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PubMed1989

Clinicopathological studies of carcinoma oesophagus with special reference to changes in surrounding epithelium.

A total 17 cases of carcinoma oesophagus were studied in a period of 2 years. Ten patients (58.82%) were males and rest were females. Maximum cases (64.70%) were seen in 5th and 6th decades. Majority of the patients belonged to low socio-economic group (47.05%) followed by middle socio-economic group (41.17%). Dysphagia was present in all cases, followed by weight loss 52.94% and other symptoms. Cancer was equally distributed in middle third and lower third of the oesophagus (41.18% in each group) only in 3 cases it was in upper third of the oesophagus. Histologically 70.5% tumours were squamous cell carcinoma, 17.64% were adenocarcinoma and 11.76% were undifferentiated carcinoma. Surrounding epithelium in 17.64 per cent cases showed chronic oesophagitis, 4 cases (23.52%) showed acanthosis and dysplasia, and two cases revealed carcinoma in situ. Hence findings of oesophagitis, acanthosis, dysplasia, carcinoma in situ suggest that oesophagitis and acanthosis may be considered as precancerous lesions.

Adenocarcinoma↗
PubMed1984

Endoscopic study of chronological changes leading to cancer in the esophagus of dogs induced by N-ethyl-N'-nitro-N-nitrosoguanidine.

An endoscopical study of chronological change during the carcinogenetic process of cancer of the esophagus induced by N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) in 16 male beagle dogs was performed to clarity whether or not precancerous lesions exist in the esophagus. Redness was first observed in the mucosa in the lower and/or middle portions of the esophagus. A small nodule developed in the redness, followed by a nodule. The nodule then developed into a flat polyp which finally developed into lesions such as an elevated lesions, protrusions or elevations with depressions. Histologically, esophagitis or acanthosis in the redness and acanthosis were found in most of the small nodules. With regard to the nodules, papillomatosis was observed in half of the lesions, while either acanthosis or atypical epithelial proliferation were found in most of the flat polyps. Almost all the elevated or protruding lesions were found to be carcinoma.

Animals↗
PubMed1990

Rearrangement of chromosome 15 in the region q11.2----q12 in an individual with obesity syndrome and her normal mother.

Rearrangement of the proximal long arm of chromosome 15 have been found in most patients with the Prader-Willi syndrome (PWS) and in some with Angelman syndrome. We present an individual with syndromic obesity and her normal mother, who both have an abnormal chromosome 15. The proposita is a 26-year-old women with marked obesity, acanthosis, nigricans, short fingers, and severe cone degeneration of the retina. She has high plasma insulin levels, hypothyroidism, and an empty sella on CT scan. High-resolution chromosome banding demonstrated an increase in band 15q12. Further analysis showed the same abnormal 15 in her normal mother but not in her normal sister. This case and recent reports in the literature indicate that duplication of chromosome 15q in the PWS region may be associated with a syndrome of obesity, acanthosis nigricans, empty sella, and rodcore dystrophy as well as with a normal phenotype. Whether normal individuals with such a duplication carry increased risk of having offspring with an obesity syndrome is yet to be determined.

Acanthosis Nigricans↗
PubMed1983

Pancreatic A and B cell hyperfunction in the Mendenhall syndrome.

A 16-year-old boy with persistent hyperglycaemia (approximately 16 mmol/l in the fasting state) and acanthosis nigricans had insulin resistance and received daily up to 2800 U of short-acting, soluble, highly purified porcine insulin. The number and affinity of insulin receptors were markedly decreased. No significant insulin binding to IgG could be detected. Immunoreactive insulin varied between 1344 and 2400 mU/l. Endogenous insulin secretion and proinsulin levels were grossly elevated in the fasting state (C-peptide 2.2-3.5 pmol/ml; proinsulin approximately 1 pmol/ml). After an oral glucose tolerance test and intravenous arginine infusion, B cell hypersecretion was confirmed. The molar ratio of C-peptide to immunoreactive insulin, normally approximately 7, was about 0.3, clearly indicating that most of the immunoreactive insulin was exogenous. The molar ratio of proinsulin to C-peptide, which is about 0.05 in fasting control subjects, was 0.23-0.45, clearly showing that too high a proportion of proinsulin was being secreted. This may indicate that the constant hyperstimulation of the B cell leads to reduced conversion of proinsulin to insulin. Immunoreactive glucagon levels were within normal limits fasting but were above normal after intravenous arginine infusion. Thus, in this case of diabetes with acanthosis nigricans, the severe insulin resistance, probably caused by a receptor defect, was associated with markedly increased B cell function.

Acanthosis Nigricans↗
PubMed2004

Cardiovascular risk factors in Mexican-American children at risk for type 2 diabetes mellitus (T2DM).

PURPOSE: To assess risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) with the hypothesis that risk for T2DM in children would be associated with an increase in risk factors for CVD. METHODS: Subjects from a group of Mexican-American school children (aged 10-12 years) identified to be at risk for T2DM, and their siblings, were selected for this study. There were 68 children with acanthosis nigricans (AN+), and 71 without AN (AN-). Both AN+ and AN- children were assessed for T2DM and CVD risk factors. Probands and siblings were evaluated by physical examination, family history, and fasting serum parameters: glucose, insulin, body mass index (BMI), serum lipoproteins, and oxidized lipids. Data were analyzed by descriptive, univariate, and multivariate procedures. RESULTS: BMI, waist/hip ratio, systolic and diastolic blood pressure were all significantly higher (p <.002) in AN+, whereas Tanner stages were similar in both groups. Fasting serum glucose was in the normal range, whereas insulin was elevated in AN+ compared with AN- (30.0 +/- 1.9 microU/mL vs. 14.8 +/- 1.0 p <.0001). Insulin resistance as assessed by the homeostasis assessment model (HOMA-IR) was elevated in both groups, although higher among AN+ (p <.0001). High-density lipoprotein-cholesterol (HDL-C) was lower (6.2 mg/dL) in the AN+ group (p <.003). The lower HDL-C in AN+ was associated with elevated triglycerides and a higher serum total cholesterol TC/HDL-C ratio when contrasted with the AN- values (145.9 +/- 7.6 mg/dL vs. 97.1 +/- 0.07, p <.0001; 4.1 +/- 0.2 vs. 3.4 +/- 0.1, p <.0001, respectively). In addition to the high prevalence of overweight/obesity (BMI > 85th percentile) in this population (76.3%, 106/139), elevated insulin (59.7% >15 microU/mL), low HDL-C (27.3% <40 mg/dL), and elevated low-density lipoprotein cholesterol (LDL-C) (41.0% >100 mg/dL) were also detected. CONCLUSIONS: The altered metabolic pattern observed in this group of Mexican-American children is characteristic of metabolic syndrome, a condition associated with obesity and increased risk for both T2DM and CVD in adults. This study points to the value of BMI and acanthosis nigricans as easily accessible markers for children and nuclear families at increased risk for developing T2DM and CVD.

Acanthosis Nigricans↗
PubMed1988

The role of hyperinsulinemia in the pathogenesis of ovarian hyperandrogenism.

The evidence that supports the hypothesis that insulin and LH both regulate ovarian androgen production was presented. The most dramatic clinical example of the association between hyperinsulinemia and hyperandrogenism is the HAIR-AN syndrome. Our hypothesis is that, in the HAIR-AN syndrome, the severe insulin resistance causes a compensatory hyperinsulinemia, which stimulates ovarian androgen production if adequate LH is present. The acanthosis nigricans is an epiphenomenon of the syndrome. Acanthosis nigricans is a dermatologic manifestation of severe insulin resistance. In vitro evidence suggests that insulin and IGF-I stimulate androgen production in incubations of human stroma and theca. The stromatropic effects of insulin may sensitize the stroma to the stimulatory effects of LH. In some hyperandrogenic-insulin-resistant women, a glucose load appears to produce an acute rise in circulating androgens. The magnitude of the rise in circulating androgens is proportional to the magnitude of the insulin response to the glucose load. These data suggest that hyperinsulinemia may play a central role in the development of ovarian hyperandrogenism.

Acanthosis Nigricans↗
PubMed1996

Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome.

Beare-Stevenson cutis gyrata syndrome (MIM 123790) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death. Many of these features are characteristic of some of the autosomal dominant craniosynostotic syndromes. Mutations in Crouzon, Jackson-Weiss, Pfeiffer and Apert syndromes have been reported in the FGFR2 extracellular domain. In Crouzon syndrome patients with acanthosis nigricans, a recurrent mutation occurs in the transmembrane domain of FGFR3. We now describe the detection of FGFR2 mutations in the Beare-Stevenson cutis gyrata syndrome. In three sporatic cases, a novel missense mutation was found causing an amino acid to be replaced by a cysteine; two had the identical Ty375Cys mutation in the transmembrane domain and one had a Ser372Cys mutation in the carboxyl-terminal end of the linker region between the immunoglobulin III-like (Iglll) and transmembrane domains. In two patients, neither of these mutations were found suggesting further genetic heterogeneity.

Abnormalities, Multiple↗
PubMed2004

Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): a 30-year prospective.

The interaction of insulin with its cell surface receptor is the first step in insulin action and the first identified target of insulin resistance. The insulin resistance in several syndromic forms of extreme insulin resistance has been shown to be caused by mutations in the receptor gene. We studied 8 female patients with the type A form of extreme insulin resistance and 3 patients (2 male and 1 female) with the Rabson-Mendenhall syndrome and followed the natural history of these patients for up to 30 years. The 11 patients ranged in age from 7 to 32 years at presentation. All 11 patients had extreme insulin resistance, acanthosis nigricans, and hyperandrogenism in the female patients, and all but 1 were of normal body weight. This phenotype strongly predicts mutations in the insulin receptor: of the 8 patients studied, 7 were found to have mutations. Similar results from the literature are found in other patients with type A and Rabson-Mendenhall syndromes and leprechaunism. The hyperandrogenic state resulting from hyperinsulinemia and insulin resistance in these patients was extreme: 6 of 8 patients had ovarian surgery to correct the polycystic ovarian syndrome and elevation of serum testosterone. By contrast, a larger group of insulin-resistant patients who were obese with hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN syndrome) did not have a high probability of mutations in the insulin receptor. The morbidity and mortality of these patients were high: 3 of 11 died, 9 of 11 were diabetic and 1 had impaired glucose tolerance, and 7 of 9 patients had 1 or more severe complication of diabetes. Our literature review revealed that the mortality of leprechaunism is so high that the term leprechaunism should be restricted to infants or young children under 2 years of age. Analogous to patients with the common forms of type 2 diabetes, these patients had a heterogeneous course. In 2 patients who were able to maintain extremely high endogenous insulin production, the fasting blood glucose remained normal even though post-glucose-challenge levels were elevated. Most patients, however, required large doses of exogenous insulin to ameliorate the severe hyperglycemia. Preliminary results of a recent study suggest that recombinant leptin administration may benefit these patients with severe insulin resistance.

Acanthosis Nigricans↗
PubMed2006

Androgen excess disorders in women: the severe insulin-resistant hyperandrogenic syndrome, HAIR-AN.

HAIR-AN syndrome (hyperandrogenism, insulin resistance, acanthosis nigricans) is a subset of the polycystic ovary syndrome, where the patients demonstrate severe insulin resistance. It is theorized that both genetic and environmental factors, such as obesity, give rise to the development of HAIR-AN. Diagnosis is primarily clinical, with laboratory values lending further support. Treatment is aimed at decreasing insulin resistance, regulating ovulation, and decreasing acne, acanthosis nigricans, and hirsutism.

Acanthosis Nigricans↗
PubMed1993

Psoriasis-like lesions in guinea pigs receiving propranolol.

BACKGROUND: beta-Blockers cause a psoriasiform eruption. We investigated the skin effects of systemic propranolol in a formal protocol. METHODS: Propranolol, 0.1 mg/day, was used systemically by gavage in eight albino guinea pigs. Normal saline was given to another group of seven guinea pigs. RESULTS: Propranolol produced psoriasiform lesions in five of seven guinea pigs on the 30th day. Biopsies showed acanthosis, parakeratosis, microabscesses, and cellular infiltration of upper dermis. Topical application of propranolol did not produce clinical psoriasiform changes, while acanthosis and papillomatosis was observed in six of the six guinea pigs.

Acanthosis Nigricans↗
PubMed2004

Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment.

We present the fourth case of an adult man (29 yr old) affected by aromatase deficiency resulting from a novel homozygous inactivating mutation of the CYP19 (P450(arom)) gene. At first observation, continuing linear growth, eunuchoid body proportions, diffuse bone pain, and bilateral cryptorchidism were observed. The patient presented also a complex dysmetabolic syndrome characterized by insulin resistance, diabetes mellitus type 2, acanthosis nigricans, liver steatohepatitis, and signs of precocious atherogenesis. The analysis of the effects induced by the successive treatment with high doses of testosterone, alendronate, and estradiol allows further insight into the roles of androgens and estrogens on several metabolic functions. High doses of testosterone treatment resulted in a severe imbalance in the estradiol to testosterone ratio together with the occurrence of insulin resistance and diabetes mellitus type 2. Estrogen treatment resulted in an improvement of acanthosis nigricans, insulin resistance, and liver steatohepatitis, coupled with a better glycemic control and the disappearance of two carotid plaques. Furthermore, the study confirms previous data concerning the key role of estrogens on male bone maturation, at least in part, and regulation of gonadotropin secretion. The biopsy of the testis showed a pattern of total germ cell depletion that might be due to the concomitant presence of bilateral cryptorchidism. Thus, a possible role of estrogen in male reproductive function is suggested but without revealing a direct cause-effect relationship. Data from this case provide new insights into the role of estrogens in glucose, lipid, and liver metabolism in men. This new case of aromatase deficiency confirms previous data on bone maturation and mineralization, and it reveals a high risk for the precocious development of cardiovascular disease in young aromatase-deficient men.

Acanthosis Nigricans↗
PubMed1989

Acromegaloid patients with type A insulin resistance: parallel defects in insulin and insulin-like growth factor-I receptors and biological responses in cultured fibroblasts.

A subset of patients with the syndrome of acanthosis nigricans and insulin resistance type A is characterized by acromegaloid features in addition to hyperinsulinemia, hyperandrogenemia, and an inherent defect in insulin receptor function. It has been proposed that the acromegaloid features result from the interaction of insulin at concentrations encountered in vivo, with a functionally intact insulin-like growth factor-I (IGF-I) receptor closely related to the insulin receptor. We investigated this possibility by examining binding and hormone-stimulated [14C]glucose uptake, [3H]thymidine uptake, and receptor autophosphorylation by both insulin and IGF-I in cultured fibroblasts from two affected patients. In comparison to normal fibroblasts, [125I]insulin binding, insulin-stimulated [14C]glucose, and [3H]thymidine uptake, and insulin-stimulated autophosphorylation were each reduced by approximately 50-60% of the absolute values in controls. In contrast to expectation, each of these apparent defects in insulin binding and action were mirrored by a parallel decrease in IGF-I binding and action. Thus, [125I]IGF binding was approximately 50%, IGF-I stimulated [3H]thymidine uptake was approximately 40% and 60% of the control value, and IGF-I-stimulated receptor autophosphorylation was reduced by 40%. Incubation of fibroblasts with insulin at 25 ng/mL reduced subsequent binding of [125I]IGF-I by approximately 20% and did not enhance maximal stimulation of [3H]thymidine incorporation. We conclude that in some patients with acanthosis nigricans and acromegaloid features, IGF-I receptors of cultured fibroblasts may share the inherent defects of insulin receptor function. These in vitro data do not explain the acromegaloid features observed in vivo, suggesting that acromegaloid features are mediated by other mechanisms.

Acanthosis Nigricans↗
PubMed1993

[A case of familial insulin resistance due to type A insulin receptor disorder].

We report a case of familial insulin resistance due to Type A insulin receptor disorder. The patient, a product of consanguineous marriage, was a 34-year-old man who had had diabetes mellitus since the age of 14 years. He was treated by insulin therapy but became blind due to diabetic retinopathy at the age of 25 years. He was 154 cm tall and weighed 41kg. He had hirsutism and acanthosis nigricans. Laboratory data revealed hyperinsulinemia (140-350 microU/ml), and glucose clamp study showed insulin resistance, i.e. decreased glucose metabolic clearance rate, 20% of normal. Insulin binding was decreased to 10.7-16.6% of normal in erythrocytes, cultured fibroblasts and transformed lymphocytes. Glucagon stimulated C-peptide levels decreased gradually during a 3 year follow-up period. Homologous missense mutation from Proline193 to Leucine193 was found in this patient. Heterologous mutation was found in his mother who showed mild diabetes but did not show hirsutism or acanthosis nigricans. These findings suggested that the patient's father had this mutation in his insulin receptor gene and that the homologous mutation gene provoked more severe diabetes mellitus than heterologous mutation in this case. The efficacy of sulfonylurea agents was seen in this patient. Furthermore, sulfonyl urea agents may be indicated for treating these patients, probably by increasing insulin sensitivity.

Acanthosis Nigricans↗
PubMed1997

Characteristics of youth-onset noninsulin-dependent diabetes mellitus and insulin-dependent diabetes mellitus at diagnosis.

OBJECTIVE: To describe the characteristics of youth-onset noninsulin-dependent diabetes mellitus (NIDDM) at diagnosis and compare them with youths with insulin-dependent diabetes mellitus (IDDM) when matched for age, sex, and geographic region of residence. STUDY DESIGN: Medical records of youths referred for evaluation of diabetes to a pediatric tertiary care center from 1988 to 1995 were reviewed to identify youths diagnosed with NIDDM. Patients selected for study met National Diabetes Data Group criteria for type of diabetes. RESULTS: Fifty patients with NIDDM were reviewed and compared with similar IDDM patients. The NIDDM female:male ratio was 1.6:1 and 74% were African-American. Only 18% of the IDDM patients were African-American. The mean body mass index +/- standard error at diagnosis of NIDDM patients was 35 +/- 1.1 kg/m in contrast to IDDM, 20 +/- .8 kg/m. Ninety-six percent of NIDDM and 24% of IDDM youths had a body mass index >/=85th percentile. More then 30% of NIDDM youths presented with hypertension. Diabetic ketoacidosis was present in >25% of NIDDM patients. Acanthosis nigricans was documented in 86% of NIDDM and 0% of IDDM patients. CONCLUSIONS: In Arkansas, youths with NIDDM are characterized by significant obesity in contrast to youths with IDDM. Physical characteristics such as obesity, acanthosis nigricans, and hypertension on examination of any youth with new-onset diabetes should raise suspicion of NIDDM.

Acanthosis Nigricans↗
PubMed2004

Crouzonodermoskeletal syndrome.

Crouzon craniostenosis [MIM 123500], is identified on the basis of the additional phenotypical manifestations of acanthosis nigricans, vertebral changes and cementomas of the jaws. Choanal atresia and hydrocephalus are other features. The molecular defect in CDSS is a point mutation in the FGFR3 gene on chromosome 4p, whereas, the mutation in the Crouzon syndrome is in the FGFR2 gene at 10q25.3-26. An affected girl aged 2 years presented at the UWC dental genetics unit with a prior diagnosis of Crouzon syndrome. Choanal atresia had necessitated a permanent tracheostomy, and hydrocephalus was managed by a shunt operation. Clinical examination revealed acanthosis nigricans in the axilliary regions, a diagnosis confirmed by a biopsy of the lesion. Eruption of the primary dentition was delayed with only six out of twenty teeth present. Radiographic examination conducted shortly after birth revealed the presence of several tooth buds in both the maxillae and the mandible. The delayed eruption of the teeth will be of significance in future orthodontic and maxillofacial measures for the improvement of the patient's facial Crouzonodermoskeletal syndrome (CDSS) was separated from the classical appearance. Molecular investigations in the girl and her parents are underway. If the specific mutation in FGFR3 is observed, a positive diagnosis of CDSS will be confirmed and the status of her parents and other family members will be determined. On this basis, appropriate genetic management can be offered to the kindred.

Acanthosis Nigricans↗
PubMed2002

Dermatological complications of obesity.

Obesity is a health problem of considerable magnitude in the Western world. Dermatological changes have been reported in patients with obesity, including: acanthosis nigricans and skin tags (due to insulin resistance); hyperandrogenism; striae due to over extension; stasis pigmentation due to peripheral vascular disease; lymphedema; pathologies associated with augmented folds; morphologic changes in the foot anatomy due to excess load; and complications that may arise from hospitalization. Acanthosis nigricans plaques can be managed by improved control of hyperinsulinemia; the vitamin D3 analog calcipitriol has also been shown to be effective. Skin tags can be removed by snipping with curved scissors, by cryotherapy or by electrodesiccation. Hyperandrogenism, a result of increased production of endogenous androgens due to increased volumes of adipose tissue (which synthesizes testosterone) and hyperinsulinemia (which increases the production of ovarian androgens) needs to be carefully assessed to ensure disorders such as virilizing tumors and congenital adrenal hyperplasia are treated appropriately. Treatment of hyperandrogenism should be centred on controlling insulin levels; weight loss, oral contraceptive and antiandrogenic therapies are also possible treatment options. The etiology of striae distensae, also known as stretch marks, is yet to be defined and treatment options are unsatisfactory at present; striae rubra and alba have been treated with a pulsed dye laser with marginal success. The relationship between obesity and varicose veins is controversial; symptoms are best prevented by the use of elastic stockings. Itching and inflammation associated with stasis pigmentation, the result of red blood cells escaping into the tissues, can be treated with corticosteroids. Lymphedema is associated with dilatation of tissue channels, reduced tissue oxygenation and provides a culture medium for bacterial growth. Lymphedema treatment is directed towards reducing the limb girth and weight, and the prevention of infection. Intertrigo is caused by friction between skin surfaces, combined with moisture and warmth, resulting in infection. This infection, most commonly candidiasis, is best treated with topical antifungal agents; systemic antifungal therapy may be required in some patients. Excess load on the feet can result in morphological changes that require careful diagnosis; insoles may offer some symptom relief while control of obesity is achieved. Obesity-related dermatoses associated with hospitalization, such as pressure ulcers, diminished wound healing, dermatoses secondary to respiratory conditions, and incontinence, must all be carefully managed with an emphasis on prevention where possible. Recognition and control of the dermatological complications of obesity play an important role in diminishing the morbidity of obesity.

Acanthosis Nigricans↗
PubMed1993

Trial of insulinlike growth factor I therapy for patients with extreme insulin resistance syndromes.

Extreme insulin resistance occurs in patients with primary defects in insulin action at the receptor or postreceptor levels. The condition commonly is associated with acanthosis nigricans and ovarian masculinization. Despite a marked increase in insulin secretion, some patients develop frank diabetes mellitus that does not respond adequately to insulin therapy. Insulinlike growth factor I exerts metabolic effects similar to those of insulin. This study assessed the potential effectiveness of IGF-I as a blood glucose lowering agent in patients with extreme insulin resistance syndromes, including type A insulin resistance, congenital generalized lipodystrophy, and leprechaunism. Among the 11 patients studied, some exhibited mutated insulin receptors, whereas others were suspected to have defects in postreceptor sites. In each patient, plasma glucose levels decreased in response to subcutaneous injections of recombinant human IGF-I (0.1-0.3 mg/kg body wt). The degree of the decrease was roughly comparable with that observed in normal individuals. IGF-I also reduced plasma insulin concentrations. A long-term trial of IGF-I (up to 16 mo) showed that IGF-I (0.1-0.4 mg/kg body wt twice daily) is effective in lowering both fasting and postprandial plasma glucose concentrations with decreases in both fructosamine and HbA1c values. Improvement of acanthosis nigricans was observed in some of the patients. These results suggest that recombinant human IGF-I could be used clinically as a hypoglycemic agent in diabetic patients with extreme insulin resistance in whom insulin treatment is ineffective.

Acanthosis Nigricans↗
PubMed1994

Prevalence of mutations in the insulin receptor gene in subjects with features of the type A syndrome of insulin resistance.

Mutations of the insulin receptor gene are a cause of the type A syndrome of extreme insulin resistance. This study assessed the prevalence of such mutations in women with clinical features of the type A syndrome including ovarian hyperandrogenism, moderate-to-severe degrees of insulin resistance, and acanthosis nigricans. We studied 22 unrelated women with insulin resistance (fasting insulin > 300 pM [50 microU/ml] and/or peak during an oral glucose tolerance test (OGTT) > 1,800 pM [300 microU/ml]), acanthosis nigricans, and the polycystic ovary syndrome (hyperandrogenemia, oligoamenorrhea, and hirsutism). Two insulin-resistant probands with congenital generalized lipodystrophy and one male proband with severe insulin resistance also were included in the study. Southern blotting experiments were performed to exclude gross gene deletions, insertions, or rearrangements. Exons 2-22 of the insulin receptor gene were polymerase chain reaction (PCR) amplified from genomic DNA and screened for nucleotide variation using single-strand conformation polymorphism (SSCP). No nucleotide variation between study subjects was detected in exons 4-6, 10-12, 15, 16, 18, 19, or 21. Sequencing of amplified DNA revealed that SSCP variants in exons 2, 3, 8, 9, and 17 corresponded to known silent polymorphisms within the coding region. Variants in exons 2, 9, 13, and 14 were caused by novel silent polymorphisms; variants in exons 7 and 22 were caused by nucleotide substitutions in flanking introns. One proband was found to have a heterozygous point mutation in exon 20 (CGG-->CAG, Arg1174-->Gln) that involves the intracellular receptor beta-subunit.(ABSTRACT TRUNCATED AT 250 WORDS)

Acanthosis Nigricans↗