Letícia Esposito Sewaybricker

Clinical and Laboratorial Features That May Differentiate 46,XY DSD due to Partial Androgen Insensitivity and 5α-Reductase Type 2 Deficiency

The aim of this study was to search for clinical and laboratorial data in 46,XY patients with ambiguous genitalia (AG) and normal testosterone (T) synthesis that could help to distinguish partial androgen insensitivity syndrome (PAIS) from 5α-reductase type 2 deficiency (5α-RD2) and from cases without molecular defects in the AR and SRD5A2 genes. Fifty-eight patients (51 families) were included. Age at first evaluation, weight and height at birth, consanguinity, familial recurrence, severity of AG, penile length, LH, FSH, T, dihydrotestosterone (DHT), Δ4-androstenedione (Δ4), and T/DHT and T/Δ4 ratios were evaluated. The AR and SRD5A2 genes were sequenced in all cases. There were 9 cases (7 families) of 5α-RD2, 10 cases (5 families) of PAIS, and 39 patients had normal molecular analysis of SRD5A2 and AR genes. Age at first evaluation, birth weight and height, and T/DHT ratio were lower in the undetermined group, while penile length was higher in this group. Consanguinity was more frequent and severity of AG was higher in 5α-RD2 patients. Familial recurrence was more frequent in PAIS patients. Birth weight and height, consanguinity, familial recurrence, severity of AG, penile length, and T/DHT ratio may help the investigation of 46,XY patients with AG and normal T synthesis.

Pharmacogenetics of Risperidone and Cardiovascular Risk in Children and Adolescents

Objective. To identify the frequency of obesity and metabolic complications in child and adolescent users of risperidone. Potential associations with clinical parameters and SNPs of the HTR2C, DRD2, LEP, LEPR, MC4R, and CYP2D6 genes were analyzed. Methods. Samples from 120 risperidone users (8–20 years old) were collected and SNPs were analyzed, alongside assessment of chronological and bone ages, prescribed and weight-adjusted doses, use of other psychotropic drugs, waist circumference, BMI z-scores, blood pressure, HOMA-IR index, fasting levels of serum glucose, insulin, cholesterol, triglycerides, transaminases, and leptin. Results. Thirty-two (26.7%) patients were overweight and 5 (4.2%) obese. Hypertension was recorded in 8 patients (6.7%), metabolic syndrome in 6 (5%), and increased waist circumference in 20 (16.7%). The HOMA-IR was high for 22 patients (18.3%), while total cholesterol and triglycerides were high in 20 (16.7%) and 41 (34.2%) patients, respectively. SNP associations were found for LEP, HTR2C, and CYP2D6 with BMI; CYP2D6 with blood pressure, ALT, and HOMA-IR; HTR2C and LEPR with leptin levels; MC4R and DRD2 with HOMA-IR; HTR2C with WC; and LEP with ALT. Conclusions. Although not higher than in the general pediatric population, a high frequency of patients was overweight/obese, with abnormalities in metabolic parameters and some pharmacogenetic associations.

Brazilian Pediatric Reference Data for Quantitative Ultrasound of Phalanges According to Gender, Age, Height and Weight

Aims To establish normative data for phalangeal quantitative ultrasound (QUS) measures in Brazilian students. Methods The sample was composed of 6870 students (3688 females and 3182 males), aged 6 to 17 years. The bone status parameter, Amplitude Dependent Speed of Sound (AD-SoS) was assessed by QUS of the phalanges using DBM Sonic BP (IGEA, Carpi, Italy) equipment. Skin color was obtained by self-evaluation. The LMS method was used to derive smoothed percentiles reference charts for AD-SoS according to sex, age, height and weight and to generate the L, M, and S parameters. Results Girls showed higher AD-SoS values than boys in the age groups 7–16 (p<0.001). There were no differences on AD-SoS Z-scores according to skin color. In both sexes, the obese group showed lower values of AD-SoS Z-scores compared with subjects classified as thin or normal weight. Age (r2 = 0.48) and height (r2 = 0.35) were independent predictors of AD-SoS in females and males, respectively. Conclusion AD-SoS values in Brazilian children and adolescents were influenced by sex, age and weight status, but not by skin color. Our normative data could be used for monitoring AD-SoS in children or adolescents aged 6–17 years.

46,XX DSD and Antley-Bixler syndrome due to novel mutations in the cytochrome P450 oxidoreductase gene

Deficiency of the enzyme P450 oxidoreductase is a rare form of congenital adrenal hyperplasia with characteristics of combined and partial impairments in steroidogenic enzyme activities, as P450 oxidoreductase transfers electrons to CYP21A2, CYP17A1, and CYP19A1. It results in disorders of sex development and skeletal malformations similar to Antley-Bixley syndrome. We report the case of a 9-year-old girl who was born with virilized genitalia (Prader stage V), absence of palpable gonads, 46,XX karyotype, and hypergonadotropic hypogonadism. During the first year of life, ovarian cyst, partial adrenal insufficiency, and osteoarticular changes, such as mild craniosynostosis, carpal and tarsal synostosis, and limited forearm pronosupination were observed. Her mother presented severe virilization during pregnancy. The molecular analysis of P450 oxidoreductase gene revealed compound heterozygosis for the nonsense p.Arg223*, and the novel missense p.Met408Lys, inherited from the father and the mother, respectively.

Ovotesticular disorder of sex development with unusual karyotype: patient report

Abstract Background: Ovotesticular disorder of sex development (OT-DSD) (true hermaphroditism) is an anatomopathological diagnosis based on the findings of testicular and ovarian tissues in the same subject, in the same gonad (ovotestis), or in separate gonads. OT-DSD is a rare cause of sex ambiguity, and the most common karyotype is 46,XX; mosaics and chimeras are found only in 10%–20%. Aim: To report a case of an OT-DSD patient with a rare karyotype constitution. Case report: A 2-month-old child with male sex assignment was referred to our clinic for investigation of sex ambiguity. He was the second child of healthy unrelated parents; pregnancy and labor were uneventful. On physical examination, he had a 2.3-cm phallus and perineal hypospadias (Prader grade III); the right gonad was in the labioscrotal fold and the left was found in the inguinal channel. Karyotype was 46,XX/47,XXY/48,XXYY. Anatomopathological examination of gonads revealed right testis and left ovotestis. The male sex assignment was maintained; the child underwent left gonadectomy, removal of Mullerian structures and urethroplasty. Conclusion: A thorough revision of literature revealed a single case of OT-DSD with the same chromosome constitution. Gonadal biopsy is necessary to establish diagnosis in cases of sex chromosome mosaicism.

Síndrome de Klinefelter: diagnóstico raro na faixa etária pediátrica

OBJECTIVE: To identify clinical and laboratory data which differentiate Klinefelter syndrome (KS) patients according to age group. METHODS: The study included all cases of hypogonadism, gynecomastia and/or infertility whose karyotype was performed at a university hospital from January 1989 to December 2011, in a total of 105 subjects. The following data were retrospectively analyzed: age at first visit, ratio of arm span to height, pubic hair, gynecomastia, testicular volume, luteinizing hormone (LH), follicle stimulating hormone (FSH), total testosterone (T), and spermiogram. RESULTS: During the study period, 33 patients were diagnosed with Klinefelter syndrome (KS+) and 72 were not (KS-). Out of all KS cases, only seven (21.2%) were diagnosed before 20 years old and two (6.1%) before 10 years old. Age at first consultation (in years) was similar in both groups (KS+ = 31.3±12.9 and KS- = 27.6±12.1), as were ratio of arm span to height and frequency of gynecomastia. However, in KS+ patients, pubic hair was less developed, testicular volume was smaller and testosterone levels were lower, while LH and FSH levels and frequency of azoospermia were higher. CONCLUSIONS: Klinefelter syndrome is both an under and late diagnosed condition. The most important data for diagnosis are testicular volume, hormone levels and presence of azoospermia in spermiogram, especially in puberty and adult life.OBJECTIVE To identify clinical and laboratory data which differentiate Klinefelter syndrome (KS) patients according to age group. METHODS The study included all cases of hypogonadism, gynecomastia and/or infertility whose karyotype was performed at a university hospital from January 1989 to December 2011, in a total of 105 subjects. The following data were retrospectively analyzed: age at first visit, ratio of arm span to height, pubic hair, gynecomastia, testicular volume, luteinizing hormone (LH), follicle stimulating hormone (FSH), total testosterone (T), and spermiogram. RESULTS During the study period, 33 patients were diagnosed with Klinefelter syndrome (KS+) and 72 were not (KS-). Out of all KS cases, only seven (21.2%) were diagnosed before 20 years old and two (6.1%) before 10 years old. Age at first consultation (in years) was similar in both groups (KS+ = 31.3±12.9 and KS- = 27.6±12.1), as were ratio of arm span to height and frequency of gynecomastia. However, in KS+ patients, pubic hair was less developed, testicular volume was smaller and testosterone levels were lower, while LH and FSH levels and frequency of azoospermia were higher. CONCLUSIONS Klinefelter syndrome is both an under and late diagnosed condition. The most important data for diagnosis are testicular volume, hormone levels and presence of azoospermia in spermiogram, especially in puberty and adult life.

Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a cohort of MODY families

Maturity‐onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. GCK ‐MODY and HNF1A ‐MODY are the prevalent subtypes. Currently, there is growing concern regarding the correct interpretation of molecular genetic findings. The American College of Medical Genetics and Genomics (ACMG) updated guidelines to interpret and classify molecular variants. This study aimed to determine the prevalence of MODY ( GCK / HNF1A ) in a large cohort of Brazilian families, to report variants related to phenotype, and to classify them according to ACMG guidelines. One hundred and nine probands were investigated, 45% with clinical suspicion of GCK ‐MODY and 55% with suspicion of HNF1A ‐MODY. Twenty‐five different variants were identified in GCK gene (30 probands—61% of positivity), and 7 variants in HNF1A (10 probands—17% of positivity). Fourteen of them were novel (12— GCK /2— HNF1A ). ACMG guidelines were able to classify a large portion of variants as pathogenic (36%— GCK /86%— HNF1A ) and likely pathogenic (44%— GCK /14%— HNF1A ), with 16% (5/32) as uncertain significance. This allows us to determine the pathogenicity classification more efficiently, and also reinforces the suspected associations with the phenotype among novel variants.

Corrigendum to “Pharmacogenetics of Risperidone and Cardiovascular Risk in Children and Adolescents”

[This corrects the article DOI: 10.1155/2016/5872423.].

Performance of Phalangeal Quantitative Ultrasound Parameters in the Evaluation of Reduced Bone Mineral Density Assessed By DX in Patients with 21 Hydroxylase Deficiency

The purpose of this study was to verify the performance of quantitative ultrasound (QUS) parameters of proximal phalanges in the evaluation of reduced bone mineral density (BMD) in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21 OHD). Seventy patients with 21 OHD (41 females and 29 males), aged between 6-27 y were assessed. The QUS measurements, amplitude-dependent speed of sound (AD-SoS), bone transmission time (BTT), and ultrasound bone profile index (UBPI) were obtained using the BMD Sonic device (IGEA, Carpi, Italy) on the last four proximal phalanges in the non-dominant hand. BMD was determined by dual energy X-ray (DXA) across the total body and lumbar spine (LS). Total body and LS BMD were positively correlated to UBPI, BTT and AD-SoS (correlation coefficients ranged from 0.59-0.72, p < 0.001). In contrast, when comparing patients with normal and low (Z-score < -2) BMD, no differences were found in the QUS parameters. Furthermore, UBPI, BTT and AD-SoS measurements were not effective for diagnosing patients with reduced BMD by receiver operator characteristic curve parameters. Although the AD-SoS, BTT and UBPI showed significant correlations with the data obtained by DXA, they were not effective for diagnosing reduced bone mass in patients with 21 OHD.

Metabolic syndrome in obese adolescents: what is enough?

OBJECTIVE To study the agreement among three distinct criteria for metabolic syndrome (MS) adapted to adolescents, and to identify associated factors for MS. METHODS Cross-sectional study with 65 obese subjects aged 10 to 18 years, attended to at the Outpatient Clinic for Obese Children and Adolescents at the Clinical Hospital of the Universidade Estadual de Campinas (Unicamp). MS was defined using the criteria of the World Health Organization (WHO), the International Diabetes Federation (IDF), and the Adult Treatment Panel III (ATP III). Clinical, anthropometrical, and laboratorial data were associated to MS. RESULTS From the 65 subjects, none had MS according to the WHO criteria, while 18 were diagnosed with MS (27.6%) according to the IDF, and 19 (29.2%) according to the ATP III. Agreement between IDF and ATP III was excellent (kappa 81%). In this study, puberty and triglycerides levels showed significant statistical difference when comparing subjects with and without MS, the first for ATP III (p = 0.03), and the second for IDF (p = 0.005) and ATP III (p = 0.001) criteria. CONCLUSION The WHO criteria does not seem to be adequate for adolescents. IDF and ATP III criteria had an excellent agreement. Puberty and triglycerides were associated with MS.