27 research outputs found
Genotype versus phenotype in families with androgen insensitivity syndrome
Androgen insensitivity syndrome encompasses a wide range of phenotypes,
which are caused by numerous different mutations in the AR gene. Detailed
information on the genotype/phenotype relationship in androgen
insensitivity syndrome is important for sex assignment, treatment of
androgen insensitivity syndrome patients, genetic counseling of their
families, and insight into the functional domains of the AR. The commonly
accepted concept of dependence on fetal androgens of the development of
Wolffian ducts was studied in complete androgen insensitivity syndrome
(CAIS) patients. In a nationwide survey in The Netherlands, all cases (n =
49) with the presumptive diagnosis androgen insensitivity syndrome known
to pediatric endocrinologists and clinical geneticists were studied. After
studying the clinical phenotype, mutation analysis and functional analysis
of mutant receptors were performed using genital skin fibroblasts and in
vitro expression studies. Here we report the findings in families with
multiple affected cases. Fifty-nine percent of androgen insensitivity
syndrome patients had other affected relatives. A total of 17 families
were studied, seven families with CAIS (18 patients), nine families with
partial androgen insensitivity (24 patients), and one family with female
prepubertal phenotypes (two patients). No phenotypic variation was
observed in families with CAIS. However, phenotypic variation was observed
in one-third of families with partial androgen insensitivity resulting in
different sex of rearing and differences in requirement of reconstructive
surgery. Intrafamilial phenotypic variation was observed for mutations
R846H, M771I, and deletion of amino acid N682. Four newly identified
mutations were found. Follow-up in families with different AR gene
mutations provided information on residual androgen action in vivo and the
development of the prepubertal and adult phenotype. Patients with a
functional complete defective AR had some pubic hair, Tanner stage P2, and
vestigial Wolffian duct derivatives despite absence of AR expression.
Vaginal length was functional in most but not all CAIS patients. The
minimal incidence of androgen insensitivity syndrome in The Netherlands,
based on patients with molecular proof of the diagnosis is 1:99,000.
Phenotypic variation was absent in families with CAIS, but distinct
phenotypic variation was observed relatively frequent in families with
partial androgen insensitivity. Molecular observations suggest that
phenotypic variation had different etiologies among these families. Sex
assignment of patients with partial androgen insensitivity cannot be based
on a specific identified AR gene mutation because distinct phenotypic
variation in partial androgen insensitivity families is relatively
frequent. In genetic counseling of partial androgen insensitivity
families, this frequent occurrence of variable expression resulting in
differences in sex of rearing and/or requirement of reconstructive surgery
is important information. During puberty or normal dose androgen therapy,
no or only minimal virilization may occur even in patients with
significant (but still deficient) prenatal virilization. Wolffian duct
remnants remain detectable but differentiation does not occur in the
absence of a functional AR. In many CAIS patients, surgical elongation of
the vagina is not indicated
f(R,L_m) gravity
We generalize the type gravity models by assuming that the
gravitational Lagrangian is given by an arbitrary function of the Ricci scalar
and of the matter Lagrangian . We obtain the gravitational field
equations in the metric formalism, as well as the equations of motion for test
particles, which follow from the covariant divergence of the energy-momentum
tensor. The equations of motion for test particles can also be derived from a
variational principle in the particular case in which the Lagrangian density of
the matter is an arbitrary function of the energy-density of the matter only.
Generally, the motion is non-geodesic, and takes place in the presence of an
extra force orthogonal to the four-velocity. The Newtonian limit of the
equation of motion is also considered, and a procedure for obtaining the
energy-momentum tensor of the matter is presented. The gravitational field
equations and the equations of motion for a particular model in which the
action of the gravitational field has an exponential dependence on the standard
general relativistic Hilbert--Einstein Lagrange density are also derived.Comment: 6 pages, no figures; minor modifications, references added; accepted
for publication in EPJ
Static Anisotropic Solutions in f(T) Theory
In a previously work, we undertook a static and anisotropic content in
theory and obtained new spherically symmetric solutions considering a constant
torsion and some particular conditions for the pressure. In this paper, still
in the framework of theory, new spherically symmetric solutions are
obtained, first considering the general case of an isotropic fluid and later
the anisotropic content case in which the generalized conditions for the matter
content are considered such that the energy density, the radial and tangential
pressures depend on the algebraic and its derivative .
Moreover, we obtain the algebraic function through the reconstruction
method for two cases and also study a polytropic model for the stellar
structure.Comment: 23 pages, Published in Euro. Phys. J.
Disorders of sexual development in a cultural context
BACKGROUND: Disorders of sexual development (DSD) are congenital conditions in which the development of the chromosomal, gonadal or anatomical sex can be deemed atypical. The external genitalia should appear ‘normal’ in size and shape from birth, with no question of abnormality, and the individual must receive appropriate social-environmental feedback in the course of the sexual maturation process. METHODS: We review regional differences in the variables considered important for gender assignment in individuals with DSD. Various approaches to certain forms of DSD are analysed within their cultural context. RESULTS: The decision to leave the sex of rearing undisturbed or to change it is difficult. It depends on the patient’s age and the extent to which the gender identity has been established with parental gender preference, social, cultural and religious factors. Severe forms of genetically female congenital adrenal hyperplasia, androgen insensitivity syndrome, 17β-hydroxysteroid dehydrogenase-3, 5α-reductase and cytochrome P450 oxidoreductase deficiencies are found to be the most difficult cases to diagnose and/or manage. CONCLUSION: Gender assignment in children with DSD is a subject of intense debate. Each case of DSD must be evaluated individually and on its merits and potentials. Although early admission and appropriate diagnostic facilities could provide the correct diagnosis, this is not the case in some cultures. It is seen that ‘gender panic’, social and religious concepts affect the decision-making process in gender assignment, especially in delayed cases
Risk factors for pediatric intensive care admission in children with acute asthma.
Contains fulltext :
109416.pdf (Publisher’s version ) (Closed access)INTRODUCTION: Severe acute asthma in children is associated with substantial morbidity and may require pediatric ICU (PICU) admission. The aim of the study was to determine risk factors for PICU admission. METHODS: The study used a retrospective multicenter case-control design. The cases included children admitted to the PICU because of severe acute asthma and a history of out-patient treatment by pediatricians or pediatric pulmonologists. Controls were children with asthma without a PICU admission for severe acute asthma. The children were matched for sex, age, hospital, and time elapsed since the diagnosis of asthma. Fourteen possible risk factors were analyzed. RESULTS: Sixty-six cases were matched to 164 controls. In univariate analysis, all but one of the analyzed variables were significantly associated with PICU-hospitalization. After multivariate conditional logistic regression analysis, 4 risk factors remained significant. These included active or passive smoking, allergies, earlier hospitalization for asthma, and non-sanitized home. CONCLUSIONS: Physicians and parents should be aware of these risk factors, and efforts should be made to counteract them.1 september 201
Leydig cell hypoplasia: cases with new mutations, new polymorphisms and cases without mutations in the luteinizing hormone receptor gene.
BACKGROUND: Defective male sex differentiation in patients with hypoplasia of Leydig cells (LCH) is caused by deficient LH receptor signal transduction. To further investigate the variety of LH receptor gene mutations present in LCH patients and their influence on the phenotype, we examined 10 nonrelated patients with the clinical presentation of LCH. PATIENTS AND METHODS: Ten patients with a clinical phenotype of LCH were analysed for mutations in the complete coding region of the LH receptor gene. Exons 1-10 and two overlapping fragments of exon 11 of the LH receptor gene including all intron-exon boundaries were amplified by polymerase chain reaction and sequenced. To screen for frequencies of DNA changes, mutation analysis was performed on 45-59 healthy persons using denaturation high-performance liquid chromatography. RESULTS: Six new DNA alterations were identified. Three of them appear to be new polymorphisms. A G to C change at the 28th nucleotide of intron 1 on one allele and a heterozygous CGA to CAA transition at codon 124 (R124Q) were found. Both findings in these two patients are polymorphisms that occur with a frequency of 17% and 1.7%, respectively. A silent heterozygous CTA to TTA change at codon 204 was identified. In a patient with micropenis, the analysis revealed a homozygous missense mutation at codon 625 (I625K). As reported previously, this alteration significantly impaired signal transduction and explains the partial phenotype. Finally, in one compound heterozygous patient, two different mutations were discovered. At the polymorphic site in exon 1, a 27-bp insertion (CTG)2 AAG (CTG)5 CAG and a premature stop codon in the transmembrane segment 4 (W491*) were found. Both mutations disrupt signal transduction and explain the complete phenotype of this patient. In five patients, no DNA alterations could be identified. CONCLUSIONS: Three mutations (33 bp insertion in exon 1; W491* and I625K) were identified that explain the phenotype in two patients. In addition, most of the patients with the clinical phenotype of LCH did not have causative mutations, suggesting that changes in other regions of the LH receptor gene, such as the large introns or the promoter region, may be responsible for the majority of cases. Alternatively, the displayed phenotype may be the result of other genetic defects. Our work further underscores the importance of thorough clinical analysis of patients before molecular analysis of a particular gene is performed