Publications by authors named "Laurence Michel-Calemard"

18 Publications

  • Page 1 of 1

A novel disease-causing mutation in the Renin gene in a Tunisian family with autosomal dominant tubulointerstitial kidney disease.

Int J Biochem Cell Biol 2019 12 3;117:105625. Epub 2019 Oct 3.

Laboratory of Human Molecular Genetics, Faculty of Medicine, Magida Boulila Street, 3029 Sfax, University of Sfax, Tunisia; Medical Genetics Department of Hedi Chaker Hospital, Route El Ain, Sfax 3089, Tunisia.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare group of disease that affect the tubules of the kidney. There are 4 known subtypes of ADTKD classified based on causative genes and clinical features. In our study, we aimed to identify the causative subtypes of ADTKD in a Tunisian ADTKD family (3 affected members), in whom standard nephrological diagnosis did not provide clear subtype of ADTKD, until genetic testing was performed. Sanger sequencing was performed for UMOD, HNF1β and REN genes. Mutational analysis allowed us to detect a heterozygous mutation in the REN gene: c.1172C > G, (p.T391R) in exon 10. In silico analyses predicted that the novel likely pathogenic mutation affect protein stability and 3D structure. Our study highlights the importance of establishing a genetic diagnosis to identify the subtype of ADTKD for better patient care. To the best of our knowledge, we report here a first Tunisian ADTKD-REN family.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biocel.2019.105625DOI Listing
December 2019

School level of children carrying a HNF1B variant or a deletion.

Eur J Hum Genet 2020 01 3;28(1):56-63. Epub 2019 Sep 3.

Service de Pédiatrie, CHU de Limoges, Limoges, France.

The prevalence of neurological involvement in patients with a deletion of or a variant in the HNF1B gene remains discussed. The aim of this study was to investigate the neuropsychological outcomes in a large cohort of children carrying either a HNF1B whole-gene deletion or a disease-associated variant, revealed by the presence of kidney anomalies. The neuropsychological development-based on school level-of 223 children included in this prospective cohort was studied. Data from 180 children were available for analysis. Patients mean age was 9.6 years, with 39.9% of girls. Among these patients, 119 carried a HNF1B deletion and 61 a disease-associated variant. In the school-aged population, 12.7 and 3.6% of patients carrying a HNF1B deletion and a disease-associated variant had special educational needs, respectively. Therefore, the presence of a HNF1B deletion increases the risk to present with a neuropsychiatric involvement when compared with the general population. On the other hand, almost 90% of patients carrying a HNF1B disease-associated variant or deletion have a normal schooling in a general educational environment. Even if these findings do not predict the risk of neuropsychiatric disease at adulthood, most patients diagnosed secondary to kidney anomalies do not show a neurological outcome severe enough to impede standard schooling at elementary school. These results should be taken into account in prenatal counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-019-0490-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906503PMC
January 2020

Clinical courses and complications of young adults with Autosomal Recessive Polycystic Kidney Disease (ARPKD).

Sci Rep 2019 05 28;9(1):7919. Epub 2019 May 28.

Department of Pediatrics, University Hospital of Cologne, Cologne, Germany.

Autosomal recessive polycystic kidney disease (ARPKD) is a severe pediatric hepatorenal disorder with pronounced phenotypic variability. A substantial number of patients with early diagnosis reaches adulthood and some patients are not diagnosed until adulthood. Yet, clinical knowledge about adult ARPKD patients is scarce. Here, we describe forty-nine patients with longitudinal follow-up into young adulthood that were identified in the international ARPKD cohort study ARegPKD. Forty-five patients were evaluated in a cross-sectional analysis at a mean age of 21.4 (±3.3) years describing hepatorenal findings. Renal function of native kidneys was within CKD stages 1 to 3 in more than 50% of the patients. Symptoms of hepatic involvement were frequently detected. Fourteen (31%) patients had undergone kidney transplantation and six patients (13%) had undergone liver transplantation or combined liver and kidney transplantation prior to the visit revealing a wide variability of clinical courses. Hepatorenal involvement and preceding complications in other organs were also evaluated in a time-to-event analysis. In summary, we characterize the broad clinical spectrum of young adult ARPKD patients. Importantly, many patients have a stable renal and hepatic situation in young adulthood. ARPKD should also be considered as a differential diagnosis in young adults with fibrocystic hepatorenal disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-43488-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538621PMC
May 2019

A National French consensus on gene lists for the diagnosis of myopathies using next-generation sequencing.

Eur J Hum Genet 2019 03 14;27(3):349-352. Epub 2018 Dec 14.

CHRU Montpellier, Laboratoire de Génétique moléculaire, Montpellier, France.

Next-generation sequencing (NGS) gene-panel-based analyses constitute diagnosis strategies which are adapted to the genetic heterogeneity within the field of myopathies, including more than 200 implicated genes to date. Nonetheless, important inter-laboratory diversity of gene panels exists at national and international levels, complicating the exchange of data and the visibility of the diagnostic offers available for referring neurologists. To address this issue, we here describe the initiative of the genetic diagnosis section of the French National Network for Rare Neuromuscular Diseases (Filière Nationale des Maladies Rares Neuromusculaires, FILNEMUS), which led to set up a consensual nationwide diagnostic strategy among the nine French genetic diagnosis laboratories using NGS for myopathies. The strategy is based on the determination of 13 clinical and/or histological entry-diagnosis groups, and consists for each group either in a successive NGS analysis of a "core gene list" followed in case of a negative result by the analysis of an "exhaustive gene list", or in the NGS analysis of a "unique exhaustive gene list".
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-018-0305-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460575PMC
March 2019

[PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD): Genotype-phenotype correlations from a series of 308 cases to improve prenatal counselling].

Nephrol Ther 2018 Nov 25;14(6):474-477. Epub 2018 Apr 25.

UM pathologies endocriniennes, rénales, musculaires et mucoviscidose, CBPE, groupement hospitalier Est, 59, boulevard Pinel, 69677 Bron cedex, France.

Objectives: ARPKD is a recessive rare disease due to PKHD1 mutation. The main objective of the study was to characterize the phenotypic variability according to the different types of PKHD1 mutations.

Methods: This study was performed in 308 ARPKD patients with a genetic diagnosis from our genetic center. Related physicians provided minimal clinical and biological data.

Results: Patients were divided into three genotypic groups: the first group (G1; n=65) consisted of patients with two truncating mutations, the second group (G2; n=117) of patients with one truncating and one non-truncating mutation, and the third group (G3; n=126) of patients with two non-truncating mutations. In the entire cohort, the outcomes consisted of 31% of pregnancy termination, 18% of neonatal deaths and 51% of patient survival after the neonatal period. The proportion of severe ARPKD (pregnancy termination or neonatal death) was significantly greater in G1: 94% versus 47% in G2 and 27% in G3 (P<0.001).

Conclusion: The presence of two truncating mutations in PKHD1 is associated with the most severe perinatal phenotype. However, the phenotypic variability observed in the other genotypic groups requires caution for prenatal counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nephro.2018.03.002DOI Listing
November 2018

Fetal anomalies associated with HNF1B mutations: report of 20 autopsy cases.

Prenat Diagn 2016 Aug 6;36(8):744-51. Epub 2016 Jul 6.

SOFFOET, Société Française de Fœtopathologie, Lyon, Rennes, France.

Objectives: To describe macroscopic and microscopic anomalies present in fetuses carrying hepatocyte nuclear factor-1 β mutation, their frequency, and genotype/phenotype correlations.

Methods: Clinical data, ultrasound findings, genetic studies, and autopsy reports of 20 fetal autopsies were analyzed. Histology was reviewed by two pathologists.

Results: Macroscopic findings were typically unilateral or bilateral renal enlargement and cortical cysts. Renal lesions were associated with congenital anomalies of the kidney and urinary tract in 25% of cases. Microscopic renal anomalies were dominated by glomerulocystic kidney and renal dysplasia. Extra-renal manifestations such as pancreatic hypoplasia (75%) and genital anomalies (68%) were only detected at autopsy. In 40% of cases, there was heterozygous deletion of the whole gene. There were de novo mutations in 40%.

Conclusion: This study underlines the importance of considering hepatocyte nuclear factor-1 β mutations in fetuses with congenital anomalies of the kidney and urinary tract, especially when associated with pancreatic hypoplasia. No correlation between phenotype and genotype was found, highlighting high intra-familial variability in cases with inherited mutations. © 2016 John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.4858DOI Listing
August 2016

Compound heterozygous PKHD1 variants cause a wide spectrum of ductal plate malformations.

Am J Med Genet A 2015 Dec 8;167A(12):3046-53. Epub 2015 Sep 8.

Service de p, é, diatrie 1 et de génétique médicale, Centre Hospitalo-Universitaire, Dijon, France.

Ductal plate malformations (DPM) present with a wide phenotypic spectrum comprising Von Meyenburg complexes (VMC), Caroli disease (CD), Caroli syndrome (CS), and autosomal recessive polycystic kidney disease (ARPKD). Variants in PKHD1 are responsible for ARPKD and CS with a high inter- and intra-familial phenotypic variability. Rare familial cases of CD had been reported and exceptional cases of CD are associated with PKHD1 variants. In a family of three siblings presenting with a wide spectrum of severity of DPM, we performed whole exome sequencing and identified two PKHD1 compound heterozygous variants (c.10444G>A; p.Arg3482Cys and c.5521C>T; p.Glu1841Lys), segregating with the symptoms. Two compound heterozygous PKHD1 variants, including one hypomorphic variant, were identified in two other familial cases of DPM with at least one patient presenting with CD. This report widens the phenotypic variability of PKHD1 variants to VMC, and others hepatic bile ducts malformations with inconstant renal phenotype in adults and highlights the important intra-familial phenotypic variability. It also showed that PKHD1 might be a major gene for CD. This work adds an example of the contribution of exome sequencing, not only in the discovery of new genes but also in expanding the phenotypic spectrum of well-known disease-associated genes, using reverse phenotyping.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.37352DOI Listing
December 2015

A splicing mutation in the DMD gene detected by next-generation sequencing and confirmed by mRNA and protein analysis.

Clin Chim Acta 2015 Aug 3;448:146-9. Epub 2015 Jul 3.

Laboratoire d'Endocrinologie Moléculaire et Maladies Rares, Hospices Civils de Lyon, Lyon, France.

Background: Dystrophinopathies, either the severe Duchenne Muscular Dystrophy (DMD) or the milder Becker Muscular Dystrophy (BMD), are X-linked recessive disorders caused by mutations in the DMD gene. DMD is one of the longest human genes. Large deletions or duplications account for 60-80% of the mutations. Remaining anomalies consist in point mutations or small rearrangements. Routinely, the molecular diagnosis is done by a Multiplex Ligation-dependent Probe Amplification (MLPA) or array Comparative Genome Hybridization (aCGH), followed, if negative, by Sanger sequencing of all exons.

Methods: In this study, massive parallel sequencing (MPS) or next generation sequencing (NGS) was used to make a rapid and costless molecular diagnosis in a young boy suspected of DMD.

Results: A small deletion: NM_004006.2:c.2803+5_2803+8del was identified. The diagnosis was performed in one single manipulation and within a week. The consequence of this intronic mutation is a skipping of exon 21 confirmed by mRNA and protein analysis.

Conclusions: NGS appears to be an efficient new strategy in DMD molecular diagnosis. It highlights the major evolution of the diagnostic strategy towards high throughput technologies, where bioinformatics analysis becomes the real challenge for variations detection. This is the first study reporting in vivo impact of this intronic mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cca.2015.07.002DOI Listing
August 2015

Genotype-phenotype correlations in fetuses and neonates with autosomal recessive polycystic kidney disease.

Kidney Int 2010 Feb 25;77(4):350-8. Epub 2009 Nov 25.

Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Hôpital Robert Debré, Laboratoire de Biochimie Génétique, INSERM U722, Paris, France.

The prognosis of autosomal recessive polycystic kidney disease is known to correlate with genotype. The presence of two truncating mutations in the PKHD1 gene encoding the fibrocystin protein is associated with neonatal death while patients who survive have at least one missense mutation. To determine relationships between genotype and renal and hepatic abnormalities we correlated the severity of renal and hepatic histological lesions to the type of PKHD1 mutations in 54 fetuses (medical pregnancy termination) and 20 neonates who died shortly after birth. Within this cohort, 55.5% of the mutations truncated fibrocystin. The severity of cortical collecting duct dilatations, cortical tubule and glomerular lesions, and renal cortical and hepatic portal fibrosis increased with gestational age. Severe genotypes, defined by two truncating mutations, were more frequent in patients of less than 30 weeks gestation compared to older fetuses and neonates. When adjusted to gestational age, the extension of collecting duct dilatation into the cortex and cortical tubule lesions, but not portal fibrosis, was more prevalent in patients with severe than in those with a non-severe genotype. Our results show the presence of two truncating mutations of the PKHD1 gene is associated with the most severe renal forms of prenatally detected autosomal recessive polycystic kidney disease. Their absence, however, does not guarantee survival to the neonatal period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ki.2009.440DOI Listing
February 2010

Unexpected diagnosis of 45,X/47,XX,+18 mosaicism in a girl with mild phenotype.

Am J Med Genet A 2009 Nov;149A(11):2584-7

Service de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, Bron Cedex, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.32772DOI Listing
November 2009

Familial acampomelic form of campomelic dysplasia caused by a 960 kb deletion upstream of SOX9.

Am J Med Genet A 2009 Jun;149A(6):1183-9

CHU Nantes, Service de Génétique Médicale, Nantes, France.

Campomelic dysplasia (CD) is a rare autosomal dominant osteochondrodysplasia with or without XY disorders of sexual development (DSD). Campomelia is absent in about 10% of the cases, referred to as the acampomelic form of CD (ACD). Most CDs are caused by mutations within the SOX9 coding region. Several CD patients with balanced chromosome rearrangements involving the 17q24 region have been reported suggesting the presence of cis-regulatory elements upstream and/or downstream of the gene. Deletions upstream of SOX9 represent a third mechanism of mutation. To date, a 1.5 Mb de novo deletion in the SOX9 upstream region has been identified in a single 46,XY patient with ACD and DSD. We report here for the first time on a familial ACD caused by an inherited deletion mapping upstream of the SOX9 gene. Using high-density oligoarray comparative genomic hybridization (CGH), we showed that the size of the deletion was 960 kb in the XY-DSD child and her mother, both affected. The deletion lying from 517 kb to 1.477 Mb upstream of SOX9 remove several highly conserved elements and reduce the minimum critical size and therefore the number of highly conserved sequence elements responsible for ACD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.32830DOI Listing
June 2009

Genotype-phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD-DMD database: a model of nationwide knowledgebase.

Hum Mutat 2009 Jun;30(6):934-45

Université Montpellier 1, Faculté de Médecine, Montpellier, France.

UMD-DMD France is a knowledgebase developed through a multicenter academic effort to provide an up-to-date resource of curated information covering all identified mutations in patients with a dystrophinopathy. The current release includes 2,411 entries consisting in 2,084 independent mutational events identified in 2,046 male patients and 38 expressing females, which corresponds to an estimated number of 39 people per million with a genetic diagnosis of dystrophinopathy in France. Mutations consist in 1,404 large deletions, 215 large duplications, and 465 small rearrangements, of which 39.8% are nonsense mutations. The reading frame rule holds true for 96% of the DMD patients and 93% of the BMD patients. Quality control relies on the curation by four experts for the DMD gene and related diseases. Data on dystrophin and RNA analysis, phenotypic groups, and transmission are also available. About 24% of the mutations are de novo events. This national centralized resource will contribute to a greater understanding of prevalence of dystrophinopathies in France, and in particular, of the true frequency of BMD, which was found to be almost half (43%) that of DMD. UMD-DMD is a searchable anonymous database that includes numerous newly developed tools, which can benefit to all the scientific community interested in dystrophinopathies. Dedicated functions for genotype-based therapies allowed the prediction of a new multiexon skipping (del 45-53) potentially applicable to 53% of the deleted DMD patients. Finally, such a national database will prove to be useful to implement the international global DMD patients' registries under development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.20976DOI Listing
June 2009

Identification of two novel mutations and long-term follow-up in abetalipoproteinemia: a report of four cases.

Eur J Pediatr 2009 Aug 9;168(8):983-9. Epub 2008 Dec 9.

Fédération de Biochimie et Biologie Spécialisée, Hôpital E HERRIOT, Hospices Civils de Lyon, Lyon, France.

Abetalipoproteinemia (ABL; OMIM 200100) is an inherited disorder resulting from mutations in the microsomal triglyceride transfer protein gene and characterized by a major lipid malabsorption leading to extremely low plasma cholesterol and triglyceride levels and fat-soluble vitamins deficiencies. We report two novel mutations (c.59del17 and c.582C>A) and the long-term follow-up of four ABL subjects treated with vitamin E. The good outcome of the early-treated patients contrasts with severe ataxia and retinopathy observed in the patient with delayed treatment. In conclusion, early diagnosis and early management are essential to prevent the manifestations following the fat-soluble vitamin deficiencies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00431-008-0888-6DOI Listing
August 2009

Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy.

Hum Mutat 2007 Feb;28(2):196-202

Laboratoire de Génétique Moléculaire, Institut Universitaire de Recherche Clinique, Unité de Formation et de Recherche Médecine Site Nord Unité Pédagogique Médicale/IURC, Montpellier, France.

Approximately two-thirds of Duchenne muscular dystrophy (DMD) patients show intragenic deletions ranging from one to several exons of the DMD gene and leading to a premature stop codon. Other deletions that maintain the translational reading frame of the gene result in the milder Becker muscular dystrophy (BMD) form of the disease. Thus the opportunity to transform a DMD phenotype into a BMD phenotype appeared as a new treatment strategy with the development of antisense oligonucleotides technology, which is able to induce an exon skipping at the pre-mRNA level in order to restore an open reading frame. Because the DMD gene contains 79 exons, thousands of potential transcripts could be produced by exon skipping and should be investigated. The conventional approach considers skipping of a single exon. Here we report the comparison of single- and multiple-exon skipping strategies based on bioinformatic analysis. By using the Universal Mutation Database (UMD)-DMD, we predict that an optimal multiexon skipping leading to the del45-55 artificial dystrophin (c.6439_8217del) could transform the DMD phenotype into the asymptomatic or mild BMD phenotype. This multiple-exon skipping could theoretically rescue up to 63% of DMD patients with a deletion, while the optimal monoskipping of exon 51 would rescue only 16% of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.20428DOI Listing
February 2007

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2004-0670DOI Listing
October 2004

Campomelic acampomelic dysplasia presenting with increased nuchal translucency in the first trimester.

Prenat Diagn 2004 Jul;24(7):519-23

Laboratoire de Biochimie, Hôpital Debrousse, Lyon, France.

This is the first report of a fetus affected with campomelic acampomelic dysplasia presenting with increased nuchal translucency. Ultrasonography at 13 weeks of amenorrhea showed a nuchal translucency 5.6 mm thick. The karyotype performed on amniotic fluid cells was normal (46,XY). Ultrasonography at 22 weeks revealed a normal femoral length and female genitalia. A second amniocentesis was performed to confirm the karyotype and for dosage of steroid hormones. Testosterone dosage was low, corresponding to a female fetus. Ultrasonography at 32 weeks showed growth retardation of the long bones (< 3rd centile) that were not curved. A severe malformation syndrome was suspected and the pregnancy was terminated at 33 weeks. The fetus displayed macrocephaly, facial dysmorphism and female external genitalia. X ray showed straight and thickened long bones, hypoplastic scapulae and moderate platyspondyly. In view of the association of sex reversal, hypoplasia of the scapulae, and the presence of straight long bones, campomelic acampomelic dysplasia was suspected and confirmed by the finding of a SOX9 mutation. This case shows the importance of a careful echographic survey in a fetus with a nuchal translucency > 4 mm, especially if there is discordance between phenotypic and genotypic sex, since growth retardation may occur later during the pregnancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.935DOI Listing
July 2004

Aetiological diagnosis of male sex ambiguity: a collaborative study.

Eur J Pediatr 2002 Jan;161(1):49-59

Unité de Recherches sur la Pathologie Hormonale Moléculaire (INSERM), Hôpital Debrousse, Lyon, France.

Unlabelled: A collaborative study, supported by the Biomed2 Programme of the European Community, was initiated to optimise the aetiological diagnosis in genetic or gonadal males with intersex disorders, a total of 67 patients with external sexual ambiguity, testicular tissue and/or a XY karyotype. In patients with gonadal dysgenesis or true hermaphroditism, the incidence of vaginal development was 100%, a uterus was present in 60%; uni or bilateral cryptorchidism was seen in nearly all cases of testicular dysgenesis (99%) but in only 57% of true hermaphrodites. Mean serum levels of anti-mullerian hormone and of serum testosterone response to chorionic gonadotropin stimulation were significantly decreased in both conditions, by comparison with patients with unexplained male pseudohermaphroditism or partial androgen insensitivity (PAIS). Mutations in the androgen receptor, 90% within exons 2-8, were detected in patients with PAIS. Clinically, a vaginal pouch was present in 90%, cryptorchidism in 36%. In 52% of cases, no diagnosis could be reached, despite an exhaustive clinical and laboratory work-up, including routine sequencing of exons 2-8 of the androgen receptor. By comparison with PAIS, unexplained male pseudohermaphroditism was characterised by a lower incidence of vaginal pouch (55%) and cryptorchidism (22%) but a high incidence of prematurity/intrauterine growth retardation (30%) or mild malformations (14%).

Conclusion: reaching an aetiological diagnosis in cases of male intersex is difficult because of the variability of individual cases. Hormonal tests may help to discriminate between partial androgen insensitivity and gonadal dysgenesis/true hermaphroditism but are of less use for differentiating from unexplained male pseudohermaphroditism. Sequencing of exons 2-8 of the androgen receptor after study of testosterone precursors following human chorionic gonadotrophin stimulation is recommended when gonadal dysgenesis and true hermaphroditism can be excluded.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00431-001-0854-zDOI Listing
January 2002