Patient and Caregiver Attitudes toward Disorders of Sex Development Nomenclature.

PURPOSE: The medical terminology applied to differences/disorders of sex development has been viewed negatively by some affected individuals. A clinical population of patients with differences/disorders of sex development and their caregivers were surveyed regarding current nomenclature, hypothesizing that those unaffiliated with support groups would have more favorable attitudes. MATERIALS AND METHODS: We recruited English and Spanish speaking patients 13 years old or older with differences/disorders of sex development and their caregivers at 5 national tertiary care clinics from July 2016 to December 2018. No diagnoses were excluded. Participants completed a survey rating terminology commonly applied to differences/disorders of sex development. Responses were compared between subgroups, including members vs nonmembers of a support group. RESULTS: Of 185 potential participants approached 133 completed the survey (72% response rate). Congenital adrenal hyperplasia (33%) was the most common diagnosis. "Variation of sex development" was the most liked term (37%) but was not liked more significantly than "disorders of sex development" (27%, p=0.16). No term was liked by a majority of respondents. "Disorders of sex development" (37%) and "intersex" (53%) were the only terms most frequently viewed unfavorably. Support group members were significantly more likely to dislike the term "intersex" (p=0.02) and to like "variation of sex development" (p=0.02). CONCLUSIONS: A clinical population of patients and their caregivers had generally neutral attitudes toward nomenclature applied to differences/disorders of sex development. Members of a support group had clearer terminology preferences. "Variation of sex development" was the most liked term, and "disorders of sex development" and "intersex" were the most disliked. No term was liked by most respondents, and no clear alternative to the present nomenclature was identified.

Evidence-Based Management of Patients with 45,X/46,XY Gonadal Dysgenesis and Male Sex Assignment: from Infancy to Adulthood.

45,X/46,XY gonadal dysgenesis is a disorder of sexual differentiation with a wide clinical presentation, ranging from Turner-like females to individuals with genital ambiguity to azoospermic but otherwise normal-appearing males. Hence, patients can be assigned female or male sex. Female patients are managed according to the Turner Syndrome Guidelines, whereas males are managed on a case-by-case basis. Male patients present with multiple medical challenges: undervirilization, hypogonadism, gonadoblastoma risk, and short stature. Many require surgeries and hormonal treatments that are time-sensitive and irreversible. Nonetheless, these therapeutic decisions are made without evidence-based guidelines. This review describes the medical concerns and possible interventions in male patients with 45,X/46,XY dysgenesis for each stage of development. Interventions should be addressed within a patient-centered framework by a multidisciplinary team and after thorough discussion with the family. We use the GRADE system to appraise the existing evidence and provide recommendations based on the available evidence.

A Multidisciplinary Approach to Puberty and Fertility in Girls with Turner Syndrome.

Women with Turner Syndrome (TS) have a variety of medical needs throughout their lives; however, the peripubertal years are particularly challenging. From a medical perspective, the burden of care increases during this time due to growth optimization strategies, frequent health screenings, and puberty induction. Psychologically, girls begin to comprehend the long-term implications of the condition, including their diminished fertility potential. Unfortunately, clear guidelines for how to best approach this stage have not been established. It remains to be determined what is the best age to begin treatment; the best compound, dose, or protocol to induce puberty; how, when or what to discuss regarding fertility and potential fertility preservation options; and how to support them to accept their differences and empower them to take an active role in their care. Given the complexity of this life stage, a multidisciplinary treatment team that includes experts in endocrinology, gynecology, and psychology is optimal.

Neurocognitive profile of a young adolescent with DK phocomelia/von Voss phocomelia/von Voss Cherstvoy syndrome.

DK phocomelia/von Voss Cherstvoy syndrome is a rare condition characterized by upper limb and urogenital abnormalities and various brain anomalies. Previously reported cases have noted significant developmental delays, although no formal testing of cognitive abilities has been reported. In this paper we describe results from a comprehensive neuropsychological evaluation of a 12-year-old male with DK phocomelia syndrome. Test findings indicated mild impairment in intellectual functioning, with more significant impairment in adaptive skills and academic achievement. The neuropsychological profile converged with neurological findings, showing a distinct pattern of strengths and weaknesses that suggests functional compromise of posterior brain regions with relatively well-preserved functioning of more anterior regions. Specifically, impairments were evident in perceptual reasoning, visual perception, and visuomotor integration, whereas normal or near normal functioning was evident in memory, receptive language, social cognition, attention, and most aspects of executive functioning. To our knowledge this is the first report to describe the neurocognitive profile of an individual with DK phocomelia syndrome.

Androgen Insensitivity Syndrome: Management Considerations from Infancy to Adulthood.

Androgen insensitivity syndrome (AIS) is an undervirilization syndrome in individuals with 46, XY karyotype. The undervirilization can be complete feminization or incomplete virilization with grades of ambiguity. AIS is caused by mutations in the androgen receptor, resulting in resistance to the physiologic activities of androgens. Differing degrees of resistance lead to three phenotypes: a complete form with female-appearing external genitalia, a partial form with a wide range of virilization, and a mild form with only minor undervirilization. AIS presents different challenges depending on whether resistance is complete or partial. Challenges include sex assignment, which impacts other medical decisions such as gonadectomy, hormonal replacement, and other surgical interventions. This review describes medical, psychosocial, and ethical concerns for each stage of development in complete and partial AIS, from the neonatal period to adulthood. These aspects of care should be addressed within an ethical framework by a multidisciplinary team, with the patients and families being the stakeholders in the decision-making process. We use the GRADE system when appropriate to appraise the existing evidence and provide recommendations and guidelines for management of AIS and appropriate transition of patients from pediatric to adult care.

State of the art review in hypospadias: challenges in diagnosis and medical management.

Hypospadias is a common congenital malformation in males, the cause of which may be genetic, hormonal, or environmental, although it usually is idiopathic or possibly multifactorial. Determining the optimal diagnostic testing and management remains a challenge. Hypospadias is corrected with surgery, and androgen therapy often is used preoperatively as an adjunctive therapy, although its use, timing, and effectiveness are unclear. No standardized approach has been established for the diagnostic testing for hypospadias or for preoperative androgen therapy. We reviewed current literature and used the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence and provide recommendations for a diagnostic testing algorithm from an endocrine and genetic perspective and for the optimal use of preoperative androgen therapy. These recommendations are an important step towards standardizing the use of diagnostic testing and the management of patients with hypospadias.

Intrafamilial phenotypic heterogeneity in siblings with pseudohypoparathyroidism 1B due to maternal STX16 deletion.

OBJECTIVES: Pseudohypoparathyroidism (PHP1B) is most commonly caused by epigenetic defects resulting in loss of methylation at the GNAS locus, although deletions of STX16 leading to GNAS methylation abnormalities have been previously reported. The phenotype of this disorder is variable and can include hormonal resistances and severe infantile obesity with hyperphagia. A possible time relationship between the onset of obesity and endocrinopathies has been previously reported but remains unclear. Understanding of the condition's natural history is limited, partly due to a scarcity of literature, especially in children. CASE PRESENTATION: We report three siblings with autosomal dominant PHP1B caused by a deletion in STX16 who presented with early childhood onset PTH-resistance with normocalcemia with a progressive nature, accompanied by TSH-resistance and severe infantile obesity with hyperphagia in some, not all of the affected individuals. CONCLUSIONS: PHP1B from a STX16 deletion displays intrafamilial phenotypic variation. It is a novel cause of severe infantile obesity, which is not typically included in commercially available gene panels but must be considered in the genetic work-up. Finally, it does not seem to have a clear time relationship between the onset of obesity and hormonal resistance.

Differences in Hyperandrogenism Related to Early Detection of Non-Classical Congenital Adrenal Hyperplasia on Second Newborn Screen.

Screening for congenital adrenal hyperplasia (CAH) remains heterogenous across geographies-we sought to determine the proportion of non-classical CAH (NCAH) detection by one vs. two newborn screens (NBS) in two U.S. regions. Data were collected at tertiary centers in Houston (HOU) and Los Angeles (LA) on 35 patients with NCAH, comparing patients identified via the NBS vs. during childhood, 17-hydroxyprogesterone (17-OHP) levels, genotype, and phenotype. The NBS filter-paper 17-OHP levels and daily cutoffs were recorded on initial and second screens. In all, 53% of patients with NCAH in the HOU cohort were identified as infants via the second NBS. Patients identified clinically later in childhood presented at a similar age (HOU: n = 9, 5.5 ± 3.1 years; LA: n = 18, 7.9 ± 4 years) with premature pubarche in almost all. Patients in LA had more virilized phenotypes involving clitoromegaly and precocious puberty and were older at treatment onset compared with those identified in HOU by the second NBS (HOU: 3.2 ± 3.9 years; LA: 7.9 ± 4.0 years, p = 0.02). We conclude that the early detection of NCAH could prevent hyperandrogenism and its adverse consequences, with half of the cases in HOU detected via a second NBS. Further studies of genotyping and costs are merited.

Neurofibromatosis Type 1 Has a Wide Spectrum of Growth Hormone Excess.

Overgrowth due to growth hormone (GH) excess affects approximately 10% of patients with neurofibromatosis type 1 (NF1) and optic pathway glioma (OPG). Our aim is to describe the clinical, biochemical, pathological, and genetic features of GH excess in a retrospective case series of 10 children and adults with NF1 referred to a tertiary care clinical research center. Six children (median age = 4 years, range of 3−5 years), one 14-year-old adolescent, and three adults (median age = 42 years, range of 29−52 years) were diagnosed with NF1 and GH excess. GH excess was confirmed by the failure to suppress GH (<1 ng/mL) on oral glucose tolerance test (OGTT, n = 9) and frequent overnight sampling of GH levels (n = 6). Genetic testing was ascertained through targeted or whole-exome sequencing (n = 9). Five patients (all children) had an OPG without any pituitary abnormality, three patients (one adolescent and two adults) had a pituitary lesion (two tumors, one suggestive hyperplasia) without an OPG, and two patients (one child and one adult) had a pituitary lesion (a pituitary tumor and suggestive hyperplasia, respectively) with a concomitant OPG. The serial overnight sampling of GH levels in six patients revealed abnormal overnight GH profiling. Two adult patients had a voluminous pituitary gland on pituitary imaging. One pituitary tumor from an adolescent patient who harbored a germline heterozygous p.Gln514Pro NF1 variant stained positive for GH and prolactin. One child who harbored a heterozygous truncating variant in exon 46 of NF1 had an OPG that, when compared to normal optic nerves, stained strongly for GPR101, an orphan G protein-coupled receptor causing GH excess in X-linked acrogigantism. We describe a series of patients with GH excess and NF1. Our findings show the variability in patterns of serial overnight GH secretion, somatotroph tumor or hyperplasia in some cases of NF1 and GH excess. Further studies are required to ascertain the link between NF1, GH excess and GPR101, which may aid in the characterization of the molecular underpinning of GH excess in NF1.

Thyroid surgery outcomes at a children's hospital: The value of a multidisciplinary team approach.

BACKGROUND: Our purpose is to describe the structure, function and outcomes of our multidisciplinary pediatric thyroid program and to evaluate our experience in comparison to other high-volume centers. METHODS: We reviewed all thyroid operations performed 10/2012 through 09/2019, and examined number of cases per year, patient demographics, procedures, final diagnoses and results. Primary outcomes were hypoparathyroidism and recurrent laryngeal nerve (RLN) injury at 12 months. Data were analyzed using descriptive statistics and univariate analyses. RESULTS: We performed 294 thyroid operations on 279 patients. Seventy-nine percent were female. Median age was 15 years (IQR: 12-17). Operations included total thyroidectomy (65%), lobectomy (30%) and completion thyroidectomy (5%). Most common diagnoses were Graves' disease (35%), malignancy (29%), and benign nodule (20%). We developed an evidence-based clinical pathway and conducted weekly multidisciplinary meetings. A clinical data specialist reviewed process and outcome measures routinely. Overall, 6 patients (2.0%) had hypoparathyroidism and 2 (0.7%) had unilateral RLN injury at 12 months. Two of the patients with clinical suspicion of permanent hypoparathyroidism were ultimately weaned off calcium. Both patients with RLN injury had extensive locally advanced malignant disease involving the nerve. CONCLUSIONS: Our multidisciplinary team achieved excellent long-term outcomes for pediatric thyroid surgery comparable to other high-volume pediatric and adult centers.

Pituitary and systemic autoimmunity in a case of intrasellar germinoma.

Germinomas arising in the sella turcica are difficult to differentiate from autoimmune hypophysitis because of similar clinical and pathological features. This differentiation, nevertheless, is critical for patient care due to different treatments of the two diseases. We report the case of an 11-year-old girl who presented with diabetes insipidus and growth retardation, and was found to have an intra- and supra-sellar mass. Initial examination of the pituitary biopsy showed diffuse lymphocytic infiltration of the adenohypophysis and absent placental alkaline phosphatase expression, leading to a diagnosis of hypophysitis and glucocorticoid treatment. Because of the lack of clinical and radiological response, the pituitary specimen was re-examined, revealing this time the presence of scattered c-kit and Oct4 positive germinoma cells. The revised diagnosis prompted the initiation of radiotherapy, which induced disappearance of the pituitary mass. Immunological studies showed that the patient's serum recognized antigens expressed by the patient's own germinoma cells, as well as pituitary antigens like growth hormone and systemic antigens like the Sjögren syndrome antigen B and alpha-enolase. The study first reports the presence of pituitary and systemic antibodies in a patient with intrasellar germinoma, and reminds us that diffuse lymphocytic infiltration of the pituitary gland and pituitary antibodies does not always indicate a diagnosis of autoimmune hypophysitis.

Testosterone versus hCG in Hypogonadotropic Hypogonadism - Comparing Clinical Effects and Evaluating Current Practice.

Background. Gonadotropin therapy is not typically used for pubertal induction in hypogonadotropic hypogonadism (HH), however, represents a promising alternative to testosterone. It can potentially lead to the maintenance of future fertility in addition to testicular growth. We compared the pubertal effects of human chorionic gonadotropin (hCG) versus testosterone in adolescent males with HH. We evaluated the current practice, among pediatric endocrinologists, to identify barriers against gonadotropin use. Methods. In this retrospective review, we compared the effect of testosterone versus hCG therapy on mean testicular volume (MTV), penile length, growth velocity, and testosterone levels. We surveyed pediatric endocrinologists at our center, using RedCap. Results. Outcomes were assessed in 52 male patients with HH (hCG, n = 4; T, n = 48) after a mean treatment duration of 13.4 (testosterone) and 13.8 months (hCG; P = .79). Final MTV was higher with hCG (8.25 mL) than testosterone (3.4 mL; P < .001). The groups did not differ in penile length, growth velocity, or testosterone levels. Survey results showed that more than half the providers were aware of the benefits of gonadotropins, however, 91% were uncomfortable prescribing hCG. Commonly reported barriers to prescribing hCG were lack of experience (62%) and insurance coverage concerns (52%). Conclusions. Larger testicular volume predicts faster induction of spermatogenesis. Since hCG promoted better testicular growth, compared to testosterone, it may potentially improve future fertility outcomes in HH patients. Our results identify an opportunity to improve current practice among pediatric endocrinologists worldwide and reduce barriers to prescribing gonadotropins in the adolescent population.

Type 1 Doing Well: Pilot Feasibility and Acceptability Study of a Strengths-Based mHealth App for Parents of Adolescents with Type 1 Diabetes.

Background: We evaluated the feasibility and acceptability of a pilot behavioral intervention delivered to parents of adolescents with type 1 diabetes (T1D) via mobile-friendly web app. The Type 1 Doing Well app aimed to promote supportive family diabetes management by helping parents recognize and reinforce teens' positive diabetes-related behaviors ("strengths"). Methods: Parents (n = 80, 74% recruitment) of adolescents (age range = 12-17 years, M = 15.3 ± 1.5 years, 59% female, 56% insulin pump, M hemoglobin A1c (HbA1c) = 9.0% ± 2.1%) were randomized 2:1 to intervention or control (i.e., usual medical care with or without app) for 3-4 months between diabetes appointments. The app prompted parents daily to track adolescents' strengths and generated weekly summaries of their teen's top strengths. Parents could access a library of text messages to praise their teens. Exploratory pre/post data included questionnaires (98% completed) and HbA1c. Results: Parents used the app for M = 106.1 ± 37.1 days, logging in ≥once/day on 80% of days. Ninety-one percent of parents used the app ≥2 days/week on average. Parents viewed M = 5.6 ± 4.7 weekly summaries and "favorited" 15 praise texts in the library. App acceptability ratings (7-point scale) were high: Satisfaction 5.0 ± 1.5, Usefulness 4.8 ± 1.5, Ease of Use 6.2 ± 0.8, and Ease of Learning 6.5 ± 0.8. Parents (n = 48) and adolescents (n = 47) gave positive feedback and suggestions via qualitative interviews. There were no significant between-group differences for change in exploratory outcomes (HbA1c, questionnaires). Conclusions: Type 1 Doing Well was feasible to deliver and highly acceptable and engaging for parents of adolescents with T1D. It may have a larger impact on behavioral or clinical outcomes as part of a multicomponent intervention protocol. Trial Registration: ClinicalTrials.gov NCT02877680.

X-linked hypophosphatemic rickets associated with respiratory failure.

We report a 5-year-old girl who presented to our emergency room with respiratory arrest and limb deformities and was subsequently diagnosed with X-linked hypophosphatemic rickets. On normalization of the serum phosphorus concentration, her respiratory distress resolved, illustrating that untreated X-linked hypophosphatemic rickets can lead to life-threatening respiratory distress.

Strengths-Based Behavioral Intervention for Parents of Adolescents With Type 1 Diabetes Using an mHealth App (Type 1 Doing Well): Protocol for a Pilot Randomized Controlled Trial.

BACKGROUND: Supportive parent involvement for adolescents' type 1 diabetes (T1D) self-management promotes optimal diabetes outcomes. However, family conflict is common and can interfere with collaborative family teamwork. Few interventions have used explicitly strengths-based approaches to help reinforce desired management behaviors and promote positive family interactions around diabetes care. OBJECTIVE: The aim of this protocol was to describe the development of a new, strengths-based behavioral intervention for parents of adolescents with T1D delivered via a mobile-friendly Web app called Type 1 Doing Well. METHODS: Ten adolescent-parent dyads and 5 diabetes care providers participated in a series of qualitative interviews to inform the design of the app. The 3- to 4-month pilot intervention will involve 82 parents receiving daily prompts to use the app, in which they will mark the diabetes-related strength behaviors (ie, positive attitudes or behaviors related to living with or managing T1D) their teen engaged in that day. Parents will also receive training on how to observe diabetes strengths and how to offer teen-friendly praise via the app. Each week, the app will generate a summary of the teen's most frequent strengths from the previous week based on parent reports, and parents will be encouraged to praise their teen either in person or from a library of reinforcing text messages (short message service, SMS). RESULTS: The major outcomes of this pilot study will include intervention feasibility and satisfaction data. Clinical and behavioral outcomes will include glycemic control, regimen adherence, family relationships and conflict, diabetes burden, and health-related quality of life. CONCLUSIONS: This strengths-based, mobile health (mHealth) intervention aims to help parents increase their awareness of and efforts to support their adolescents' engagement in positive diabetes-related behaviors. If efficacious, this intervention has the potential to reduce the risk of family conflict, enhance collaborative family teamwork, and ultimately improve diabetes outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02877680; https://clinicaltrials.gov/ct2/show/NCT02877680 (Archived by WebCite at http://www.webcitation.org/6xTAMN5k2).

Rapid resolution of consumptive hypothyroidism in a child with hepatic hemangioendothelioma following liver transplantation.

We report a unique case of a 3-mo-old female with consumptive hypothyroidism and liver hemangioendothelioma who required pharmacological doses of thyroid hormones and was cured following liver transplantation. Liver hemangioendotheliomas are capable of producing an excess of the thyroid hormone inactivating enzyme, type-3 iodothyronine deiodinase. The increased tumoral enzyme activity leads to rapid degradation of thyroid hormones, resulting in consumptive hypothyroidism. Review of similar cases indicated variable outcomes. We focus on our patient's clinical course and describe in detail the thyroid hormone replacement therapy and a unique outcome of this rare type of hypothyroidism. This first example of a prompt and complete resolution of consumptive hypothyroidism in an infant after liver transplantation confirms the concept and the reversibility of consumptive hypothyroidism and provides novel insights into the rapidity of response of the infant's hypothalamic-pituitary-thyroid axis to thyroid hormone replacement.

Osteopenic effects of MgSO4 in multiple pregnancies.

OBJECTIVE: To describe the effects of prolonged maternal treatment with MgSO4 in infants who were products of multiple pregnancies. STUDY DESIGN: Case series of infants presenting with osteopenia secondary to MgSO4 administration for preterm labor. RESULTS: Ten premature infants with hypermagnesemia (4.5+/-0.2 mg/dl), hypocalcemia (6.0 +/-0.3 mg/dl), and high serum alkaline phosphatase (574+/-96 U/l) underwent imaging studies that showed diffuse osteopenia of the long bones and probable rib fractures. All mothers had isolated premature labor, for which they were given MgSO4; (average dose 3.66+/-0.08 kg/ pregnancy over 10.0+/-0.5 weeks). On follow-up (to 9 months), all infants had complete or near complete resolution of the osteopenia. CONCLUSIONS: Premature infants who are exposed to large doses of MgSO4, especially those of multiple pregnancies, have an increased risk of developing hypocalcemia, osteopenia, and fractures. Our findings indicate that these infants should be identified at birth and managed prospectively.