Is interstitial 8p23 microdeletion responsible of 46,XY gonadal dysgenesis? One case report from birth to puberty.

BACKGROUND: Chromosome 8p deletions are associated with a variety of conditions, including cardiac abnormalities, mental, behavioral problems with variable morphotype and genitourinary anomalies in boys. METHODS: We describe the follow-up over almost 15 years of a boy who initially presented with perineal hypospadias with a micropenis and cryptorchidism with 46,XY DSD. RESULTS: Imaging, pathology, and hormonal exploration suggested gonadal dysgenesis. Further genetic studies were deemed necessary during follow-up. The child's further development recommended further genetic analyses. High-resolution analysis showed an interstitial deletion on the short arm of a chromosome 8: 46,XY,del(8)(p23.1p23.1). We reviewed the literature and found 102 cases including 54 boys: 62.7% had mental problems, 50.9% a dysmorphic disorder, 55.9% cardiac anomalies, and 46.3% of the boys had genitourinary anomalies. Our patient's genital abnormalities can be explained by the haploinsufficiency of the genes, such as GATA4 (OMIM 600576) that are included in the deleted area. CONCLUSION: This case of severe 46,XY DSD raises the question of the role played by 8p23 microdeletion in gonadal dysgenesis. Clinicians are encouraged to look for this anomaly on chromosome 8 in cases of unexplained gonadal dysgenesis even when few signs suggestive of this anomaly are present.

Endocrine Disrupting Chemicals Interfere With Leydig Cell Hormone Pathways During Testicular Descent in Idiopathic Cryptorchidism.

Cryptorchidism, a frequent genital malformation in male newborn, remains in most cases idiopathic. On the basis of experimental, epidemiological, and clinical data, it has been included in the testicular dysgenesis syndrome and believed to be influenced, together with genetic and anatomic factors, by maternal exposure to endocrine disrupting chemicals (EDCs). Here, we analyze how EDCs may interfere with the control of testicular descent, which is regulated by two Leydig cell hormones, testosterone, and insulin like peptide 3 (INSL3).

A negative correlation between insulin-like peptide 3 and bisphenol A in human cord blood suggests an effect of endocrine disruptors on testicular descent during fetal development.

STUDY QUESTION: Does a relationship exist between insulin-like peptide 3 (INSL3) and selected environmental endocrine disruptors (EEDs) in human cord blood (cb)? SUMMARY ANSWER: In the whole population (cryptorchid and control boys) cbINSL3 correlated negatively with cb free bisphenol A (BPA) providing indirect evidence for an impact of EEDs on fetal Leydig cell INSL3 production. WHAT IS KNOWN ALREADY: INSL3 is a major regulator of testicular descent. This hormone has been shown to be decreased in cord blood from boys with idiopathic cryptorchidism, the most frequent male malformation. Fetal exposure to several EEDs has been suspected to be involved in the occurrence of idiopathic cryptorchidism. STUDY DESIGN, SIZE, DURATION: Correlations between cb INSL3 or testosterone and cb free bioactive BPA and maternal milk polychlorinated biphenyls (PCB153), dichlorodiphenyldichloroethylene (DDE), and monobutyl phthalate (mBP) were assessed in newborn boys in a prospective case-control study. All boys (n = 6246) born after 34 weeks of gestation were systematically screened at birth for cryptorchidism over a 3-year period (2002-2005), and a diagnosis of cryptorchidism confirmed by a senior paediatrician. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied 52 cryptorchid (26 transient, 26 persistent) and 128 control boys born at two hospitals in southern France. INSL3 was assayed in CB by a modified validated enzyme-linked immunosorbent assay. Testosterone was measured in CB after diethyl-ether extraction by means of ultra-pressure liquid chromatography-tandem mass spectrometry. Free cbBPA was measured after an extraction step with a radioimmunoassay validated after comparison of values obtained by high-pressure liquid chromatography-mass spectrometry. The xenobiotic analysis in mothers' milk was performed after fat extraction by gas chromatography-mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE: EED concentrations were not increased in the cryptorchid versus control group although a trend for increased mBP (P = 0.09) was observed. In the whole study population, cb levels of BPA correlated negatively with INSL3 (P = 0.01; R² = 0.05) but not with testosterone. No other EED correlated with INSL3 or with testosterone. LIMITATIONS, REASONS FOR CAUTION: The levels of BPA and INSL3 in cb may not reflect chronic fetal exposure to EEDs. The deleterious impact of EEDs on fetal testicular descent during specific windows of development has yet to be demonstrated. WIDER IMPLICATIONS OF THE FINDINGS: The negative correlation between cb free BPA and INSL3 provides indirect evidence for an impact of EEDs on human fetal Leydig cell INSL3 production and points to cbINSL3 as a possible target of EED action during fetal testis development.

Cord blood insulin-like peptide 3 (INSL3) but not testosterone is reduced in idiopathic cryptorchidism.

BACKGROUND: Cryptorchidism, the most frequent congenital malformation in full-term male newborns, increases the risk of hypofertility and testicular cancer. Most cases remain idiopathic but epidemiological and experimental studies have suggested a role of both genetic and environmental factors. Physiological testicular descent is regulated by two major Leydig hormones: insulin-like peptide 3 (INSL3) and testosterone. OBJECTIVES: To study the endocrine context at birth as a reflection of late pregnancy in isolated idiopathic cryptorchidism and to analyse the possible disruptions of INSL3 and/or testosterone. METHODS: From a prospective case-control study at Nice University Hospital, we assessed 180 boys born after 34 weeks gestation: 52 cryptorchid (48 unilateral, 4 bilateral; 26 transient, 26 persistent), and 128 controls matched for term, weight and time of birth. INSL3 and testosterone were measured in cord blood and compared in both groups as were other components of the pituitary-gonadic axis: LH, HCG, FSH, AMH and SHBG. RESULTS: INSL3 was decreased in cryptorchid boys (P = 0·031), especially transient cryptorchid (P = 0·029), while testosterone was unchanged as were the other hormones measured. INSL3 was significantly decreased (P = 0·018) in the group of 20 with nonpalpable testes compared with the group of 21 with palpable testes (15 suprascrotal, five inguinal, one high scrotal) according to Scorer classification. In the whole population, INSL3 correlated positively with LH and negatively with AMH, but with no other measured hormones. CONCLUSIONS: INSL3 but not testosterone is decreased at birth in idiopathic cryptorchidism, especially in transient forms. This hormonal decrease may contribute to the impaired testicular descent along with genetic and anatomical factors. Whether foetal environment (nutritional and/or toxicological) interferes with INSL3 secretion in humans remains to be confirmed.

Delineation of a region responsible for panhypopituitarism in 20p11.2.

We report on the case of a young woman with a de novo 20p11.21p11.23 deletion, discovered by array-CGH. She has behavioral troubles with autistic traits, intellectual disability, panhypopituitarism, severe hypoglycemia, epilepsy, and scoliosis. The majority of the reported 20p deletions are located on the 20p12 region, covering the JAG1 gene responsible for the Alagille syndrome. More proximal deletions are even rarer, with very few cases described in the literature to date. The deletion carried by our patient is, to our knowledge, the smallest described de novo proximal 20p11.2 deletion. It was first discovered by 0.5 Mb BAC array-CGH, further delineated using an oligonucleotide array, and finally confirmed by fluorescence in situ hybridization. The deletion is 4.22 Mb in size, with the exact location on chr20: 19.810.034-24.031.344 (Feb. 2009, GRCh37/hg19). In light of the other reported cases that display genomic and phenotypic overlap with our patient, we discuss the phenotype of our patient, in order to further delineate the 20p proximal deletion phenotype. We propose a minimal critical region responsible for panhypopituitarism with global developmental delay, intellectual disability, scoliosis and facial dysmorphism. Moreover, considering the deleted genes, we highlight the impact of the deletion of this minimal critical region on the Shh signaling pathway.

Cord blood thyroid tests in boys born with and without cryptorchidism: correlations with birth parameters and in utero xenobiotics exposure.

BACKGROUND: In utero exposure to environmental chemicals can result in reproductive toxicity via endocrine disruption mechanisms. Whether some of those contaminants also have an impact on fetal thyroid function or pathways, and, thus, potentially on neuropsychological development, is still debated. METHODS: We used samples from a cord blood (CB) and milk bank, established for a research on cryptorchidism and xenobiotic exposure to compounds known for their anti-androgenic and/or estrogenic activity, to study CB thyroid tests and their correlation with CB and milk xenobiotics concentrations in boys born in Nice area. RESULTS: No difference was found in thyroid tests between 60 cryptorchid boys and 76 matched controls (median thyroid stimulating hormone 5.97 vs. 6.55 mUI/L, free thyroxine [fT4] 13.1 vs. 12.9 pmol/L, free triiodothyronine [fT3] 1.9 vs. 2.1 pmol/L), with no influence of season of birth, gestational age, maternal smoking, or mode of delivery (except for higher fT4 in control boys born vaginally). FT4 was correlated with fetal growth only in cryptorchid boys. Since we had previously shown differences between cryptorchid and controls exposure, we studied correlations of thyroid tests with xenobiotics in control boys only. All tested CB or maternal milk was contaminated by one or more selected xenobiotics, mainly polychlorinated biphenyls (PCBs), dichloro diphenyl dichloroethylène (DDE), dibutylphthalate, hexachlorobenzene, and bisphenol A. We found a significant negative correlation between fT4 and concentrations of PCB118, PC180, and DDE in milk (respectively r = -0.342, p < 0.03, r = -0.296, p = 0.031, r = -0.315, p = 0.016), persisting after adjustment for mode of delivery. There was a significant positive correlation of fT3 with milk concentrations of PCB138, PCB153, ΣPCB, and dibutylphthalate (respectively r = 0.31, p = 0.016, r = 0.28, p = 0.029; r = 0.34, p = 0.0079 and r = 0.272, p = 0.0295), with a trend for PCB180 (r = 0.259, p = 0.061). There was no correlation of thyroid stimulating hormone with any of the measured xenobiotics, except for a weak negative trend with CB bisphenol A (r = -0.25, p = 0.077). CONCLUSIONS: CB thyroid tests are within normal range in cryptorchid boys, similar to controls. Our data in controls suggest a possible weak correlation between in utero exposure to some xenobiotics (PCBs, DDE) and fT3 and fT4 CB concentrations, with usually negative correlations with fT4 and positive with fT3 concentrations, which we speculate could suggest an impact on deiodinases.

Exposure to selected endocrine disruptors and neonatal outcome of 86 healthy boys from Nice area (France).

In utero and lactational exposure to endocrine disruptors is thought to be potentially harmful on fetal and infant development. Data of exposure in France is scarce. This is a prospective study with (1) collection of 84 cord bloods (CB) and 69 milks from 86 mothers delivering healthy boys (gestational age >or= 34 weeks) at two maternity wards in Southern France, between 2002 and 2005 and (2) screening for 15 xenobiotics with anti-androgenic and/or estrogenic effects: DDE, 7 PCBs, dibutylphthalate and its metabolite mBP, HCB, lindane, linuron, procymidone and vinclozoline. Correlations were made with delivery and neonatal outcomes. All CB and milks were contaminated by one or more xenobiotics (mainly PCBs, DDE, HCB, and phthalates) with good correlation between CB and milk concentrations. Compared to other geographical areas, exposure was usually in the lower bracket. Milk [PCB180] was associated with lower birth weight. Infant head circumference correlated negatively with [HCB] and positively with [mBP] in CB. There was a similar but not significant trend for birth weight and length. [DDE] in milk was higher in older mothers and in women born in Africa. In utero and lactational exposure is ubiquitous in our area. Contamination of milk with HCB, mBP, and PCB 180 showed weak correlations with infant growth. This snapshot of exposure in an area with no major industry will serve for further monitoring.

Cryptorchidism at birth in Nice area (France) is associated with higher prenatal exposure to PCBs and DDE, as assessed by colostrum concentrations.

BACKGROUND: Since fetal exposure to anti-androgenic and/or estrogenic compounds has adverse effect on animal reproduction, such exposure could be harmful to human fetus. Data are scarce on cryptorchidism and human exposure to endocrine disruptors. METHODS: We performed a prospective case-control study to assess the incidence of cryptorchidism and fetal exposure to selected chemicals in the Nice area. One hundred and fifty-one cord bloods (67 cryptorchid, 84 tightly matched controls) and 125 colostrums (56 for cryptorchid and 69 for controls) were screened for xenobiotics, including anti-androgenic dichloro-diphenyl-trichloro-ethylene (DDE), polychlorinated biphenyls (PCBs), and dibutylphthalate (and metabolite monobutylphthalate, mBP). RESULTS: Median concentrations in colostrum were higher, although not statistically significantly, in cryptorchid versus controls. Cryptorchid boys were more likely to be classified in the most contaminated groups in colostrum for DDE, Sigma PCBs and the composite score PCB + DDE. The same trend, but again not statistically significantly was observed for mBP. Odds ratio for cryptorchidism was increased for the highest score of Sigma PCB, with a trend only for DDE and Sigma PCB + DDE versus the lowest score of those components. CONCLUSIONS: Our results support an association between congenital cryptorchidism and fetal exposure to PCBs and possibly DDE. Higher concentrations in milk could be a marker of higher exposure or for an impaired detoxification pattern in genetically predisposed individuals.