Male Phenotype Research Articles

The first case of bilateral gynandromorphic plumage type in the bearded reedling Panurus biarmicus

Bilateral gynandromorphism is a condition in which an individual has both male and female phenotypes distributed symmetrically on the body. We describe the first case of a likely gynandromorphic bearded tit, which was trapped in Poland. The bird had a black moustache and grey-blue plumage on the right side of the head, which is typical for males, and lacked this plumage coloration on the left side, which is typical of females. The entire bill was brown, consistent with a typical female, while the undertail coverts were buff with randomly distributed black spots, which represents a mixture feature of both sexes. The observation is discussed in light of earlier cases of gynandromorphic birds.

MAOA methylation is associated with impulsive and antisocial behaviour: dependence on allelic variation, family environment and diet.

Congenital absence of monoamine oxidase A (MAO-A) activity predisposes to antisocial impulsive behaviour, and the MAOA uVNTR low-expressing genotype (MAOA-L) together with childhood maltreatment is associated with similar phenotypes in males. A possible explanation of how family environment may lead to such behaviour involves DNA methylation. We have assessed MAOA methylation and impulsive/antisocial behaviour in 121 males from the Estonian Children Personality Behaviour and Health Study. Of the 12 CpG sites measured, methylation levels at the locus designated CpG3 were significantly lower in subjects with antisocial behaviour involving police contact. CpG3 methylation was lower in subjects with alcohol use disorder by age 25, but only in MAOA-H genotype. No correlation between MAOA CpG3 methylation levels and adaptive impulsivity was found at age 15, but in MAOA-L genotype a positive correlation appeared by age 18. By age 25, this positive correlation was no longer observed in subjects with better family relationships but had increased further with experience of adversity within the family. MAOA CpG3 methylation had different developmental dynamics in relation to maladaptive impulsivity. At age 18, a positive correlation was observed in MAOA-L genotype with inferior family relationships and a negative correlation was found in MAOA-H with superior home environment; both of these associations had disappeared by age 25. CpG3 methylation was associated with dietary intake of several micronutrients, most notable was a negative correlation with the intake of zinc, but also with calcium, potassium and vitamin E; a positive correlation was found with intake of phosphorus. In conclusion, MAOA CpG3 methylation is related to both maladaptive and adaptive impulsivity in adolescence in MAOA-L males from adverse home environment. By young adulthood, this relationship with maladaptive impulsivity had disappeared but with adaptive impulsivity strengthened. Thus, MAOA CpG3 methylation may serve as a marker for adaptive developmental neuroplasticity in MAOA-L genotype. The mechanisms involved may include dietary factors.

No sex differences in core autism features, social functioning, cognition or co-occurring conditions in young autistic children: A systematic review and meta-analysis

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition with more males than females diagnosed, and researchers have considered whether the existence of a female-specific ASD phenotype may contribute to differences in rates of diagnosis. We sought to inform this issue through a systematic review and meta-analysis of potential sex differences specifically in young autistic children across a range of domains including core ASD features, social functioning, cognition, and co-occurring internalising and/or externalising conditions. The systematic review identified 35 studies examining sex differences in young autistic children. Conflicting results were evident across studies, with some reporting small sex differences and others reporting no sex differences. Meta-analysis revealed no overarching significant sex differences in the domains investigated. However, the meta-analytic effect for the RRB domain approached significance, with females demonstrating fewer RRBs than males. Many of the primary studies included here utilised data from standardised diagnostic instruments to measure autism features, so while this study suggests non-significant sex differences in early childhood ASD, it remains possible that current tools are insufficiently sensitive to detect differences in ASD presentation by sex at this age. It is also possible that the diagnostic criteria may reflect a predominately ‘male phenotype’ and this may obscure the detection of genuine sex differences in young autistic children.

Phosphoproteomics Reveal New Candidates in Abnormal Spermatogenesis of Pseudomales in Cynoglossus semilaevis.

Phosphorylation is a post-translational modification that contributes to versatile protein functions in spermatogenesis, and the variations they generate usually results in abnormal spermatogenesis or sperm dysfunction. The sex-reversal phenomenon exists in Chinese tongue sole under certain conditions such that individuals with a ZW genotype can acquire a male phenotype and are thus called pseudomales. Pseudomale tongue sole can reach sexual maturity but produce only Z-type sperm, and the Z sperm carries paternal epigenetic information. Whether phosphorylation plays a role in the sperm abnormality of pseudomales is unknown. In this study, a phosphoproteomic analysis was performed to compare protein phosphorylation profiles between pseudomale and male testes. Altogether, we identified 14,253 phosphopeptides matching with 4843 proteins, with 1329 differentially phosphorylated peptides corresponding to 1045 differentially phosphorylated proteins (DPPs). Phosphorylation at 781 sites was upregulated and at 548 sites was downregulated. Four motifs were identified among differentially phosphorylated peptides, which were "SP", "SD", "RxxS", and "TP". Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggested that the cell cycle and DNA/RNA processing were significantly enriched with the genes encoding DPPs. To analyze DPP function in depth, a protein-protein interaction network was constructed, and Ran-binding protein 2 was found to play a central role in spermatogenesis by regulating several processes such as the cell cycle, eukaryotic translation, ubiquitination, and minichromosome maintenance. In kinase-associated network analyses, two "mitogen-activated protein kinase (Mapk)-centered" clusters were identified that may account for abnormal spermatogenesis in pseudomales. One cluster was centered on Mapk6, which predominantly regulated the cell cycle by interacting with several cyclin-dependent kinases, and the other was centered on the "testis-expressed kinase 1-like (Tesk1l)/Pim1l-Mapk4l- testis-expressed 14 (Tex14)" kinase cascade, which might contribute to spermatogenesis by regulating β-catenin. Taken together, these data suggested the new candidates involved in pseudomale sperm abnormalities and provided clues to discover the phosphorylated regulatory mechanism underlying tongue sole spermatogenesis.

Metabolic consequences of sex reversal in two lizard species: a test of the like-genotype and like-phenotype hypotheses.

Vertebrate sex is typically determined genetically, but in many ectotherms sex can be determined by genes (genetic sex determination, GSD), temperature (temperature-dependent sex determination, TSD), or interactions between genes and temperature during development. TSD may involve GSD systems with either male or female heterogamety (XX/XY or ZZ/ZW) where temperature overrides chromosomal sex determination to cause a mismatch between genetic sex and phenotypic sex (sex reversal). In these temperature-sensitive lineages, phylogenetic investigations point to recurrent evolutionary shifts between genotypic and temperature-dependent sex determination. These evolutionary transitions in sex determination can occur rapidly if selection favours the reversed sex over the concordant phenotypic sex. To investigate the consequences of sex reversal on offspring phenotypes, we measured two energy-driven traits (metabolism and growth) and 6month survival in two species of reptile with different patterns of temperature-induced sex reversal. Male sex reversal occurs in Bassiana duperreyi when chromosomal females (female XX) develop male phenotypes (maleSR XX), while female sex reversal occurs in Pogona vitticeps when chromosomal males (male ZZ) develop female phenotypes (femaleSR ZZ). We show metabolism in maleSR XX was like that of male XY; that is, reflective of phenotypic sex and lower than genotypic sex. In contrast, for Pogona vitticeps, femaleSR ZZ metabolism was intermediate between male ZZ and female ZW metabolic rate. For both species, our data indicate that differences in metabolism become more apparent as individuals become larger. Our findings provide some evidence for an energetic advantage from sex reversal in both species but do not exclude energetic processes as a constraint on the distribution of sex reversal in nature.

The alternate pathway of androgen metabolism and window of sensitivity.

Since the discovery in 1968 that dihydrotestosterone (DHT) is a major mediator of androgen action, a convincing body of evidence has accumulated to indicate that the major pathway of DHT formation is the 5α-reduction of circulating testosterone in androgen target tissues. However, we now know that DHT can also be formed in peripheral tissues by the oxidation of 5α-androstane-3α,17β-diol (adiol). This pathway is responsible for the formation of the male phenotype. We discuss the serendipitous discovery in the tammar wallaby of an alternate pathway by which adiol is formed in the testes, secreted into plasma and converted in peripheral tissues to DHT. This alternate pathway is responsible for virilisation of the urogenital system in this species and is present in the testes at the onset of male puberty of all mammals studied so far. This is the first clear-cut function for steroid 5α-reductase 1 in males. Unexpectedly, the discovery of this pathway in this Australian marsupial has had a major impact in understanding the pathophysiology of aberrant virilisation in female newborns. Overactivity of the alternate pathway appears to explain virilisation in congenital adrenal hyperplasia CAH, in X-linked 46,XY disorders of sex development. It also appears to be important in polycystic ovarian syndrome (PCOS) since PCOS ovaries have enhanced the expression of genes and proteins of the alternate pathway. It is now clear that normal male development in marsupials, rodents and humans requires the action of both the classic and the alternate (backdoor) pathways.

1675-P: Reproductive and Intergenerational Impacts of Metformin

Recent data suggest that metformin can influence male reproductive health, directly or indirectly. Lastly, an epidemiologic cohort study demonstrated an association between preconceptional use of metformin in men and genital birthdefects in their offsprings. Given the need to test these associations in the absence of complex genetic and environmental factors in humans, we assessed the impact of metformin on both male reproductive health and health of offspring in C57/BL6J mice. Male mice age 8 weeks were treated with low fat (10% fat) or high fat (60% fat) diet to induce obesity; after two weeks, mice were randomized to continued dietary treatment, with or without metformin 350 mg/kg/day (n=8/group). After 12 weeks of treatment, metabolic status was assessed by glucose and insulin tolerance tests; as expected, metformin improved insulin sensitivity (21% improvement vs. HFD, p=0.008) despite no significant difference in body weight or glucose tolerance. To determine effect of male metformin treatment on reproductive success, HFD and HFD-MET males were bred with 6-8 week old females. Breeding was successful for 87.5% of HFD males, as compared with 37.5% for HFD-MET males (P=0.038). In both groups, insulin resistance (HOMA-IR) was strongly correlated with body weight (HFD: r=0.86, P=0.006; HFD-MET: r=0.92, P=0.001). However insulin resistance was inversely correlated with successful pregnancy rates only in HFD-MET mice (HFD: r=-0.3, P=0.21; HFD-MET: r=-0.68, P=0.04), suggesting that insulin sensitivity is a stronger and more significant determinant of fertility in metformin treated mice. Thus, we hypothesize that metformin may have dual impact on male reproductive health, with both beneficial increases in insulin sensitivity and potential adverse impact to reduce fertility. Additional studies are in progress to determine impact of male metformin treatment on hormonal and germ cell aspects of male reproductive health and offspring developmental phenotypes. Disclosure B.Ozturk: None. R.Ferraz-bannitz: None. V.Efthymiou: None. L.Poulos: None. V.Navarrete: None. M.Patti: Consultant; MBX Biosciences, AstraZeneca, Hanmi Pharm. Co., Ltd., Other Relationship; Fractyl Health, Inc. Funding National Institutes of Health (R01DK106193)

#3067 ALPORT SYNDROME NATURAL HISTORY FROM THE RADAR REGISTRY: ASSOCIATIONS WITH GENE, VARIANT TYPE AND SEX

Abstract Background and Aims Alport Syndrome (AS) is caused by pathogenic variants in COL4A3, COL4A4 & COL4A5 genes. The clinical course of AS can be highly variable, depending on gene affected, mutation type and Male (M) or Female (F) sex. Proteinuria is associated with worse prognosis. Previous genotype-phenotype correlation studies have shown protein length altering variants are associated with a more severe phenotype in males with COL4A5 variants, however studies in females have shown contradicting results. This study aims to describe demographics and investigate renal outcomes associated with pathogenic variant type in M vs F AS patients, using longitudinal data from the National Registry of Rare Kidney Diseases (RaDaR) which recruits patients at 108 UK renal clinics. Method RaDaR is linked to Regional Genetics hubs for clinical genetic reports, renal IT systems for routine test results and the UK Renal Registry for Renal Replacement Therapy (RRT) initiation data. eGFR was calculated using CKD-EPI Cr equation (2021) or Schwartz equation for those ≤ 16 yrs. eGFR slope was calculated over the last 3 years (or 3 years prior to End Stage Kidney Disease (ESKD)/death for patients who reached those outcomes), with patients required to have a minimum of 4 values over 2 years. For genotype data, variants classified in clinically issued reports as “Pathogenic” or “Likely Pathogenic” were included and classed as: 1. Protein Length Altering and 2. Missense variants. Where both protein length altering and missense variants in the same gene were identified in an individual, the missense variant was used. Data are presented as percentages for categorical variables and mean ± SD for continuous variables. Kaplan Meier analysis and the log rank statistic were used to compare age at RRT start, stratified by gender and variant types. Lower quartile (LQ) (25%) estimates are presented where too few events have occurred to calculate a median (50%) estimate. Results Between Jan 2013–Jul 2022, 920 AS patients were recruited; 53% M vs. 47% F. Genetic test reports were available for 343/920 (37%) patients. 294/343 (86%) reported a pathogenic or likely pathogenic variant, 140 protein length altering and 154 missense. Individuals with 2x COL4A3/COL4A4 variants were youngest at RRT start, whilst females with COL4A5 variants were oldest (LQ 20.1 vs 60.9 yrs, log-rank p<0.0001) (Figure 1a). COL4A5 variants Males with protein length altering COL4A5 variants were younger at ESKD compared with missense variants (median age 30.2 vs 52.1 yrs, p = 0.01). Conversely 0/36 females with protein length altering COL4A5 variants had started RRT, compared with 6/37 with missense variants (p = 0.01) (Figure 1bi-ii). COL4A3 or COL4A4 variants Whilst females with heterozygous protein length altering COL4A3/4 variants were younger at RRT start vs. those with missense variants (LQ 47.1 vs 64.9 yrs, p = 0.05), age at RRT start did not differ by mutation type for males with COL4A3/4 heterozygous variants (Figure 1b iii-iv). However, males with homozygous or 2x protein length altering COL4A3/4 variants were younger at RRT start than those with missense variants (median age 20.1 vs 24.3 yrs, P = 0.05), whilst no difference was observed by variant type for females with 2x COL4A3/4 variants (Figure 1b v-vi). Proteinuria and eGFR slope were generally correlated with age at ESKD. Conclusion The observed effect of pathogenic variant type on renal outcomes varied by gene affected, number of mutations and sex. The relatively reduced severity among females harbouring a protein length altering COL4A5 variant may represent an effect of skewed X-inactivation or a missense gain-of-function mechanism. RaDaR recruits patients with a clinical diagnosis of Alport syndrome or Thin Basement Membrane Nephropathy; ascertainment of individuals with a single COL4A3 or COL4A4 variant is therefore likely to favour those with more severe kidney disease. Linkage of the RaDaR AS cohort with genetic report data is ongoing; further correlations may be observed with larger numbers.

Industrial chicory genome gives insights into the molecular timetable of anther development and male sterility.

Industrial chicory (Cichorium intybus var. sativum) is a biannual crop mostly cultivated for extraction of inulin, a fructose polymer used as a dietary fiber. F1 hybrid breeding is a promising breeding strategy in chicory but relies on stable male sterile lines to prevent self-pollination. Here, we report the assembly and annotation of a new industrial chicory reference genome. Additionally, we performed RNA-Seq on subsequent stages of flower bud development of a fertile line and two cytoplasmic male sterile (CMS) clones. Comparison of fertile and CMS flower bud transcriptomes combined with morphological microscopic analysis of anthers, provided a molecular understanding of anther development and identified key genes in a range of underlying processes, including tapetum development, sink establishment, pollen wall development and anther dehiscence. We also described the role of phytohormones in the regulation of these processes under normal fertile flower bud development. In parallel, we evaluated which processes are disturbed in CMS clones and could contribute to the male sterile phenotype. Taken together, this study provides a state-of-the-art industrial chicory reference genome, an annotated and curated candidate gene set related to anther development and male sterility as well as a detailed molecular timetable of flower bud development in fertile and CMS lines.

Half-chromatid mutation as a possible cause of mosaic males and females in Hymenoptera and rare fertile male tortoiseshell cats.

Half-chromatid mutations occur when a single base change in a gamete is transmitted to the zygote, which, after DNA replication and cleavage, will result in a mosaic individual. These mutations will be passed on through the germ plasm and also may be expressed somatically. Half-chromatid mutation has been suggested to account for the observed lower frequency of males than expected for lethal X-linked recessive disorders in humans, such as Lesch-Nyhan syndrome, incontinentia pigmenti, and Duchene muscular dystrophy. Although attention has been paid to half-chromatid mutation in humans, it otherwise has been ignored. Here I show that half-chromatid mutation in haplodiploid organisms, such as Hymenoptera, has some interesting and important consequences: (i) since all genes follow the X-linked pattern of inheritance, half-chromatid mutations should be relatively easier to detect; (ii) recessive mutations of all viabilities may be expected; (iii) mosaics of both sexes are expected in haplodiploids with half-chromatid mutation; (iv) gynandromorphs could result from half-chromatid mutation at the sex-determination locus, in species with single-locus complementary sex-determination. Finally, half-chromatid mutation can account for the rare fertile male tortoiseshell phenotype observed in the domestic cat, Felis catus, and which still has not been fully accounted for by other mechanisms.

Reorganization of the ancestral sex-determining regions during the evolution of trioecy in Pleodorina starrii

The coexistence of three sexual phenotypes (male, female and bisexual) in a single species, ‘trioecy’, is rarely found in diploid organisms such as flowering plants and invertebrates. However, trioecy in haploid organisms has only recently been reported in a green algal species, Pleodorina starrii. Here, we generated whole-genome data of the three sex phenotypes of P. starrii to reveal a reorganization of the ancestral sex-determining regions (SDRs) in the sex chromosomes: the male and bisexual phenotypes had the same “male SDR” with paralogous gene expansions of the male-determining gene MID, whereas the female phenotype had a “female SDR” with transposition of the female-specific gene FUS1 to autosomal regions. Although the male and bisexual sex phenotypes had the identical male SDR and harbored autosomal FUS1, MID and FUS1 expression during sexual reproduction differed between them. Thus, the coexistence of three sex phenotypes in P. starrii is possible.

Remodeling male coercion and the evolution of sexual autonomy by mate choice.

Models of sexual conflict over mating, including conflict over indirect benefits of mate choice, have generally presumed that female resistance to male coercion must involve direct confrontation, which can lead to sexually antagonistic coevolutionary arms-races. We built a quantitative model examining the largely ignored possibility that females may evolve new, additional mate preferences for new male traits that undermine male capacity to coerce. Thus, females may "remodel" the coercive capacity of the male phenotype in order to enhance their own sexual autonomy-a novel alternative mechanism by which females may avoid arms-races. We demonstrate that evolutionary "remodeling" is possible, in spite of costs to males, because females that prefer males with protective, autonomy-enhancing traits (traits correlated with lower coercion effectiveness) are likelier to gain indirect benefits of having attractive mates. Our analysis reveals new possibilities for the evolution of systems of sexual conflict over indirect benefits, showing that autonomy-enhancing male traits can act as a "public good," benefiting all females regardless of mating preferences, leading to oscillatory dynamics; and that preferences for more protective male traits will often be favored relative to preferences for less protective traits, potentially leading to an evolutionary "snowball" of expanding sexual autonomy.

A case of 17-beta-hydroxysteroid dehydrogenase deficiency type 3 in adult endocrinologist practice

17β-Hydroxysteroid dehydrogenase 3 deficiency (17HSD3) is a rare autosomal recessive cause of 46, XY disorders of sex development resulting from HSD17B3 gene mutations, in which conversion of androstenedione to testosterone is impared. The clinical signs of 17HSD3 deficiency depend on the residual activity of the enzyme. The diagnosis of 17HSD3 deficiency is based on reduced testosterone/androstenedione ratio (T/AD < 0.8). Patients are usually assigned at birth and raise as female. If the diagnosis is made before puberty, gonadectomy is recommended, taking into account the risk of masculinization during the puberty and estrogen therapy initiation in this period. If the diagnosis of 17HSD3 deficiency is established during puberty, when virilization manifests, the therapeutic strategy is based on the results of comprehensive psychological testing and gender identity of a patient. In patients with more pronounced masculinization or diagnosis established shortly after birth, who are assigned at birth and raise as male, testosterone therapy is used to achieve a male phenotype. The 17HSD3 deficiency and virilization often result in a change of gender identity during puberty. The article presents a clinical case of 17-βhydroxysteroid dehydrogenase type 3 deficiency with late diagnosis due to parental will. The diagnostic approaches and management of the disease are also described.

Environmental and Genetic (vgll3) Effects on the Prevalence of Male Maturation Phenotypes in Domesticated Atlantic Salmon

Pre-harvest male maturation is problematic for Atlantic salmon (Salmo salar) farmers and is regulated by the environment and genetics (e.g., vgll3). Five families of all-male salmon parr (produced using YY males crossed with XX females) with different vgll3 genotypes were split between three environmental regimes in January 2018. The “advanced maturation” regime used elevated temperature (16 °C) and continuous light from January 2018 with post-smolt maturation assessed in March 2018. The “extended freshwater” regime used ambient freshwater (1–16 °C) and simulated natural photoperiod (SNP) with post-smolt maturation assessed in November 2018. The “sea transfer” regime used ambient temperatures (1–14 °C) and SNP in freshwater until May 2018 when they were transferred to 9 °C seawater with natural photoperiod for 2.5 years (final mean weight of circa. 14 kg) and assessed for post-smolt maturation, 1 sea-winter (1 SW) maturation, and 2 sea-winter (2 SW) maturation in the autumn (November/December) of 2018, 2019, and 2020, respectively. Post-smolt maturation was highest in the advanced maturation and extended freshwater regimes (39–99% depending on family) and lowest in the sea transfer regime (0–95% depending on family). In the sea transfer regime, maturity incidence increased over time (0–95% post-smolt maturation, 1–100% 1 SW, and 50–90% 2 SW maturation, depending on family). In all regimes, those homozygous for the pre-designated vgll3 “early” maturing allele had the highest incidences of maturation whilst those homozygous for the “late” allele had the lowest. A low percentage of 2 SW phenotypic and genetic females were found (0–5% depending on family), one of which was successfully crossed with an XY male resulting in progeny with an approx. 50/50 sex ratio. These results show (i) post-smolt maturation varies dramatically depending on environment although genetic regulation by vgll3 was as expected, and (ii) crossing YY sperm with XX eggs can result in XX progeny which can themselves produce viable progeny with an equal sex ratio when crossed with an XY male.

(273) A Tight Tuck – More Than Meets the Eyes

Abstract Introduction Tucking is a common practice within the transwomen community. One study estimates that 70% of transwomen engage in this non-surgical gender affirming technique. It entails placement of the testes superiorly towards the inguinal canal and the penis inferiorly towards the rectum to conceal a male phenotype and create a female silhouette. By prolonged distortion of the normal anatomical lie of the penis and testes, several genitourinary complications should be expected to result including low sperm quality, genital pain, genitourinary tract infections, lower urinary tract symptoms, and testicular torsion. However, no formal review or survey has been conducted to better inform physicians on how to appropriately incorporate the practice of tucking into formation of a differential diagnoses. Objective To assess common genitourinary complications and complaints associated with the practice of tucking. Methods We performed a content analysis of posts on Reddit related to tucking and health complaints related to the practice. Reddit is an online forum with various sub-communities known as “subreddits” where anonymous users post and have discussions about a shared interest. In fact, there exist specific forums for the transgender community including r/asktrangender and r/MtF with 142,000 and 161,000 members respectively. A short survey was then created based on common themes of our analysis and posted to the 3 subreddits related to the transgender community with the most members. Results Content analysis first demonstrated distrust and displeasure in physicians’ understanding of genitourinary implications of tucking. Whether this reaction is well founded or not, it is true that there is little understanding within the medical community in this area with many physicians likely ignorant to the degree of anatomical distortion tucking entails. Analysis of common complaints revealed themes similar to those expected from review of what literature has been performed. We expect survey results to support our analysis. Conclusions Formal study is indicated of the genitourinary complications of tucking for physicians to adequately serve our transfemale patients. Disclosure No

A rare case of mixed gonadal dysgenesis in adulthood: diagnostic delay and unique outcomes

Mixed gonadal dysgenesis (MGD) is a rare sex development disorder, diagnosed by mosaic karyotype of 45,X/46,XY (classical form) with the presence of Müllerian structures, unilateral testis and contralateral streak gonad. MGD expresses diverse phenotypes, from female phenotype with virilization or turner stigmata, to ambiguous genitalia or male phenotype. Early diagnosis is crucial for effective correction of height, sexual development and cancer prevention. The study reports on a case of a 25-year-old patient, reared as female, presenting a large abdominal mass later confirmed as a mixed germ cell tumor. Associated findings were primary amenorrhea, ambiguous genitalia, short statue, gender dysphoria and hyperlipidemia. The study is the first to report on hyperlipidemia in MGD.

КЛАСТЕРНЫЙ АНАЛИЗ КАК ИНТЕГРАТОР РАЗНЫХ МЕТОДИК ОЦЕНКИ ФИЗИЧЕСКОГО РАЗВИТИЯ ПРАКТИЧЕСКИ ЗДОРОВЫХ ЛИЦ ЮНОШЕСКОГО ВОЗРАСТА

The influence of external factors can significantly deviate the distribution of somatotypes from the indicators of the general population, which makes researchers select the most suitable scheme of so-matotyping from the already known ones or construct their own. Applicants of military universities are a particular case of such samples, formed as a result of a complex of factors, including the work of military medical commissions. The aim was to use cluster analysis to develop an integrative classifica-tion for assessing the physical development of practically healthy adolescents. Materials and meth-ods. The object of the study was 280 applicants (234 boys and 46 girls), who were examined by spe-cialists in the medical commissions of military commissariats and were considered to be practically healthy. Anthropometric data were analyzed: body length, body weight, length of the torso, limbs, girth dimensions of the torso and limbs, as well as body component composition. Hierarchical cluster analysis by the Ward method and Kendall's correlation coefficient were used in the study. Results. By means of cluster analysis of the physical development indicators of the virtually healthy individuals, we identified a significant contribution of body mass index, weight, body length in the formation of three major groups, which we characterized as: the male macrosomatic phenotype, the male mesoso-matic phenotype, and the female phenotype. Based on the proportion of muscle and fat tissue, visceral fat, distal diameter of the forearm as an indicator of bone development, body mass index and thick-ness of the skin-fat fold of the anterior abdominal wall, the following subgroups were identified: male macrosomatic phenotype, with hyperstenic features, male macrosomatic phenotype, with normosthen-ic features, male mesosomatic phenotype with digestive features, male mesosomatic phenotype with mesotonic features, male mesosomatic muscle phenotype, female megalosomic athletic and subathletic phenotype, female stenoplastic phenotype. Conclusion. The used statistical approach allows to change the classical paradigm of searching for a universal methodology of somatotyping, to the creation of algorithms of compilation of well-known schemes of physical development evaluation in the selected population groups.

Differential expression of some termite neuropeptides and insulin/IGF-related hormones and their plausible functions in growth, reproduction and caste determination.

Insulin-like growth factor (IGF) and other insulin-like peptides (ilps) are important hormones regulating growth and development in animals. Whereas most animals have a single female and male adult phenotype, in some insect species the same genome may lead to different final forms. Perhaps the best known example is the honeybee where females can either develop into queens or workers. More extreme forms of such polyphenism occur in termites, where queens, kings, workers and soldiers coexist. Both juvenile hormone and insulin-like peptides are known to regulate growth and reproduction as well as polyphenism. In termites the role of juvenile hormone in reproduction and the induction of the soldier caste is well known, but the role of IGF and other ilps in these processes remains largely unknown. Here the various termite ilps are identified and hypotheses regarding their functions suggested. Genome assemblies and transcriptome short read archives (SRAs) were used to identify insulin-like peptides and neuropeptides in termites and to determine their expression in different species, tissues and castes. Termites have seven different ilps, i.e. gonadulin, IGF and an ortholog of Drosophila insulin-like peptide 7 (dilp7), which are commonly present in insects, and four smaller peptides, that have collectively been called short IGF-related peptides (sirps) and individually atirpin, birpin, cirpin and brovirpin. Gonadulin is lost from the higher termites which have however amplified the brovirpin gene, of which they often have two or three paralogs. Based on differential expression of these genes it seems likely that IGF is a growth hormone and atirpin an autocrine tissue factor that is released when a tissue faces metabolic stress. Birpin seems to be responsible for growth and in the absence of juvenile hormone this may lead to reproductive adults or, when juvenile hormone is present, to soldiers. Brovirpin is expressed both by the brain and the ovary and likely stimulates vitellogenesis, while the function of cirpin is less clear.

Clinical and hormonal characteristics and growth data of 45,X/46,XY mosaicism in 38 Chinese patients.

45,X/46,XY mosaicism is the most common type of sex chromosomal abnormality in disorders of sex development (DSD). We investigated the clinical manifestations, serum sex hormone levels and growth data of 38 45,X/46,XY mosaicism patients, which provides better insight into this disease. We prospectively evaluated 38 patients who were diagnosed with 45,X/46,XY mosaicism at the Department of Endocrinology of Shanghai Children's Hospital from 2010 to 2020. We analyzed clinical data from the patients, including hormone levels, height, weight, body mass index (BMI) and gonadal pathology results. Among the 38 cases of 45,X/46,XY mosaicism, 18 cases showed a female external genitalia phenotype (the female group) with an external masculinization score (EMS) of 1 (0-3) [median (range)], and 20 cases showed a male external genitalia phenotype (the male group) with an EMS of 7.63 (3-11) [median (range)]. The age at diagnosis ranged from 0.7 to 16.1 years. Under 2 years of age, the standard deviation scores of height (HtSDS) were in the normal range and then they gradually decreased. The inhibin B (INHB), anti-Mullerian hormone (AMH), and testosterone (T) levels after human chorionic gonadotropin (HCG) stimulation and the T:DHT ratio in the male group were significantly higher than those in the female group (P < 0.001). The basal luteinizing hormone (LH), basal follicle-stimulating hormone (FSH), peak LH and peak FSH in females were significantly higher than those in males (P < 0.05). Their height showed a positive correlation with T levels after HCG stimulation (r = 0.636, P < 0.01), T:DHT ratio (r = 0.724, P < 0.01), growth hormone (GH) (r = 0.827, P < 0.05), and insulin-like growth factor 1 (IGF-1) (r = 0.067, P > 0.05) and a negative correlation with gonadal pathology in ovarian tissue (r = -0.663, P < 0.05) and the number of chimaeric XY cells (r = -0.533, P < 0.05). Patients with 45,X/46,XY mosaicism have specific growth patterns. Their HtSDS was in the normal range during 0-2 years of age and then they began to show a short stature after 2 years of age. The probability of short stature in females was higher than that in males. WtSDS were all in the normal range, but below the median. BMISDS was in the normal range, and there was no evidence of obesity. The gonads in the male group retained a certain androgen secretion function, while the gonadal damage is more severe in the female group.

Revisiting TOP2B-related phenotypes: Three new cases and literature review.

DNA Topoisomerase IIβ (TOP2B) acts on DNA topology during transcription and has a critical role in neural development. Heterozygous pathogenic changes in its encoding gene, TOP2B (MIM *126431), has been linked with three overlapping phenotypes characterized by immunodeficiency, acral and urogenital anomalies: Hoffman, BILU and Ablepharon-macrostomia-like syndrome. We herein report on a mother and two sons with distinct TOP2B-phenotype. Two males reported further delineated genital phenotype of males and all reported patients were reviewed for genotype-phenotype correlation. We believe the patients reported herein along with the previously defined 11 represent a phenotypic spectrum from mild-to-severe immunological, acral and urogenital involvement, for which we propose the acronym "TOP2B-related Immunodeficiency and Congenital Anomalies Spectrum (TICAS)".