Carcinoma medular de tiroides: estudio multicéntrico. Presentación y evolución en 219 pacientes / Medullary Thyroid Carcinoma: Clinical Presentation and Outcome in 219 Patients

Ante la baja frecuencia del carcinoma medular de tiroides (CMT), en el Departamento de Tiroides de SAEM nos propusimos realizar un estudio de cohorte, observacional, retrospectivo y multicéntrico. Se incluyeron 219 pacientes con diagnóstico histológico de CMT. El 65 % fueron mujeres, la edad promedio fue de 39 ± 20 años (1 a 84 años); 44-% de los casos fueron familiares. Las formas de presentación más frecuentes fueron nódulo tiroideo (58 %) y pesquisa genética por antecedente familiar (22 %). Si bien la citología tiroidea fue diagnóstica de CMT en el 39 % de los casos, fue determinante de indicación quirúrgica en el 79 %. En el 47 % de los pacientes el diagnóstico de CMT se obtuvo previamente al tratamiento quirúrgico inicial por punción aspiración con aguja fina (PAAF), estudio genético o nivel de calcitonina (CT)). El 65 % se presentó en estadios avanzados (TNM III y IV). El estudio del protoncogen RET se realizó en 162 pacientes (74 %). En el 49 % se observó mutación siendo la más frecuente (76 %) en el codón 634. La forma hereditaria más frecuentemente observada fue el síndrome de neoplasia endocrina múltiple (NEM) 2A (57 % de los casos familiares), seguida por carcinoma medular familiar (25 %) y NEM 2B (13 %). Los casos familiares tuvieron menor edad al diagnóstico y mayor frecuencia de diagnóstico prequirúrgico. Los casos índice tuvieron mayor edad al momento del diagnóstico, mayores niveles de antígeno carcinoembrionario (CEA) y CT prequirúrgicos, mayor proporción de estadios III y IV y mayor porcentaje de evidencia de enfermedad al momento de la última consulta que aquellos detectados por pesquisa. En 143 pacientes (65 %) se obtuvieron registros completos de seguimiento en los que se analizaron los factores relacionados con la evolución. La mediana de seguimiento fue de 44 meses: fallecieron 21 pacientes (14,6 %) y 122 (86 %) viven; 76 de estos (54 %) se encuentran libres de enfermedad. El grupo con evidencia de enfermedad se presentó en estadios más avanzados. Resultaron factores de mayor riesgo para evidencia de enfermedad: sexo masculino, CMT esporádico, niveles elevados de CT prequirúrgicos, estadio IV y presencia de metástasis. Los niveles de CT posquirúrgicos fueron menores en aquellos pacientes que en la evolución final no presentaron evidencia de enfermedad. El principal factor pronóstico de la evolución de los pacientes con CMT fue el estadio de presentación, determinando la importancia del diagnóstico precoz con el fin de poder implementar un tratamiento quirúrgico curativo en estadios menos avanzados.

Due to the low frequency of medullary thyroid cancer (MTC), an observational, cohort, retrospective multicenter study was conducted at the Thyroid Department of the Endocrine and Metabolism Argentine Society (SAEM). We included 219 patients with histologically proven MTC, with a mean age of 39 ± 20 yr (range 1-84 years). Sixty five percent were women and 44% were familial cases. The most common presentations were thyroid nodule (58 %) and genetic screening due to family history (22 %). In 39 % of patients, diagnosis of MTC was made by fine needle aspiration, but cytology led to surgery in 79 %. In 47 % of patients, MTC was diagnosed by cytology, calcitonin (CT) levels or genetic studies prior to initial surgery. Sixty five percent of patients had advanced stages of the disease (TNM III or IV) at diagnosis. Proto-oncogene RET was studied in 162 patients (74 %). In 49% a mutation was reported, most frequently in codon 634 (76 %). Regarding hereditary forms of MTC, MEN 2A was the most frequent (57%), followed by familial MTC in 25 % and MEN 2B in 13 % of cases. Familial cases were younger subjects and had more frequently a pre-surgery diagnosis. Index cases were older, with higher CEA and CT levels, presented in more advanced stages and had more frequently evidence of disease at final assessment than patients who were diagnosed by genetic screening. Follow-up records of 143 patients were analyzed (65%); median time was 44 months; 21 patients died (14.6 %) and 122 survived (86 %), 76 showed no evidence of disease (NED) (54 %). High risk factors for evidence of disease at the final evaluation were: male gender, sporadic MTC, higher CT pre-surgery levels, stage IV and metastasis. Post surgery CT levels were lower in patients with NED. Stage at initial diagnosis was the main prognostic factor in patients with MTC, determining the importance of early detection for performing curative surgery in less advanced stages.

Carcinoma medular de tiroides: estudio multicéntrico. Presentación y evolución en 219 pacientes / Medullary Thyroid Carcinoma: Clinical Presentation and Outcome in 219 Patients

Ante la baja frecuencia del carcinoma medular de tiroides (CMT), en el Departamento de Tiroides de SAEM nos propusimos realizar un estudio de cohorte, observacional, retrospectivo y multicéntrico. Se incluyeron 219 pacientes con diagnóstico histológico de CMT. El 65 % fueron mujeres, la edad promedio fue de 39 ± 20 años (1 a 84 años); 44-% de los casos fueron familiares. Las formas de presentación más frecuentes fueron nódulo tiroideo (58 %) y pesquisa genética por antecedente familiar (22 %). Si bien la citología tiroidea fue diagnóstica de CMT en el 39 % de los casos, fue determinante de indicación quirúrgica en el 79 %. En el 47 % de los pacientes el diagnóstico de CMT se obtuvo previamente al tratamiento quirúrgico inicial por punción aspiración con aguja fina (PAAF), estudio genético o nivel de calcitonina (CT)). El 65 % se presentó en estadios avanzados (TNM III y IV). El estudio del protoncogen RET se realizó en 162 pacientes (74 %). En el 49 % se observó mutación siendo la más frecuente (76 %) en el codón 634. La forma hereditaria más frecuentemente observada fue el síndrome de neoplasia endocrina múltiple (NEM) 2A (57 % de los casos familiares), seguida por carcinoma medular familiar (25 %) y NEM 2B (13 %). Los casos familiares tuvieron menor edad al diagnóstico y mayor frecuencia de diagnóstico prequirúrgico. Los casos índice tuvieron mayor edad al momento del diagnóstico, mayores niveles de antígeno carcinoembrionario (CEA) y CT prequirúrgicos, mayor proporción de estadios III y IV y mayor porcentaje de evidencia de enfermedad al momento de la última consulta que aquellos detectados por pesquisa. En 143 pacientes (65 %) se obtuvieron registros completos de seguimiento en los que se analizaron los factores relacionados con la evolución. La mediana de seguimiento fue de 44 meses: fallecieron 21 pacientes (14,6 %) y 122 (86 %) viven; 76 de estos (54 %) se encuentran libres de enfermedad. El grupo con evidencia de enfermedad se presentó en estadios más avanzados. Resultaron factores de mayor riesgo para evidencia de enfermedad: sexo masculino, CMT esporádico, niveles elevados de CT prequirúrgicos, estadio IV y presencia de metástasis. Los niveles de CT posquirúrgicos fueron menores en aquellos pacientes que en la evolución final no presentaron evidencia de enfermedad. El principal factor pronóstico de la evolución de los pacientes con CMT fue el estadio de presentación, determinando la importancia del diagnóstico precoz con el fin de poder implementar un tratamiento quirúrgico curativo en estadios menos avanzados.(AU)

Due to the low frequency of medullary thyroid cancer (MTC), an observational, cohort, retrospective multicenter study was conducted at the Thyroid Department of the Endocrine and Metabolism Argentine Society (SAEM). We included 219 patients with histologically proven MTC, with a mean age of 39 ± 20 yr (range 1-84 years). Sixty five percent were women and 44% were familial cases. The most common presentations were thyroid nodule (58 %) and genetic screening due to family history (22 %). In 39 % of patients, diagnosis of MTC was made by fine needle aspiration, but cytology led to surgery in 79 %. In 47 % of patients, MTC was diagnosed by cytology, calcitonin (CT) levels or genetic studies prior to initial surgery. Sixty five percent of patients had advanced stages of the disease (TNM III or IV) at diagnosis. Proto-oncogene RET was studied in 162 patients (74 %). In 49% a mutation was reported, most frequently in codon 634 (76 %). Regarding hereditary forms of MTC, MEN 2A was the most frequent (57%), followed by familial MTC in 25 % and MEN 2B in 13 % of cases. Familial cases were younger subjects and had more frequently a pre-surgery diagnosis. Index cases were older, with higher CEA and CT levels, presented in more advanced stages and had more frequently evidence of disease at final assessment than patients who were diagnosed by genetic screening. Follow-up records of 143 patients were analyzed (65%); median time was 44 months; 21 patients died (14.6 %) and 122 survived (86 %), 76 showed no evidence of disease (NED) (54 %). High risk factors for evidence of disease at the final evaluation were: male gender, sporadic MTC, higher CT pre-surgery levels, stage IV and metastasis. Post surgery CT levels were lower in patients with NED. Stage at initial diagnosis was the main prognostic factor in patients with MTC, determining the importance of early detection for performing curative surgery in less advanced stages.(AU)

Programa nacional de bocio nodular (PRONBONO): Estudio multicéntrico de bocio nodular único palpable / National Program for Nodular Goiter (PRONBONO): Multicenter study of single palpable thyroid nodules

Introducción: La presencia de nódulos tiroideos palpables en la población general, es uno de los signos clínicos tiroideos más frecuentes en la práctica diaria. Objetivos: 1) establecer la prevalencia de las distintas patologías en bocio nodular único palpable y analizar sus características y su relación con los resultados citológicos. 2) analizar la existencia de diferencias regionales en Argentina. Pacientes y Métodos: Estudio prospectivo de 739 pacientes con bocio nodular único palpable evaluados entre el 1/1/2000 y el 31/12/2001 en Centros de Buenos Aires, Bahía Blanca, Mendoza y La Pampa. Se recabaron datos de examen clínico, ecografía tiroidea, TSH, ATPO y citología por punción con aguja fina. (PAAF). Fue utilizado para el análisis estadístico Correlación de Pearson, X2 y Test de Fisher. Resultados: la edad (X ± DS) fue 46,3 ± 14 años, 93,1 % eran de sexo femenino. El 1,6 % tenía historia de radiación en cuello y el 29,9 % antecedentes familiares de patología tiroidea. Hallazgos clínicos: disfagia en el 7,9 %, disfonía 3,5 %, crecimiento nodular en los últimos 6 meses 19,2 %, consistencia dura el 24,7 %, fijeza a estructuras adyacentes 1,5 % y adenopatías en el 3 %. Hallazgos bioquímicos: TSH normal en el 81,2 % y ATPO positivos en el 30,3 % de los casos. Características Ecográficas: nódulos sólidos: 53,1 %, hipoecoicos: 63,8 %, microcalcificaciones 10,3 %, halo incompleto: 15 %, multinodular: 30,5 %, tiroides heterogénea: 60,2 % y adenopatías: 3,8 %. Hallazgos citológicos: En el 86,8 % de los casos fue necesario solo una punción para llegar al diagnóstico. Insatisfactorio (excluyendo quiste): 3,2 %: benignos: 77,3 %; sospechosos: 12,6 % y cáncer: 7 % (42 papilar, 2 medular y 3 sin especificar). Una correlación significativa (p<0,02) fue observada entre citología maligna y crecimiento rápido, dureza, fijeza a estructuras vecinas, nódulo sólido, halo incompleto y adenopatías aunque estos parámetros son más frecuentes en números absolutos en nódulos benignos. La mayoría de las cirugías fueron indicadas en base al hallazgo citológico. El diagnóstico histológico de los 96 pacientes que fueron operados mostró 51 carcinomas, de los cuales solo dos tenían citología benigna y 31 adenomas. Conclusión: Los nódulos palpables únicos fueron más frecuentes en mujeres eutiroideas en la edad media de la vida. Un tercio tenía historia familiar de patología tiroidea, similar al porcentaje hallado de ATPO positivos. Por ecografía los nódulos fueron predominantemente sólidos, hipoecoicos, únicos con resto de la glándula tiroides heterogénea. La PAAF fue predominantemente benigna. El crecimiento rápido, la dureza, la fijeza a estructuras adyacentes, el halo incompleto y la presencia de adenopatías fueron relacionados con malignidad, pero la benignidad fue más frecuente. En la mayoría de los pacientes la cirugía fue recomendada por los hallazgos citológicos. Nuestros resultados son similares a los reportados en otras áreas geográficas.

Introduction: the presence of palpable thyroid nodules in the general population is one of the most common clinical signs of thyroid disease in daily practice. Objectives: 1) To assess the prevalence of pathologies, clinical and cytological findings of single palpable thyroid nodules (SPTN) in Argentina. 2) Analyze the regional differences in Argentina. Methods: Prospective study of 739 patients with STPN were evaluated at centres in Buenos Aires, Bahía Blanca, Mendoza, and La Pampa between 1/1/00 and 12/31/01. Clinical examination, thyroid ultrasound scan (US), TSH, TPOAb and fine needle aspirations (FNA) were performed. Statistics: Pearson Correlation, X2 & Fisher Tests. Results: Age (X ± SD) 46 ± 14ys: 93.1 % were women. Previous history of neck radiation & familial thyroid disease were found in 1.6 and 29.9 % respectively. Clinical findings: dysphagia: 7.9 %; dysphonia: 3.5%; nodule growth: 19.2 %; hard consistence: 24.7 %; fixation to adjacent structure: 1.5 % and lymphadenopathies (ADP): 3 %. Biochemical findings: TSH was normal in 81.2 % & TPOAb+ in 30.3 %. US features: solid: 53.1 %; hypoechoic: 63.8 %; microcalcifications: 10.3 %; incomplete halo: 15 %; more than 1 nodule: 30.5 %; thyroid heterogeneity: 60.2 % and ADP: 3.8 %. Cytology: Only 1 FNA was needed in 86.8%. Unsatisfactory (excluding cysts): 3.2 %; benign: 77.2%; suspicious: 12.6 % and cancer: 7 % (42 papillary, 2 medullary and 3 non specified). A significant correlation (p<0.02) was established between malignant nodules and rapid growth, hard, fixed, solid nodule, incomplete halo and ADP, though these parameters were more frequent (in absolute number) in benign nodules. Surgery was mainly indicated based on FNA results. Histological diagnosis of 96 patients who underwent surgery showed 51 carcinomas, of which only 2 were cytologically benign and 31 adenomas. Conclusion: Palpable single nodules were more frequent in middle aged euthyroid women. One third had familial thyroid pathology, similar to the presence of TPOAb. On US, nodules were predominantly solid, hypoechoic, single with heterogeneous thyroid gland. FNA was predominantly benign. Rapid growth, hard, fixed, solid nodule, incomplete halo and ADP were associated with malignancy, but benignity was more common. In most of the patients surgery was recommended based on cytological findings. Our results are similar to those reported in other geographic areas.

[A new methodology for the preoperative localization of occult insulinomas]. / Nueva metodología para la localizacion preoperatoria de insulinomas ocultos.

UNLABELLED: In patients with hypoglycemic syndrome, preoperative localization of the insulinoma highly contributes to surgical removal. When the ultrasonography, computed tomography, magnetic resonance and pancreatic angiography fail to visualize the tumor, they are called occult insulinomas (OI). In this paper we describe the results of a new diagnostic method to localize OI, performed in 5 patients with hypoglycemic syndrome secondary to endogenous hyperinsulinism. In four out of five patients, computed tomography, magnetic resonance and angiography failed to show any tumor. In just one single case, these imaging methods showed the pancreatic tumor. All patients were studied by selective intraarterial pancreatic stimulation (SIPS): a) infusion of calcium gluconate (0.025 mEq/kg) in each artery that supplies the pancreas: gastroduodenal, superior mesenteric and splenic arteries as well as the hepatic artery; b) insulin venous sampling in the right supra-hepatic vein at 30 and 60 seconds after arterial stimulation (in one patient an additional sample at 90 seconds was obtained). The study was considered pathologic when the gradient (basal vs post-stimulus) increased at least 100%. RESULTS: In all five patients a pathological gradient was found. The suspected preoperative localization of the tumor was confirmed at surgery in four cases. The anatomopathologic examination revealed insulinoma in four cases and malignant insulinoma in the remaining. It is concluded that the results of this preliminary experience show the usefulness of SIPS in the preoperative localization of occult insulinomas.

[Hypervitaminosis D in institutionalized elderly in Buenos Aires]. / Hipovitaminosis D en ancianos institucionalizados de Buenos Aires.

Several studies have shown that vitamin D (Vit. D) deficiency in elderly people enhances bone mass loss. Most of these studies have been carried out in areas of low solar irradiation. In order to establish Vit. D circulating levels in elderly people in our community (34 degrees S) and their relationship with bone metabolism, 34 men and 33 women were studied at the end of the summer. These subjects, all residents of nursing homes, had a mean age of 81.9 + 8.1 years (range 69-99). Calcemia, parathyroid hormone (PTH and 25-hydroxyvitamin D (25(HO)D) were measured in serum and bone markers in serum and urine. Bone densitometry (BMD) of cortical and trabecular bone in the forearm (distal third of the radius (R33%) and ultradistal (RUD), respectively) were performed using X-ray absorptiometry. We found: 1) Low serum 25(HO)D (14.4 + 1.7 ng/ml) at summer's end. 40.5% showed levels < 10 ng/ml. 2) Secondary hyperparathyroidism (PTH: 169.4 + 30.9 pg/ml), 3) Hypocalcemia was observed in 34.5% of elderly people, 4) increased bone turnover in the subpopulation with hypovitaminosis D. 5) The serum levels of 25(HO)D correlated with BMD R33% (r = 0.55, n = 54, P < 0.001), with BMD RUD (r = 0.50, n = 54, P < 0.001) and with PTH (r = -0.44, n = 42, P < 0.01). A deficiency of Vit.D was found in our population of elderly people, probably due to diminished epidermic production of its precursors and/or to scant exposure to sunlight in the elderly. The decrease is associated to age. The positive correlation of 25(HO)D with bone mass (cortical and trabecular bone) underscores its importance for the preservation of bone mass. Hyperparathyroidism, triggered by Vit. D deficit, enhances bone loss.

Hypothalamic-pituitary thyroid abnormalities in children after renal transplantation.

Patients with a successful renal transplant may have abnormalities in thyroid function. We evaluated serum thyroid hormone levels, serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH), and the circadian pattern of serum TSH in 18 children aged 6.6-19.4 years (median 12.6 years), 4.0 +/- 2.9 years after renal transplantation. In 14 children, immunosuppressive therapy included methylprednisone [mean (+/-SD) 0.17 +/- 0.05 mg/ kg per day], while in 11 it included deflazacort (0.32 +/- 0.1 mg/kg per day). Seven children were studied twice, under methylprednisone and again while on deflazacort therapy. Mean total and free thyroxine (T4) values were significantly below the mean control levels (total T4 108.5 +/- 21.5 vs. 118.7 +/- 22.1 nmol/l, P < 0.05 and free T4 14.4 +/- 4.0 vs. 18 +/- 4.9 pmol/l, P < 0.001). Morning basal TSH levels were within the normal range. The mean TSH increment after TRH was 4.4 +/- 3.5 mU/l, significantly lower than that of controls (10.8 +/- 4.26, P < 0.001). Of 7 patients on methylprednisone, 4 had nocturnal TSH surges below the normal range (95% confidence limits 47%-300%); this occurred in 3 of 8 patients on deflazacort therapy. The TSH response to TRH was correlated with deflazacort dose. Patients on methylprednisone and deflazacort therapy had similar thyroid alterations. Our findings support the hypothesis that after renal transplantation some children have hypothalamic-pituitary thyroid abnormalities in which glucocorticoids may play a significant role.

Gene targeting to the centromeric DNA of a human minichromosome.

A human supernumerary minichromosome (MC), previously identified as a derivative of chromosome 9, has been introduced into Chinese hamster ovary (CHO) cells by means of cell fusion. A hybrid clone containing the MC as the only free human chromosome was isolated. A selectable marker gene (neo) inserted into a yeast artificial chromosome (YAC) has been successfully targeted to the MC centromeric DNA via co-transfection with chromosome-9-specific alpha satellite DNA. In situ hybridization and Southern blotting experiments demonstrated that the intact neo gene was integrated into the MC centromeric DNA. Studies on the clonal distribution and on the stability of the MC either in the presence or in the absence of the selective agent have been carried out. The MC is susceptible to further manipulations and may thus represent a model for the construction of a large-capacity vector for somatic gene therapy.

Insulin effect on renal sodium reabsorption in adolescent offspring of essential hypertensive parents.

We previously showed that children and adolescent offspring of patients with essential hypertension have an increased proximal renal sodium reabsorption as measured by lithium fractional excretion. Insulin has been shown to have antinatriuretic properties and to be increased (hyperinsulinemia) in essential hypertension. The aim of this study was to evaluate the role of insulin on the increased proximal renal sodium reabsorption previously reported. Lithium and sodium fractional excretions were measured 3 hours before and 3 hours after an intravenous glucose tolerance test in 20 normotensive adolescents with a family history of essential hypertension (F+, 14.8 +/- 0.5 years) and 10 normotensive control subjects without a family history of hypertension (F-, 15.2 +/- 0.9 years). Results are mean +/- SEM. Lithium fractional excretion before glucose loading was 16.1 +/- 1.8% in F+ versus 23.5 +/- 2.0% in F- (P < .02) and after glucose loading was 14.7 +/- 1.3% in F+ versus 20.9 +/- 1.7% in F- (P = NS). Lithium fractional excretion did not change after intravenous glucose loading in either group. The insulin area under the curve was 2815 +/- 499 in F+ versus 2290 +/- 418 microU/mL per hour in F- (P = NS). There was no correlation between lithium fractional excretion and insulin area under the curve. Fractional excretion of sodium before glucose loading was 0.99 +/- 0.1% in F+ versus 0.99 +/- 0.1% in F- (P = NS) and after glucose loading was 0.77 +/- 0.1 in F+ versus 0.85 + 0.1% in F- (P < .01 versus values before loading in both groups).(ABSTRACT TRUNCATED AT 250 WORDS)

Thyroid function and serum IGF-1 in children before and after liver transplantation.

We report results of serum thyroid hormone and IGF-1 concentrations in 20 children, 1.2 to 13.6 years old, with various degrees of chronic liver dysfunction (CLD), before and after successful orthotopic liver transplantation (OLT). Ten children presented with moderate chronic liver disease (CLD-M) with prothrombin time (PT) > 50% and serum albumin concentration > 3 g/dl; 7 children had severe chronic liver disease (CLD-S) with PT < 50% and serum albumin concentration < 3 g/dl; and 7 children who had received an OLT, who had normal liver function at the time of the study. Four of the latter group were also studied before OLT. Patients with CLD-M had normal mean +/- SD serum levels of total T3 (2.0 +/- 0.7 nmol/l), total T4 (125 +/- 25.9 nmol/l) and fT4 concentrations (16 +/- 2.8 pmol/l). In contrast, children with CLD-S showed a significant decrease in thyroid hormones together with normal basal TSH values (T3 0.8 +/- 0.0 nmol/l; T4 45.6 +/- 19.5 nmol/l; fT4 7.4 +/- 1.1 pmol/l; TSH 3.8 +/- 0.9 mU/l). Patients who received a successful OLT showed mean peripheral thyroid hormone concentrations significantly higher than CLD-S patients (T3 1.7 +/- 0.7 nmol/l, p < 0.005; T4 92.8 +/- 18.2 nmol/l, p < 0.001; fT4 14.5 +/- 3.1 pmol/l, p < 0.001). A significant correlation was found between thyroid hormone levels and PT or serum albumin. In the nine patients with CLD-M and CLD-S in whom serum IGF-1 concentration was measured, values found (mean +/- SD 0.08 +/- 0.05 U/ml) were below the 95% confidence limit of matched controls.

Assignment of the human cytokeratin 3 gene (KRT3) to 12q12-->q13 by FISH.

We used fluorescence in situ hybridization to localize the human gene for cytokeratin 3 (KRT3), a member of the type II subfamily of cytokeratins, within the human genome. The results show that KRT3 is located within chromosome region 12q12-->q13. All human type II keratin genes mapped to date have been assigned to chromosome 12, where they are likely to be organized into one homotypic cluster.

Molecular cloning and chromosomal localization of the human alpha 7-nicotinic receptor subunit gene (CHRNA7).

We have isolated cDNA and genomic clones coding for the human alpha 7 neuronal nicotinic receptor subunit, the major component of brain nicotinic receptors that are blocked by alpha-bungarotoxin. The human alpha 7 neuronal nicotinic cDNA encodes a mature protein of 479 amino acids that is highly homologous to the rat alpha 7 neuronal nicotinic subunit (90%). We have mapped the human alpha 7-nicotinic receptor subunit gene to chromosome 15, band q14, a region frequently rearranged in patients carrying a bisatellite 15 chromosome, large inv dup (15), whose clinical features include mental retardation and seizures.

Evidence of hypothalamic-pituitary thyroid abnormalities in children with end-stage renal disease.

Patients with end-stage renal disease may have abnormalities of growth and of gonadal and thyroid hormones, so we attempted to determine the mechanisms that may be involved in the altered thyroid function. We evaluated serum thyroid hormone levels, their changes immediately after hemodialysis, the serum thyrotropin (thyroid-stimulating hormone (TSH) response to thyrotropin releasing hormone, and the circadian pattern of serum TSH in nine children with end-stage renal disease who were between 7 1/2 years and 17 years 1 month of age. Seven patients had been receiving hemodialysis for a median of 3.3 years; the other two were receiving continuous ambulatory peritoneal dialysis. Four patients had low serum total thyroxine (T4) values, and all nine had low free T4 values. Mean concentrations of total T4, free T4, and total triiodothyronine (T3), which were significantly less than normal before hemodialysis, returned to normal levels immediately after dialysis. Postdialysis thyroid hormone increases did not correlate with the decrease in weight or the increase in hematocrit observed immediately after dialysis. All but one patient had basal TSH levels within the normal range. Three patients had a deficient TSH response to thyrotropin releasing hormone, and the TSH response was prolonged in all of them. The mean (+/- SD) nocturnal TSH surge was 50 +/- 68%. Five of the eight patients studied had a nocturnal TSH surge below the normal range (95% confidence limits 47% to 300%). Serum free T4 values correlated with the TSH nocturnal surge (r, 0.73; p less than 0.05). Our findings support the hypothesis that some patients with end-stage renal disease have central hypothyroidism.