Mammalian sex determination—insights from humans and mice

Disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. Many of the genes required for gonad development have been identified by analysis of DSD patients. However, the use of knockout and transgenic mouse strains have contributed enormously to the study of gonad gene function and interactions within the development network. Although the genetic basis of mammalian sex determination and differentiation has advanced considerably in recent years, a majority of 46,XY gonadal dysgenesis patients still cannot be provided with an accurate diagnosis. Some of these unexplained DSD cases may be due to mutations in novel DSD genes or genomic rearrangements affecting regulatory regions that lead to atypical gene expression. Here, we review our current knowledge of mammalian sex determination drawing on insights from human DSD patients and mouse models

Vitamin D Deficiency in Children with a Chronic Illness-Seasonal and Age-Related Variations in Serum 25-hydroxy Vitamin D Concentrations

Peer reviewe

Etiologic study of primary congenital hypothyroidism

The underlying causes of 35 children with primary congenital hypothyroidism at the Children's Hospital were studied. There were 21 girls and 14 boys. Serum T4 and TSH level, 24 hours 131I uptake, and technetium-99m thyroid scintigraphy were performed after discontinuation of synthetic thyroid hormone for 4-6 weeks. Athyrosis was the most common cause and accounted for forty-three per cent of the patients. Twenty per cent of the patients had thyroid hypoplasia. Ectopic thyroid was found in thirty-three per cent of the patients. Only a patient whose diagnosis was organification defect had slightly enlarged thyroid gland, high retention of 131I and positive perchlorate discharge test. Onset of symptoms before 9 months of age may be helpful for distinguishing between lingual thyroid and the others. Serum T4 level less than 2 micrograms/dL was observed to be more common in athyrosis and lingual thyroid groups than thyroid hypoplasia group

A child with BK virus infection: inadequacy of current therapeutic strategies

In this report, we describe the development of BKVN in the native kidneys of a child with a cardiac transplant. Elevated BK viral DNA load by PCR necessitated a prolonged course of treatment with escalating doses of cidofovir. Despite a reduction in plasma BK viral load, the infection evolved into an invasive CNS disease, resulting in rhomboencephalitis. This case highlights the need for awareness of the possibility of developing multiorgan complications from BKV infection. The current treatment options for BKV tissue invasive disease are inadequate and need to be improved

Umbilical artery histomorphometry: a link between the intrauterine environment and kidney development

Prematurity is a risk factor for hypertension, vascular stiffness, nephron deficit and adult onset cardiorenal disease. The vascular tree and kidneys share morphogenic drivers that promote maturation in utero before 36 weeks of gestation. Vascular elastin accrual terminates after birth leaving collagen to promote vascular stiffness. Our objective was to determine if the histomorphometry of the umbilical artery, an extension of the aorta, parallels nephron mass across gestational age groups. From a cohort of 54 newborns, 32 umbilical cord specimens were adequate for evaluation. The umbilical cord was sectioned, stained with trichrome, and digitalized. Muscular and collagenous areas of the umbilical artery were measured in pixels using the Image J 1.48q software. Total kidney volume was measured by ultrasound and factored by body surface area (TKV/BSA). The umbilical artery total area was significantly greater in term v. preterm infants (9.3±1.3 v. 7.0±2.0 mm2; P<0.05) and increased with gestational age; while the percent muscular and collagen areas were independent of gestational age (R 2=0.04; P=ns). Percent muscular area correlated positively with TKV/BSA (r=0.53; P=0.002); while an increase in collagen correlated inversely with kidney mass (r=−0.53; P=0.002). In conclusion, an enhanced % muscular area and presumed vascular elasticity was associated with increased renal mass in all infants. Umbilical artery histomorphometry provides a link between the intrauterine environment, vascular and kidney development

Utility of the 2018 Revised ISN/RPS Thresholds for Glomerular Crescents in Childhood-Onset Lupus Nephritis: A Pediatric Nephrology Research Consortium Study

Background The revised 2018 ISN/RPS Classification System for lupus nephritis (LN) includes calculations for both activity index (A.I.) and chronicity index (C.I.). Unchanged were the thresholds of \u3c 25%, 25–50%, and \u3e 50% crescents to distinguish between mild, moderate, and severe activity/chronicity. We aimed to evaluate these thresholds for percent crescents in childhood-onset LN. Methods Eighty-six subjects \u3c 21 years of age were enrolled from the Pediatric Glomerulonephritis with Crescents Registry, a retrospective multi-center cohort sponsored by the Pediatric Nephrology Research Consortium. Thresholds of 10%, 25%, and 50% for both cellular/fibrocellular and fibrous crescents were interrogated for primary outcomes of kidney failure, eGFR, and eGFR slope. Results Median age at time of initial biopsy was 14 years (range 1–21). Median follow-up time was 3 years (range 1–11). Cumulative incidence of kidney failure was 6% at 1 year and 10% at latest follow-up. Median eGFR slope was − 18 mL/1.73 m 2 /min (IQR − 51 to + 8) at 1 year and − 3 mL/min/1.73 m 2 /year (IQR − 19 to + 6) at latest follow-up. We found no difference in kidney failure at the proposed \u3c 25% and 25–50% cellular crescents thresholds, and thus added a new provisional threshold of 10% that better predicted outcomes in children. Moreover, use of 10% and 25% thresholds for fibrous crescents showed a fourfold and sevenfold increase in risk of kidney failure. Conclusions In children with crescentic LN, use of 10% and 25% thresholds for cellular crescents better reflects disease activity, while these thresholds for fibrous crescents better discriminates kidney disease outcomes

Utility of the 2018 Revised ISN/RPS Thresholds for Glomerular Crescents in Childhood-Onset Lupus Nephritis: A Pediatric Nephrology Research Consortium Study

Background The revised 2018 ISN/RPS Classification System for lupus nephritis (LN) includes calculations for both activity index (A.I.) and chronicity index (C.I.). Unchanged were the thresholds of \u3c 25%, 25–50%, and \u3e 50% crescents to distinguish between mild, moderate, and severe activity/chronicity. We aimed to evaluate these thresholds for percent crescents in childhood-onset LN. Methods Eighty-six subjects \u3c 21 years of age were enrolled from the Pediatric Glomerulonephritis with Crescents Registry, a retrospective multi-center cohort sponsored by the Pediatric Nephrology Research Consortium. Thresholds of 10%, 25%, and 50% for both cellular/fibrocellular and fibrous crescents were interrogated for primary outcomes of kidney failure, eGFR, and eGFR slope. Results Median age at time of initial biopsy was 14 years (range 1–21). Median follow-up time was 3 years (range 1–11). Cumulative incidence of kidney failure was 6% at 1 year and 10% at latest follow-up. Median eGFR slope was − 18 mL/1.73 m 2 /min (IQR − 51 to + 8) at 1 year and − 3 mL/min/1.73 m 2 /year (IQR − 19 to + 6) at latest follow-up. We found no difference in kidney failure at the proposed \u3c 25% and 25–50% cellular crescents thresholds, and thus added a new provisional threshold of 10% that better predicted outcomes in children. Moreover, use of 10% and 25% thresholds for fibrous crescents showed a fourfold and sevenfold increase in risk of kidney failure. Conclusions In children with crescentic LN, use of 10% and 25% thresholds for cellular crescents better reflects disease activity, while these thresholds for fibrous crescents better discriminates kidney disease outcomes

Tescalcin, a Novel Gene Encoding a Putative EF-Hand Ca2+-Binding Protein, Col9a3, and Renin Are Expressed in the Mouse Testis during the Early Stages of Gonadal Differentiation**This work was supported in part by the Department of Pediatrics at the University of Miami School of Medicine.

To identify genes that are differentially expressed in the developing testis we used representational difference analysis of complementary DNA from gonads of mouse embryos at 13.5 days postcoitum (dpc). Three genes were identified. One of them was a novel gene termed tescalcin that encoded a putative EF-hand Ca2+-binding protein. The open reading frame consisted of 642 nucleotides encoding a protein with 214 amino acids. Analysis of the predicted amino acid sequence revealed an N-myristoylation motif and several phosphorylation sites in addition to an EF-hand Ca2+-binding domain. Tescalcin messenger RNA (mRNA) was present in fetal testis, but not in ovary or mesonephros, and was restricted to the testicular cords. Its expression was first detected in the male gonad at 11.5 dpc and demonstrated a pattern consistent with a role in the testis at the early stages of testis differentiation. Tescalcin is expressed in the testis of KitW/W-v mice, indicating that it is not dependent on the presence of germ cells. The other two genes identified were collagen IX α3 (Col9a3) and Renin. Col9a3 expression was present at low levels in male and female gonads at 11.5 dpc. Thereafter, it was markedly up-regulated in the male, but remained very low in the female. Expression of Col9a3 was restricted to testicular cords and was also detected in testis of KitW/W-v mice. Renin mRNA was first detected in testis at 12.5 dpc, increased thereafter, and reached a peak at 16.5 dpc. Renin mRNA was localized in cells of the interstitium and cells at the border between the gonad and mesonephros. Expression of Renin in the ovary was not detected using standard conditions