2020

Reversion SAMD9 Mutations Modifying Phenotypic Expression of MIRAGE Syndrome and Allowing Inheritance in a Usually Disorder.

Front Endocrinol (Lausanne) 2019 11;10:625. Epub 2019 Sep 11.

Laboratoire de Biochimie et Biologie Moléculaire Grand Est, UM Pathologies Endocriniennes Rénales Musculaires et Mucoviscidose, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.

MIRAGE (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes, Enteropathy) syndrome is a severe multisystem disorder with high mortality. It is caused by a heterozygous gain of function mutation in the growth repressor gene . The increasing number of reported cases displays a spectrum of phenotypes that may be explained by an adaptation mechanism, with appearance of a somatic second hit mutation with revertant effects. To determine the genetic basis of the MIRAGE syndrome rapidly corrected in a living and healthy 46,XY patient. A 46,XY patient born with growth restriction and disorders of sex development had thrombocytopenia and necrotizing enterocolitis during the neonatal period suggestive of the syndrome. Faced with the rapid improvement of the patient's phenotype, an adaptation mechanism was sought by repeating genetic analysis at different ages; her parents also underwent genetic analysis. The previously described p.(Thr778Ile) mutation was identified and surprisingly transmitted by the asymptomatic mother in this usually syndrome. To explain the rapid improvement of the patient's phenotype and absence of symptoms in the mother, an adaptation mechanism was sought. For the mother, a non-sense mutation was found (p.(Arg221)) in , and most likely appeared . It was not transmitted to her child. The child harbored a different non-sense mutation (p.(Arg285)) that most likely appeared near day 20. We show that pathogenic variants can be inherited from a healthy parent as the adaptation mechanism may arise early in life and mask symptoms. Presence of revertant mosaicism mutations could explain "incomplete penetrance" in other disease. For a better management and outcomes in patients, appearance of this natural gene therapy should be sought by repeating genetic analysis.
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http://dx.doi.org/10.3389/fendo.2019.00625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749008PMC
September 2019

Optimized nested PCR enhances biological diagnosis and phylogenetic analysis of human parvovirus B19 infections.

Arch Virol 2019 Nov 10;164(11):2775-2781. Epub 2019 Aug 10.

Hospices Civils de Lyon, Laboratoire de Virologie, Institut des Agents Infectieux, Centre de Biologie et de Pathologie Nord, 103, grande rue de la Croix-Rousse, 69 317, Lyon cedex 04, France.

Diagnosis and epidemiological analysis of human parvovirus B19 (hB19V) infections are essential for disease management in severely ill patients. This study aimed to evaluate the performance of an optimized NS1-VP1u nested PCR for detection and sequencing of viruses in clinical samples using 224 clinical and five reference samples. PCR sensitivity, specificity, and positive and negative predictive values were perfect (100%). While phylogenetic analysis of a 615 bp-long fragment demonstrated that the viruses in all of the samples belonged to genotype 1, this study confirmed that this optimized PCR could detect all known hB19V with high performance.
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http://dx.doi.org/10.1007/s00705-019-04368-wDOI Listing
November 2019

Letter to the Editor: "Characterization of the CYP11A1 Nonsynonymous Variant p.E314K in Children Presenting With Adrenal Insufficiency".

J Clin Endocrinol Metab 2019 05;104(5):1413-1414

Laboratoire de Biochimie et Biologie Moléculaire Grand Est, UM Pathologies Endocriniennes Rénales Musculaires et Mucoviscidose, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.

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http://dx.doi.org/10.1210/jc.2018-02415DOI Listing
May 2019

Aberrant Splicing Is the Pathogenicity Mechanism of the p.Glu314Lys Variant in Gene.

Front Endocrinol (Lausanne) 2018 5;9:491. Epub 2018 Sep 5.

Laboratoire de Biochimie et Biologie Moléculaire Grand Est, UM Pathologies Endocriniennes Rénales Musculaires et Mucoviscidose, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.

The cholesterol side chain cleavage enzyme (CYP11A1) catalyzes the conversion of cholesterol to pregnenolone, the first rate-limiting step of steroidogenesis. mutations are associated with primary adrenal insufficiency (PAI) as well as disorders of sex development (DSD) in 46,XY patients. To define the pathogenicity mechanism for the p.Glu314Lys variant, previously reported, and found in four additional patients with CYP11A1 deficiency. DNA of four patients presenting with delayed PAI and/or 46,XY DSD were studied by Sanger or Massively Parallel sequencing. Three mutations were characterized and , and one by mRNA analysis on testicular tissue. All patients were compound heterozygous for the previously described p.Glu314Lys variant. studies predicted this mutation as benign with no effect on splicing but mRNA analysis found that it led to incomplete exon 5 skipping. This mechanism was confirmed by minigene experiment. The protein carrying this mutation without exon skipping should conserve almost normal activity, according to studies. Two other mutations found in , the p.Arg120Gln and p.Arg465Trp, had similar activity compared to negative control, consistent with the studies. We provide biological proof that the p. Glu314Lys variant is pathogenic due to its impact on splicing and seems responsible for the moderate phenotype of the four patients reported herein. The present study highlights the importance of considering the potential effect of a missense variant on splicing when it is not predicted to be disease causing.
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http://dx.doi.org/10.3389/fendo.2018.00491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134065PMC
September 2018

P450 Oxidoreductase Deficiency: Loss of Activity Caused by Protein Instability From a Novel L374H Mutation.

J Clin Endocrinol Metab 2016 12 7;101(12):4789-4798. Epub 2016 Sep 7.

Pediatric Endocrinology, Diabetology, and Metabolism (S.P., C.E.F., A.V.P.), University Children's Hospital, and Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland; Service d'Endocrinologie Moléculaire et Maladies Rares (F.R.-B., D.M., Y.M.), Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Université Lyon 1, 69002 Bron-Lyon, France; and Endocrinologie Pédiatrique Département de Pédiatrie Médicale (A.L.-R.), Hôpital de la Mère et de l'Enfant, 87042 Limoges, France.

Context: P450 oxidoreductase (POR) is required for the activities of steroid-metabolizing cytochrome P450 enzymes in the endoplasmic reticulum. POR deficiency (PORD) is a form of congenital adrenal hyperplasia. Objective and Aim: Enzymatic and structural analysis of a novel L374H POR mutation from a patient with 46,XX disorder of sexual development. Design, Setting, Patient, and Intervention: The patient was a 46,XX girl with nonconsanguineous Turkish parents. She had virilized external genitalia at birth, a uterus and ovaries, and no sign of Antley-Bixler syndrome. The initial diagnosis was CYP21A2 deficiency with no mutations in CYP21A2, but POR mutations were found. Functional testing was done after producing recombinant POR proteins for analyzing enzymatic and structural properties.

Main Outcome: Novel mutations were causing severe loss of POR activities for metabolism of steroids and small molecules.

Results: The L374H mutation reduced activities by 80% in cytochrome c, 97% in thiazolyl blue tetrazolium bromide, and 86% in ferricyanide reduction assays. The catalytic efficiency of the 17 α-hydroxylation of progesterone and the 17,20-lyase reaction of 17-OH pregnenolone was decreased by 87 and 90%, respectively; 21-hydroxylation of progesterone was decreased by 96%, and androstenedione aromatization was decreased by 90%. Analysis of the mutant structure by molecular dynamics simulations revealed structural instability. Flavin release and fast proteolysis assays showed that the L374H mutant is less stable than wild-type POR, confirming the bioinformatics prediction.

Conclusions: This is the first report of a mutation causing PORD by affecting protein stability that causes severe reduction in POR activities. Detailed characterization of individual mutations in POR is required for understanding novel molecular mechanisms causing PORD.
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http://dx.doi.org/10.1210/jc.2016-1928DOI Listing
December 2016

Evolution of steroids during pregnancy: Maternal, placental and fetal synthesis.

Ann Endocrinol (Paris) 2016 Jun 4;77(2):82-9. Epub 2016 May 4.

Service d'hormonologie, endocrinologie moléculaire et maladies rares, CPBE, groupement hospitalier Lyon-Est, 69677 Lyon-Bron, France.

Progesterone, estrogens, androgens and glucocorticoids are involved in pregnancy from implantation to parturition. Their biosynthesis and their metabolism result from complex pathways involving the fetus, the placenta and the mother. The absence of expression of some steroïdogenic enzymes as CYP17 in placenta and in adrenal fetal zone and the better determination of the onset and variation of others especially HSD3B2 during the pregnancy explain the production of the steroid hormones. Moreover the consequences of some disorders of steroidogenesis (especially aromatase, POR, CYP11A1 and 21-hydroxylase deficiencies) in fetus and mother during the pregnancy have permit to elucidate these complex pathways. This better knowledge of steroid hormones production associated with their dosages in maternal plasma/urine or amniotic fluid using new specific assays as LC-MS MS could facilitate the follow-up of normal and pathological pregnancies. Moreover, these advances should be a basis to evaluate the impact of multiple pathologies of the pregnancy and pharmacologic and xenobiotic consequences on their metabolism.
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http://dx.doi.org/10.1016/j.ando.2016.04.023DOI Listing
June 2016

A late 17α-hydroxylase deficiency diagnosis that leads to the discovery of a new CYP17 gene mutation.

Ann Endocrinol (Paris) 2015 Feb 19;76(1):71-4. Epub 2015 Jan 19.

Service d'endocrinologie, centre hospitalier Yves-Le-Foll, 10, rue Marcel-Proust, 22000 Saint-Brieuc, France.

17α-Hydroxylase deficiency is a rare form of congenital adrenal hyperplasia. It leads to a reduced production of cortisol and sex steroids and thus an increase in adrenocorticotrophic hormone and gonadotrophins levels. High adrenocorticotrophic hormone levels result in an accumulation of 17-deoxysteroids, such as deoxycorticosterone and corticosterone. Deoxycorticosterone and corticosterone have an important mineralocorticoid activity. We report the case of a 66-year-old woman who presented with hypertension and symptomatic hypokalaemia. Primary hyperaldosteronism was suspected and a right adrenal mass was removed. After surgery, the patient was referred to the endocrinology department for persistant hypokalaemia. Actually, she presented some signs of hypogonadism (impuberism, primary amenorrhea, infertility). Cortisol and 17OH-progesterone serum levels were low. Deoxycorticosterone and corticosterone were markedly elevated. The hypothesis of 17α-hydroxylase deficiency was considered and confirmed by genetic exploration. A non-sense mutation c.938G>A (p.Trp313X) in exon 5 of the CYP17 gene was found that had never been reported so far to our knowledge. Moreover, the patient's karyotype found a mosaic Turner syndrome. This case is particularly interesting because of the delay of diagnosis. The 17α-hydroxylase deficiency diagnosis is to be considered when hypertension is associated with hypokalaemia and hypogonadism, even in adult patients.
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http://dx.doi.org/10.1016/j.ando.2014.11.003DOI Listing
February 2015

Genetic of gonadal determination.

Ann Endocrinol (Paris) 2014 May 29;75(2):32-9. Epub 2014 Apr 29.

Service d'hormonologie, d'endocrinologie moléculaire et des maladies rares, centre de biologie et pathologie Est, université Lyon 1, groupement hospitalier Est- HCL, 59, boulevard Pinel, 69677 Bron cedex, France.

Fetal sexual differentiation results from complex subsequent intracellular signaling and hormonal events that interact together in a definite timing. This process contributes to the setting of gonad determination, internal and external genitalia resulting in a female or male phenotype. Here, we review our current knowledge of gonadal determination drawing on insights from knock-out and transgenic mouse models and analysis of patients with disorders of sex development (DSD).
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http://dx.doi.org/10.1016/j.ando.2014.04.005DOI Listing
May 2014

Complementarity of rotating video and underwater visual census for assessing species richness, frequency and density of reef fish on coral reef slopes.

PLoS One 2014 2;9(1):e84344. Epub 2014 Jan 2.

IFREMER, Unité de Recherche Lagons, Ecosystèmes et Aquaculture Durable en Nouvelle Calédonie (LEAD-NC), Nouméa, New Caledonia.

Estimating diversity and abundance of fish species is fundamental for understanding community structure and dynamics of coral reefs. When designing a sampling protocol, one crucial step is the choice of the most suitable sampling technique which is a compromise between the questions addressed, the available means and the precision required. The objective of this study is to compare the ability to sample reef fish communities at the same locations using two techniques based on the same stationary point count method: one using Underwater Visual Census (UVC) and the other rotating video (STAVIRO). UVC and STAVIRO observations were carried out on the exact same 26 points on the reef slope of an intermediate reef and the associated inner barrier reefs. STAVIRO systems were always deployed 30 min to 1 hour after UVC and set exactly at the same place. Our study shows that; (i) fish community observations by UVC and STAVIRO differed significantly; (ii) species richness and density of large species were not significantly different between techniques; (iii) species richness and density of small species were higher for UVC; (iv) density of fished species was higher for STAVIRO and (v) only UVC detected significant differences in fish assemblage structure across reef type at the spatial scale studied. We recommend that the two techniques should be used in a complementary way to survey a large area within a short period of time. UVC may census reef fish within complex habitats or in very shallow areas such as reef flat whereas STAVIRO would enable carrying out a large number of stations focused on large and diver-averse species, particularly in the areas not covered by UVC due to time and depth constraints. This methodology would considerably increase the spatial coverage and replication level of fish monitoring surveys.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0084344PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879308PMC
November 2014

Remote high-definition rotating video enables fast spatial survey of marine underwater macrofauna and habitats.

PLoS One 2012 27;7(2):e30536. Epub 2012 Feb 27.

Unité de Recherche Lagons, Ecosystèmes et Aquaculture Durable en Nouvelle-Calédonie, French Institute for the Exploitation of the Sea, Nouméa, New Caledonia.

Observing spatial and temporal variations of marine biodiversity from non-destructive techniques is central for understanding ecosystem resilience, and for monitoring and assessing conservation strategies, e.g. Marine Protected Areas. Observations are generally obtained through Underwater Visual Censuses (UVC) conducted by divers. The problems inherent to the presence of divers have been discussed in several papers. Video techniques are increasingly used for observing underwater macrofauna and habitat. Most video techniques that do not need the presence of a diver use baited remote systems. In this paper, we present an original video technique which relies on a remote unbaited rotating remote system including a high definition camera. The system is set on the sea floor to record images. These are then analysed at the office to quantify biotic and abiotic sea bottom cover, and to identify and count fish species and other species like marine turtles. The technique was extensively tested in a highly diversified coral reef ecosystem in the South Lagoon of New Caledonia, based on a protocol covering both protected and unprotected areas in major lagoon habitats. The technique enabled to detect and identify a large number of species, and in particular fished species, which were not disturbed by the system. Habitat could easily be investigated through the images. A large number of observations could be carried out per day at sea. This study showed the strong potential of this non obtrusive technique for observing both macrofauna and habitat. It offers a unique spatial coverage and can be implemented at sea at a reasonable cost by non-expert staff. As such, this technique is particularly interesting for investigating and monitoring coastal biodiversity in the light of current conservation challenges and increasing monitoring needs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0030536PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3287995PMC
August 2012

Congenital lipoid adrenal hyperplasia (a rare form of adrenal insufficiency and ambiguous genitalia) caused by a novel mutation of the steroidogenic acute regulatory protein gene.

Eur J Pediatr 2012 May 15;171(5):787-93. Epub 2011 Nov 15.

Department of Pediatrics, Mount Sinai School of Medicine, Box 1198, One Gustave L. Levy Place, New York, NY 10029, USA.

Unlabelled: Congenital lipoid adrenal hyperplasia (lipoid CAH) is a rare autosomal recessive disorder of adrenal and gonadal steroidogenesis. It is most frequently caused by mutations in the steroidogenic acute regulatory protein (StAR) gene. Patients with lipoid CAH typically present with adrenal crisis in early infancy, and those with a 46,XY karyotype have female genitalia. However, it has been recently recognized that the phenotype can be quite variable, in that adrenal insufficiency is detected later in life and patients may have partially masculinized or even normal male genitalia. We report a patient assigned and reared as a female with a 46,XY karyotype and with a homozygous intron 2 (c.178+1G>C) splice site mutation of the StAR gene, which is a novel mutation that causes lipoid CAH. Her clinical presentation was somewhat atypical for a patient with classic lipoid CAH, marked by mild masculinization of the genitalia, detectable adrenal steroids at baseline, and ability to tolerate the stress of a surgical procedure with anesthesia without receiving glucocorticoid treatment.

Conclusion: There is significant phenotypic variability among patients with lipoid CAH. While splice site mutations in the StAR gene lead to premature translational termination, resulting in truncated and non-functional proteins, there is phenotypic variability among patients with such mutations. Our patient appears to have the more atypical phenotype compared to reported patients with similar mutations. The molecular mechanism underlying this heterogeneity remains unclear.
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http://dx.doi.org/10.1007/s00431-011-1620-5DOI Listing
May 2012

Disruption of a long distance regulatory region upstream of SOX9 in isolated disorders of sex development.

J Med Genet 2011 Dec 2;48(12):825-30. Epub 2011 Nov 2.

INSERM U-781, Hôpital Necker-Enfants Malades, Paris, France.

Background: The early gonad is bipotential and can differentiate into either a testis or an ovary. In XY embryos, the SRY gene triggers testicular differentiation and subsequent male development via its action on a single gene, SOX9. The supporting cell lineage of the bipotential gonad will differentiate as testicular Sertoli cells if SOX9 is expressed and conversely will differentiate as ovarian granulosa cells when SOX9 expression is switched off.

Results: Through copy number variation mapping this study identified duplications upstream of the SOX9 gene in three families with an isolated 46,XX disorder of sex development (DSD) and an overlapping deletion in one family with two probands with an isolated 46,XY DSD. The region of overlap between these genomic alterations, and previously reported deletions and duplications at the SOX9 locus associated with syndromic and isolated cases of 46,XX and 46,XY DSD, reveal a minimal non-coding 78 kb sex determining region located in a gene desert 517-595 kb upstream of the SOX9 promoter.

Conclusions: These data indicate that a non-coding regulatory region critical for gonadal SOX9 expression and subsequent normal sex development is located far upstream of the SOX9 promoter. Its copy number variations are the genetic basis of isolated 46,XX and 46,XY DSDs of variable severity (ranging from mild to complete sex reversal). It is proposed that this region contains a gonad specific SOX9 transcriptional enhancer(s), the gain or loss of which results in genomic imbalance sufficient to activate or inactivate SOX9 gonadal expression in a tissue specific manner, switch sex determination, and result in isolated DSD.
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http://dx.doi.org/10.1136/jmedgenet-2011-100255DOI Listing
December 2011

Deletion of P399_E401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency.

Biochem Biophys Res Commun 2011 Sep 6;412(4):572-7. Epub 2011 Aug 6.

Pediatric Endocrinology, Diabetology and Metabolism, University Children's Hospital, Bern, Switzerland.

P450 oxidoreductase (POR) is the electron donor for all microsomal P450s including steroidogenic enzymes CYP17A1, CYP19A1 and CYP21A2. We found a novel POR mutation P399_E401del in two unrelated Turkish patients with 46,XX disorder of sexual development. Recombinant POR proteins were produced in yeast and tested for their ability to support steroid metabolizing P450 activities. In comparison to wild-type POR, the P399_E401del protein was found to decrease catalytic efficiency of 21-hydroxylation of progesterone by 68%, 17α-hydroxylation of progesterone by 76%, 17,20-lyase action on 17OH-pregnenolone by 69%, aromatization of androstenedione by 85% and cytochrome c reduction activity by 80%. Protein structure analysis of the three amino acid deletion P399_E401 revealed reduced stability and flexibility of the mutant. In conclusion, P399_E401del is a novel mutation in POR that provides valuable genotype-phenotype and structure-function correlation for mutations in a different region of POR compared to previous studies. Characterization of P399_E401del provides further insight into specificity of different P450s for interaction with POR as well as nature of metabolic disruptions caused by more pronounced effect on specific P450s like CYP17A1 and aromatase.
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http://dx.doi.org/10.1016/j.bbrc.2011.08.001DOI Listing
September 2011

Craniosynostosis, hydrocephalus, Chiari I malformation and radioulnar synostosis: probably a new syndrome.

Eur J Med Genet 2009 Jan-Feb;52(1):17-22. Epub 2008 Nov 6.

UO Neurochirurgia, Istituto G. Gaslini, 16148 Genova, Italy.

We report on clinical and molecular findings of two brothers that both presented with sagittal craniosynostosis, hydrocephalus, Chiari I malformation, blepharophimosis, small low-set ears, hypoplastic philtrum, radioulnar synostosis, kidney malformation, and hypogenitalism. Their father presented mild brachydactyly. Conventional cytogenetic and array CGH screening did not show any chromosomal gains or losses. Furthermore, molecular genetic screening of genes involved in different craniosynostosis syndromes, namely FGFR1, FGFR2, FGFR3, TWIST, RECQL4, and POR genes failed to detect any mutations in genomic DNA. The unique range of clinical manifestations in these two patients and the negative findings of the molecular genetic screening suggest the hypothesis of a previously unrecognized syndrome.
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http://dx.doi.org/10.1016/j.ejmg.2008.10.005DOI Listing
April 2009

CBP/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 2, and pre-B-cell leukemia transcription factor 1 in human adrenal development and disease.

J Clin Endocrinol Metab 2009 Feb 4;94(2):678-83. Epub 2008 Nov 4.

Developmental Endocrinology Research Group, University College London Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, United Kingdom.

Context: Disorders of adrenal development result in significant morbidity and mortality. However, the molecular basis of human adrenal development, and many forms of disease, is still poorly understood.

Objectives: We evaluated the role of two new candidate genes, CBP/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 2 (CITED2), and pre-B-cell leukemia transcription factor 1 (PBX1), in human adrenal development and disease.

Design: CITED2 and PBX1 expression in early human fetal adrenal development was assessed using RT-PCR and in situ hybridization. The regulation of CITED2 and PBX1 by steroidogenic factor-1 (SF-1) and dosage-sensitive sex reversal, adrenal hypoplasia congenital, critical region on the X chromosome, gene-1 (DAX1) was evaluated in NCI-H295R human adrenocortical tumor cells by studying promoter regulation. Finally, mutational analysis of CITED2 and PBX1 was performed in patients with primary adrenal disorders.

Results: CITED2 and PBX1 are expressed in the human fetal adrenal gland during early development. Both genes are activated by SF-1 in a dose-dependent manner in NCI-H295R cells, and, surprisingly, PBX1 is synergistically activated by SF-1 and DAX1. Mutational analysis failed to reveal significant coding sequence changes in individuals with primary adrenal disorders.

Conclusions: CITED2 and PBX1 are likely to be important mediators of adrenal development and function in humans, but mutations in these genes are not common causes of adrenal failure in patients in whom a molecular diagnosis remains unknown. The positive interaction between DAX1 and SF-1 in regulating PBX1 may be an important mechanism in this process.
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http://dx.doi.org/10.1210/jc.2008-1064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2814552PMC
February 2009

Heterozygous mutation of steroidogenic factor-1 in 46,XY subjects may mimic partial androgen insensitivity syndrome.

J Clin Endocrinol Metab 2007 Aug 8;92(8):2868-73. Epub 2007 May 8.

Department of Pediatric Endocrinology, University Hospital, 4 rue Larrey, 49033 Angers Cedex 01, France.

Context: The clinical and biological features of Sertoli cell and Leydig cell dysfunction are usually investigated when characterizing disorders of sex development in 46,XY individuals: This allows gonadal dysgenesis, a defective development of the gonad, to be distinguished from defects restricted to androgen synthesis or sensitivity. In humans, mutations in steroidogenic factor-1 (SF-1), one of the critical factors involved in testis development, have been reported to cause gonadal dysgenesis with or without adrenal failure in 46,XY individuals.

Objective: We report a SF-1 mutation that caused ambiguous genitalia associated with strikingly different hormonal phenotypes in two affected 46,XY children from the same family.

Methods: Hormonal evaluation included testosterone (T), anti-Mullerian hormone (AMH), inhibin B, FSH, and LH measurements during the first weeks of life, a period when physiological activation of the gonadotropin-gonadal system occurs. Direct DNA sequencing of the coding sequence of the SF-1 and the androgen receptor (AR) genes was performed.

Results: Both 46,XY children had ambiguous genitalia with no Mullerian structures and no adrenal insufficiency. The older child showed normal elevation of T (up to 7.6 nmol/liter, 2.2 ng/ml), AMH (504 pmol/liter, 70.6 ng/ml), inhibin B (245 pg/ml), FSH, and LH during the first weeks, which led to a presumptive diagnosis of partial androgen insensitivity syndrome. The AR sequence was, however, normal. In the second child, T, AMH, and inhibin B were low, suggesting gonadal dysgenesis. In both children and their mother, a c.536delC frameshift mutation in the SF-1 gene was found. This mutation terminates translation at position 295, removing the ligand-binding domain and the activation function 2 (AF-2) domain, a critical domain for SF-1 transactivating activity.

Conclusions: The usual markers of testis dysgenesis may be normal in 46,XY individuals with SF-1 mutation. Screening for SF-1 mutation should be performed in subjects with apparent partial androgen insensitivity syndrome and no mutation in the AR gene.
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http://dx.doi.org/10.1210/jc.2007-0024DOI Listing
August 2007

A novel mutation L260P of the steroidogenic acute regulatory protein gene in three unrelated patients of Swiss ancestry with congenital lipoid adrenal hyperplasia.

J Clin Endocrinol Metab 2005 Sep 28;90(9):5304-8. Epub 2005 Jun 28.

Biochimie Endocrinienne et Moléculaire, Hopital Debrousse, 29 Rue Soeur Bouvier, F-69322 Lyon Cedex 05, France.

Context: Lipoid congenital adrenal hyperplasia (CAH) is the most severe form of CAH leading to impaired production of all adrenal and gonadal steroids. Mutations in the gene encoding steroidogenic acute regulatory protein (StAR) cause lipoid CAH.

Objective: We investigated three unrelated patients of Swiss ancestry who all carried novel mutations in the StAR gene. All three subjects were phenotypic females with absent Müllerian derivatives, 46,XY karyotype, and presented with adrenal failure.

Methods And Results: StAR gene analysis showed that one patient was homozygous and the other two were heterozygous for the novel missense mutation L260P. Of the heterozygote patients, one carried the novel missense mutation L157P and one had a novel frameshift mutation (629-630delCT) on the second allele. The functional ability of all three StAR mutations to promote pregnenolone production was severely attenuated in COS-1 cells transfected with the cholesterol side-chain cleavage system and mutant vs. wild-type StAR expression vectors.

Conclusions: These cases highlight the importance of StAR-dependent steroidogenesis during fetal development and early infancy; expand the geographic distribution of this condition; and finally establish a new, prevalent StAR mutation (L260P) for the Swiss population.
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http://dx.doi.org/10.1210/jc.2005-0874DOI Listing
September 2005

Delayed diagnosis of congenital adrenal hyperplasia with salt wasting due to type II 3beta-hydroxysteroid dehydrogenase deficiency.

J Clin Endocrinol Metab 2005 Apr 25;90(4):2076-80. Epub 2005 Jan 25.

University Department of Growth and Reproduction, GR-5064, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.

Classical 3beta-hydroxysteroid dehydrogenase (3beta-HSD) deficiency is a rare cause of congenital adrenal hyperplasia. We report two sisters presenting with delayed diagnoses of classical 3beta-HSD, despite salt wasting (SW) episodes in infancy. Sibling 1 was referred for premature pubarche, slight growth acceleration, and advanced bone age, whereas sibling 2 had no signs of virilization. At referral, increased 17alpha-hydroxyprogesterone associated with premature pubarche at first suggested a nonclassical 21-hydroxylase deficiency. Sequencing of the CYP21 gene showed both girls only heterozygotes (V281L mutation). This result, combined with SW in infancy, suggested a 3beta-HSD deficiency because of increased dehydroepiandrosterone sulfate levels. Further hormonal studies showed markedly elevated Delta5-steroids, in particular 17alpha-hydroxypregnenolone greater than 100 nmol/liter (the clue to the diagnosis) and elevated Delta5-/Delta4-steroid ratios. Sequencing of the type II 3beta-HSD gene documented that both girls were compound heterozygotes for T181I and 1105delA mutations. Retrospectively, elevated levels of 17alpha-hydroxyprogesterone were found on blood spots from Guthrie's test. There is no previous report of the combination of SW and premature pubarche due to mutations in the type II 3beta-HSD gene. Because neonatal diagnosis could have prevented life-threatening crises in these girls, this report further supports the benefits for neonatal screening for congenital adrenal hyperplasia whatever the etiology.
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http://dx.doi.org/10.1210/jc.2004-1374DOI Listing
April 2005

Gonadal dysgenesis without adrenal insufficiency in a 46, XY patient heterozygous for the nonsense C16X mutation: a case of SF1 haploinsufficiency.

J Clin Endocrinol Metab 2004 Oct;89(10):4829-32

Laboratoire de Biochimie Endocrinienne et Moléculaire, Hôpital Debrousse, and EA3739, Université Claude Bernard, Lyon, France.

Targeted disruption of the orphan nuclear receptor SF1 results in the absence of adrenals and gonads, establishing that this transcription factor is implicated in gonadal determination and adrenal development. Four human SF1 gene mutations have been described to date: three (G35E, R92Q, R255L) were responsible for adrenal insufficiency associated with a gonadal dysgenesis in two 46, XY individuals, one (8 bp deletion in exon 6) resulted in gonadal dysgenesis without adrenal insufficiency. We identified a new heterozygous SF1 gene mutation, C16X, in a 46, XY patient showing gonadal dysgenesis with normal adrenal function: low basal levels of AMH and testosterone (T), weak T response to hCG, hypoplastic testes with abundant seminiferous tubules but rare germ cells. This mutation causes premature termination of translation and should abolish all SF1 activity. Therefore haploinsufficiency could explain the deleterious effect of this mutation in our patient suggesting that testis development is more SF1 dose-dependent than adrenal development. Although the same mechanism explains the deleterious effects of SF1 missense mutations, recent studies have demonstrated an additional dominant negative effect. These data suggest that heterozygous mutation impaired adrenal development only if the two mechanisms, gene dosage and dominant negative effects occur.
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http://dx.doi.org/10.1210/jc.2004-0670DOI Listing
October 2004

Endocrine screening in 32 consecutive patients with hypospadias.

J Urol 2002 Aug;168(2):720-5; discussion 725

Department of Pediatric Urology, and INSERM U329, Biochimie Endocrinienne et Métabolique, Hôpital Debrousse, Hospices Civils de Lyon, Lyon, France.

Purpose: Various endocrine studies performed in the hypospadias population show an unsatisfactory response to the human chorionic gonadotropin (HCG) test and abnormal androgen biosynthesis with possible enzyme defects. We evaluated the incidence of disorders in androgen production in boys with isolated hypospadias.

Materials And Methods: A total of 32 consecutive children (46,XY) with hypospadias were prospectively enrolled in the study. Severity of the defect was assessed with a new classification based on the location of the division of the corpus spongiosum. Endocrine evaluation consisted of measuring luteinizing hormone, follicle-stimulating hormone, anti-müllerian hormone (AMH), testosterone, dihydrotestosterone, progesterone, 17alpha-hydroxypregnenolone, 17alpha-hydroxyprogesterone, dehydroepiandrosterone sulfate and delta4-androstenedione. In all but 3 patients gonadal stimulation with 1,500 IU HCG every other day for 12 days was performed and steroid concentrations were reassessed after the test. An adrenocorticotropic hormone test was performed in 2 patients and molecular study of the androgen receptor was performed in 28.

Results: An increase to 37.37 nmol./l. progesterone (normal 0.1 to 0.5) and 17alpha-hydroxyprogesterone to 25.48 nmol./l. (normal 1.18 +/- 0.66) before HCG stimulation was noted in 1 patient. These abnormal results were not found after HCG stimulation but reappeared after the adrenocorticotropic hormone test. This result might be related to a partial mix of 17alpha-hydroxylase/17,20-lyase deficiency but no mutation was found after complete sequencing of gene CYP17. Of the 32 patients 4 had an insufficient response to HCG stimulation (testosterone less than 10 nmol./l.), including 1 with a low AMH level of 180 pmol./l. (normal 451 +/- 198) and an increased dehydroepiandrosterone sulfate level of 1,995 nmol./l. (normal 59 +/- 41) before HCG stimulation. Partial androgen insensitivity was suspected in 1 patient because he had a high testosterone response (29.96 nmol./l.) after HCG stimulation but no mutation of the gene of the androgen receptor was detected. Two patients with proximal hypospadias had isolated decreased AMH levels, which was evidence of Sertoli cell insufficiency.

Conclusions: Although our series of 32 patients had several abnormal endocrine screenings, these results indicate no significant endocrine defects.
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August 2002