Catherine Dacou-Voutetakis

Complete androgen insensitivity syndrome is frequently due to premature stop codons in exon 1 of the androgen receptor gene: an international collaborative report of 13 new mutations.

OBJECTIVEnTo confirm the clinical diagnosis of complete androgen insensitivity syndrome (CAIS) by molecular genetic analysis and to determine the prevalence of exon 1 mutations in the androgen receptor (AR) transactivation defects of a large series of CAIS patients.nnnDESIGNnInternational retrospective study.nnnSETTINGnUniversity Hospital of Montpellier, Department of Hormonology.nnnPATIENT(S)n105 patients with normal female external genitalia, bilateral intra-abdominal or inguinal testis, normal breast development, absent or sparse pubic hair, normal or high endogenous testosterone production, hypoplastic or absent wolffian structures, and 46,XY karyotype.nnnINTERVENTION(S)nSequencing of the AR gene.nnnMAIN OUTCOME MEASURE(S)nPrevalence of AR exon 1 mutations.nnnRESULT(S)nOver a 10-year period (1997 to 2007), we identified 78 AR gene mutations in 105 patients with CAIS; 21 of them were located in exon 1, and 13 of these were new mutations. We report 13 new mutations in the AR gene. All but one were stop codons, and the last was a splicing abnormality.nnnCONCLUSION(S)nThe finding that 27% of the mutations in our cohort were localized in exon 1 versus 15% in previous works justifies the sequencing of this exon in patients with CAIS.

Clinical and genetic characterization of Chanarin-Dorfman syndrome patients: first report of large deletions in the ABHD5 gene.

BackgroundChanarin-Dorfman syndrome (CDS) is a rare autosomal recessive disorder characterized by nonbullous congenital ichthyosiform erythroderma (NCIE) and an intracellular accumulation of triacylglycerol (TG) droplets in most tissues. The clinical phenotype involves multiple organs and systems, including liver, eyes, ears, skeletal muscle and central nervous system (CNS). Mutations in ABHD5/CGI58 gene are associated with CDS.MethodsEight CDS patients belonging to six different families from Mediterranean countries were enrolled for genetic study. Molecular analysis of the ABHD5 gene included the sequencing of the 7 coding exons and of the putative 5 regulatory regions, as well as reverse transcript-polymerase chain reaction analysis and sequencing of normal and aberrant ABHD5 cDNAs.ResultsFive different mutations were identified, four of which were novel, including two splice-site mutations (c.47+1G>A and c.960+5G>A) and two large deletions (c.898_*320del and c.662-1330_773+46del). All the reported mutations are predicted to be pathogenic because they lead to an early stop codon or a frameshift producing a premature termination of translation. While nonsense, missense, frameshift and splice-site mutations have been identified in CDS patients, large genomic deletions have not previously been described.ConclusionsThese results emphasize the need for an efficient approach for genomic deletion screening to ensure an accurate molecular diagnosis of CDS. Moreover, in spite of intensive molecular screening, no mutations were identified in one patient with a confirmed clinical diagnosis of CDS, appointing to genetic heterogeneity of the syndrome.

Conception and pregnancy outcome in a patient with 11-bp deletion of the steroidogenic acute regulatory protein gene

OBJECTIVEnTo report the pregnancy outcome of a patient with congenital lipoid adrenal hyperplasia (CLAH) due to an 11-bp deletion of the steroidogenic acute regulatory protein (StAR) gene.nnnDESIGNnCase report.nnnSETTINGnUniversity-based pediatric endocrinology unit and private IVF clinic.nnnPATIENT(S)nA 24-year-old woman homozygous for a StAR gene deletion, married to a man heterozygous for the same molecular defect.nnnINTERVENTION(S)nOvarian stimulation, oocyte retrieval followed by IVF, blastomere biopsy, preimplantation genetic diagnosis, and additional estrogen support until placental function initiation.nnnMAIN OUTCOME MEASURE(S)nNormal pregnancy outcome and delivery of a healthy newborn.nnnRESULT(S)nA female patient with CLAH gave birth to a normal newborn after IVF and preimplantation genetic diagnosis.nnnCONCLUSION(S)nPregnancy is feasible in patients with StAR gene mutations, provided that extra estrogens are offered until placental function ensues.

Psoriasis and blue sclerae in girls with Turner syndrome

found in house dust, beach sand, and swimming pools, and N. asteroides is a part of the normal flora of the oral cavity and upper respiratory tract. 5, 7 Infection has also been reported to be caused by insect bite 8 and cat scratch. 9 Sulfonamides are the treatment of choice for cutaneous Nocardia infections, although there have been a few reports of treatment failures. 4,5 Minocycline or amikacin may also be used as primary therapy. Other drugs reported to be successful are imipenem and third-generation cephalosporins.4, 5,7 The duration of therapy for cutaneous Nocardia infection, but most sources recommend treatment periods of 6 weeks to 6 months. Some relapses have been reported after 15 months. 4 Therefore it is important to observe patients for a minimum of 6 to 12 months and to repeat tissue cultures if recurrence is suspected. Some authors advocate continuation of antibiotics for 3 months after resolution of infection in some patients .7 R E F E R E N C E S

Low serum insulin values in children with multiple lesions of granuloma annulare: a prospective study

Backgroundu2002 The relationship between granuloma annularae (GA) and diabetes mellitus (DM) is controversial.

A Favorable Metabolic and Antiatherogenic Profile in Carriers of CYP21A2 Gene Mutations Supports the Theory of a Survival Advantage in This Population

Context: The very high carrier frequency of 21-hydroxylase deficiency worldwide has been postulated as indicating a survival advantage. The ‘mediators’ of such an effect remain speculative. Objective: To look for possible differences in the metabolic and atherogenic risk profile of carriers and noncarriers of CYP21A2 gene mutations at puberty in order to identify possible mediators of the presumed survival advantage for the carriers. It is anticipated that by studying atherogenic risk factors at such an early developmental stage, age-related alterations in these factors may be minimized. Methods: The study group included 45 adolescent girls diagnosed in our center with premature pubarche, 29 of whom were noncarriers and 16 carriers of CYP21A2 mutations. The two groups did not differ in chronological age, age at pubarche or menarche, pubertal stage, body mass index and waist-to-hip ratio. Biochemical and hormonal profile markers as well as markers of endothelial dysfunction were determined by appropriate methodology. Additionally, in each subject, an oral glucose tolerance test and a gonadotrophin-releasing hormone GnRH analogue stimulation test were carried out. Results: Endothelin-1 values were lower in the carriers compared to the noncarriers (p = 0.031). Higher tissue plasminogen activator and lower plasminogen activator inhibitor-1 values were found in carriers compared to noncarriers (p = 0.02 and <0.001, respectively). The ratio of the insulinogenic index/homeostasis model assessment for insulin resistance, which reflects β-cell function, was higher in carriers (p = 0.048), indicating a more favorable β-cell function in the carriers. Conclusions: Our findings that carriers of CYP21A2 gene mutations have a more favorable internal milieu with regard to the metabolic syndrome and atherogenesis support the theory that heterozygous CYP21A2 mutations provide a survival advantage. The mechanisms involved may be related to the insulin secretion-action pathway, hypothalamic-pituitary-adrenal axis responsiveness or other still unrecognized factors.

The Dilemma of Sex Reassignment in an Adolescent with 17β-HSD-3 Deficiency Raised as a Female: Ten-Year Follow-Up

A number of patients with defective differentiation of the genital system, described in the literature by various terminologies (Dacou-Voutetakis, 2007; Hughes et al., 2006), wish to have sex reassignment in adolescence or adulthood. One of the disorders prompting the request for sex reassignment after childhood is the deficiency of 17b-hydroxysteroid dehydrogenase-3 (17b-HSD-3) caused by mutations in the HSD17B3 gene. The enzyme 17b-HSD-3 is involved in the terminal phase of testicular steroidogenesis and specifically catalyzes the conversion of androstenedione (A) to testosterone (T). Persons with this defect have near-normal or ambiguous female external genitalia at birth due to the absence of testosterone and dihydrotestosterone when the external genitalia differentiate (Gooren, 2002). Individuals with 17b-HSD-3 deficiency are considered as females and are raised as girls. At puberty, however, they become virilized as a result of an increase in T and dihydrotestosterone levels due to the action of 17b-HSD-isoenzymes and peripheral conversion of A to T (Sobel & Imperato-McGinley, 2004). In a recent review dealing with these patients, the opinion expressed was that genital appearance at birth does not determine psychosexual outcome and that the general appearance of the child in combination with masculine behavior are stronger determinants for the development of male gender identity (Cohen-Kettenis, 2005). In the present report, we describe an XY individual with 17b-HSD-3 deficiency raised as female, the dilemmas arising at age 17 years when the question of sex reassignment was seriously considered, as well as her follow-up of 10 years post-feminizing surgery of the external genitalia. The patient, currently 27-years-old, is the fourth oldest of five children of a family living in a rural area of a small Greek island. The family does not belong to any specific religious group. At birth, no abnormality of the external genitalia was identified. Shortly thereafter, however, the mother questioned the appearance of the external genitalia but refused testing in Athens as recommended by the local pediatrician. The patient attended primary school up to the 6th grade but was unable to learn reading, writing, and arithmetic, similar to her mother and one brother and in contrast to two other children of the family. A school for children with special needs was not available in the area at that time. Quite early, the patient started to work at the family farm located some distance away from home, caring for sheep and other animals and thus living a rather isolated life. At the age of 8 years, the patient was brought by her father to our hospital but after a few consultations they left, stating that they would come back later ‘‘after finishing with jobs on the farm.’’ At that time, the patient had the appearance of a normal girl and presented only mild clitoral enlargement without hypertrichosis. With the girl’s onset of puberty, however, the pediatrician noted evidence of virilization. One member of our team (CDV), accompanied by the local pediatrician, visited the M. Liakopoulou (&) Child Psychiatry Department, ‘‘Aghia Sophia’’ Children’s Hospital, Athens University School of Medicine, Athens 11527, Greece e-mail: mliakopo@otenet.gr

Severe hyperinsulinemia, decreased GLUT3 and GLUT4 expression, and increased retinol binding protein 4 in a patient with chronic graft-versus-host disease post bone marrow transplantation

Livadas S, Voutetakis A, Bourhis J‐C, Maratou E, Dimitriadis G, Margeli A, Chandrinou H, Goussetis E, Papassotiriou I, Dacou‐Voutetakis C. Severe hyperinsulinemia, decreased GLUT3 and GLUT4 expression, and increased retinol binding protein 4 in a patient with chronic graft‐versus‐host disease post bone marrow transplantation. u2028Pediatr Transplantation 2011.

Ichthyosis and Hypogonadism in Two Brothers with Deletion of the Short Arm of the X Chromosome

Two brothers were examined because of ichthyosis and hypogonadism. Their testes were small. There was no response of plasma testosterone to human chorionic gonadotropin and no response of plasma luteinizing hormone and follicle-stimulating hormone to intravenous luteinizing-hormone-releasing hormone. They both had hyposmia. Steroid sulfatase activity in white blood cells was zero. Flow cytometry and the use of special probes indicated that these two brothers had a large deletion of the short arm of the X chromosome which included the STS locus, the closely linked locus DXS237 and probably the gene for hypogonadism, findings which offer the opportunity for speculations on the locus of control of normal testicular development and function.

PROP-1 gene mutations in a 63-year-old woman presenting with osteoporosis and hyperlipidaemia.

PROP-1 gene mutations have been reported as a cause of combined pituitary hormone deficiency. Physical and hormonal phenotypes of affected individuals are variable. We report a 63-year-old female who presented with osteoporosis. She was short, did not enter puberty spontaneously and had primary amenorrhea. Biochemical evaluation revealed secondary hypothyroidism and mixed hyperlipidaemia, while dynamic testing of pituitary function was diagnostic of hypopituitarism. Bone density in the lumbar spine disclosed osteoporosis. DNA analysis showed that the patient was homozygote for the R73H mutation of the PROP-1 gene. The unfavourable long-term course of an untreated patient with PROP-1 gene mutation emphasizes the need for early aetiologic classification and proper management and follow-up of patients with short stature and/or disturbances of pubertal development.