Prevalence and clinical characteristics of isolated forms of central precocious puberty: a cohort study at a single academic center.

OBJECTIVE: Isolated central precocious puberty (CPP) includes sporadic, familial and adoption-related forms, and the characterization of its etiology is challenging. This study investigated the prevalence and clinical characteristics of isolated CPP. DESIGN AND METHODS: This observational cohort study included all patients (n = 395) with CPP included in the database of a single academic pediatric care center over a period of 11.5 years. RESULTS: In total, 332 of the 395 patients (84%) had isolated forms of CPP; the proportion of male patients was lower in this group than for non-isolated CPP (4 vs 33%, P < 0.0001). These patients had sporadic (n = 228, 68.5%), familial (n = 82, 25%) or adoption-related (n = 22, 6.5%) forms. Clinical characteristics at diagnosis were similar between groups, but girls with sporadic CPP were older at referral than those with familial or adoption-related CPP (P < 0.02), and birth weight SDS was lower in adopted patients than in those from the sporadic and familial groups (P < 0.01). In the 72 families containing patients with familial forms, both recessive and dominant transmissions were observed between first-degree relatives. Potential maternal or paternal transmission was identified in two-thirds of the studied families, in similar proportions. An autosomal dominant mode of transmission with low penetrance was suggested by the high proportion of affected parents (33 of the 72 families, 46%). Clinical presentation was similar whatever the mode of inheritance. CONCLUSION: These findings highlight the need for careful monitoring of the various forms of CPP. Future studies should explore pathophysiological mechanisms, particularly for familial forms.

Long-term mortality after childhood growth hormone treatment: the SAGhE cohort study.

BACKGROUND: Recombinant human growth hormone has been used for more than 30 years and its indications have increased worldwide. There is concern that this treatment might increase mortality, but published data are scarce. We present data from the entire dataset of all eight countries of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) consortium, with the aim of studying long-term overall and cause-specific mortality in young adult patients treated with recombinant human growth hormone during childhood and relating this to the underlying diagnosis. METHODS: This cohort study was done in eight European countries (Belgium, France, Germany, Italy, The Netherlands, Sweden, Switzerland, and the UK). Patients were classified a priori based on pre-treatment perceived mortality risk from their underlying disease and followed up for cause-specific mortality. Person-years at risk of mortality and expected rates from general population data were used to calculate standardised mortality ratios (SMRs). FINDINGS: The cohort comprised 24 232 patients treated with recombinant human growth hormone during childhood, with more than 400 000 patient-years of follow-up. In low-risk patients with isolated growth hormone deficiency or idiopathic short stature, all-cause mortality was not significantly increased (SMR 1·1, 95% CI 0·9-1·3). In children born small for gestational age, all-cause mortality was significantly increased when analysed for all countries (SMR 1·5, CI 1·1-1·9), but this result was driven by the French subcohort. In patients at moderate or high risk, mortality was increased (SMR 3·8, 3·3-4·4; and 17·1, 15·6-18·7, respectively). Mortality was not associated with mean daily or cumulative doses of recombinant human growth hormone for any of the risk groups. Cause-specific mortality from diseases of the circulatory and haematological systems was increased in all risk groups. INTERPRETATION: In this cohort, the largest, to our knowledge, with long-term follow-up of patients treated with recombinant human growth hormone during childhood, all-cause mortality was associated with underlying diagnosis. In patients with isolated growth hormone deficiency or idiopathic short stature, recombinant human growth hormone treatment was not associated with increased all-cause mortality. However, mortality from certain causes was increased, emphasising the need for further long-term surveillance. FUNDING: European Union.

Risk of Meningioma in European Patients Treated With Growth Hormone in Childhood: Results From the SAGhE Cohort.

Context: There has been concern that GH treatment of children might increase meningioma risk. Results of published studies have been inconsistent and limited. Objective: To examine meningioma risks in relation to GH treatment. Design: Cohort study with follow-up via cancer registries and other registers. Setting: Population-based. Patients: A cohort of 10,403 patients treated in childhood with recombinant GH in five European countries since this treatment was first used in 1984. Expected rates from national cancer registration statistics. Main Outcome Measures: Risk of meningioma incidence. Results: During follow-up, 38 meningiomas occurred. Meningioma risk was greatly raised in the cohort overall [standardized incidence ratio (SIR) = 75.4; 95% CI: 54.9 to 103.6], as a consequence of high risk in subjects who had received radiotherapy for underlying malignancy (SIR = 658.4; 95% CI: 460.4 to 941.7). Risk was not significantly raised in patients who did not receive radiotherapy. Risk in radiotherapy-treated patients was not significantly related to mean daily dose of GH, duration of GH treatment, or cumulative dose of GH. Conclusions: Our data add to evidence of very high risk of meningioma in patients treated in childhood with GH after cranial radiotherapy, but suggest that GH may not affect radiotherapy-related risk, and that there is no material raised risk of meningioma in GH-treated patients who did not receive radiotherapy.

High prevalence of syndromic disorders in patients with non-isolated central precocious puberty.

Objective Non-idiopathic CPP is caused by acquired or congenital hypothalamic lesions visible on MRI or is associated with various complex genetic and/or syndromic disorders. This study investigated the different types and prevalence of non-isolated CPP phenotypes. Design and Methods This observational cohort study included all patients identified as having non-idiopathic CPP in the database of a single academic pediatric care center over a period of 11.5 years. Patients were classified on the basis of MRI findings for the CNS as having either hypothalamic lesions or complex syndromic phenotypes without structural lesions of the hypothalamus. Results In total, 63 consecutive children (42 girls and 21 boys) with non-isolated CPP were identified. Diverse diseases were detected, and the hypothalamic lesions visible on MRI (n = 28, 45% of cases) included hamartomas (n = 17; either isolated or with an associated syndromic phenotype), optic gliomas (n = 8; with or without neurofibromatosis type 1), malformations (n = 3) with interhypothalamic adhesions (n = 2; isolated or associated with syndromic CNS midline abnormalities, such as optic nerve hypoplasia, ectopic posterior pituitary) or arachnoid cysts (n = 1). The patients with non-structural hypothalamic lesions (n = 35, 55% of cases) had narcolepsy (n = 9), RASopathies (n = 4), encephalopathy or autism spectrum disorders with or without chromosomal abnormalities (n = 15) and other complex syndromic disorders (n = 7). Conclusion Our findings suggest that a large proportion (55%) of patients with non-isolated probable non-idiopathic CPP may have complex disorders without structural hypothalamic lesions on MRI. Future studies should explore the pathophysiological relevance of the mechanisms underlying CPP in these disorders.

Increased risk of bone tumors after growth hormone treatment in childhood: A population-based cohort study in France.

The association between growth hormone (GH) treatment and cancer risk has not been thoroughly evaluated and there are questions about any increased risk of bone tumors. We examined cancer risk and especially bone tumor risk in a population-based cohort study of 6874 patients treated with recombinant GH in France for isolated GH deficiency, short stature associated with low birth weight or length or idiopathic short stature. Adult mortality and morbidity data obtained from national databases and from questionnaires. Case ascertainment completeness was estimated with capture-recapture methods. Standardized mortality and incidence ratios were calculated using national reference data. 111 875 person-years of observation were analyzed and patients were followed for an average of 17.4 ± 5.3 years to a mean age of 28.4 ± 6.2 years. For cancer overall, mortality and incidence were not different from expected figures. Five patients developed bone tumors (chondrosarcoma, 1, Ewing sarcoma, 1, osteosarcoma, 3) of whom 3 died (Ewing sarcoma, 1, osteosarcoma, 2), whereas only 1.4 case and 0.6 deaths were expected: standardized mortality ratio, 5.0 and standardized incidence ratio from 3.5 to 3.8 accounting or not accounting for missed cases. Most patients received conventional doses of GH, although one patient with osteosarcoma had received high dose GH (60 µg/kg/d). This study confirms an increased risk of bone tumors but not overall cancer risk in subjects treated with GH in childhood for isolated GH deficiency or childhood short stature. Further work is needed to elucidate the mechanisms involved.

Developmental milestones at one year for the offspring of mothers with congenital hypothyroidism: a population-based study

OBJECTIVE: Maternal thyroid dysfunction during pregnancy is associated with neurodevelopmental impairment in the offspring. No data are currently available for the offspring of patients treated early for congenital hypothyroidism (CH). The aim of this study was to investigate motor and language milestones at one year of age in a population-based registry of children born to young women with CH. DESIGN AND METHODS: We assessed 110 children born to mothers with CH, and 1367 children from the EDEN French population-based birth cohort study prospectively, at the age of one year, with identical questionnaires. Outcomes were assessed in terms of scores for childhood developmental milestones relating to mobility, motor coordination, communication, motricity and language skills. RESULTS: After adjustment for confounding factors, children born to mothers with CH were found to have a higher risk of poor motor coordination than those of the EDEN cohort (OR: 4.18, 95% CI: 2.52-6.93). No differences were identified for the other four domains investigated. Children born to mothers with gestational diabetes have a higher risk of low motor coordination score than their peers (OR: 2.10, 95% CI: 1.21-3.66). Children born to mothers with TSH ≥ 10 IU/L during the first six months of pregnancy were more likely to have low motricity or communication skills scores than those born to mothers with lower TSH concentrations (56% vs 21% for each score, P < 0.04). CONCLUSIONS: Maternal CH may have slight adverse effects on some developmental milestones in the child at one year of age, particularly for children born to mothers with uncontrolled hypothyroidism. However, it remains unclear whether these adverse effects modify subsequent neurodevelopment.

Can growth hormone treatment improve growth in children with severe growth failure due to anorexia nervosa? A preliminary pilot study.

BACKGROUND/AIMS: Growth failure is a difficult but key aspect of care in children with anorexia nervosa (AN). The effects of hGH therapy have not been studied. The aim was to investigate the effect of hGH treatment on height velocity (HV) in children with AN. METHODS: We carried out a retrospective observational study. Ten girls diagnosed with AN at 10.0 ± 1.9 years, with prolonged severe growth failure (HV < 2.5 cm/year for at least 18 months) at the age of 13.3 ± 1.1 years and delayed puberty after nutritional rehabilitation, were treated with hGH (0.040 mg/kg/day) from a bone age of 10.9 ± 1.7 years until they reached adult height. Height and HV were measured before treatment and at 12-month intervals during treatment. RESULTS: Mean body mass index SDS remained unchanged, but HV increased significantly, from a median of 1.0 (0.7-2.1) to 7.1 (6.0-9.5) cm/year after one year (P < 0.002) and 5.6 (4.8-6.2) cm/year after two years of treatment. Height SDS increased from -2.2 ± 1.3 to -1.6 ± 1.3 after one year (P < 0.002) and -1.1 ± 1.5 after two years of GH treatment. Adult height (-0.1 ± 1.0 SDS) was close to target height after 3.6 ± 1.4 years of GH treatment. Serum IGF-I levels increased significantly during treatment (P < 0.01). The treatment was well tolerated. CONCLUSIONS: This proof-of-concept study shows that hGH treatment is associated with significant improvements in linear growth in adolescents with AN and severe growth failure. A randomized placebo-controlled trial is required to determine the ultimate impact of GH treatment in patients with this severe, rare condition.

Risk of Diabetes Treated in Early Adulthood After Growth Hormone Treatment of Short Stature in Childhood.

Context: Growth hormone (GH) is known to be diabetogenic, but the risk of diabetes in individuals treated with GH in childhood has been little evaluated, and conflicting results have been obtained. Objective: To investigate the prevalence of diabetes and gestational diabetes in a population-based cohort of patients treated with GH for short stature in childhood in France. Design, Setting, and Participants: Participants were a population-based cohort of 5100 children with idiopathic isolated GH deficiency, idiopathic short stature, or short stature in children born short for gestational age who started GH treatment between 1985 and 1996. Data on the delivery of diabetes drugs in 2009 and 2010 were obtained from the French national health insurance database. Cases in patients and controls were identified from diabetes drugs deliveries. Main Outcome Measure: The prevalence of diabetes was calculated and compared with that in the general population, determined on the basis of data from the same source, with the same definition. Results: At a mean age of 30 years, no difference in the prevalence of treated diabetes (oral drugs or insulin) was found between subjects treated with GH and the general population in France, regardless of sex. Similarly, the risk of insulin-treated gestational diabetes was similar in patients and in the reference population. Conclusions: No difference in the risk of diabetes was found between GH-treated patients and the reference population. These results are reassuring, but further studies with a longer follow-up are required to evaluate the risk of diabetes with age in these patients.

Cancer Risks in Patients Treated With Growth Hormone in Childhood: The SAGhE European Cohort Study.

Context: Growth hormone (GH) is prescribed for an increasing range of indications, but there has been concern that it might raise cancer risk. Published data are limited. Objective: To examine cancer risks in relation to GH treatment. Design: Cohort study. Setting: Population-based. Patients: Cohort of 23,984 patients treated with recombinant human GH (r-hGH) in eight European countries since this treatment was first used in 1984. Cancer expectations from country-specific national population statistics. Main Outcome Measures: Cancer incidence and cancer mortality. Results: Incidence and mortality risks in the cohort were raised for several cancer sites, largely consequent on second primary malignancies in patients given r-hGH after cancer treatment. There was no clear raised risk in patients with growth failure without other major disease. Only for bone and bladder cancers was incidence significantly raised in GH-treated patients without previous cancer. Cancer risk was unrelated to duration or cumulative dose of r-hGH treatment, but for patients treated after previous cancer, cancer mortality risk increased significantly with increasing daily r-hGH dose (P trend < 0.001). Hodgkin lymphoma (HL) incidence increased significantly with longer follow-up (P trend = 0.001 for patients overall and 0.002 for patients without previous cancer). Conclusions: Our results do not generally support a carcinogenic effect of r-hGH, but the unexplained trend in cancer mortality risk in relation to GH dose in patients with previous cancer, and the indication of possible effects on bone cancer, bladder cancer, and HL risks, need further investigation.

Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty.

CONTEXT AND OBJECTIVE: Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic-pituitary-gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations. DESIGN: An observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients. RESULTS: MKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4-6.0) vs 7.0 years (6.0-7.0), P=0.01). CONCLUSIONS: MKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis.

Description of the SAGhE Cohort: A Large European Study of Mortality and Cancer Incidence Risks after Childhood Treatment with Recombinant Growth Hormone.

BACKGROUND: The long-term safety of growth hormone treatment is uncertain. Raised risks of death and certain cancers have been reported inconsistently, based on limited data or short-term follow-up by pharmaceutical companies. PATIENTS AND METHODS: The SAGhE (Safety and Appropriateness of Growth Hormone Treatments in Europe) study assembled cohorts of patients treated in childhood with recombinant human growth hormone (r-hGH) in 8 European countries since the first use of this treatment in 1984 and followed them for cause-specific mortality and cancer incidence. Expected rates were obtained from national and local general population data. The cohort consisted of 24,232 patients, most commonly treated for isolated growth failure (53%), Turner syndrome (13%) and growth hormone deficiency linked to neoplasia (12%). This paper describes in detail the study design, methods and data collection and discusses the strengths, biases and weaknesses consequent on this. CONCLUSION: The SAGhE cohort is the largest and longest follow-up cohort study of growth hormone-treated patients with follow-up and analysis independent of industry. It forms a major resource for investigating cancer and mortality risks in r-hGH patients. The interpretation of SAGhE results, however, will need to take account of the methods of cohort assembly and follow-up in each country.

Pregnancy outcomes and relationship to treatment adequacy in women treated early for congenital hypothyroidism: a longitudinal population-based study.

CONTEXT: Untreated hypothyroidism is associated with a higher risk of adverse obstetric and neonatal outcomes. Pregnancy complications have yet to be evaluated in patients treated early for congenital hypothyroidism (CH). OBJECTIVE: This study aimed to investigate pregnancy outcomes and their determinants in a population-based registry of young adult women with CH. SETTING AND DESIGN: In total, 1748 subjects were diagnosed with CH in the first 10 years after the introduction of neonatal screening in France; 1158 of these subjects completed a questionnaire on fecundity at a mean age of 25.3 years. We analyzed all declared singleton pregnancies ending after greater than 22 weeks of gestation before the initial survey (n = 207 pregnancies) and in the 3 years following the initial survey (prospective study, n = 174 pregnancies). The reference group comprised 7245 subjects from the French National Perinatal Survey. MAIN OUTCOME MEASURES: Pregnancy outcomes. Serum TSH concentrations and thyroid hormone requirements. RESULTS: In both the overall and prospective analyses, CH was associated with gestational hypertension, emergency cesarean delivery, induced labor for vaginal delivery, and prematurity. For the prospective population with CH, the adjusted odds ratios (aOR) (95% confidence interval [CI]) were 2.19 (1.26-3.81), 1.88 (1.17-3.02), 1.58 (1.12-2.24), and 1.85 (1.06-3.25), respectively. TSH concentrations at least 10 mIU/l during the first 3 or 6 months of pregnancy were associated with a higher risk of preterm delivery (aOR, 5.6; 95% CI, 1.6-20.0) and fetal macrosomia (aOR, 4.5; 95% CI, 1.03-20.1), respectively, whereas no such relationship was observed for TSH concentrations of 5.0-9.9 mIU/l. CONCLUSION: CH may result in adverse pregnancy outcomes. These nationwide data suggest that better thyroid disease management is required, particularly during the first two trimesters of pregnancy, together with vigilant monitoring.

Growth hormone treatment for childhood short stature and risk of stroke in early adulthood.

OBJECTIVES: We investigated the incidence of stroke and stroke subtypes in a population-based cohort of patients in France treated with growth hormone (GH) for short stature in childhood. METHODS: Adult morbidity data were obtained in 2008-2010 for 6,874 children with idiopathic isolated GH deficiency or short stature who started GH treatment between 1985 and 1996. Cerebrovascular events were validated using medical reports and imaging data and classified according to standard definitions of subarachnoid hemorrhage, intracerebral hemorrhage, and ischemic stroke. Case ascertainment completeness was estimated with capture-recapture methods. The incidence of stroke and of stroke subtypes was calculated and compared with population values extracted from registries in Dijon and Oxford, between 2000 and 2012. RESULTS: Using both Dijon and Oxford population-based registries as references, there was a significantly higher risk of stroke among patients treated with GH in childhood. The excess risk of stroke was mainly attributable to a very substantially and significantly higher risk of hemorrhagic stroke (standardized incidence ratio from 3.5 to 7.0 according to the registry rates considered, and accounting or not accounting for missed cases), and particularly subarachnoid hemorrhage (standardized incidence ratio from 5.7 to 9.3). CONCLUSIONS: We report a strong relationship between hemorrhagic stroke and GH treatment in childhood for isolated growth hormone deficiency or childhood short stature. Patients treated with GH worldwide should be advised about this association and further studies should evaluate the potentially causal role of GH treatment in these findings.

Validation of a French version of the quality of life "Celiac Disease Questionnaire".

BACKGROUND AND OBJECTIVE: Celiac disease (CD) is a common chronic autoimmune disorder. Both the manifestations of the disease and the burden of the compulsory life-long gluten-free diet (GFD) have been shown to be associated with impairment of health-related quality of life. The objectives of this study were to provide a cross-cultural adaptation of the specific quality of life "Celiac Disease Questionnaire" (CDQ) and to analyze its psychometric properties. MATERIALS AND METHODS: A cross-cultural French adaptation of the CDQ (F-CDQ) was obtained according to the revised international guidelines. The questionnaire was administered at baseline to 211 patients with biopsy proven CD followed-up in a single tertiary referral centre. The questionnaire was also administered after 7 days and 6 months. Reliability (intraclass correlation coefficients (ICC), Cronbach's alpha and Bland and Altman graphical analysis), validity (factorial structure and Rasch analysis, convergent validity), and responsiveness (effect size) of the F-CDQ were studied. RESULTS: The reliability of the F-CDQ was excellent with ICC and Cronbach's alpha coefficients being between 0.79 and 0.94 for the four subscales and the total score. The factorial structure and the Rasch analysis showed that the four dimensions of the original instrument were retained. Correlations with external measures (a generic measure of quality of life, an anxiety and depression instrument, a self-assessed disease severity, and clinical manifestations) were all in the expected direction confirming the validity of the instrument. Responsiveness was studied and effect sizes ≥ 0.20 were demonstrated for most of the subscales for patients who reported improvement or deterioration after 6 months. CONCLUSION: The F-CDQ retains the psychometric properties of the original instrument and should be useful in cross-national surveys and to assess outcome in clinical trials involving patients with CD.

Rasch analysis for assessing unidimensionality and identifying measurement biases of malignancy scores in oncology. The example of the Weiss histopathological system for the diagnosis of adrenocortical cancer.

PURPOSE: Many malignancy scores have been developed without comprehensive statistical or measurement validation, and in particular without verification of the necessary property of unidimensionality. Here, we used Rasch analysis to assess unidimensionality and identify measurement biases of malignancy scores. METHODS: The Weiss histopathological system (WHS), summing nine items of histopathological alteration, was used to evaluate 247 adrenocortical tumors. Rasch model analysis was implemented and compared to classical factor analytic methods to investigate the validity of item-score summation for both the original and modified WHS, to assess differential functioning of the WHS items across various factors related to patient and tumors, and to identify items or subtypes of tumors that could be considered for removal or exclusion from the WHS with the aims of improving measurement and relieving the burden on pathologists. RESULTS: The WHS does not meet the necessary property of unidimensionality and is severely affected by differential item functioning in relation to size and weight of the tumor. Moreover, items are not well distributed along the spectrum of malignancy, most being located in the upper part and several at the same place. CONCLUSION: The WHS in its present form should be applied only to small or moderate size tumors, and better scoring systems could be developed by using more appropriately distributed items. Rasch analysis is a powerful method for developing, evaluating, refining and simplifying malignancy scores.

Factors associated with hearing impairment in patients with congenital hypothyroidism treated since the neonatal period: a national population-based study.

CONTEXT: Untreated hypothyroidism is known to impair hearing, but little is known about the long-term hearing of patients treated for congenital hypothyroidism (CH) since the neonatal period. OBJECTIVE: The purpose of this study was to assess hearing and its determinants in a population-based registry of young adult patients with CH. DESIGN, SETTING, AND PARTICIPANTS: Self-declared hearing loss was evaluated in 1202 of the 1748 eligible patients with CH who completed a questionnaire on health status at a median age of 23.4 years. Audiograms were obtained for one third of the patients declaring hearing loss (37 of 107). MAIN OUTCOME MEASURES: Self-declared hearing loss and audiogram characteristics for patients reporting hearing impairment were measured. RESULTS: These patients had a risk of self-declared hearing loss more than 3 times higher than that for the reference population (relative risk [RR] = 3.7; 95% confidence interval [CI], 2.9-4.7). Hearing impairment was diagnosed at a median age of 7.0 (25th-75th percentiles, 3.4-19.0) years, and 17% of affected patients required hearing support in early adulthood. Hearing loss was associated with the type of CH (patients with athyreosis and gland in situ were more frequently affected than those with an ectopic gland [RR = 2.61; 95% CI, 1.77-3.88]), with disease severity, as assessed by bone maturation delay at the time of diagnosis, with at least one knee epiphyseal ossification center absent in the most severe form (RR = 2.29; 95% CI, 1.39-3.79), and with other associated chronic diseases (RR = 3.64; 95% CI, 2.35-5.62). A trend for association with serum free T4 concentration at diagnosis was also observed (RR = 1.47; 95% CI, 0.96-2.23). Hearing loss was mostly bilateral (90%), mild to moderate (96%), of the sensorineural type (76%), and concerned high or very high frequencies. CONCLUSION: Despite major improvements in prognosis, hearing loss remains a significant problem, particularly in patients with severe CH. Parents and primary care providers should be aware of this risk, because early diagnosis and intervention could improve the long-term prognosis in these patients.

All-cause and disease-specific mortality and morbidity in patients with congenital hypothyroidism treated since the neonatal period: a national population-based study.

CONTEXT: Little is known about the long-term health of patients treated for congenital hypothyroidism since the neonatal period. OBJECTIVE: To evaluate the causes of mortality and comorbidity in a population-based registry of young adult patients. DESIGN, SETTING, AND PARTICIPANTS: All 1772 eligible patients diagnosed during the first decade after the introduction of neonatal screening in France participated in the study. Follow-up data on vital status were available, in May 2010, for 99.5% of the patients. Completed questionnaires were obtained from 1202 of the selected patients. MAIN OUTCOME MEASURES: All-cause and cause-specific mortality and comorbidity. RESULTS: All-cause mortality in the congenital hypothyroidism (CH) patients was slightly higher than expected on the basis of year, age, and sex (standardized mortality ratio [SMR] 1.24, 95% CI: 0.81-1.82). SMRs for each category of underlying cause of death showed mortality due to diseases of the central nervous system (SMR 5.22, 95% CI: 1.68-12.17) and congenital malformations (SMR 3.15, 95% CI: 1.86-6.49) to be significantly higher than expected in the CH patients. The risk of developing an associated chronic disease in the 1202 patients who completed the questionnaire was twice that for the reference population (odds ratio 2.0 [1.32-3.03]). Neurologic or mental diseases and congenital malformations were the most frequent (odds ratios 2.54 [1.12-5.86], 4.18 [1.27-13.76], and 4.36 [1.24-15.34], respectively). Overall, mortality and morbidity were not affected by sex, disease severity, cause of CH, or adequacy of treatment. CONCLUSION: Prognosis has improved considerably, but a few patients diagnosed during the first 10 years of screening in France nonetheless displayed comorbidity and mortality due to various neurodevelopmental disorders and associated malformations. These results reveal a continuing need for improvements in care and studies to provide knowledge about the full spectrum of the disease and the mechanisms underlying these developmental abnormalities.

Using extended Rasch models to assess validity of diagnostic tests in the presence of a reference standard.

We show that extended Rasch models, built to deal with continuous latent variables, may be useful for assessing validity of medical diagnostic tests in the presence of a reference standard, particularly for chronic diseases. We derive estimates for sensitivity and specificity under the Rasch model assumptions. Our estimations can be computed conditionally on the level of potential confounding covariates, making use of a variety of extended Rasch models, namely log-linear Rasch models, to examine the association between covariates and both disease intensity and response to the tests. Also, another variety of extended Rasch models, partial credit models, can determine appropriate thresholds for quantitative diagnostic tests. As an example, we study the validity of some diagnostic tests of heart failure.

Parental origin of the X-chromosome does not influence growth hormone treatment effect in Turner syndrome.

CONTEXT: The parental origin of the intact X-chromosome has been reported to affect phenotype and response to GH treatment in Turner syndrome (TS). OBJECTIVE: Our objective was to evaluate the influence of the parental origin of the X-chromosome on body growth and GH treatment effect in TS. DESIGN AND SETTING: We conducted a population-based cohort study of TS patients previously treated with GH. PARTICIPANTS: Participants included patients with a nonmosaic 45,X karyotype; 556 women were identified as eligible, 233 (49%) of whom participated, together with their mothers. Data were analyzed for 180 of these patients. MAIN OUTCOME MEASURES: We performed fluorescence in situ hybridization analysis to exclude mosaicism and microsatellite analysis of nine polymorphic markers in DNA from the patients and their mothers. The influence on growth and effect of GH were analyzed by univariate and multivariate methods. RESULTS: The X-chromosome was of paternal origin (X(pat)) in 52 (29%) of 180 and of maternal origin (X(mat)) in 128 (71%) of 180 patients. Height gain from the start of GH treatment to adult height was similar in X(mat) and X(pat) patients (+2.1 ± 0.9 vs. +2.2 ± 0.8 TS sd score, P = 0.45). The lack of influence of parental origin of the X-chromosome was confirmed in multivariate analysis. Parental origin of the X-chromosome also had no effect on the other growth characteristics studied, including growth velocity during the first year on GH treatment. Patient height was correlated with the heights of both parents and was not influenced by the parental origin of the X-chromosome. CONCLUSION: In this, the largest such study carried out to date, the parental origin of the X-chromosome did not alter the effect of GH treatment or affect any other features of growth in TS.

Fecundity in young adults treated early for congenital hypothyroidism is related to the initial severity of the disease: a longitudinal population-based cohort study.

CONTEXT: Untreated hypothyroidism is known to impair fecundity. Patients treated early for congenital hypothyroidism (CH) have yet to be evaluated in adulthood, because screening programs have been running for only the last 30 years in most industrialized countries. OBJECTIVE: Our objective was to assess the fecundity of young adults treated early for CH and its determinants. DESIGN, SETTING, AND PARTICIPANTS: Of the 1748 subjects diagnosed with CH in the first 10 yr after the introduction of neonatal screening in France, 1158 completed a questionnaire on fecundity at a mean age of 25.3 yr. This self-administered questionnaire focused on first attempts to have a child and time to pregnancy. The control group was that used in an analogous study on subjects born between 1971 and 1985. MAIN OUTCOME MEASURES: Fecundability hazard ratios (HR) were estimated with Cox regression models and adjusted for known fecundity confounders (age, smoking, and reproductive history). RESULTS: Fecundability was similar for the CH and control groups: HR = 1.14 (0.89-1.47) for women, and HR = 0.98 (0.58-1.66) for men. In women, the most severe initial forms of the disease, athyreosis, absence of bone maturation at the knee epiphyseal ossification centers, and a low serum free T(4) concentration at diagnosis (<5 pmol/liter), were associated with lower fecundity: HR = 0.68 (0.50-0.98) (P = 0.02); HR = 0.65 (0.45-0.94) (p = 0.02) and HR = 0.70 (0.50-0.97) (P = 0.03), respectively. However, fecundability was not associated with age at the start of treatment, initial levothyroxine dose, or the adequacy of hypothyroidism control. CONCLUSION: There is no evidence that fecundity is generally lower in young adults treated early than in the general population. However, fecundity was lower in women suffering from the most severe form of the disease.