Illness stress-induced transient hyperglycemia in a patient with a novel YIPF5 homozygous missense variant: expanding the phenotype.

A recently described type of neonatal diabetes mellitus is caused by mutations in the YIPF5 gene and is combined with manifestations from the central nervous system, including developmental delay, epilepsy, and microcephaly. The molecular pathophysiology behind this phenotype involves the breakdown of the endoplasmic reticulum stress response due to the loss of protein folding capacity. This results in overt diabetes present from very early in life. Herein, we describe a patient with a newly reported variant in the YIPF5 gene, who presented with short events of severe hyperglycemia, induced by the stress of common illnesses, which completely resolved after recovery. We discuss the nature of transient hyperglycemia in the context of the YIPF5 gene variant and compare this phenotype with the previously described cases.

Evaluation of copeptin in children after stimulation with clonidine or L-Dopa.

OBJECTIVES: Arginine-stimulated serum copeptin has been proposed as a new method to diagnose arginine vasopressin (AVP) deficiency in children and adolescents. Herein we investigated the secretagogic potential of clonidine or L-Dopa on the copeptin serum levels in children. METHODS: Eight stimulation tests (4 with clonidine and 4 with L-Dopa) were performed in eight children (5 boys and 3 girls) with a median age of 6.5 years-old, evaluated for short stature due to possible growth hormone deficiency. Serum copeptin levels were measured at 30, 60, 90, and 120 min after administration of clonidine or L-Dopa. RESULTS: Copeptin levels in serum did not show any significant change in either test (clonidine or L-Dopa). The values of copeptin levels compared to the baseline value did not deviate more than 5 % in the clonidine arm (p=0.60) or 8 % in the L-Dopa arm (p=0.75) respectively. CONCLUSIONS: Data do not support the use of L-Dopa or clonidine as stimulants for evaluating AVP relating disorders in clinical pediatric practice.

Osteoprotegerin in infection-induced acute inflammatory states in children.

Background and aims: Osteoprotegerin (OPG) is a tumor necrosis factor receptor superfamily member which increases in chronic inflammation and is associated with altered bone turnover and cardiovascular complications. In this study, we investigated whether OPG increases during acute inflammatory states induced by infections in children and correlated its levels with other biomarkers. Materials and methods: This is a prospective study that included 59 patients with documented bacterial infections, 20 with viral infections and 20 healthy controls. OPG, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cells (WBC) were measured. Results: OPG serum levels were significantly increased during inflammation induced by a bacterial infection, compared to viral infection and controls (4.17 pmol/l (2.40-12.12) vs 3.2 (1.66-5.33) and 3 pmol/l (2.13-4.76), respectively, p < 0.001). In addition, OPG correlated well with CRP (rho = 0.428, p = 0.0011), ESR (rho = 0.3, p = 0.026), and WBC (rho = 0.266, p = 0.05) only in the group with bacterial infection. The sensitivity of CRP in detecting a bacterial infection was superior to OPG (67.3% vs 38.3%). Conclusion: This study provides proof of concept that OPG increases differentially in bacterial infections, although with a lower sensitivity than CRP. Further studies are needed to define the role of OPG during the inflammatory states of infection in pediatric infections.

Reversibility of disturbed pituitary function in pediatric conditions with psychological stressors: implications for clinical practice.

The complex communication network between the central nervous system and the hypothalamic-pituitary axis forms the basis of endocrine functional plasticity, which facilitates adaptation to changing internal and external conditions, but also makes it vulnerable to the negative effects of stressful psychological factors. Herein, clinical conditions such as functional hypothalamic amenorrhea, eating disorders, growth faltering, post-traumatic stress disorder, and pubertal disorders that may emerge during childhood or adolescence, their origin possibly including psychological stressors, are analyzed regarding their genetic susceptibility and reversibility of endocrine function. A discussion on the optimization of therapeutic management defined by managing stress and maximizing the degree and rate of reversibility follows.

Safety and Efficacy of Bilateral Epiphysiodesis Surgery to Reduce Final Height in Extremely Tall Adolescents - A Follow-up Study.

INTRODUCTION: Treatment options in patients with extreme tall stature are limited. Bilateral epiphysiodesis has emerged as a possible treatment method aiming to reduce final height. However, there is still insufficient data on long-term safety and final height outcome. Therefore, the aim of this study was to assess the efficacy and safety of bilateral epiphysiodesis to reduce final adult height in tall adolescents. METHODS: The study population consisted of 72 patients with extreme tall stature who were followed at the Pediatric Endocrine Clinic at the Karolinska University Hospital, Stockholm (Sweden) and subsequently underwent bilateral epiphysiodesis around the knees (girls n=45, boys n=27). RESULTS: When compared to the final height prediction at time of surgery, the procedure significantly reduced the achieved final height by a mean of 3.6 cm ± 0.4 cm in girls (p<0.001; 26.0 ± 2.9 % reduction) and 8.6 ± 0.9 cm in boys (p<0.001; 40.5 ± 3.0 % reduction). Furthermore, a negative correlation was observed between the absolute height reduction and the bone age at time of surgery, which was stronger in boys (r=-0.63, p<0.001) than in girls (r=-0.44, p<0.001). Besides reducing final height, body proportions were affected in all patients subjected to bilateral epihyseodesis. However, as tall individuals typically have relatively long legs, body proportions were rather normalized after the surgery. There were no serious complications reported. CONCLUSION: This study suggests that bilateral epiphysiodesis is an efficient and safe method to reduce final height in extremely tall adolescent girls and boys. The achieved height reduction was higher in boys and when performed at an earlier bone age. Importantly, no serious side-effects were reported. However, a continued follow-up is still warranted to detect any potential rare complications.

Diabetic ketosis vs ketoacidosis as initial presentation of pediatric type 1 diabetes mellitus. Associated features and rate of progression during the first two years after diagnosis.

AIMS: In this study we described the clinical and laboratory features of children presented with diabetic ketosis or diabetic ketoacidosis at diagnosis of type 1 diabetes (T1DM) and evaluated its course up to 2 years after initial diagnosis to investigate the progression rate of T1DM in both groups. METHODS: This was a prospective longitudinal cohort study that included 59 children and adolescents presented with either diabetic ketosis (DK) (n = 27) or diabetic ketoacidosis (DKA) (n = 32) at their first diagnosis with T1DM. RESULTS: Apart from the metabolic state of presentation at diagnosis, differences in the other basic clinical and laboratory features of both DK and DKA were not statistically significant (age, BMI, pre- diagnosis symptomatic period, HbA1c, multiplicity of autoantibodies positivity, fasting insulin, and total IgG levels), except from the C-peptide and IgA levels which were lower in DKA (p < 0.05). Regarding family history, only the DK group had individuals with a parent diagnosed with T1DM (p = 0.001). During follow-up there was no difference in the levels of HbA1c, basal insulin dose, and insulin/carbohydrate ratio between the DK and DKA group at 3,6,12 and 24 months' time points. CONCLUSIONS: The severity of presentation of T1DM (DK or DKA) is not associated to the rate of progression of the disease course after diagnosis.

A Novel, Heterozygous, de novo Splicing Variant Affecting the Intracellular Domain of the Growth Hormone Receptor causing a mild short stature.

INTRODUCTION: Although the majority of Growth Hormone insensitivity syndrome (GHIS) cases are classical, the spectrum of clinical phenotypes has expanded to include "atypical" GHIS subjects with milder phenotypes due to very rare heterozygous growth hormone receptor (GHR) mutations with dominant negative effects. CASE PRESENTATION: A 13-year-old pubertal boy presented with short stature (-1.7 SDS) and delayed bone age (11.5 years). His serum IGF-1 was low (16 ng/ml; reference range: 179-540). IGFBP-3 (1.3 mg/L; 3.1-9.5), and ALS (565 mU/ml; 1500-3500) were also low. GH stimulation test was normal, and GHBP markedly elevated (6300pmol/L; 240-3000). Additionally, the boy had insulin resistance and liver steatosis. His final height reached -1.8 SDS, which was 3.0 SDS below his mid-parental height. GHR gene from genomic DNA and established primary fibroblast culture was analyzed and a synonymous heterozygous GHR: c.945G>A variant, in the last nucleotide of exon 9 (encoding intracellular domain of GHR) was identified. In vitro analysis of the GHR cDNA demonstrated a splicing defect, leading to the heterozygous excision of exon 9. The final predicted product was a truncated GHR protein which explained the elevated GHBP levels. CONCLUSION: We describe the first synonymous heterozygous GHR splicing variant in exon 9 encoding part of the intracellular domain of GHR identified in a patient with mild short stature, thus supporting the continuum of genotype-phenotype of GHIS.

A mild and transient form of autosomal recessive pseudohypoaldosteronism type 1 caused by a novel mutation in the SCNN1A gene.

We investigate the genetic etiology in a cohort of patients with a clinical, biochemical, and hormonal profile suggestive of a mild and transient form of pseudohypoaldosteronism type 1 (PHA1). Twelve patients with PHA1 from four different families with clinical and biochemical data were analyzed. The coding regions of NR3C2 and SCNN1A genes were sequenced. Human α-epithelial sodium channel (ENaC) wild-type (wt), αPhe226Cys and αPhe226Ser ENaC variants were expressed in Xenopus laevis oocytes to evaluate ENaC activity. The protein expression of α-ENaC wt and mutants was determined by Western blot. All patients were homozygotes for the p.Phe226Cys mutation of the α subunit of ENaC. In functional studies in X. laevis oocytes, p.Phe226Cys caused a significant reduction of ENaC activity (83% reduction), reduced the number of active ENαC mutant channels, and reduced the basal open probability compared with wt. Quantitative Western blot analysis revealed that the reduced activity of ENαC mutant channels was due to a reduced ENaC protein expression for the αPhe226Cys compared with wt. We present 12 patients from four different families with a mild and transient autosomal recessive PHA1 due to a novel homozygous missense mutation in the SCNN1A gene. Functional studies showed that the p.Phe226Cys substitution mutation in ENaC leads to a partial loss of function resulting mainly from both a decrease in the intrinsic ENaC activity and a reduction in channel expression at the protein level. The partial loss of ENaC function could explain the mild phenotype, variable expressivity, and the transient course of the disorder in these patients.NEW & NOTEWORTHY This paper demonstrates that mild autosomal recessive pseudohypoaldosteronism type 1 (PHA1) due to p.Phe226Cys missense mutation in the extracellular domain of ENαC α subunit can be transient, with phenotypic variability even with the normal sweat test, and incomplete penetrance. Functional studies explain the phenotype and denote the importance of the location on the extracellular domain of the SCNN1A p.Phe226Cys mutation for the intrinsic ENaC activity and the channel expression at the protein level.

Dominant-negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes.

Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disease characterized by severe and childhood onset organ-specific autoimmunity caused by mutations in the autoimmune regulator (AIRE) gene. More recently, dominant-negative mutations within the PHD1, PHD2, and SAND domains have been associated with an incompletely penetrant milder phenotype with later onset familial clustering, often masquerading as organ-specific autoimmunity. Patients with immunodeficiencies or autoimmunity where genetic analyses revealed heterozygous AIRE mutations were included in the study and the dominant-negative effects of the AIRE mutations were functionally assessed in vitro. We here report additional families with phenotypes ranging from immunodeficiency, enteropathy, and vitiligo to asymptomatic carrier status. APS-1-specific autoantibodies can hint to the presence of these pathogenic AIRE variants although their absence does not rule out their presence. Our findings suggest functional studies of heterozygous AIRE variants and close follow-up of identified individuals and their families.

Acquired idiopathic isolated ACTH deficiency with associated autoimmune thyroiditis in pediatrics: case report and review of the literature.

OBJECTIVES: Isolated ACTH deficiency (IAD) is defined as an impaired secretion of ACTH from the pituitary gland without any other anterior pituitary hormonal deficits. The idiopathic form of IAD has been described mainly in adults and is thought to be caused by an autoimmune mechanism. CASE PRESENTATION: Herein, we present an 11-year-old _prepubertal previously healthy boy, who suffered a severe hypoglycemic episode short after the initiation of thyroxine for autoimmune thyroiditis and was finally diagnosed with secondary adrenal failure due to idiopathic IAD, after all other etiologies were excluded, thought an extensive diagnostic work-up. CONCLUSIONS: Idiopathic IAD is a rare entity of adrenal insufficiency in pediatrics that should be considered as an etiology of secondary adrenal failure in children, when clinical signs of glucocorticoid deficiency are present and other causes are excluded.

Fear of hyperglycaemia in parents of children with type 1 diabetes mellitus - A multi-centre multinational study.

AIMS: Study aims: (1) developing and validating a novel questionnaire for measuring fear of hyperglycaemia among parents of children with type 1 diabetes (T1D) - the Hyperglycaemia Fear Survey - Parent version (FoHyper-P); (2) investigating correlations between parental fear of hyperglycaemia and objective measures of glycaemic control. METHODS: A multi-centre, multinational study of 152 parents of children with T1D was conducted in three large diabetes clinics from Israel, Poland, and Greece. Inclusion criteria were parents of children aged 6-16 years, at least 6 months from diagnosis, at least 3 months of CGM use and parental involvement in care. Parents filled the FoHyper-P and the Hypoglycaemia Fear Survey - Parent Version (HFS-P). Patient data were obtained via electronic medical records and informative questionnaires. Bonferroni correction was performed to counteract multiple comparisons. RESULTS: Significant strong-moderate correlations were found between FoHyper-P and HFS-P including total questionnaires scoring (r = 0.747, pBonf < 0.001), worries subscales (r = 0.735, pBonf <0.001), and behaviour subscales (r = 0.532, pBonf <0.001). Using linear regression models, we found a positive association between the worry subscale and HbA1C. Weak correlations (p < 0.05, not significant after Bonferroni correction) were found between time in range, time above range and parental fear of hyperglycaemia as well as between worry subscales and a higher HbA1C in the past year, percent of hyperglycaemia and lower TIR. CONCLUSIONS: The FoHyper-P is a novel, validated tool for assessing parental fear of hyperglycaemia. Integrating it into clinical practice addresses an underestimated aspect of parental diabetes management, enabling better care for children with T1D.

Primary Thyroid Diffuse Large B-cell Lymphoma in a Child with Hashimoto's Thyroiditis: A Case Report

Primary thyroid lymphoma (PTL) is a rare thyroid gland cancer, with diffuse large B-cell lymphomas (DLBCL) being extremely rare in children and adolescents. Thus, optimal therapy is debatable. We describe a rare case of thyroid DLBCL in an adolescent girl with a history of Hashimoto thyroiditis (HT), the difficulty in diagnosis and the outcome of treatment. A 12-year-old girl with a nine-year history of HT was admitted with a right-sided painless progressive swelling of the neck. Physical examination and imaging including ultrasound (US), computed tomography (CT) and positron emission tomography/CT revealed an enlarged thyroid gland with right side lymphadenopathy and no metastasis. Two fine needle aspirations were done showing suspected lymphoblastic lesions for non-Hodgkin lymphoma without precise diagnosis. US guided core needle biopsy was finally performed confirming the diagnosis of DLBCL. She was treated according to LMB 96-group B protocol with no surgical removal of thyroid. The patient responded very well to treatment and 14 months later there is no evidence of relapse or metastases. PTL is an extremely rare cause of thyroid malignancy in children. However, it should be considered in the differential diagnosis of a thyroid mass in adolescents presenting with a rapidly enlarging neck mass and a history of HT. It is a treatable condition with a good prognosis, even in aggressive histological subtypes, with no need for thyroidectomy.

Addison's disease without hyperpigmentation in pediatrics: pointing towards specific causes.

INTRODUCTION: Hyperpigmentation of skin and mucous membranes comprises a hallmark of the clinical diagnosis of Addison's disease. However, there have been reports of patients with adrenal insufficiency from diverse causes who did not develop hyperpigmentation. The pathophysiology responsible for the absence of increased pigmentation is not clearly defined in many cases. CASE PRESENTATION: We present a patient with isolated glucocorticoid deficiency due to two novel heterozygous variants in the sphingosine-1-phosphate lyase 1 (SPGL1) gene that did not develop any hyperpigmentation. DISCUSSION: We elaborate on the presumed mechanism of the absence of hyperpigmentation in adrenal insufficiency due to SPGL1 deficiency and discuss the other reported cases of Addison's disease without hyperpigmentation and the possible mechanism accounted for. CONCLUSION: Absence of hyperpigmentation, a basic component of the clinical diagnosis of Addison's disease, may lead to delay of a critical diagnosis, while causes that result in adrenal insufficiency without hyperpigmentation should explicitly be considered in pediatric cases where adrenal failure is documented by clinical symptomatology and biochemistry.

NMR-based metabolic profiling of children with premature adrenarche.

INTRODUCTION: Premature adrenarche (PA) for long time was considered a benign condition but later has been connected to various diseases in childhood and adulthood which remains controversial. OBJECTIVE: To investigate the effect of premature adrenarche on the metabolic phenotype, and correlate the clinical and biochemical data with the metabolic profile of children with PA. METHODS: Nuclear magnetic resonance (NMR)-based untargeted and targeted metabolomic approach in combination with multivariate and univariate statistical analysis applied to study the metabolic profiles of children with PA. Plasma, serum, and urine samples were collected from fifty-two children with Idiopathic PA and forty-eight age-matched controls from the division of Pediatric Endocrinology of the University Hospital of Patras were enrolled. RESULTS: Metabolomic results showed that plasma and serum glucose, myo-inositol, amino acids, a population of unsaturated lipids, and esterified cholesterol were higher and significantly different in PA children. In the metabolic profiles of children with PA and age-matched control group a gradual increase of glucose and myo-inositol levels was observed in serum and plasma, which was positively correlated their body mass index standard deviation score (BMI SDS) values respectively. Urine 1H NMR metabolic fingerprint of PA children showed positive correlation and a clustering-dependent relationship with their BMI and bone age (BA) respectively. CONCLUSION: This study provides evidence that PA driven metabolic changes begin during the childhood and PA may has an inductive role in a BMI-driven increase of specific metabolites. Finally, urine may be considered as the best biofluid for identification of the PA metabolism as it reflects more clearly the PA metabolic fingerprint.

A human paradigm of LHX4 and NR5A1 developmental gene interaction in the pituitary gland and ovary?

The pituitary gland, as a nodal component of the endocrine system, is responsible for the regulation of growth, reproduction, metabolism, and homeostasis. Although pituitary formation though the hierarchical action of different transcription factors is well studied in mouse models, there is little evidence of the analogous developmental processes in humans. Herein, we present a female patient with a phenotype that includes blepharoptosis-ptosis-epicanthus syndrome and premature ovarian failure. Clinical exome sequencing revealed two heterozygous variants in two genes, LHX4 (pathogenic) and NR5A1 (VUS) genes and no mutation in FOXL2 gene. We propose a model of genetic interaction between LHX4 and NR5A1 during pituitary and ovarian development that may lead to a similar phenotype mediated by reduced FOXL2 expression.

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.

Insulin-like growth factor ternary complex components as biomarkers for the diagnosis of short stature.

OBJECTIVE: The diagnosis of growth hormone deficiency (GHD) in children is not always straightforward because insulin-like growth factor 1 (IGF-I) or GH stimulation tests may not be able to discriminate GHD from constitutional delay of growth and puberty (CDGP) or other causes of short stature. DESIGN: Boys and girls (n = 429, 0.7-16 years) who attended our department for short stature participated in this study. They were followed up for an average period of 9 years. At the end of follow-up after reaching the final height, a definitive diagnosis was assigned, and all the components of ternary complex (IGF-I, IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), and IGF-I/IGFBP-3 ratio) were evaluated as biomarkers for the respective diagnosis. RESULTS: All the components of the ternary complex were tightly correlated with each other and were positively related to age. IGF-I, IGFBP-3, ALS, and IGF-I/IGFBP-3 ratio differed significantly between GHD and normal groups. IGF-I and ALS levels were lower in GHD compared to children with familial short stature, while IGF-I and IGF-I/IGFBP-3 ratio was significantly lower in GHD compared to children with CDGP. IGF-I and IGF-I/IGFBP-3 receiver operating curve cutoff points were unable to discriminate between GHD and normal groups or between GHD and CDGP groups. CONCLUSION: Despite the tight correlation among all the components of the ternary complex, each one shows a statistically significant diagnosis-dependent alteration. There is a superiority of IGF-I, ALS, and IGF-I/IGFBP-3 ratio in the distinction between GHD and CDGP or between GHD and normal groups but without usable discriminating power, making auxology as the primary criterion for establishing the diagnosis.

The effect of feeding patterns on serum zonulin levels in infants at 3-4 months of age.

Zonulin so far is the only known endogenous modulator of intercellular tight junctions which regulate the intestinal permeability. Breastfeeding is considered to enhance the integrity of the gastrointestinal tract; however, limited data are available about the effect of feeding patterns on intestinal permeability. We aimed to investigate the potential association between the mode of feeding (breast versus formula milk) and the serum zonulin levels as a marker of intestinal permeability. One hundred fifty-seven full-term, healthy infants, born after an uncomplicated pregnancy, were enrolled within 72-96 h of life. Blood samples from 105 infants were obtained at 3 to 4 months of life. Serum zonulin levels were measured by ELISA. Out of 105 infants, 52.4% (55) were female, and 58.1% (61) were delivered by caesarian section at a mean gestational age of 38.9 (SD ± 1.0) weeks. At the time of blood sampling, median age was 3.4 (IQR 3.20-3.50) months, and mean weight was 6332 (SD ± 692) gr. Infants were divided in three groups according to the feeding patterns: exclusive breastfeeding (n = 42), mixed feeding (n = 41), and cow's milk formula (n = 22). The feeding pattern had no impact on infants' serum zonulin levels. Moreover, zonulin levels were not affected by infant's clinical and epidemiological characteristics such as body weight or family history of autoimmune disease.Conclusion: In our study, different feeding patterns were not associated with serum zonulin levels in healthy infants at 3-4 months of age. What is Known: • Serum zonulin is upregulated in conditions with increased intestinal permeability • Breast milk favors the physiological decline of the intestinal permeability after birth in the neonates What is New: • Serum zonulin levels were not affected by the feeding pattern (breast milk versus formula) in infants at 3-4 months of age • Clinical and epidemiological characteristics of infants had no impact on zonulin levels.

Molecular Analysis of the CYP11B2 Gene in 62 Patients with Hypoaldosteronism Due to Aldosterone Synthase Deficiency.

CONTEXT: Isolated congenital hypoaldosteronism presents in early infancy with symptoms including vomiting, severe dehydration, salt wasting, and failure to thrive. The main causes of this rare autosomal recessive disorder is pathogenic variants of the CYP11B2 gene leading to aldosterone synthase deficiency. OBJECTIVE: To investigate the presence of CYP11B2 pathogenic variants in a cohort of patients with a clinical, biochemical, and hormonal profile suggestive of aldosterone synthase deficiency. DESIGN: Clinical and molecular study. SETTING: Tertiary academic Children's Hospital, Center for Rare Pediatric Endocrine Diseases. PATIENTS AND METHODS: Sixty-two patients (56 unrelated patients and 6 siblings), with hypoaldosteronism and their parents, underwent CYP11B2 gene sequencing after its selective amplification against the highly homologous CYP11B1 gene. In silico analysis of the identified novel variants was carried out to evaluate protein stability and potential pathogenicity. RESULTS: CYP11B2 gene sequencing revealed that 62 patients carried a total of 12 different pathogenic CYP11B2 gene variants, 6 of which are novel. Importantly, 96% of the 56 patients carried the previously reported p.T185I variant either in homozygosity or in compound heterozygosity with another variant. The 6 novel variants detected were: p.M1I, p.V129M, p.R141Q, p.A165T, p.R448C, and the donor splice site variant of intron 8, c.1398 + 1G > A. CONCLUSION: Molecular diagnosis was achieved in 62 patients with aldosterone synthase deficiency, the largest cohort thus far reported. Six novel genetic variants were identified as possibly pathogenic, extending the spectrum of reported molecular defects of the CYP11B2 gene.