María Clemente

Objective: Adiposity rebound is the first rise in BMI that occurs after the initial decrease during infancy. Early adiposity rebound, before age 5, is a risk factor for later obesity and metabolic problems. We investigated adiposity rebound in children with Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency (CAH). Design: Longitudinal observational registry study. Methods: Height, weight, and BMI from patients younger than 20 years in the I-CAH Registry was described by non-linear mixed-effects models. Covariates of glucocorticoid dose, mineralocorticoid dose, 17-Hydroxyprogesterone were assessed on growth and bone age. Results: A total of 10 261 visits within 573 patients (43.6% male) showed significant variation in age at latest peak height velocity [8.4 years (SD = 3.0) in boys; 9.0 years (SD = 1.6) in girls]. Peak height velocity was more blunted in boys [7.7 cm/year (SD = 1.4)] than girls [7.4 cm/year (SD = 1.3)] in comparison to normative values. Adiposity rebound occurred earlier than age 5 years in 82% of the cohort, mean age 3.7 years (SD = 1.3) in boys and 3.9 years (SD = 0.9) in girls. Girls prescribed higher doses of glucocorticoid were associated with heavier weight in adolescence and earlier adiposity rebound. Bone age was increasingly advanced in those prescribed higher doses in both sexes. Conclusions: There is a large variation in the timing of adiposity rebound and SITAR-estimated latest peak height velocity in children with CAH. In addition to identifying individuals with CAH who may be at risk of adverse cardiometabolic outcomes these metrics may serve as early surrogate outcomes in future research investigating early-life treatment strategies.

Congenital hyperinsulinism (CHI) is a rare disorder causing persistent hypoglycaemia in infants due to excessive insulin secretion from pancreatic β-cells. It has genetic causes, primarily mutations in ATP-sensitive potassium channel genes (ABCC8, KCNJ11). CHI manifests in three forms—focal, diffuse, and atypical—distinguished by histology and genetics, influencing treatment strategies. Early diagnosis and tailored management are vital to prevent neurological damage. While transient CHI resolves spontaneously, permanent CHI often requires complex medical and/or surgical intervention. Despite advances, long-term neurodisability remains high, highlighting increased need to improve monitoring as well as better therapies with lesser side effects. Acute treatment aims to rapidly normalize glucose levels and long-term treatments include diazoxide (KATP channel agonist) to suppress insulin secretion, though its effectiveness depends on genetic mutation type. Other therapies include somatostatin analogues. Newer emerging therapies include novel glucagon analogues, monoclonal antibodies targeting insulin receptors, GLP-1 receptor antagonist, and selective somatostatin receptor agonist, currently under clinical trials. Along with medical treatment, children may require additional feeding support with carbohydrate supplementation using glucose polymers and special formulas. Continuous glucose monitoring aids detection but has limitations. Surgery is preferred for focal lesions to potentially cure CHI.

To evaluate the baseline and follow-up clinical and radiological characteristics of a paediatric cohort initially diagnosed with isolated congenital growth hormone deficiency (IGHD) and pituitary morphology abnormality in MRI. Observational, ambispective and longitudinal review of paediatric patients with an initial diagnosis of growth hormone deficiency with pituitary morphology abnormality in MRI followed-up in a single tertiary hospital. After mean 11.3 (± 3.5DS) years of follow-up, the thirty patients (20 males) were classified into two groups: (1) isolated congenital growth hormone deficiency (IGHD) with 24 patients (9.5 years median follow up), and (2) combined pituitary hormone deficiencies (CPHD) with 6 patients (13.5 years median follow up). Median age at diagnosis was IGHD 3.0 [2.0–4.0] and CPHD 3.0 [1.5–5.2] years. Regarding the cerebral MRI scan results, 2 patients had septo-optic dysplasia (CPHD), 5 had pituitary stalk interruption syndrome (3 IGHD), one had ectopic posterior pituitary (IGHD), 16 had anterior pituitary hypoplasia (15 IGHD) and 6 had the latter two conditions combined (5 IGHD). In genetic studies, 1 of 25 patients had positive NGS panel results and it was in the IGHD group. The target gene detected was GLI2. Clinical exome sequencing was performed with six patients, yielding inconclusive results (1 in the IGHD group and 5 in the CPHD group). Array CGH was performed with eight patients (4 in the IGHD group and 4 in the CPHD group) and was negative in all patients. In the CPHD group, associated deficiencies begin to appear after 5 years [4.0–6.0] median follow-up, with thyrotropin being the most frequent (80%), followed by gonadotropin deficiency. ACTH and AVP deficiencies were less frequent. Multiple hormone deficiencies were diagnosed during this cohort’s follow-up evaluation, whose first presentation was isolated growth hormone deficiency and pituitary morphology abnormality in MRI. Pathogenic gene variant involved in congenital hypopituitarism (GLI2) was found in one patient. Regular follow up of pituitary hormonal function in such patients is advisable due to the risk of new added deficiencies.

Genetic defects in the TSH receptor (TSHR) can cause poor thyroid differentiation (thyroid dysgenesis) and/or thyroid malfunction (thyroid dyshormonogenesis). The phenotype spectrum is wide: from severe congenital hypothyroidism to mild hyperthyrotropinemia. Over 250 TSHR variants have been published, many uncharacterized in vitro. We aimed to genetically characterize patients with thyroid dyshormonogenesis with TSHR defects and to study in vitro the effect of the genetic variants to establish the genotype–phenotype relationship. Pediatric patients with thyroid dyshormonogenesis (160 patients, Catalan CH neonatal screening program, confirmation TSH range: 18.4–100 mIU/L), were analyzed by a high-throughput gene panel. In vitro studies measuring the TSH-dependent cAMP–response–element activation were performed. Five patients with mild or severe thyroid dyshormonogenesis presented six TSHR variants, two unpublished. Each variant showed a different in vitro functional profile that was totally or partially deleterious. Depending on the genotype, some of the variants showed partial deficiency in both genotypes, whereas others presented a different effect. In conclusion, the percentage of patients with thyroid dyshormonogenesis and candidate variants in TSHR is 3.13%. Our in vitro studies contributed to the confirmation of the pathogenicity of the variants and highlighted the importance of studying the effect of the patient’s genotype for a correct diagnostic confirmation.

Thyroid dyshormonogenesis (THD) is a heterogeneous group of genetic diseases caused by the total or partial defect in the synthesis or secretion of thyroid hormones. Genetic variants in DUOX2 can cause partial to total iodination organification defects and clinical heterogeneity, from transient to permanent congenital hypothyroidism. The aim of this study was to undertake a molecular characterization and genotype–phenotype correlation in patients with THD and candidate variants in DUOX2. A total of 31 (19.38%) patients from the Catalan Neonatal Screening Program presented with variants in DUOX2 that could explain their phenotype. Fifteen (48.39%) patients were compound heterozygous, 10 (32.26%) heterozygous, and 4 (12.90%) homozygous. In addition, 8 (26.67%) of these patients presented variants in other genes. A total of 35 variants were described, 10 (28.57%) of these variants have not been previously reported in literature. The most frequent variant in our cohort was c.2895_2898del/p.(Phe966SerfsTer29), classified as pathogenic according to reported functional studies. The final diagnosis of this cohort was permanent THD in 21 patients and transient THD in 10, according to reevaluation and/or need for treatment with levothyroxine. A clear genotype–phenotype correlation could not be identified; therefore, functional studies are necessary to confirm the pathogenicity of the variants.

Prolyl endopeptidase-like (PREPL) deficiency (MIM#616224) is a rare congenital disorder characterised by neonatal hypotonia and feeding difficulties, growth hormone (GH) deficiency and hypergonadotropic hypogonadism. This syndrome is an autosomal recessive disease resulting from mutations in the PREPL gene (MIM#609557). Herein we report a 7-year-old female patient with biallelic mutations in PREPL (c.1528C>T in one allele and whole gene deletion in the other) with early growth impairment in infancy. GH deficiency was confirmed at 20 months of life. Recombinant GH treatment was introduced with a good response. Her clinical features were similar to those of previously reported cases. The description of new patients with PREPL deficiency syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease.

Introduction Patients with congenital hyperinsulinism due to ABCC8 variants generally present severe hypoglycaemia and those who do not respond to medical treatment typically undergo pancreatectomy. Few data exist on the natural history of non-pancreatectomised patients. This work aims to describe the genetic characteristics and natural history in a cohort of non-pancreatectomised patients with congenital hyperinsulinism due to variants in the ABCC8 gene. Subjects and Methods Ambispective study of patients with congenital hyperinsulinism with pathogenic or likely pathogenic variants in ABCC8 treated in the last 48 years and who were non-pancreatectomised. Continuous Glucose Monitoring (CGM) has been periodically performed in all patients since 2003. An oral glucose tolerance test (OGTT) was performed if hyperglycemia was detected in the CGM. Results Eighteen non-pancreatectomised patients with ABCC8 variants were included. Seven (38.9%) patients were heterozygous, eight (44.4%) compound heterozygous, two (11.1%) homozygous, and one patient carried two variants with incomplete familial segregation studies. Seventeen patients were followed-up and twelve (70.6%) of them evolved to spontaneous resolution (median age 6.0±4years; range:1-14). Five out of these twelve patients (41.7%) subsequently progressed to diabetes with insufficient insulin secretion. Evolution to diabetes was more frequent in patients with biallelic variants in the ABCC8 gene. Conclusion The high remission rate observed in our cohort makes conservative medical treatment a reliable strategy for the management of patients with congenital hyperinsulinism due to ABCC8 variants. In addition, a periodic follow-up of glucose metabolism after remission is recommended as a significant proportion of patients evolved to impaired glucose tolerance or diabetes (biphasic phenotype).

Preterm and low birth weight (LBW) neonates may present with thyroid dysfunction during a critical period for neurodevelopment. These alterations can be missed on routine congenital hypothyroidism (CH) screening which only measures thyroid stimulating hormone (TSH). The objective of this study was to evaluate a protocol for thyroid function screening (TFS) six years after national implementation. Serum TSH and free thyroxine (fT4) were measured during the second week of life in neonates below 31 weeks. Patients with abnormal TFS (fT4 5 mU/L) were followed up with repeated tests until normal levels were reported. Patients who were still on levothyroxine (LT4) at three years of age were re-evaluated. Five-hundred and nine neonates were included. Thyroid dysfunction was detected in 170 neonates (33%); CH n=20 (3.9%) including typical CH n=1; delayed TSH elevation CH n=19; hypothyroxinemia of prematurity (HOP) n=15 (2.9%); and transient hyperthyrotropinemia n=135 (26.5%). Twenty-one neonates (4.1%) were treated (20 for CH and 1 for HOP). At 3-year follow-up only three patients were diagnosed with permanent CH and still need treatment. LBW infants tended to have TSH levels higher than those with adequate weight. This protocol was able to detect thyroid dysfunction in preterm neonates who were not identified by the current program based on TSH determination in whole-blood. This thyroid dysfunction seems to resolve spontaneously in a few months in the great majority of neonates, but in some cases LT4 could be needed. There is a critical need for specific guidelines regarding the follow-up and re-evaluation of transient CH in preterm neonates.

To investigate the incidence of pseudotumor cerebri syndrome in children treated with growth hormone in a paediatric hospital and to identify risk factors of this complication. Prospective pilot study of paediatric patients treated with growth hormone, prescribed by the Paediatric Endocrinology Department, between February 2013 and September 2017. In all these patients, a fundus examination was performed before starting treatment and 3-4 months later. 289 patients were included: 244 had a growth hormone deficiency, 36 had short stature associated with small for gestational age, six had a mutation in the SHOX gene and three had Prader-Willi Syndrome. Five patients developed papilledema, all were asymptomatic and had a growth hormone deficiency: one had a craniopharyngioma, two a polymalformative syndrome associated with hypothalamic-pituitary axis anomalies, one patient a non-specified genetic disease with hippocampal inversion and one patient with normal magnetic resonance imaging who had developed a primary pseudotumor cerebri syndrome years before. Growth hormone treatment is a cause of pseudotumor cerebri syndrome. In our series, at risk patients had growth hormone deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosome diseases. Fundus examination should be systematically screened in all patients in this at-risk group irrespective of the presence or not of symptoms.