Whole exome sequencing and functional characterization increase diagnostic yield in siblings with a 46, XY difference of sexual development (DSD).

Pathogenic biallelic variants in HSD17B3 result in 17ß-hydroxysteroid dehydrogenase 3 (17ß-HSD3) deficiency, variable disruption of testosterone production, and phenotypic diversity among 46, XY individuals with differences of sexual development (DSDs). We performed quad whole exome sequencing (WES) on two male siblings with microphallus, perineal hypospadias, and bifid scrotum and their unaffected parents. Both male siblings were compound heterozygous for a rare pathogenic HSD17B3 variant (c.239 G > A, p.R80Q) previously identified among individuals with 17ß-HSD3 deficiency and a HSD17B3 variant (c.641A > G, p.E214 G) of uncertain significance. Following WES, the siblings underwent hCG stimulation testing with measurement of testosterone, androstenedione, and dihydrotestosterone which was non-diagnostic. To confirm pathogenicity of the HSD17B3 variants, we performed transient transfection of HEK-293 cells and measured conversion of radiolabeled androstenedione to testosterone. Both HSD17B3 variants decreased conversion of radiolabeled androstenedione to testosterone. As pathogenic HSD17B3 variants are rare causes of 46, XY DSD and hCG stimulation testing may not be diagnostic for 17ß-HSD3 deficiency, WES in 46, XY individuals with DSDs can increase diagnostic yield and identify genomic variants for functional characterization of disruption of testosterone production.

The Role of Patient Advocacy and the Declining Rate of Clitoroplasty in 46,XX Patients With Congenital Adrenal Hyperplasia.

Prior to the 1990s, most 46,XX infants with clitoromegaly secondary to congenital adrenal hyperplasia were treated with feminizing genitoplasty to make their cosmetic appearance congruent with their genotypic sex. A 2006 consensus statement for the management of intersex disorders accepted input from patient advocates and did not support purely cosmetic surgery for clitoromegaly. This study examined the extent to which the desired change was implemented in practice. Retrospective chart review was performed at a single Midwestern tertiary care medical center for patients born between 1979 and 2013. Of 45 virilized patients, 40 had clitoromegaly and 39 had urogenital sinus or posterior labial fusion. Twenty-seven (67.5%) patients underwent clitoroplasty and 33 (84.6%) underwent perineoplasty, including vaginoplasty, urethroplasty, imperforate vagina repair, and/or posterior labial fusion repair. There was a linear decline in the rate of clitoroplasty over time for the patient cohort. This study demonstrates the power of patient advocacy to improve medical practice.

Height Growth Impairment in Children With Neurofibromatosis Type 1 Is Characterized by Decreased Pubertal Growth Velocity in Both Sexes.

Previous studies have suggested that children with neurofibromatosis type 1 are shorter than their unaffected counterparts as an effect of a germline NF1 gene mutation. The pathophysiology of this effect is still uncertain. The purpose of this study was to characterize longitudinal growth in children with neurofibromatosis type 1 in order to assess growth velocity and its influence on stature. Longitudinal height data were collected for 188 patients with a confirmed clinical diagnosis of neurofibromatosis type 1. Children with neurofibromatosis type 1 had population mean heights statistically different from the general population, with a reduced peak height velocity during pubertal growth. In addition, there were no significant differences in the timing of peak height velocity during puberty between the general population and those with neurofibromatosis type 1. These data demonstrate that short stature in neurofibromatosis type 1 is due in part to subnormal height acquisition during puberty.

Gnathodiaphyseal dysplasia: Severe atypical presentation with novel heterozygous mutation of the anoctamin gene (ANO5).

Gnathodiaphyseal dysplasia (GDD; OMIM #166260) is an ultra-rare autosomal dominant disorder caused by heterozygous mutation in the anoctamin 5 (ANO5) gene and features fibro-osseous lesions of the jawbones, bone fragility with recurrent fractures, and bowing/sclerosis of tubular bones. The physiologic role of ANO5 is unknown. We report a 5-year-old boy with a seemingly atypical and especially severe presentation of GDD and unique ANO5 mutation. Severe osteopenia was associated with prenatal femoral fractures, recurrent postnatal fractures, and progressive bilateral enlargement of his maxilla and mandible beginning at ~2months-of-age that interfered with feeding and speech and required four debulking operations. Histopathological analysis revealed benign fibro-osseous lesions resembling cemento-ossifying fibromas of the jaw without psammomatoid bodies. A novel, de novo, heterozygous, missense mutation was identified in exon 15 of ANO5 (c.1553G>A; p.Gly518Glu). Our findings broaden the phenotypic and molecular spectra of GDD. Fractures early in life with progressive facial swelling are key features. We assessed his response to a total of 7 pamidronate infusions commencing at age 15months. Additional reports must further elucidate the phenotype, explore any genotype-phenotype correlation, and evaluate treatments.

Risk association of congenital anomalies in patients with ambiguous genitalia: A 22-year single-center experience.

BACKGROUND: Ambiguous genitalia refers to a form of differences of sex development (DSD) wherein the appearance of the external genitalia is atypical. This rare condition presents challenges in decision-making and clinical management. Review of historical data may reveal areas for clinical research to improve care for patients with ambiguous genitalia. OBJECTIVE: This chart review was performed to identify patients with ambiguous genitalia, and to classify them as having 46,XX DSD, 46,XY DSD, or sex chromosome DSD. Within these categories, we looked at establishment of specific diagnoses, type and frequency of other congenital anomalies and neoplasms, and gender assignment, as well as incidence of gender reassignment and transition. METHODS: We performed a retrospective chart review of patients diagnosed with DSD conditions from 1995 to 2016 using ICD9 codes. For the purpose of this study, review was limited to individuals assessed to have neonatal "ambiguous genitalia" or "indeterminate sex." RESULTS: Review identified 128 patients evaluated for ambiguous genitalia from 22 years of experience (Figure). Approximately half of these (53%) had 46,XY karyotype, 35% had 46,XX, and the remaining 12% had sex chromosome aberrations. Diagnostic rate for 46,XX DSD was higher at 64%, all of which were congenital adrenal hyperplasia, while diagnostic rate for 46,XY DSD was 11.7% for a molecularly confirmed diagnosis and 24% if clinical diagnoses were included. The most common anomalies included cardiac anomalies in 28/128 (22%), skeletal anomalies in 19/128 (15%), and failure to thrive or growth problems in 19/128 (15%). Additional congenital anomalies were found in 53 out of 128 patients (41%). There were three reported neoplasms in this group: gonadoblastoma, hepatoblastoma, and myelodysplastic syndrome with monosomy 7. Gender assignment was consistent with chromosomes in approximately 90% of XX and XY patients. There were three recorded gender reassignments or transitions. DISCUSSION: Diagnostic rate for ambiguous genitalia is low, especially in 46,XY DSD. Most neonates were assigned gender consistent with their chromosomes. Given the high rate of associated anomalies, screening for cardiac or other anomalies in patients with ambiguous genitalia may be beneficial. CONCLUSION: Patients with ambiguous genitalia often have additional congenital anomalies. Establishment of a specific diagnosis is uncommon in 46,XY patients. A few patients have gender reassignment outside of the newborn period. Ongoing collection of clinical data on this population may reveal new information regarding long-term health, quality of life, and establishment of more diagnoses with improved molecular techniques.

Moyamoya syndrome causing stroke in young women with type 1 diabetes.

CONTEXT: Moyamoya syndrome is an idiopathic brain vasculopathy characterized by stenosis of major intracranial arteries. It often presents in patients with type 1 diabetes or thyroid disease and may have an autoimmune etiology. Moyamoya-related stroke poses a diagnostic challenge as initial symptoms and deficits vary greatly from classic ischemic stroke to encephalopathy, psychiatric, or seizure disorder. CASE DESCRIPTION: We report 4 patients with type 1 diabetes and other autoimmune diseases who developed moyamoya-related stroke at a young age. Despite having long-term diabetes, these patients exhibited no evidence of dyslipidemia or other typical risk factors for atherosclerosis which might contribute to premature stroke. Three of the four patients underwent revascularization surgery while one patient received conservative management. All patients had improved neurologic function after treatment, some with residual deficits. CONCLUSION: We highlight the importance of recognizing moyamoya syndrome in patients with pre-existing autoimmune diseases such as type 1 diabetes, as prompt diagnosis and treatment can have major impact on patient outcome and quality of life.

Integrated small copy number variations and epigenome maps of disorders of sex development.

Small copy number variations (CNVs) have typically not been analyzed or reported in clinical settings and hence have remained underrepresented in databases and the literature. Here, we focused our investigations on these small CNVs using chromosome microarray analysis (CMA) data previously obtained from patients with atypical characteristics or disorders of sex development (DSD). Using our customized CMA track targeting 334 genes involved in the development of urogenital and reproductive structures and a less stringent analysis filter, we uncovered small genes with recurrent and overlapping CNVs as small as 1 kb, and small regions of homozygosity (ROHs), imprinting and position effects. Detailed analysis of these high-resolution data revealed CNVs and ROHs involving structural and functional domains, repeat elements, active transcription sites and regulatory regions. Integration of these genomic data with DNA methylation, histone modification and predicted RNA expression profiles in normal testes and ovaries suggested spatiotemporal and tissue-specific gene regulation. This study emphasized a DSD-specific and gene-targeted CMA approach that uncovered previously unanalyzed or unreported small genes and CNVs, contributing to the growing resources on small CNVs and facilitating the narrowing of the genomic gap for identifying candidate genes or regions. This high-resolution analysis tool could improve the diagnostic utility of CMA, not only in patients with DSD but also in other clinical populations. These integrated data provided a better genomic-epigenomic landscape of DSD and greater opportunities for downstream research.

Cost effectiveness of proton versus photon radiation therapy with respect to the risk of growth hormone deficiency in children.

BACKGROUND: Proton therapy in pediatrics may improve the risk/benefit profile of radiotherapy at a greater upfront financial cost, but it may prove to be cost effective if chronic medical complications can be avoided. Tools to assist with decision making are needed to aid in selecting pediatric patients for protons, and cost-effectiveness models can provide an objective method for this. METHODS: A Markov cohort-simulation model was developed to assess the expected costs and effectiveness for specific radiation doses to the hypothalamus with protons versus photons in pediatric patients. Costing data included cost of investment and the diagnosis and management of growth hormone deficiency. Longitudinal outcomes data were used to inform risk parameters for the model. With costs in 2012 US dollars and effectiveness measured in quality-adjusted life years, incremental cost-effectiveness ratios were used to measure outcomes. RESULTS: Proton therapy was cost effective for some scenarios based on the difference in hypothalamic sparing. Although some scenarios were not cost effective, others were not only cost effective for proton therapy but also demonstrated that protons were cost saving compared with photons. CONCLUSIONS: The current results provide the first evidence-based guide for identifying children with brain tumors who may benefit the most from proton therapy with respect to endocrine dysfunction. Proton therapy may be more cost effective for scenarios in which radiation dose to the hypothalamus can be spared, but protons may not be cost effective when tumors are involving or directly adjacent to the hypothalamus if there is a high dose to this structure.

Cost effectiveness of proton therapy compared with photon therapy in the management of pediatric medulloblastoma.

BACKGROUND: Proton therapy has been a hotly contested issue in both scientific publications and lay media. Proponents cite the modality's ability to spare healthy tissue, but critics claim the benefit gained from its use does not validate its cost compared with photon therapy. The objective of this study was to evaluate the cost effectiveness of proton therapy versus photon therapy in the management of pediatric medulloblastoma. METHODS: A cost-effective analysis was performed from the societal perspective using a Monte Carlo simulation model. A population of pediatric medulloblastoma survivors aged 18 years was studied who had received treatment at age 5 years and who were at risk of developing 10 adverse events, such as growth hormone deficiency, coronary artery disease, ototoxicity, secondary malignant neoplasm, and death. Costing data included the cost of investment and the costs of diagnosis and management of adverse health states from institutional and Medicare data. Longitudinal outcomes data and recent modeling studies informed risk parameters for the model. Incremental cost-effectiveness ratios were used to measure outcomes. RESULTS: Results from the base case demonstrated that proton therapy was associated with higher quality-adjusted life years and lower costs; therefore, it dominated photon therapy. In 1-way sensitivity analyses, proton therapy remained the more attractive strategy, either dominating photon therapy or having a very low cost per quality-adjust life year gained. Probabilistic sensitivity analysis illustrated the domination of proton therapy over photon therapy in 96.4% of simulations. CONCLUSIONS: By using current risk estimates and data on required capital investments, the current study indicated that proton therapy is a cost-effective strategy for the management of pediatric patients with medulloblastoma compared with standard of care photon therapy.

Height assessments in children with neurofibromatosis type 1.

Previous studies have suggested that children with neurofibromatosis type 1 (NF1) are shorter than their unaffected counterparts. Unfortunately, these reports did not consider other contributing factors that might also influence short stature. The purpose of the current study was to characterize the genetic influence of NF1 on the growth of children. Height data were measured and recorded for 170 patients, whereas parental measurements were obtained for 61 patients to calculate sex-corrected mid-parental target heights. Children with NF1 had population mean height and mid-parental height z scores statistically different from the general population. Importantly, these differences were pronounced when neither parent had NF1 but were not significant when one of the parents had NF1. Moreover, height z scores for children with NF1 were also statistically different than their unaffected siblings. Collectively, these data establish a clear effect of a germline NF1 gene mutation on stature in children with NF1.

Radiation therapy for pilocytic astrocytomas of childhood.

PURPOSE: Though radiation therapy is generally considered the most effective treatment for unresectable pilocytic astrocytomas in children, there are few data to support this claim. To examine the efficacy of radiation therapy for pediatric pilocytic astrocytomas, we retrospectively reviewed the experience at our institution. METHODS AND MATERIALS: Thirty-five patients 18 years old or younger with unresectable tumors and without evidence of neurofibromatosis have been treated since 1982. Patients were treated with local radiation fields to a median dose of 54 Gy. Six patients were treated with radiosurgery to a median dose of 15.5 Gy. Five patients were treated with initial chemotherapy and irradiated after progression. RESULTS: All patients were alive after a median follow-up of 5.0 years. However, progression-free survival was 68.7%. None of 11 infratentorial tumors progressed compared with 6 of 20 supratentorial tumors. A trend toward improved progression-free survival was seen with radiosurgery (80%) compared with external beam alone (66%), but this difference did not reach statistical significance. Eight of the 9 patients progressing after therapy did so within the irradiated volume. CONCLUSIONS: Although the survival of these children is excellent, almost one third of patients have progressive disease after definitive radiotherapy. Improvements in tumor control are needed in this patient population, and the optimal therapy has not been fully defined. Prospective trials comparing initial chemotherapy to radiation therapy are warranted.

Detection of surreptitious administration of analog insulin to an 8-week-old infant.

An 8-week-old infant presented to the emergency department with lethargy, tachycardia, and a blood glucose concentration of 1.8 mmol/L. After admission, hypoglycemia recurred on 3 additional occasions. Initial urinalysis results were negative for ketones, and the results of additional laboratory tests did not support the diagnosis of cortisol or growth hormone deficiency, oral hypoglycemic ingestion, or an inborn error of metabolism. Difficulty restoring and maintaining glucose concentrations along with a transient response to glucagon during 1 hypoglycemic episode suggested hyperinsulinism. In 1 hypoglycemic episode, elevated insulin and low C-peptide concentrations suggested exogenous insulin administration, but 2 subsequent blood samples obtained during hypoglycemia contained appropriately decreased concentrations of insulin. The insulin immunoassay initially used in this case (Roche ElecSys/cobas [Roche Diagnostics, Indianapolis, IN]) was insensitive to insulin analogs. Two additional immunoassays, 1 with intermediate (Immulite [Siemens, Deerfield, IL]) and 1 with broad (radioimmunoassay [Millipore, Inc, Billerica, MA]) reactivity to insulin analogs were used to characterize insulin in each of the critical blood samples. Samples obtained during hypoglycemia displayed a graded reactivity similar to that observed in type 1 diabetic patients prescribed insulin analogs, whereas a sample obtained from the patient and a control subject during euglycemia showed equal reactivity among the 3 assays. These data suggested administration of insulin analog to the child, and further characterization of insulin by using tandem mass spectrometry confirmed the presence of Humalog. The child was subsequently placed in foster care with no further recurrence of hypoglycemia.

Long-term outcome in children treated for craniopharyngioma with and without radiotherapy.

OBJECT: The authors report the results of surgery alone or in combination with radiotherapy in the management of craniopharyngiomas in children. METHODS: The authors retrospectively reviewed the outcomes in 31 patients treated for craniopharyngiomas at the Department of Radiation Oncology at Washington University in St. Louis and the St. Louis Children's Hospital. The median age at diagnosis was 8.1 years (range 1.1-21 years). Fourteen patients underwent gross-total resection (GTR) with observation, and 6 patients underwent subtotal resection (STR) with observation. Ten patients underwent STR or cyst aspiration followed by external-beam radiotherapy, and 1 patient underwent cyst aspiration followed by intracystic 32P installation. RESULTS: The median follow-up for all surviving patients was 78.2 months. Overall survival and local control rates at 10 years were 96 and 58%, respectively. One patient died of the disease, and 12 patients had subsequent recurrences. Of those with recurrences, 6 patients had undergone initial STR with observation and 6 had been treated with GTR and observation. The median time to progression was 17.9 months in the patients who underwent limited resection, and 55 months for those who underwent GTR. There were no recurrences in the patients who received radiotherapy at the time of initial diagnosis. CONCLUSIONS: Radiotherapy delivered as part of the initial management of craniopharyngiomas in children or at the time of recurrence provides effective local control.

Fatal malignant hyperthermia-like syndrome with rhabdomyolysis complicating the presentation of diabetes mellitus in adolescent males.

OBJECTIVE: This report describes a new fatal syndrome observed in adolescent males at the initial presentation of diabetes mellitus. The features include hyperglycemic hyperosmolar coma complicated by a malignant hyperthermia-like picture with fever, rhabdomyolysis, and severe cardiovascular instability. DESIGN: Case series. SETTING: Pediatric intensive care units of 3 tertiary care facilities in the United States. PATIENTS: Six adolescent males, 5/6 obese with acanthosis nigricans, 4/6 black. RESULTS: Four of 6 patients died. Four of 6 patients did not have significant ketosis. Six of 6 patients had increased temperature after the administration of insulin. CONCLUSIONS: The underlying etiology of this syndrome remains unclear. Possibilities include an underlying metabolic disorder such as a fatty acid oxidation defect, an unrecognized infection, exposure to an unknown toxin, or a genetic predisposition to malignant hyperthermia. Evaluation for all these possibilities and empiric treatment with dantrolene should be considered for this type of patient until this syndrome is better characterized.