Background: Adrenal hypoplasia congenita (AHC) is a rare disease (1:70.000 men) characterized by reduction in all cortical adrenal hormones and also by hypogonadism. NR0B1 -related AHC includes both X-linked AHC and Xp21 deletion. AHC gene mutation was first described in 1994 and occurs in less than 1% of adrenal insufficiency (AI) cases and it is imperative that clinical endocrinologists increase their knowledge on this condition to recognize it as promptly as they were used to do so in other causes of pediatric AI.Clinical Cases: We describe here two sporadic cases and three familial cases from one family, all of them attending at our Endocrine Unit at HCPA, in the South of Brazil. The median age of AI first symptoms was 1 month old in two patients (acute infantile onset due to a salt wasting crises), and eleven years old in the remaining patients (childhood onset). Their exams confirmed the clinical suspicion of primary AI because of low plasma cortisol (from < 0.5 to 4 mcg/dl - reference range from 7-24 mcg/dl), as well as all adrenal steroids levels, high ACTH levels (from 672 to 2225 pg/ml - reference range from 7-63 pg/ml) and high plasmatic renin (from 92 to 448 mcUI/ml - reference range from 2.8-39.9 mcUI/ml). They were also extensively investigated searching for the AI pathophysiology. After some years of lost follow-up, one of the familial cases that had first been seen in 1993, returned to our hospital and was diagnosed with hypogonadism, leading to NR5OB1 gene evaluation.Regarding the genetic etiology, one of the sporadic cases developed a clinical picture including profound developmental delay, seizures and strabismus suggestive of a contiguous gene syndrome that involves Duchenne muscular dystrophy, glycerol kinase deficiency and AHC. A CGH array was performed and identified a Xp21.3-p21.1 deletion. The affected family had an extensive history suggestive of a genetic disease with X-linked inheritance pattern, as shown by the premature death of 3 uncles and a male cousin. A deleterious variant (c.131_212delinsTGAGACCTGTACCGT) in NR5OB1 gene was identified by Sanger sequencing in hemizygous state in the 46,XY affected patients.Conclusion: Albeit a rare disease, it is crucial that endocrinologist all around the World could be aware about clinical characteristics of this condition in order to properly diagnose it. And it is even possible, as it occurred with one of our patient, to make a late pathophysiologic diagnosis, making possible to treat the associated hypogonadism. Reference: Acherman JC, Vilain EJ. NR0B1- related adrenal hypoplasia congenita. GeneReviews 1993-2019.
Pelvic ultrasonography (US) is a quick, non-invasive and low-cost method, and doppler analysis facilitates assessment of flow impedance measurement in the uterine vascular tree. The pulsatility index (PI) reflects blood flow impedance in the vessel distal to the sampling point and has been suggested as a parameter to define pubertal development. In order to evaluate the PI and US measurements of uterus and ovaries in girls with different pubertal stages, we performed a cross-sectional study in girls with normal pubertal development. US and Doppler assessed PI of the uterine arteries (defined as the difference between the peak systolic flow and end-diastolic flow divided by the mean maximum flow velocity), endometrial thickness, uterine and ovarian volumes were evaluated. All the US exams were performed with the same equipment by the same radiologist. Clinical data such as the age of menarche, pubarche and thelarche were recorded. Statistical analyses were performed in SPSS, with ANOVA test, Spearman correlation and ROC curve with Youden. One hundred and sixty-nine girls aged 5-16 years (mean 11.3 ± 1.8) who performed two hundred and two pelvic US were included (Tanner 1=20%, Tanner 2=22%, Tanner 3=23%, Tanner 4=17%, Tanner 5=17%). Mean age of thelarche, pubarche and menarche were 11.1 ± 1.8, 10.2 ± 1.2 and 12.2 ± 1.1 years respectively. Prepubertal girls (Tanner 1) had mean PI significantly higher than girls in initial puberty (Tanner 2 and 3 grouped) and in late puberty (Tanner 4 and 5 grouped), respectively 6.5 ± 2.27 vs. 4.15 ± 1.55 vs. 2.82 ± 1.06, p<0.001 for all the comparisons. ROC curve analysis demonstrated that the PI is able to identify the onset of puberty with an area under the curve of 0.80 ± 0.04, P<0.001, and a cutoff point of IP=5.05 presented a sensitivity of 0.77 and a specificity of 0.80 to identify the onset of puberty. When we combined the cutoffs of IP <5.05 plus uterine volume >3.75 cm³, we found a sensitivity of 0.72 and specificity of 0.90 to detect puberty. We identified a strong negative correlation between PI and uterine volume (rs=-0.72, p<0.001) and a moderate negative correlation with endometrial thickness (rs=-0.68, p<0.001) and right (rs=-0.60, p<0.001) and left (rs=-0.59, p<0.001) ovarian volumes. In conclusion, we found a significant reduction of the PI during pubertal development, reflecting a progressive increase in blood flow to the uterus, which can be a valuable non-invasive and highly specific tool to confirm the onset of puberty.
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