Publications (13)150.99 Total impact
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Article: Screening of MAMLD1 mutations in 70 children with 46,XY DSD: identification and functional analysis of two new mutations.
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ABSTRACT: More than 50% of children with severe 46,XY disorders of sex development (DSD) do not have a definitive etiological diagnosis. Besides gonadal dysgenesis, defects in androgen biosynthesis, and abnormalities in androgen sensitivity, the Mastermind-like domain containing 1 (MAMLD1) gene, which was identified as critical for the development of male genitalia, may be implicated. The present study investigated whether MAMLD1 is implicated in cases of severe 46,XY DSD and whether routine sequencing of MAMLD1 should be performed in these patients.Seventy children with severe non-syndromic 46,XY DSD of unknown etiology were studied. One hundred and fifty healthy individuals were included as controls. Direct sequencing of the MAMLD1, AR, SRD5A2 and NR5A1 genes was performed. The transactivation function of the variant MAMLD1 proteins was quantified by the luciferase method.TWO NEW MUTATIONS WERE IDENTIFIED: p.S143X (c.428C>A) in a patient with scrotal hypospadias with microphallus and p.P384L (c.1151C>T) in a patient with penile hypospadias with microphallus. The in vitro functional study confirmed no residual transactivating function of the p.S143X mutant and a significantly reduced transactivation function of the p.P384L protein (p = 0.0032). The p.P359S, p.N662S and p.H347Q variants are also reported with particularly high frequency of the p.359T- p.662G haplotype in the DSD patients.Severe undervirilization in XY newborns can reveal mutations of MAMLD1. MAMLD1 should be routinely sequenced in these patients with otherwise normal AR, SRD5A2 and NR5A1genes.PLoS ONE 01/2012; 7(3):e32505. · 4.09 Impact Factor -
Article: Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance.
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ABSTRACT: The skeletal dysplasia characteristic of acrodysostosis resembles the Albright's hereditary osteodystrophy seen in patients with pseudohypoparathyroidism type 1a, but defects in the α-stimulatory subunit of the G-protein (GNAS), the cause of pseudohypoparathyroidism type 1a, are not present in patients with acrodysostosis. We report a germ-line mutation in the gene encoding PRKAR1A, the cyclic AMP (cAMP)-dependent regulatory subunit of protein kinase A, in three unrelated patients with acrodysostosis and resistance to multiple hormones. The mutated subunit impairs the protein kinase A response to stimulation by cAMP; this explains our patients' hormone resistance and the similarities of their skeletal abnormalities with those observed in patients with pseudohypoparathyroidism type 1a.New England Journal of Medicine 06/2011; 364(23):2218-26. · 53.30 Impact Factor -
Article: Phenotypic variation of SF1 gene mutations.
Advances in experimental medicine and biology 01/2011; 707:67-72. · 1.09 Impact Factor -
Article: Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome.
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ABSTRACT: Cryopyrin-associated periodic syndromes (CAPS) are a group of rare autoinflammatory diseases. Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, articular syndrome (CINCA syndrome) is the most severe phenotype, with fever, rash, articular manifestations, and neurologic and neurosensory involvement. CAPS are caused by mutations in CIAS1, the gene encoding NLRP3, which plays a critical role in interleukin-1 (IL-1) processing. Anakinra, an IL-1 receptor antagonist, has been shown to be an effective treatment; however, data on long-term efficacy and safety have been sparse. This study was undertaken to assess the long-term efficacy and safety of anakinra treatment in patients with NOMID/CINCA syndrome. We retrospectively analyzed the medical records of NOMID/CINCA syndrome patients referred to 2 centers, who had started anakinra treatment before June 2007. There were 10 patients with NOMID/CINCA syndrome who had been treated with anakinra. The patients' ages at the time anakinra treatment was initiated ranged from 3 months to 20 years. They had been followed up for 26-42 months. Sustained efficacy in the treatment of systemic inflammation and, in some cases, neurologic involvement and growth parameters, was achieved. The dosage of anakinra required for efficacy ranged from 1 to 3 mg/kg/day in the 8 oldest patients and from 6 to 10 mg/kg/day in the 2 youngest. Residual central nervous system inflammation and deafness persisted in some patients, especially if there had been a delay in diagnosis and treatment. Secondary amyloidosis persisted in cases in which it was present at treatment initiation, but no new lesions developed. No effect on overgrowth arthropathy was observed. Adverse events consisted of mild injection-site reactions. The present results indicate that anakinra treatment is effective over the long term in NOMID/CINCA syndrome. However, treatment has to be initiated before irreversible lesions develop, and, particularly in very young patients, dosage adjustment is required.Arthritis & Rheumatism 01/2010; 62(1):258-67. · 7.87 Impact Factor -
Article: Effectiveness of anastrozole and cyproterone acetate in two brothers with familial male precocious puberty.
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ABSTRACT: Testotoxicosis is a rare form of precocious puberty caused by a constitutively activating mutation in the luteinizing hormone receptor (LHR) gene. Symptoms include rapid virilization, accelerated growth and reduced adult height. We describe a rare association of testotoxicosis with a metaphyseal chondrodysplasia called cartilage-hair hypoplasia (CHH) and report two brothers with testotoxicosis after 4 years of treatment. The brothers had a T577I mutation in the LHR gene. One brother also presented CHH. The older brother was treated with ketoconazole, then with the aromatase inhibitor anastrozole and the anti-androgen cyproterone acetate. The younger brother received this combination as first-line therapy. Clinical improvements included reductions in growth velocity and bone maturation rate, which should result in taller adult stature. Tolerance was good. CONCLUSION: Combined treatment with anastrozole and cyproterone acetate is effective in improving the prognosis of adult height in testotoxicosis.Journal of pediatric endocrinology & metabolism: JPEM 11/2008; 21(10):995-1002. · 0.88 Impact Factor -
Article: Delineation of late onset hypoventilation associated with hypothalamic dysfunction syndrome.
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ABSTRACT: Late Onset Central Hypoventilation Syndrome associated with Hypothalamic Dysfunction (LO-CHS/HD) is a distinct entity among the clinical and genetic heterogeneous group of patients with late onset central hypoventilation. Here we report a series of 13 patients with LO-CHS/HD. Rapid onset obesity is the first symptom of HD followed by hypoventilation with a mean delay of 18 mos. The outcome remains poor for this group of patients and would benefit from early diagnosis to anticipate ventilation and possible metabolic disorders. Tumor predisposition is more frequent than initially suspected and as high as 40% in this series. These tumors of the sympathetic nervous system (TSNS) are usually differentiated and do not significantly worsen the prognosis. We report a familial case with recurrence in siblings. The cause underlying LO-CHS/HD remains poorly understood although recurrence in siblings argues for a monogenic disorder. We ruled out PHOX2B, ASCL1, and NECDIN as disease-causing genes by direct sequencing in our series of patients and discuss possible disease-causing mechanisms.Pediatric Research 08/2008; 64(6):689-94. · 2.70 Impact Factor -
Article: Mutations in the iodotyrosine deiodinase gene and hypothyroidism.
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ABSTRACT: DEHAL1 has been identified as the gene encoding iodotyrosine deiodinase in the thyroid, where it controls the reuse of iodide for thyroid hormone synthesis. We screened patients with hypothyroidism who had features suggestive of an iodotyrosine deiodinase defect for mutations in DEHAL1. Two missense mutations and a deletion of three base pairs were identified in four patients from three unrelated families; all the patients had a dramatic reduction of in vitro activity of iodotyrosine deiodinase. Patients had severe goitrous hypothyroidism, which was evident in infancy and childhood. Two patients had cognitive deficits due to late diagnosis and treatment. Thus, mutations in DEHAL1 led to a deficiency in iodotyrosine deiodinase in these patients. Because infants with DEHAL1 defects may have normal thyroid function at birth, they may be missed by neonatal screening programs for congenital hypothyroidism.New England Journal of Medicine 05/2008; 358(17):1811-8. · 53.30 Impact Factor -
Article: 11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations.
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ABSTRACT: Russell-Silver syndrome (RSS), characterized by intrauterine and postnatal growth retardation, dysmorphic features, and frequent body asymmetry, spares cranial growth. Maternal uniparental disomy for chromosome 7 (mUPD7) is found in 5-10% of cases. We identified loss of methylation (LOM) of 11p15 Imprinting Center Region 1 (ICR1) domain (including IGF-II) as a mechanism leading to RSS. The aim was to screen for 11p15 epimutation and mUPD7 in RSS and non-RSS small-for-gestational-age (SGA) patients and identify epigenetic-phenotypic correlations. STUDIED POPULATION AND METHODS: A total of 127 SGA patients were analyzed. Clinical diagnosis of RSS was established when the criterion of being SGA was associated with at least three of five criteria: postnatal growth retardation, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties. Serum IGF-II was evaluated for 82 patients. Of the 127 SGA patients, 58 were diagnosed with RSS; 37 of these (63.8%) displayed partial LOM of the 11p15 ICR1 domain, and three (5.2%) had mUPD7. No molecular abnormalities were found in the non-RSS SGA group (n = 69). Birth weight, birth length, and postnatal body mass index (BMI) were lower in the abnormal 11p15 RSS group (ab-ICR1-RSS) than in the normal 11p15 RSS group [-3.4 vs.-2.6 SD score (SDS), -4.4 vs.-3.4 SDS, and -2.5 vs.-1.6 SDS, respectively; P < 0.05]. Among RSS patients, prominent forehead, relative macrocephaly, body asymmetry, and low BMI were significantly associated with ICR1 LOM. All ab-ICR1-RSS patients had at least four of five criteria of the scoring system. Postnatal IGF-II levels were within normal values. The 11p15 ICR1 epimutation is a major, specific cause of RSS exhibiting failure to thrive. We propose a clinical scoring system (including a BMI < -2 SDS), highly predictive of 11p15 ICR1 LOM, for the diagnosis of RSS.Journal of Clinical Endocrinology & Metabolism 08/2007; 92(8):3148-54. · 6.50 Impact Factor -
Article: GH deficiency with central precocious puberty: a new rare disorder associated with a developmental defect of the hypothalamic-pituitary area.
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ABSTRACT: GH deficiency (GHD) associated with central precocious puberty (CPP) has been widely reported in cases of arachnoid cyst, septo-optic dysplasia, brain tumors, or after cerebral radiation therapy. However, idiopathic GHD associated with CPP has been reported in only one isolated case. To evaluate the occurrence and clinical features of the association of nonacquired GHD and CPP. This was a retrospective multicenter study. The study population was identified through a French nationwide multicenter network (about 3000 patients). We reviewed the medical records of all subjects diagnosed with nonacquired GHD and CPP, with or without developmental abnormalities of the hypothalamic-pituitary axis on cerebral magnetic resonance imaging (MRI), and without any known associated anomaly. We identified four patients with either isolated GHD (n=1) or multiple anterior pituitary hormone deficiencies (n=3). Clinical signs of CPP occurred at 6.4 +/- 2.3 years in boys and 7.5 +/- 0.5 years in girls, and GnRH analog therapy was started at 4.2 +/- 1.6 years after the initiation of recombinant human GH treatment. Cerebral MRI demonstrated ectopic neurohypophysis associated with anterior pituitary hypoplasia in three out of the four patients. The morphology and position of the anterior pituitary and neurohypophysis were normal in one patient who displayed a persistence of the craniopharyngeal canal. CPP is very rare in patients with nonacquired GHD and is mostly associated with developmental defects in the hypothalamic-pituitary area. Whether molecular mechanisms governing development and activation of the hypothalamic-pituitary axis share dependent factors remains to be explored.European Journal of Endocrinology 05/2007; 156(4):463-9. · 3.42 Impact Factor -
Article: Long-term outcome of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
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ABSTRACT: Conflicting results exist regarding bone mineral density (BMD), metabolism and reproductive function of adult patients with congenital adrenal hyperplasia (CAH). We evaluated the long-term outcome and the impact of chronic glucocorticoid replacement in these patients. Physical characteristics, serum hormone concentrations, BMD and metabolism were studied in 45 consecutive CAH adult patients. Among the 36 women, only 14 (39%) had regular menses. Among the 27 women with classical CAH, the mean number of surgical reconstructions of virilized genitalia was 2.1 +/- 0.2. Twenty of them (74%) were sexually active. Three men presented with testicular adrenal rest tumors. Twenty-five patients (55%) had decreased BMD at the femoral neck and/or at the lumbar spine. BMI was correlated with the BMD T-score at the femoral neck (p < 0.001) and at the lumbar spine (p < 0.01). Hydrocortisone dose was negatively correlated with the BMD T-score at the femoral neck (p = 0.04). Subjects with osteopenia had a significantly lower BMI and received higher hydrocortisone dose than those with normal BMD. Overweight was found in 21 patients (47%). There was a significantly positive correlation between HOMA and BMI (p < 0.001), and between HOMA and 17-OHP levels (p = 0.016). Adult patients with CAH treated with long-term glucocorticoids are at risk for decreased BMD, increased BMI, and disturbed reproductive function.Hormone Research 02/2007; 67(6):268-76. · 2.48 Impact Factor -
Article: Paternal deletion of the GNAS imprinted locus (including Gnasxl) in two girls presenting with severe pre- and post-natal growth retardation and intractable feeding difficulties.
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ABSTRACT: Deletions of the long arm of chromosome 20 are rare. Here, we report on two girls with a very small interstitial deletion of the long arm of chromosome 20 presenting with severe pre- and post-natal growth retardation, intractable feeding difficulties, abnormal subcutaneous adipose tissue, similar facial dysmorphism, psychomotor retardation and hypotonia. Standard cytogenetic studies were normal, but high-resolution chromosomes analysis showed the presence of a chromosome (20)(q13.2-q13.3) interstitial deletion. Karyotypes of both parents were normal. Molecular studies using FISH and microsatellite polymorphic markers showed that the deletion was of paternal origin and was approximatively 4.5 Mb in size. A review of other reported patients with similar deletions of the long arm of chromosome 20 shows that the observed phenotype might be explained in the light of the GNAS imprinted locus in particular by the absence of the Gnasxl paternally imprinted gene and the TFA2PC gene in the deleted genetic interval.European Journal of HumanGenetics 10/2005; 13(9):1033-9. · 4.40 Impact Factor -
Article: Androgen insensitivity syndrome: somatic mosaicism of the androgen receptor in seven families and consequences for sex assignment and genetic counseling.
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ABSTRACT: Androgen insensitivity syndrome (AIS) is caused by numerous mutations of the androgen receptor (AR) gene. The phenotype may range from partial AIS (PAIS) with ambiguous genitalia to complete AIS (CAIS) with female genitalia. In 70% of the cases, AR mutations are transmitted in an X-linked recessive manner through the carrier mothers, but in 30%, the mutations arise de novo. When de novo mutations occur after the zygotic stage, they result in somatic mosaicisms, which are an important consideration for both virilization in later life-because both mutant and wild-type receptors are expressed-and genetic counseling. We report here six patients with AIS due to somatic mutations of the AR and one mother with somatic mosaicism who transmitted the mutation twice. Of the four patients with PAIS, three presented spontaneous or induced virilization at birth or puberty. These cases underline the crucial role of the remnant wild-type AR for virilization because the same mutations, when they are inherited, lead to CAIS. We also report two novel mutations of the AR, with somatic mosaicism, detected in patients with CAIS. Thus, the remnant wild-type receptor does not always lead to virilization. In one of these patients, a high ratio of wild-type to mutant AR expression was found in the gonads and genital skin fibroblasts. Although no prenatal virilization occurred, the possibility of virilization at puberty could not be excluded, and early gonadectomy was performed. A seventh patient had a CAIS with a novel germline AR mutation. The mutation was inherited from the mother, in whom mosaicism was detected in blood and who transmitted the mutation to a second, XX, offspring. The detection of somatic AR mutations is particularly important for the clinical management and genetic counseling of patients with AIS. Before definite sex assignment, a testosterone treatment trial should be performed in all patients with PAIS, but it becomes crucial when an AR mosaicism has been detected. In patients with CAIS or severe PAIS raised as female, there is no consensus about when (early childhood or puberty) gonadectomy should be performed. When somatic AR mutations are detected, however, gonadectomy should be performed earlier because of the risk of virilization during puberty. When a germline de novo mutation is identified in the index case, the risk of transmission to a second child due to a possible germ cell mosaicism in the mother cannot be excluded. However, given the high number of AR de novo mutations and the rarity of such reports, this risk appears to be very low.Journal of Clinical Endocrinology & Metabolism 02/2005; 90(1):106-11. · 6.50 Impact Factor -
Article: A novel developmental and immunodeficiency syndrome associated with intrauterine growth retardation and a lack of natural killer cells.
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ABSTRACT: To describe a novel syndrome characterized by severe prenatal and postnatal growth failure, mild skeletal and facial abnormalities, and primary immunodeficiency. The syndrome was observed in 2 sisters. The elder child died of cytomegalovirus infection when she was 18 months old, whereas the younger sister is doing well at 5 years old. We report here clinical, hematologic, and immunologic data for both sisters and compare them with all known inherited disorders with similar clinical or immunologic features. The immune defect consists of a lack of detectable natural killer cells and small numbers of CD8 alphabeta T cells and polymorphonuclear neutrophils. This is the first report of prenatal and postnatal growth failure associated with mild skeletal and facial abnormalities and primary immunodeficiency. This novel syndrome probably is caused by an autosomal recessive gene defect impairing both intrauterine growth and natural killer cell development. The identification of other kindreds with this syndrome would facilitate the search for its genetic basis.PEDIATRICS 02/2004; 113(1 Pt 1):136-41. · 4.47 Impact Factor
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2005–2011
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Centre Hospitalier Universitaire de Montpellier
Montpellier, Languedoc-Roussillon, France
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