Parent Perspectives of School/Daycare Experiences in Young Children Newly Diagnosed With Diabetes.

OBJECTIVE: A central part of family adjustment to a new diagnosis of type 1 diabetes (T1D) is integrating T1D management into the child's school/daycare. This may be particularly challenging for young children who rely on adults for their diabetes management. This study aimed to describe parent experiences with school/daycare during the first 1.5 years following a young child's T1D diagnosis. METHODS: As part of a randomized controlled trial of a behavioral intervention, 157 parents of young children with new-onset (<2 months) T1D reported on their child's school/daycare experience at baseline and at 9- and 15-month post-randomization. We used a mixed-methods design to describe and contextualize parents' experiences with school/daycare. Qualitative data were collected via open-ended responses, and quantitative data were collected from a demographic/medical from. RESULTS: While most children were enrolled in school/daycare at all time points, over 50% of parents endorsed that T1D affected their child's enrollment, rejection, or removal from school/daycare at 9 or 15 months. We generated five themes related to parents' school/daycare experiences: Child factors, Parent factors, School/Daycare factors, Cooperation between Parents and Staff, and Socio-historical factors. Parents of younger children and those with lower subjective socioeconomic status were significantly more likely to endorse challenges with school/daycare enrollment. CONCLUSIONS: School/daycare settings present challenges for parents of young children with T1D. Changes may need to occur across contexts to support early childhood education, including advocacy resources for parents to navigate school policies, increased training for school staff, and healthcare team outreach initiatives to parents and schools.

Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes.

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

Up all night? Sleep disruption in parents of young children newly diagnosed with type 1 diabetes.

BACKGROUND: Despite the known challenges of parental adjustment to new-onset type 1 diabetes (T1D) in young children, little is known about parental sleep soon after diagnosis. METHODS: Parents (n = 157) of young children (4.5 ± 1.6 years) with new-onset T1D (29 ± 15 days) self-reported their sleep (Pittsburgh Sleep Quality Index, PSQI) at the baseline of a behavioral randomized control trial. We examined sleep patterns and relations with continuous glucose monitor (CGM) use. RESULTS: Over two-thirds (68.8%) reported poor sleep quality (PSQI > 5, M = 8.3 ± 4.1). The mean reported sleep duration was 5.9 ± 1.4 h/night. PSQI scores did not significantly differ by CGM use. CONCLUSIONS: Sleep disruption is a pervasive self-reported problem among parents of young children emerging early after the T1D diagnosis. Healthcare providers should discuss parental sleep as part of diabetes care soon after diagnosis. Further interventions targeting parental sleep may be of benefit.

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.

Sudden infant death with dysgenesis of the testes syndrome in a non-Amish infant: A case report.

Sudden Infant Death with Dysgenesis of the Testes syndrome (SIDDT) is a very rare condition associated with biallelic pathogenic variants in the TSPYL1 gene first reported in 2004. It is characterized by sudden cardiac or respiratory arrest, disordered testicular development, neurologic dysfunction, and is uniformly fatal before the age of 12 months. There were previously 21 reported cases of SIDDT in the literature, all from nine Old Order Amish families published in a single paper. In this report, we describe a non-Amish, phenotypically female infant with poor feeding and abnormal motor movements noted at birth. Initial testing showed that she had a 46,XY chromosome complement, and chromosomal microarray showed a significant absence of heterozygosity (AOH) totalling roughly 600 Mb across multiple different chromosomes, indicating consanguinity. Further workup with exome sequencing revealed homozygosity for a frameshift variant in TSPYL1 (c.725_726delTG, p.Val242GlufsTer52) consistent with a diagnosis of SIDDT, explaining many of her clinical features. However, she was also noted to have a mild T-cell lymphopenia and developed intractable epilepsy after hospital discharge. These features have not previously been reported in SIDDT and may represent phenotypic expansion. To our knowledge, this patient is the 22nd case of SIDDT to be reported in the literature, and the first to be of non-Amish heritage.

Review of the phenotypic spectrum associated with haploinsufficiency of MYRF.

The myelin regulatory factor gene (MYRF) encodes a transcription factor that is widely expressed. There is increasing evidence that heterozygous loss-of-function variants in MYRF can lead to abnormal development of the heart, genitourinary tract, diaphragm, and lungs. Here, we searched a clinical database containing the results of 12,000 exome sequencing studies. We identified three previously unreported males with putatively deleterious variants in MYRF: one with a point mutation predicted to affect splicing and two with frameshift variants. In all cases where parental DNA was available, these variants were found to have arisen de novo. The phenotypes identified in these subjects included a variety of congenital heart defects (CHD) (hypoplastic left heart syndrome, scimitar syndrome, septal defects, and valvular anomalies), genitourinary anomalies (ambiguous genitalia, hypospadias, and cryptorchidism), congenital diaphragmatic hernia, and pulmonary hypoplasia. The phenotypes seen in our subjects overlap those described in individuals diagnosed with PAGOD syndrome [MIM# 202660], a clinically defined syndrome characterized by pulmonary artery and lung hypoplasia, agonadism, omphalocele, and diaphragmatic defects that can also be associated with hypoplastic left heart and scimitar syndrome. These cases provide additional evidence that haploinsufficiency of MYRF causes a genetic syndrome whose cardinal features include CHD, urogenital anomalies, congenital diaphragmatic hernia, and pulmonary hypoplasia. We also conclude that consideration should be given to screening individuals with PAGOD for pathogenic variants in MYRF, and that individuals with MYRF deficiency who survive the neonatal period should be monitored closely for developmental delay and intellectual disability.

A Multicenter Retrospective Review of Pediatric Leydig Cell Tumor of the Testis.

Leydig cell tumors (LCTs) are rare tumors arising from testosterone-producing Leydig cells. Although LCTs are usually benign, malignancy has been reported in 10% of cases in adults, and local recurrence or metachronous tumors of the contralateral testis have been described. Radical orchiectomy is the current standard of care. We report on 12 children with LCT at 3 institutions between 2000 and 2016. Presenting symptoms included precocious puberty, palpable testicular mass, and scrotal swelling. Radical orchiectomy was performed in 9 patients. Three patients were treated with enucleation. All patients were alive at last follow-up without evidence of local recurrence or metastasis.

Hormones and their Structural and Functional Effects on the Brain: How Can We Change our Practice Moving Forward?

Is hormone treatment an invasive procedure? In this paper, we discuss aspects related to the choice of treating disorders of sex development (DSD) using hormones. Specifically, we focus on some of the challenging issues related to this treatment and the need to establish a standard of care for the use of hormone therapy in this patient population. The objectives of this paper are to: 1) Enhance understanding of the uncertainties in the decision-making process regarding hormonal interventions to treat patients with DSD. 2) Recognize that the effects of hormonal interventions might require a consent process similar to that applied for surgical procedures. 3) Emphasize the need to establish treatment algorithms that could form the basis of a standard of care for this patient population.

Selective Serotonin Reuptake Inhibitors Reduce Longitudinal Growth in Risperidone-Treated Boys.

OBJECTIVES: To examine whether selective serotonin reuptake inhibitors (SSRIs) inhibit longitudinal growth in children and adolescents, particularly in the early stages of puberty, using a sample of convenience comprising risperidone-treated boys. STUDY DESIGN: Data from four clinic-based studies in risperidone-treated 5- to 17-year-old boys with no general medical conditions were combined for this analysis. Anthropometric measurements and psychotropic treatment history were extracted from the medical and pharmacy records. Linear mixed effects regression analyses examined the association between SSRI use and change in age-sex-specific height and body mass index z scores, after adjusting for relevant confounders. RESULTS: Risperidone-treated boys (n = 267; age: 12.7 ± 2.7 years), 71% of whom had ever taken an SSRI, contributed to the analysis. After adjusting for age, psychostimulant and antipsychotic use, and time in the study, both the duration of SSRI use as well as the cumulative dose were inversely associated with height z score after age 11 years (P < .0001). After adjusting for baseline height, duration of SSRI use was most strongly inversely associated with height z score in Tanner stages 3 and 4 boys who took SSRIs continuously (r = -0.69, P < .009). No association was observed with body mass index z score. CONCLUSIONS: In risperidone-treated boys, SSRI use is associated with reduced longitudinal growth, particularly in those undergoing puberty. Whether adult height or other metabolic or psychological outcomes are affected remains to be determined.

Challenges in Prenatal Treatment with Dexamethasone.

Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency causes elevated androgen levels, which can lead to virilization of female external genitalia. Prenatal dexamethasone treatment has been shown to be effective in preventing virilization of external genitalia when started prior to 7-9 weeks of gestation in females with classic CAH. However, CAH cannot be diagnosed prenatally until the end of the first trimester. Treating pregnant women with a fetus at risk of developing classic CAH exposes a significant proportion of fetuses unnecessarily, because only 1 in 8 would benefit from treatment. Consequently, prenatal dexamethasone treatment has been met with much controversy due to the potential adverse outcomes when exposed to high-dose steroids in utero. Here, we review the short- and long-term outcomes for fetuses and pregnant women exposed to dexamethasone treatment, the ethical considerations that must be taken into account, and current practice recommendations.

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.

Nonclassical congenital adrenal hyperplasia: targets of treatment and transition.

Nonclassical congenital adrenal hyperplasia (NCCAH) caused by 21-hydroxylase deficiency is a common autosomal recessive condition that can present with a wide range of hyperandrogenemic signs in childhood or adulthood. The management of children with NCCAH can be challenging, as no universally accepted guidelines have been established. Our goal was to evaluate the literature and develop an evidence-based guideline for the medical management of children and adolescents with NCCAH. We reviewed the published literature and used the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system when appropriate to grade the evidence and provide recommendations for the medical management of children and adolescents with NCCAH, appropriate transition practices from pediatric to adult endocrine care, and psychological issues that should be addressed in parents and patients with NCCAH. We offer recommendations, based on the available evidence, for the management of NCCAH at the different developmental stages from diagnosis through transition to adulthood.

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.