Should 45,X/46,XY boys with no or mild anomaly of external genitalia be investigated and followed up?

OBJECTIVE: Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development. METHODS: Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France. RESULTS: Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. -2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% (n = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels). CONCLUSION: This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies.

Dietary protein excess during neonatal life alters colonic microbiota and mucosal response to inflammatory mediators later in life in female pigs.

The interplay between the colonic microbiota and gut epithelial and immune cells during the neonatal period, which establishes the structure of the microbiota and programs mucosal immunity, is affected by the diet. We hypothesized that protein-enriched milk formula would disturb this interplay through greater flux of protein entering the colon, with consequences later in life. Piglets were fed from postnatal day (PND) 2 to 28 either a normal-protein formula (NP; 51 g protein/L) or high-protein formula (HP; 77 g protein/L) and weaned at PND28, when they received standard diets until PND160. HP feeding transiently increased the quantity of protein entering the colon (PND7) but did not change the microbiota composition at PND28, except for a higher production of branched-chain fatty acids (BCFAs) in an in vitro fermentation test (P < 0.05). HP piglets had greater colonic mucosa densities of cluster of differentiation (CD) 3(+) and CD172(+) cells and lower Il-1ß and Tnfα mRNA levels at PND28 (P < 0.05). Later in life (PND160), HP females, but not males, had a higher increase in colonic permeability after ex vivo oxidative stress and higher cytokine secretion in response to lipopolysaccharide in colonic explant cultures than NP females (P < 0.05). HP females also had lower colonic amounts of F. prausnitzii and BCFAs (P < 0.05). BCFAs displayed a dose-dependent protection against inflammation-induced alteration of barrier function in Caco-2 cells (P < 0.05). In conclusion, protein-enriched formula had little impact on colonic microbiota, but it modified colonic immune cell development and had a long-term effect on adult colonic mucosa sensitivity to inflammatory insults, probably through microbiotal and hormonal factors.

The level of protein in milk formula modifies ileal sensitivity to LPS later in life in a piglet model.

BACKGROUND: Milk formulas have higher protein contents than human milk. This high protein level could modify the development of intestinal microbiota, epithelial barrier and immune functions and have long-term consequences. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the effect of a high protein formula on ileal microbiota and physiology during the neonatal period and later in life. Piglets were fed from 2 to 28 days of age either a normoprotein (NP, equivalent to sow milk) or a high protein formula (HP, +40% protein). Then, they received the same solid diet until 160 days. During the formula feeding period ileal microbiota implantation was accelerated in HP piglets with greater concentrations of ileal bacteria at d7 in HP than NP piglets. Epithelial barrier function was altered with a higher permeability to small and large probes in Ussing chambers in HP compared to NP piglets without difference in bacterial translocation. Infiltration of T cells was increased in HP piglets at d28. IL-1ß and NF-κB sub-units mRNA levels were reduced in HP piglets at d7 and d28 respectively; plasma haptoglobin also tended to be reduced at d7. Later in life, pro-inflammatory cytokines secretion in response to high doses of LPS in explants culture was reduced in HP compared to NP piglets. Levels of mRNA coding the NF-κB pathway sub-units were increased by the challenge with LPS in NP piglets, but not HP ones. CONCLUSIONS/SIGNIFICANCE: A high protein level in formula affects the postnatal development of ileal microbiota, epithelial barrier and immune function in piglets and alters ileal response to inflammatory mediators later in life.