[Differences in sexual development-S2k guideline update]. / Varianten der Geschlechtsentwicklung ­ Aktualisierung der S2k-Leitlinie.

BACKGROUND: Human beings with a difference in sexual development (DSD) often underwent gender reassignment surgery during early childhood. However, the medical decision was often not congruent with the gender identity that affected persons developed later on. OBJECTIVES: To represent the interests of affected persons, an interdisciplinary guideline in cooperation with support groups was written. MATERIALS AND METHODS: The revision of the first version of the guideline, published in 2016, was edited by 18 professional societies and working groups as well as 3 support groups. A literature search was performed for each of the 12 chapters. Recommendations and statements created by the working groups were voted on during four consensus conferences. RESULTS: The guideline highlights the right of self-determination of affected persons. In this context, new legal requirements are reported. Other than necessary primary diagnostics, medical procedures should be postponed. Most important is the psychological support of parents and patients. Tumor risk of the gonads and protection of fertility are analyzed and discussed in detail. CONCLUSION: The content of the guideline represents a paradigm shift in dealing with human beings with a difference of sexual development. Projects as DSD Care and Empower-DSD help to promote the practical implementation of the guideline's recommendations.

Establishment of Clinical and Lab Algorithms for the Identification of Carriers of Mutations in CYP21A2 - A Study of 365 Children and Adolescents.

BACKGROUND: Mutations of CYP21A2 encoding 21-hydroxylase are the most frequent cause of congenital adrenal hyperplasia (CAH) and are associated either with elevated basal or ACTH-stimulated levels of 17-hydroxyprogesterone (17OHP) in blood. OBJECTIVE: The study objective was to identify the most suitable of 12 different test algorithms and appropriate cut-off levels for that test to recognize patients with non-classical congenital adrenal hyperplasia (NCCAH) and carriers of clinically relevant mutations in CYP21A2. METHOD AND PATIENTS: Between July 2006 and July 2015 ACTH-tests were conducted in 365 children and adolescents (Age 1-20 y) suspected to have NCCAH. As a reference, results from subsequent gene sequencing of CYP21A2 was used. Inclusion criteria that were used were premature pubarche with accelerated bone age, hyperandrogenism, hirsutism, or menstrual irregularities. Receiver operating characteristics (ROC) were plotted. Evaluated test algorithms were composed around 17OHP measurements by radioimmunoassays. The most suitable test was identified by the greatest area under the curve (AUC). RESULTS: Among the 12 tested algorithms, the sum of 30 min and 60 min stimulated 17OHP values (sum17OHPstim) showed the highest AUC of 0.774 for identifying heterozygous and bi-allelic mutations. A cut-off of 10.1 µg/l was advisable. Bi-allelic mutations only were best identified calculating the difference between 30 min and basal 17OHP values (Δ17OHP30). A cut-off of 9.4 µg/l was most effective. CONCLUSION: Alternatively to the above mentioned cut-offs the difference of 60 min after stimulation to basal 17OHP (Δ17OHP60) can be used for the benefit of a combined test to identify both heterozygotes and bi-allelic patients. There are minimal decreases in sensitivity and specificity compared to an approach that applies two tests. However, it denotes a simpler approach in the clinical routine.

Variations of sex development: The first German interdisciplinary consensus paper.

INTRODUCTION: The term variations of sex development subsumes a large number of congenital conditions including chromosomal mosaics and variations of chromosomal, gonadal, and phenotypic sex. A situation of this nature may cause severe distress to both, parents and affected persons. One of the reasons for this is the binary form of gender classification in the society. In the past, because of a fear of possible stigmatization and an inability to cope with complex situations, it has been medical policy and practice for newborns to undergo early, mostly 'feminizing' elective surgery with the aim of achieving an outer genital appearance that is unambiguously male or female. Protests by advocacy groups for the most part as well as the results of outcome studies have shown that the development of affected persons may be very different to what has been expected and often does not result in the intended clear female or male gender identity as had been intended. It, therefore, seemed a matter of urgency to implement this new awareness as well as the ethical and personal human rights perspectives in the recommendations for the medical and psychosocial management of diverse sex development (DSD) in the future. STUDY DESIGN: In 2012, an interdisciplinary group of German academics engaged in the field of DSD decided to work on a consensus paper for this topic. It involved the participation of all faculties and non-scientific groups dealing with DSD, in particular advocacy and service-user groups. In a structured consensus, process recommendations were developed based on scientific literature as well as personal experiences of clinicians and affected individuals. RESULTS: Finally, 37 recommendations were agreed on. The strength of consensus is reflected in the degree of agreement as expressed in percentages. CONCLUSION: The introduction of the consensus paper reflects on the emerging paradigm shift and the necessity for a more open view of gender within society. The paper is intended to aid the performance of appropriate diagnostics in DSD-affected newborns and especially to help parents and affected persons cope with the biological and social consequences of DSD. With regard to medical or surgical therapy, it gives information about the most recent treatment trends.

Gonadal function in adult male patients with congenital adrenal hyperplasia.

CONTEXT: Current knowledge on gonadal function in congenital adrenal hyperplasia (CAH) is mostly limited to single-center/country studies enrolling small patient numbers. Overall data indicate that gonadal function can be compromised in men with CAH. OBJECTIVE: To determine gonadal function in men with CAH within the European 'dsd-LIFE' cohort. DESIGN: Cross-sectional clinical outcome study, including retrospective data from medical records. METHODS: Fourteen academic hospitals included 121 men with CAH aged 16-68 years. Main outcome measures were serum hormone concentrations, semen parameters and imaging data of the testes. RESULTS: At the time of assessment, 14/69 patients had a serum testosterone concentration below the reference range; 7 of those were hypogonadotropic, 6 normogonadotropic and 1 hypergonadotropic. In contrast, among the patients with normal serum testosterone (55/69), 4 were hypogonadotropic, 44 normogonadotropic and 7 hypergonadotropic. The association of decreased testosterone with reduced gonadotropin concentrations (odds ratio (OR) = 12.8 (2.9-57.3)) was weaker than the association between serum androstenedione/testosterone ratio ≥1 and reduced gonadotropin concentrations (OR = 39.3 (2.1-732.4)). Evaluation of sperm quality revealed decreased sperm concentrations (15/39), motility (13/37) and abnormal morphology (4/28). Testicular adrenal rest tumor (TART)s were present in 39/80 patients, with a higher prevalence in patients with the most severe genotype (14/18) and in patients with increased current 17-hydroxyprogesterone 20/35) or androstenedione (12/18) serum concentrations. Forty-three children were fathered by 26/113 patients. CONCLUSIONS: Men with CAH have a high risk of developing hypothalamic-pituitary-gonadal disturbances and spermatogenic abnormalities. Regular assessment of endocrine gonadal function and imaging for TART development are recommended, in addition to measures for fertility protection.

Drinking to cope with negative emotions moderates alcohol use disorder treatment response in patients with co-occurring anxiety disorder.

BACKGROUND: Epidemiological studies and theory implicate drinking to cope (DTC) with anxiety as a potent moderator of the association between anxiety disorder (AnxD) and problematic alcohol use. However, the relevance of DTC to the treatment of alcohol use disorder (AUD) in those with a co-occurring AnxD has not been well studied. To address this, we examined whether DTC moderates the impact of two therapies: (1) a cognitive behavioral therapy (CBT) designed to reduce DTC and anxiety symptoms; (2) a progressive muscle relaxation training (PMRT) program designed to reduce anxiety symptoms only. METHODS: Patients undergoing a standard AUD residential treatment with a co-occurring AnxD (N=218) were randomly assigned to also receive either the CBT or PMRT. DTC in the 30 days prior to treatment was measured using the Unpleasant Emotions subscale of the Inventory of Drinking Situations. RESULTS: Confirming the predicted moderator model, the results indicated a significant interaction between treatment group and level of pre-treatment DTC behavior. Probing this interaction revealed that for those reporting more pre-treatment DTC behavior, 4-month alcohol outcomes were superior in the CBT group relative to the PMRT group. For those reporting less pre-treatment DTC behavior, however, 4-month alcohol outcomes were similar and relatively good in both treatment groups. CONCLUSIONS: These findings establish a meaningful clinical distinction among those with co-occurring AUD-AnxD based on the degree to which the symptoms of the two disorders are functionally linked through DTC. Those whose co-occurring AUD-AnxD is more versus less strongly linked via DTC are especially likely to benefit from standard AUD treatment that is augmented by a brief CBT designed to disrupt this functional link.

CT imaging correlates of genomic expression for oral cavity squamous cell carcinoma.

BACKGROUND AND PURPOSE: Imaging correlates of genetic expression have been found for prognostic and predictive biomarkers of some malignant diseases, including breast and brain tumors. This study tests the hypothesis that imaging findings correlate with relevant genomic biomarkers in oral cavity squamous cell carcinoma. MATERIALS AND METHODS: Surplus frozen tissue from 27 untreated patients with oral cavity squamous cell carcinoma who underwent preoperative CT imaging was analyzed for gene expression. A team of neuroradiologists blinded to the genomic analysis results reviewed an extensive list of CT findings. The imaging correlated with genomic expression for cyclin D1, angiogenesis-related genes (vascular endothelial growth factor receptors and ligands), which relate to enhancement on the basis of other tumor types; and epidermal growth factor receptor, which may relate to proliferation and mass effect. RESULTS: Expression of vascular endothelial growth factor receptors 1 and 2 correlated with the enhancement of the primary tumor (P = .018 and P = .025, respectively), whereas the epidermal growth factor receptor correlated with mass effect (P = .03). Other exploratory correlations included epidermal growth factor receptor to perineural invasion (P = .05), and certain vascular endothelial growth factor receptors and ligands to mass effect (P = .03) and increased (P = .01) or decreased (P = .02) primary tumor size. CONCLUSIONS: We report that CT imaging correlates with gene expression in untreated oral cavity squamous cell carcinoma. Enhancement of the primary tumor and degree of mass effect correlate with relevant genomic biomarkers, which are also potential drug targets. Eventually, treatment decisions may be aided by combining imaging findings into meaningful phenotypes that relate directly to genomic biomarkers.

No correlation between androgen receptor CAG and GGN repeat length and the degree of genital virilization in females with 21-hydroxylase deficiency.

CONTEXT: In 21-hydroxylase (CYP21A2) deficiency (21OHD), the level of in vitro enzymatic function allows for classification of mutation groups (null, A, B, C) and prediction of disease severity. However, genital virilization in affected females correlates only weakly with CYP21A2 mutation groups, suggesting the influence of genetic modifiers. OBJECTIVE: The objective of the study was to investigate the influence of the polymorphic CAG and GGn repeats of the androgen receptor (AR) gene on the degree of genital virilization in 21OHD females. DESIGN AND PATIENTS: Design of the study was the determination of CYP21A2 genotype, degree of genital virilization (Prader stage), and X-weighted biallelic mean of AR CAG and GGn repeat length in 205 females with 21OHD. OUTCOME MEASUREMENTS: Correlation of AR CAG and GGn repeat lengths with Prader stages using nested stepwise logistic regression analysis was measured. RESULTS: CYP21A2 mutation groups null and A showed significantly higher levels of genital virilization than groups B and C (P < 0.01). However, Prader stages varied considerably within mutation groups: null, Prader I-V (median IV); A, Prader I-V (median IV); B, Prader I-V (median III); C, 0-III (median I). Mean GGn repeat length of patients was not significantly associated with Prader stages, classified as low (0-I), intermediate (II-III), or severe (IV-V) (odds ratio per repeat: 0.98, 95% confidence interval 0.71-1.35). In contrast, patients with Prader 0-I showed a trend toward longer CAG repeats without reaching statistical significance (P = 0.07, odds ratio per repeat: 0.82, 95% confidence interval 0.65-1.02). CONCLUSION: Neither CAG nor GGn repeat lengths are statistically significant modifiers of genital virilization in females with 21OHD.

Functional constraints on nest characteristics of pebble mounds of breeding male hornyhead chub Nocomis biguttatus.

Breeding male hornyhead chub Nocomis biguttatus constructed nests in areas with relatively high but less than maximum flow rate and greater than average water depth. Nests comprised c. 3000 pebbles for a total mass of 11 kg. Males selected pebbles of smaller diameter but higher density than pebbles in the immediate vicinity. Thus, nests balanced the risk of mound erosion and energetic cost of nest construction with the benefits of protection from egg predators and a stable internal flow rate for oxygenation. These data help establish environmental management goals for the conservation of N. biguttatus and the lotic ecosystems dependent upon them.

Mutation analysis of FOXF2 in patients with disorders of sex development (DSD) in combination with cleft palate.

In contrast to disorders of sexual differentiation caused by lack of androgen production or inhibited androgen action, defects affecting development of the bipotent genital anlagen have rarely been investigated in humans. We have previously documented that the transcription factor FOXF2 is highly expressed in human foreskin. Moreover, Foxf2 knockout mice present with cleft palate in combination with hypoplasia of the genital tubercle. We hypothesized that humans with disorders of sex development (DSD) in combination with cleft palate could have mutations in the FOXF2 gene. Eighteen children with DSD and cleft palate were identified in the Lübeck DSD database (about 1,500 entries). Genomic DNA sequence analysis of the FOXF2 gene was performed and compared with 10 normal female and 10 normal male controls, respectively. Two heterozygous DNA sequence variations were solely present in one single patient each but in none of the 20 normal controls: a duplication of GCC (c.97GCC[9]+[10]) resulting in an extra alanine within exon 1 and a 25*G>A substitution in the 3'-untranslated region. Two patients carried a c.262G>A sequence variation predicting for an Ala88Thr exchange which was also detected in 2 normal controls. Two silent mutations, c.1272C>T (Ser424Ser) and c.1284T>C (Tyr428Tyr), respectively, occurred in the coding region of exon 2, again in both patients and normal controls. In conclusion, the majority of the detected sequence alterations were polymorphisms without obvious functional relevance. However, it cannot be excluded that the 2 unique DNA sequence alterations could have affected FOXF2 on the mRNA or protein level thus contributing to the observed disturbances in genital and palate development.

Altered transcription profiles of key-enzymes of androgen biosynthesis in genital skin fibroblasts from patients with 46,XY disorders of sex development (DSD).

Normal synthesis and action of androgens is essential for normal male sex differentiation. 17Beta-hydroxysteroid dehydrogenase (17beta-HSD) and 5alpha-reductase isoenzymes play essential roles in normal androgen biosynthesis. We hypothesized that differences in expression of these enzymes in genital skin could contribute to the pathogenesis of 46,XY disorders of sex development (DSD). We investigated the mRNA transcription patterns of 17beta-hydroxysteroid dehydrogenase-isoenzymes type 1, 2, 3, 4, 5, 7, and 10, 5alpha-reductase type 1 and 2 and the androgen receptor in genital skin fibroblasts from foreskin and scrotal skin obtained from healthy males and patients with unclassified 46,XY DSD. mRNA expression was semi-quantified by real-time PCR. Although no systematic differences of gene expression of any enzyme between normal controls and hypospadias patients could be detected, we found in nearly half of all investigated patients' samples noticeable differences in the transcription profiles of 17beta-hydroxysteroid dehydrogenase type 5. In scrotal skin samples of patients a significantly higher transcription of the androgen receptor was detected. A role for an altered expression pattern of different enzymes of steroidogenesis in the etiology of genital malformations in some patients may be postulated.

Clinical characteristics of type 2 diabetes mellitus in overweight European caucasian adolescents.

AIM: To present the clinical features of Type 2 diabetes mellitus (T2DM) in overweight European Caucasian children and adolescents. METHODS: We report the clinical characteristics of 16 non-syndromal overweight European Caucasian adolescents with T2DM (10 boys, 6 girls, SDS-BMI in median +2.8, range +1.6 to +3.4) treated in 5 specialised centres for obesity and diabetes. RESULTS: None of the adolescents manifested with ketoacidosis. 13 were asymptomatic (3 adolescents with polyuria), 12 showed features of metabolic syndrome (dyslipidaemia or hypertension), 8 demonstrated acanthosis nigricans and 12 had relatives with T2DM. 11 adolescents were extremely obese and all patients were pubertal. Mean age at diagnosis was 14.2 years (range 11.0 - 16.9). Median insulin was 19 microU/ml, insulin resistance index (HOMA) 8.5, C-peptide 2.3 ng/ml, HbA1c 6.9 %, fasting blood glucose 176 mg/dl and blood glucose at 2 hours with the oGTT 229 mg/dl at manifestation. Fasting blood glucose and HBA1c were in the normal range in 4 and 6 adolescents respectively, while oGTT always fitted the diagnosis of T2DM. CONCLUSION: Since T2DM occurred in Caucasian overweight adolescents and is frequently asymptomatic, it is essential that clinicians perform diagnostic procedures to identify T2DM in high-risk groups of overweight Caucasian adolescents (extreme obesity, features of metabolic syndrome, relatives with T2DM).

Novel insertion frameshift mutation of the LH receptor gene: problematic clinical distinction of Leydig cell hypoplasia from enzyme defects primarily affecting testosterone biosynthesis.

Leydig cell hypoplasia (LCH) is a rare autosomal recessive condition that interferes with normal development of male external genitalia in 46,XY individuals and is caused by inactivating mutations of the LH receptor gene. The clinical and biochemical diagnostic parameters of LCH are not always specific and may therefore show significant overlap with other causes of insufficient testicular steroid biosynthesis. We have studied a 46,XY newborn with completely female external genitalia and palpable testes. Due to an increased basal serum ratio of androstenedione/testosterone, 17 beta-hydroxysteroid dehydrogenase type 3 (17 beta-HSD 3) deficiency was initially suspected. DNA analysis of the corresponding HSD17B3 gene, however, showed no abnormalities in the entire coding region. In contrast, direct sequencing of the LH receptor gene revealed a novel homozygous single nucleotide insertion in exon 11 (codon A589fs) producing a frame shift in the open reading frame predicting for premature termination of translation 17 amino acids downstream. From the genetic perspective, this mutation represents the first frame shift mutation in the LH receptor gene ever reported to date. From the clinical standpoint, LCH should always be considered in the differential diagnosis as steroid profiles may not be informative. Therefore, molecular genetic analysis should be warranted for androgen biosynthesis defects in all cases.

Leydig cell hypoplasia: absent luteinizing hormone receptor cell surface expression caused by a novel homozygous mutation in the extracellular domain.

Leydig cell hypoplasia is a rare autosomal recessive condition that interferes with normal development of male external genitalia in 46,XY individuals. We have studied a family with a 46,XY girl due to a new homozygous mutation (V144F) in the extracellular ligand-binding domain. HEK 293 cells transfected with the mutant LH receptor exhibited a marked impairment of human chorionic gonadotropin binding. Using Western blotting of the expressed V144F mutant LH receptor protein showed the absence of the glycosylated cell surface form. Treatment of the mutant LH receptor with N-glycosidase F or endoglycosidase-H demonstrated that the mutant receptor is retained in the endoplasmic reticulum. Expression and study of enhanced green fluorescent protein-tagged receptors confirmed that the mutant LHR-V144F receptors do not migrate to the cell surface, and the fluorescence remains intracellular and colocalizes with an endoplasmic reticulum marker, ER-tracker Blue-white DPX. Comparison of the theoretical molecular models of the extracellular domain of the wild-type and the mutant receptor suggests that the mutation LHR-V144F, located in the outer circumference in a alpha-helix of the leucine-rich repeat 4, may induce a conformational strain on the molecule. F144 of the mutant LH receptor has overlapping interactions with F119, which V144 in the wild-type receptor has not.

Mutant luteinizing hormone receptors in a compound heterozygous patient with complete Leydig cell hypoplasia: abnormal processing causes signaling deficiency.

Over the past 5 yr several inactivating mutations in the LH receptor gene have been demonstrated to cause Leydig cell hypoplasia, a rare autosomal recessive form of male pseudohermaphroditism. Here, we report the identification of two new LH receptor mutations in a compound heterozygous case of complete Leydig hypoplasia and determine the cause of the signaling deficiency at a molecular level. On the paternal allele of the patient we identified in codon 343 a T to A transversion that changes a conserved cysteine in the hinge region of the receptor to serine (C343S); on the maternal allele a T to C transition causes another conserved cysteine at codon 543 in trans-membrane segment 5 to be altered to arginine (C543R). Both of these mutant receptors are completely devoid of hormone-induced cAMP reporter gene activation. Using Western blotting of expressed LH receptor protein with a hemagglutinin tag, we further show that despite complete absence of total and cell surface hormone binding, protein levels of both mutant LH receptors are only moderately affected. The expression and study of enhanced green fluorescent protein-tagged receptors confirmed this view and further indicated that initial translocation to the endoplasmic reticulum of these mutant receptors is normal. After that, however, translocation is halted or misrouted, and as a result, neither mutant ever reaches the cell surface, and they cannot bind hormone. This lack of processing is also indicated by reduced presence of an 80-kDa protein, the only N-linked glycosylated protein in the LH receptor protein profile. Thus, complete lack of signaling by the identified mutant LH receptors is caused by insufficient processing from the endoplasmic reticulum to the cell surface and results in complete Leydig cell hypoplasia in this patient.

Male LH-independent sexual precocity in a 3.5-year-old boy caused by a somatic activating mutation of the LH receptor in a Leydig cell tumor.

We describe the clinical features of severe sexual precocity in a 3.5-yr-old boy. Hormonal evaluation showed LH-independent T hypersecretion. Initial examination of the adrenals and testes revealed no evidence of congenital adrenal hyperplasia, hCG- or androgen-secreting tumors, or McCune-Albright syndrome. In the coding sequence of the LH receptor gene no activating mutation was found. Spironolactone (5.7 mg/kg x d) and testolactone (40 mg/kg x d) were unsuccessful in suppressing the elevated concentration of T. To further determine the origin of the elevated serum T, a selective venous sampling procedure was planned. However before the sampling procedure, high resolution ultrasound examination showed a small tumor in the left testis, which was removed. Histology proved the tumor to be a Leydig cell adenoma. Sequencing of the tumor LH receptor gene revealed a heterozygous mutation in exon 11 encoding a replacement of aspartic acid at position 578 with histidine, which has been shown to be a constitutively activating mutation. These findings indicate that in male patients with gonadotropin-independent sexual precocity, the presence of small testicular Leydig cell tumors harboring a somatic mutation of the LH receptor gene should be considered.

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.

Clinical and novel molecular findings in a 6.8-year-old Turkish boy with triple A syndrome.

BACKGROUND: The triple A syndrome is characterized by the main features adrenal insufficiency, achalasia and alacrima. Other organ systems can be involved in a variable manner. PATIENT: We report clinical and novel molecular findings in a 6.8-year-old Kurdish boy, who presented with relapsing vomiting and failure to thrive. He was diagnosed as having achalasia and primary adrenocortical hypofunction. History and clinical examination showed that the boy was unable to produce tears. In addition, a large number of associated neurological and dermatological features was present in this patient. Thus, the clinical diagnosis of triple A syndrome was made. RESULTS: Initial molecular marker analysis supported linkage to the triple A critical region on chromosome 12q13. Further, a homozygous G -->A transition in exon 9 of the newly identified AAAS gene, resulting in a stop codon (W295X) and predicting a truncated protein with loss of function, confirmed the diagnosis. This new mutation was also detected in another family of Kurdish origin. In turned out that both families were related.

The occupation of gardening in life-threatening illness: a qualitative pilot project.

This qualitative pilot study was completed as an exploratory study of the meaning of gardening using attention restoration theory. Three women with breast cancer who garden for leisure were recruited from a cancer support group. Each participant was interviewed at her home on two occasions. To complement the qualitative data, participants also completed the Perceived Restorativeness Scale (PRS) (Hartig, Korpela, Evans, & Garling, 1996). The interviews revealed six major themes some of which were concerned with the interactions between the gardener and the garden, and others which focused on gardening within the context of having cancer. The qualitative and quantitative outcomes supported the perspective of attention restoration theory. Spirituality was interwoven throughout the comments of two participants but was less important for one participant. The implications of this study for practice and future research are discussed.

Does gender affect appraisal of pain and pain coping strategies?

OBJECTIVE: To investigate the impact of gender and a set of pain characteristics on the threat or challenge appraisal of pain and the impact of these appraisals on the coping strategies used to manage the pain. DESIGN: This study used a community telephone survey to examine these relationships for a troublesome pain experienced by respondents in the 2 weeks preceding the interview. STUDY RESPONDENTS: The sampling frame consisted of 1,430 households randomly selected from the Halifax-Dartmouth-Bedford community. Of the 390 respondents with a troublesome pain in the 2 weeks preceding the interview, 309 respondents agreed to participate (79% response rate). RESULTS: Women tended to report more pain located in the head and more somatic problems. They reported significantly more intense pain. For women and men, the most important impact on threat appraisal of pain was overall interference of pain and emotional upset due to pain. These two variables accounted for 48% of the variance in threat appraisal for women and 37% of the variance for men. There was no gender difference in emotional upset due to pain or in the impact of emotional upset on threat appraisal. There was no gender difference in challenge appraisal. Threat appraisal was associated with increased catastrophizing whereas challenge appraisal was associated with positive self-statements. Women reported significantly more problem solving, social support, positive self-statements, and palliative behaviors than did men. CONCLUSIONS: Interference of pain has a greater impact on threat appraisal of pain for women. Increasing threat appraisal is associated with health care utilization for women, but women's more frequent use of several coping strategies is unrelated to their appraisal of pain. Appraisal of pain may have important implications on coping and overall well-being of women and men.