Objective When diabetes is associated with congenital malformations, without autoimmune antibodies, a genetic cause is suspected. Here, we aimed to identify a defective gene that led to diabetes. Research Design and Methods We performed an exome analysis of an index case and his healthy parents. Results The child presented with childhood‐onset diabetes, congenital hypopituitarism, cardiac malformation, and anal atresia. A DNA analysis revealed a heterozygous de novo pathogenic variant in the developmental transcription factor, forkhead box A2 (FOXA2). The mutation resided in the DNA‐binding domain, which is highly conserved among species. Tridimensional molecular dynamics simulation modeling predicted an altered interaction between the mutated protein and DNA. Conclusions A defect in the FOXA2 DNA‐binding domain was associated with childhood‐onset diabetes and multiple congenital anomalies, which reflected the pleiotropic nature of the gene. This report extends the recently described phenotype of neonatal hypoglycemia to later‐onset diabetes. We suggest to include FOXA2 analysis for neonatal hypoglycemia and to implement a long‐term follow‐up, particularly for the risk of diabetes.
13,14-Dihydro-15-keto-prostaglandin F2α (13,14-DHK-PGF2α) represents a stable product of degradation after pulmonary flow and it is shown to be reliably measured by radioimmunoassay. In patients with urogenital tumors, serum levels of 13,14-DHK-PGF2α are distinctly elevated when compared to a control group. The rate of synthesis of this compound in urogenital tumors, however, appears to be different.
Congenital adrenal hyperplasia (CAH) is one of the most frequent autosomal recessive diseases in Europe. Treatment is a challenge for pediatric endocrinologists. Important parameters to judge the outcome are adult height and menstrual cycle. We report the follow-up from birth to adulthood of two Caucasian sisters with salt-wasting CAH due to the same mutation, homozygosity c.290-13A>G (I2 splice), in the 21-hydroxylase gene. Their adherence to treatment was excellent. Our objective was to distinguish the effects of treatment with hydrocortisone (HC) and fludrocortisone (FC) on final height (FH) from constitutional factors. The older girl (patient 1), who showed virilized genitalia Prader scale III–IV at birth, reached FH within familial target height at 18 years of age. Menarche occurred at the age of 15. Her menstrual cycles were always irregular. Total pubertal growth was normal (29 cm). She showed a growth pattern consistent with constitutional delay. The younger sister (patient 2) was born without masculinization of the genitalia after her mother was treated with dexamethasone starting in the fourth week of pregnancy. She reached FH at 16 years of age. Her adult height is slightly below familial target height. Menarche occurred at the age of 12.5, followed by regular menses. Total pubertal growth was normal (21 cm). The average dose of HC from birth to FH was 16.7 mg/m2 in patient 1 and 16.8 mg/m2 in patient 2. They received FC once a day in doses from 0.05 to 0.1 mg. Under such therapy, growth velocity was normal starting from the age of 2.5 years with an overall average of +0.2 SD in patient 1 and −0.1 SD in patient 2, androstenedione levels were always within normal age range. Similarly, BMI and blood pressure were always normal, no acne and no hirsutism ever appeared. In conclusion, two siblings with the same genetic form of 21-hydroxylase deficiency and excellent adherence to medication showed different growth and menstrual cycle patterns, rather related to constitutional factors than to underlying CAH. In addition, the second patient represents an example of successful in utero glucocorticoid treatment to prevent virilization of the external genitalia.
DAX-1 mutation must be considered when diagnosis of primary adrenocortical insufficiency is made, especially if there is a history of unexplained death of maternal male relatives.
Objective. -Steroidogenic factor 1 (SF-1/NR5A1) plays a crucial role in regulating adrenal development, gonad determination and differentiation, and in the hypothalamic-pituitary control of reproduction and metabolism. In men (46, XY), it is known that mutations in SF-1/NR5A1 gene cause a wide phenotypic spectrum with variable degrees of undervirilization. In recent years, the role of SF-1 in the ovarian function was increasingly discussed and alterations in the gene were related to primary ovarian insufficiency. We describe the follow-up of a 46, XX affected woman with a SF-1 mutation and by comparing our case with the known manifestations reported in the literature, we try to further elucidate the function of SF-1 in the ovary. Results. -During infancy, adrenal insufficiency was the only clinical sign of the loss-of-function as ovarian development and function seemed normal. To date, this young woman aged 16.5 years shows normal growth, normal BMI and psychomotor development, has a normal puberty and regular menstruation. Conclusion. -This report shows one, to date uniquely described, phenotypic variant of SF-1 mutation in a 46, XX affected person with adrenocortical insufficiency but no ovarian dysfunction nor disturbance of pubertal development. To follow the natural history of SF-1 mutation in a 46, XX individual will further shed light on its role in the ovarian function and thus will help to counsel affected patients in future.Keywords: Steroidogenic factor 1; Adrenal insufficiency; Primary ovarian insufficiency; Disorder of sexual development RésuméObjectif. -Le facteur 1 stéroïdogénique (SF-1/NR5A1) joue un rôle critique dans la régulation du développement des surrénales, la détermination et différentiation des gonades ainsi que dans le contrôle hypothalamo-pituitaire de la reproduction et du métabolisme. Chez les hommes (46, XY), il est connu que les mutations du gène SF-1 peuvent entraîner de multiples phénotypes avec différents degrés d'impubérisme. Durant les dernières années, l'influence de SF-1 sur la fonction ovarienne a été étudié et les altérations de ce gène ont été mises en relation avec l'insuffisance ovarienne primaire. Nous décrivons le suivi d'une femme 46, XX porteuse d'une mutation du gène SF-1 et nous comparons notre cas clinique avec ceux de la littérature afin d'éclaircir l'influence du gène SF-1 sur la fonction ovarienne. Résultats. -Durant l'enfance, une insuffisance des surrénales fut le seul signe clinique de cette mutation, le développement des ovaires ainsi que leurs fonctions semblèrent alors normales. Actuellement cette adolescente de 16 ans a une croissance, un indice de masse corporelle et un développement psychomoteur normal, une puberté normale ainsi que des menstruations régulières. Conclusion. -Cette étude décrit une variante phénotypique, d'une personne 46, XX, atteinte d'une affection de SF-1 avec insuffisance surrénale mais sans dysfonctionnement ovarien ni perturbation de la puberté. Cette observation nous offre une opportunité unique de suivre l'histoire na...
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