Parenting Children with Disorders of Sex Development (DSD): A Developmental Perspective Beyond Gender.

Advances in therapeutics for specific conditions have contributed to a categorical psychological approach to chronic diseases that affect children. Consensus statements and clinical guidelines recognize stress associated with disorders of sex development (DSD) for patients and their caregivers - yet much remains to be learned concerning the social adjustment, mental health, and quality of life of affected children and their families. We present preliminary data on the psychosocial comorbidities of caregivers of children with DSD, including stigma, isolation, stress, anxiety, and depressive symptomatology. Evidence is offered in support of individualized psychological approaches for families according to such variables as: 1) gender of the caregiver, 2) gender of the affected child and 3) presence of genital ambiguity at birth. Development of feasible, targeted interventions to ameliorate psychosocial comorbidities among caregivers is needed to optimize social adjustment, mental health, and health-related quality of life (HRQoL) for children with DSD.

Promoting Shared Decision Making in Disorders of Sex Development (DSD): Decision Aids and Support Tools.

Specific complaints and grievances from adult patients with disorders of sex development (DSD), and their advocates center around the lack of information or misinformation they were given about their condition and feeling stigmatized and shamed by the secrecy surrounding their condition and its management. Many also attribute poor sexual function to damaging genital surgery and/or repeated, insensitive genital examinations. These reports suggest the need to reconsider the decision-making process for the treatment of children born with DSD. This paper proposes that shared decision making, an important concept in adult health care, be operationalized for the major decisions commonly encountered in DSD care and facilitated through the utilization of decision aids and support tools. This approach may help patients and their families make informed decisions that are better aligned with their personal values and goals. It may also lead to greater confidence in decision making with greater satisfaction and less regret. A brief review of the past and current approach to DSD decision making is provided, along with a review of shared decision making and decision aids and support tools. A case study explores the need and potential utility of this suggested new approach.

Disorders of Sex Development (DSD): Networking and Standardization Considerations.

Syndromes resulting in Disorders of Sex Development (DSD) are individually rare. Historically, this fact has hindered both clinical research and the delivery of evidence-based care. Recognizing the need for advancement, members of European and North American medical societies produced policy statements, notably the Consensus Statement on Management of Intersex Disorders, which recognize that optimal healthcare in DSD requires multidisciplinary teams in conjunction with networking of treatment centers and continued development of patient registries. This paper summarizes efforts in Europe and the U.S. toward creating networks focused on expanding discovery and improving healthcare and quality of life outcomes in DSD. The objectives and function of registry-based networks (EuroDSD/I-DSD), learning collaboratives (DSD-net), clinical outcomes research (DSD-Life), and networking hybrids (DSD-TRN) are reviewed. Opportunities for, and barriers to standardization in research and care are highlighted in light of practical considerations, for example, limitations in reliably classifying anatomic phenotypes and gaps in behavioral health staffing resources. The role of patient-reported outcomes is considered, with emphasis on integrating patient perspectives, given findings of limited agreement in outcome ratings by healthcare providers and patients. Finally, the characteristics of clinical centers likely to deliver the highest quality outcomes are discussed.

Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development.

Disorders of sex development (DSD) are rare disorders in which there is discordance between chromosomal, gonadal, and phenotypic sex. Only a minority of patients clinically diagnosed with DSD obtains a molecular diagnosis, leaving a large gap in our understanding of the prevalence, management, and outcomes in affected patients. We created a novel DSD-genetic diagnostic tool, in which sex development genes are captured using RNA probes and undergo massively parallel sequencing. In the pilot group of 14 patients, we determined sex chromosome dosage, copy number variation, and gene mutations. In the patients with a known genetic diagnosis (obtained either on a clinical or research basis), this test identified the molecular cause in 100% (7/7) of patients. In patients in whom no molecular diagnosis had been made, this tool identified a genetic diagnosis in two of seven patients. Targeted sequencing of genes representing a specific spectrum of disorders can result in a higher rate of genetic diagnoses than current diagnostic approaches. Our DSD diagnostic tool provides for first time, in a single blood test, a comprehensive genetic diagnosis in patients presenting with a wide range of urogenital anomalies.

Intrathecal drug delivery in the era of nanomedicine.

Administration of substances directly into the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord is one approach that can circumvent the blood-brain barrier to enable drug delivery to the central nervous system (CNS). However, molecules that have been administered by intrathecal injection, which includes intraventricular, intracisternal, or lumbar locations, encounter new barriers within the subarachnoid space. These barriers include relatively high rates of turnover as CSF clears and potentially inadequate delivery to tissue or cellular targets. Nanomedicine could offer a solution. In contrast to the fate of freely administered drugs, nanomedicine systems can navigate the subarachnoid space to sustain delivery of therapeutic molecules, genes, and imaging agents within the CNS. Some evidence suggests that certain nanomedicine agents can reach the parenchyma following intrathecal administration. Here, we will address the preclinical and clinical use of intrathecal nanomedicine, including nanoparticles, microparticles, dendrimers, micelles, liposomes, polyplexes, and other colloidalal materials that function to alter the distribution of molecules in tissue. Our review forms a foundational understanding of drug delivery to the CSF that can be built upon to better engineer nanomedicine for intrathecal treatment of disease.

Fate of nanoparticles in the central nervous system after intrathecal injection in healthy mice.

Cerebrospinal fluid (CSF) is produced in the cerebral ventricles and circulates within the subarachnoid space (SAS) of the brain and spinal cord, where it exchanges with interstitial fluid of the parenchyma. The access of CSF to the entire central nervous system (CNS) makes it an attractive medium for drug delivery. However, few intrathecal (IT) therapies have reached the clinic due, in part, to limited distribution and rapid clearance. Given the success of nanoparticle (NP) carriers in prolonging circulation and improving delivery of systemically administered agents, we sought to evaluate the distribution of IT injected NPs within the CNS. We administered fluorescent, 100 nm PEGylated-NPs into the cisterna magna of healthy mice and studied their distribution along the brain and spinal cord. Our data demonstrate that NPs are capable of distributing rapidly through the SAS along the entire neuraxis with reproducible, anatomically defined patterns of delivery. NPs were well retained within the leptomeninges for over 3 weeks, showing preference for ventral surfaces and minimal penetration into the CNS parenchyma. Clearance of NPs occurred across the cribriform plate into the nasal mucosa, with a small fraction of NPs localizing with nerve roots exiting the spinal column. Larger 10 µm particles were also capable of moving through the SAS but did not achieve as widespread distribution. These studies demonstrate the ability of NPs to achieve widespread delivery along the neuraxis and highlight IT administration as a potentially significant route of administration for delivery of nanomedicine to the subarachnoid space.

Coming Up Short: Risks of Bias in Assessing Psychological Outcomes in Growth Hormone Therapy for Short Stature.

CONTEXT: Two often cited assumptions for treating children with GH are that short stature (SS), as an isolated physical characteristic, is associated with psychosocial morbidity and that GH treatment may increase height and improve psychological adjustment. Findings across studies regarding the psychological consequences associated with GH management of children with SS are variable and frequently contradictory. The purpose of this systematic review is to evaluate the degree to which any conclusions about the relative risks or benefits of GH treatment on psychological outcomes can be made based on the published literature. EVIDENCE ACQUISITION: Electronic databases were searched for randomized clinical trials and nonrandomized studies, published between 1958-2014, in which GH was administered for management of children with SS and psychosocial, cognitive, academic, or health-related quality of life outcomes were assessed. Methodological quality of each study was assessed using the Cochrane Collaboration's tool for assessing risk of bias. EVIDENCE SYNTHESIS: Eighty studies were evaluated. No studies were rated as having a low risk of bias, the risk of bias was unclear in seven study outcome areas, and the remaining studies were judged as having a high risk of bias. CONCLUSIONS: The high risk of bias present in the majority of the literature on GH treatment effects on psychological outcomes (in particular, lack of blinding) substantially weakens confidence in their results. This may serve to explain the variability of findings for these outcomes across studies.

A comparison of sodium bicarbonate and sodium lactate infusion in the induction of panic attacks.

Infusion of sodium lactate has been shown by a number of investigators to induce panic in patients with panic disorder, but the pathophysiology underlying this phenomenon is unknown. One theory to explain lactate's anxiety-producing effects involves its ability to induce alkalosis because of metabolic conversion to bicarbonate. To test this hypothesis, we administered both sodium lactate and sodium bicarbonate infusions in counterbalanced order to patients with panic disorder. Thirteen of 22 subjects panicked in response to lactate and nine of 20 subjects panicked in response to bicarbonate. Although the rate of panic between the two infusion responses was not significantly different, several aspects of response to the two infusions indicated that lactate may be a more potent producer of anxiety than bicarbonate. An unexpected finding was that bicarbonate panickers had a reduction in arterial carbon dioxide pressure during the infusion, while bicarbonate nonpanickers had an increase in arterial carbon dioxide pressure during the infusion. Induction of hyperventilation and subsequent hypocapnia appears to be a common denominator between lactate- and bicarbonate-induced panic.

Quality of life among formerly treated childhood-onset growth hormone-deficient adults: a comparison with unaffected siblings.

Several studies have investigated the quality of life (QOL) of GH-deficient (GHD) adults who, as children, had been treated with GH. Variable findings are probably related to sample heterogeneity and disparate research methodologies and designs, particularly the choice of control or comparison groups. In addition to comparing a relatively large sample to questionnaire norms, the present study is the first to compare the QOL adjustment of GHD patients to that of same sex siblings. A total of 140 former patients (76% of those eligible; mean age, 26 yr; n = 95 isolated GHD, n = 45 multiple pituitary hormone deficiencies; 117 males and 23 females) and 53 same sex siblings (84% participation), 18 yr and older, participated in the telephone questionnaire survey. The majority of interviews with GHD patients (78%) and siblings (87%) were conducted blind to the subject's clinical status. Comparisons between GHD patients and norms for standardized questionnaires indicated both better and worse functioning in several domains. In contrast, very limited differences were detected between GHD cases and same sex siblings. Isolated GHD patients were functioning better than those with multiple pituitary hormone deficiencies, but the effect sizes of these differences in most areas were relatively small. Adult height and degree of growth over the course of GH therapy were generally unrelated to QOL outcomes. Findings from the present study underscore the importance of selecting unbiased control/comparison groups in evaluating psychological outcomes among GHD adults.

Characteristics of psychiatric inpatients who stalk, threaten, or harass hospital staff after discharge.

OBJECTIVE: The purpose of this study was to identify demographic and clinical characteristics of psychiatric inpatients who stalk, threaten, or harass hospital staff after discharge. METHOD: The authors retrospectively summarized the demographic and clinical characteristics of 17 inpatients who engaged in this type of behavior and a comparison group of 326 inpatients. RESULTS: The patients who stalked, threatened, or harassed staff after discharge were significantly more likely than the comparison patients to have a diagnosis of personality disorder and/or paranoid disorder, erotomanic subtype, and to have a history of physically assaultive or fear-inducing behavior. The data suggest that they were more likely to be male and never married and to have histories of multiple hospitalizations, suicidal or self-injurious behavior, and substance abuse or dependence. CONCLUSIONS: The findings reveal several risk factors that may be useful in identifying a subgroup of patients who pose a risk of directing aggressive behavior toward hospital staff after discharge.

The content, binding, and forms of vitamin B12 in milk.

The vitamin B12 (cobalamin, Cbl) content of 19 human milks ranged from 0.33 to 3.20 ng/ml, mean 0.97 ng/ml. The milk content of 10 mothers taking 5 to 100 micrograms of supplemental cyanocobalamin daily was not significantly different from that of unsupplemented mothers. The Cbl native to milk was bound to an R type binder. The R binder was also the dominant, by far, unsaturated Cbl binder, but transcobalamin II was found in every milk. The amounts of transcobalamin II were of the same order of magnitude as in serum and seemed to increase with the interval postpartum. Methylcobalamin was the most abundant Cbl of milk. Human milk from well fed mothers contains adequate amounts of Cbl, but the Cbl may become available only if there are sufficient proteolytic enzymes to release it from binding to R binder.

Short stature: a psychosocial burden requiring growth hormone therapy?

BACKGROUND: Changes in the diagnosis of endocrine-based growth disorders and the advent of biosynthetic growth hormone have altered the long-standing policy of treating only those individuals with "classic" growth hormone deficiency. One justification for treating short children is to improve their psychosocial adaptation. The present investigation assessed the positive and negative behavioral adaptation, self-perceptions of domain-specific competencies, and global self-worth of a large, diagnostically heterogeneous sample of children and adolescents referred to pediatric endocrinologists for a growth evaluation. METHODS: All patients seen in a pediatric endocrine clinic (180 boys and 78 girls; 4 to 18 years) with a height at the fifth percentile or lower were included. Parents of all participating children completed the Child Behavior Checklist. Patients 8 years and older completed the Self-Perception Profile and those 11 years and older, in addition, completed the Youth Self Report. Short-stature (SS) subjects were compared with normative and psychiatric samples. RESULTS: The SS boys were described by parents as being significantly less socially competent and showing more behavioral and emotional problems than a normative sample selected for mental health. However, they were significantly more socially competent and showed fewer psychopathologic symptoms than a psychiatric referred sample of comparable age. The SS boys described themselves as less socially active but did not report more behavior disturbance than the normative sample. The SS boys' self-perceptions of domain-specific competencies and global self-worth were comparable to a normative comparison group with the exception that older subjects (13 years or older) described their athletic abilities more positively and their work competence more negatively. The SS girls were, with few exceptions, indistinguishable from the normal comparison groups on both parent- and self-report measures of social competency and behavior disturbance. Younger SS girls (ages 8 to 12 years) described their athletic competence and behavioral conduct more positively than the comparison group on the self-esteem questionnaire. Patient height deficit was unrelated to scores on the three questionnaires. Finally, no statistically significant differences in psychosocial functioning were detected between children with "normal-variant" SS and those with pathologic growth disorders. SS and those with pathologic growth disorders. CONCLUSIONS: Short-stature girls show more adaptive psychosocial functioning than SS boys. In either sex, SS does not appear to be associated with clinically significant psychosocial morbidity. Severity of the height deficit does not correlate with the level of behavioral adaptation. These observations challenge the justification of providing growth hormone therapy for all short children to improve their psychosocial functioning.

Nutritional dwarfing: is it a consequence of disturbed psychosocial functioning?

Nutritional dwarfing refers to a condition in which maladaptive eating patterns play a primary role in poor linear growth and delayed pubertal development. The present controlled study assesses whether nutritionally dwarfed children and adolescents differ in their psychosocial adjustment from healthy children and adolescents of comparable height in ways that might account for their undernutrition. Children with nutritional dwarfing (n = 16) were compared by standardized questionnaires with a short-stature (ie, heights below the fifth percentile) control group composed of children and adolescents with constitutional growth delay and/or familial short stature (n = 31). Scores on a self-report screening questionnaire for eating disorders did not differentiate the groups. Moreover, the vast majority of nutritionally dwarfed patients expressed a desire to have a heavier physical appearance. Whereas the groups were generally similar in self-perceptions of domain-specific competencies and positive psychosocial adjustment, the parents of nutritionally dwarfed children reported that their children showed significantly fewer externalized behavior problems. These findings suggest the existence of an eating disturbance that compromises growth in childhood and/or adolescence which, unlike anorexia nervosa, is not associated with evidence of psychopathology.

Current dosing of growth hormone in children with growth hormone deficiency: how physiologic?

The current doses of recombinant growth hormone (rGH) are two to three times those used in the pituitary growth hormone era. These rGH doses (0.025 to 0.043 mg/kg/d) are similar to or moderately greater than the physiologic requirements. Growth velocity and height gains have been shown to be greater with 0.05 mg/kg/d of rGH than with 0.025 mg/kg/d. Larger doses of GH and early initiation of treatment result in greater heights at the onset of puberty and greater adult heights. Earlier onset of puberty and more rapid maturation, as indicated by bone age, were not observed in children who were given 0.18 to 0.3 mg/kg/wk of rGH. The frequency of adverse events is very low, but diligent surveillance of all children who are treated with rGH is essential.

Effects of prenatal methadone exposure on sex-dimorphic behavior in early school-age children.

Prenatal opiate exposure has been shown to alter the pattern of sex-dimorphic behavior in male and female rats. To conduct an exploratory study of opiate effects in humans, we compared the sex-dimorphic behavior of male and female offspring of women maintained on methadone during pregnancy to that of demographically matched control subjects. Standardized questionnaires completed by the primary caretakers served as assessment instruments. The six- to eight-year-old methadone-exposed boys showed more stereotypically feminine behavior than nonexposed male control subjects. There were no significant differences between methadone-exposed girls and their female control group. Based on these preliminary findings, we recommend that future follow-up studies of opiate-exposed children be broadened to include an assessment of their gender role behavior.

Gender development in boys born with hypospadias.

Fetal testicular androgens in several mammalian species are responsible for the sexual differentiation of both the genitalia and the brain, the latter effect being related to behavioral sex-dimorphisms. Because prenatal endocrine abnormalities can be inferred from genital defects, studies of individuals born with anomalies potentially elucidate the contribution of androgens to the development of gender-related variation in human behavior. This study concerns the gender-role behavior of middle childhood boys (ages 6-10 years; n = 175) born with hypospadias, an androgen-related genital anomaly. Parents completed standardized gender behavior questionnaires in a postal survey. Hypospadias subjects did not show consistent differences from a community control group (n = 333) in feminine behavior, but significant, small, increases in masculine behavior were found. Severity of the hypospadias was unrelated to gender-role behavior. A number of surgery-related hospitalizations, however, were correlated with increased gender-atypical behavior. It is concluded that the hypoandrogenization associated with hypospadias does not interfere with the development of gender-typical masculine behavior.

New approaches in the pharmacotherapy of posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) may develop after exposure to severe stress, such as combat, accidents, assaults, and natural disasters. Pharmacotherapy can be a useful adjunct in the comprehensive treatment of these patients. The presence of comorbid conditions, including depression, panic disorder, substance abuse, and traumatic brain injury, should be carefully evaluated. Symptoms of PTSD that are associated with central nervous system hyperarousal or reexperiencing of the traumatic event appear to be the most responsive to pharmacotherapy. Social withdrawal and dulled responsiveness have not been shown to be alleviated through standard pharmacologic interventions. A therapeutic strategy is proposed that is based on the patient's symptoms and initial response to medication.

Pharmacotherapy of social phobia: an interim report of a placebo-controlled comparison of phenelzine and atenolol.

Forty-one patients meeting DSM-III criteria for social phobia completed a randomized comparative trial of the monoamine oxidase inhibitor phenelzine, the cardioselective beta-adrenergic blocker atenolol, and placebo. No significant differences were seen after 4 weeks of treatment in this preliminary trial. At the end of 8 weeks, however, phenelzine demonstrated greater efficacy than atenolol or placebo on dimensional ratings of overall severity of social phobia. No atenolol-placebo differences were observed. The authors shall present maintenance and discontinuation findings in a final report. Phenelzine may act in patients with social phobia by directly reducing interpersonal hypersensitivity.

The pharmacotherapy of moral or religious scrupulosity.

Moral or religious scrupulosity is a disabling condition which is sometimes seen in patients with obsessive compulsive disorder (OCD). The authors described 10 patients with moral or religious scrupulosity who were treated with fluoxetine or clomipramine. Seven of the 10 patients completed open treatment of at least 8 weeks without requiring adjunctive medication; 5 of those 7 patients were rated as much improved. Among the 3 patients who required adjunctive medication, 1 was rated as much improved. Of the 4 nonresponders at 3 months, 2 responded after longer treatment trials. These results suggest that extreme moral or religious concerns and behaviors might be a form of OCD and that the scrupulosity can be effectively treated with serotonin reuptake blockers.

Effects of ultrasound feedback on pregnancy anxiety, fetal activity, and neonatal outcome.

A group of pregnant women received video and verbal feedback during three ultrasound examinations. This group was compared with a no-feedback group on measures of pregnancy anxiety, fetal activity, and neonatal outcome. The feedback appeared to reduce pregnancy anxiety and fetal activity, particularly for the primiparous women. These women also experienced fewer obstetric complications and gave birth to neonates who were greater weight, more appropriate weight-for-length, less active and irritable, and showed better performance on the Brazelton neonatal behavior assessment.