Hepatomegaly and fatty liver disease secondary to central hypothyroidism in combination with macrosomia as initial presentation of IGSF1 deficiency syndrome.

PURPOSE: IGSF1 deficiency syndrome (immunoglobulin superfamily member 1) is considered the most common sex-linked cause of secondary congenital hypothyroidism and is characterized by a wide variety of other clinical and biochemical features, including hypoprolactinemia, transient and partial growth hormone deficiency, early/normal timing of testicular enlargement but delayed testosterone rise in puberty, and adult macro-orchidism. Congenital central hypothyroidism is a rare disease (1:65,000 births); the detection of which may be delayed and missed by neonatal screening programs since most neonatal screening programs are based on TSH determination in dried blood spots only. Untreated hypothyroidism may cause abnormal liver biochemistry and non-alcoholic fatty liver disease. Our aim is to report a case of secondary hypothyroidism in an infant with an uncommon initial presentation. CASE PRESENTATION (METHODS/RESULTS): A 3-month-old male baby was referred to our hospital due to elevated alpha-fetoprotein levels, hypercholesterolemia, and macrosomia. Initial investigations revealed enlarged fatty liver and central hypothyroidism. Pituitary insufficiency was biochemically excluded and a pituitary MRI showed normal findings. Upon genetic analysis, a hemizygous variant NM_001170961.1:c.2422dup, p.(His808Profs*14), in IGSF1 gene was detected, establishing the diagnosis of the IGSF1 deficiency syndrome. In our patient, no other clinical findings were identified. Treatment with levothyroxine led to the remission of liver disease. CONCLUSION: Liver disease may be the initial presentation of secondary hypothyroidism in neonates and infants. Macrosomia in patients with isolated secondary central hypothyroidism is a strong indicator of IGSF1 syndrome.

McCune-Albright Syndrome: A Case Report and Review of Literature.

McCune-Albright syndrome (MAS) is a rare sporadic condition defined by the classic triad of fibrous dysplasia of bone, café au lait skin macules, and hyperfunctioning endocrinopathies. The molecular basis of MAS has been ascribed to the post-zygotic somatic gain-of-function mutations in the GNAS gene, which encodes the alpha subunit of G proteins, leading to constitutive activation of several G Protein-Coupled Receptors (GPCRs). The co-occurrence of two of the above-mentioned cardinal clinical manifestations sets the diagnosis at the clinical level. In this case report, we describe a 27-month-old girl who presented with gonadotropin-independent precocious puberty secondary to an estrogen-secreting ovarian cyst, a café au lait skin macule and growth hormone, and prolactin excess, and we provide an updated review of the scientific literature on the clinical features, diagnostic work-up, and therapeutic management of MAS.

High frequency of autoimmune thyroiditis in euthyroid girls with premature adrenarche.

Objective: The purpose of this study was to investigate the frequency of autoimmune thyroiditis (AT) among euthyroid prepubertal girls presenting with premature adrenarche (PA). We also aimed to identify the clinical, metabolic, and endocrine profile of girls with AT and concurrent PA and compare them to girls with AT without PA, PA alone and healthy controls. Methods: Ninety-one prepubertal girls aged 5-10 years, who attended our department for AT, PA and normal variants of growth and puberty were recruited for the study: 73 girls had PA, 6 AT without PA and 12 were referred for investigation of growth. All girls underwent clinical examination, detailed biochemical and hormonal screen. Standard dose Synachten stimulation test (SDSST) and oral glucose tolerance test (OGTT) were performed in all girls with PA. The whole study population was divided in 4 groups: Group PA-/AT+ included 6 girls with AT without PA; Group PA+/AT- PA subjects without AT; Group PA+/AT+ girls with PA and concomitant AT; Group PA-/AT- twelve healthy girls without PA nor AT (controls). Results: Among 73 girls presenting with PA 19 had AT (26%). BMI, systolic blood pressure (SBP) and the presence of goiter significantly differed between the four groups (p = 0.016, p = 0.022 and p < 0.001, respectively). When comparing hormonal parameters among the four groups significant differences were found in leptin (p = 0.007), TSH (p = 0.044), anti-TPO (p = 0.002), anti-TG (p = 0.044), IGF-BP1 (p = 0.006), Δ4-Α (p = 0.01), DHEA-S (p = <0.001), IGF-1 (p = 0.012) and IGF-BP3 (p = 0.049) levels. TSH levels were significantly higher in Group PA+/AT+ compared to PA+/AT- and PA-/AT- (p = 0.043 and p = 0.016, respectively). Moreover, girls with AT (Groups PA-/AT+ and PA+/AT+) had higher TSH levels than those in Group PA+/AT- (p = 0.025). Girls in Group PA+/AT + showed higher cortisol response at 60 min post-SDSST than girls in Group PA+/AT- (p = 0.035). During the OGTT, insulin concentrations at 60 min were significantly higher in Group PA+/AT + compared to Group PA+/AT- (p = 0.042). Conclusion: A high frequency of AT among euthyroid prepubertal girls with PA was observed. The combination of PA with AT even in euthyroid state may be associated with a greater degree of insulin resistance, than PA alone.

Whole Exome Sequencing Points towards a Multi-Gene Synergistic Action in the Pathogenesis of Congenital Combined Pituitary Hormone Deficiency.

Combined pituitary hormone deficiency (CPHD) is characterized by deficiency of growth hormone and at least one other pituitary hormone. Pathogenic variants in more than 30 genes expressed during the development of the head, hypothalamus, and/or pituitary have been identified so far to cause genetic forms of CPHD. However, the etiology of around 85% of the cases remains unknown. The aim of this study was to unveil the genetic etiology of CPHD due to congenital hypopituitarism employing whole exome sequencing (WES) in two newborn patients, initially tested and found to be negative for PROP1, LHX3, LHX4 and HESX1 pathogenic variants by Sanger sequencing and for copy number variations by MLPA. In this study, the application of WES in these CPHD newborns revealed the presence of three different heterozygous gene variants in each patient. Specifically in patient 1, the variants BMP4; p.Ala42Pro, GNRH1; p.Arg73Ter and SRA1; p.Gln32Glu, and in patient 2, the SOX9; p.Val95Ile, HS6ST1; p.Arg306Gln, and IL17RD; p.Pro566Ser were identified as candidate gene variants. These findings further support the hypothesis that CPHD constitutes an oligogenic rather than a monogenic disease and that there is a genetic overlap between CPHD and congenital hypogonadotropic hypogonadism.

The Influence of Body Mass Index on the Growth Hormone Peak Response regarding Growth Hormone Stimulation Tests in Children.

INTRODUCTION: Several studies have analyzed the association between the maximal growth hormone serum level obtained during a growth hormone stimulation test (GHMax) and the body mass index-standard deviation score (BMI-SDS). However, as sample sizes were quite small, our study aimed to analyze the association between GHMax and BMI-SDS within a large cohort of 991 children. Further, we investigated other influencing factors, like test type, age, sex, puberty, and preterm birth. METHODS: Children with short stature (height <10th percentile) received growth hormone stimulation tests with arginine or glucagon at the Department of Paediatric Endocrinology of the University of Leipzig Medical Center. The study population included a total of 1,438 tests (633 tests on girls, 805 tests on boys), with the majority consisting of prepubertal children (tests = 1,138). The mean age at testing was 7.74 years. Analyses were carried out on the entire cohort as well as stratified by test types. We performed univariate and multivariate analyses using linear mixed-effect models to assess the effects on GHMax. RESULTS: GHMax and BMI-SDS were significantly negatively associated with an effect size of ß = -1.10 (p < 0.001), independent from the test type. The GHMax values were significantly (p < 0.001) higher for glucagon (mean value: 9.65 ng/mL) than those for arginine tests (mean value: 8.50 ng/mL). Age, sex, premature birth, and puberty were not significantly related to GHMax values. CONCLUSION: We confirmed the negative association between GHMax and weight status of short children found in previous studies. Therefore, considering BMI-SDS may be helpful in the assessment of growth hormone stimulation tests in short-statured children, but it should not be the determining factor for a treatment decision.

A rare case of a giant prolactinoma with atypical histological features: 5 years of follow-up.

BACKGROUND: Giant prolactinomas are rare in childhood and adolescence and represent a challenge in diagnosis and management. CASE PRESENTATION: A 15.7-year-old male adolescent presented with short stature and delayed puberty. On clinical examination, mild right central VII paresis, gait instability, decreased visual acuity, and impaired visual fields were noted. Investigations showed hyperprolactinemia (2209 ng/mL), secondary hypothyroidism, hypogonadotropic hypogonadism, and growth hormone deficiency. Imaging studies showed an enormous invasive skull base mass. Craniotomy was undertaken to debulk the tumor and perform biopsies. Histology revealed a very large atypical, prolactin-secreting pituitary macroadenoma, i.e., a giant prolactinoma. After commencing cabergoline treatment, prolactin concentrations decreased in 5 months and normalized 18 months later, while significant shrinkage of the tumor was observed. The diagnostic work-up for genetic syndromes often associated with sporadic macroadenomas was negative. CONCLUSION: Giant prolactinomas presenting with multiple pituitary hormone deficiencies in childhood or adolescence are rare and require prompt diagnosis and multidisciplinary management.

Stress hyperglycemia, Diabetes mellitus and COVID-19 infection: The impact on newly diagnosed type 1 diabetes.

Several recent studies have documented an increased incidence of newly diagnosed type 1 Diabetes (T1D) cases in children and adolescents during the COVID-19 pandemic and a more severe presentation at diabetes onset. In this descriptive study, we present the experience of the Diabetes Centre of the Division of Endocrinology, Diabetes, and Metabolism of the First Department of Pediatrics of the National and Kapodistrian University of Athens Medical School at "Aghia Sophia" Children's Hospital in Athens, Greece, concerning new cases of T1D diagnosis during the COVID-19 pandemic (March 2020- December 2021). Patients who had already been diagnosed with T1D and needed hospitalization due to poor control during the pandemic have been excluded from this study. Eighty- three children and adolescents with a mean age of 8,5 ± 4.02 years were admitted to the hospital due to newly diagnosed T1D during this 22 months' period in comparison to 34 new cases in the previous year. All patients admitted during the pandemic with a new diagnosis of T1D, presented in their majority with DKA (Ph: 7.2) representing an increase of new severe cases in comparison to previous years (Ph 7.2 versus 7.3, p value: 0.021, in the previous year), [p-value: 0.027]. 49 cases presented with DKA, of which 24 were characterized moderate and 14 severe DKA (28.9% and 16,9%, respectively), while 5 patients newly diagnosed, needed to be admitted to the ICU to recover from severe acidosis. Whether a previous COVID- 19 infection could have been the triggering factor is not supported by the SARS-Cov2 specific antibodies analysis in our cohort of patients. As far as HbA1c is concerned there was no statistically significant difference between the pre COVID-19 year and the years of the pandemic (11.6% versus 11.9%, p- value: 0.461). Triglycerides values were significantly higher in patients with new onset T1D during COVID-19 years compared to those before the pandemic (p value= 0.032). Additionally, there is a statistically significant correlation between Ph and Triglycerides for the whole period 2020-2021 (p-value<0.001), while this correlation is not significant for the year 2019. More large- scale studies are required to confirm these observations.

Myostatin serum levels in children with type 1 diabetes mellitus.

PURPOSE: Type 1 diabetes mellitus (T1DM) can cause several complications, among them myopathy, which can appear even in adolescents. This is of importance, since skeletal muscle is the largest of the insulin-sensitive tissues and thus plays a significant role in glucose homeostasis. A prime regulator of skeletal muscle mass is myostatin, a protein which has a negative role in skeletal muscle development but also in glucose homeostasis, causing insulin resistance. Since myopathy is a complication of T1DM and myostatin is a fundamental regulator of skeletal muscle and is also involved in glucose homeostasis, we investigated the serum levels of myostatin in children with T1DM. METHODS: We determined myostatin serum levels using ELISA in 87 children with T1DM aged 10.62 ± 3.94 years, and in 75 healthy children aged 10.46 ± 3.32 years old. RESULTS: Myοstatin was significantly elevated in T1DM compared to the healthy control children (23.60 ± 7.70 vs 16.74 ± 6.95 ng/ml, p < 0.0001). Myostatin was not correlated with body mass index (BMI) SD or hemoglobin A1c (HbA1c). CONCLUSION: Children with T1DM have significantly higher serum levels of myostatin compared to healthy children of the same age and BMI SD. The elevated myostatin in T1DM could reflect impaired muscle function and/or glucose metabolism, or could represent a homeostatic mechanism.

ROHHAD syndrome - A still unrecognized cause of childhood obesity: report of three cases.

Objectives Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) is a rare, potentially fatal, pediatric syndrome. Case presentations We describe three cases of ROHHAD-syndrome in Greece. The main and earliest symptom was the excessive and rapid weight gain at 5, 2, and 3 years of age. Years after the onset of obesity, the patients developed hypothalamic dysfunction with various endocrinological abnormalities (at 9, 8, and 6.8 years, respectively), autonomic dysregulation and finally, alveolar hypoventilation (at 14.6, 8, and 7.8 years, respectively), leading to the diagnosis of ROHHAD-syndrome. Conclusions The rarity of the syndrome, the variable symptoms' presentation, and the lack of specific diagnostic tests could explain why no previous cases have been reported from our country. The rapid onset of obesity was underestimated, and the patients were misdiagnosed with other more common obesity syndromes. Therefore, we propose a questionnaire to help physicians identify patients with ROHHAD-syndrome.