Congenital hypothyroidism (CH) is the most common congenital endocrine disorder. The early treatment of CH patients has successfully improved the prognosis and management of this disorder. Optimal treatment and management throughout the patient's life, beginning in the neonatal period, are required to ensure long-term health. Affected patients should be offered assessments of associated medical conditions and provided with accurate information about their condition throughout their lives, but particularly during the transition from pediatric to adult services. This review provides a summary of current knowledge about the long-term outcomes of these patients and appropriate management into early adulthood. We carried out a systematic search of the Medline database to identify relevant articles. Despite major improvements in prognosis, the impact of CH is clearly not uniform, and management should take into account a broader range of relevant indicators, including CH severity, associated comorbid conditions and the adequacy of treatment during childhood and adulthood. The early diagnosis and management of associated medical conditions, and better educational strategies to improve compliance with treatment, should improve the long-term prognosis. Further studies are required to explore changes with aging.
Juliane Léger and Jean-Claude Carel
Graves’ disease is an autoimmune disorder. It is the leading cause of hyperthyroidism, but is rare in children. Patients are initially managed with antithyroid drugs (ATDs), such as methimazole/carbimazole. A major disadvantage of treatment with ATD is the high risk of relapse, exceeding 70% of children treated for duration of 2 years, and the potential major side effects of the drug reported in exceptional cases. The major advantage of ATD treatment is that normal homeostasis of the hypothalamus–pituitary–thyroid axis may be restored, with periods of drug treatment followed by freedom from medical intervention achieved in approximately 40–50% of cases after prolonged treatment with ATD, for several years, in recent studies. Alternative ablative treatments such as radioactive iodine and, less frequently and mostly in cases of very high volume goiters or in children under the age of 5 years, thyroidectomy, performed by pediatric surgeons with extensive experience should be proposed in cases of non-compliance, intolerance to medical treatment or relapse after prolonged medical treatment. Ablative treatments are effective against hyperthyroidism, but they require the subsequent administration of levothyroxine throughout the patient’s life. This review considers data relating to the prognosis for Graves’ disease remission in children and explores the limitations of study designs and results; and the emerging proposal for management through the prolonged use of ATD drugs.
Juliane Léger, Isabelle Mercat, Corinne Alberti, Didier Chevenne, Priscilla Armoogum, Jean Tichet and Paul Czernichow
There is evidence to suggest that IGF-I plays a role in regulating bone turnover.
To evaluate the relationships between serum concentrations of IGF-I and IGF-binding protein-3 (IGFBP-3), and bone metabolism markers in healthy children.
Design and setting
Prospective cross-sectional study.
Subjects and methods
A cohort of 579 boys and 540 girls, all healthy Caucasian, were included in this study. Serum IGF-I and IGFBP-3 concentrations, bone alkaline phosphatase (BAP) and CrossLaps (markers of bone formation and bone resorption respectively) levels were evaluated as a function of age, gender, pubertal stage and body mass index.
Serum IGF-I SDS levels were positively correlated with BAP and CrossLaps SDS levels before and after puberty, and also with CrossLaps during puberty (weak correlation). Serum IGFBP-3 SDS levels were positively correlated with BAP and CrossLaps levels before, during (weak correlation) and after puberty (for BAP levels only).
This study demonstrated the independent association between serum IGF-I and IGFBP-3 concentrations with both serum bone formation and resorption markers in healthy children. Physiological differences before, during and after puberty in the association of serum IGF-I and IGFBP-3 levels with the serum bone metabolism markers were found. These differences may be related to differences in interactions between sex steroid hormones and the GH/IGF-I system, bone metabolism and growth during the pubertal transition. Improvements in our understanding of life course determinants of the IGF-I system and bone metabolism are required to shed further light on the role of the GH/IGF-I axis in bone remodelling.
Juliane Léger, Anne Forhan, Sophie Dos Santos, Béatrice Larroque, Emmanuel Ecosse, Marie-Aline Charles and Barbara Heude
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.
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).
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.
Asmahane Ladjouze, Sylvie Soskin, Catherine Garel, Marc Jullien, Catherine Naud-Saudreau, Graziella Pinto, Paul Czernichow and Juliane Léger
Context: GH deficiency (GHD) associated with central precocious puberty (CPP) has been widely reported in cases of arachnoid cyst, septo-optic dysplasia, brain tumors, or after cerebral radiation therapy. However, idiopathic GHD associated with CPP has been reported in only one isolated case.
Objective: To evaluate the occurrence and clinical features of the association of nonacquired GHD and CPP.
Design and setting: This was a retrospective multicenter study.
Patients and methods: The study population was identified through a French nationwide multicenter network (about 3000 patients). We reviewed the medical records of all subjects diagnosed with nonacquired GHD and CPP, with or without developmental abnormalities of the hypothalamic–pituitary axis on cerebral magnetic resonance imaging (MRI), and without any known associated anomaly.
Results: We identified four patients with either isolated GHD (n = 1) or multiple anterior pituitary hormone deficiencies (n = 3). Clinical signs of CPP occurred at 6.4 ± 2.3 years in boys and 7.5 ± 0.5 years in girls, and GnRH analog therapy was started at 4.2 ± 1.6 years after the initiation of recombinant human GH treatment. Cerebral MRI demonstrated ectopic neurohypophysis associated with anterior pituitary hypoplasia in three out of the four patients. The morphology and position of the anterior pituitary and neurohypophysis were normal in one patient who displayed a persistence of the craniopharyngeal canal.
Conclusions: CPP is very rare in patients with nonacquired GHD and is mostly associated with developmental defects in the hypothalamic–pituitary area. Whether molecular mechanisms governing development and activation of the hypothalamic–pituitary axis share dependent factors remains to be explored.
Joëlle Le Moal, Annabel Rigou, Alain Le Tertre, Perrine De Crouy-Channel, Juliane Léger and Jean-Claude Carel
Precocious puberty seems to be increasing but epidemiological data are scarce. Our objective was to improve the epidemiologic knowledge on this disease. We analyzed the national incidence and spatial trends of idiopathic central precocious puberty in France in 2011–2013 in a cross-sectional descriptive study.
We used an indicator based on treatment reimbursements recorded in the national insurance database, in girls under the age of nine years and in boys under the age of 10 years. We considered a time lag of up to one year from the onset of puberty to first drug delivery. We tested four different predictive spatial models at the département scale, selecting the model best fitting the data. We carried out semi-structured interviews with qualified hospital teams in five selected regions to investigate spatial differences in medical practices.
The national annual incidence was 2.68 (95% CI: 2.55, 2.81) per 10 000 girls under the age of 9 years and 0.24 (95% CI: 0.21, 0.27) per 10 000 boys under the age of 10 years. Incidence rates conformed to a purely spatial heterogeneity model in girls, consistent between age groups, with a large incidence range. A similar pattern was observed for boys, with peaks in the South West and Center East. Differences in medical practices may have slightly affected incidence locally, but could not entirely explain the marked geographic pattern.
The results suggest that the risk factors are similar for boys and girls and justify further investigations of the role of the environment.
Maritza Vivanco, Jean-Hugues Dalle, Corinne Alberti, Brigitte Lescoeur, Karima Yakouben, Jean-Claude Carel, André Baruchel and Juliane Léger
The risk of radiation-induced benign and malignant thyroid nodules is well known.
The aim of this study was to determine the occurrence of thyroid nodules and carcinomas after fractionated total body irradiation (TBI) preceding hematopoietic stem cell transplantation (HSCT) for malignant hematological disease during childhood.
We conducted a retrospective university hospital-based observational study. The participants were 76 patients receiving fractionated TBI between 1989 and 2009 as part of the conditioning regimen for HSCT to treat malignant hematological disease, with a median age of 8.2 (5.7–11.4) years, for whom the last ultrasound examination was performed at a median age of 14.2 (11.2–17) years. The main outcome measure was cumulative incidence of thyroid nodules detected by ultrasound scans followed by biopsy if necessary.
Thyroid nodules were examined in 21 (28%) patients, six (29%) of whom were diagnosed with thyroid carcinoma at the age of 2.2–18.6 years after TBI. The cumulative incidence of nodule occurrence increased with increasing time from diagnosis. The 10-year cumulative incidence of benign and malignant thyroid nodules was 16% (95% confidence interval (CI) 4–27%) and 8% (95% CI 0–16%) respectively. Seventeen (22%) patients had hypothyroidism (compensated n=12, in five patients it was transient). No significant independent risk factors were identified in the multivariable competing risk model as a function of nodule occurrence.
Short-term and life-long monitoring, with screening for nodules of the thyroid gland using ultrasound scans, is recommended for survivors subjected to TBI for HSCT during childhood.
Thomas Blanc, Ahmed Ayedi, Alaa El-Ghoneimi, Hendy Abdoul, Yves Aigrain, Françoise Paris, Charles Sultan, Jean-Claude Carel and Juliane Léger
There are few studies of outcome in male patients with undefined 46 XY disorder of sex development (DSD). We aimed to assess testicular function and clinical characteristics after puberty in men with idiopathic 46 XY DSD.
We conducted a University Hospital-based observational follow-up study.
Nineteen patients with severe hypospadias associated with other signs of defective virilization, such as microphallus, cryptorchidism, and/or bifid scrotum, who were initially managed during childhood between 1988 and 1994, were evaluated at a median age of 17.6 (16.3; 17.8) years. Outcome measures included clinical findings and serum testosterone, FSH, LH, and inhibin B concentrations.
Testicular function was normal in only five (26%) patients. Impaired testicular function was observed in 14 (74%) patients and was partial (n=6; 32%) or total (n=8; 42%), requiring testosterone treatment for the initial (n=2) or secondary (n=6) induction of puberty. Undescended testis (unilateral n=3, bilateral n=2) was found and surgically managed only in the 14 patients with testicular impairment. Testosterone treatment in early childhood greatly increased penis length in all patients, but persistent microphallus following surgical treatment was observed at the end of puberty in most patients, with no difference between patients with and without testicular dysfunction (penis length of 68 (60; 75) vs 65 (60; 65) mm; P=0.42). Half the patients presented an adult height more than 5 cm below their target height.
Men diagnosed with idiopathic 46 XY DSD during childhood are at high risk of testicular insufficiency and persistent micropenis, and this should be taken into account during the follow-up.
Juliane Léger, Damir Mohamed, Sophie Dos Santos, Myriam Ben Azoun, Delphine Zénaty, Dominique Simon, Anne Paulsen, Laetitia Martinerie, Didier Chevenne, Corinne Alberti, Jean-Claude Carel and Sophie Guilmin-Crepon
Regular monitoring of serum IGF-I levels during growth hormone (GH) therapy has been recommended, for assessing treatment compliance and safety.
To investigate serum IGF-I SDS levels during GH treatment in children with GH deficiency, and to identify potential determinants of these levels.
Design, patients and methods
This observational cohort study included all patients (n = 308) with childhood-onset non-acquired or acquired GH deficiency (GHD) included in the database of a single academic pediatric care center over a period of 10 years for whom at least one serum IGF-I SDS determination during GH treatment was available. These determinations had to have been carried out centrally, with the same immunoradiometric assay. Serum IGF-I SDS levels were determined as a function of sex, age and pubertal stage, according to our published normative data.
Over a median of 4.0 (2–5.8) years of GH treatment per patient, 995 serum IGF-I SDS determinations were recorded. In addition to BMI SDS, height SDS and GH dose (P < 0.01), etiological group (P < 0.01) had a significant effect on serum IGF-I SDS levels, with patients suffering from acquired GHD having higher serum IGF-I SDS levels than those with non-acquired GHD, whereas sex, age, pubertal stage, treatment duration, hormonal status (isolated GHD (IGHD) vs multiple pituitary hormone deficiency (MPHD)) and initial severity of GHD, had no effect.
These original findings have important clinical implications for long-term management and highlight the need for careful and appropriate monitoring of serum IGF-I SDS and GH dose, particularly in patients with acquired GHD, to prevent the unnecessary impact of potential comorbid conditions.
Elodie Fiot, Delphine Zenaty, Priscilla Boizeau, Jeremy Haigneré, Sophie Dos Santos, Juliane Léger and on behalf of The French Turner Syndrome Study Group
Short stature is a key aspect of the phenotype of patients with Turner syndrome (TS). SHOX haploinsufficiency is responsible for about two-thirds of the height deficit. The aim was to investigate the effect of X-chromosome gene dosage on anthropometric parameters at birth, spontaneous height, and adult height (AH) after growth hormone (GH) treatment.
We conducted a national observational multicenter study.
Birth parameter SDS for gestational age, height, and AH before and after GH treatment respectively, and height deficit with respect to target height (SDS) were classified by karyotype subgroup in a cohort of 1501 patients with TS: 45,X (36%), isoXq (19%), 45,X/46,XX (15%), XrX (7%), presence of Y (6%), or other karyotypes (17%).
Birth weight, length (P<0.0001), and head circumference (P<0.001), height and height deficit with respect to target height (SDS) before GH treatment, at a median age of 8.8 (5.3–11.8) years and after adjustment for age and correction for multiple testing (P<0.0001), and AH deficit with respect to target height at a median age of 19.3 (18.0–21.8) years and with additional adjustment for dose and duration of GH treatment (P=0.006), were significantly associated with karyotype subgroup. Growth retardation tended to be more severe in patients with XrX, isoXq, and, to a lesser extent, 45,X karyotypes than in patients with 45,X/46,XX karyotypes or a Y chromosome.
These data suggest that haploinsufficiency for an unknown Xp gene increases the risk of fetal and postnatal growth deficit and short AH with respect to target height after GH therapy.