RESUMEN
Definitive neonatal diagnosis of congenital adrenal hyperplasia (CAH) is frequently complicated by normal 17-hydroxyprogesterone levels in 21-hydroxylase-deficient patients, residual maternal steroids, and other interfering substances in neonatal blood. In an effort to improve the diagnosis, we developed a gas chromatography/mass spectrometry method for simultaneous measurement of 15 urinary steroid metabolites as early as the first day of life. Furthermore, we developed 11 precursor/product ratios that diagnose and clearly differentiate the four enzymatic deficiencies that cause CAH. Random urine samples from 31 neonatal 21-hydroxylase-deficient patients and 59 age-matched normal newborns were used in the development. Additionally, samples from two 11 beta-hydroxylase-deficient patients and one patient each for 17 alpha-hydroxylase and 3 beta-hydroxysteroid dehydrogenase deficiencies were used. The throughput for one bench-top gas chromatography/mass spectrometry instrument is 20 samples per day. Thus, this method affords an accurate, rapid, noninvasive means for the differential diagnosis of CAH in the newborn period without the need for invasive testing and ACTH stimulation.
Asunto(s)
Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/orina , Cromatografía de Gases y Espectrometría de Masas , 17-alfa-Hidroxiprogesterona/análisis , 17-alfa-Hidroxiprogesterona/orina , 3-Hidroxiesteroide Deshidrogenasas/deficiencia , Diagnóstico Diferencial , Humanos , Recién Nacido , Tamizaje Masivo/métodosRESUMEN
INTRODUCTION: Hyperinsulinism associated with Beckwith-Wiedemann syndrome (BWS) can occur in about 50% of cases, causing hypoglycemia of variable severity. Parenteral use of octreotide may be indicated if unresponsive to diazoxide. There is limited data on use of octreotide in BWS. OBJECTIVE: Chart review describing 2 cases with BWS and hypoglycemia treated with long acting Octreotide as a monthly injection. CASES: We describe two unrelated females born large for gestational age found to have clinical features consistent with BWS, who developed severe hypoglycemia. Genetic diagnosis of BWS was confirmed. The first patient was born at 37 weeks and developed hypoglycemia shortly after birth. She was initially started on diazoxide but developed pulmonary congestion and was therefore switched to depot octreotide (LAR). She maintained euglycemia with LAR. In the second patient (born at 26-4/7 weeks), onset of hypoglycemia was delayed till 11 weeks of age due to hydrocortisone (indicated hemodynamically) and continuous feeding, and was partially responsive to diazoxide. She was switched to octreotide 4 times daily, treated till at age 18 months. Despite frequent feeds, she required treatment again between ages 4-6.5 years, initially with diazoxide but due to severe hypertrichosis she was switched to LAR with an excellent response. Both patients treated with LAR for over two years achieved euglycemia above 70 mg/dl and had normal height gain, without side effects. CONCLUSION: Successful treatment of hypoglycemia can be achieved and maintained with LAR in infants and children with BWS who are either resistant or cannot tolerate diazoxide.
RESUMEN
CONTEXT: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available. OBJECTIVE: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort. DESIGN: The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries. RESULTS: We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17α-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 18 46,XX and seven of 12 46,XY individuals. Homozygosity for p.A287P was invariably associated with 46,XX DSD but normal genitalia in 46,XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles. CONCLUSIONS: We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing.
Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , NADPH-Ferrihemoproteína Reductasa/genética , Adolescente , Hiperplasia Suprarrenal Congénita/orina , Insuficiencia Suprarrenal/genética , Insuficiencia Suprarrenal/metabolismo , Insuficiencia Suprarrenal/orina , Adulto , Niño , Estudios de Cohortes , Análisis Mutacional de ADN/métodos , Trastornos del Desarrollo Sexual , Femenino , Estudios de Asociación Genética , Genitales/anomalías , Hormonas Esteroides Gonadales/orina , Humanos , Masculino , Metaboloma , Modelos Biológicos , Modelos Moleculares , Reacción en Cadena de la Polimerasa Multiplex/métodos , NADPH-Ferrihemoproteína Reductasa/deficiencia , NADPH-Ferrihemoproteína Reductasa/fisiología , Adulto JovenAsunto(s)
Síndrome Metabólico , Síndrome del Ovario Poliquístico , Adolescente , Andrógenos/sangre , Glucemia/análisis , Presión Sanguínea , Femenino , Intolerancia a la Glucosa/diagnóstico , Humanos , Hiperinsulinismo , Hiperlipidemias , Insulina/sangre , Síndrome del Ovario Poliquístico/epidemiología , Síndrome del Ovario Poliquístico/etiología , Síndrome del Ovario Poliquístico/terapiaRESUMEN
Children were virilized by contact with adults using cutaneous steroid preparations. Parents were unaware of the dangers of passive transfer. Laboratory data were consistent with exogenous androgen exposure. Each child had opportunity for passive exposure, and discontinuation of contact resulted in a decrease of androgen levels or regression of symptoms.