Premature Breast Development Research Articles

Peak serum luteinising hormone cut-off during gonadotropin-releasing hormone analogue test for diagnosing central precocious puberty was lower in girls with obesity as compared with girls with normal weight.

Serum luteinising hormone (LH) concentration has been reported to be lower in girls with overweight and obesity (OW/OB) as compared with girls with normal weight (NW). This study aimed to evaluate peak serum LH concentration during gonadotropin-releasing hormone analogue (GnRHa) test in girls with OW/OB and NW who had central precocious puberty (CPP) and to determine peak serum LH cut-off for diagnosing CPP in girls with OW/OB. Medical records of 971 girls with premature breast development who underwent subcutaneous GnRHa (100 µgof triptorelin acetate) test were reviewed. All girls were classified as either CPP or premature thelarche. All of them were further classified into two groups according to their body mass index as NW and OW/OB groups for each Tanner stage. There were 634 and 337 girls in NW and OW/OB groups, respectively. CPP was diagnosed in 600 girls (249 had Tanner stage II and 351 had Tanner stage III). There were no differences in peak serum LH concentrations between CPP girls with NW and OW/OB. Peak serum LH cut-off of 5 IU/L (the current widely used cut-off) had a sensitivity and a specificity of 75% and 90%, respectively in NW group. Peak serum LH cut-off for CPP diagnosis was lower at 4 IU/L in the OW/OB group with greater sensitivity and specificity of 86% and 93%, respectively. The results were reproducible for each Tanner stage of breasts. Lower peak serum LH cut-off to 4 IU/L for diagnosing CPP in girls with OW/OB should be considered to avoid underdiagnosis of the condition.

THU197 Peripheral Precocious Puberty In A 6-year-old Girl With Extreme Estradiol Elevation With Rapid Normalization: A Case Report

Abstract Disclosure: L. Meller: None. M. Marinkovic: None. M.E. Patterson: None. Background: Peripheral precocious puberty (PPP) in girls is typically associated with ovarian or adrenal tumors, ovarian cysts, McCune-Albright syndrome (MAS), or exogenous hormone exposure. We present an unusual case of PPP with extreme estradiol elevation and rapid normalization. Clinical Case: A 6.5-year-old previously healthy girl presented with two-month history of bilateral breast growth and tenderness, associated with daily cramping. Subsequently, she developed clear, odorless vaginal discharge. Two days prior to the visit she started light vaginal bleeding. Parents denied any medication intake or use of lavender or essential oils. She had no family history of early puberty. On the exam, she was tall for her age (95%) with a recent growth spurt. She had breast buds (Tanner 2) and vaginal bleeding without pubic hair (Tanner 1) or signs of hyperandrogenemia. There were no skin lesions or gross bone abnormalities. Bone age was equal to chronological age. She had an extreme elevation of estradiol of 156pg/mL and 170pg/mL (reference range<=16pg/mL) measured two weeks apart with prepubertal LH/FSH. Thyroid tests were normal. Pelvic ultrasound and abdomen/pelvis CT showed no abnormalities of ovaries and adrenal glands. Nine days after the onset, vaginal bleeding and cramping spontaneously resolved. Estradiol levels measured two days after cessation of vaginal bleeding normalized (7pg/mL) while LH/FSH remained prepubertal. Interestingly, two weeks after the bleeding stopped her pelvic ultrasound showed significantly enlarged ovaries (R 4.1mL, L 4.3mL), while her estradiol remained normal (5pg/mL). Conclusion: We describe an unusual presentation of PPP in a young girl with extreme estradiol elevation causing simultaneous premature breast development and vaginal bleeding. We suspect PPP was secondary to ruptured ovarian cyst that was not captured by imaging. Other differentials include MAS, exogenous hormone exposure, adrenal or ovarian tumors. These were unlikely due to lack of abnormal skin or bone findings, environmental hormone exposure and normal imaging. Her ovarian enlargement could be secondary to high endogenous estrogen exposure, and she may be at risk of developing central precocious puberty. This unique case emphasizes the importance of prompt assessment of children with precocious puberty and discusses the differential diagnosis process for PPP with markedly elevated estradiol with rapid normalization. Presentation: Thursday, June 15, 2023

THU196 Insulin-like Growth Factor-1 As A Screening Tool For Central Precocious Puberty

Abstract Disclosure: L. Chung: None. M. Im: None. Gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard test for diagnosing central precocious puberty (CPP), which needs time and effort to perform. Recently, many studies confirmed that Insulin-like growth factor-1 (IGF-1) is involved in the initiation and progression of puberty. With this inspection, we assumed that the IGF-1 level might be correlated with the pubertal stage in central precocious puberty. This study aimed to investigate the value of IGF-1 levels in screening central precocious puberty. The medical records of 359 patients with a chief complaint of premature breast development and visited the pediatric endocrinology clinic in Myongji Hospital from January 2017 to October 2022 were reviewed. Two hundred thirty-three girls with central precocious puberty (CPP) and 126 girls with premature thelarche (PT) diagnosed were enrolled. Each subject had IGF-1 and GnRH stimulation test results. The anthropometric data between CPP and PT showed no statistical differences except for weight and the existence of lipomastia. The hormonal indicators including peak luteinizing hormone (peak LH), peak follicular stimulating hormone (peak FSH), and estradiol were statistically different between the two groups (P < 0.001). IGF-1 levels were significantly higher in CPP group than in PT group. The IGF-1 levels were positively correlated with peak LH, the diagnostic indicator of CPP. The area under the curve (AUC) of IGF-1 was 0.709. IGF-1 levels were correlated with the diagnostic indicator of CPP. IGF-1 would be a useful tool for screening CPP. Keywords: girls; IGF-1; GnRH stimulation test; precocious puberty. Presentation: Thursday, June 15, 2023

Combined diagnostic value of insulin-like growth factor-1, insulin-like growth factor binding protein-3, and baseline luteinizing hormone levels for central precocious puberty in girls.

The golden standard test for diagnosing central precocious puberty (CPP) is the gonadotropin releasing hormone stimulation test, which has many limitations. This study aimed to investigate the value of insulin-like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), and basal luteinizing hormone (LH) levels in diagnosing CPP. Cross-sectional study of the levels of IGF-1, IGFBP-3, and basal LH in girls with a chief complaint of premature breast development. Seventy-nine girls with CPP and 37 girls with premature thelarche (PT) diagnosed at West China Second University Hospital from January 2016 to October 2018 were recruited. All patients underwent physical examination, laboratory tests, uterine and ovarian ultrasound, and bone age tests, only CPP patients underwent pituitary magnetic resonance imaging (MRI). Statistical analysis was performed using the SPSS software 21.0. A receiver operating characteristic curve was used to determine diagnostic value. The anthropometric data and hormone indicators between CPP and PT were statistically different (p<0.001), except for peak follicle stimulating hormone (FSH) levels (p=0.181). IGF-1, IGFBP-3, and basal LH levels were significantly higher in the subjects with CPP than in those with PT; IGF-1 and basal LH were positively correlated with peak LH and LH/FSH (peak) (p<0.001). The area under the curve (AUC) of IGF-1, IGFBP-3, and basal LH were 0.880, 0.853, and 0.915, respectively. When combined, the AUC reached the highest value of 0.978. IGF-1, IGFBP-3, and baseline LH levels were useful in diagnosing CPP. The combined analysis improved the diagnostic effectiveness.

Fenilketonüri ve Puberte Prekoks Birlikteliği: Bir vaka sunumu

Phenylketonuria (PKU) is one of the most common preventable causes of intellectual disability resulting from deficiency of phenylalanine hydroxylase enzyme activity. Precocious puberty (PP) is characterized by premature breast and pubic hair development, and advanced bone age development before 8 years of age for girls and 9 years of age for boys. We present a 7 years old girl with phenylketonuria and overweight, who has developed early puberty. PKU was confirmed by plasma amino acid analysis at newborn.At the age of 7, the first signs of PP appeared (T3). Laboratory tests were detected as luteinizing hormone 0.36 mIU/mL; follicule stimulating hormone 1.1 mIU/mL; estradiol 20 pg/mL; and bone age was 9 years. The response to gonadotropin-releasing hormone stimulation test was characteristic for true PP (LH 5.4 mIU/mL; FSH 8 mIU/mL). According to our current knowledge, the reason for this union isn’t clear. However, this association may be incidental or secondary to overweight and may also be secondary to phenylketonuria - good / bad metabolic control. It’s thought that PP cases may be seen more frequently due to the increase of obesity frequency in PKU patients.

The prevalence of premature thelarche in girls and gynecomastia in boys and the associated factors in children in Southern China

BackgroundTo investigate the prevalence and risk factors of premature thelarche (PT) in girls and gynecomastia (GM) in boys in Southern China.MethodsWe conducted a cross-sectional study of preschool children across 9 cities in Zhejiang province. A total of 6273 children in the age-group of 2–7 years were recruited from January 2014 to March 2015. Relevant information was collected from mothers through face-to-face interviews. Logistic regression models were used to examine the correlates of PT and GM. Odds ratios (ORs) with 95% confidence intervals (CIs) are reported.ResultsThe prevalence of PT among girls was 4.8% and that of GM among boys was 0.8%. One hundred girls were diagnosed with PT before the age of 2 years; 69 (69.0%) of these girls experienced spontaneous resolution of PT. Twenty-four boys were diagnosed with GM before the age of 2 years; 10 (41.7%) of these experienced spontaneous resolution of GM. Children borne of mothers with early onset of menarche and those belonging to high-income families were at a higher risk of premature breast development. Greater consumption of eggs was associated with premature breast development in early childhood.ConclusionsSocioeconomic status of family, early onset of menarche in mother, and consumption of eggs were strongly associated with premature breast development in early childhood.

Prospective association between early adiposity rebound and adolescent development in girls

Objective: To determine possible relations between early adiposity rebound and adolescent development. Methods: Prospective children cohort from 2 kindergartens selected through clustering convenience sampling method in Anhui Province was established since Sep. 2010. Participants were classified as Cohort 1 (2010), Cohort 2 (2011) and Cohort 3 (2012) according to the recruiting year. Till Sep. 2015, a toal of 802 girls were included in this study, and received follow-up till primary school. During kindergarten period, physical examination was carried out every 3 months, 8 times in total. In primary school, physical examination was carried out annually; till Sep.2015, the cohort 1, 2, 3 took physical examination for 12, 11, 10 times, respectively. Information on household economic status and child physical activity was acquired through parents questionnaire survey, and breast development were assessed through visual inspection and palpation. Adiposity rebound was determined according to Rolland-Cachera's method for each girl. Differences between early adiposity rebound and normal adiposity rebound groups were compared by using t test and χ(2) test. Multivariate regression analysis was applied to explore the association between early adiposity rebound and breast development. Results: The average age of participants was (8.90±0.87) years old and the BMI was (17.48±2.70) kg/m(2). The average age at adiposity rebound was (6.16±0.90) years old and the BMI was (15.33±1.82) kg/m(2). Premature breast development was found significantly higher in girls in early adiposity rebound group (27.8%, 54/802) than it in normal adiposity rebound group (13.7%) (P<0.001). After current adiposity, age, household economic status, childhood physical activity adjusted, the OR of premature beast development in early adiposity rebound group was 2.41(95%CI: 1.41-4.12). Conclusion: Early adiposity rebound increases the risk of premature puberty in girls.

The Effect of Bisphenol A on Puberty: A Critical Review of the Medical Literature.

Many scientific studies have revealed a trend towards an earlier onset of puberty and have disclosed an increasing number of children that display precocious puberty. As an explanation, some authors have considered the global socio-economic improvement across different populations, and other authors have considered the action of endocrine disrupting chemicals (EDCs). Among these, bisphenol A (BPA), an aromatic compound largely used worldwide as a precursor of some plastics and chemical additives, is well known for its molecular oestrogen-like and obesogenic actions. We reviewed the medical literature of the previous 20 years that examined associations between BPA exposure and the age of puberty in humans, considering only those referring to clinical or epidemiological data. Of 19 studies, only 7 showed a correlation between BPA and puberty. In particular, the possible disruptive role of BPA on puberty may be seen in those with central precocious puberty or isolated premature breast development aged 2 months to 4 years old, even if the mechanism is undefined. Some studies also found a close relationship between urinary BPA, body weight, and early puberty, which can be explained by the obesogenic effect of BPA itself. The currently available data do not allow establishment of a clear role for BPA in pubertal development because of the conflicting results among all clinical and epidemiological studies examined. Further research is needed to fully understand the potential role of exposure to EDCs and their adverse endocrine health outcomes.

Precocious Puberty or Premature Thelarche: Analysis of a Large Patient Series in a Single Tertiary Center with Special Emphasis on 6- to 8-Year-Old Girls.

We describe the etiology, MRI findings, and growth patterns in girls who had presented with signs of precocious puberty (PP), i.e., premature breast development or early menarche. Special attention was paid to the diagnostic findings in 6- to 8-year-olds. We reviewed the medical records of 149 girls (aged 0.7-10.3 years) who had been evaluated for PP in the Helsinki University Hospital between 2001 and 2014. In 6- to 8-year-old girls, PP was most frequently caused by idiopathic gonadotropin-releasing hormone (GnRH)-dependent PP (60%) and premature thelarche (PT; 39%). The former subgroup grew faster (8.7 ± 2.0 cm/year, n = 58) than the girls with PT (7.0 ± 1.1 cm/year, n = 32) (P < 0.001), and the best discrimination for GnRH-dependent PP was achieved with a growth velocity cut-off value of 7.0 cm/year (sensitivity 92% and specificity 58%) [area under the curve 0.82, 95% confidence interval (CI) 0.73-0.91, P < 0.001]. Among asymptomatic and previously healthy 6- to 8-year-old girls with GnRH-dependent PP, one (1.7%, 95% CI 0.3-9.7%) had a pathological brain MRI finding requiring surgical intervention (craniopharyngioma). In girls younger than 3 years, the most frequent cause of breast development was PT, and, in 3- to 6-year-olds, GnRH-dependent PP. In 6- to 8-year-old girls, analysis of growth velocity is helpful in differentiating between PT and GnRH-dependent PP. Although the frequency of clinically relevant intracranial findings in previously healthy, asymptomatic 6- to 8-year-old girls was low, they can present without any signs or symptoms, which favors routine MRI imaging also in this age group.

The usefulness of the leuprolide stimulation test as a diagnostic method of idiopathic central precocious puberty in girls.

Central precocious puberty (CPP) diagnosis is based on clinical evaluation, but hormonal evaluation is crucial. The aim of the study was to evaluate the usefulness of the leuprolide stimulation test for diagnosis of idiopathic CPP. Sixty-one girls, aged 5-8 years, were evaluated retrospectively for premature breast development. According to clinical evolution, 28 had progressive puberty and 33 nonprogressive puberty. All underwent a leuprolide stimulation test. Cutoff points, sensitivity, and specificity for gonadotropins and estradiol were determined by receiver operating characteristic (ROC) curves. Cutoff points for CPP were: baseline LH: > 0.1 mUI/l, FSH: > 2.3 mUI/l, LH/FSH ratio: > 0.23, estradiol: > 12 pg/ml; and stimulated LH: > 5.5 mUI/l, LH/FSH ratio: > 0.24, estradiol: > 79.67 pg/ml. The best diagnostic efficiency for progressive puberty were stimulated LH/FSH ratio (sensitivity: 100%, specificity 94%) followed by stimulated LH (sensitivity: 93%, specificity: 100%). Stimulated LH/FSH ratio and LH resulted in the most useful parameters for the diagnosis of CPP. Stimulated estradiol did not add more information.

Increased serum estrogenic bioactivity in girls with premature thelarche: a marker of environmental pollutant exposure?

The aim of the work was to investigate the pathophysiology of isolated premature thelarche (IPT) by determining the impact of pre/postnatal exposure to endocrine disrupting chemicals (EDCs) through evaluation of total serum estrogenic bioactivity (EBA). The pathophysiology remains elusive, although recent investigations suggested the role of EDCs in premature female breast development. We investigated 15 girls with IPT. Plasma estradiol, follicle-stimulating hormone, and luteinizing hormone were measured in basal state and after gonadotropin-releasing hormone testing; bone age and uterine length were also assessed for all patients. Total EBA of patient serum was analyzed with an ultrasensitive bioassay that we previously developed and compared with that of 18 age-matched control girls. Parents were interviewed about their environmental/occupational exposure to EDCs during the patient’s prenatal/postnatal life. Nine families reported parental occupational/environmental EDCs exposure during prenatal/postnatal patient life; the mean total EBA found in these 9 IPT girls was significantly elevated (12.31 ± 6.64 pg/mL) in comparison with that of the 6 patients without exposure (2.53 ± 0.73 pg/mL) and the 18 age-matched controls (3.53 ± 2.23 pg/mL; p < 0.01). The significant increase in total EBA in these 9 girls with IPT suggests that premature female breast development may be related in some cases to higher pre/postnatal contamination by EDCs.

Report of the first case of precocious puberty in Rett syndrome

Rett syndrome is an X-linked dominant disorder frequently caused by the mutations in the methyl-CpG-binding protein 2 gene (MECP2). Its prevalence in the population is 1/15,000-20,000. Patients with Rett syndrome present apparently normal psychomotor developments during the first 6-18 months of life. Subsequently, they show a short period of developmental stagnation followed by a rapid regression in language and motor development. Precocious puberty is characterized by premature breast and pubic hair development, and advanced bone age development at 8 years of age. We present a case of Rett syndrome and precocious puberty in a 6-year-old girl. At the age of 6, the first signs of precocious puberty appeared (Tanner stage 3). Laboratory measurements were detected as follows: luteinizing hormone (LH), 0.2 mIU/mL; follicle-stimulating hormone (FSH), 1.1 mIU/mL; estradiol, 36 pg/mL; bone age, 9 years. The response to luteinizing hormone releasing hormone (gonadotropin-releasing hormone stimulation test) was characteristic for true precocious puberty (LH, 32 mIU/mL; FSH, 26 mIU/mL). This is the first reported case of precocious puberty related to Rett syndrome.

High diagnostic accuracy of subcutaneous Triptorelin test compared with GnRH test for diagnosing central precocious puberty in girls

The GnRH test is the gold standard to confirm the diagnosis of central precocious puberty (CPP); however, this compound is not always readily available. Diagnostic accuracy of subcutaneous GnRH analogues tests compared to classical GnRH test has not been reported. To evaluate the diagnostic accuracy of Triptorelin test (index test) compared to the GnRH test (reference test) in girls with suspicion of CPP. A prospective, case-control, randomized clinical trial was performed. CPP or precocious thelarche (PT) was diagnosed according to maximal LH response to GnRH test and clinical characteristics during follow-up. Forty-six girls with premature breast development randomly underwent two tests: (i) intravenous GnRH 100 μg, (ii) subcutaneous Triptorelin acetate (0.1 mg/m(2), to a maximum of 0.1 mg) with blood sampling at 0, 3 and 24 h for LH, FSH and estradiol ascertainment. Gonadotrophins and estradiol responses to Triptorelin test were measured by ultrasensitive assays. Clinical features were similar between CPP (n = 33) and PT (n = 13) groups. Using receiver operating characteristic curves, maximal LH response (LH-3 h) under Triptorelin test ≥ 7 IU/l by immunofluorometric assay (IFMA) or ≥ 8 IU/l by electrochemiluminescence immunoassay (ECLIA) confirmed the diagnosis of CPP with specificity of 1.00 (95% CI: 0.75-1.00) and sensitivity 0.76 (95% CI: 0.58-0.89). Considering either LH-3 h or maximal estradiol response at 24 h (cut-off value, 295 pm), maintaining the specificity at 1.00, the test sensitivity increased to 0.94 (95% CI: 0.80-0.99) and the diagnostic efficiency to 96%. The Triptorelin test had high accuracy for the differential diagnosis of CPP vs PT in girls providing a valid alternative to the classical GnRH test. This test also allowed a comprehensive evaluation of the pituitary-ovarian axis.

Effects of pesticides used in agriculture on the development of precocious puberty

The present study aims to evaluate the effects of pesticides on premature breast development. Forty-five girls (group 1) with premature breast development living in the Menderes region, where greenhouse cultivation is the main income, 16 girls (group 2) living in Izmir city with early puberty, and 33 girls (group 3) who had no signs of puberty were included in the study. Endosulphan 1, endosulphan 2, endosulphan sulphate, methoxychlor, vinclozolin, 4,4-dichlorodiphenyldichlorethylene (DDE), 4,-dichlorodiphenyltrichloroethane (DDT), and 2,4-DDT were evaluated in the serum and adipose tissues of the groups by using a gas chromatography-mass spectrometry method. With the exception of 4,4'-DDE, the pesticides studied were undetectable in the serum and adipose tissue samples. The levels of basal luteinizing hormone (LH), stimulated LH, follicle-stimulating hormone, and the long axis of the uterus and both ovaries were significantly different in the girls who had premature thelarche and detectable 4,4'-DDE levels compared to the girls who had premature thelarche and undetectable 4,4'-DDE levels in serum and adipose tissues. The presence and levels of pesticides in serum and adipose tissues were not related to precocious puberty (PP). The mechanisms that lead to PP may also result in obesity, and obesity may be the underlying cause for PP in this group.

Deletions flanked by breakpoints 3 and 4 on 15q13 may contribute to abnormal phenotypes

Non-allelic homologous recombination (NAHR) between segmental duplications in proximal chromosome 15q breakpoint (BP) regions can lead to microdeletions and microduplications. Several individuals with deletions flanked by BP3 and BP4 on 15q13, immediately distal to, and not including the Prader-Willi/Angelman syndrome (PW/AS) critical region and proximal to the BP4-BP5 15q13.3 microdeletion syndrome region, have been reported; however, because the deletion has also been found in normal relatives, the significance of these alterations is unclear. We have identified six individuals with deletions limited to the BP3-BP4 interval and an additional four individuals with deletions of the BP3-BP5 interval from 34 046 samples submitted for clinical testing by microarray-based comparative genomic hybridization (aCGH). Of four individuals with BP3-BP4 deletions for whom parental testing was conducted, two were apparently de novo and two were maternally inherited. A comparison of clinical features, available for five individuals in our study (four with deletions within BP3-BP4 and one with a BP3-BP5 deletion), with those in the literature show common features of short stature and/or failure to thrive, microcephaly, hypotonia, and premature breast development in some individuals. Although the BP3-BP4 deletion does not yet demonstrate statistically significant enrichment in abnormal populations compared with control populations, the presence of common clinical features among probands and the presence of genes with roles in development and nervous system function in the deletion region suggest that this deletion may have a role in abnormal phenotypes in some individuals.

Non-Peutz-Jeghers syndrome associated ovarian sex cord tumor with annular tubules: a case report

Sex cord tumors with annular tubules (SCTAT) are a rare subtype of sex cord stromal tumor of the ovary. An evidence-based management plan with follow-up evaluations is difficult to outline because of the rarity of these tumors. We describe the case of a premenarcheal patient with a SCTAT. Case report. The patient was encountered during routine patient care process. The patient presented with a pelvic mass and precocious puberty. Her condition was diagnosed as SCTAT. Her clinical presentation was consistent with an estrogen-secreting tumor, resulting in early menarche and premature breast development. Inhibin and estradiol levels were markedly elevated preoperatively and normalized 5 weeks after surgical removal of the tumor. The preoperative computed tomography scan demonstrated a 12-cm abdominopelvic mass, which appeared to be mostly cystic. The patient was treated surgically. She underwent laparotomy, right salpingo-oophorectomy, ipsilateral pelvic and paraaortic lymph node sampling, and partial omentectomy. Peritoneal biopsy samples were obtained from the abdomen and pelvis. The patient did well postoperatively. She is being observed with serial examinations and serum inhibin measurements. Normalization of serum estradiol and inhibin along with cessation of menstruation were seen 5 weeks postoperatively, with persistence of morphologic signs of precocious puberty and advanced bone age at 11 months after the diagnosis. The diagnosis of SCTAT was established on final pathology examination based on morphologic features of the tumor microscopically and the marker expression profile on immunohistochemistry. Primary management was surgical.

Management of Benign Tumors of the Adolescent Breast

After studying this article, the participant should be able to: 1. Describe the differential diagnosis of breast tumors in adolescent girls. 2. Compare and contrast surgical options for the management of adolescent breast tumors. 3. Recognize the utility of a reduction mammaplasty technique when resecting these larger tumors in adolescents. Although 99 percent of breast lesions in female adolescents are benign tumors, surgical intervention is commonly required. This article reviews the differential diagnosis, evaluation, and management of these benign tumors. A modified surgical technique for resection of large fibroadenomas and reconstruction of the remaining breast is described. The authors review the approach to five specific breast lesions: fibroadenomas, phyllodes tumors, juvenile hypertrophy, inflammatory processes, and premature breast development.

Regional rearrangements in chromosome 15q21 cause formation of cryptic promoters for the CYP19 (aromatase) gene

Production of appropriate quantities of estrogen in various tissues is essential for human physiology. A single gene (CYP19), regulated via tissue-specific promoters, encodes the enzyme aromatase, which catalyzes the key step in estrogen biosynthesis. Aromatase excess syndrome is inherited as autosomal dominant and characterized by high systemic estrogen levels, short stature, prepubertal gynecomastia and testicular failure in males, and premature breast development and uterine pathology in females. The underlying genetic mechanism is poorly understood. Here, we characterize five distinct heterozygous rearrangements responsible for aromatase excess syndrome in three unrelated families and two individuals (nine patients). The constitutively active promoter of one of five ubiquitously expressed genes located within the 11.2 Mb region telomeric to the CYP19 gene in chromosome 15q21 cryptically upregulated aromatase expression in several tissues. Four distinct inversions reversed the transcriptional direction of the promoter of a gene (CGNL1, TMOD3, MAPK6 or TLN2), placing it upstream of the CYP19 coding region in the opposite strand, whereas a deletion moved the promoter of a fifth gene (DMXL2), normally transcribed from the same strand, closer to CYP19. The proximal breakpoints of inversions were located 17-185 kb upstream of the CYP19 coding region. Sequences at the breakpoints suggested that the inversions were caused by intrachromosomal nonhomologous recombination. Splicing the untranslated exon downstream of each promoter onto the identical junction upstream of the translation initiation site created CYP19 mRNA encoding functional aromatase protein. Taken together, small rearrangements may create cryptic promoters that direct inappropriate transcription of CYP19 or other critical genes.

Polycyclic aromatic hydrocarbons (PAHs), organic matter quality and meiofauna in Galician sandy beaches, 6 months after the Prestige oil-spill

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Inhalation and ingestion of phthalate compounds from use of synthetic modeling clays.

Phthalate esters, including di-2-ethylhexyl phthalate (DEHP), benzylbutyl phthalate (BBP) and di-n-octyl phthalate (DNOP), are plasticizers used to soften polyvinyl chloride (PVC). This PVC is used for many household items such as flooring, shower curtains, medical devices, food packaging, and toys. Phthalates have been the focus of numerous studies that aim to assess their potential to cause birth defects and/or reproductive abnormalities. Animal experiments have indicated that low exposures to phthalates have the potential to alter the organs that produce and deliver sperm, and phthalates also exhibit adverse effects on other organs and systems (Raloff 2000b). Ema and Miyawaki (2002) demonstrated that the phthalate, BBP, causes adverse effects on the development of the reproductive system in male rats. Phthalates have also been shown to cause thelarche, premature breast development, in young girls aged 6 to 24 months. In a study conducted in San Juan, Puerto Rico, 41 girls with thelarche and 35 girls with normal development were tested to find possible reasons for the premature development. About 68% of the girls with thelarche had detectable phthalate levels, opposed to only 17% of the girls with normal development (Raloff 2000a). The results of studies like these prompted the Environmental Protection Agency to establish a drinking water standard for the phthalate, DEHP, of6.0 ppb in 1994 (USEPA 2002), and DEHP has been labeled as a "probable human carcinogen" for over a decade (USEPA 1993). Children and infants are likely to experience phthalate exposure when mouthing, sucking, or chewing on toys or other objects that contain phthalates (Shea 2003). When children suck on teethers or old pacifiers made of soft PVC, the phthalates are released from the PVC and into the child's saliva. Although the European Union put a temporary ban on phthalate softeners in baby toys, so far, no limits have been put in place for phthalate content in toys or other products in the United States (Christen