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.

Parent experience with volunteers and support groups in a multidisciplinary DSD clinic.

OBJECTIVE: Despite recommendations that clinics for children with a difference of sex development (DSD) should include peer support, information on how to provide this support is lacking. We utilized a mixed-methods program evaluation to evaluate family satisfaction with our clinic-based volunteers (who either have DSD themselves or are a parent of a child with DSD) and to understand the experience of these volunteers. METHODS: Parents (n=29) of a child with DSD completed an electronic survey. Interviews were conducted with three clinic volunteers. RESULTS: Most participants (72%) met with a clinic volunteer and majority (81%) rated their interaction as helpful. Most common topics discussed between parents and volunteers included: connecting to support groups (81%), their child's future (62%), and learning about their child's diagnosis (48%). Half of parents (48%) attended an after-clinic support group lunch, and 43% of these attendees rated the lunch session as helpful. Parents who attended a lunch liked the experience because they met other families with a child with a similar medical condition (100%), met volunteers with a similar medical condition (64%), and it helped them think more positively about their child's future (64%). Those who did not attend a lunch cited logistical reasons for not attending. CONCLUSIONS: Incorporating clinic volunteers into a multidisciplinary DSD clinic is associated with high reported rates of satisfaction by families and volunteers.

Exome sequencing for the diagnosis of 46,XY disorders of sex development.

CONTEXT: Disorders of sex development (DSD) are clinical conditions where there is a discrepancy between the chromosomal sex and the phenotypic (gonadal or genital) sex of an individual. Such conditions can be stressful for patients and their families and have historically been difficult to diagnose, especially at the genetic level. In particular, for cases of 46,XY gonadal dysgenesis, once variants in SRY and NR5A1 have been ruled out, there are few other single gene tests available. OBJECTIVE: We used exome sequencing followed by analysis with a list of all known human DSD-associated genes to investigate the underlying genetic etiology of 46,XY DSD patients who had not previously received a genetic diagnosis. DESIGN: Samples were either submitted to the research laboratory or submitted as clinical samples to the UCLA Clinical Genomic Center. Sequencing data were filtered using a list of genes known to be involved in DSD. RESULTS: We were able to identify a likely genetic diagnosis in more than a third of cases, including 22.5% with a pathogenic finding, an additional 12.5% with likely pathogenic findings, and 15% with variants of unknown clinical significance. CONCLUSIONS: Early identification of the genetic cause of a DSD will in many cases streamline and direct the clinical management of the patient, with more focused endocrine and imaging studies and better-informed surgical decisions. Exome sequencing proved an efficient method toward such a goal in 46,XY DSD patients.

Disorders of sex development: clinically relevant genes involved in gonadal differentiation.

After the characterization of the sex-determining region of Y (SRY) in 1990, there have been an increasing number of genes recognized to play a role in sex development. The most common disorders of sex development (DSD) result from disruption of androgen levels and activity that affect later embryonal development, such as congenital adrenal hyperplasia and androgen insensitivity syndrome. However, genetic diagnosis of mutations affecting early gonadal development is becoming increasingly accessible to clinicians. More powerful genetic techniques are allowing for interrogation of the entire genome for causative changes and it is important to be able to critically assess the flood of genetic data for meaningful information. Recent discoveries have clarified the role of a variety of transcription factors in DSD such as SOX9, SF1, and WT1. Additionally, disruptions of signaling molecules such as hedgehog, WNT, cyclin-dependent kinase, and Ras/MAP kinase are now known to cause DSD. The dosage-dependence of genes involved in gonadal development is a recurrent theme, and genetic changes in promoter and repressor regions are being revealed by chromosomal microarray analysis and other techniques. In some cases, there are multiple different phenotypes caused by deletion, duplication, homozygous, heterozygous, and regulatory-region changes in the same gene. We aim to provide a concise and clinically-applicable overview of recent developments in the understanding of DSD caused by genetic changes affecting gonadal development.

Pediatric thyroidectomy: a collaborative surgical approach.

INTRODUCTION: We have developed a collaborative approach to pediatric thyroid surgery, with operations performed at a children's hospital by a pediatric surgeon and an endocrine surgeon. We hypothesize that this strategy minimizes specialist-specific limitations and optimizes care of children with surgical thyroid disease. METHODS: Data from all partial and total thyroidectomies performed by the pediatric-endocrine surgery team at a tertiary children's hospital between 1995 and 2009 were collected and analyzed retrospectively. Statistical analyses were performed with IBM SPSS software (SPSS, Chicago, IL). RESULTS: Thirty-five children met the inclusion criteria (69% female; median age, 13 years; median follow-up, 1119 days). The indications for operation were thyroid nodule (71%), genetic abnormality with predisposition to thyroid malignancy (17%), multinodular goiter (5.7%), Grave disease (2.9%), and Hashimoto thyroiditis (2.9%). Sixteen children (46%) underwent thyroid lobectomy, and 19 children (54%) underwent total thyroidectomy. Median length of stay was 1 day (1 day after lobectomy vs 2 days after total thyroidectomy, P < .0001). There were 4 cases of transient hypocalcemia after total thyroidectomy, but there were no nerve injuries or other in-hospital complications in either group (overall complication rate, 11%). CONCLUSIONS: For pediatric thyroidectomy and thyroid lobectomy, collaboration of high-volume endocrine and pediatric surgeons as well as pediatric endocrinologists at a dedicated pediatric medical center provides optimal surgical outcomes.

Supraclavicular swelling in hypothyroidism.

Hypothyroidism can have a variety of presentations. We report here a case of acquired hypothyroidism in a pediatric patient who first presented with bilateral supraclavicular swelling. Hypothyroidism and its presenting signs and symptoms are discussed with a focus on the less common findings that can be associated with hypothyroidism in children.

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.

Testosterone, obesity and insulin resistance in young males: evidence for an association between gonadal dysfunction and insulin resistance during puberty.

OBJECTIVE: To assess the relationships among obesity, insulin sensitivity, and testosterone in pubertal boys. PARTICIPANTS: This study included 20 lean, obese, and type 2 diabetic (T2DM) males, the majority of whom underwent a hyperinsulinemic-euglycemic clamp (n=16). METHODS: Glucose disposal (M value), serum testosterone, and body mass index (BMI) z-score were measured. Differences in testosterone were evaluated by group (lean vs. obese vs. T2DM), while regression was performed to evaluate the relationships among testosterone, obesity and insulin sensitivity. RESULTS: Controlling for Tanner stage, testosterone concentration was significantly lower in obese (p=0.02) and T2DM males (p=0.001) compared to lean males. Furthermore, M value was significantly associated with serum testosterone, even after controlling for BMI and Tanner stage. CONCLUSIONS: These data suggest that obese adolescent boys have lower serum testosterone than controls of the same Tanner stage, and echo the data in adult males associating obesity and insulin resistance with hypogonadism.

A molecular basis for variation in clinical severity of isolated growth hormone deficiency type II.

CONTEXT: Dominant-negative GH1 mutations cause familial isolated growth hormone deficiency type II (IGHD II), which is characterized by GH deficiency, occasional multiple anterior pituitary hormone deficiencies, and anterior pituitary hypoplasia. The basis of the variable expression and progression of IGHD II among relatives who share the same GH1 mutation is poorly understood. OBJECTIVE: We hypothesized that the cellular ratios of mutant/normal GH1 transcripts would correlate with the severity of the IGHD II phenotype. We determined the relative amounts of mutant and normal GH1 transcripts in cell lines and correlated transcript ratios with severity. DESIGN AND PATIENTS: Members of the same IGHD II kindred were genotyped for the GH1 E3+1 G/A mutation by DNA sequencing. Ratios of their 17.5-kDa (mutant)/22-kDa (normal) GH1 transcripts were determined in cultured lymphocytes (CLs), and these ratios were correlated with height sd scores obtained before GH replacement therapy. RESULTS: Ratios of 17.5-/22-kDa GH1 transcripts in CLs from family members with the same IGHD II mutation correlated with differences in their height SD scores. CONCLUSIONS: Our findings suggest that expression levels of both the mutant and normal GH1 allele are important in the pathogenesis of IGHD II, that the ratio of mutant/normal transcripts may be a predictive marker of the penetrance and severity of IGHD II, and that CLs may be useful as surrogates to study GH1 transcript expression of subjects whose anterior pituitary cells are not available.

Case report: thyroid hormone resistance and its therapeutic challenges.

Thyroid hormone resistance occurs when a genetic mutation in the thyroid hormone receptor leads to reduced hormone binding affinity; the concentration of free thyroid hormone in the circulation is inversely correlated with the hormone binding affinity of the mutant receptor. Thyroid hormone resistance mutations are associated with a wide variety of phenotypes and subsequent treatment challenges. Among the more common symptoms are hyperactivity, emotional lability, a below average intelligence quotient, and short stature. We report here a patient who presented with thyroid hormone resistance at an early age, providing an opportunity to optimize her overall growth and development. We review the limited information currently available in the literature addressing the treatment of thyroid hormone resistance in children and describe the approach used to determine the treatment plan in this young child.

Case report: WT1 exon 6 truncation mutation and ambiguous genitalia in a patient with Denys-Drash syndrome.

Denys-Drash syndrome is a rare genetic disorder featuring the triad of congenital nephropathy, Wilms tumor, and intersex disorders (XY under-virilization or XY female). Denys-Drash syndrome is associated with constitutional mutations in the Wilms tumor suppressor gene WT1. Unlike WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome, with its complete deletion of one copy of WT1, Denys-Drash syndrome is generally caused by a dominant-negative mutation. We present a new case of Denys-Drash syndrome in a patient initially diagnosed with XY ambiguous genitalia/partial androgen insensitivity syndrome, who was found to have a novel nonsense mutation in exon 6 leading to a stop codon and hence a truncated protein. Based on lessons learned from this patient, the diagnosis of Denys-Drash syndrome should be considered in the presence of ambiguous genitalia and partial androgen insensitivity.

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.

Gonadoblastoma and Turner syndrome.

PURPOSE: The presence of a Y chromosome in the extrascrotal gonad of patients with intersex disorders has been associated with a high risk of GB and, potentially, GCT. Recently, modern sophisticated genotyping has revealed a subgroup of TS cases with a mosaic karyotype expressing a Y chromosome. We sought to evaluate this group of patients and address their risk of gonadoblastoma. MATERIALS AND METHODS: We reviewed the records and genotyping of all females newly diagnosed with TS between 1990 and 2002 at Children's Hospital in Denver. All patients with TS and Y chromosome mosaicism underwent gonadectomy, and the specimens were evaluated for the presence of gonadoblastoma on histological analysis and to identify Y chromosome on genotyping. RESULTS: A total of 192 girls with a clinical diagnosis of TS were identified between January 1990 and December 2002. Seven records were unavailable and 19 patients did not have karyotypic analyses available in the hospital charts. Of the remaining 166 patients 67 exhibited mosaic cell lines, of whom 8 had 45,X0/46,XY mosaic pattern and 59 had mosaic patterns without Y chromosomal elements. All 8 patients with Y mosaicism underwent uneventful laparoscopic gonadectomy on an outpatient basis. One patient observed to have bilateral dysgenetic gonads after gonadectomy was excluded from the study. Gonadoblastoma (bilateral 2 patients, unilateral 1) was detected in 3 of 7 patients (43%) with Y mosaicism. CONCLUSIONS: In our series 4.8% of evaluable patients with TS carried a 45,X0/46,XY karyotype. Gonadoblastoma can be evident even at an early age in streak gonads with Y mosaicism and may be bilateral. We recommend prophylactic laparoscopic gonadectomy of streak gonads in patients with TS who carry a Y mosaic genotype, because fertility is not an issue, surgical morbidity is minor and there may be a high potential for malignant transformation of gonadoblastomas in this population.

Is this patient insulin resistant? How much does it matter?

Alex was an obese 10-year-old girl with a family history of type 2 diabetes, hypertension, and perhaps polycystic ovarian syndrome. Her physical examination was significant for a central accumulation of body fat and acanthosis nigricans. Although the laboratory studies indicated that Alex was not diabetic and probably not glucose intolerant, she could be insulin resistant (IR). Should any further evaluation be done? If Alex is IR, what kind of treatment should be offered? The following discussion addresses these questions by reviewing the pathophysiology, diagnosis, and consequences of isolated IR.

Insulin resistance during puberty and future fat accumulation.

Insulin resistance is a known sequela of obesity; however, the relationship of insulin resistance to future weight gain remains unclear. In several studies, insulin resistance has been associated with weight stabilization. For the most part, this relationship has been found in adults who are overweight. To evaluate the relationship of insulin resistance to future fat accumulation in pubertal children, a 3-yr prospective study was carried out. Insulin sensitivity (Si) was determined by Bergman's minimal model in 111 healthy children, aged 9.7-14.5 yr. All children were Tanner stage II or III pubertal development at baseline. Body composition was assessed by body mass index, skinfold thickness, hydrodensitometry, and bioelectric impedance analysis at baseline and annually thereafter for an additional 3 yr. A repeated-measures analysis showed that the change in percentage body fat estimated from skinfold thickness [%BF(SF)] over time changed with increasing Si (P < 0.0001). Si was divided into tertiles for each gender, with the lowest tertile representing the most insulin-resistant children. For girls, those in the lowest tertile maintained their %BF(SF) over 3 yr, whereas those girls in the middle and upper tertile had an increase in their %BF(SF). For boys, those in the lowest tertile showed a decrease in their %BF(SF), whereas those boys in the middle and upper tertile maintained their %BF(SF). These results suggest that during puberty, children who are more insulin resistant have decreased sc fat gain.