Long-term weight gain in children with craniopharyngioma.

OBJECTIVE: Adamantinomatous craniopharyngioma mainly affects children. Excessive weight gain is a major long-term complication. The primary objective of this study was to assess long-term weight changes in children treated for craniopharyngioma. The secondary objectives were to identify risk factors for excessive weight gain and to look for associations with hypothalamic damage by the tumour or treatment. DESIGN: Single-centre retrospective cohort study. METHOD: Children managed for craniopharyngioma at our centre between 1990 and 2019 were included. The body mass index (BMI) standard deviation scores (SDS) at baseline and at last follow-up were compared. Univariate and multivariate analyses were performed in order to identify variables associated with the long-term BMI-SDS variation. RESULTS: The 108 patients had a mean follow-up of 10.4 years. The mean BMI-SDS increase over time was 2.11 (P < .001) overall, 1.21 (P < .001) in the group without hypothalamic involvement by the tumour, and 1.95 (P < .001) in the group managed using intended hypothalamus-sparing surgery. The absence of hypothalamic involvement by the tumour or treatment was significantly associated with less weight gain (P = .046 and P < .01, respectively). After adjustment, factors associated with a BMI-SDS change greater than 2 were female sex (P = .023), tumour involving the hypothalamus (P = .04), and higher baseline BMI (P < .001). CONCLUSION: Clinically significant weight gain occurred in nearly all children treated for craniopharyngioma, including those whose hypothalamus was spared by the tumour and intentionally by treatment. However, hypothalamus integrity was associated with less weight gain. Despite hypothalamus-sparing strategies, hypothalamic obesity remains a major concern, indicating a need for novel treatment approaches.

Glucose pattern in children with classical congenital adrenal hyperplasia: evidence from continuous glucose monitoring.

BACKGROUND: While the risk for hypoglycemia during acute illness is well described in children with classical congenital adrenal hyperplasia (CAH), there is little evidence for the prevalence of asymptomatic hypoglycemia and the daily glucose patterns in CAH. Herein, we explored the daytime glucose profile of children with classical CAH. METHODS: We conducted an observational study in 11 children (6 female; age 3.1 years [1.4, 5.1]; body mass index 17.3 kg/m2 [15.6, 17.9]) with a genetic diagnosis of classical CAH receiving hydrocortisone and fludrocortisone replacement therapy. Participants underwent 2 14-day continuous glucose monitoring (CGM) sessions and an inpatient 24 h series cortisol and adrenocorticotropic hormone (ACTH) measures. Data were analyzed for 3 daytime lags (7 Am-4 Pm, 4 Pm-10pm, 10 Pm-7 Am) corresponding to the hydrocortisone dosing period with cortisol and ACTH measured before the hydrocortisone dose. RESULTS: Eleven participants completed at least 1 CGM session, and 7 out of 11 underwent both the CGM session and the cortisol/ACTH serial measures. In the whole cohort, the percentage of time of sensor glucose values <70 mg/dL was higher during the 10 Pm-7 Am and the 7 Am-4 Pm time slots than in the late afternoon period (17% [7, 54] and 15% [6.8, 24] vs 2% [1.1, 16.7] during the periods 7 Am-4 Pm and 4 Pm-10 Pm, respectively [P = .006 and P = .003]). Nighttime hypoglycemia was mostly spent below the 65 mg/dL (10.9% [4.1, 34]). The glycemic pattern paralleled the nadir of daily cortisol at 7 Am (10.3±4.4 µg/dL). A greater percentage of time in hypoglycemia was associated with lower cortisol concentration at 7 Am and 10 Pm (P < .001 and P = .005). CONCLUSIONS: Continuous glucose monitoring demonstrated a disrupted daily glucose pattern in children with CAH, paralleled by a lower cortisol concentration. CLINICALTRIALS.GOV REGISTRATION: NCT04322435.

GH and Childhood-onset Craniopharyngioma: When to Initiate GH Replacement Therapy?

CONTEXT: Craniopharyngioma is a benign brain tumor with frequent local recurrence or progression after treatment. GH replacement therapy (GHRT) is prescribed in children with GH deficiency resulting from childhood-onset craniopharyngioma. OBJECTIVE: To evaluate whether a shorter delay of GHRT initiation after childhood-onset craniopharyngioma completion therapy increased the risk of a new event (progression or recurrence). METHODS: Retrospective, observational, monocenter study. We compared a cohort of 71 childhood-onset patients with craniopharyngiomas treated with recombinant human GH (rhGH). Twenty-seven patients were treated with rhGH at least 12 months after craniopharyngioma treatment (>12-month group) and 44 patients before 12 months (<12-month group), among which 29 patients were treated between 6 and 12 months (6-12 month group). The main outcome was the risk of tumor new event (progression of residual tumor or tumor recurrence after complete resection) after primary treatment in the >12-month group and in the <12 month or in the 6- to 12-month group patients. RESULTS: In the >12-month group, the 2- and 5-year event-free survivals were respectively 81.5% (95% CI, 61.1-91.9) and 69.4% (95% CI, 47.9-83.4) compared with 72.2% (95% CI, 56.3-83.1) and 69.8% (95% CI, 53.8-81.2) in the <12-month group. The 2- and 5-year event-free survivals were the same in the 6- to 12-month group (72.4%; 95% CI, 52.4-85.1). By log-rank test, the event-free survival was not different between groups (P = .98 and P = .91).The median time for event was not statistically different.In univariate and multivariate analysis, the risk of craniopharyngioma new event was not associated with the GHRT time delay after craniopharyngioma treatment. CONCLUSIONS: No association was found between GHRT time delay after childhood-onset craniopharyngioma treatment and an increased risk of recurrence or tumor progression, suggesting GH replacement therapy can be initiated 6 months after last treatment for craniopharyngiomas.

Age at diagnosis in patients with chronic congenital endocrine conditions: a regional cohort study from a reference center for rare diseases.

BACKGROUND: For chronic congenital endocrine conditions, age at diagnosis is a key issue with implications for optimal management and psychological concerns. These conditions are associated with an increase in the risk of comorbid conditions, particularly as  it concerns growth, pubertal development and fertility potential. Clinical presentation and severity depend on the disorder and the patient's age, but diagnosis is often late. OBJECTIVE: To evaluate age at diagnosis for the most frequent congenital endocrine diseases affecting growth and/or development. PATIENTS AND METHODS: This observational cohort study included all patients (n = 4379) with well-defined chronic congenital endocrine diseases-non-acquired isolated growth hormone deficiency (IGHD), isolated congenital hypogonadotropic hypogonadism (ICHH), ectopic neurohypophysis (NH), Turner syndrome (TS), McCune-Albright syndrome (MAS), complete androgen insensitivity syndrome (CAIS) and gonadal dysgenesis (GD)-included in the database of a single multisite reference center for rare endocrine growth and developmental disorders, over a period of 14 years. Patients with congenital hypothyroidism and adrenal hyperplasia were excluded as they are generally identified during neonatal screening. RESULTS: Median age at diagnosis depended on the disease: first year of life for GD, before the age of five years for ectopic NH and MAS, 8-10 years for IGHD, TS (11% diagnosed antenatally) and CAIS and 17.4 years for ICHH. One third of the patients were diagnosed before the age of five years. Diagnosis occurred in adulthood in 22% of cases for CAIS, 11.6% for TS, 8.8% for GD, 0.8% for ectopic NH, and 0.4% for IGHD. A male predominance (2/3) was observed for IGHD, ectopic NH, ICHH and GD. CONCLUSION: The early recognition of growth/developmental failure during childhood is essential, to reduce time-to-diagnosis and improve outcomes.

Puberty and fertility in classic galactosemia.

Classic galactosemia is a rare inborn error of galactose metabolism with a birth prevalence of about 1/30,000-60,000. Long-term complications occurring despite dietary treatment consist of premature ovarian insufficiency (POI) and neurodevelopmental impairments. We performed with the French Reference Centers for Rare Diseases a multisite collaborative questionnaire survey for classic galactosemic patients. Its primary objective was to assess their puberty, pregnancy, gonadotropic axis, and pelvic morphology by ultrasound. The secondary objective was to determine predictive factors for pregnancy without oocyte donation. Completed questionnaires from 103 patients, 56 females (median age, 19 years (3-52 years)) and 47 males (median age, 19 years (3-45 years)), were analyzed. Among the 43 females older than 13 years old, mean age for breast development first stage was 13.8 years; spontaneous menarche occurred in 21/31 females at a mean age of 14.6 years. In these 21 women, 62% had spaniomenorrhea and 7/17 older than 30 years had amenorrhea. All age-groups confounded, FSH was above reference range for 65.7% of the patients, anti-Müllerian hormone and inhibin B were undetectable, and the ovaries were small with few or no follicles detected. Among the 5 females who sought to conceive, 4 had pregnancies. Among the 47 males, 1 had cryptorchidism, all have normal testicular function and none had a desire to conceive children. Thus, spontaneous puberty and POI are both common in this population. Spontaneous menarche seems to be the best predictive factor for successful spontaneous pregnancy.

Pituitary deficiency and precocious puberty after childhood severe traumatic brain injury: a long-term follow-up prospective study.

Objectives Childhood traumatic brain injury (TBI) is a public health issue. Our objectives were to determine the prevalence of permanent pituitary hormone deficiency and to detect the emergence of other pituitary dysfunctions or central precocious puberty several years after severe TBI. Design Follow-up at least 5 years post severe TBI of a prospective longitudinal study. Patients Overall, 66/87 children, who had endocrine evaluation 1 year post severe TBI, were included (24 with pituitary dysfunction 1 year post TBI). Main outcome measures In all children, the pituitary hormones basal levels were assessed at least 5 years post TBI. Growth hormone (GH) stimulation tests were performed 3-4 years post TBI in children with GH deficiency (GHD) 1 year post TBI and in all children with low height velocity (<-1 DS) or low IGF-1 (<-2 DS). Central precocious puberty (CPP) was confirmed by GnRH stimulation test. Results Overall, 61/66 children were followed up 7 (5-10) years post TBI (median; (range)); 17/61 children had GHD 1 year post TBI, and GHD was confirmed in 5/17 patients. For one boy, with normal pituitary function 1 year post TBI, GHD was diagnosed 6.5 years post TBI. 4/61 patients developed CPP, 5.7 (2.4-6.1) years post-TBI. Having a pituitary dysfunction 1 year post TBI was significantly associated with pituitary dysfunction or CPP more than 5 years post TBI. Conclusion Severe TBI in childhood can lead to permanent pituitary dysfunction; GHD and CPP may appear after many years. We recommend systematic hormonal assessment in children 1 year after severe TBI and a prolonged monitoring of growth and pubertal maturation. Recommendations should be elaborated for the families and treating physicians.

Improved General and Height-Specific Quality of Life in Children With Short Stature After 1 Year on Growth Hormone.

OBJECTIVE: Short stature in children and adolescents may lead to social and emotional stress, with negative effects on quality of life (QoL). GH treatment may improve QoL through height normalization. Our objective here was to evaluate general and height-specific QoL after 1 year of GH treatment. DESIGN: Prospective, single-center, observational cohort study. METHODS: Children ≥ 4 years of age starting GH at our center from 2012 to 2015 to treat short stature were studied. Patients with serious diseases, syndromic short stature, or developmental delay were excluded. At treatment initiation and 1 year later, patients and their parents completed the general PedsQL 4.0 and height-specific Quality of Life in Short Stature Youth (QoLiSSY) questionnaires. Correlations between self-report and parent-report scores and between height gain and QoL improvements were assessed based on Pearson correlation coefficients. RESULTS: Seventy-four children (42 boys, 32 girls), median age (± SD), 10.2 ± 3.0 years (range, 4.1 to 16.6 years), were included. The self-report PedsQL indicated significant improvements in emotional (P = 0.02) and social (P = 0.03) QoL. As assessed by the QoLiSSY, children reported improvement of social QoL (+0.2 SD; P = 0.04), and parents reported improvement of children's physical (+0.1 SD; P < 0.0001), emotional (+0.3 SD; P < 0.0001), and social (+0.3 SD; P < 0.0001) QoL. Height SD score (SDS) gains showed moderate positive correlations with QoLISSY self-report score gains (R = 0.53, R2 = 0.28; P < 0.001) and QoLISSY parent-report gains (R = 0.60, R2 = 0.41; P < 0.00001). CONCLUSIONS: After 1 year of GH treatment, children had significant gains in emotional and social QoL, as assessed by a general self-report questionnaire and height-specific parent-report questionnaire.

Surgery is not superior to dilation for the management of vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome: a multicenter comparative observational study in 131 patients.

BACKGROUND: Vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome can be managed either by various surgeries or dilation. The choice still depends on surgeon's preferences rather than on quality comparative studies and validated protocols. OBJECTIVE: We sought to compare dilation and surgical management of vaginal agenesis in Mayer-Rokitansky-Küster-Hauser syndrome, in terms of quality of life, anatomical results, and complications in a large multicenter population. STUDY DESIGN: Our multicenter study included 131 patients >18 years, at least 1 year after completing vaginal agenesis management. All had an independent gynecological evaluation including a standardized pelvic exam, and completed the World Health Organization Quality of Life instrument (general quality of life) as well as the Female Sexual Function Index and Female Sexual Distress Scale-Revised (sexual quality of life) scales. Groups were: surgery (N = 84), dilation therapy (N = 26), and intercourse (N = 20). One patient was secondarily excluded because of incomplete surgical data. For statistics, data were compared using analysis of variance, Student, Kruskal-Wallis, Wilcoxon, and Student exact test. RESULTS: Mean age was 26.5 ± 5.5 years at inclusion. In all groups, World Health Organization Quality of Life scores were not different between patients and the general population except for lower psychosocial health and social relationship scores (which were not different between groups). Global Female Sexual Function Index scores were significantly lower in the surgery and dilation therapy groups (median 26 range [2.8-34.8] and 24.7 [2.6-34.4], respectively) than the intercourse group (30.2 [7.8-34.8], P = .044), which had a higher score only in the satisfaction dimension (P = .004). However, the scores in the other dimensions of Female Sexual Function Index were not different between groups. The Female Sexual Distress Scale-Revised median scores were, respectively, 17 [0-52], 20 [0-47], and 10 [10-40] in the surgery, dilation therapy, and intercourse groups (P = .38), with sexual distress in 71% of patients. Median vaginal depth was shorter in dilatation therapy group (9.6 cm [5.5-12]) compared to surgery group (11 cm [6-15]) and intercourse group (11 cm [6-12.5]) (P = .039), but remained within normal ranges. One bias in the surgery group was the high number of sigmoid vaginoplasties (57/84, 68%), but no differences were observed between surgeries. Only 4 patients achieved vaginas <6.5 cm. Delay between management and first intercourse was 6 months (not significant). Seventy patients (53%) had dyspareunia (not significant), and 17 patients all from the surgery group had an abnormal pelvic exam. In the surgery group, 34 patients (40.5%) had complications, requiring 20 secondary surgeries in 17 patients, and 35 (42%) needed postoperative dilation. In the dilation therapy group, 13 (50%) needed maintenance dilation. CONCLUSION: Surgery is not superior to therapeutic or intercourse dilation, bears complications, and should therefore be only a second-line treatment. Psychological counseling is mandatory at diagnosis and during therapeutic management.

Can school health check-ups serve as screening tool for growth anomalies and obesity in children?

OBJECTIVE: To evaluate the prevalence of growth disorders and obesity in schoolchildren and determine whether school health check-ups are effective in their screening. Subjects-methods: Analysis of anonymized growth and body mass index (BMI) data from 2887 children attending the 3rd grade from 2008 to 2009 after selection of 75 elementary schools in Paris. RESULTS: Linear growth velocity was abnormal in 198 children. Height and weight were above the French reference values (+ 0.9 ± 1.2 SD and + 1 ± 1.7 SD, respectively). BMI was higher, compared to reference values (+ 0.4 ± 1.4 SD). At their last check-up, 20.9% of children had a BMI > + 2 SD. CONCLUSIONS: School health check-ups constitute a good screening tool for growth and obesity. However, further work is needed to determine the most effective modality. The reference values currently used in France are no longer suitable and new reference charts need to be established. The high prevalence of obesity in schoolchildren remains a public health challenge.

Efficacy and safety of growth hormone treatment in children with hypochondroplasia: comparison with an historical cohort.

BACKGROUND/AIMS: Hypochondroplasia (HCH) is a skeletal dysplasia characterized by disproportionate short stature. The aims of the study are to evaluate efficacy and safety of recombinant human growth hormone (r-hGH) therapy in HCH children, when compared with a historical cohort of untreated HCH children. METHODS: Nineteen HCH patients with an initial height standard deviation score (SDS) ≤-2 and a mean age of 9.3 ± 3.1 years were treated with a mean r-hGH dose of 0.053 mg/kg/day over 3 years. Growth charts were derived from the historical cohort (n = 40). RESULTS: Height gain in the treated population was +0.62 ± 0.81 SDS greater than in the general population, and +1.39 ± 0.9 SDS greater than in the historical untreated HCH cohort (mean gain of 7.4 ± 6.6 cm gain). A negative correlation between height gain and age at treatment initiation was reported (p = 0.04). There was no significant difference in response between patients with fibroblast growth factor receptor 3 mutations and those without. No treatment-related serious adverse events were reported. CONCLUSIONS: r-hGH treatment is well tolerated and effective in improving growth in HCH patients, particularly when started early. The treatment effect varies greatly and must be evaluated for each patient during treatment to determine the value of continued therapy.

Prevalence of pituitary dysfunction after severe traumatic brain injury in children and adolescents: a large prospective study.

CONTEXT: Traumatic brain injury (TBI) in childhood is a major public health issue. OBJECTIVE: We sought to determine the prevalence of pituitary dysfunction in children and adolescents after severe TBI and to identify any potential predictive factors. DESIGN: This was a prospective longitudinal study. SETTING: The study was conducted at a university hospital. PATIENTS: Patients, hospitalized for severe accidental or inflicted TBI, were included. The endocrine assessment was performed between 6 and 18 months after the injury. MAIN OUTCOME MEASURES: Basal and dynamic tests of pituitary function were performed in all patients and GH dynamic testing was repeated in patients with low stimulated GH peak (<7 ng/mL). The diagnosis of proven severe GH deficiency (GHD) was based on the association of two GH peaks less than 5 ng/mL on both occasions of testing and IGF-I levels below -2 SD score. Initial cranial tomography or magnetic resonance imaging was analyzed retrospectively. RESULTS: We studied 87 children and adolescents [60 males, median age 6.7 y (range 0.8-15.2)] 9.5 ± 3.4 months after the TBI (73 accidental, 14 inflicted). The second GH peak, assessed 4.9 ± 0.1 months after the first evaluation, remained low in 27 children and adolescents. Fifteen patients had a GH peak less than 5 ng/mL (mean IGF-I SD score -1.3 ± 1.5) and five (5.7%) strict criteria for severe GHD. Two children had mild central hypothyroidism and one had ACTH deficiency. We did not find any predictive factors associated with existence of GHD (demographic characteristics, growth velocity, trauma severity, and radiological parameters). CONCLUSION: At 1 year after the severe TBI, pituitary dysfunction was found in 8% of our study sample. We recommend systematic hormonal assessment in children and adolescents 12 months after a severe TBI and prolonged clinical endocrine follow-up.

RESICARD: East Paris network for the management of heart failure: absence of effect on mortality and rehospitalization in patients with severe heart failure admitted following severe decompensation.

BACKGROUND: Heart failure presents a major public health problem due to its high prevalence and the increasing number of hospital admissions for this condition. A coordinated healthcare network involving general practitioners and cardiologists was set up in the east of Paris in an effort to improve the management and outcomes of patients with severe heart failure. AIMS: To reinforce patient education, improve compliance with medications and identify symptoms requiring treatment modification. METHODS: In this 'before and after' study, the control group comprised patients hospitalized for severe heart failure who received conventional management in the year preceding the network set-up. The comparative group consisted of patients hospitalized for severe heart failure who underwent network-led care. RESULTS: No significant differences were found between rates of first rehospitalization and all-cause mortality at 1 year between control and network groups, or between rates of first hospitalization due to cardiac causes, time to the first event, duration of hospitalization, rates of cardiac death or time to death. CONCLUSIONS: In this non-randomized study, we found no benefit from management according to the RESICARD healthcare network in terms of mortality or hospitalization in patients with severe chronic heart failure.