S. Faisal Ahmed

Psychological outcomes and gender-related development in complete androgen insensitivity syndrome.

We evaluated psychological outcomes and gender development in 22 women with complete androgen insensitivity syndrome (CAIS). Participants were recruited through a medical database (n = 10) or through a patient support group (n = 12). Controls included 14 males and 33 females, of whom 22 were matched to women with CAIS for age, race, and sex-of-rearing. Outcome measures included quality of life (self-esteem and psychological general well-being), gender-related psychological characteristics (gender identity, sexual orientation, and gender role behavior in childhood and adulthood), marital status, personality traits that show sex differences, and hand preferences. Women recruited through the database versus the support group did not differ systematically, and there were no statistically significant differences between the 22 women with CAIS and the matched controls for any psychological outcome. These findings argue against the need for two X chromosomes or ovaries to determine feminine-typical psychological development in humans and reinforce the important role of the androgen receptor in influencing masculine-typical psychological development. They also suggest that psychological outcomes in women with CAIS are similar to those in other women. However, additional attention to more detailed aspects of psychological well-being in CAIS is needed.

Summary of Consensus Statement on Intersex Disorders and Their Management

Advances in understanding of genetic control of sexual determination and differentiation, improvements in diagnostic testing and surgical genital repair, and the persistent controversies inherent to clinical management were all compelling factors that led to the organization of an international consensus conference. The goals were to acknowledge and discuss the more controversial issues in intersex management, provide management guidelines for intersex patients, and identify and prioritize questions that need additional investigation. This is a summary statement. Advances in molecular genetic causes of abnormal sexual development and heightened awareness of the ethical and patient-advocacy issues mandate reexamination of existing nomenclature for patients with intersex.1 Terminology such as “pseudohermaphroditism” is controversial, potentially pejorative to patients,2 and inherently confusing. Therefore, the term “disorders of sex development” (DSD) is proposed to indicate congenital conditions with atypical development of chromosomal, gonadal, or anatomic sex. Additional rationale for new classification is the need for modern categorization to integrate the modern molecular genetic aspects, to maximize precision when applying definitions and diagnostic labels,3 and to meet the need for psychologically sensitive yet descriptive medical terminology. Nomenclature should be flexible enough to incorporate new information, robust enough to maintain a consistent framework, use descriptive terms, reflect genetic etiology, accommodate phenotypic variation spectrum, and be useful for clinicians, scientists, patients, and families. Hence, we propose a new classification (see “Consensus Statement on Management of Intersex Disorders”4 in this months issue of Pediatrics Electronic Edition ). Three traditionally conceptualized domains of psychosexual development are gender identity (ones self-representation [ie, male or female]), gender role (sexually dimorphic behaviors within the general population, such as toy preferences, aggression, and spatial ability), and sexual orientation (direction[s] of erotic interest). Gender dissatisfaction denotes unhappiness with assigned sex and may result in gender self-reassignment. Psychosexual developmental factors relate to parental psychopathology, parent-child … Address correspondence to Peter A. Lee, MD, PhD, Department of Pediatrics, MC-H085, Penn State College of Medicine, Milton S. Hershey Medical Center, Box 850, 500 University Dr, Hershey, PA 17033-0850. E-mail: plee{at}psu.edu

Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care

The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possible outcome improves QoL. The evolution of diagnosis and care continues, while it is still impossible to predict gender development in an individual case with certainty. Such decisions and decisions regarding surgery during infancy that alters external genital anatomy or removes germ cells continue to carry risk.

Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial

BACKGROUND Children with osteogenesis imperfecta are often treated with intravenous bisphosphonates. We aimed to assess the safety and efficacy of risedronate, an orally administered third-generation bisphosphonate, in children with the disease. METHODS In this multicentre, randomised, parallel, double-blind, placebo-controlled trial, children aged 4-15 years with osteogenesis imperfecta and increased fracture risk were randomly assigned by telephone randomisation system in a 2:1 ratio to receive either daily risedronate (2·5 or 5 mg) or placebo for 1 year. Study treatment was masked from patients, investigators, and study centre personnel. Thereafter, all children received risedronate for 2 additional years in an open-label extension. The primary efficacy endpoint was percentage change in lumbar spine areal bone mineral density (BMD) at 1 year. The primary efficacy analysis was done by ANCOVA, with treatment, age group, and pooled centre as fixed effects, and baseline as covariate. Analyses were based on the intention-to-treat population, which included all patients who were randomly assigned and took at least one dose of assigned study treatment. The trial is registered with ClinicalTrials.gov, number NCT00106028. FINDINGS Of 147 patients, 97 were randomly assigned to the risedronate group and 50 to the placebo group. Three patients from the risedronate group and one from the placebo group did not receive study treatment, leaving 94 and 49 in the intention-to-treat population, respectively. The mean increase in lumbar spine areal BMD after 1 year was 16·3% in the risedronate group and 7·6% in the placebo group (difference 8·7%, 95% CI 5·7-11·7; p<0·0001). After 1 year, clinical fractures had occurred in 29 (31%) of 94 patients in the risedronate group and 24 (49%) of 49 patients in the placebo group (p=0·0446). During years 2 and 3 (open-label phase), clinical fractures were reported in 46 (53%) of 87 patients in the group that had received risedronate since the start of the study, and 32 (65%) of 49 patients in the group that had been given placebo during the first year. Adverse event profiles were otherwise similar between the two groups, including frequencies of reported upper-gastrointestinal and selected musculoskeletal adverse events. INTERPRETATION Oral risedronate increased areal BMD and reduced the risk of first and recurrent clinical fractures in children with osteogenesis imperfecta, and the drug was generally well tolerated. Risedronate should be regarded as a treatment option for children with osteogenesis imperfecta. FUNDING Alliance for Better Bone Health (Warner Chilcott and Sanofi).

UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional DSD team acts as the first point of contact. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents are as fully informed as possible and have access to specialist psychological support. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.

Contemporary Risk of Hip Fracture in Type 1 and Type 2 Diabetes: A National Registry Study From Scotland

The purpose of this study was to compare contemporary risk of hip fracture in type 1 and type 2 diabetes with the nondiabetic population. Using a national diabetes database, we identified those with type 1 and type 2 diabetes who were aged 20 to 84 years and alive anytime from January 1, 2005 to December 31, 2007. All hospitalized events for hip fracture in 2005 to 2007 for diabetes patients were linked and compared with general population counts. Age‐ and calendar‐year‐adjusted incidence rate ratios were calculated by diabetes type and sex. One hundred five hip fractures occurred in 21,033 people (59,585 person‐years) with type 1 diabetes; 1421 in 180,841 people (462,120 person‐years) with type 2 diabetes; and 11,733 hip fractures over 10,980,599 person‐years in the nondiabetic population (3.66 million people). Those with type 1 diabetes had substantially elevated risks of hip fracture compared with the general population incidence risk ratio (IRR) of 3.28 (95% confidence interval [CI] 2.52–4.26) in men and 3.54 (CI 2.75–4.57) in women. The IRR was greater at younger ages, but absolute risk difference was greatest at older ages. In type 2 diabetes, there was no elevation in risk among men (IRR 0.97 [CI 0.92–1.02]) and the increase in risk in women was small (IRR 1.05 [CI 1.01–1.10]). There remains a substantial elevation relative risk of hip fracture in people with type 1 diabetes, but the relative risk is much lower than in earlier studies. In contrast, there is currently little elevation in overall hip fracture risk with type 2 diabetes, but this may mask elevations in risk in particular subgroups of type 2 diabetes patients with different body mass indexes, diabetes duration, or drug exposure.

The genetics of male undermasculinization

A review of the genetics of male undermasculinization must encompass a description of the embryology of the genital system. The dimorphism of sex development consequent upon the formation of a testis and the subsequent secretion of hormones to impose a male phenotype is highlighted. Thus, an understanding of the causes of male undermasculinization (manifest as XY sex reversal, complete and partial) includes reviewing the genetic factors which control testis determination and the production and action of testicular hormones. The study of disorders of male sex development has contributed substantially to knowledge of normal male development before birth. This knowledge has been complimented in recent years by the use of targeted murine gene disruption experiments to study the sex phenotype, although murine and human phenotypes are not always concordant. The investigation of disorders associated with male undermasculinization of prenatal onset is described briefly to complete the review.

Society for Endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development (Revised 2015)

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional DSD team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional team acts commonly as the first point of contact. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents have access to specialist psychological support and that their information needs are comprehensively addressed. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.

The testosterone:androstenedione ratio in male undermasculinization

Recent reports suggest that low testosterone:androstenedione (T:A) ratio following hCG stimulation may be a useful method of diagnosing 17β‐hydroxysteroid dehydrogenase‐3 (17 βHSD3) deficiency. The aim of this study was to establish the range of T:A ratios in cases of undermasculinization with proven aetiologies other than 17 βHSD3.

Novel associations in disorders of sex development: Findings from the I-DSD registry

Context: The focus of care in disorders of sex development (DSD) is often directed to issues related to sex and gender development. In addition, the molecular etiology remains unclear in the majority of cases. Objective: To report the range of associated conditions identified in the international DSD (I-DSD) Registry. Design, Setting, and Patients: Anonymized data were extracted from the I-DSD Registry for diagnosis, karyotype, sex of rearing, genetic investigations, and associated anomalies. If necessary, clarification was sought from the reporting clinician. Results: Of 649 accessible cases, associated conditions occurred in 168 (26%); 103 (61%) cases had one condition, 31 (18%) had two conditions, 20 (12%) had three conditions, and 14 (8%) had four or more conditions. Karyotypes with most frequently reported associations included 45,X with 6 of 8 affected cases (75%), 45,X/46,XY with 19 of 42 cases (45%), 46,XY with 112 of 460 cases (24%), and 46,XX with 27 of 121 cases (22%). In the 112 cases of 46,XY DSD, the commonest conditions included small for gestational age in 26 (23%), cardiac anomalies in 22 (20%), and central nervous system disorders in 22 (20%), whereas in the 27 cases of 46,XX DSD, skeletal and renal anomalies were commonest at 12 (44%) and 8 (30%), respectively. Of 170 cases of suspected androgen insensitivity syndrome, 19 (11%) had reported anomalies and 9 of these had confirmed androgen receptor mutations. Conclusions: Over a quarter of the cases in the I-DSD Registry have an additional condition. These associations can direct investigators toward novel genetic etiology and also highlight the need for more holistic care of the affected person.