ABSTRACT
BACKGROUND: Pathogenic variants in the nicotinamide nucleotide transhydrogenase gene (NNT) are a rare cause of primary adrenal insufficiency (PAI), as well as functional impairment of the gonads. OBJECTIVE: Despite the description of different homozygous and compound heterozygous NNT variants in PAI patients, the extent to which the function and expression of the mature protein are compromised remains to be clarified. DESIGN: The activity and expression of mitochondrial NAD(P)+ transhydrogenase (NNT) were analyzed in blood samples obtained from patients diagnosed with PAI due to genetically confirmed variants of the NNT gene (n = 5), heterozygous carriers as their parents (n = 8), and healthy controls (n = 26). METHODS: NNT activity was assessed by a reverse reaction assay standardized for digitonin-permeabilized peripheral blood mononuclear cells (PBMCs). The enzymatic assay was validated in PBMC samples from a mouse model of NNT absence. Additionally, the PBMC samples were evaluated for NNT expression by western blotting and reverse transcription quantitative polymerase chain reaction and for mitochondrial oxygen consumption. RESULTS: NNT activity was undetectable (<4% of that of healthy controls) in PBMC samples from patients, independent of the pathogenic genetic variant. In patients' parents, NNT activity was approximately half that of the healthy controls. Mature NNT protein expression was lower in patients than in the control groups, while mRNA levels varied widely among genotypes. Moreover, pathogenic NNT variants did not impair mitochondrial bioenergetic function in PBMCs. CONCLUSIONS: The manifestation of PAI in NNT-mutated patients is associated with a complete lack of NNT activity. Evaluation of NNT activity can be useful to characterize disease-causing NNT variants.
Subject(s)
Addison Disease , NADP Transhydrogenases , Animals , Humans , Mice , Leukocytes, Mononuclear/metabolism , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , NAD , NADP Transhydrogenase, AB-Specific/genetics , NADP Transhydrogenase, AB-Specific/metabolism , NADP Transhydrogenases/genetics , NADP Transhydrogenases/metabolismABSTRACT
INTRODUCTION: Although it was common in the 1970s-1990s to assign female gender of rearing to 46,XY infants with limited virilization of varying etiologies, including those with partial androgen insensitivity syndrome (PAIS), long-term data on outcomes for these individuals are sparse. Therefore, our goal was to use the power of an international registry to evaluate clinical features, surgical management, and pubertal data in patients with a molecularly confirmed diagnosis of PAIS who were born before 2008 and were raised as girls. METHODS: The current study interrogated the International Disorders of Sex Development Registry for available data on management and pubertal outcomes in individuals with genetically confirmed PAIS who were raised as girls. RESULTS: Among the 11 individuals who fulfilled the key criteria for inclusion, the external masculinization score (EMS) at presentation ranged from 2 to 6 (median 5); 7 girls underwent gonadectomy before the age of 9 years, whereas 4 underwent gonadectomy in the teenage years (≥ age 13). Clitoral enlargement at puberty was reported for 3 girls (27%) who presented initially at the time of puberty with intact gonads. In the 9 individuals (82%) for whom gonadal pathology data were provided, there was no evidence of germ cell tumor at median age of 8.1 years. All girls received estrogen replacement, and 8/11 had attained Tanner stage 4-5 breast development at the last assessment. CONCLUSION: In general, although it appears that female assignment in PAIS is becoming uncommon, our data provide no evidence to support the practice of prophylactic prepubertal gonadectomy with respect to the risk of a germ cell tumor.
Subject(s)
Androgen-Insensitivity Syndrome , Neoplasms, Germ Cell and Embryonal , Male , Infant , Adolescent , Humans , Female , Child , Androgen-Insensitivity Syndrome/pathology , Gonads/pathology , Castration , Sexual Development , Neoplasms, Germ Cell and Embryonal/pathologyABSTRACT
Abstract Obesity is considered an important global public health challenge, and its prevalence is rapidly increasing in children. We investigated in this study if the upper-normal TSH level may be associated with metabolic syndrome parameters, including obesity, high blood pressure, and dyslipidemia and changes in insulin sensitivity in overweight and obese children. We also investigated whether there is a relationship between BMI and these parameters. This prospective case-control study comprised 145 participants (74 females, 71 males) aged 5-18 years. Participants were divided into three groups according to their BMI z-score, as overweight, obese and control. The control group included 35 age and sex-matched healthy subjects. Thyroid stimulating hormone levels of control, overweight and obese groups were 2.14 ± 1.27, 2.97 ± 1.26 and 3.13 ± 1.11, respectively (p<0.05). There was a significant positive correlation between TSH and the BMI, BMI z-scores between overweight and obese groups (r=0.302, p=0.000), (r=0.121, p=0.004), respectively. The current study suggests that increased serum TSH levels, even within the normal range, in overweight and obese children is associated with the impairment of metabolic parameters, including dyslipidemia and insulin sensitivity. For that reason, TSH levels in the high-normal range should be considered as a risk factor for metabolic syndrome and its components.
Resumen La obesidad se considera un importante desafío de salud pública mundial y su prevalencia está aumentando rápidamente en los niños. En este estudio, se investigó si el nivel normal superior de TSH puede estar asociado con los parámetros del síndrome metabólico, incluida la obesidad, la presión arterial elevada, cambios en los lípidos y la sensibilidad a la insulina, en niños con sobrepeso y obesidad. También investigamos si existe una relación entre el IMC y estos parámetros. En este estudio prospectivo de casos y controles se incluyeron a 145 participantes (74 hembras, 71 varones) de entre 5 y 18 años. Los participantes se dividieron en 3 grupos según el puntaje z del IMC, como sobrepeso, obesidad y control. El grupo de control incluyó 35 sujetos sanos emparejados por edad y sexo. Los niveles de hormona estimulante de la tiroides de los grupos de control, con sobrepeso y obesos fueron 2,14 ± 1,27, 2,97 ± 1,26 y 3,13 ± 1,11, respectivamente (p <0,05). Hubo una correlación positiva significativa entre la TSH y el BMI, la puntuación z del IMC entre los grupos con sobrepeso y obesidad (r = 0,302, p = 0,000), (r = 0,121, p = 0,004), respectivamente. Por esa razón, el nivel de TSH en el rango normal alto debe considerarse como un factor de riesgo del síndrome metabólico y sus componentes.