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Introduction. Hypercalcemia is infrequent in pediatrics, of diverse etiology, and with multiorgan morbidity. Objective. Describe the etiology, biochemistry, clinical, and treatment in pediatric patients with hypercalcemia. Population and methods. Retrospective and descriptive study of a cohort of patients with hypercalcemia between 2008 and 2022. They were classified into three groups (G): hypercalcemia of iatrogenic cause (G1), parathyroid hormone (PTH) independent (G2), or PTH-dependent (G3). Results. One hundred forty-seven patients were included; 57% were male, with a median age of 3.7 years, median calcemia of 11.8 mg/dl, and mean phosphatemia of 4.9 mg/dl. Symptoms were present in 29% of patients, and 28.6% required additional treatments to those of the first line. In G1, 76 patients (51.7%) were included; in G2, 58 (39.4%), and in G3, 13 (8.8%). Median calcemia was lower in G1 vs. G2 and G3 (11.6 mg/dl, 12.6 mg/dl, and 12.3 mg/dl), and mean phosphatemia was lower in G3 vs. G1 and G2 (3.7 mg/dl, 5.3 mg/dl, and 4.9 mg/dl). Most of the patients with hypercalcemia were asymptomatic and did not require additional treatments. The percentage of symptomatic patients and the percentage requiring additional treatment were lower in G1 than in the other two groups. Conclusions. Iatrogenesis was the most frequent cause, presenting lower calcemia, while PTH-dependent causes presented the lowest phosphatemia. PTH-independent causes represented a diagnostic and therapeutic challenge due to lacking a characteristic biochemical profile.
Introducción. La hipercalcemia es infrecuente en pediatría, de etiología diversa y con morbilidad multiorgánica. Objetivo. Describir etiología, bioquímica, clínica y tratamiento en pacientes pediátricos con hipercalcemia. Población y métodos. Estudio retrospectivo y descriptivo de una cohorte de pacientes con hipercalcemia entre 2008 y 2022. Se clasificaron en tres grupos (G): hipercalcemia de causa iatrogénica (G1), paratohormona (PTH) independiente (G2) o PTH dependiente (G3). Resultados. Se incluyeron 147 pacientes; el 57 % eran varones, edad mediana de 3,7 años, calcemia mediana 11,8 mg/dl y fosfatemia media 4,9 mg/dl. El 29,9 % de los pacientes fueron sintomáticos y el 28,6 % requirió tratamientos adicionales a los de la primera línea. En G1 se incluyeron 76 pacientes (51,7 %); en G2, 58 (39,4 %), y en G3, 13 (8,8 %). La calcemia mediana fue menor en G1 vs. G2 y G3 (11,6 mg/dl, 12,6 mg/dl y 12,3 mg/dl). La fosfatemia media fue menor en G3 vs. G1 y G2 (3,7 mg/dl, 5,3 mg/dl y 4,9 mg/dl). La mayoría de los pacientes con hipercalcemia fueron asintomáticos sin requerimientos de tratamientos adicionales. El porcentaje de pacientes sintomáticos y el de requerimiento de tratamientos adicionales fue menor en G1 que en los otros dos grupos. Conclusiones. La iatrogenia fue la causa más frecuente, y se presentó con calcemias más bajas; mientras que las causas PTH dependientes presentaron las fosfatemias más bajas. Las causas PTH independientes representaron un desafío diagnóstico y terapéutico por la falta de un perfil bioquímico característico.
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Los transportadores de monocarboxilatos (MCT) permiten el ingreso celular de hormonas tiroideas, especialmente en el sistema nervioso central (SNC), donde son indispensables para el neurodesarrollo. La deficiencia de MCT8 produce la combinación de hipotiroidismo en SNC e hipertiroidismo periférico, caracterizada por T3 elevada. El único tratamiento actualmente disponible es el ácido 3,3',5-triyodotiroacético (TRIAC), un análogo de hormonas tiroideas que tiene como objetivo mejorar la tirotoxicosis periférica y prevenir la progresión del deterioro neurológico. En el presente artículo, se evalúan las características clínicas, imagenológicas, bioquímicas y genéticas de 4 pacientes con deficiencia de MCT8 tratados con TRIAC hasta la fecha, las dosis utilizadas y la respuesta al tratamiento.
Monocarboxylate transporters (MCTs) allow the cellular entry of thyroid hormones, especially into the central nervous system (CNS), where they are crucial for neurodevelopment. MCT8 deficiency results in the combination of hypothyroidism in the CNS and peripheral hyperthyroidism, characterized by elevated T3 levels. The only treatment currently available is 3,3',5-triiodothyroacetic acid (TRIAC), a thyroid hormone analogue aimed at improving peripheral thyrotoxicosis and preventing the progression of neurological impairment. Here we assess the clinical, imaging, biochemical, and genetic characteristics of 4 patients with MCT8 deficiency who have received TRIAC to date, the doses used, and the response to treatment.
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Humanos , Lactante , Niño , Simportadores/genética , Hormonas Tiroideas , Triyodotironina , Transportadores de Ácidos Monocarboxílicos/genéticaRESUMEN
Monocarboxylate transporters (MCTs) allow the cellular entry of thyroid hormones, especially into the central nervous system (CNS), where they are crucial for neurodevelopment. MCT8 deficiency results in the combination of hypothyroidism in the CNS and peripheral hyperthyroidism, characterized by elevated T3 levels. The only treatment currently available is 3,3',5-triiodothyroacetic acid (TRIAC), a thyroid hormone analogue aimed at improving peripheral thyrotoxicosis and preventing the progression of neurological impairment. Here we assess the clinical, imaging, biochemical, and genetic characteristics of 4 patients with MCT8 deficiency who have received TRIAC to date, the doses used, and the response to treatment.
Los transportadores de monocarboxilatos (MCT) permiten el ingreso celular de hormonas tiroideas, especialmente en el sistema nervioso central (SNC), donde son indispensables para el neurodesarrollo. La deficiencia de MCT8 produce la combinación de hipotiroidismo en SNC e hipertiroidismo periférico, caracterizada por T3 elevada. El único tratamiento actualmente disponible es el ácido 3,3',5-triyodotiroacético (TRIAC), un análogo de hormonas tiroideas que tiene como objetivo mejorar la tirotoxicosis periférica y prevenir la progresión del deterioro neurológico. En el presente artículo, se evalúan las características clínicas, imagenológicas, bioquímicas y genéticas de 4 pacientes con deficiencia de MCT8 tratados con TRIAC hasta la fecha, las dosis utilizadas y la respuesta al tratamiento.
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Simportadores , Humanos , Niño , Simportadores/genética , Transportadores de Ácidos Monocarboxílicos/genética , Triyodotironina , Hormonas TiroideasRESUMEN
Background: Differences/disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. Objective: The aim of this study is to report the histological characteristics and immunoexpression patterns of gonadal parenchyma in patients with 46,XX testicular and ovotesticular DSD, with a focus on the detection of germ cell malignancies. Design: Inclusion criteria were SRY-negative 46,XX testicular and ovotesticular DSD with available samples from gonadal biopsy or gonadectomy for the review of histological findings. Gonadal histology was assessed on hematoxylin and eosin-stained sections and immunohistochemical analysis. Histopathological criteria from the last World Health Organization classification of urogenital tumors were used to identify undifferentiated gonadal tissue, gonadoblastoma, and dysgerminoma. Results: Median age at first histological evaluation of gonadal samples was 1.46 years (range: 0.16-16 years). Totally 15 patients were classified as ovotesticular and only 1 as testicular DSD. Most individuals had bilateral ovotestes (12/15). No histological alterations were found in the ovarian parenchyma, while signs of dysgenesis were seen in all cases of testicular parenchyma. In 4/15 ovotesticular DSD, a prepubertal biopsy failed to identify ovarian parenchyma. We detected early prepubertal preinvasive and invasive malignancies in this cohort (five patients had undifferentiated gonadal tissue, five gonadoblastoma, and one dysgerminoma). Conclusion: 46,XX disorders of gonadal development are historically considered at a low risk for germ cell cancer, and the need for assessment of gonadal histology has been questioned. The finding of early germ cell malignancies in our cohort brings awareness and needs further research.
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Trastornos del Desarrollo Sexual , Disgerminoma , Gonadoblastoma , Neoplasias de Células Germinales y Embrionarias , Neoplasias Ováricas , Trastornos Ovotesticulares del Desarrollo Sexual , Trastornos del Desarrollo Sexual/diagnóstico , Disgerminoma/genética , Femenino , Gonadoblastoma/genética , Gonadoblastoma/patología , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias Ováricas/patología , Trastornos Ovotesticulares del Desarrollo Sexual/diagnóstico , Trastornos Ovotesticulares del Desarrollo Sexual/genéticaRESUMEN
Langerhans cell histiocytosis (LCH) is a disorder of the mononuclear phagocyte system that can affect almost any organ and system. The most common central nervous system (CNS) manifestation in LCH is the infiltration of the hypothalamic-pituitary region leading to destruction and neurodegeneration of CNS tissue. The latter causes the most frequent endocrinological manifestation, that is, central diabetes insipidus (CDI), and less often anterior pituitary hormone deficiency (APD). The reported incidence of CDI is estimated between 11.5 and 24% and is considered a risk factor for neurodegenerative disease and APD. Three risk factors for development of CDI are recognized in the majority of the studies: (1) multisystem disease, (2) the occurrence of reactivations or active disease for a prolonged period, and (3) the presence of craniofacial bone lesions. Since CDI may occur as the first manifestation of LCH, differential diagnosis of malignant diseases like germ cell tumours must be made. APD is almost always associated with CDI and can appear several years after the diagnosis of CDI. Growth hormone is the most commonly affected anterior pituitary hormone. Despite significant advances in the knowledge of LCH in recent years, little progress has been made in preventing long-term sequelae such as those affecting the hypothalamic-pituitary system.
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Diabetes Insípida Neurogénica/etiología , Histiocitosis de Células de Langerhans/complicaciones , Hipopituitarismo/etiología , Niño , HumanosRESUMEN
CONTEXT: The syndrome CAH-X is due to a contiguous gene deletion of CYP21A2 and TNXB resulting in TNXA/TNXB chimeras. OBJECTIVE: To analyze TNXB gene status and to clinically evaluate the Ehlers-Danlos syndrome phenotype in a large cohort of Argentine congenital adrenal hyperplasia (CAH) patients to assess the prevalence of this condition in our population. METHODS: TNXB gene analysis was performed in 66 nonrelated CAH patients that were carriers of the CYP21A2 gene deletion. A molecular strategy based on multiplex ligation-dependent probe amplification and Sanger sequencing analysis was developed allowing for the detection of different, previously described TNXA/TNXB chimeras, named CH1, CH2, and CH3. The main outcome measures were TNXB status of CAH patients that were carriers of the CYP21A2 deletion in the homozygous or heterozygous state. RESULTS: TNXA/TNXB CH1 was found in 41%, CH2 in 29%, and CH3 in 1% of nonrelated alleles carrying the CYP21A2 deletion. Thus, overall 71% of alleles were found to carry a contiguous gene deletion. Sixty-seven percent of patients analyzed had a monoallelic form and 6% a biallelic form. All patients with the biallelic form had severe skin hyperextensibility and generalized joint hypermobility. CONCLUSION: Based on the high frequency of TNXB alterations found in CYP21A2 deletion carrier alleles, we recommend evaluating TNXB status in these patients, and assessing connective tissue dysplasia, including cardiologic alterations in positive cases. The number of patients undergoing cardiological evaluation should be expanded to determine the incidence of structural and functional abnormalities in this cohort.
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Hiperplasia Suprarrenal Congénita/genética , Quimera/genética , Síndrome de Ehlers-Danlos/epidemiología , Tenascina/genética , Adolescente , Adulto , Argentina/epidemiología , Niño , Preescolar , Síndrome de Ehlers-Danlos/genética , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Fenotipo , Prevalencia , Esteroide 21-Hidroxilasa/genética , Adulto JovenRESUMEN
CONTEXT: The low-dose (1 µg) ACTH test (LDT) is widely used to assess central adrenal insufficiency (CAI); however, the serum cortisol cutoff value is controversial. Salivary cortisol (SC) may be a more accurate measurement for CAI. OBJECTIVE: To assess a new maximum cutoff value of serum cortisol after LDT in pediatric patients, taking into account serum and SC measurements. DESIGN AND SETTING: Prospective study in a pediatric tertiary referral center. WORKING HYPOTHESIS: The combined analysis of serum and SC response to LDT might improve LDT for CAI diagnosis. PARTICIPANT AND OUTCOME MEASUREMENT: A total of 145 pediatric patients underwent LDT. Serum and SC levels were measured. A central adrenal sufficient (CAS) response was established according to the reference serum cortisol cutoff value of ≥497 nmol/L. RESULTS: The LDT study showed central adrenal sufficiency in 72 patients and CAI in 73 patients. Considering the lower quartile of maximum SC value (21 nmol/L) in the CAS group, an intermediate CAI (InCAI) group and a real CAI (RCAI) group were defined. Regarding the median maximum value of serum cortisol levels in the InCAI group, a new serum cortisol cutoff value of 450 nmol/L was established. Furthermore, 91% of the patients in the RCAI group were below this cutoff value. CONCLUSION: The combined evaluation of maximum serum and SC levels to LDT might be useful to define an InCAI group and to avoid unnecessary hormone replacement therapy. However, rigorous patient follow-up is required.
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Insuficiencia Suprarrenal/diagnóstico , Hormona Adrenocorticotrópica/farmacología , Hidrocortisona/sangre , Sistema Hipófiso-Suprarrenal/fisiopatología , Glándulas Salivales/metabolismo , Adolescente , Insuficiencia Suprarrenal/sangre , Hormona Adrenocorticotrópica/sangre , Niño , Estudios de Cohortes , Femenino , Humanos , Masculino , Pediatría , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Estudios Prospectivos , Curva ROC , Sensibilidad y EspecificidadRESUMEN
El prolactinoma gigante es un adenoma pituitario poco frecuente caracterizado por su gran invasión local. Se reporta el caso de un varón de 15 años de edad con dolor retroocular izquierdo y exoftalmos ipsilateral de 4 meses de evolución secundario a un tumor en la base del cráneo que invadía la órbita. Los estudios hormonales revelaron prolactina sérica de 6913,7 ng/ml (valor normal < 20), que confirmó el diagnóstico de prolactinoma gigante. El paciente inició un tratamiento con el agonista dopaminérgico cabergolina en dosis crecientes. Luego de 7 meses de seguimiento, la prolactina había descendido a 349,8 ng/ml y el volumen del tumor se redujo un 70%, sin efectos adversos al tratamiento. El paciente se encontraba asintomático y había reiniciado la pubertad. La rápida remisión de los síntomas sin necesidad de tratamientos invasores subraya la importancia de considerar el diagnóstico de prolactinoma entre los posibles diagnósticos diferenciales de tumor de la base del cráneo.
Giant prolactinomas are rare pituitary adenomas characterized by their great local invasion. In this paper, we report a 15-year-old male with left retro-ocular pain and ipsilateral exophthalmos of 4 months of evolution, secondary to a tumour in the base of the skull that invaded the orbit. Hormonal studies revealed serum prolactin of 6913,7 ng/ml (normal value < 20), confirming the diagnosis of giant prolactinoma. The patient started treatment with the dopaminergic agonist cabergoline in increasing doses. After 7 months of follow-up the prolactin had decreased to 349.8 ng/ml and the tumor volume was reduced by 70%, without presenting adverse effects to the treatment. The patient was asymptomatic and had restarted puberty. The rapid remission of symptoms without the need for invasive treatments underlines the importance of considering the diagnosis of prolactinoma among the possible differential diagnoses of tumor of the skull base.
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Humanos , Masculino , Adolescente , Neoplasias Hipofisarias/diagnóstico , Prolactinoma/diagnóstico , Neoplasias Hipofisarias/patología , Prolactinoma/patologíaRESUMEN
Giant prolactinomas are rare pituitary adenomas characterized by their great local invasion. In this paper, we report a 15-year-old male with left retro-ocular pain and ipsilateral exophthalmos of 4 months of evolution, secondary to a tumour in the base of the skull that invaded the orbit. Hormonal studies revealed serum prolactin of 6913,7 ng/ml (normal value < 20), confirming the diagnosis of giant prolactinoma. The patient started treatment with the dopaminergic agonist cabergoline in increasing doses. After 7 months of follow-up the prolactin had decreased to 349.8 ng/ml and the tumor volume was reduced by 70%, without presenting adverse effects to the treatment. The patient was asymptomatic and had restarted puberty. The rapid remission of symptoms without the need for invasive treatments underlines the importance of considering the diagnosis of prolactinoma among the possible differential diagnoses of tumor of the skull base.
El prolactinoma gigante es un adenoma pituitario poco frecuente caracterizado por su gran invasión local. Se reporta el caso de un varón de 15 años de edad con dolor retroocular izquierdo y exoftalmos ipsilateral de 4 meses de evolución secundario a un tumor en la base del cráneo que invadía la órbita. Los estudios hormonales revelaron prolactina sérica de 6913,7 ng/ml (valor normal < 20), que confirmó el diagnóstico de prolactinoma gigante. El paciente inició un tratamiento con el agonista dopaminérgico cabergolina en dosis crecientes. Luego de 7 meses de seguimiento, la prolactina había descendido a 349,8 ng/ml y el volumen del tumor se redujo un 70%, sin efectos adversos al tratamiento. El paciente se encontraba asintomático y había reiniciado la pubertad. La rápida remisión de los síntomas sin necesidad de tratamientos invasores subraya la importancia de considerar el diagnóstico de prolactinoma entre los posibles diagnósticos diferenciales de tumor de la base del cráneo.
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Neoplasias Hipofisarias/diagnóstico , Prolactinoma/diagnóstico , Adolescente , Humanos , Masculino , Neoplasias Hipofisarias/patología , Prolactinoma/patologíaRESUMEN
Los niños con restricción del crecimiento intrauterino (RCIU) presentan en la vida posnatal una serie de alteraciones metabólicas y hormonales, y tienen predisposición al desarrollo de obesidad, hipertensión arterial, enfermedad cardiovascular, resistencia a la insulina y diabetes tipo 2. La exposición a un ambiente intrauterino desfavorable en fases críticas del desarrollo puede tener un efecto deletéreo sobre la gónada en formación. Se realizó una revisión bibliográfica y puesta al día sobre la posible asociación entre RCIU y alteraciones de la función gonadal en niños y adolescentes de ambos sexos. Para facilitar la actualización, se dividió por etapas en: 1, prenatal; 2, posnatal y prepuberal; 3, puberal, y 4, adulta. La mayoría de los niños que nacen muy prematuros o con muy bajo peso al nacer hacen una transición sin obstáculos desde la infancia a la edad adulta con respecto a la salud reproductiva. Sin embargo, en los varones se puede observar criptorquidia, hipospadias, cáncer testicular y menor fertilidad, y en las niñas, pubertad y menarca temprana, hiperandrogenismo y síndrome de ovario poliquístico. Existen datos controvertidos y se necesitan más estudios para aclarar la relación entre el RCIU y la función hipotálamo-hipófiso-gonadal.
Low birth weight due to intrauterine growth restriction (IUGR) is associated with an increased risk of obesity, hypertension, cardiovascular disease, insulin resistance, and type 2 diabetes during postnatal life. Exposure to an unfavourable intrauterine environment in critical phases of development may have a deleterious effect on the forming gonad. The objective was to carry out a bibliographic review and update on the possible association between IUGR and alterations of gonadal function in children and adolescents of both sexes. To facilitate the update, this was divided into stages: 1, prenatal; 2, postnatal and pre-pubertal; 3, puberal, and 4, adult. Most children born preterm or with low birth weight make a normal transition from childhood to adulthood with respect to reproductive health. However, cryptorchidism, hypospadias, testicular cancer and lower fertility could be observed in boys, and early puberty and menarche, hyperandrogenism and polycystic ovarian syndrome in girls. However, the data are controversial, and further studies are needed to clarify the relationship between IUGR and pituitary gonadal function.
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Humanos , Masculino , Femenino , Recién Nacido Pequeño para la Edad Gestacional/crecimiento & desarrollo , Retardo del Crecimiento Fetal/fisiopatología , Trastornos Gonadales/etiología , Pubertad Precoz/embriología , Hiperandrogenismo/embriología , Criptorquidismo/embriología , Hipospadias/embriologíaRESUMEN
BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder of unknown etiopathogenesis. Central diabetes insipidus (CDI) is the most frequent endocrine manifestation and is a known risk factor for the development of further anterior pituitary hormone deficiencies (APD). However, not all CDI patients develop APD, as observed during prolonged periods of follow-up. AIM: To find predictors of developing APD in LCH children with CDI followed in our institution. METHODS: We retrospectively analysed 44 patients over a median period (quartiles) of 12.3 years (8.79-14.24). Patients were subdivided into group 1 and group 2, according to absence or presence of APD, respectively. The main variables studied were: (1) chronological age (CA) at LCH diagnosis, (2) the primary site of LCH at diagnosis: low risk (LR) and multisystemic risk organs, and (3) the presence of reactivation. RESULTS: Multivariate Cox regression analysis showed that APD was positively associated with CA at LCH diagnosis [relative risk (RR) 1.14, p < 0.01], the LR clinical form (RR 8.6, p < 0.03), and negatively associated with the presence of reactivations (RR 0.3, p < 0.01). CONCLUSIONS: Patients with older CA at LCH diagnosis, LR clinical forms, and fewer reactivation episodes might represent a subgroup of paediatric LCH CDI patients with a higher risk of developing APD.
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Diabetes Insípida , Histiocitosis de Células de Langerhans , Hormonas Adenohipofisarias/deficiencia , Adolescente , Niño , Diabetes Insípida/sangre , Diabetes Insípida/complicaciones , Diabetes Insípida/diagnóstico , Femenino , Histiocitosis de Células de Langerhans/sangre , Histiocitosis de Células de Langerhans/complicaciones , Histiocitosis de Células de Langerhans/diagnóstico , Humanos , Masculino , Factores de RiesgoRESUMEN
BACKGROUND: Central adrenal insufficiency (CAI) is due to a decrease of CRH and/or ACTH secretion. ACTH-dependent dehydroepiandrosterone sulphate (DHEAS) has been postulated as a possible marker of adrenal function in adult patients. AIMS: To evaluate the usefulness of basal serum DHEAS determination to diagnose CAI in pubertal patients with a suspected diagnosis of CAI. METHODS: Ninety-four pubertal patients suspected of having CAI were divided into two groups according to sufficient (group 1) or insufficient (group 2) low-dose ACTH test serum cortisol response. Concordance with low (<2.5th percentile) or normal (≥2.5th percentile) basal serum DHEAS levels for age and sex, respectively, was analysed. RESULTS: Fifty patients (53.2%) in group 1 and 44 (46.8%) in group 2 were included. The median value of serum DHEAS levels in group 2 (0.7 µmol/l, interquartile range 0.44-1.49) was significantly lower than in group 1 (2.13 µmol/l, interquartile range 0.87-3.5; p < 0.03). Nevertheless, serum basal DHEAS levels as a diagnostic marker of CAI showed 39% sensitivity and 80% specificity. CONCLUSION: In pubertal patients, basal serum DHEAS levels do not seem to be a useful tool to diagnose either sufficiency or insufficiency of secondary adrenal function.
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Insuficiencia Suprarrenal/sangre , Deshidroepiandrosterona/sangre , Pubertad/sangre , Adolescente , Hormona Adrenocorticotrópica/sangre , Adulto , Biomarcadores/sangre , Niño , Humanos , Hidrocortisona/sangre , MasculinoRESUMEN
StAR facilitates cholesterol entry into the mitochondria as part of the transduceosome complex. Recessive mutations in the gen STAR cause classic and nonclassic congenital lipoid adrenal hyperplasia. The aim of the study was to analyze the molecular consequences of a novel heterozygous STAR mutation in a 46,XY patient with ambiguous genitalia and adrenal insufficiency. We found a de novo heterozygous IVS-2A>G STAR mutation and the reported heterozygous p.G146A SF1 polymorphism with normal CYP11A1, FDXR, FDX1, VDAC1 and TSPO genes. RT-PCR and sequencing from patient's testicular RNA showed a -exon2 transcript and the wild-type (WT) transcript. Both 37 kDa precursor and 30 kDa mature protein were detected in COS-7 cell transfected with mutant and WT plasmids. Immunofluorescence showed almost no co-localization of mitochondria and mutant protein (delta22-59StAR). Delta22-59StAR activity was 65±13% of WT. Cotransfection with WT and delta22-59StAR plasmids reduced WT activity by 62.0% ± 13.9. Novel splice-junction heterozygous STAR mutation (IVS-2A>G) resulted in the in-frame loss of amino acids 22 to 59 in the N-terminal mitochondrial targeting signal. A misfolded p.G22_L59delStAR might interfere with WT StAR activity by blocking the transduceosome complex, causing an autosomal dominant form of StAR deficiency, explaining the clinical phenotype.
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Hiperplasia Suprarrenal Congénita/genética , Trastorno del Desarrollo Sexual 46,XY/genética , Mutación/genética , Fosfoproteínas/genética , Insuficiencia Suprarrenal/genética , Animales , Células COS , Chlorocebus aethiops , Humanos , Recién Nacido , Masculino , Linaje , Fenotipo , Polimorfismo Genético , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
StAR facilitates cholesterol entry into the mitochondria as part of the transduceosome complex. Recessive mutations in the gen STAR cause classic and nonclassic congenital lipoid adrenal hyperplasia. The aim of the study was to analyze the molecular consequences of a novel heterozygous STAR mutation in a 46,XY patient with ambiguous genitalia and adrenal insufficiency. We found a de novo heterozygous IVS-2A>G STAR mutation and the reported heterozygous p.G146A SF1 polymorphism with normal CYP11A1, FDXR, FDX1, VDAC1 and TSPO genes. RT-PCR and sequencing from patients testicular RNA showed a -exon2 transcript and the wild-type (WT) transcript. Both 37 kDa precursor and 30 kDa mature protein were detected in COS-7 cell transfected with mutant and WT plasmids. Immunofluorescence showed almost no co-localization of mitochondria and mutant protein (delta22-59StAR). Delta22-59StAR activity was 65±13
of WT. Cotransfection with WT and delta22-59StAR plasmids reduced WT activity by 62.0
± 13.9. Novel splice-junction heterozygous STAR mutation (IVS-2A>G) resulted in the in-frame loss of amino acids 22 to 59 in the N-terminal mitochondrial targeting signal. A misfolded p.G22_L59delStAR might interfere with WT StAR activity by blocking the transduceosome complex, causing an autosomal dominant form of StAR deficiency, explaining the clinical phenotype.
Asunto(s)
Fosfoproteínas/genética , Hiperplasia Suprarrenal Congénita/genética , Mutación/genética , /genética , Animales , Chlorocebus aethiops , Células COS , Fenotipo , Humanos , Insuficiencia Suprarrenal/genética , Linaje , Masculino , Polimorfismo Genético , Reacción en Cadena en Tiempo Real de la Polimerasa , Recién NacidoRESUMEN
CONTEXT: Steroid acute regulatory (StAR) protein is a mitochondria-targeted protein that is part of the transduceosome complex crucial for transport of cholesterol to mitochondria. Recessive mutations cause classic and nonclassic congenital lipoid adrenal hyperplasia. OBJECTIVE: The aim of this study was to report the clinical, hormonal, genetic, and functional data of a novel heterozygous mutation in the StAR gene found in a 46,XY patient with ambiguous genitalia and neonatal severe steroidogenic deficiency. PATIENT: Undetectable serum steroids with high ACTH and plasma renin activity but normal acute GnRH response were found in infancy. After gonadectomy (at 3 yr of age), serum LH and testosterone were undetectable, whereas FSH was normal but increased slowly afterward. Estrogen replacement therapy, started at 10.2 yr of age, suppressed gonadotropins (for 2 yr). However, after 1 month off estrogens, the patient showed castrated levels. At 11.9 yr old, after fludrocortisone withdrawal because of hypertension, plasma renin activity and aldosterone remained normal, suggesting mineralocorticoid recovery by a StAR-independent mechanism. RESULTS: We found a de novo heterozygous IVS-2A>G StAR mutation and the reported heterozygous p.G146A SF1 polymorphism with normal CYP11A1, FDXR, FDX1, VDAC1, and TSPO genes. The mutant StAR transcript lacked exon 2, resulting in the in-frame loss of amino acids 22 to 59 in the N-terminal mitochondrial targeting signal. In vitro, the mutant protein exhibited reduced StAR activity in a dominant-negative manner and almost no mitochondria localization. CONCLUSIONS: A misfolded p.G22_L59del StAR might interfere with wild-type StAR activity by blocking the transduceosome complex, causing an autosomal dominant form of StAR deficiency, explaining the clinical phenotype. We speculated that estrogen might have modulated mineralocorticoid function and pubertal maturation in a human natural model lacking endogenous steroid production.
Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , Trastorno del Desarrollo Sexual 46,XY/genética , Mitocondrias/metabolismo , Mutación Missense , Fosfoproteínas/genética , Señales de Clasificación de Proteína/genética , Animales , Células COS , Niño , Chlorocebus aethiops , Trastornos del Desarrollo Sexual/genética , Femenino , Genes Dominantes/genética , Humanos , Recién Nacido , Masculino , Mutación Missense/fisiología , Linaje , Polimorfismo de Nucleótido Simple/fisiología , Estructura Terciaria de Proteína/genética , Transporte de Proteínas/genéticaRESUMEN
StAR facilitates cholesterol entry into the mitochondria as part of the transduceosome complex. Recessive mutations in the gen STAR cause classic and nonclassic congenital lipoid adrenal hyperplasia. The aim of the study was to analyze the molecular consequences of a novel heterozygous STAR mutation in a 46,XY patient with ambiguous genitalia and adrenal insufficiency. We found a de novo heterozygous IVS-2A>G STAR mutation and the reported heterozygous p.G146A SF1 polymorphism with normal CYP11A1, FDXR, FDX1, VDAC1 and TSPO genes. RT-PCR and sequencing from patients testicular RNA showed a -exon2 transcript and the wild-type (WT) transcript. Both 37 kDa precursor and 30 kDa mature protein were detected in COS-7 cell transfected with mutant and WT plasmids. Immunofluorescence showed almost no co-localization of mitochondria and mutant protein (delta22-59StAR). Delta22-59StAR activity was 65±13
of WT. Cotransfection with WT and delta22-59StAR plasmids reduced WT activity by 62.0
± 13.9. Novel splice-junction heterozygous STAR mutation (IVS-2A>G) resulted in the in-frame loss of amino acids 22 to 59 in the N-terminal mitochondrial targeting signal. A misfolded p.G22_L59delStAR might interfere with WT StAR activity by blocking the transduceosome complex, causing an autosomal dominant form of StAR deficiency, explaining the clinical phenotype.
Asunto(s)
Trastorno del Desarrollo Sexual 46,XY/genética , Hiperplasia Suprarrenal Congénita/genética , Mutación/genética , Fosfoproteínas/genética , Insuficiencia Suprarrenal/genética , Animales , Células COS , Chlorocebus aethiops , Humanos , Recién Nacido , Masculino , Linaje , Fenotipo , Polimorfismo Genético , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
BACKGROUND: Growth retardation is a considerable clinical problem in children with chronic kidney disease (CKD). Optimization of metabolic and nutritional parameters does not always lead to improved growth. Recombinant human growth hormone (rhGH) treatment has been used to improve height. Several studies in the literature have shown increased growth velocity, although data on the final height (FH) reached are scarce. AIMS: We assessed the effect of rhGH on FH standard deviation score (SDS) in children with CKD following renal transplantation (RTx), comparing it with patients who did not receive rhGH (control group) but were treated with the same protocol and followed up in a single Center. METHODS: Thirty-three patients received rhGH treatment until FH. Fourteen who refused rhGH therapy were included in the controls. Prognostic factors for FH and changes in glomerular filtration rate (GFR) during follow-up were also analyzed RESULTS: FH SDS in rhGH-treated patients was significantly higher than in controls (-1.88 ± 1.14 vs -3.48 ± 1.19 SDS, respectively, p <0.05). In both groups, a similar reduction in GFR was observed. Height (SDS) at onset of rhGH treatment was the only statistically significant variable useful to predict response to treatment (p = 0.001). CONCLUSION: Our findings confirm that rhGH is effective to improve FH in CKD RTx patients, without affecting kidney function.
Asunto(s)
Estatura/efectos de los fármacos , Trastornos del Crecimiento/tratamiento farmacológico , Hormona de Crecimiento Humana/uso terapéutico , Enfermedades Renales/cirugía , Trasplante de Riñón , Adolescente , Análisis de Varianza , Argentina , Estudios de Casos y Controles , Niño , Enfermedad Crónica , Femenino , Tasa de Filtración Glomerular , Trastornos del Crecimiento/etiología , Trastornos del Crecimiento/fisiopatología , Humanos , Enfermedades Renales/complicaciones , Enfermedades Renales/fisiopatología , Masculino , Proteínas Recombinantes/uso terapéutico , Análisis de Regresión , Factores de Tiempo , Resultado del TratamientoRESUMEN
INTRODUCTION: Prader-Willi syndrome (PWS) is a genetic disorder caused by the loss of expression of paternally transcribed genes in a highly imprinted region of chromosome 15q11-13. The clinical phenotype has been well characterized, mostly related to hypothalamic dysfunction. Even though central hypothyroidism has been documented in 20-30% of patients with PWS, thyroid function during the first 2 years of life has not been clearly defined. OBJECTIVE: To evaluate hypothalamic-pituitary-thyroid function in infant PWS patients. STUDY DESIGN: Eighteen patients with PWS, aged 0.16-2 years, were included in a prospective study. PWS diagnosis was based on clinical features and molecular analysis. Serum total (T) T4, free (F) T4, T3 and thyroid-stimulating hormone (TSH) were evaluated in the patients with PWS included in the study. Serum hormone values were compared to those of a large reference population of the same age. RESULTS: In 13 of 18 patients with PWS (72.2%), serum TT4 and/or FT4 levels were below the 2.5th percentile of the reference population, while in only one PWS patient serum T3 was below this cut-off. CONCLUSION: The results of this study suggest that transient or definitive thyrotropin-releasing hormone (TRH)-TSH thyroid axis dysfunction may frequently be present in infant PWS patients. Paediatricians should be aware of this dysfunction in this critical period of thyroid hormone action on neurological development.
Asunto(s)
Sistema Hipotálamo-Hipofisario/fisiopatología , Síndrome de Prader-Willi/fisiopatología , Glándula Tiroides/fisiopatología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Tirotropina/sangre , Hormona Liberadora de Tirotropina/fisiología , Tiroxina/sangreRESUMEN
BACKGROUND: There is little information on the outcome of patients with retinoblastoma and tumor at the resection margin of the optic nerve. PROCEDURE: Retrospective evaluation of three successive prospective protocols. Twenty-six consecutive patients were analyzed (International Staging System-IRSS-stage 2 = 21, stage 3 = 5) from three successive prospective protocols (1988-2006). Patients with stage 2 were enucleated upfront and those with stage 3 had neoadjuvant chemotherapy followed by enucleation and adjuvant therapy. Both groups received adjuvant chemotherapy and orbital radiotherapy after enucleation. Patients in protocol 1 received 1 year of the lower-dose chemotherapy regimen including cyclophosphamide, vincristine and doxorubicin along with intrathecal chemotherapy. Patients of protocols 2 and 3 received a more intense and shorter intravenous regimen including carboplatin and etoposide alternating with cyclophosphamide, idarubicin and vincristine with no intrathecal treatment. The components of protocol 2 and 3 were similar except for the dose of carboplatin which was 10% lower in protocol 3. RESULTS: Thirteen were treated in protocol 1 and 13 in protocols 2 and 3. The probability of event-free survival was 0.70 at 5 years. Events included: CNS relapse = 3, second malignancies = 3, death in complete remission = 2. There were no significant differences in outcome between protocols or stages. Endocrinological disturbances related to the hypothalamus-hypophysis axis were evident in 6/8 patients evaluated. Severe orbital sequelae occurred in 12 cases. CONCLUSIONS: A substantial number of patients with tumor at the resection margin of the optic nerve can be cured with current therapy; however, therapy related sequelae are frequent.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Nervio Óptico/patología , Retinoblastoma/complicaciones , Retinoblastoma/terapia , Adolescente , Adulto , Niño , Preescolar , Terapia Combinada , Enucleación del Ojo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias , Estudios Prospectivos , Radioterapia , Recurrencia , Inducción de Remisión , Resultado del Tratamiento , Adulto JovenRESUMEN
P450 aromatase (P450Aro), involved in androgen to estrogen conversion, is encoded by the CYP19 gene. P450Aro c655G>A mutation described in heterozygous form in a girl and in homozygous form in an adult male with P450Aro deficiency results in an aberrant splicing due to disruption of a donor splice site. A truncated inactive protein would be expected if intron5 is retained. Surprisingly, the girl described with this mutation showed spontaneous breast development and pubertal estradiol (E2) levels suggesting residual P450Aro activity (AA). Formerly, we postulate the in frame E5 skipping as a consequence of this mutation generating a protein with some degree of activity. When P450Aro mRNA expression was analysed from patient's lymphocytes, an aberrant spliced mRNA lacking E5 (-E5mRNA) was detected, suggesting an association between E5 skipping and the presence of the mutation. Splicing assays in Y1 cells confirmed this association. -Ex5 cDNA expression in Y1 cells resulted in an inactive protein that could not explain patient's phenotype. Exon 5 might be predicted as a poorly defined exon suggesting a susceptibility to splicing mutations and physiological alternative splicing (AS) events. Therefore, -Ex5mRNA was assessed as a natural occurring alternative transcript in normal human steroidogenic tissues. As P450Aro -E5mRNA expression was detected in human term placenta, prepubertal testis and prepubertal adrenal, we might speculate that AS of P450Aro coding region would occur in humans and would be involved in the complex AA regulation. Furthermore, tissue specific regulation of AS might suggest low expression of +E5mRNA from the c655G>A allele explaining residual AA evidenced in the affected girl.