Mild long-lasting untreated idiopathic SH may be associated with subtle proatherogenic abnormalities. Although it is difficult to establish whether these mild abnormalities represent the early steps in the initiation of atherogenesis, these children need to be carefully monitored for metabolic complications.

Subclinical hypothyroidism is defined as serum levels of TSH above the upper limit of the reference range, in the presence of normal concentrations of total T or free T. This biochemical profile might be an indication of mild hypothyroidism, with a potential increased risk of metabolic abnormalities and cardiovascular disease recorded among adults. Whether subclinical hypothyroidism results in adverse health outcomes among children is a matter of debate and so management of this condition remains challenging. Mild forms of untreated subclinical hypothyroidism do not seem to be associated with impairments in growth, bone health or neurocognitive outcome. However, ongoing scientific investigations have highlighted the presence of subtle proatherogenic abnormalities among children with modest elevations in their TSH levels. Although current findings are insufficient to recommend levothyroxine treatment for all children with mild asymptomatic forms of subclinical hypothyroidism, they highlight the potential need for assessment of cardiovascular risk among children with this condition. Increased understanding of the early metabolic risk factors associated with subclinical hypothyroidism in childhood will help to improve the management of affected individuals.

Objective: The treatment of children with subclinical hypothyroidism (SH) is controversial for TSH values between 4.5 and 10 mU/l. The aim of this cross-sectional, controlled study was to evaluate growth and intellectual outcome in children with persistent SH who have never been treated with levothyroxine. Design and methods: Clinical and auxological parameters, thyroid function, and intellectual outcome were evaluated in 36 children with persistent SH at the age of 9.7G0.6 (range 4-18.0) years. Children had been followed longitudinally for 3.3G0.3 (range 2.0-9.3) years, from first diagnosis of SH until enrollment in the study. Thirty-six age-and sex-matched children were enrolled in the study as controls. Results: At study entry, height (K0.8G0.2 SDS), bone age/chronological age (BA/CA ratio 0.92 G0.6), and body mass index (BMI K0.1G0.2 SDS) in SH children were normal. Despite long-term duration of SH, none of these parameters showed a worsening with respect to height (K0.7G0.2 SDS), BA/CA (0.97G0.03), and BMI (K0.1G0.2) at the time of first SH detection. None of the children showed overt signs or symptoms of hypothyroidism during the follow-up. Verbal (99.1G2.2), performance (100.4G1.9), and full-scale (99.7G1.9) intelligence quotient (IQ) scores in SH children were normal and comparable to those of controls. No relationship was detected between IQ scores and the degree or duration of SH. Conclusions: Persistent SH in children is not associated with alterations in growth, bone maturation, BMI, and cognitive function or other complaints that could be ascribed to SH even after several years without therapeutic intervention.

Objective: To investigate the effect of levothyroxine (L-T4) treatment on early markers of atherosclerotic disease in children with mild idiopathic subclinical hypothyroidism (SH). Design: Two-year, open, case-control prospective study. Methods: A total of 39 children, aged 9.18 ± 3.56 years, with SH and 39 healthy controls were enrolled in the study. Waist-to-height ratio (WHtR), blood pressure, triglycerides, total cholesterol (total-C), HDL-C, LDL-C, non-HDL-C, triglycerides/HDL-C, atherogenic index (AI), homocysteine (Hcy), asymmetric dimethylarginine (ADMA), flow-mediated dilation (FMD) and intima-media thickness (IMT) were evaluated at baseline and after 2 years of L-T4 treatment in SH children and after 2 years of follow-up in controls. Results: At study entry WHtR was higher in SH subjects compared with controls (0.56 ± 0.08 vs 0.49 ± 0.07, P = 0.04) and significantly decreased after 2 years of treatment (0.50 ± 0.06, P < 0.0001). Mean HDL-C levels (50.47 ± 11.43 vs 61.06 ± 13.83 mg/dL, P = 0.002) were lower, while triglycerides/HDL-C (1.63 ± 1.07 vs 1.19 ± 0.69, P = 0.05), AI (3.32 ± 0.90 vs 2.78 ± 0.68, P = 0.005), and Hcy (9.35 ± 2.61 vs 7.71 ± 1.94 μmol/L, P = 0.01) were higher in SH subjects compared with controls and improved after 2 years of treatment (HDL-C 56.26 ± 13.76 mg/dL, P < 0.0001; triglycerides/HDL-C 1.23 ± 0.78, P = 0.006; AI 2.82 ± 0.68, P < 0.0001; and Hcy 8.25 ± 2.09 μmol/L, P = 0.06). ADMA concentrations at baseline were higher in SH subjects compared with controls (0.77 ± 0.21 vs 0.60 ± 0.16 μmol/L, P = 0.001) and decreased after therapy (0.58 ± 0.13 μmol/L, P < 0.0001). FMD, IMT and other metabolic parameters were not different among SH subjects and controls at baseline and after 2 years. Conclusions: Children with SH may have subtle pro-atherogenic abnormalities. Although L-T4 treatment exerts some beneficial effects, the long-term impact of therapy on metabolic outcomes in SH children still remains unclear.

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BackgroundSubclinical hypothyroidism (SH) is a relatively common condition characterized by a mild persistent thyroid failure. The management of children with SH is still a controversial issue and the decision to treat with L-thyroxine represents a clinical dilemma. Thyroid hormone and TSH play an important role in skeletal growth and bone mineral homeostasis.AimTo evaluate whether untreated idiopathic SH may affect bone health in childhood and to compare two different diagnostic tools such as dual-energy X-ray densitometry (DXA) and quantitative ultrasound (QUS).Patients and MethodsTwenty-five children and adolescents (11 males) aged 9.8 ± 3.5 years (range 4.2-18.7) with untreated idiopathic SH were enrolled in the study. SH was diagnosed on the basis of normal FT4 levels with TSH concentrations between 4.2 and 10 mU/l. Children have been followed for 3.3 ± 0.3 years from the time of SH diagnosis. Twenty-five healthy children, age- and sex-matched, were enrolled as controls. Patients and controls underwent DXA to evaluate lumbar spine bone mineral density (BMD) and QUS at proximal phalanges of the non-dominant hand to assess bone quality, measured as amplitude-dependent speed of sound (Ad-SoS) and bone transmission time (BTT).ResultsMean BMD Z-score was −0.4 ± 1.36 in patients and −0.2 ± 1.2 in controls. Mean Ad-SoS Z-score was 0.01 ± 1.0 in patients and 0.1 ± 1.2 in controls and mean BTT Z-score was −0.03 ± 0.8 and 0.04 ± 1.1 respectively. All values were within the normal range, both in patients and in controls. There were no statistically significant differences between the two groups.ConclusionBone health, evaluated by lumbar spine DXA and phalangeal QUS, is not impaired in our children, despite long-term duration of idiopathic SH. Data about bone status provided by QUS are comparable to those provided by DXA. Therefore, QUS may represent a good, cheaper and safe screening test for bone evaluation in children with SH.

The Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome is an autosomal recessive disease presenting with immunodeficiency secondary to hypo- or agammaglobulinemia, developmental delay, and facial anomalies. Centromeric instability is the cytogenetic hallmark of the disorder which results from targeted chromosomal rearrangements related to a genomic methylation defect. We describe a patient carrying a homozygous mutation of the ZBTB24 gene, which has been recently shown to be responsible for ICF syndrome type 2. Our patient presented with intellectual disability, multiple café-au-lait spots, and a large cerebral arachnoidal cyst. Although laboratory signs of impaired immune function, such as reduced serum IgM were detected, our patient did not present clinical manifestations of immunodeficiency. Brain malformations have not been reported so far in ICF syndrome and it can be speculated that ZBTB24 mutations may alter cerebral development. Nevertheless, we cannot rule out that the presence of the cerebral cyst in the patient is coincidental. In summary, our patient illustrates that clinical evidence of immunodeficiency is not a universal feature of ICF2 syndrome type 2 and suggests that brain malformations may be present in other ICF cases.

Background: Septo-optic dysplasia (SOD) is a heterogeneous congenital condition. The aim of this study was to investigate the clinical phenotypes of a large cohort of children with SOD, Multiple Pituitary Hormone Deficiency (MPHD) and Optic Nerve Hypoplasia (ONH), with a focus on endocrine testing. Methods: Retrospective single-centre longitudinal study of children with SOD (n:171), MPHD (n:53) and ONH (n:35). SOD+ and SOD-indicate patients with or without hypopituitarism, respectively. Findings: All deficits were more frequent and occurred earlier in MPHD than SOD+ [Hazard Ratios (HR): 0¢63 (0¢45,0¢89) for GH, 0¢48(0¢34,0¢69) for TSH, 0¢55(0¢38,0¢80) for ACTH, 0¢28(0¢11,0¢68) for gonadotropins], except Diabetes Insipidus (DI) [HR: 2¢27(0¢88,5¢9)]. Severe hypothalamo-pituitary (H-P) abnormalities were more frequent in MPHD [80¢0% vs 41¢6%, p<0¢0001 for Ectopic Posterior Pituitary (EPP)]. Stalk and PP abnormalities were associated with more severe endocrine phenotypes and placed a subgroup of SOD+ at risk of developing deficits earlier. SOD and ONH shared heterogeneous phenotypes ranging from pubertal delay to precocity and from leanness to extreme obesity, whilst MPHD had GnD and obesity only. Mortality was recorded in 4¢2% (6/144) SOD and 3¢2% (1/31) ONH, and only in patients with multisystem phenotypes. Interpretation: More than a single disease, SOD represents a spectrum of malformative conditions involving different brain structures and characterised by a dynamic and sequential nature of endocrine. In contrast, MPHD displays a more homogeneous phenotype of (mainly) anterior pituitary early-onset failure. Stalk and PP abnormalities place a subgroup of SOD+ at a higher risk of early-onset deficits. Additionally, there are striking differences between the SOD and MPHD cohorts in terms of pubertal progression. The shared phenotypes between ONH and SOD could be partly explained by common hypothalamic dysfunction. The differences between the cohorts are important as they may aid in planning management and preventing morbidity by dictating earlier interventions. Funding: M.C., M.G., and N.I. were supported by the European Society of Paediatric Endocrinology (ESPE) through ESPE Clinical Fellowships.