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Biomedical subjects

C A Stratakis

Publications and source records attributed to C A Stratakis.

At least 91 records · Page 5Linked to original sources
PubMed1998

P450arom gene expression in peripheral blood lymphocytes: identification of a cryptic splice site for exon-1 after Epstein-Barr virus transformation.

The human aromatase gene (P450arom) is widely expressed, albeit in a tissue-specific manner. In the present study, we measured aromatase activity and investigated the transcribed and translated products of the P450arom gene before and after Epstein-Barr virus (EBV) transformation in peripheral blood lymphocytes (PBLs) from normal individuals. Aromatase activity was determined by [3H]-delta4-androstenedione (A) to [3H]-estrone (E1) conversion. Cellular total RNA and protein lysates were subjected to RT-PCR and Western analysis, respectively. Rapid amplification of cDNA ends (RACE) was used for the detection of novel 5'-untranslated ends of the P450arom mRNA, which were subsequently sequenced and compared to the known transcripts of this gene. In untransformed PBLs, two known variants of exon 1 of the P450arom gene were expressed, corresponding to promoters PI.3 and PII, or 1c and 1d, respectively. In EBV-transformed PBLs, a cryptic splice site was revealed and a new 5'-untranslated product was found. RNase protection assay confirmed that this splice variant is not a RACE artifact. The 53 K P450arom protein was detectable in PBLs both before and after EBV transformation. We conclude that (i) the P450arom mRNA is present in human PBLs and (ii) EBV transformation of the latter leads to novel alternative splicing of the 5' end of this gene.

Alternative Splicing↗
PubMed1998

Carney complex and the familial lentiginosis syndromes: link to inherited neoplasias and developmental disorders, and genetic loci.

Lentigines, synonymous but not identical to freckles or ephelides, are common skin lesions. In a small number of patients, however, these lesions constitute part of genetic syndromes that are associated with inherited forms of neoplasias or other pathologic processes of the cardiovascular, endocrine, and gastrointestinal systems. The familial lentiginoses, as these syndromes are collectively known, include Carney complex, the LEOPARD and Peutz-Jeghers syndromes, and the newly described 'syndrome of arterial dissections with lentiginosis'; isolated, familial lentiginosis has also been described. In the majority of the reported kindreds with these syndromes, the lesions were inherited in an autosomal dominant manner. The specific genes that are responsible for these disorders have remained elusive, but the genetic loci of Carney complex and Peutz-Jeghers syndromes were recently identified on chromosomes 2p 16 and distal 19p, respectively. Cytogenetic studies of tumours from patients with Carney complex suggest that the gene responsible for most patients with this syndrome may not have a tumour suppression function. We suggest that the genes responsible for the lentiginosis syndromes are important regulators of melanocyte function, they participate in the pleiotropy of human pigmentation, and are involved in the function, growth and proliferation of neural crest and mesenchymal cells.

Diagnosis, Differential↗
PubMed1998

Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3.

Aldosterone synthase (AS) is encoded by the CYP11B2 gene, a candidate for familial hypertension. CYP11B2 was previously mapped to chromosome 8q but its precise localization is necessary for genetic studies of hypertension. The present study reports the genetic mapping of the human CYP11B2 gene by radiation hybrid (RH) analysis, the isolation of a bacterial artificial chromosome (BAC) containing this gene and its physical mapping by fluorescent in situ hybridization (FISH). The CYP11B2 locus is on the most distal segment of the long arm of chromosome 8, proximal to the microsatellite polymorphic marker D8S1704. This location, which was confirmed by FISH, is approximately 60cM telomeric to the currently listed human gene locus (chromosome 8q21-22) and corresponds to cytogenetic band 8q24.3. The BACs containing the gene and a high-resolution map of the CYP11B2 locus are useful for genetic studies of hypertension and other endocrine disorders.

Chromosome Mapping↗
PubMed1998

The aromatase excess syndrome is associated with feminization of both sexes and autosomal dominant transmission of aberrant P450 aromatase gene transcription.

Increased extraglandular aromatization has been reported as the cause of familial gynecomastia. We studied a kindred with aromatase excess inherited in an autosomal dominant manner, in which affected males had heterosexual precocity and/or gynecomastia, and affected females had isosexual precocity and/or macromastia. The propositus was a 9-yr-old boy with gynecomastia. His 7.5-yr-old sister had precocious puberty, and their father and paternal grandmother had peripubertal gynecomastia and macromastia, respectively. Serum concentrations of gonadal and adrenal steroid hormones were determined before and after the administration of corticotropin and/or hCG. Aromatase activity was determined by [3H]delta4-androstenedione to [3H]estrone conversion by cultured skin fibroblasts and/or Epstein-Barr virus-transformed lymphocytes and was detected by immunohistochemistry and/or Western analysis. Linkage was examined with a polymorphism of the aromatase (P450arom) gene. The P450arom messenger ribonucleic acid was analyzed by rapid amplification of complementary DNA (cDNA) ends, ribonuclease protection assay, and RT-PCR. hCG testing demonstrated a high rate of conversion of delta4-androstenedione to estrone and of testosterone to estradiol in the propositus and his father. Treatment of the propositus and his sister was initiated with an aromatase inhibitor (testolactone) and a GnRH analog, which successfully delayed skeletal and pubertal development in both children. Markedly increased aromatase activity was found in the patients' fibroblasts and Epstein-Barr virus-transformed lymphocytes. The P450arom polymorphism segregated with the disease in the family. A new 5'-splice variant was present in the patients' P450arom messenger ribonucleic acid, thus identifying yet another first exon of this gene, which appears to be aberrantly expressed in this family. In conclusion, a family with the aromatase excess syndrome is described, in which the condition was inherited in an autosomal dominant manner, led to feminizing manifestations in both sexes, and was associated with the aberrant utilization of a novel transcript of the P450arom gene.

Adult↗
PubMed1998

Carney complex, Peutz-Jeghers syndrome, Cowden disease, and Bannayan-Zonana syndrome share cutaneous and endocrine manifestations, but not genetic loci.

Carney complex (CC), Peutz-Jeghers syndrome (PJS), Cowden disease (CD), and Bannayan-Zonana syndrome (BZS) share clinical features, such as mucocutaneous lentigines and multiple tumors (thyroid, breast, ovarian, and testicular neoplasms), and autosomal dominant inheritance. A genetic locus has been identified for CC on chromosome 2 (2p16), and the genes for PJS, CD, and BZS were recently identified; genetic heterogeneity appears likely in both CC and PJS. The genes for PJS and CD/BZS, STK11/LKB1 and PTEN, respectively, may act as tumor suppressors, because loss of heterozygosity (LOH) of the PJS and CD/BZS loci has been demonstrated in tumors excised from patients with these disorders. We studied 2 families with CC in whom the disease could not be shown to segregate with polymorphic markers from the 2p16 locus. Their members presented with lesions frequently seen in PJS and the other lentiginosis syndromes. We also tested 16 tumors and cell lines established from patients with CC for LOH involving the PJS and CD/BZS loci. DNA was extracted from peripheral blood, tumor cell lines, and tissues and subjected to PCR amplification with primers from microsatellite sequences flanking the STK11/LKB1 and PTEN genes on 19p13 and 10q23, respectively, and a putative PJS locus on 19q13. All loci were excluded as candidates in both families with LOD scores less than 2 and/or by haplotype analysis. LOH for these loci was not present in any of the tumors that were histologically identical to those seen in PJS. The overall rate of LOH for the PJS and CD/BZS loci in tumors from patients with CC was less than 10%. We conclude that despite substantial clinical overlap among CC, PJS, CD, and BZS, LOH for the STK11 and PTEN loci is an infrequent event in CC-related tumors. Linkage analysis excluded the PJS and CD/BZS loci on chromosomes 19 (19p13 and 19q13) and 10 (10q23) from harboring the gene defect(s) responsible for the phenotype in these 2 families.

Adolescent↗
PubMed1998

Familial hyperaldosteronism type II: description of a large kindred and exclusion of the aldosterone synthase (CYP11B2) gene.

Familial hyperaldosteronism type II (FH-II) is characterized by autosomal dominant inheritance and hypersecretion of aldosterone due to adrenocortical hyperplasia or an aldosterone-producing adenoma; unlike FH type I (FH-I), hyperaldosteronism in FH-II is not suppressible by dexamethasone. Of a total of 17 FH-II families with 44 affected members, we studied a large kindred with 7 affected members that was informative for linkage analysis. Family members were screened with the aldosterone/PRA ratio test; patients with aldosterone/PRA ratio greater than 25 underwent fludrocortisone/salt suppression testing for confirmation of autonomous aldosterone secretion. Postural testing, adrenal gland imaging, and adrenal venous sampling were also performed. Individuals affected by FH-II demonstrated lack of suppression of plasma A levels after 4 days of dexamethasone treatment (0.5 mg every 6 h). All patients had negative genetic testing for the defect associated with FH-I, the CYP11B1/CYP11B2 hybrid gene. Genetic linkage was then examined between FH-II and aldosterone synthase (the CYP11B2 gene) on chromosome 8q. A polyadenylase repeat within the 5'-region of the CYP11B2 gene and 9 other markers covering an approximately 80-centimorgan area on chromosome 8q21-8qtel were genotyped and analyzed for linkage. Two-point logarithm of odds scores were negative and ranged from -12.6 for the CYP11B2 polymorphic marker to -0.98 for the D8S527 marker at a recombination distance (theta) of 0. Multipoint logarithm of odds score analysis confirmed the exclusion of the chromosome 8q21-8qtel area as a region harboring the candidate gene for FH-II in this family. We conclude that FH-II shares autosomal dominant inheritance and hyperaldosteronism with FH-I, but, as demonstrated by the large kindred investigated in this report, it is clinically and genetically distinct. Linkage analysis demonstrated that the CYP11B2 gene is not responsible for FH-II in this family; furthermore, chromosome 8q21-8qtel most likely does not harbor the genetic defect in this kindred.

Aldosterone↗
PubMed1998

Structure of the gene coding for calcineurin B (PPP3R1) and mapping to D2S358-D2S1778 (chromosomal region 2p15).

Calcineurin is a protein phosphatase with an important role in signal transduction; its calcium-binding regulatory subunit, calcineurin B, is widely present in the brain and is coded by the PPP3R1 gene which was mapped recently to human chromosome 2. Calcineurin has long been considered a candidate for psychiatric and/or monogenic brain disorders. The present study reports the intron-exon structure of the PPP3R1 gene with the proximal intronic sequences, its genetic mapping to D25358-D251778 on chromosome 2p15, and its exclusion in a genetic disorder mapped proximal to this locus.

Base Sequence↗
PubMed1998

Epithelioid blue nevus and psammomatous melanotic schwannoma: the unusual pigmented skin tumors of the Carney complex.

Carney complex, a familial multitumoral syndrome, comprises spotty skin pigmentation (lentigines and blue nevi), myxomas (heart, skin, and breast), endocrine tumors (adrenal cortex, pituitary, testis, and thyroid), and schwannomas. The skin pigmentary abnormality included two unusual conditions, epithelioid blue nevus and psammomatous melanotic schwannoma. The former tumor occurred on the extremities and trunk, less frequently on the head and neck; was multiple; and did not recur or metastasize. Clinically, it was pigmented, domed, and small (< 1 cm). Microscopically, it displayed two types of melanocytes--one intensely pigmented, globular, and fusiform and the other lightly pigmented, polygonal, and spindle. Nuclei of the latter cells were vesicular, with pale chromatin and single prominent nucleolus. None recurred or metastasized. The psammomatous melanotic schwannoma occurred in posterior spinal nerve roots, upper alimentary tract, bone, and skin. Microscopically, it was circumscribed but incompletely encapsulated and contained spindle and epithelioid cells, melanin, psammoma bodies, and fat. The spindle cells were arranged in interlacing fascicles, with whorling and occasional nuclear palisading. Twenty-one patients (68%) were alive without evidence of the neoplasm; two of these each had two local recurrences. Seven patients died, three (10%) as a result of metastasis.

Adolescent↗
PubMed1997

Thyroid function in children with Cushing's disease before and after transsphenoidal surgery.

The degree of thyroid impairment and the effects on growth have not been investigated in children with Cushing's disease. We followed the thyroid function of 24 children and adolescents (12 males and 12 females) with CD (age, 12.9 +/- 3.2 years; mean +/- SD), who were successfully treated by transsphenoidal surgery. Patients were evaluated before, and 3, 6, and 12 months after TSS. Analysis of variance and linear correlation were performed between thyroid function tests and body weight and mass index and bone age. Preoperative free thyroxine levels (1.37 +/- 0.03 ng/dl) were significantly higher than those at 3 months (1.17 +/- 0.05 ng/dl, p < 0.05), but similar to those at 6 and 12 months postoperatively. Preoperative T3 (114.2 +/- 7.7 ng/dl) and TSH (1.36 +/- 0.2 IU/ml) were significantly lower than the postoperative values at 3 (158.9 +/- 6.8 and 2.3 +/- 0.3, respectively), 6 (159.1 +/- 10.8 and 2.5 +/- 0.3, respectively), and 12 months (136 +/- 6.5 and 2.2 +/- 0.3, respectively) (all p < 0.05). One patient had frank hypothyroidism (fT4 < 1 ng/dl) before surgery. Five additional patients had secondary hypothyroidism in the immediate postsurgical period; two of them had normal thyroid function 2 and 3 years postoperatively. One patient has remained hypothyroid for more than 5 years since surgery. No significant correlation was found between thyroid function and body weight, BMI, or BA. We conclude that hypothyroidism was an infrequent complication of CD and TSS. Mild suppression of thyroid function occurs in most children and adolescents with CD before and in the first few months after TSS, but it fully resolves after 6 months and does not correlate with the growth delay and obesity of these patients.

Adolescent↗
PubMed1997

Syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas (Carney complex): breast imaging findings.

PURPOSE: To study the imaging appearances of breast lesions in female patients with Carney complex. MATERIALS AND METHODS: Seven patients with Carney complex underwent mammography (n = 5), ultrasound (US) (n = 6), or magnetic resonance (MR) imaging (n = 6) in a prospective study. Previous breast images in three patients were reviewed. Mammograms in two additional patients were retrospectively reviewed. Thus, nine patients aged 16-61 were included in this study. RESULTS: Mammograms showed well-defined, iso- or hypodense masses; most were not calcified. Two lesions contained calcifications; both were biopsy-proved ductal adenomas. US demonstrated solid, hypoechoic, well-circumscribed masses in six patients and complex cystic masses (myxoid fibroadenomas) in one patient. MR imaging with a fat-suppressed, fast spin-echo, T2-weighted sequence demonstrated high-signal-intensity lesions (n = 5). Fat-suppressed, spoiled gradient-recalled-echo MR images demonstrated hypointense lesions with variable contrast material enhancement (n = 5). Five of seven patients in the prospective review had multiple breast lesions on at least one study. Mammograms and US scans were negative in three patients each. Chest and breast MR images were negative in only one patient. CONCLUSION: Female patients with Carney complex often have multiple breast masses with variable imaging appearances that probably represent myxoid fibroadenomas or ductal adenomas. MR imaging showed the most lesions. These lesions all demonstrate benign characteristics and should not prompt multiple biopsies.

Adolescent↗
PubMed1997

Rapid eye movement sleep correlates with the overall activities of the hypothalamic-pituitary-adrenal axis and sympathetic system in healthy humans.

To assess the association of the overall amount of rapid eye movement (REM) sleep and the activities of the hypothalamic-pituitary-adrenal axis and sympathetic system, we performed polysomnography and measured 24-h urinary free cortisol and catecholamine excretion in 21 healthy adults. After an adaptation night, each subject was recorded in the sleep laboratory for 3 consecutive nights while 24-h urine specimens were collected. Urinary free cortisol, epinephrine, dihydroxyphenylglycol, and dihydroxyphenylacetic acid levels were significantly and positively correlated with the average values of percent REM sleep (P < 0.05). There were no correlations between hormone values and REM latency, other variables of REM distribution, or REM density, an index of phasic activity during REM sleep. The positive correlations between stress system activity and REM sleep are consistent with hormonal and sleep alterations in melancholic depression, a state characterized by increased cortisol and catecholamine secretion.

Adult↗
PubMed1997

Primary pigmented nodular adrenocortical disease: reevaluation of a patient with carney complex 27 years after unilateral adrenalectomy.

A 45-yr-old man with primary pigmented nodular adrenocortical disease (PPNAD) is described. This patient underwent unilateral adrenalectomy for ACTH-independent Cushing's syndrome (CS) in 1969. Although his daily urinary free cortisol (UFC) excretion rate normalized, and the major clinical manifestations of CS subsided, loss of a circadian cortisol rhythm persisted after surgery. Twenty-seven years later, the patient presented again with short stature, severe osteopenia, skeletal deformities, thinning of the skin, and myopathy.

Adrenal Cortex Diseases↗
PubMed1997

Thyroid gland abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas (Carney complex)

Carney complex is a multiple neoplasia and lentiginosis syndrome that affects endocrine glands, including the pituitary, adrenals, and testes; thyroid gland involvement has not been unequivocally demonstrated. In the present study, the medical records of 12 families with Carney complex (53 affected patients) were reviewed for evidence of thyroid abnormality; 2 patients with thyroid carcinoma (1 papillary and 1 follicular; 3.8%) and 1 with follicular adenoma were identified in 3 unrelated kindreds. Six affected members of these kindreds were then screened for the presence of thyroid disease (familial cases). We also studied 5 patients with the complex who had no affected relatives (sporadic cases). These 11 patients consisted of 5 adults [mean age, 33.2 +/- 9.2 (+/- SD) yr] and 6 children and adolescents (mean age, 13.8 +/- 2.5 yr). All had normal results of physical and biochemical examination of the thyroid gland (total and free T4, T3, and TSH levels). Thyroid ultrasonography showed hypoechoic, cystic, solid, or mixed lesions in 3 of the 5 adults (60%) and 4 of the 6 children (67%). Two patients underwent fine needle aspiration biopsy, which identified follicular lesions. Thyroid gland abnormalities were documented in 5 siblings and 1 parent-child pair. We conclude that thyroid gland pathology is 1) common in patients with Carney complex; 2) includes a spectrum of abnormalities ranging from follicular hyperplasia and/or cystic changes to carcinoma; and 3) is inherited in an autosomal dominant manner, like the other manifestations of the syndrome, it is therefore, a candidate component of the syndrome. Ultrasonography is useful in the detection and clinical follow-up of these lesions.

Adenoma↗
PubMed1997

Segregation of Allgrove (triple-A) syndrome in Puerto Rican kindreds with chromosome 12 (12q13) polymorphic markers.

Allgrove syndrome (AS), also known as triple-A syndrome, is a rare cause of congenital adrenal insufficiency due to adrenocorticotropic hormone resistance. It is inherited in an autosomal recessive manner and is associated with achalasia, alacrima, and other neurological abnormalities, including autonomic, sensory, and upper- and lower-motor neuropathy, deafness, and mental retardation. Although the etiology of AS remains unknown, recently the disease was linked to a chromosome 12 locus (corresponding cytogenetic band 12q13) in consanguineous families of European ancestry. In the present study, we investigated four nonconsanguineous families with documented inheritance of AS for linkage with the reported 12q13 locus. Eighteen subjects were studied, of whom five were affected by AS. DNA was extracted from peripheral blood lymphocytes and amplified by standard methods with primers from polymorphic sequence tagged sites (STSs) located in the chromosome 12q13 region. Two-point logarithm-of-odds (LOD) score analysis revealed a maximum LOD score of 1.7 for STSs D12S361 and D12S368 without any recombinants [recombination distance (theta) = 0]. Multipoint linkage analysis defined an area of estimated genetic distance less than 0.5 cM (approximately 500,000 bp) between STSs D12S361 and D12S359 that is most likely to contain the AS gene(s). We conclude that, in Puerto Rican families, AS segregates with polymorphic markers that have been mapped to the chromosome 12q13 locus, revealing the absence of heterogeneity for this syndrome in a genetically distinct population. Candidate genes in the region include those that code for several of the keratin proteins, transcription factors, and others.

Abnormalities, Multiple↗
PubMed1996

Dopamine affects the in vitro basal secretion of rat placenta opioids in an opioid and dopamine receptor type-specific manner.

Opioid peptides and their receptors are present in the placenta of many species. Dopamine plays an important role in the regulation of opioid release in the nervous system and it may play a similar role in placenta since dopamine receptors are also present in this tissue. The aim of the present work was to examine the effect of dopamine on the basal release of rat placental opioids. The effect of several dopamine receptor agonists and antagonists was tested on the release of immunoreactive beta-endorphin and immunoreactive dynorphin from perfused rat placenta fragments. We found that dopamine and apomorphine stimulated the secretion of immunoreactive beta-endorphin in a dose-dependent manner. The selective D1 dopamine receptor agonist (+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride or SKF-38393 reproduced the effect of dopamine while the selective D1 dopamine receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl 1,2,3,4,5-tetrahydro-1 H-benzazepine hydrochloride or SCH-23390, prevented the dopamine- and SKF-38393-induced increase of immunoreactive beta-endorphin secretion. The selective and potent D2 dopamine receptor agonist (+/-)-2-(N-phenylethyl-N-propyl) amino-5-hydroxytetralin hydrochloride or PPHT had no effect on immunoreactive beta-endorphin. Finally, none of the agonists tested had any effect on the in vitro secretion of placental immunoreactive dynorphin. Our results suggest that dopamine affects the basal release of placental opioids in an opioid and dopamine receptor-specific manner, its effect being different from the effect it exerts on beta-endorphin in the rat neurointermediate pituitary lobe.

Animals↗
PubMed1996

Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2.

Carney complex is an autosomal dominant syndrome characterized by multiple neoplasias, including myxomas at various sites and endocrine tumors, and lentiginosis. The genetic defect(s) responsible for the complex remain(s) unknown. We studied 101 subjects, including 51 affected members, from 11 North American kindreds with Carney complex. Blood samples were collected from patients and their family members. Hospital records, photographs, and tissue specimens of deceased individuals were reviewed. DNA was extracted from blood samples, patient-derived cell lines, and/or paraffin-embedded tissues. Linkage analysis was performed with highly polymorphic microsatellite markers, distributed over areas of the human genome harboring the most likely candidate genes. The most prevalent clinical manifestation in patients with Carney complex was spotty skin pigmentation, similar to that observed in Peutz-Jeghers and other lentiginosis syndromes. Skin and cardiac myxomas, Cushing syndrome, and acromegaly were present in 62, 30, 31 and 8 percent of the patients, respectively. Linkage was obtained for three markers on the short arm of chromosome 2 (2p16), with a maximum two-point lod score of 5.97 at theta = 0.03 for the marker CA-2 (odds in favor of linkage 10(6):1. The flanking markers CA7 and D2S378 defined a region of approximately 6.4 cM that is likely to contain the gene(s) associated with Carney complex. Candidate genes in the proximity, including the propiomelanocortin and the DNA-mismatch repair hMSH2 genes, were excluded. We conclude that the genetic defect(s) responsible for Carney complex map(s) to the short arm of chromosome 2 (2p16). This region has exhibited cytogenetic aberrations in atrial myxomas associated with the complex, and has been characterized by microsatellite instability in human neoplasias.

Canada↗