Cardiovascular Manifestations of Turner Syndrome: Phenotypic Differences Between Karyotype Subtypes.

Turner syndrome (TS) is a genetic disorder presenting in phenotypic females with total or partial monosomy of the X chromosome. Cardiovascular abnormalities are common, including congenital heart defects (CHD) and aortic dilation. Although mosaic TS is suspected to have less severe phenotype as compared to non-mosaic TS, differences in cardiovascular manifestations between karyotypes are not well studied. This is a single-center retrospective cohort study including patients with TS seen from 2000 to 2022. Demographic data, chromosomal analysis, and imaging were reviewed. Karyotypes were categorized as monosomy X (45X), 45X mosaicism, isochromosome Xq, partial X deletions, ring X (r(X)), TS with Y material, and others. Prevalence of CHD and aortic dilation were compared between monosomy X and other subtypes using Pearson's chi-square test and Welch two-sample t-test. We included 182 TS patients with median age 18 (range 4-33) years. CHD was more common in monosomy X as compared with others (61.4% vs. 26.8%, p < 0.001), including bicuspid aortic valve (44.3% vs. 16.1%, p < 0.001), partial anomalous pulmonary venous return (12.9% vs. 2.7%, p = 0.023), persistent left superior vena cava (12.9% vs. 1.8%, p = 0.008), and coarctation of the aorta (20.0% vs. 4.5%, p = 0.003). Cardiac surgery (24.3% vs. 8.9%, p = 0.017) was more prevalent in the monosomy X group. There was no statistically significant difference for presence of aortic dilation (7.1% vs 1.8%, p = 0.187). Although CHD and need for cardiac surgery are more common in TS with monosomy X as compared to others, all TS subtypes may have similar risk of developing aortic dilation. All TS patients should have similar cardiovascular surveillance testing to monitor for aortic dilation.

Scoliosis and Kyphosis Prevalence in Turner Syndrome: A Retrospective Review at a Pediatric Tertiary Care Medical Center.

BACKGROUND: The prevalence of major coronal and sagittal spinal curves (scoliosis and kyphosis) in Turner syndrome (TS) is not well established due to limited reporting. The relationship between growth hormone (GH) therapy and its effect on TS spinal curve incidence is also not well established. METHODS: A retrospective chart review of 306 TS patients from 2007 to 2021 evaluated major coronal and sagittal spinal curves, progression of the curve, and treatment with GH. Statistical significance (defined as P <0.05) between curvature rates and curve progression was compared between GH-treated patients and non-GH-treated patients using a χ 2 or Fisher exact test when appropriate. RESULTS: Thirty-seven of 306 (12%) TS patients had a radiographically relevant spinal deformity. Twenty-seven of 37 (73%) had mild; 4 of 37 (11%) had moderate, and 6 of 37 (16%) had severe curves. Of those with severe, 4 underwent spinal fusion, 1 was treated with bracing, and 1 was braced before a cardiovascular-related death. Regarding GH use among TS patients, 190 of 306 (62%) used GH versus 116 of 306 (38%) who did not. Of those with a spinal curve, 24 of 37 (65%) used GH compared with 13 of 37 (35%) who did not. On univariate analysis, GH therapy was not a risk factor for the diagnosis of a major spinal curve, a more severe degree of the curve at the time of diagnosis, or spinal curve progression ( P >0.05 for all). CONCLUSIONS: This is the largest single institution retrospective review of a TS cohort known to the authors assessing spinal curve prevalence and relation to GH treatment and demonstrates a TS spinal curve rate of 12% (37/306). Four of six (11%) TS patients with a severe curve underwent corrective spine fusion. There was no relationship between the use of GH and the presence of a spinal curve or curve progression. Further study is warranted to determine risk factors for curve progression. LEVEL OF EVIDENCE: Level III. CLINICAL RELEVANCE: This retrospective case series serves to review and address the prevalence of spinal deformity in TS patients and whether GH impacts worsening deformity.

A Novel Form of Familial Vasopressin Deficient Diabetes Insipidus Transmitted in an X-linked Recessive Manner.

CONTEXT: Familial pituitary diabetes insipidus has been described only in an autosomal dominant or recessive mode of inheritance. OBJECTIVE: This work aims to determine the cause of a novel form of familial diabetes insipidus (DI) that is controlled by desmopressin therapy but segregates in an X-linked recessive manner. METHODS: Thirteen members from 3 generations of the kindred with familial DI were studied. Water intake, urine volume, urine osmolality, plasma osmolality, and plasma vasopressin were measured under basal conditions, during fluid deprivation, 3% saline infusion, and water loading. Magnetic resonance images of the posterior pituitary also were obtained. In affected males, the effects of desmopressin therapy and linkage of the DI to markers for chromosome Xq28 were determined. In addition, the genes encoding vasopressin, aquaporin-2, the AVPR2 receptor, and its flanking regions were sequenced. RESULTS: This study showed that 4 males from 3 generations of the kindred have DI that is due to a deficiency of vasopressin, is corrected by standard doses of desmopressin, and segregates with markers for the AVPR2 gene in Xq28. However, no mutations were found in AVPR2 or its highly conserved flanking regions. Exome sequencing confirmed these findings and also revealed no deleterious variants in the provasopressin and aquaporin-2 genes. The 4 obligate female carriers osmo-regulated vasopressin in the low normal range. CONCLUSION: X-linked recessive transmission of DI can be due to a defect in either the secretion or the action of vasopressin. Other criteria are necessary to differentiate and manage the 2 disorders correctly.

Creation of a Novel Hands-on Model to Teach Breast Tanner Staging to Pediatric Learners.

INTRODUCTION: Pubertal Tanner staging is a standard part of the pediatric physical examination and provides valuable insight into a child's growth and development. In practice, pediatric care practitioners have varying levels of confidence and expertise with Tanner staging. Currently, breast Tanner staging is taught via illustrated images or limited hands-on practice on real patients during pediatric residency training. METHODS: We used synthetic materials to develop a lifelike, 3-dimensional, hands-on educational tool aimed at teaching medical students and pediatric resident physicians how to identify and distinguish among the 5 breast Tanner stages. This tool was evaluated by a group of experienced pediatric endocrinologists. RESULTS: Thirty pediatric endocrinologists with an average of 16.7 years of clinical experience evaluated the model, and all participants believed the model was a valuable teaching tool for medical students and pediatric resident physicians. Tanner stages 1, 2, 3, 4, and 5 were correctly identified by 100%, 93%, 90%, 100%, and 73% of participants, respectively. CONCLUSIONS: We show that the use of a synthetic, 3-dimensional, lifelike breast model to teach breast Tanner staging may be valuable within the context of pediatric medical education. Further refinement of the model as well as curriculum development and evaluation is necessary before broadly disseminating this model as an educational tool.

Is Gadolinium Contrast Necessary for Pituitary MRI in the Evaluation of Pediatric Short Stature and Growth Hormone Deficiency?

INTRODUCTION: Short stature is a common concern that necessitates pediatric endocrinology evaluation. Growth hormone deficiency (GHD) is a commonly considered etiology. Brain and pituitary magnetic resonance imaging (MRI) with gadolinium-based contrast agents (GBCAs) is the most widely used imaging in assessing patients with GHD. Given the significant strides made in MRI technology, the need for contrast material should be reassessed. METHOD: We performed a retrospective review of healthy patients with short stature and/or GHD who underwent brain and pituitary MRI with and without contrast to assess the added value of contrast administration. RESULTS: 227/318 identified patients underwent growth hormone (GH) stimulation testing; 28 (12.3%) with normal GH response and 62 (27.3%) with severe GHD. We found a low incidence of sellar and suprasellar pathologies. When comparing noncontrast and contrast MRI, we found perfect agreement in detecting abnormal posterior pituitary bright spots (kappa:1.0) and substantial agreement in detecting pars intermedia cysts and posterior superior sellar cysts (kappa: 0.74 and 0.71, respectively). Initially, only moderate agreement was found in detecting infundibular abnormalities (kappa: 0.51), although a revised noncontrast MRI protocol with high-resolution 3D images enabled visualization of the infundibulum. CONCLUSION: The MRI evaluation of healthy patients with short stature and/or isolated GHD may be completed without the use of GBCAs. The slight overestimation of pituitary stalk interruption by noncontrast images can be overcome by adding newer high-resolution sequences.

Prevention of Growth Failure in Turner Syndrome: Long-Term Results of Early Growth Hormone Treatment in the "Toddler Turner" Cohort.

INTRODUCTION: In the randomized "Toddler Turner" study, girls who received growth hormone (GH) starting at ages 9 months to 4 years (early-treated [ET] group) had marked catch-up growth and were 1.6 ± 0.6 SD taller than untreated (early-untreated [EUT]) control girls after 2 years. However, whether the early catch-up growth would result in greater near-adult height (NAH) was unknown. Therefore, this extension study examined the long-term effects of toddler-age GH treatment on height, pubertal development, and safety parameters. METHODS: Toddler Turner study participants were invited to enroll in a 10-year observational extension study for annual assessments of growth, pubertal status, and safety during long-term GH treatment to NAH for both ET and EUT groups. RESULTS: The ET group was taller than the EUT group at all time points from preschool to maturity and was significantly taller at the onset of puberty (p = 0.016), however, the difference was not significant at NAH. For the full cohort (ET + EUT combined, n = 50) mean (± SD) NAH was 151.2 ± 7.1 cm at age 15.0 ± 1.3 years. NAH standard deviation score (SDS) was within the normal range (>-2.0) for 76% of ET and 60% of EUT subjects (68% overall) and correlated strongly with height SDS at GH start (r = 0.78; p < 0.01), which in turn had a modest inverse correlation with age at GH start (i.e., height SDS declined with increasing age in untreated girls [r = -0.30; p = 0.016]). No new safety concerns arose. CONCLUSION: Although the ET group was taller throughout, height SDS at NAH was not significantly different between groups due to catch-down growth of ET girls during lapses in GH treatment after the Toddler study and similar long-term GH exposure overall. Early initiation of GH by age 6 years, followed by uninterrupted treatment during childhood, can prevent ongoing growth failure and enable attainment of height within the normal range during childhood, adolescence, and adulthood.

Turner Syndrome with Y Chromosome: Spontaneous Thelarche, Menarche, and Risk of Malignancy.

STUDY OBJECTIVE: Girls with Turner syndrome with Y-chromosome material (TS + Y) are assumed to have nonfunctional gonads with increased tumor risk, therefore prophylactic gonadectomy is recommended at diagnosis. In this study we aimed to determine rates of spontaneous thelarche (ST) and spontaneous menarche (SM), and prevalence of gonadal tumor and malignancy in girls with TS + Y, to further inform discussions about gonadectomy. DESIGN: Retrospective review of clinical and pathology data. SETTING: Multicenter study involving 4 United States children's hospitals. PARTICIPANTS: Patients included those with a genetically proven diagnosis of TS + Y and phenotypically female genitourinary exam. INTERVENTIONS: Demographic characteristics, pubertal development, and gonadal pathology data were abstracted from clinical records. Data for ST were analyzed for patients aged 13 years and older and SM for patients older than 15 years. MAIN OUTCOME MEASURES: ST, SM, prevalence of gonadal tumor, and malignancy. RESULTS: Forty-four patients met inclusion criteria. Nineteen patients were 13 years or older; 8/19 (42%) had ST and reached Tanner stages 2-4 and 2 (11%) had normal ovarian pathology. Nineteen patients were 15 years or older; 2/19 (11%) had SM. Thirty-seven patients underwent gonadectomy; 35 had available pathology results. Gonadoblastoma was identified in 35/7 patients (19%), 1 in situ germ cell neoplasia, and 1 dysgerminoma (3%). One patient with bilateral gonadoblastoma had ST and SM. CONCLUSION: In this multicenter cohort, 42% of girls with TS + Y entered puberty spontaneously and 11% had SM, supportive of gonadal function. Risk of tumor was similar to previous reports. To achieve informed decision-making, discussions about gonadectomy should incorporate potential for gonadal function and tumor risk.

Turner Syndrome Systematic Review: Spontaneous Thelarche and Menarche Stratified by Karyotype.

BACKGROUND: Girls with Turner syndrome (TS) have a high incidence of primary ovarian insufficiency. Recent data show rates of spontaneous thelarche (ST) of 38% and spontaneous menarche (SM) of 15-16%, with higher rates in those with mosaicism. SUMMARY: We systematically reviewed the literature for evidence regarding rates of ST and SM in TS and evaluated rates based on the type of chromosomal mosaicism. We searched MEDLINE via PubMed, Embase, and the Cochrane Database of Controlled Trials. Reference lists were screened. Studies reporting outcomes of ST and SM in girls with TS, diagnosed by genetic analysis, were included. Data was collected regarding study design, cohort type, cohort age, the number of participants with ST and SM, the individual age at diagnosis of ST and SM, the mean age of patients with ST and SM, sample size, the number of participants with secondary amenorrhea, and karyotype. Key Messages: In total 2,699 patients were assessed for ST and 2,890 for SM from 43 articles. Overall the rates of ST were 32% (95% CI 26.4-38.9) and SM 20.8% (95% CI 19.3-22.4). Girls with X monosomy had the lowest rates of ST (i.e., 13%; 95% CI 8.7-19.7) and SM (i.e., 9.1%; 95% CI 7.3-11.3). Girls with 45,X/47,XXX had the highest rates of ST (i.e., 88.1%; 95% CI 62-97.1) and SM (i.e., 66.2%; 95% CI 49.3-79.6). CONCLUSIONS: Rates of ST and SM differ by karyotype in TS. When counseling patients, the karyotype should strongly influence discussions regarding pubertal development and the future reproductive potential.

Refractory hypoglycemia in a pediatric patient with desmoplastic small round cell tumor.

Background Tumor-induced hypoglycemia is a rare and serious complication that is usually a consequence of either excessive insulin secretion (insulinoma) or because of non-islet cell tumor hypoglycemia (NICTH). NICTH is a rare phenomenon seen most often in adult patients. It is associated with different tumor types. Here, we report the first case to the best of our knowledge in the literature of a pediatric patient with NICTH associated with desmoplastic small round cell tumor (DSRT). Case presentation This is a 15-year-old girl who presented with symptomatic hypoglycemia and abdominal mass. She required an intravenous glucose infusion rate as high as 9 mg/kg/min in addition to glucose containing oral supplements in order to maintain her blood glucose above 60 mg/dL. Computed tomography (CT) scan of the chest, abdomen and pelvis showed multiple hepatic lesions with an intraperitoneal soft tissue mass which subsequently was diagnosed as DSRT. When the blood glucose was 45 mg/dL, the insulin, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels were suppressed with an appropriate elevation of cortisol. Subsequently, an insulin-like growth factor-2 (IGF-2) level was sent and the IGF-2:IGF-1 ratio was found to be elevated >10 consistent with NICTH. After the first dose of chemotherapy, hypoglycemia improved, and she was weaned off glucose containing fluids. Conclusions NICTH should be considered in all cancer patients regardless of their age with refractory hypoglycemia.

Extensive miRNA expression analysis in craniopharyngiomas.

PURPOSE: Craniopharyngiomas are benign tumors of the sellar or parasellar regions. They arise from the remnants of Rathke's pouch and are considered a "developmental disease." microRNAs are short non-coding RNAs that play a key regulatory role in the control of expression of entire gene networks. We performed an extensive analysis of miRNAs in craniopharyngiomas aiming to identify a miRNA expression signature that might aid in the prognosis of disease progression and outcome. METHODS: Thirty-seven craniopharyngioma samples from twenty-three patients, ten age-matched controls from autopsy, and ten infant controls from the developing pituitary from autopsy were evaluated for the expression of 754 miRNAs using TaqMan® Low Density Arrays (TLDAs) v2.0 (Applied Biosystems, Foster City, CA). RESULTS: Among the most differentially expressed miRNAs, downregulation of miR-132 appears to be a marker of aggressiveness and also plays a role in epithelial-mesenchymal transition. CONCLUSIONS: This is the first time that an extensive study of miRNA expression has been performed in craniopharyngiomas. Further research needs to be performed to investigate the potential role of miR-132 in the development and progression of craniopharyngiomas, and its value as a prognostic marker of aggressiveness.

Growth Hormone Excess in Children with Optic Pathway Tumors Is a Transient Phenomenon.

BACKGROUND/AIMS: Growth hormone (GH) excess in children with chiasmal optic pathway tumors (OPT), often associated with neurofibromatosis type 1 (NF1), is likely underrecognized. These children have elevated insulin-like growth factor 1 (IGF-1) levels, evidence of rapid growth despite treatment of precocious puberty, and failure to suppress GH levels following oral glucose challenge. The aim of this report is to describe the treatment course and natural history of this rare clinical condition in 7 patients. METHODS: This is a descriptive case series of 5 children previously described and 2 additional children more recently diagnosed at our institution. All 7 children had clinical and biochemical evidence of GH excess and received treatment with the somatostatin analog octreotide. RESULTS: Length of treatment varied among the patients. Five of the 7 patients have had resolution of GH excess and currently have normal IGF-1 levels without treatment. CONCLUSIONS: Unrestrained GH secretion occurs in a subset of children with OPT with potential adverse outcomes. Since GH excess appears to resolve over time, the benefit of treatment to alter outcomes or prevent tumor progression is unclear.

Growth hormone excess in children with neurofibromatosis type 1-associated and sporadic optic pathway tumors.

OBJECTIVE: To describe the clinical manifestations of growth hormone (GH) excess in children with optic pathway tumors (OPT). STUDY DESIGN: Descriptive case series of 5 children with OPT, 3 with associated neurofibromatosis type 1, referred for evaluation of accelerated linear growth. GH excess was evaluated by oral glucose tolerance tests with frequent sampling of GH levels. Precocious puberty was evaluated by basal luteinizing hormone and sex steroid hormone levels. Stimulation testing with leuprolide acetate (20 µg/kg subcutaneously) was conducted in patients with normal baseline testing. RESULTS: All patients had OPT involving both the hypothalamus and optic chiasm. All patients had elevated levels of the growth factor insulin-like growth factor 1 and on stimulation testing demonstrated an inability to suppress GH levels to < 1.0 ng/mL, indicating the presence of unregulated GH secretion. Additionally, all patients displayed biochemical evidence of precocious puberty. CONCLUSIONS: GH excess may be an under-recognized occurrence in the setting of neurofibromatosis type 1 and OPT. GH excess in such patients may contribute to continued brain tumor growth. Given the potential adverse consequences of unrestrained GH excess, all children with chiasmal or hypothalamic tumors who have rapid growth should be evaluated for both precocious puberty and GH excess.

Central and gonadal hypogonadism in X-linked lissencephaly.

OBJECTIVE: To directly test gonadal function in a patient with X-linked lissencephaly with ambiguous genitalia (XLAG) in light of lack of previous functional data. STUDY DESIGN AND RESULTS: We studied an infant who failed to increase testosterone levels in response to hCG stimulation. CONCLUSION: In XLAG, the gonads are not only structurally dysgenetic but also functionally abnormal.