Thyroid complications after hemopoietic stem cell transplantation in children and adolescents.

PURPOSE: To evaluate the prevalence of thyroid dysfunction and its association with possible contributing factors related to diagnosis and treatment in children who received hematopoietic stem cell transplantation (HSCT) in the only national transplant unit in Greece. METHODS: This is an observational, retrospective, single center cohort study that included 194 patients (58.6% boys) who survived for at least 1 year following allogeneic HSCT. Conditioning regimens depended upon diagnosis and protocols active at the time of transplantation. Some patients received irradiation, either central nervous system prophylaxis (n = 20), or total body irradiation (TBI) (n = 8). Thyroid gland evaluation included thyroid-stimulating hormone, free thyroxine, thyroid autoantibodies, and sonogram. Univariate and multivariate logistic models were used to examine the association of the above-mentioned factors with hypothyroidism. RESULTS: The mean age at diagnosis and at bone marrow transplant (BMT) in years was 7.51 ± 0.46 and 7.58 ± 0.36, respectively. The median follow-up time was 4.83 years. Hypothyroidism was detected in 33 cases (17.7%), four of those patients having received TBI. Factors contributing to hypothyroidism as per the multivariate analysis were male sex, [OR: 3.005, 95% CI (1.145-7.890)], irradiation, [OR: 2.876, 95% CI (1.120-7.386)], and years after HSCT [OR: 1.148, 95% CI (1.042-1.266)], while malignancy was identified only in the univariate analysis. The multivariate model presents a good class separation capacity [AUC = 72%, 95% CI (61.4%-82.4%)], Two patients had papillary thyroid cancer, both among children who had received TBI. CONCLUSION: These data highlight the fact that male sex and radiotherapy are two independent factors that lead to increased risk for hypothyroidism. Furthermore, the prevalence of hypothyroidism increases with time post HSCT.

A toddler with severe vitamin D-dependent rickets type 1 A (VDDR1A), hungry bone syndrome, and severe RSV infection: presentation and therapeutic challenges.

BACKGROUND: Vitamin D-dependent rickets type 1 A (VDDR1A) is an autosomal recessive disorder due to mutations in the CYP27B1 gene which result in inability to generate 1,25(OH)2D. CASE PRESENTATION: An 18-month-old boy with VDDR1A presented with hypotonia and respiratory distress. He had been diagnosed 2 months earlier, having been evaluated for stunted growth, hypotonia, and delayed developmental milestones. He was stabilized with oxygen and bronchodilators for his bronchiolitis and high doses of alfacalcidol, calcium, and phosphate supplements for his hungry bone syndrome. Of note, the patient sustained upper limb fractures after a fall from his bed during admission. Overall, he had a protracted disease course; however, his bone profile gradually improved and he steadily recovered. CONCLUSION: VDDR1A causes failure to thrive, hypotonia, and increased fracture risk and may complicate the clinical course of lower respiratory tract infections. Furthermore, management of hungry bone syndrome requires supraphysiologic doses of vitamin D metabolites and calcium.

A novel mutation in the AMHR2 gene, resulting in persistent Müllerian duct syndrome presenting with bilateral cryptorchidism and obstructed inguinal hernia.

OBJECTIVES: To highlight important clinical aspects of Persistent Müllerian duct syndrome (PMDS). PMDS belongs to the group of differences of sex development. It is attributed to mutations in genes encoding for the anti-Müllerian hormone or its type II receptor (AMHR2) and inherited via an autosomal recessive transmission. CASE PRESENTATION: An 18-day-old male infant with known bilateral cryptorchidism, presented with left-sided obstructed inguinal hernia. The diagnosis of PMDS was considered during inguinal exploration as both testes together with uterus and fallopian tubes were recognized in the hernial sac. Histology confirmed the presence of Müllerian-derived tissues. Genetic testing revealed two different mutations of the AMHR2 gene, both with autosomal recessive transmission: a frequently encountered deletion of 27 pairs bases on exon 10 of this 11 exon gene and a novel deletion of 2 pairs bases on exon 6. CONCLUSIONS: This case is notable being the rarest type of PMDS, that of transverse testicular ectopia and associated with a novel AMHR2 gene mutation.

In vivo magnetic resonance spectroscopy for the differential diagnosis of a cerebral mass in a boy with precocious puberty: a case report and review of the literature.

PURPOSE: To highlight the role of in vivo magnetic resonance spectroscopy (MRS) as a non-invasive tool that can clarify the etiology of sellar tumors by presenting the case of a boy with central precocious puberty (CPP) and to review the current literature. METHODS: A 4-year-old boy was admitted to our hospital due to repeated episodes of focal and gelastic seizures in the previous year. Clinical examination (testicular volume 4-5 ml bilaterally, penile length of 7.5 cm, and absence of axillary or pubic hair) and laboratory tests (FSH, LH, and testosterone) were indicative of CPP. The combination of gelastic seizures with CPP in a 4-year-old boy raised the suspicion of hypothalamic hamartoma (HH). Brain MRI revealed a lobular mass in the suprasellar-hypothalamic region. The differential diagnosis included glioma, HH, and craniopharyngioma. To further investigate the CNS mass, an in vivo brain MRS was performed. RESULTS: Οn conventional MRI, the mass demonstrated isointensity to gray matter on T1 weighted images but slight hyperintensity on T2-weighted images. It did not show restricted diffusion or contrast enhancement. On MRS, it showed reduced N-acetyl aspartate (NAA) and slightly elevated myoinositol (MI) compared with values in normal deep gray matter. The MRS spectrum, in combination with the conventional MRI findings, were consistent with the diagnosis of a HH. CONCLUSION: MRS is a state-of-the-art, non-invasive imaging technique that compares the chemical composition of normal tissue to that of abnormal regions by juxtaposing the frequency of measured metabolites. MRS, in combination with clinical evaluation and classic MRI, can provide identification of CNS masses, thus eliminating the need for an invasive biopsy.

The impact of physical activity, quality of life and eating habits on cardiometabolic profile and adipokines in youth with T1D.

PURPOSE: Individuals with Type-1-Diabetes (T1D) are at higher risk of having premature cardiovascular-disease (CVD). Physical activity and healthy lifestyle are major components in the prevention of diabetes' related comorbidities and complications. The aim of this study was to investigate the impact of physical activity, eating habits and quality of life in children and adolescents with T1D on diabetic control, cardiovascular and biochemical profile, infection indices, and adipokine levels. METHODS: This cross-sectional study involved 80 participants (36 boys/44 girls) with T1D, aged (mean ± SD) 14.9 ± 3.4 years, who attended the Diabetes and Metabolism Clinic of a University Children's Hospital, using anthropometric studies, lipid profile, high-sensitivity-C-Reactive-Protein(hs-CRP), Interleukin-6(IL6), leptin and adiponectin levels. Physical activity was assessed with pedometers (total-steps/week) and questionnaire. RESULTS: In 20(25%) children the level of exercise was >75th percentile, in 20(25%) <25th percentile and in 40(50%) children ranged between 25-75th percentile, respectively. Higher levels of physical activity were associated with weight (beta = -0.053, p < 0.001), waist circumference (beta = -0.077, p < 0.001), BMI (beta = -0.167, p = 0.009), muscle mass (beta = -0.0619, p = 0.001) and HDL-C (beta = 0.039, p = 0.033). Quality of life was positively related to weight (beta = 5.49511, p = 0.002), waist circumference (beta = 6.593345, p = 0.012), muscle mass (beta = 7.324088, p < 0.001) and T1D duration (beta = 19.22442, p = 0.005). Lipid profile was positively associated with sweets and chocolate consumption (beta = 0.348, p < 0.05), while vegetable (beta = -0.245, p < 0.05) and white milk consumption (beta = -0.2295, p < 0.05) were negatively associated with waist/height ratio. CONCLUSIONS: In the present study, higher levels of physical activity were associated with improved lipid profile (HDL-C, triglycerides) and body composition [waist circumference, Body-Mass-Index (BMI] of children and adolescents with T1D. Higher scoring in quality-of-life questionnaires were related to older children with longer diabetes duration. Unhealthy eating habits unfavorably affected lipid profile and body composition in T1D youth.

An 11-year-old girl with Autoimmune Polyglandular Syndrome (APS) type 2: a case report and review of literature.

OBJECTIVES: Autoimmune polyglandular syndrome type 2 (APS2) is characterized by autoimmune adrenal insufficiency (AI) in conjunction with autoimmune thyroid disease (AITD) and/or type 1 diabetes mellitus (T1DM). The aim is to report an 11-year-old girl with concurrence of Addison disease, celiac disease and thyroid autoimmunity. CASE PRESENTATION: She initially presented at the age of 5 with vomiting, dehydration, hyponatremia, hyperkalemia and low glucose. She recovered with intravenous hydration but the diagnosis was not established. She presented again at the age of 11 with hyperpigmentation, weakness and signs of impending adrenal crisis. Diagnosis of autoimmune AI was established together with celiac disease and thyroid autoimmunity. Thus, she met criteria for APS, being the third pediatric case report of APS2 with this combination. CONCLUSIONS: This case is notable for the atypical age of onset, given that APS2 is rare in the pediatric population. Furthermore, it depicts the insidious course of Addison disease with symptoms fluctuating for years before diagnosis.

Hypertriglyceridemic Waist Phenotype and Its Association with Metabolic Syndrome Components, among Greek Children with Excess Body Weight.

The hypertriglyceridemic waist (HTGW) phenotype is characterized by abdominal obesity and elevated serum triglycerides. We aimed to assess the prevalence of the HTGW phenotype among children with overweight or obesity and its association with indices of insulin resistance (IR) and dyslipidemia. A total of 145 children with mean age of 10.2 years (SD = 2.31 years), 97.2% of whom with obesity, were analyzed. The HTGW phenotype was defined as WC > 90th Centers for Disease Control and Prevention (CDC) percentile and triglyceride levels of ≥100 mg/dL and ≥130 mg/dL for children 0 to 9 or >10 years of age, respectively. In total, 77.9% of the children had a waist circumference above the 90th percentile and 22.8% had elevated triglycerides. The prevalence of the HTGW phenotype in this sample was 19.3%. Patients with the HTGW phenotype had significantly lower levels of High-Density Lipoprotein (p < 0.001) and were insulin-resistant, as evident by an increased mean Triglycerides Glucose Index 8.64 (SD = 0.24) vs. 7.92 (SD = 0.41) for those without the HTGW phenotype (p < 0.001), and increased prevalence (54.5%) of Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) in ≥2.5 in patients with HTGW (p = 0.045). Children with the HTGW phenotype were more likely to have increased HOMA-IR [OR 7.9 95% CI (1.94, 32.1)]. The HTGW phenotype is a low-cost and easily available index that might help to identify children with increased cardiometabolic risk.

The Role of Exercise on Cardiometabolic Profile and Body Composition in Youth with Type 1 Diabetes.

Exercise has a direct positive effect on glycemic control by promoting insulin secretion from ß-pancreatic islet-cells and by increasing skeletal muscle glucose uptake. The reduction in daily insulin needs and the optimization of glycemic control improves the patient's quality of life, self-esteem, mental wellness, as well as diabetes-related mobility and mortality. The aim of this study was to investigate the effect of physical activity in children and adolescents with type-1 diabetes (T1D) on diabetic control, cardiovascular, and biochemical profiles; hs-CRP; IL6; leptin; and adiponectin levels of the population under study. This is a prospective cross-sectional study that involved 80 participants (36 boys and 44 girls) with T1D, who were aged 6-21 years and who attended the Diabetes and Metabolism Clinic of the 2nd Pediatric Department, University of Athens, "P & A Kyriakou" Children's Hospital of Athens. Twenty (25%) children were above the 75th percentile regarding total levels of physical activity, while 40 (50%) and 20 (25%) were between the 25th and 75th percentile, as well as below the 25th percentile, respectively. In the group with an intermediate level of exercise, physical activity was negatively associated with the participant's family situation (traditional, single parent, grandparent, with others, or by himself/herself) (p = 0.013), ferritin (p = 0.031), lipoprotein(a) [Lp(a)] (p = 0.016), and squared leptin levels (p = 0.040). Whereas in the groups with extreme vs. no exercise there was a negative association with the number of daily glucose measurements (p = 0.047). However, in the group with non-vigorous exercise, physical activity was positively associated with high density lipoprotein-c (HDL-c) levels (p = 0.048). The findings of this study are indicative of the beneficial role of exercise on children and adolescents with T1D, which is achieved by primarily improving their cardiometabolic profile through the amelioration of lipid profile [HDL-c, Lp(a)] and leptin levels, as well as by reducing chronic systemic inflammatory response (ferritin) and ultimately decreasing the overall diabetes morbidity.

Predicting VO2max in Children and Adolescents Aged between 6 and 17 Using Physiological Characteristics and Participation in Sport Activities: A Cross-Sectional Study Comparing Different Regression Models Stratified by Gender.

Background: The aim of this study is to use different regression models to capture the association between cardiorespiratory fitness VO2max (measured in mL/kg/min) and somatometric characteristics and sports activities and making better predictions. Methods: multiple linear regression (MLR), quantile regression (QR), ridge regression (RR), support vector regression (SVR) with three different kernels, artificial neural networks (ANNs), and boosted regression trees (RTs) were compared to explain and predict VO2max and to choose the best performance model. The sample consisted of 4908 children (2314 males and 2594 females) aged between 6 and 17. Cardiorespiratory fitness was assessed by the 20 m maximal multistage shuttle run test and maximal oxygen uptake (VO2max) was calculated. Welch t-tests, Mann−Whitney-U tests, X2 tests, and ANOVA tests were performed. The performance measures were root mean square error (RMSE), mean absolute error (MAE), and coefficient of determination (R2). All analyses were stratified by gender. Results: A comparison of the statistical indices for both the predicted and actual data indicated that in boys, the MLR model outperformed all other models in all indices, followed by the linear SVR model. In girls, the MLR model performed better than the other models in R2 but was outperformed by SVR-RBF in terms of RMSE and MAE. The overweight and obesity categories in both sexes (p < 0.001) and maternal prepregnancy obesity in girls had a significant negative effect on VO2max. Age, weekly football training, track and field, basketball, and swimming had different positive effects based on gender. Conclusion: The MLR model showed remarkable performance against all other models and was competitive with the SVR models. In addition, this study's data showed that changes in cardiorespiratory fitness were dependent, to a different extent based on gender, on BMI category, weight, height, age, and participation in some organized sports activities. Predictors that are not considered modifiable, such as gender, can be used to guide targeted interventions and policies.

Safety and Efficacy of Pediatric Growth Hormone Therapy: Results From the Full KIGS Cohort.

CONTEXT: The Kabi/Pfizer International Growth Database (KIGS) is a large, international database (1987-2012) of children treated with recombinant human growth hormone (rhGH) in real-world settings. OBJECTIVE: This work aimed to evaluate the safety and efficacy of rhGH from the full KIGS cohort. METHODS: Data were collected by investigators from children with growth disorders treated with rhGH (Genotropin [somatropin]; Pfizer). Safety was evaluated in all treated patients, and efficacy in those treated for 1 year or more. A subgroup included patients treated for 5 years or more (≥ 2 years prepubertal) who had reached near-adult height (NAH). Main outcomes included adverse events (AEs), serious AEs (SAEs), and height growth. RESULTS: The full KIGS cohort (N = 83 803 [58% male]) was treated for idiopathic GH deficiency (IGHD; 46.9%), organic GHD (10.0%), small for gestational age (SGA; 9.5%), Turner syndrome (TS; 9.2%), idiopathic short stature (ISS; 8.2%), and others (16.2%). Median rhGH treatment duration was 2.7 years and observation 3.1 years. SAEs occurred in 3.7% of patients and death in 0.4%. The most common SAEs were recurrence of craniopharyngioma (n = 151), neoplasm (n = 99), and cancer (n = 91); and scoliosis (n = 91). Median first-year delta height-SD score (SDS) (Prader) in prepubertal patients was 0.66 (IGHD), 0.55 (ISS), 0.58 (TS), and 0.71 (SGA). Median gains in NAH-SDS were 1.79 (IGHD), 1.37 (ISS), and 1.34 (SGA) for boys, and 2.07 (IGHD), 1.62 (ISS), 1.07 (TS), and 1.57 (SGA) for girls. CONCLUSION: Data from KIGS, the largest and longest running international database of rhGH-treated children, show that rhGH is safe and increases short-term height gain and adult height across GHD and non-GHD conditions.

Adherence to Treatment Recommendations in Chronic Disease: What Is (Im)Possible? Expert Conclusions from the 30th ECOG Workshop 2021.

Obesity is a chronic disease, in which treatment outcomes are highly dependent on patient and family adherence to behavioural recommendations. The role of healthy eating, physical activity, medication adherence as well as adherence to pre- and post-bariatric surgery protocols are of utmost importance for long-term treatment outcomes. Even the best interventions are not likely to reach their maximum benefit without significant levels of adherence on the part of the individual and family. Traditionally, the annual meeting of the European Childhood Obesity Group (ECOG) includes an expert workshop addressing one specific topic within the field of childhood obesity. During the 30th annual meeting, hosted by the University of Pécs, Hungary, as a virtual meeting, "adherence to treatment recommendations in obesity as a chronic disease" was addressed. The discussions that developed during the workshop are summarized in the following article.

The Effect of Metabolic Profile on Leptin, Adiponectin, and hs-CRP in Children and Adolescents with Type 1 Diabetes.

Adipokines are a superfamily of cell signaling proteins produced by the adipose tissue. This study's purpose was to reveal the association of adipokines (leptin, adiponectin), hs-CRP, and IL-6 with well-known cardiovascular risk factors (lipid profile, diabetes control, obesity, physical activity) in children and adolescents with T1D. This cross-sectional study included 80 participants (36 boys) with T1D, aged (mean ± SD) 14.8 ± 3.4 years. Body Mass Index (BMI), metabolic profile, and level of physical activity were assessed (using pedometers) for evaluation of their effect on serum leptin, adiponectin, IL-6, and hs-CRP. Leptin levels were associated with BMI (beta = 0.184, p < 0.001), waist to hip ratio (beta = −2.017, p = 0.022), Low Density Lipoprotein-C (LDL-C) (beta = 0.021, p = 0.005), and fat mass (beta = 14.07, p < 0.001). Adiponectin was correlated with waist to height ratio (beta = 0.048, p = 0.006), ΒΜΙ (beta = −0.056, p = 0.005), and muscle mass (beta = −0.013, p = 0.020). Interestingly, hs-CRP was associated with weight (beta = 0.035, p < 0.001), ΒΜI (beta = 0.186, p < 0.001), fat mass (beta = 5.2859, p = 0.004), and muscle mass (beta = 0.027, p = 0.008). Multiple regression analysis of muscle mass unveiled associations with log hs-CRP (beta = −1.237, p = 0.014) and inverse IL−6 (beta = 18.57, p = 0.01). Finally, multiple regression models of fat mass unveiled associations with physical activity (7-day-total-step-count) (beta = −3.90 × 10−7, p = 0.027), Inverse IL-6 (beta = −0.1572, p = 0.009), and squared leptin (beta = 0.0077, p = 0.03). This study reports a positive association of leptin with LDL-C, BMI, fat mass, and hip circumference and a negative association of adiponectin with BMI and muscle mass. Finally, hs-CRP was associated with HbA1c, fat mass, and BMI. We propose that leptin, adiponectin, and hs-CRP could be used as prognostic indicators of cardiovascular risk in children with T1D.

There Is a Clinical Need to Consider the Physical Activity: Sedentary Pattern in Children with Obesity - Position Paper of the European Childhood Obesity Group.

INTRODUCTION: While international prevention guidelines recently advocated, in addition to moderate and vigorous physical activity (MVPA) guidelines, for a minimization of sedentary (SED) time, recommendations remain to be developed for youths with obesity. METHODS: A literature search was conducted in PubMed, the Cochrane Library, plus the reference lists of selected articles for relevant publications in English, including original papers, systematic reviews, and meta-analyses, with search terms "sedentary behaviors" or "sedentary time" or "screen time" AND "children" or "adolescents" AND "obesity" or "adiposity" or "cardiometabolic risk" or "cardiometabolic disease." The results were summarized as a narrative review and presented to the scientific board of the European Childhood Obesity Group (ECOG), who then discussed their implication in clinical practice and proposed the position outlined in this paper. RESULTS: SED and screen times are associated with adiposity and cardiometabolic risks, independently of youths' physical activity (PA) level. Besides considering MVPA and SED times as separate variables, comprehensive studies have questioned the impact of different patterns of MVPA and SED levels. Although lower body adiposity and better cardiometabolic health are achieved among those with desirable movement behavior patterns (i.e., more MVPA/less SED or active/not SED), youths with intermediate patterns (i.e., high MVPA/high SED and low MVPA/low SED, or active/SED and inactive/not SED) have been found to be associated with intermediate risks. CONCLUSION: There is a need to decrease SED behaviors irrespective of MVPA and to consider PA-SED patterns in youth with obesity. The ECOG encourages anti-obesity strategies targeting both PA and SED behaviors to support the shift from long periods of SED time, especially screen time, to daily routines incorporating bouts of PA. Stepwise or sequential approaches to movement behavior counseling might start with targeting SED at first to decrease cardiometabolic risks when implementing MVPA is not yet possible.

Safety and Efficacy of Lonapegsomatropin in Children With Growth Hormone Deficiency: enliGHten Trial 2-Year Results.

PURPOSE: The objectives of the ongoing, Phase 3, open-label extension trial enliGHten are to assess the long-term safety and efficacy of weekly administered long-acting growth hormone lonapegsomatropin in children with growth hormone deficiency. METHODS: Eligible subjects completing a prior Phase 3 lonapegsomatropin parent trial (heiGHt or fliGHt) were invited to participate. All subjects were treated with lonapegsomatropin. Subjects in the United States switched to the TransCon hGH Auto-Injector when available. Endpoints were long-term safety, annualized height velocity, pharmacodynamics [insulin-like growth factor-1 SD score (SDS) values], and patient- and caregiver-reported assessments of convenience and tolerability. RESULTS: Lonapegsomatropin treatment during enliGHten was associated with continued improvements in height SDS through week 104 in treatment-naïve subjects from the heiGHt trial (-2.89 to -1.37 for the lonapegsomatropin group; -3.0 to -1.52 for the daily somatropin group). Height SDS also continued to improve among switch subjects from the fliGHt trial (-1.42 at fliGHt baseline to -0.69 at week 78). After 104 weeks, the average bone age/chronological age ratio for each treatment group was 0.8 (0.1), showing only minimal advancement of bone age relative to chronological age with continued lonapegsomatropin treatment among heiGHt subjects. Fewer local tolerability reactions were reported with the TransCon hGH Auto-Injector compared with syringe/needle. CONCLUSIONS: Treatment with lonapegsomatropin continued to be safe and well-tolerated, with no new safety signals identified. Children treated with once-weekly lonapegsomatropin showed continued improvement of height SDS through the second year of therapy without excess advancement of bone age.

Efficacy and Safety of Weekly Somatrogon vs Daily Somatropin in Children With Growth Hormone Deficiency: A Phase 3 Study.

CONTEXT: Somatrogon is a long-acting recombinant human growth hormone (rhGH) in development for once-weekly treatment of children with growth hormone deficiency (GHD). OBJECTIVE: We aimed to compare the efficacy and safety of once-weekly somatrogon with once-daily somatropin in prepubertal children with GHD. METHODS: In this 12-month, open-label, randomized, active-controlled, parallel-group, phase 3 study, participants were randomized 1:1 to receive once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. A total of 228 prepubertal children (boys aged 3-11 years, girls aged 3-10 years) with GHD, impaired height and height velocity (HV), and no prior rhGH treatment were randomized and 224 received ≥1 dose of study treatment (somatrogon: 109; somatropin: 115). The primary endpoint was annualized HV at month 12. RESULTS: HV at month 12 was 10.10 cm/year for somatrogon-treated subjects and 9.78 cm/year for somatropin-treated subjects, with a treatment difference (somatrogon-somatropin) of 0.33 (95% CI: -0.24, 0.89). The lower bound of the 2-sided 95% CI was higher than the prespecified noninferiority margin (-1.8 cm/year), demonstrating noninferiority of once-weekly somatrogon vs daily somatropin. HV at month 6 and change in height standard deviation score at months 6 and 12 were similar between both treatment groups. Both treatments were well tolerated, with a similar percentage of subjects experiencing mild to moderate treatment-emergent adverse events in both groups (somatrogon: 78.9%, somatropin: 79.1%). CONCLUSION: The efficacy of once-weekly somatrogon was noninferior to once-daily somatropin, with similar safety and tolerability profiles. (ClinicalTrials.gov no. NCT02968004).

3ß-Hydroxysteroid Dehydrogenase Type 2 (3ßHSD2) Deficiency due to a Novel Compound Heterozygosity of a Missense Mutation (p.Thr259Met) and Frameshift Deletion (p.Lys273ArgFs*7) in an Undervirilized Infant Male with Salt Wasting.

Deficiency of 3ß-hydroxysteroid dehydrogenase type 2 (3ßHSD2) is a rare type of congenital adrenal hyperplasia (CAH), causing impaired steroid hormone production in both adrenals and gonads. Phenotype ranges, according to the genetic defect, from the salt-wasting form in both sexes to undervirilization in males and virilization in females. We present a 13-month-old male infant who was admitted to the hospital with signs of adrenocortical insufficiency and genital ambiguity. Clinical presentation, hormonal profile, laboratory evaluation, and karyotype were suggestive of the salt-wasting form of CAH due to 3ßHSD2 deficiency. Mutational analysis revealed a missense mutation c.776C>T (p.Thr259Met), inherited by the mother, and a frameshift deletion c.818-819delAA (p.Lys273ArgFs*7), inherited by the father. Both mutations are considered pathogenic. To our knowledge this is the first case of an undervirilized male infant with salt wasting bearing this pathogenic frameshift deletion p.Lys273ArgFs*7 in compound heterozygosity with the missense mutation p.Thr259Met.