White matter microstructure and functional connectivity in the brains of infants with Turner syndrome.

Turner syndrome, caused by complete or partial loss of an X-chromosome, is often accompanied by specific cognitive challenges. Magnetic resonance imaging studies of adults and children with Turner syndrome suggest these deficits reflect differences in anatomical and functional connectivity. However, no imaging studies have explored connectivity in infants with Turner syndrome. Consequently, it is unclear when in development connectivity differences emerge. To address this gap, we compared functional connectivity and white matter microstructure of 1-year-old infants with Turner syndrome to typically developing 1-year-old boys and girls. We examined functional connectivity between the right precentral gyrus and five regions that show reduced volume in 1-year old infants with Turner syndrome compared to controls and found no differences. However, exploratory analyses suggested infants with Turner syndrome have altered connectivity between right supramarginal gyrus and left insula and right putamen. To assess anatomical connectivity, we examined diffusivity indices along the superior longitudinal fasciculus and found no differences. However, an exploratory analysis of 46 additional white matter tracts revealed significant group differences in nine tracts. Results suggest that the first year of life is a window in which interventions might prevent connectivity differences observed at later ages, and by extension, some of the cognitive challenges associated with Turner syndrome.

Turner syndrome: language profile of young girls at 12 and 24 months of age.

BACKGROUND: Turner syndrome (TS) is a genetic disorder associated with complete or partial absence of an X chromosome affecting approximately 1/2000 live female births. Available evidence suggests that, in the school-age years, girls with TS often require speech and language services; however, little is known about the language development of infants and toddlers. METHOD: This study (N = 31) explored the language profiles of 12- and 24-month-old girls with TS, as well as the percentage of girls who might be "at risk" for language delays. We also followed a subset of 12-month-old girls with TS to 24 months of age to determine the stability of the 12-month findings. RESULTS: Although all mean scores were within the average range at both time points, results revealed a higher prevalence of 24-month-old girls with TS "at risk" for receptive language difficulties. In addition, expressive language skills significantly exceeded receptive language skills at both time points. We found 12-month-old girls to be "at risk" for social and symbolic difficulties based on clinical assessment; only symbolic difficulties were significant based on caregiver report. At 24 months, clinical assessment indicated greater use of speech sounds and words than normative expectations. Caregivers reported greater use of speech sounds, and also, greater use of gestures. Although some changes occurred over a 1-year time span (12 to 24 months), all mean test scores remained within the average range and the changes in the percentage of girls manifesting "at risk" status on either the PLS-4 or CSBS-DP were non-significant. CONCLUSIONS: Although within normal limits, receptive language skills were found to be significantly lower than expressive language skills at both ages. Social and symbolic communication skills also were in the average range, with both showing significant improvement from 12 to 24 months based on clinical assessment. Caregiver report found that use of gestures and production of speech sounds not only improved from 12 to 24 months, but also exceeded normative expectations. Findings suggest the presence of relatively intact speech and language abilities during the first 2 years of life, with perhaps some emergent concerns for receptive language development. Ongoing developmental surveillance will be important.

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.

Early Development of Infants with Turner Syndrome.

OBJECTIVE: To examine the early cognitive, temperament, and adaptive functioning of infants and toddlers with Turner syndrome (TS). METHODS: Cognitive abilities were measured using the Mullen Scales of Early Learning at 1 year of age for 31 girls with TS and compared with neurotypical female (N = 53) and male (N = 54) control groups. Temperament (Carey Toddler Temperament Scales) and adaptive functioning (Vineland Adaptive Behavior Scales-Second Edition) were measured at 1 year of age and compared with normative data. An exploratory analysis of cognitive/developmental trajectories was also conducted comparing age 12-month to 24-month time points for 22 TS subjects. RESULTS: Infants with TS performed largely within the average range for adaptive behavior, temperament, and early cognitive development with some increased risk for delays in language and significant increased risk for delays in motor skills (p < 0.001). Although exploratory, there was some suggestion of slower rates of progression in fine-motor and visual reception skills from 12 to 24 months of age. CONCLUSIONS: Infants and toddlers with TS exhibit a relatively positive neurodevelopmental profile overall, with some indication of an increasing gap in function in fine-motor and visual perceptual abilities as compared to neurotypical peers. It is unclear whether these apparent differences represent normal variability in this very young population or, perhaps, are early precursors of later phenotypic characteristics of TS in the school-age and young adult years.

Near Adult Height in Girls with Turner Syndrome Treated with Growth Hormone Following Either Induced or Spontaneous Puberty.

OBJECTIVE: To understand whether spontaneous vs induced puberty and the type and route of estrogen influence the height of girls with Turner syndrome on growth hormone (GH). STUDY DESIGN: Search of an international database of children treated with GH revealed 772 girls with Turner syndrome followed from GH initiation to near adult height. Data from girls with sustained spontaneous puberty (n = 145) were compared with those requiring estrogens for induction or maintenance of puberty (n = 627). RESULTS: At GH start, mean age (7.5 vs 7.9 years), weight (-1.7 vs -1.7 SDS), and body mass index (0.2 SDS vs 0.1 SDS) were similar for girls with spontaneous puberty and with induced puberty. Although those girls with spontaneous puberty were shorter than those with induced puberty, when midparental height was taken into consideration, starting heights in both groups averaged -2.8 SDS. Both groups received approximately 0.3 mg/kg/week of GH. Girls with spontaneous puberty initiated puberty and reached near adult height earlier than girls with induced puberty (12.6 ± 1.8 years vs 13.4 ± 1.4 years and 16.0 ± 1.3 years vs 16.9 ± 1.4 years, respectively). Although girls with spontaneous puberty grew more in the first year of GH therapy and between the onset of puberty and near adult height (11.0 cm vs 9.3 cm), height SDS at near adult height and the length of time in puberty before reaching near adult height were comparable. A 45,X karyotype was detected in 22.1% of girls with spontaneous puberty and in 58.4% of girls with induced puberty. Patients receiving transdermal estrogens did not grow better than those on oral estrogens. Adverse event reporting was comparable between groups. CONCLUSIONS: Girls with Turner syndrome with spontaneous puberty tended to grow better in response to GH than girls with induced puberty, but not enough to produce a difference in height SDS at near adult height.

Increasing Rates of Opioid Misuse Among Older Adults Visiting Emergency Departments.

OBJECTIVE: This study sought to investigate factors associated with opioid misuse-related emergency department (ED) visits among older adults and changes in outcomes associated with these visits, using multiple years of nationally representative data. METHODS: A retrospective analysis of the Nationwide Emergency Department Sample was conducted. Study inclusion was limited to adults aged 65 years and older. Diagnostic codes were used to identify opioid misuse disorder; sampling weights were used to adjust standard estimates of the errors. Descriptive and multivariate procedures were used to describe risk and visit outcomes. RESULTS: ED visits by older adults with opioid misuse identified in the ED increased sharply from 2006 to 2014, representing a nearly 220% increase over the study period. Opioid misuse was associated with an increased number of chronic conditions, greater injury risk, and higher rates of alcohol dependence and mental health diagnoses. CONCLUSION: The steep increase in opioid misuse observed among older adult ED visits underscores the critical need for additional research to better understand the national scope and impact of opioid misuse on older adults, as well as to better inform policy responses to meet the needs of this particular age group.

Cleft palate and hypopituitarism in a patient with Noonan-like syndrome with loose anagen hair-1.

Noonan syndrome (NS), the most common of the RASopathies, is a developmental disorder caused by heterozygous germline mutations in genes encoding proteins in the RAS-MAPK signaling pathway. Noonan-like syndrome with loose anagen hair (NSLH, including NSLH1, OMIM #607721 and NSLH2, OMIM #617506) is characterized by typical features of NS with additional findings of macrocephaly, loose anagen hair, growth hormone deficiency in some, and a higher incidence of intellectual disability. All NSLH1 reported cases to date have had an SHOC2 c.4A>G, p.Ser2Gly mutation; NSLH2 cases have been reported with a PPP1CB c.146G>C, p.Pro49Arg mutation, or c.166G>C, p.Ala56Pro mutation. True cleft palate does not appear to have been previously reported in individuals with NS or with NSLH. While some patients with NS have had growth hormone deficiency (GHD), other endocrine abnormalities are only rarely documented. We present a female patient with NSLH1 who was born with a posterior cleft palate, micrognathia, and mild hypotonia. Other findings in her childhood and young adulthood years include hearing loss, strabismus, and hypopituitarism with growth hormone, thyroid stimulating hormone (TSH), and gonadotropin deficiencies. The SHOC2 mutation may be responsible for this patient's additional features of cleft palate and hypopituitarism.

T Follicular Helper Cell-Dependent Clearance of a Persistent Virus Infection Requires T Cell Expression of the Histone Demethylase UTX.

Epigenetic changes, including histone methylation, control T cell differentiation and memory formation, though the enzymes that mediate these processes are not clear. We show that UTX, a histone H3 lysine 27 (H3K27) demethylase, supports T follicular helper (Tfh) cell responses that are essential for B cell antibody generation and the resolution of chronic viral infections. Mice with a T cell-specific UTX deletion had fewer Tfh cells, reduced germinal center responses, lacked virus-specific immunoglobulin G (IgG), and were unable to resolve chronic lymphocytic choriomeningitis virus infections. UTX-deficient T cells showed decreased expression of interleukin-6 receptor-α and other Tfh cell-related genes that were associated with increased H3K27 methylation. Additionally, Turner Syndrome subjects, who are predisposed to chronic ear infections, had reduced UTX expression in immune cells and decreased circulating CD4(+) CXCR5(+) T cell frequency. Thus, we identify a critical link between UTX in T cells and immunity to infection.

Improving detection of hypertension in girls with turner syndrome using ambulatory blood pressure monitoring.

BACKGROUND/AIMS: Turner syndrome (TS) is associated with increased mortality due to cardiovascular disease and a dramatically higher rate of aortic dissection. The recognition and treatment of hypertension in this population is critical. We sought to assess the ability to detect blood pressure (BP) abnormalities comparing ambulatory blood pressure monitoring (ABPM) with conventional BP measurement methods. We hypothesized that ABPM would improve detection of hypertension and alter management strategies. METHODS: Twenty-three girls with TS underwent BP measurements using an automated oscillometric method and a manual mercury sphygmomanometer. Twenty-four-hour ABPM was performed (Spacelabs 90217, Issaquah, Wash., USA). BP values were compared to normative data based on height and sex for ABPM, and for age, height and sex for automated oscillometric and manual measurements. RESULTS: Five (22%) subjects were found to have ambulatory hypertension (3 of these with severe hypertension). Three subjects had prehypertension using ABPM measurements. Only 1 of the 5 patients with ambulatory hypertension was categorized as hypertensive using manual BP measurements. Twelve subjects (52%) had nocturnal hypertension. ABPM data led to a change in medical management of hypertensive patients with initiation of antihypertensive therapy. CONCLUSIONS: ABPM is advantageous in TS, as it improves detection of hypertension, identifies those with non-dipping BP patterns, and changes medical management of patients.

Prevalence of pilomatricoma in Turner syndrome: findings from a multicenter study.

IMPORTANCE: The absence of data on the prevalence of pilomatricoma among patients with Turner syndrome served as the catalyst for this multicenter investigation. OBJECTIVES: To ascertain the prevalence of pilomatricoma among patients with Turner syndrome and to determine any association between the development of pilomatricomas and the use of exogenous hormones in patients with Turner syndrome. DESIGN: A retrospective medical record review from January 1, 2000, through January 1, 2010, was performed of all patients with Turner syndrome. Data on pilomatricomas and the use of hormone therapy were collected. SETTING: University of California-Davis Medical Center, University of Nebraska Medical Center, and The University of North Carolina at Chapel Hill. PARTICIPANTS: Patients with a diagnosis of Turner syndrome. MAIN OUTCOME MEASURES: Prevalence of concomitant pilomatricoma and diagnosis of Turner syndrome. Secondary outcome measures included the use of the exogenous hormones estrogen or recombinant human growth hormone (rhGH). RESULTS: In total, 311 patients with Turner syndrome were identified from these 3 institutions. Among them, 8 patients (2.6%) were diagnosed as having pilomatricomas. Before the development of pilomatricomas, 5 patients had been treated with rhGH but not estrogen, 1 patient had received estrogen but not rhGH, and 2 patients did not receive either therapy. CONCLUSIONS AND RELEVANCE: Although the prevalence of pilomatricoma among the general population is unknown, this study demonstrates a high prevalence (2.6%) of pilomatricomas among patients with Turner syndrome. No apparent relationship was noted among our patients or in the literature between the use of rhGH and the development of pilomatricomas.

Growth hormone therapy in Turner syndrome.

Short stature is the single most common physical abnormality in Turner syndrome (TS) with adult stature averaging 20 cm shorter than that of the general population. Randomized, placebo-controlled studies to final adult height have proven that GH therapy is effective in increasing stature in TS. Recently, randomized, controlled studies have demonstrated that adjunctive therapies with low-dose estrogen or low-dose oxandrolone enhance stature further. These therapies may provide benefits beyond height augmentation.

Turner syndrome and sexual differentiation of the brain: implications for understanding male-biased neurodevelopmental disorders.

Turner syndrome (TS) is one of the most common sex chromosome abnormalities. Affected individuals often show a unique pattern of cognitive strengths and weaknesses and are at increased risk for a number of other neurodevelopmental conditions, many of which are more common in typical males than typical females (e.g., autism and attention-deficit hyperactivity disorder). This phenotype may reflect gonadal steroid deficiency, haploinsufficiency of X chromosome genes, failure to express parentally imprinted genes, and the uncovering of X chromosome mutations. Understanding the contribution of these different mechanisms to outcome has the potential to improve clinical care for individuals with TS and to better our understanding of the differential vulnerability to and expression of neurodevelopmental disorders in males and females. In this paper, we review what is currently known about cognition and brain development in individuals with TS, discuss underlying mechanisms and their relevance to understanding male-biased neurodevelopmental conditions, and suggest directions for future research.

Approach to the patient with Turner syndrome.

Turner syndrome (TS) occurs in about 1:4000 live births and describes females with a broad constellation of problems associated with loss of an entire sex chromosome or a portion of the X chromosome containing the tip of its short arm. TS is associated with an astounding array of potential abnormalities, most of them thought to be caused by haploinsufficiency of genes that are normally expressed by both X chromosomes. A health care checklist is provided that suggests screening tests at specific ages and intervals for problems such as strabismus, hearing loss, and autoimmune thyroid disease. Four areas of major concern in TS are discussed: growth failure, cardiovascular disease, gonadal failure, and learning disabilities. GH therapy should generally begin as soon as growth failure occurs, allowing for rapid normalization of height. Cardiac imaging, preferably magnetic resonance imaging, should be performed at diagnosis and repeated at 5- to 10-yr intervals to assess for congenital heart abnormalities and the emergence of aortic dilatation, a precursor to aortic dissection. Hypertension should be aggressively treated. For those with gonadal dysgenesis, hormonal replacement therapy should begin at a normal pubertal age and be continued until the age of 50 yr. Transdermal estradiol provides the most physiological replacement. Finally, nonverbal learning disabilities marked by deficits in visual-spatial-organizational skills, complex psychomotor skills, and social skills are common in TS. Neuropsychological testing should be routine and families given support in obtaining appropriate therapy, including special accommodations at school.

Growth hormone treatment does not affect incidences of middle ear disease or hearing loss in infants and toddlers with Turner syndrome.

CONTEXT: No randomized, controlled, prospective study has evaluated the effect of growth hormone (GH) on the rates of middle ear (ME) disease and hearing loss in girls with Turner syndrome (TS). DESIGN: A 2-year, prospective, randomized, controlled, open-label, multicenter, clinical trial ('Toddler Turner Study'; August 1999 to August 2003) was carried out. SETTING: The study was conducted at 11 US pediatric endocrine centers. SUBJECTS: Eighty-eight girls with TS, aged 9 months to 4 years, were enrolled. INTERVENTION: The interventions comprised recombinant GH (50 microg/kg/day, n = 45) or no treatment (n = 43) for 2 years. MAIN OUTCOME MEASURES: The outcome measures included occurrence rates of ear-related problems, otitis media (OM) and associated antibiotic treatments, tympanometric assessment of ME function and hearing assessment by audiology. RESULTS: At baseline, 57% of the girls (mean age = 1.98 +/- 1.00 years) had a history of recurrent OM, 33% had undergone tympanostomy tube (t-tube) insertion and 27% had abnormal hearing. There was no significant difference between the treatment groups for annual incidence of OM episodes (untreated control: 1.9 +/- 1.4; GH-treated: 1.5 +/- 1.6, p = 0.17). A quarter of the subjects underwent ear surgeries (mainly t-tube insertions) during the study. Recurrent or persistent abnormality of ME function on tympanometry was present in 28-45% of the girls without t-tubes at the 6 postbaseline visits. Hearing deficits were found in 19-32% of the girls at the annual postbaseline visits. Most of these were conductive deficits, however, 2 girls had findings consistent with sensorineural hearing loss, which was evident before 3 years of age. CONCLUSIONS: Ear and hearing problems are common in infants and toddlers with TS and are not significantly influenced by GH treatment. Girls with TS need early, regular and thorough ME monitoring by their primary care provider and/or otolaryngologist, and at least annual hearing evaluations by a pediatric audiologist.

Moving toward an understanding of hormone replacement therapy in adolescent girls: looking through the lens of Turner syndrome.

Turner syndrome (TS) is a relatively common disorder of phenotypic females caused by loss of all or part of the second sex chromosome. Most individuals with TS have short stature and gonadal dysgenesis and are at risk for many other medical and learning problems. In the 45,X ovary, germs cells multiply quite normally during fetal development, but there is accelerated atresia of oocytes in the second half of pregnancy that produces gonadal insufficiency by birth. In girls with other karyotypes, especially those mosaic for 45,X/46,XX, gonadal function may be normal or near-normal. In this chapter, management goals for gonadal insufficiency in girls with TS are presented. The effects of estrogen deficiency and its replacement on three specific problems associated with TS-short stature, cardiovascular disease, and developmental differences in brain structure and function-are explored. General guidelines for estrogen replacement therapy using transdermal estrogen, the most physiologic option, are provided and future research goals are outlined.

College and university compliance with a required meningococcal vaccination law.

OBJECTIVE: Maryland became the first state to pass a vaccination law requiring college and university students living on campus to obtain a meningococcal vaccination or to sign a waiver refusing vaccination because college students are at increased risk for disease. The authors sought to identify how Maryland colleges addressed the law and determine whether schools were in full compliance. PARTICIPANTS: The authors surveyed 32 college/university administrators via a self-administered questionnaire. METHODS: The authors calculated vaccination and waiver rates and assessed compliance with the law overall and with specific law components. RESULTS: Among 28 participating schools, annual vaccination rates and waiver rates among students during 2000-2004 ranged from 66%-76% and 12%-17%, respectively. Two (7%) schools were compliant with all components of the law. CONCLUSIONS: Mandatory vaccination laws do not ensure compliance at the college and university level. Mandatory reporting, increased education, and collaboration between colleges and universities and public health agencies are needed.

Growth hormone treatment of early growth failure in toddlers with Turner syndrome: a randomized, controlled, multicenter trial.

CONTEXT: Typically, growth failure in Turner syndrome (TS) begins prenatally, and height sd score (SDS) declines progressively from birth. OBJECTIVE: This study aimed to determine whether GH treatment initiated before 4 yr of age in girls with TS could prevent subsequent growth failure. Secondary objectives were to identify factors associated with treatment response, to determine whether outcome could be predicted by a regression model using these factors, and to assess the safety of GH treatment in this young cohort. DESIGN: This study was a prospective, randomized, controlled, open-label, multicenter clinical trial (Toddler Turner Study, August 1999 to August 2003). SETTING: The study was conducted at 11 U.S. pediatric endocrine centers. SUBJECTS: Eighty-eight girls with TS, aged 9 months to 4 yr, were enrolled. INTERVENTIONS: Interventions comprised recombinant GH (50 mug/kg.d; n = 45) or no treatment (n = 43) for 2 yr. MAIN OUTCOME MEASURE: The main outcome measure was baseline-to-2-yr change in height SDS. RESULTS: Short stature was evident at baseline (mean length/height SDS = -1.6 +/- 1.0 at mean age 24.0 +/- 12.1 months). Mean height SDS increased in the GH group from -1.4 +/- 1.0 to -0.3 +/- 1.1 (1.1 SDS gain), whereas it decreased in the control group from -1.8 +/- 1.1 to -2.2 +/- 1.2 (0.5 SDS decline), resulting in a 2-yr between-group difference of 1.6 +/- 0.6 SDS (P < 0.0001). The baseline variable that correlated most strongly with 2-yr height gain was the difference between mid-parental height SDS and subjects' height SDS (r = 0.32; P = 0.04). Although attained height SDS at 2 yr could be predicted with good accuracy using baseline variables alone (R(2) = 0.81; P < 0.0001), prediction of 2-yr change in height SDS required inclusion of initial treatment response data (4-month or 1-yr height velocity) in the model (R(2) = 0.54; P < 0.0001). No new or unexpected safety signals associated with GH treatment were detected. CONCLUSION: Early GH treatment can correct growth failure and normalize height in infants and toddlers with TS.

Differences in follicle-stimulating hormone secretion between 45,X monosomy Turner syndrome and 45,X/46,XX mosaicism are evident at an early age.

CONTEXT: Little information exists regarding FSH values in very young girls with Turner syndrome (TS). OBJECTIVES: The objective of the study was to evaluate the pattern, natural progression, and karyotype-related differences in FSH secretion in young, prepubertal girls with TS. STUDY DESIGN: FSH was measured at study entry and annually for 2 yr. SETTING: The Toddler Turner study was conducted at 11 U.S. pediatric endocrine centers. STUDY PARTICIPANTS: Eighty-eight girls with karyotype-proven TS aged 9 months to 4 yr participated in the study. MAIN OUTCOME MEASURES: By-karyotype differences in FSH concentration and age-related changes in FSH were measured. RESULTS: Mean (+/- SD) FSH was markedly elevated in the 45,X (n = 56: 68.3 +/- 36.0 IU/liter) and Other groups [n = 15 (excluding three subjects with Y-containing karyotypes): 52.7 +/- 50.8 IU/liter] but was minimally elevated in girls with 45,X/46,XX mosaicism (n = 14: 10.1 +/- 13.5 IU/liter, P < 0.005 both comparisons). Over the 2-yr period, FSH declined in the 45,X group (-13.4 IU/liter.yr, P < 0.0001). Nonetheless, only three of 159 FSH values fell within normal range for age at any time during the 2-yr study. FSH decline was similar in the Other group (-14.3 IU/liter.yr, P = 0.0032). In contrast, no significant decrease in FSH with age was observed in the 45,X/46,XX group. CONCLUSIONS: In contrast to the original report of FSH concentrations in individuals with TS, this study demonstrates distinct differences in patterns of FSH secretion between young girls with monosomy TS, who have persistent elevation of FSH to age 6 yr, and those with 45,X/46,XX mosaicism, whose FSH values suggest retained ovarian function in the majority. These findings have implications for patient management and family counseling.