Audrey Cartault

New candidate loci identified by array‐CGH in a cohort of 100 children presenting with syndromic obesity

Syndromic obesity is defined by the association of obesity with one or more feature(s) including developmental delay, dysmorphic traits, and/or congenital malformations. Over 25 syndromic forms of obesity have been identified. However, most cases remain of unknown etiology. The aim of this study was to identify new candidate loci associated with syndromic obesity to find new candidate genes and to better understand molecular mechanisms involved in this pathology. We performed oligonucleotide microarray‐based comparative genomic hybridization in a cohort of 100 children presenting with syndromic obesity of unknown etiology, after exhaustive clinical, biological, and molecular studies. Chromosomal copy number variations were detected in 42% of the children in our cohort, with 23% of patients with potentially pathogenic copy number variants. Our results support that chromosomal rearrangements are frequently associated with syndromic obesity with a variety of contributory genes having relevance to either obesity or developmental delay. A list of inherited or apparently de novo duplications and deletions including their enclosed genes and not previously linked to syndromic obesity was established. Proteins encoded by several of these genes are involved in lipid metabolism (ACOXL, MSMO1, MVD, and PDZK1) linked with nervous system function (BDH1 and LINGO2), neutral lipid storage (PLIN2), energy homeostasis and metabolic processes (CDH13, CNTNAP2, CPPED1, NDUFA4, PTGS2, and SOCS6).

Pituitary Stalk Interruption Syndrome from Infancy to Adulthood: Clinical, Hormonal, and Radiological Assessment According to the Initial Presentation.

Background Patients with pituitary stalk interruption syndrome (PSIS) are initially referred for hypoglycemia during the neonatal period or growth retardation during childhood. PSIS is either isolated (nonsyndromic) or associated with extra-pituitary malformations (syndromic). Objective To compare baseline characteristics and long-term evolution in patients with PSIS according to the initial presentation. Study Design Sixty-seven patients with PSIS were included. Data from subgroups were compared: neonates (n = 10) versus growth retardation patients (n = 47), and syndromic (n = 32) versus nonsyndromic patients (n = 35). Results Neonates displayed a more severe hormonal and radiological phenotype than children referred for growth retardation, with a higher incidence of multiple hormonal deficiencies (100% versus 34%; P = 0.0005) and a nonvisible anterior pituitary lobe (33% versus 2%; P = 0.0017). Regular follow-up of growth might have allowed earlier diagnosis in the children with growth retardation, as decreased growth velocity and growth retardation were present respectively 3 and 2 years before referral. We documented a progressive worsening of endocrine impairment throughout childhood in these patients. Presence of extra-pituitary malformations (found in 48%) was not associated with more severe hormonal and radiological characteristics. Growth under GH treatment was similar in the patient groups and did not vary according to the pituitary MRI findings. Conclusions PSIS diagnosed in the neonatal period has a particularly severe hormonal and radiological phenotype. The progressive worsening of endocrine impairment throughout childhood justifies periodic follow-up to check for additional hormonal deficiencies.

Kystes et tumeurs ovariennes de l’enfant prépubère : aspects hormonaux

Les tumeurs ovariennes surviennent dans 2,6 cas/ 100 000 fi lles et leur incidence augmente avec l’âge. Rarement fonctionnels et le plus souvent organiques, l’expression clinique des kystes ovariens est dominée par la douleur dont la complexité d’analyse peut faire errer le diagnostic et doit amener à poser l’indication d’une échographie pelvienne. Les kystes autonomisés existent pendant l’enfance, toute la diffi culté est devant un aspect liquidien de pouvoir en approcher la nature. Par ailleurs, il existe des kystes sécrétant des stéroïdes sexuels responsables d’un syndrome endocrinien. Ils orientent dans ce cas vers un syndrome de Mac Cune Albright ou vers une tumeur de la granulosa. Dans le cas d’image hétérogène, en complément de l’échographie de première intention, les autres techniques d’imagerie ainsi que le dosage de marqueurs tumoraux sériques sont utiles pour préciser la nature de cette masse. Seuls la chirurgie et l’examen anatomo-pathologique confi rment la nature exacte d’une masse complexe et en fi xent ainsi le pronostic, la prise en charge thérapeutique et la surveillance.

Syndrome de Turner et procréation

Ovarian failure is a typical feature in Turners syndrome. The majority of follicles disappears prematurely after a normal determination of the ovary. This results from an accelerated loss of oocytes from the ovaries after the 18th week of fetal life or over a few postnatal years, usually before the onset of puberty. The cause and mechanism of this loss are unknown. X chromosomal anomaly due to deletions or haploinsufficiency of genes can explain the various degrees of ovarian failure. Spontaneous puberty occurs in 20-30% of Turner syndrome patients and their fertility rates vary from 5 to 10%. This indicates the possible presence and maturation of follicles in their ovaries in adolescence. In ovarian failure, the hormone replacement therapy (HRT) is necessary to achieve the development of normal female sexual characteristics, the self image or social functioning and to prevent osteoporosis. Pregnancy is now possible with oocyte donation. A careful cardiovascular follow-up is necessary. Cryoconservation represents one way for preserving the future fertility, but the optimal age of ovarian biopsy has to be studied.

Syndrome de Turner et procréation: Fonction ovarienne et syndrome de Turner

Ovarian failure is a typical feature in Turners syndrome. The majority of follicles disappears prematurely after a normal determination of the ovary. This results from an accelerated loss of oocytes from the ovaries after the 18th week of fetal life or over a few postnatal years, usually before the onset of puberty. The cause and mechanism of this loss are unknown. X chromosomal anomaly due to deletions or haploinsufficiency of genes can explain the various degrees of ovarian failure. Spontaneous puberty occurs in 20-30% of Turner syndrome patients and their fertility rates vary from 5 to 10%. This indicates the possible presence and maturation of follicles in their ovaries in adolescence. In ovarian failure, the hormone replacement therapy (HRT) is necessary to achieve the development of normal female sexual characteristics, the self image or social functioning and to prevent osteoporosis. Pregnancy is now possible with oocyte donation. A careful cardiovascular follow-up is necessary. Cryoconservation represents one way for preserving the future fertility, but the optimal age of ovarian biopsy has to be studied.

Noonan syndrome males display Sertoli cell-specific primary testicular insufficiency

Context Abnormalities in the hypothalamo-pituitary-gonadal axis have long been reported in Noonan syndrome (NS) males with only few data available in prepubertal children. Objective The aim of this study was to describe the gonadal function of NS males from childhood to adulthood. Design It is a retrospective chart review. Patients and methods A total of 37 males with a genetically confirmed diagnosis of NS were included. Clinical and genetic features, as well as serum hormone levels (LH, FSH, testosterone, anti-Müllerian hormone (AMH), and inhibin B) were analysed. Results Of the 37 patients, 16 (43%) children had entered puberty at a median age of 13.5 years (range: 11.4-15.0 years); age at pubertal onset was negatively correlated with BMI SDS (r = -0.541; P = 0.022). In pubertal boys, testosterone levels were normal suggesting a normal Leydig cell function. In contrast, NS patients had significant lower levels of AMH (mean SDS: -0.6 ± 1.1; P = 0.003) and inhibin B (mean SDS: -1.1 ± 1.2; P < 0.001) compared with the general population, suggesting a Sertoli cell dysfunction. Lower AMH and inhibin B levels were found in NS-PTPN11 patients, whereas these markers did not differ from healthy children in SOS1 patients. No difference was found between cryptorchid and non-cryptorchid patients for AMH and inhibin B levels (P = 0.43 and 0.62 respectively). Four NS-PTPN11 patients had a severe primary hypogonadism with azoospermia/cryptozoospermia. Conclusions NS males display Sertoli cell-specific primary testicular insufficiency, whereas Leydig cell function seems to be unaffected.

Current Findings in Epidemiology

Puberty is a series of biological events that lead to sexual maturity. The first event is the initiation of pulsatile GnRH secretion from the hypothalamus. Physiological variability and multiple factors influence onset of puberty: ethnic, genetic, nutritional and environmental factors. We observe a secular trends of puberty in industrialized countries, but menarche is stabilized at 12 ½ years in these countries since 30 to 40 years

Traitement de l’hypogonadisme de la fille après traitement pour cancer

* Auteur correspondant. e-mail : pienkowski.c@chu-toulouse.fr Les traitements des cancers des enfants ou adolescents ont transformé le pronostic de ces maladies, améliorant considérablement les taux de survie. Malheureusement ces traitements ont une toxicité gonadique, les séquelles endocriniennes se constituent plusieurs années après la radiothérapie ou certaines chimiothérapies. Cela impacte la qualité de vie des patientes guéries et exposées au risque d’insuffi sance ovarienne prématurée (IOP) et d’infertilité. Actuellement la prise en charge consiste à proposer un traitement substitutif adapté à l’âge et de les orienter pour accéder à une maternité.

[Turner's syndrome and procreation. Ovarian function and Turner's syndrome].

Ovarian failure is a typical feature in Turners syndrome. The majority of follicles disappears prematurely after a normal determination of the ovary. This results from an accelerated loss of oocytes from the ovaries after the 18th week of fetal life or over a few postnatal years, usually before the onset of puberty. The cause and mechanism of this loss are unknown. X chromosomal anomaly due to deletions or haploinsufficiency of genes can explain the various degrees of ovarian failure. Spontaneous puberty occurs in 20-30% of Turner syndrome patients and their fertility rates vary from 5 to 10%. This indicates the possible presence and maturation of follicles in their ovaries in adolescence. In ovarian failure, the hormone replacement therapy (HRT) is necessary to achieve the development of normal female sexual characteristics, the self image or social functioning and to prevent osteoporosis. Pregnancy is now possible with oocyte donation. A careful cardiovascular follow-up is necessary. Cryoconservation represents one way for preserving the future fertility, but the optimal age of ovarian biopsy has to be studied.