Substrate specificity of the insulin receptor tyrosine kinase domain.
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Amino Acid Sequence↗
Biomedical subjects
F Grigorescu
Publications and source records attributed to F Grigorescu.
Resin immobilized synthetic peptides used to characterize phosphorylation and antigenic properties of insulin receptor autophosphorylation domains.
To develop a common strategy in peptide design for kinase assay, antibody production and affinity purification, we investigated phosphorylation and antigenic properties of peptides immobilized on an aminated polyacrylic resin (Expansin) corresponding to autophosphorylation domains of the insulin receptor tyrosine kinase. Immobilized peptides (1143-1155) and peptide (1314-1330), designated p1151 and p1322, respectively, were good substrates for the insulin receptor with Km of 0.74 and 0.78 mM. By contrast, peptide (952-963), designated p960, was poorly phosphorylated. p1151 showed distinctive behaviour as a substrate, displaying a higher basal phosphorylation, a leftward shift of the insulin dose-response curve (ED50 = 0.7 ng mL-1 insulin compared to 20 ng mL-1 for other substrates) and an inhibition by 90% of receptor autophosphorylation (ID50 = 0.5 mM). Similar substrate behaviour was observed with another tyrosine kinase, the pp60c-src. Antibodies against P1151 and p1322 have comparable reactivity in ELISA, but the antibody against p960 was poor. While purified immunoglobulins (IgG) against both p1151 and p1322 were inhibitors of receptor autophosphorylation and kinase, in immunoprecipitation the IgG against p1151 mainly interacted with the phosphorylated receptor and that against p1322 with non-phosphorylated forms. Functional mapping of the receptor with oligoclonal 1322-antibody revealed inhibition of phosphate transfer to exogenous substrate poly(Glu,Tyr) (4:1) but not towards immobilized p1151. These data provide further support for the distinctive features of endogenous phosphorylation domain 1151. We conclude that immobilized peptides on polyacrylic resin offer a major new potential for use in kinase assays, immunization, immunoabsorbent techniques and purification of well defined oligoclonal antibodies.
Amino Acid Sequence↗
Insulin-mediated pseudoacromegaly: clinical and biochemical characterization of a syndrome of selective insulin resistance.
We have performed clinical, physiological, in vitro biochemical and genetic studies of a patient with severe insulin resistance associated with the phenotype of "pseudoacromegaly," defined as the presence of acromegaloid features in the absence of elevated levels of GH or insulin-like growth factor-I (IGF-I). Despite marked hyperinsulinemia, insulin and IGF-I binding to circulating blood cells and cultured skin fibroblasts was normal. Insulin and IGF-I-stimulated autophosphorylation of their respective receptors in cultured skin fibroblasts was also normal. However, neither insulin nor IGF-I were able to stimulate 2-deoxy D-glucose uptake by cultured skin fibroblasts. In contrast, the ability of insulin and IGF-I (or IGF-II) to stimulate amino acid uptake and thymidine incorporation into DNA was not impaired. This unique discordant signaling defect through both insulin and IGF-I receptors appeared not to be the consequence of altered expression or primary structure of the insulin receptor or the GLUT-4 glucose transporter, as assessed by several genetic and biochemical techniques. GLUT-4 expression in muscle was normal on Western blots, and SSCP screening of all 11 exons of the gene for nucleotide variation revealed no variations from normal. DNA sequencing and SSCP screening of exons 2-22 of the insulin receptor gene revealed only one variation predicted to alter the amino acid sequence (Val985-->Met). No functional differences between Met985 and wild-type human insulin receptors were evident in studies performed with Chinese hamster ovary cell transfectants that overexpress either receptor. This data combined with our previously published epidemiological data concerning the frequency of the Met985 allele, indicate that this variant insulin receptor is not responsible for the insulin resistant glucose uptake or the clinical syndrome of pseudoacromegaly. We conclude that: 1) The molecular lesion responsible for the selective biochemical defect in this individual appears to involve a signaling intermediate required for insulin and IGF-I regulation of glucose transport, and/or an effector mechanism operative in this process. 2) Cells derived from this patient may be a valuable tool in the search for such molecular mechanisms. 3) The Met985 allele is a relatively common variant which has no demonstrable adverse consequences for insulin receptor function. 4) Pseudoacromegaly can be viewed as the expected result of hyperinsulinemia driving the unopposed mitogenic and anabolic actions of insulin.
Acromegaly↗
Kinase inhibition by a phosphorylated peptide corresponding to the major insulin receptor autophosphorylation domain.
We studied the inhibitory effect of non-phosphorylated and triphosphorylated synthetic peptides, corresponding to amino acids 1143-1155 of the insulin proreceptor (domain 1151) on autophosphorylation and kinase of the insulin receptor. Tyrosine-phosphorylated peptides were synthesized using the N-(9-fluorenylmethoxycarbonyl)-O-dibenzylphosphono-L- tyrosine. The triphosphorylated peptide (1151-P3) and the non-phosphorylated peptide (1151-NP), respectively, inhibited insulin receptor autophosphorylation by 65% and 70%, in a dose-dependent and additive manner. When the receptor was pre-phosphorylated for 1 min with [gamma-32P]ATP, 1151-P3 decreased autophosphorylation to 60% of maximum, whereas 1151-NP had no further effect. In both non-activated and preactivated receptors, 1151-P3 inhibition of receptor autophosphorylation was prevented by adding 2 mM vanadate. Kinase activity towards exogenous substrate poly(Glu4, Tyr) was dose-dependently inhibited by both analogues. This effect was independent of the state of receptor phosphorylation or the addition of vanadate. Since 1151-P3 inhibited the exogenous kinase without altering receptor endogenous autophosphorylation after the addition of vanadate, we investigated 1151-NP and 1151-P3 competition for the phosphorylation of a resin-immobilized 1151 peptide. While 1151-NP (at 2 mM) was highly competitive, inhibiting phosphate incorporation by 70%, 1151-P3 caused a four-fold increase in the phosphorylation of 1151-NP--resin. The receptor underwent conformational changes during autophosphorylation and an antibody directed against a peptide corresponding to amino acids 1314-1330 of the proreceptor (1322Ab) was previously shown to immunoprecipitate specifically the non-phosphorylated receptor forms. Nevertheless, the 1322Ab immunoprecipitated a fully autophosphorylated receptor in the presence of 1151-NP, but not of 1151-P3, thus suggesting a conformational change induced by the non-phosphorylated peptide. In conclusion, kinase inhibition was still observed after the addition of phosphate groups to three 1151-peptide tyrosines, but the peptide effect on receptor autophosphorylation, phosphorylation of homologous 1151-NP--resin and conformational changes induced in the receptor was altered dramatically. These data may provide a basis for further understanding the role of tyrosine phosphorylation in insulin receptor kinase activation or regulation.
Amino Acid Sequence↗
Cellular mechanism of metformin action.
Activation of the insulin receptor tyrosine kinase and tyrosine phosphorylation of intracellular substrates are important steps in insulin signalling. In order to elucidate the cellular mechanism of action of metformin (NN'dimethylbiguanide) we have focused towards the effects of metformin on the insulin receptor kinase, the phosphorylation cascade and the biological effect of insulin. Since annexins (lipocortins) have been recently recognized as substrates of several tyrosine kinases we have investigated the effect of metformin on phosphorylation of annexins after insulin stimulation or microinjection of pp60c-src kinase in Xenopus laevis oocytes. Insulin induced in oocytes progression through the cell cycle from late G2 to M phase (maturation). Microinjection of pp60c-src kinase or treatment with metformin potentiates both the rate and the level of insulin-induced oocyte maturation. In oocytes prelabeled with 32P orthophosphate metformin potentiates insulin induced phosphorylation of annexins. It is concluded that annexins are substrates of the phosphorylation cascade initiated by insulin which is synergistic to the action of pp60c-src kinase and that this early phosphorylation events correlate well with the enhanced biological effect of insulin during metformin treatment.
Animals↗
Tyrosine-kinase defect of the insulin receptor in cultured fibroblasts from patients with lipoatropic diabetes.
Postbinding defects in insulin action were described previously in cultured fibroblasts from six patients with lipoatropic diabetes. To define the contribution of the insulin receptor tyrosine kinase in these defects, we studied autophosphorylation and kinase activity of lectin purified receptors from these six patients and six normal cell lines. The patients' insulin receptors, prepared by precipitation with polyethylene glycol, had normal insulin binding characteristics and autophosphorylation properties, but a 56% decrease in the tyrosine kinase activity toward an exogenous substrate. To identify more subtle qualitative defects in autophosphorylation, insulin receptors were sequentially immunoprecipitated and analyzed for their phosphoaminoacid content. The phosphorylated receptors precipitated with an antiphosphotyrosine antibody contained labeled phosphotyrosine, whereas those in the supernatant, when further precipitated with an antireceptor antibody, contained only phosphoserine. Under these conditions, the insulin-stimulated autophosphorylation of tyrosine was significantly decreased by 54% in the patient receptors compared to normal subjects' receptors. In addition, insulin-like growth factor-I stimulation of autophosphorylation of its receptor was reduced by 59% in the patients' cells compared to those from normal subjects. We conclude that fibroblasts from patients with lipoatropic diabetes have defects in the tyrosine kinase activity of their insulin and their insulin-like growth factor-I receptors that might give rise to the in vitro hormone resistance and be related to the in vivo hormone resistance that occurs in these patients.
Adolescent↗
Defects in insulin binding and autophosphorylation of erythrocyte insulin receptors in patients with syndromes of severe insulin resistance and their parents.
Genetic forms of severe insulin resistance are often characterized by alterations in binding and/or kinase properties of the insulin receptor. To evaluate whether alterations in insulin receptor kinase of erythrocytes can be used as genetic markers, we studied patients with two apparently inherited conditions of severe insulin resistance (leprechaunism and the type A syndrome of insulin resistance) and their families. In the two propositi, [125I]insulin binding to intact erythrocytes was decreased by 64% and 45%, respectively. This was primarily due to a decrease in receptor number and was found in intact cells and solubilization of the receptors. Similar insulin binding defects were found on monocytes. Insulin-stimulated tyrosine kinase activity of the solubilized receptor from erythrocytes was also decreased and to a similar extent as binding. Parents of neither patient had clinical manifestations of leprechaunism or the type A syndrome. Furthermore, no alterations in insulin receptor binding or kinase activity were found in erythrocytes from the mothers. Insulin binding in the father of the type A patient was also normal, whereas the father of the leprechaun had decreased receptor affinity. Receptors extracted from the both fathers' cells had a 40-60% decrease in maximal insulin-stimulated phosphorylation and significant rightward shifts of the insulin dose-response curves (ED50, 141 and 42 ng/mL, respectively; control ED50, 16 ng/mL). The finding of biochemical defects in insulin receptor kinase activity in clinically unaffected parents of patients suggests that these alterations may be useful genetic markers and more sensitive than insulin binding studies for studying pattern of inheritance of these diseases.
Acanthosis Nigricans↗
Effects of heparin on insulin binding and biological activity.
The effect of heparin, a polyanionic glycosaminoglycan known to alter the function of many proteins, on insulin binding and bioactivity was studied. Cultured human lymphocytes (IM-9) were incubated with varying concentrations of heparin, then extensively washed, and 125I-labeled insulin binding was measured. Heparin at concentrations used clinically for anticoagulation (1-50 U/ml) inhibited binding in a dose-dependent manner; 50% inhibition of binding occurred with 5-10 U/ml. Scatchard analysis indicated that the decrease in binding was due to a decrease in both the affinity and the apparent number of available insulin receptors. The effect occurred within 10 min at 22 degrees C and persisted even after the cells were extensively washed. Inhibition of insulin binding also occurred when cells were preincubated with heparinized plasma or heparinized serum but not when cells were incubated with normal serum or plasma from blood anticoagulated with EDTA. By contrast, other polyanions and polycations, e.g., poly-L-glutamic acid, poly-L-lysine, succinylated poly-L-lysine, and histone, did not inhibit binding. Heparin also inhibited insulin binding in Epstein-Barr (EB) virus-transformed lymphocytes but had no effect on insulin binding to isolated adipocytes, human erythrocytes, or intact hepatoma cells. When isolated adipocytes were incubated with heparin, there was a dose-dependent inhibition of insulin-stimulated glucose oxidation and, to a lesser extent, of basal glucose oxidation. Although heparin has no effect on insulin binding to intact hepatoma cells, heparin inhibited both insulin binding and insulin-stimulated autophosphorylation in receptors solubilized from these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Cells, Cultured↗
Carbohydrate metabolism in women who used oral contraceptives containing levonorgestrel or desogestrel: a 6-month prospective study.
Blood glucose and pyruvate, plasma insulin, and glucagon levels as well as erythrocyte insulin receptors were measured during an oral glucose tolerance test in 38 normal women before and after 6 months' use of one of three new oral contraceptives containing low doses of 19 nortestosterone-derived progestogens, levonorgestrel, and desogestrel. A slight deterioration of glucose tolerance was observed, with the area under the glucose curve increasing by only 7%, 9%, and 12% after Ovidol (Aaciphar SA, Brussels, Belgium), Marvelon (Organon, SA, Brussels, Belgium), and Trigynon (Schering SA, Brussels, Belgium) administration, respectively. We did not find any argument in favor of the development of a state of insulin resistance in women using these compounds, because erythrocyte receptor binding was not modified and plasma insulin responses to glucose were decreased. The glucose-induced suppression of plasma glucagon levels seemed less effective for treatment with the desogestrel-containing preparations than with the levonorgestrel-containing oral contraceptives.
Adult↗
The human erythrocyte insulin-like growth factor I receptor: characterization and demonstration of ligand-stimulated autophosphorylation.
To characterize the insulin-like growth factor I (IGF-I) receptor on human erythrocytes, cells were purified from peripheral blood by Ficoll-Hypaque gradient centrifugation and incubated with [125I]IGF-I. Specific binding was maximal at pH 8.0 after 24 h at 4 C and increased linearly with cell number to 3.9 +/- 0.2% (+/- SEM) for 3.0 X 10(9) cells/ml. The Scatchard plot of the binding data was linear, with 7 fmol [125I]IGF-I bound/10(9) cells and an affinity constant (K) of 1.8 X 10(9) M-1. Unlabeled IGF-I inhibited tracer binding half-maximally at 6 ng/ml. Multiplication-stimulating activity (or rat IGF-II) was 40% as potent (ED50, 15 ng/ml), whereas insulin and proinsulin were 30- to 500-fold less potent. A monoclonal antibody to the IGF-I receptor (alpha IR-3) inhibited IGF-I binding by 50% at a 1:1000 dilution and by 80% at a 1:250 dilution. Insulin binding was unaffected by the same dilutions. IGF-I receptor phosphorylation was studied in erythrocyte ghosts prepared by hypotonic lysis and solubilized in 1% Triton. The extract was preincubated with and without 100 ng/ml IGF-I or porcine insulin and incubated with [gamma-32P]ATP in the presence of Mn2+, and the receptor was identified by immunoprecipitation with alpha IR-3 antibody and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. IGF-I stimulated 4-fold the incorporation of 32P into a protein of 95,000 mol wt, which was immunoprecipitated by alpha IR-3; insulin produced a 2-fold stimulation of this protein. This protein corresponds to the beta-subunit of the IGF-I receptor. These data demonstrate that human erythrocytes have specific receptors for IGF-I, and that this IGF-I receptor, like the insulin receptor, undergoes ligand-stimulated autophosphorylation. Thus, analysis of erythrocyte IGF-I binding and receptor phosphorylation may be useful tools for the study of patients with a variety of growth disorders.
Adult↗
Characterization of binding and phosphorylation defects of erythrocyte insulin receptors in the type A syndrome of insulin resistance.
The type A syndrome of insulin resistance and acanthosis nigricans is characterized by severe insulin resistance due to a cellular defect in insulin action. To better understand the molecular nature of this defect, we have investigated insulin binding to circulating monocytes, erythrocytes, and the Triton X-100-solubilized erythrocyte receptor, and insulin-stimulated receptor autophosphorylation using cells and receptor from three type A patients. Insulin binding in both circulating cells and the soluble extract of erythrocytes indicated a heterogeneity of defects. Patients A1 and A2 both presented a major decrease in tracer insulin binding to intact cells and soluble insulin receptor. Determination of stoichiometric binding parameters using a cooperative model indicated that in patient A1 this was due to a reduction in the number of receptors, whereas in patient A2 the affinity constant for binding was decreased. Patient A3 presented near-normal insulin binding to erythrocytes and normal binding in intact monocytes, solubilized erythrocyte receptors, and cultured fibroblasts. Affinity labeling of erythrocyte receptor from this patient revealed a normal alpha-subunit and also a normal relative distribution of the higher-molecular-weight, nonreduced oligomeric forms of the receptor. Receptor autophosphorylation was measured using the solubilized insulin receptor from erythrocytes. The maximal stimulated phosphorylation was reduced by 79%, 76%, and 52% in patients A1, A2, and A3, respectively, relative to the simultaneous control. In all three patients, the autophosphorylation was stimulated only 1.0-3.5 times the basal level compared with controls, in which the stimulation was 5.7-fold +/- 1.2 (mean +/- 1 SD, P less than 0.005). In addition, in patients A1 and A2 a decrease in basal phosphorylation was observed and in patient A2 there was a rightward shift of the dose-response curve for insulin stimulation. These data and the correlation of coupling of receptor phosphorylation with the fractional occupancy of the receptor measured in the same extract suggest that these patients exhibit three types of defects. In patient A1, there is a loss in receptor number manifested by a parallel decrease in insulin binding and receptor phosphorylation. In patient A2, there is an additional decrease in the affinity constant leading to a decrease in both binding and receptor phosphorylation with an almost linear coupling between receptor occupancy and receptor phosphorylation.(ABSTRACT TRUNCATED AT 400 WORDS)
Acanthosis Nigricans↗
Characterization of insulin receptor carbohydrate by comparison of chemical and enzymatic deglycosylation.
To characterize the carbohydrate moieties of the insulin receptor on IM-9 lymphocytes, the cells were surface iodinated and solubilized, and the insulin receptors were precipitated with anti-receptor antibody. The precipitates were resuspended, subjected to either enzymatic digestion or chemical treatment with trifluoromethanesulfonic acid and the relative mobilities of the alpha and beta subunits before and after treatment were analyzed by polyacrylamide gel electrophoresis and autoradiography. The results indicate that the alpha subunit possesses primarily N-linked carbohydrate which is both complex (Endoglycosidase F sensitive) and polymannose (Endoglycosidase H sensitive). The beta subunit also contains polymannose oligosaccharide units and has, in addition, a substantial amount of carbohydrate which is removed by chemical treatment but is not susceptible to Endoglycosidase F, suggesting the presence of O-linked saccharides. The apparent molecular weights of the core protein of the mature alpha and beta subunits as determined by gel electrophoresis following complete deglycosylation are 98 kDa and 80 kDa, respectively.
Carbohydrates↗
Distribution and characterization of insulin and insulin-like growth factor I receptors in normal human ovary.
Insulin-resistant hyperinsulinemic states are now widely known to be associated with ovarian hyperandrogenism, and this is thought to be due to an action of insulin on the ovary. However, the identity of the receptor that is responsible for insulin action in these patients, whose insulin receptors on classical target tissues are severely impaired, is unclear. We now report the presence of insulin receptors in stromal and follicular compartments as well as in granulosa cells obtained from normal ovaries. After 15-h incubations at 4 C with [125I]insulin and tissue fragments, specific insulin binding was 6-19% and 7-13%/mg protein (n = 8) to stroma and theca, respectively. Granulosa cells obtained in the course of in vitro fertilization were separated from red cells on a Percoll gradient; specific insulin binding ranged from 9-15%/10(6) cells. Insulin binding was characterized by sensitive insulin competition (half-maximal, 10 ng/ml), appropriately shifted proinsulin competition (20 times to the right), and complete inhibition by specific anti-insulin receptor antibodies (B-2). An antibody to the insulin-like growth factor I (IGF-I) receptor (alpha IR-3) that inhibits IGF-I binding to IGF-I receptors in other cell systems had no effect on insulin binding. Further proof that this binding is to classic insulin receptors was obtained from measurement of insulin-stimulated receptor autophosphorylation. When insulin receptors from stroma were extracted with Triton X-100 and incubated with [gamma-32P]ATP and Mn, insulin increased the incorporation of 32P into the beta-subunit of the receptor 5-fold. In parallel studies with [125I-]IGF-I and specific blocking antibodies to its receptor, no detectable IGF-I binding to stroma or follicles was found. We conclude that specific high affinity insulin receptors possessing tyrosine kinase activity are widely distributed in normal human ovary. IGF-I receptors in normal ovary are either absent or present at very low density. Binding of insulin to its own receptor (as opposed to IGF-I receptors) appears to be the most likely first step in the stimulation of ovarian steroidogenesis by insulin in normal ovaries and possibly in insulin-resistant states as well.
Adult↗
Defect in insulin receptor phosphorylation in erythrocytes and fibroblasts associated with severe insulin resistance.
The insulin receptor is a tyrosine-specific protein kinase. Upon binding of the hormone, the kinase is activated resulting in autophosphorylation of the receptor. This kinase activity has been postulated to be an early step in the transmembrane signaling produced by insulin. To evaluate the physiologic relevance of receptor phosphorylation, we have studied insulin binding and autophosphorylation properties using cells from an individual with a variant of the Type A syndrome of severe insulin resistance and acanthosis nigricans. Erythrocytes and cultured fibroblasts from this individual exhibited normal or near normal 125I-insulin binding. Receptors extracted from erythrocytes with Triton X-100 also exhibited normal 125I-insulin binding and competition curves. Despite this, receptors extracted from both erythrocytes and fibroblasts showed a 50% decrease in insulin-stimulated autophosphorylation. Partially purified receptors from the patient's fibroblasts also exhibited a 40% decrease in their ability to phosphorylate exogenous substrates. These data suggest that the insulin resistance in this syndrome is due to a genetic abnormality which impairs insulin receptor phosphorylation and kinase activity and further support the possible role of receptor phosphorylation and kinase activity in insulin action.
Acanthosis Nigricans↗
Insulin binding and insulin-dependent phosphorylation of the insulin receptor solubilized from human erythrocytes.
Insulin receptors were extracted from human erythrocytes contained in 100 ml of blood with the nonionic detergent Triton X-100 with almost 100% yield. The solubilized receptor had binding characteristics similar to those of the intact cell. Using 125I-monoiodoinsulin as tracer and a computer-assisted statistical curve-fitting program, a cooperative model gave values of 1.7 X 10(9) M-1 for the Ke (affinity of the empty receptor) and of 1.6 X 10(8) M-1 for Kf (affinity of the filled receptor). Bovine desalanine-desasparagine insulin inhibited tracer binding with 3-6% the potency of porcine insulin. Serum (B-8) containing anti-insulin receptor antibodies inhibited binding by 70% at a dilution of 1:100. Receptor autophosphorylation reaction was studied by incubation of the Triton extract with [gamma-32P]ATP and Mn2+ in the presence or absence of insulin, and the receptor was identified by immunoprecipitation with anti-receptor antibodies and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Porcine insulin stimulated 4- to 5-fold the incorporation of 32P in a protein of Mr = 95,000, corresponding to the beta-subunit of the insulin receptor. Phosphoamino acid analysis revealed phosphorylation of the tyrosyl residues exclusively. The dose-response curve for insulin stimulation was sigmoidal; some effect of insulin was observed at 1 ng/ml but maximal effect was observed at 10 micrograms/ml. Bovine desalanine-desasparagine insulin, a noncooperative analogue of insulin, was able to fully stimulate the phosphate incorporation, but the dose-response curve was shifted to the right and steeper, consistent with the intrinsic affinity of this analogue for the insulin receptor. When insulin binding was performed under the same conditions as the phosphorylation, half-maximal stimulation of phosphate incorporation occurred with 6-29% of the fractional occupancy of the receptor. These data suggest that the insulin receptor of the human erythrocyte, as in other cells, is a tyrosine-specific protein kinase. Coupling between the receptor occupancy and kinase activation is complex. Furthermore, sufficient quantities of receptor can be easily obtained from a single individual to study the binding and kinase properties of the receptor opening the opportunity to a wide field of applications in human pathology.
Amino Acids↗
[Clinical usefulness of the determination of erythrocyte insulin receptors].
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Diabetes Mellitus↗
Administration of arginine-vasotocin (AVT) to human subjects.
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Adult↗
[Incomplete chronic duodenal stenosis caused by compression by the aorta and mesenteric artery].
In the light of data from the literature, as well as on the personal observations made in 5 cases of chronic, imcomplete duodenal stenosis through aortic-mesenteric pincers that have been hospitalized and operated, the authors stress: the complexity of the syndrome, the difficulties encountered in the establishment of the diagnosis, the severe consequences of the evolution, the necessity to apply surgical treatment as soon as possible.
Adolescent↗