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PURPOSE: Fetal anomalies represent a poorly studied group of developmental disorders. Our objective was to assess the impact of whole-exome sequencing (WES) on the investigation of these anomalies. METHODS: We performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies, including renal a/dysgenesis, VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities), brain anomalies, suspected ciliopathies, multiple major malformations, and akinesia. RESULTS: A molecular diagnosis was obtained in 19 cases (19%). In 13 of these cases, the diagnosis was not initially suspected by the clinicians because the phenotype was nonspecific or atypical, corresponding in some cases to the severe end of the spectrum of a known disease (e.g., MNX1-, RYR1-, or TUBB-related disorders). In addition, we identified likely pathogenic variants in genes (DSTYK, ACTB, and HIVEP2) previously associated with phenotypes that were substantially different from those found in our cases. Finally, we identified variants in novel candidate genes that were associated with perinatal lethality, including de novo mutations in GREB1L in two cases with bilateral renal agenesis, which represents a significant enrichment of such mutations in our cohort. CONCLUSION: Our study opens a window on the distinctive genetic landscape associated with fetal anomalies and highlights the power-but also the challenges-of WES in prenatal diagnosis.
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Anomalías Congénitas/genética , Feto/anomalías , Enfermedades Renales/congénito , Riñón/anomalías , Proteínas de Neoplasias/genética , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Adulto , Canal Anal/anomalías , Esófago/anomalías , Familia , Femenino , Feto/patología , Genómica , Genotipo , Cardiopatías Congénitas/genética , Humanos , Hidrocefalia/genética , Enfermedades Renales/genética , Deformidades Congénitas de las Extremidades/genética , Masculino , Mutación , Fenotipo , Embarazo , Diagnóstico Prenatal/métodos , Columna Vertebral/anomalías , Mortinato/genética , Tráquea/anomalías , Fístula Traqueoesofágica/genética , Anomalías Urogenitales/genética , Secuenciación del Exoma/métodosRESUMEN
An 11-month-old girl with severe acidosis, lethargy and vomiting, was diagnosed with holocarboxylase synthetase deficiency. She received biotin and was stable until age 8 years when vomiting, severe acidosis, hypoglycemia, and hyperammonemia developed. Management with intravenous glucose aiming to stimulate anabolism led to hyperglycemic ketoacidosis. Insulin therapy rapidly corrected biochemical parameters, and clinical status improved. We propose that secondary Krebs cycle disturbances affecting pancreatic beta cells impaired glucose-stimulated insulin secretion, resulting in insulinopenia.
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We know that glutaric aciduria type II is an inborn metabolism. This case report highlights that polycystic kidneys with hepatomegaly in prenatal ultrasound are suggestive of glutaric aciduria type II and it identifies a new variant as pathogenic.
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BACKGROUND: Disruptions in hypothalamic-gonadal and other endocrine axes due to energy deficits are associated with low levels of the adipocyte-secreted hormone leptin and may result in hypothalamic amenorrhea. We hypothesized that exogenous recombinant leptin replacement would improve reproductive and neuroendocrine function in women with hypothalamic amenorrhea. METHODS: Eight women with hypothalamic amenorrhea due to strenuous exercise or low weight were studied for one month before receiving recombinant human leptin and then while receiving treatment for up to three months. Six control subjects with hypothalamic amenorrhea received no treatment and were studied for a mean (+/-SD) of 8.5+/-8.1 months. RESULTS: Luteinizing hormone (LH) pulsatility, body weight, ovarian variables, and hormone levels did not change significantly over time in the controls and during a one-month control period before recombinant leptin therapy in the treated subjects. In contrast, recombinant leptin treatment increased mean LH levels and LH pulse frequency after two weeks and increased maximal follicular diameter, the number of dominant follicles, ovarian volume, and estradiol levels over a period of three months. Three patients had an ovulatory menstrual cycle (P<0.05 for the comparison with an expected rate of spontaneous ovulation of 10 percent); two others had preovulatory follicular development and withdrawal bleeding during treatment (P<0.05). Recombinant leptin significantly increased levels of free triiodothyronine, free thyroxine, insulin-like growth factor 1, insulin-like growth factor-binding protein 3, bone alkaline phosphatase, and osteocalcin but not cortisol, corticotropin, or urinary N-telopeptide. CONCLUSIONS: Leptin administration for the relative leptin deficiency in women with hypothalamic amenorrhea appears to improve reproductive, thyroid, and growth hormone axes and markers of bone formation, suggesting that leptin, a peripheral signal reflecting the adequacy of energy stores, is required for normal reproductive and neuroendocrine function.
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Amenorrea/tratamiento farmacológico , Enfermedades Hipotalámicas/tratamiento farmacológico , Leptina/análogos & derivados , Leptina/deficiencia , Leptina/uso terapéutico , Adulto , Fosfatasa Alcalina/sangre , Amenorrea/etiología , Amenorrea/metabolismo , Anovulación/tratamiento farmacológico , Anovulación/etiología , Composición Corporal , Remodelación Ósea/efectos de los fármacos , Colágeno/orina , Colágeno Tipo I , Ejercicio Físico , Femenino , Hormonas/sangre , Humanos , Enfermedades Hipotalámicas/etiología , Enfermedades Hipotalámicas/metabolismo , Leptina/farmacología , Osteocalcina/sangre , Péptidos/orina , Estudios Prospectivos , Delgadez/complicacionesRESUMEN
Circulating levels of adiponectin, a hormone with insulin-sensitizing properties, are decreased in conditions related to obesity and hyperinsulinemia, which are recognized risk factors for endometrial cancer. Eighty-seven cases with incident, histologically confirmed endometrial cancer and 132 controls admitted for acute, nonneoplastic diseases were interviewed in northeastern Italy between 1999 and 2002, and blood samples were collected. Levels of adiponectin were evaluated in samples by means of a RIA. An inverse association with endometrial cancer risk emerged for plasma adiponectin levels [odds ratio (OR), 0.42; 95% confidence interval, 0.19-0.94] when comparing the highest vs. the lowest tertiles. Similar results emerged for serum adiponectin (OR, 0.30; 95% confidence interval, 0.14-0.68). The association was stronger in pre- than in postmenopausal women, but no significant heterogeneity was observed across strata of body mass index (BMI) or parity. BMI and adiponectin showed independent effects on the risk of endometrial cancer according to a multiplicative model (OR, 6.45 in the highest level of BMI and in the lowest one of adiponectin).
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Neoplasias Endometriales/sangre , Neoplasias Endometriales/epidemiología , Péptidos y Proteínas de Señalización Intercelular , Proteínas/metabolismo , Adiponectina , Adulto , Anciano , Índice de Masa Corporal , Femenino , Humanos , Persona de Mediana Edad , Plasma , Factores de Riesgo , SueroRESUMEN
N-carbamylglutamate (NCG) has been reported to decrease ammonia levels in patients with propionic aciduria (PA) and methylmalonic aciduria (MMA), but reports on clinical outcomes remain scant. Here, we report a retrospective series of four patients with neonatal PA treated with NCG at presentation. Patients presented between 2 and 9 days of age and peak plasma ammonia ranged from 524 to 1,572 µM. Patients received bolus (30-200 mg/kg) and sustaining (115-300 mg/kg per day) doses of NCG in addition to a standard treatment regimen that included ammonia scavenger drugs. Ammonia levels decreased significantly in three of the four cases within 2 h after administration of NCG and fell below 100 µM in all within 12-29 h. Two patients received NCG (bolus 200 mg/kg) while ammonia was above 500 µM (740 and 1,572) and their levels fell below 500 µM by 4 and 8 h post-treatment, respectively. Outcomes of these NGC-treated patients were not improved over previously reported PA patients who did not receive NCG: two died during the initial episode and one after his third metabolic decompensation at 46 days. The survivor is now 3 years old and has a well-controlled seizure disorder and a mild developmental delay mostly in language. We conclude that despite a trial of NCG and a rapid fall in plasma ammonia, the short-term outcome of these patients was not improved.