Hipercrecimientos con y sin obesidad: fundamentos clínicos y moleculares / Overgrowth with and without obesity: clinical and molecular principles

Los hipercrecimientos somáticos conforman una patología compleja, heterogénea y conocida parcialmente, si bien el incremento en nuestros conocimientos en biología molecular está posibilitando descubrir las bases etiológicas de muchos de los cuadros clínicos responsables. El diagnóstico diferencial de un paciente con una posible variante de la normalidad, una cromosomopatía, un síndrome dismórfico, una metabolopatía o una endocrinopatía, es esencial. La aproximación clínica inicial debe incluir una correcta anamnesis y examen físico, así como la solicitud de unas pruebas complementarias analíticas y de imagen que ayuden a orientar el diagnóstico. En efecto, es necesario practicar hemograma y bioquímica completos, determinar los niveles de IGF-I e IGFBP-3, T4 libre, TSH y homocistinuria, así como efectuar un cariotipo y una radiografía de mano y muñeca izquierdas. Sus resultados deben orientarnos ampliamente en el enfoque del paciente. La realización adicional de estudios moleculares, cuando se sospeche una enfermedad monogénica, y la necesidad de practicar estudios cardiológicos, oftalmológicos, esqueléticos, psicológicos y paidopsiquiátricos, deberá efectuarse cuando proceda a la luz de la información clínica y de los estudios complementarios antes comentados. En esta revisión se analizarán las bases etiológicas y los fundamentos diagnóstico-terapéuticos de las principales causas de hipercrecimiento(AU)

Somatic overgrowth is a complex and heterogeneous pathology that is only partially understood, although developments in molecular biology have allowed the discovery of the aetiological basis of some of these conditions. The differential diagnosis of a patient with a possible variant of normality, a chromosomopathy, a dysmorphic syndrome, a metabolic or an endocrine disease is essential. The initial clinical evaluation should include a correct anamnesis and physical examination, as well as complementary laboratory and image analyses that will help to orient the diagnosis. This should include a full blood counts and complete biochemical analysis, determinations of IGF-I, IGFBP-3, free T4, TSH and homocystinuria, as well as a karyotype and an X-ray of the left hand and wrist. These results should be very beneficial in orienting the diagnosis. Additional molecular studies should be performed when a monogenic disease is suspected. Cardiological, ophthalmological, skeletal, psychological and psychiatric studies should be performed if the clinical information and previously mentioned complementary studies so indicate. In this review, the aetiological basis and the diagnostic-therapeutic principles in the most common causes of overgrowth, will be analysed(AU)

[Overgrowth with and without obesity: clinical and molecular principles]. / Hipercrecimientos con y sin obesidad: fundamentos clínicos y moleculares.

Somatic overgrowth is a complex and heterogeneous pathology that is only partially understood, although developments in molecular biology have allowed the discovery of the aetiological basis of some of these conditions. The differential diagnosis of a patient with a possible variant of normality, a chromosomopathy, a dysmorphic syndrome, a metabolic or an endocrine disease is essential. The initial clinical evaluation should include a correct anamnesis and physical examination, as well as complementary laboratory and image analyses that will help to orient the diagnosis. This should include a full blood counts and complete biochemical analysis, determinations of IGF-I, IGFBP-3, free T4, TSH and homocystinuria, as well as a karyotype and an X-ray of the left hand and wrist. These results should be very beneficial in orienting the diagnosis. Additional molecular studies should be performed when a monogenic disease is suspected. Cardiological, ophthalmological, skeletal, psychological and psychiatric studies should be performed if the clinical information and previously mentioned complementary studies so indicate. In this review, the aetiological basis and the diagnostic-therapeutic principles in the most common causes of overgrowth, will be analysed.

Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RP-C4-CYP21-TNX (RCCX) modules in caucasians. The load of RCCX genetic diversity on major histocompatibility complex-associated disease.

The complement component C4 genes located in the major histocompatibility complex (MHC) class III region exhibit an unusually complex pattern of variations in gene number, gene size, and nucleotide polymorphism. Duplication or deletion of a C4 gene always concurs with its neighboring genes serine/threonine nuclear protein kinase RP, steroid 21-hydroxylase (CYP21), and tenascin (TNX), which together form a genetic unit termed the RCCX module. A detailed molecular genetic analysis of C4A and C4B and RCCX modular arrangements was correlated with immunochemical studies of C4A and C4B protein polymorphism in 150 normal Caucasians. The results show that bimodular RCCX has a frequency of 69%, whereas monomodular and trimodular RCCX structures account for 17.0 and 14.0%, respectively. Three quarters of C4 genes harbor the endogenous retrovirus HERV-K(C4). Partial deficiencies of C4A and C4B, primarily due to gene deletions and homoexpression of C4A proteins, have a combined frequency of 31.6%. This is probably the most common variation of gene dosage and gene size in human genomes. The seven RCCX physical variants create a great repertoire of haplotypes and diploid combinations, and a heterozygosity frequency of 69.4%. This phenomenon promotes the exchange of genetic information among RCCX constituents that is important in homogenizing the structural and functional diversities of C4A and C4B proteins. However, such length variants may cause unequal, interchromosomal crossovers leading to MHC-associated diseases. An analyses of the RCCX structures in 22 salt-losing, congenital adrenal hyperplasia patients revealed a significant increase in the monomodular structure with a long C4 gene linked to the pseudogene CYP21A, and bimodular structures with two CYP21A, which are likely generated by recombinations between heterozygous RCCX length variants.

Multiple endocrine neoplasia type 2A: a 25-year review.

BACKGROUND/PURPOSE: Before 1970, treatment decisions for the thyroid lesions in patients with multiple endocrine neoplasia (MEN) were based on physical findings. For the next 20 years, biological markers assumed a preeminent role, and at present, DNA testing is being used to define the need for therapeutic intervention. This report presents a 25-year review of 22 children with MEN-2A, with a mean follow-up of 12.5 years. METHODS: All 22 children underwent a total thyroidectomy, and four (18%) were rendered permanently hypoparathyroid. Since 1976, however, only one patient (6.7%) has lost parathyroid function. Despite the fact that biological screening studies routinely were performed once a year in the majority of our patients and surgery was recommended for any elevation in the serum calcitonin (CT) levels, medullary carcinoma of the thyroid (MTC) developed in 17 children (77%) and only five had C cell hyperplasia (CCH). Thirteen of the 17 had macroscopic tumor described by the pathologist, evidence of recurrent disease (MTC-REC) has developed in four children (24%). RESULTS: There was considerable overlap in both the basal and stimulated CT levels among the five children with CCH, the 13 with localized MTC (MTC-NED), and the four who later had recurrent MTC. The basal calcitonin levels were between 25 and 110 (mean, 58) in the CCH patients, 30 to 1,130 (mean, 184) in the MTC-NED group, and 108 to 201 (mean, 140) in those with recurrent MTC. The corresponding stimulated calcitonin levels were 45 to 417 (mean, 179) in CCH, 111 to 9,510 (mean, 1,407) in MTC-NED, and 449 to 5,093 (mean, 3,383) in MTC-REC. CONCLUSIONS: (1) Basal and pentagastrin-stimulated CT levels did not reliably discriminate between CCH and MTC and should not be used to define the timing of thyroid surgery in children with MEN-2A. (2) Surgical therapy should be undertaken early in childhood on the basis of molecular genetic testing. (3) Postoperative complications are infrequent in the modern era.

Late clinical presentation of partial carbamyl phosphate synthetase I deficiency.

OBJECTIVE: To describe the late manifestation of partial carbamyl phosphate synthetase I deficiency in an adolescent whose previous symptoms were not distinctive enough to suggest the presence of a metabolic disease. RESEARCH DESIGN: Clinical description of one patient. SETTING: Primary care children's hospital. PARTICIPANT: An adolescent boy. SELECTION PROCEDURE: Random observation. INTERVENTIONS: Intravenous sodium benzoate and sodium phenylacetate were more successful in reversing the coma than any other intervention. MEASUREMENTS/MAIN RESULTS: The patient has had no recurrence for 2 years, but he appears to have had a partial impairment of cognitive functioning. CONCLUSIONS: General pediatricians and intensivists should be aware that partial carbamyl phosphate synthetase I deficiency, and other partial urea cycle disorders, may become manifest in adolescence, even though they usually present in neonates or infants. When patients present in hyperammonemic coma, the urea cycle disorders should be considered, especially if no obvious cause is identified.

[New findings and the potential use of the growth hormone]. / Nuevas adquisiciones y uso potencial de la hormona del crecimiento.

Use and potential use of human growth hormone (GH). The benefit of GH in classical growth hormone deficiency is well known. For the past six years, the availability of biosynthetic human growth hormone has permitted the investigation of the effect of GH in a variety of growth disorders. GH has been shown to be helpful in children with idiopathic short stature, Turner's syndrome, neuroendocrine deficiency, and chronic renal insufficiency. Although the experience is limited, GH would appear helpful in short children with intrauterine growth retardation and Noonan's and Prader-Willi syndromes. GH increases muscle mass and strength and decreases fat mass in young adults with GHD and treatment is under consideration. One of the areas of present interest and potentially of great benefit is the use of growth hormone in catabolic conditions (burns, surgical operations, patients with a prolonged stay in intensive care units, malnourished patients and patients with chronic obstructive pulmonary disease). In catabolic conditions, GH is effective in decreasing nitrogen loss, in maintaining nitrogen balance, even with hypocaloric diets, and in increasing protein synthesis and skeletal muscle mass when combined with adequate nutrition. GH has proven helpful in inducing ovulation and improving fertility in patients with GHD and in patients with ovarian resistance to gonadotropins. The field of growth hormone therapy is expanding and potentially GH could be of benefit to many children and adults with a variety of disorders.

Decreased metabolic clearance of endogenous growth hormone and specific alterations in the pulsatile mode of growth hormone secretion occur in prepubertal girls with Turner's syndrome. Genentech Collaborative Group.

We have used deconvolution analysis to test the hypothesis that specific facets of GH secretion and clearance differ in young patients with Turner's syndrome and normal prepubertal girls. To this end, we sampled blood at 20-min intervals for 12 h overnight in 50 girls, 37 of whom had Turner's syndrome and 13 of whom were healthy Tanner stage I controls. Deconvolution analysis revealed that the half-life of endogenous GH in Turner's syndrome was significantly prolonged at 14 +/- 0.93 vs. 11 +/- 0.44 min in normal girls (P = 0.029). The number of significant GH secretory bursts was reduced in Turner's patients to 4.7 +/- 0.27 vs. 6.8 +/- 0.60 events/12 h in healthy girls (P less than 0.01). GH secretory burst half-duration was significantly prolonged in Turner's syndrome, viz. 23 +/- 1.3 vs. 15 +/- 0.87 min (controls; P less than 0.001). The changes in GH secretory burst frequency, duration, and half-life were specific, since neither the mass of GH secreted per burst nor the maximal rate of GH secretion attained per burst (amplitude of the secretion pulse) was significantly different in the 2 study groups. Thus, although 12-h GH secretion rates corrected for body weight were similar (3.9 +/- 0.76 in Turner's patients and 3.3 +/- 0.76 micrograms/L.kg/12 h in the control girls), equivalent GH production rates were achieved by different mechanisms in the 2 groups. We conclude that specific alterations in GH secretory burst frequency and duration and endogenous GH half-life can be documented in young girls with Turner's syndrome.

Extracellular correction of the androgen-receptor transformation defect in two families with complete androgen resistance.

We have characterized the cellular and extracellular phenotype of the mutant androgen receptor (AR) from two families who have complete androgen resistance despite a normal androgen-binding capacity (Bmax) in their genital skin fibroblasts (GSF). The cellular receptors fail to up-regulate their basal AR activity in response to prolonged incubation with 5 alpha-dihydrotestosterone (DHT), or with two synthetic androgens, methyltrienolone (MT) and mibolerone (MB), and form A-R complexes with increased equilibrium (Kd) and non-equilibrium (k) dissociation constants. In addition, they are thermolabile when recently dissociated, but not in their native state. A-R complexes made in normal or mutant cytosol at 4 degrees C elute from DEAE-Sephacel at approximately 0.25 M KCl (untransformed), with or without prior passage through Sephadex G-25; when made in cells at 37 degrees C, extracted with 0.4 M KCl in a buffer containing 10 mM Na2MoO4, and desalted by G-25, they elute at less than or equal to 0.1 M KCl. Normal KCl-extracted DHT- and MB-R complexes dissociate (37 degrees C) at the same slow, linear rate as their in-cell counterparts (transformed); the mutant ones dissociated more slowly than their rapidly-dissociating in-cell counterparts and, to a variable extent, nonlinearly-an early faster phase, a later slower (transformed). Thus, as judged by two conventional criteria of steroid-R complex transformation, the mutant A-R complexes can transform, possibly in two steps, under certain cell-free conditions. This behavior differentiates a class of structural AR mutations whose molecular definition awaits application of recombinant DNA techniques to the X-linked AR locus.

Evaluation of growth hormone release and human growth hormone treatment in children with cranial irradiation-associated short stature.

We studied nine children who had received cranial irradiation for various malignancies and subsequently experienced decreased growth velocity. Their response to standard growth hormone stimulation and release tests were compared with that in seven children with classic GH deficiency and in 24 short normal control subjects. With arginine and L-dopa stimulation, six of nine patients who received radiation had a normal GH response (greater than 7 ng/ml), whereas by design none of the GH deficient and all of the normal children had a positive response. Only two of nine patients had a normal response to insulin hypoglycemia, with no significant differences in the mean maximal response of the radiation and the GH-deficient groups. Pulsatile secretion was not significantly different in the radiation and GH-deficient groups, but was different in the radiation and normal groups. All subjects in the GH-deficient and radiation groups were given human growth hormone for 1 year. Growth velocity increased in all, with no significant difference in the response of the two groups when comparing the z scores for growth velocity of each subject's bone age. We recommend a 6-month trial of hGH in children who have had cranial radiation and are in prolonged remission with a decreased growth velocity, as there is no completely reliable combination of GH stimulation or release tests to determine their response.

Direct measurement of testosterone in a pediatric center, with use of a radioimmunoassay kit and unextracted serum.

We evaluated a commercial (Radioassay Systems) radioimmunoassay kit for testosterone in which a double-antibody method and an 125I tracer are used. The 50-microL serum sample is assayed directly with no pre-extraction step. The assay system has good sensitivity (0.01 microgram/L), good precision (CV 5.2%), and little cross reactivity between testosterone and other androgens. Results compared well with those by a tritiated radioimmunoassay involving extraction (r = 0.98). Values obtained for 97 children compared well with published pediatric normal values. Evidently, this kit provides a rapid and reliable measurement of testosterone in serum specimens and is acceptable for use with pediatric patients.

Massive edema of the ovary and virilization.

Endocrine studies of a virilized adolescent patient with massive ovarian edema are reported. The histologic features of the affected ovary consisted of diffuse edematous stroma with scattered islands of lutein-like cells and no evidence of recent ovulation. Plasma concentrations of progesterone and 17-hydroxyprogesterone (17-OHP) in the peripheral and left ovarian veins and their ovarian-peripheral vein gradients were above the range observed during normal follicular phase. The considerable increase in the ovarian vein concentrations of both steroids observed after adrenocorticotropic hormone administration was noteworthy as a direct effect of this hormone on the ovarian synthesis of steroids has not previously been observed. Peripheral vein levels of testosterone (T) were increased. The secretion of T by the ovary was demonstrated by its elevated levels in the ovarian vein and in the ovarian-peripheral vein gradient. Unexpectedly, the levels of androstenedione in the ovarian vein were normal, suggesting an alteration in the ovarian biosynthetic pathway for the production of T. Similar findings have been observed in hirsute women with hyperthecosis ovarii. After surgery, the peripheral vein levels of 17-OHP and T returned to normal, pointing toward the ovary as their source of excess. The data indicate that stromal luteinization of the massive ovarian edema may lead to changes in normal ovarian steroidogenesis that would be responsible for the clinical manifestations of this disorder.

Diabetes responsive to intravenous but not subcutaneous insulin: effectiveness of aprotinin.

Patients with diabetes that is insensitive to subcutaneous insulin but sensitive to intravenous insulin have recently been described. We have studied this phenomenon is five female diabetics (14 to 31 years of age) who required excessive amounts of insulin (2.5 to 30.0 units per kilogram of body weight per day) to avoid recurrent ketoacidosis. Known causes of insulin resistance were excluded. All patients had normal responses to conventional doses of intravenous insulin (0.35 to 0.9 unit per kilogram per day). Four patients required continuous intravenous infusion of insulin for one to six months. When a mixture of aprotinin (a protease inhibitor) and regular porcine insulin was given subcutaneously, conventional doses (0.7 to 1.4 units per kilogram per day) produced euglycemia; plasma levels of free insulin rose, and ketonuria disappeared. Four patients had episodes of spontaneous, severe hypoglycemia before and during aprotinin therapy, necessitating continuous infusion of glucose for two to 14 days. Although no insulin was administered, hyperinsulinemia (50 to 2000 muU of free insulin per milliliter [359 to 14,350 pmol per liter]) was present. These findings suggest excessive degradation or sequestration of insulin at the site of injection.