Paediatric endocrinology

This chapter covers paediatric endocrinology. It starts with normal growth, then goes on to short stature, and constitutional delay of growth and puberty. Primary and secondary growth hormone deficiency are then explained, and treatment is outlined alongside GH resistance. It goes on to hypothyroidism, coeliac disease, skeletal dysplasias, and Turner syndrome. Small gestational age, and tall stature and rapid growth are all covered, alongside normal puberty, precocious puberty, and delayed or absent puberty. Normal sexual differentiation and disorders of sexual development and the assessment of ambiguous genitalia are included.

Peculiarities of feminizing surgical correction in children with disorders of sexual development

Purpose – to analyze own results of surgical treatment of serious forms of disorders of sexual development (DSD) in children after feminizing surgeries. To define practical protocol guides on the choice of the type of surgical correction. Materials and methods. Over the past 5 years surgeons of Lviv regional paediatric clinical hospital «OHMATDYT» have examined 12 children with DSD, signs of hermaphroditism (intersex). After complex examination the following states were diagnosed: androgenital syndrome in 5 girls (referred for further treatment to Kyiv paediatric medical centres); true hermaphroditism – 1 child; mixed gonadal dysgenesis (MCG) – 3 children; female pseudohermaphroditism (without determining genesis) – 1 child; partial testicular feminization syndrome, Morris syndrome (male pseudohermaphroditism) – 2 children. In connection with marked masculinization of external genitalia two children with MCG and the girl with pseudohermaphroditism underwent feminizing surgery, namely genital zone reconstruction, mobilization and excision of urogenital sinus walls, excision of genital cavernous bodies (in children with MCG) with clitoroplasty, vulvoplasty with labioplasty and vaginoplasty. Children with Morris syndrome are being prepared to feminizing surgery. Results. Each child had a personal examination plan. Verification of a child’s state lasted from several weeks to 2–3 months. Children who underwent feminizing surgery did not have male structures and had relatively well-developed female structures. More «natural», less traumatizing correction was preformed for each specific case. In all children who underwent surgery vagina opened into urogenital sinus lower than external urethral sphincter, so there was no need to form front vagina wall (back and side walls were formed). Out of all children treated in our hospital gender was legally changed to the opposite. Conclusions. The birth of a child with DSD is a most challenging problem for parents, doctors, psychologists and social workers. Such states require complex examination. Children with severe hypospadias must undergo genetic examination. Statistic data and our own experience show higher frequency of feminizing surgeries in such cases. The most difficult part of such surgeries proves to be the excision of genital cavernous bodies with clitoroplasty and clitoris translocation; the most responsible part in functional sense is vaginoplasty. Surgical treatment is not the final stage of treatment for such patients. Children with DSD require constant further dynamic checkups by gynaecologists, urologists, oncologists, endocrinologists, psychologists with relevant therapy correction. The research was carried out in accordance with the principles of the Helsinki declaration. The study protocol was approved by the Local ethics committee of all participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: disorders of sexual development (DSD), hermaphroditism, feminizing correction.

Differences in sex development

Disorders of sexual development are a complex group of conditions with anomalies of the internal and external genitalia due to abnormal chromosomal and hormonal influences during development. Diagnosis and management, including timing of intervention, and both long-term cosmetic and functional outcomes are discussed in this chapter.

Protein Phosphatase 4 (PPP4) Prevents Female Reprogramming in the Mouse Testis After Sex Determination and Protects Male Fertility

Background: Impairment of lineage specification and function of gonadal somatic cells can lead to disorders of sexual development (DSDs) and fertility defects in humans. However, little is known about the function of protein phosphatases in testis development. Results: We showed that protein phosphatase 4 (PPP4) could maintain SOX9 expression in Sertoli cells and play an essential role in Sertoli cell lineage maintenance and male fertility. Conditional deletion of Ppp4c, a PPP4 catalytic subunit gene, caused the reprogramming of Sertoli cells to granulosa-like cells postnatally by inducing ectopic expression of FOXL2, which in turn led to testicular BTB structure damage, germ cell loss and ultimate testis to ovary-like gland transformation. Conclusion: Reprogramming of Sertoli cells due to absence of PPP4 may help explain the etiology of disorders of sexual differentiation and male infertility.

AZFa candidate gene UTY and its X homologue UTX are expressed in human germ cells

The Ubiquitous Transcribed Y (UTY) AZFa candidate gene on the human Y chromosome and its paralog on the X chromosome, UTX, encode a histone lysine demethylase removing chromatin H3K27 methylation marks at genes transcriptional start sites for activation. Both proteins harbour the conserved Jumonji C (JmjC) domain, functional in chromatin metabolism, and an extended N-terminal tetratrico peptide repeat (TPR) block involved in specific protein-interactions. Specific antisera for human UTY and UTX proteins were developed to distinguish expression of both proteins in human germ cells by immunohistochemical experiments on appropriate tissue sections. In the male germ line, UTY was expressed in the fraction of A spermatogonia located at the basal membrane probably including spermatogonia stem cells. UTX expression was more spread in all spermatogonia and in early spermatids. In female germ line, UTX expression was found in the primordial germ cells of the ovary. UTY was also expressed during fetal male germ cell development, whereas UTX expression was visible only at distinct gestation weeks. Based on these results and the conserved neighboured location of UTY and DDX3Y in Yq11 found in mammals of distinct lineages, we conclude that UTY –like DDX3Y- is part of the Azoospermia factor a (AZFa) locus functioning in human spermatogonia to support the balance of their proliferation-differentiation rate before meiosis. Comparable UTY and DDX3Y expression was also found in gonadoblastoma and dysgerminoma cells found in germ cell nests of the dysgenetic gonads of individuals with disorders of sexual development and a Y chromosome in karyotype (DSD-XY). This confirms that AZFa overlaps with GBY, the Gonadoblastoma susceptibility Y locus, and includes the UTY gene.

Clinical and Molecular Cytogenetic Characteristics of Five Cases with Isodicentric Y Chromosome

Isodicentric Y chromosome [idic(Y)] is one of the most common structural abnormalities of the Y chromosome and has been observed in patients with reproductive disorders and in patients with disorders of sexual development. Most idic(Y) chromosomes are found in mosaic form with a 45,X cell line. These chromosomes are highly unstable during mitosis due to the presence of 2 centromers, which explains their probable loss in early mitosis or mitosis of the embryo and therefore the presence of the 45,X line. It has been hypothesized that the proportion of 45,X cells in various tissues probably influences the phenotypic sex of individuals carrying an idic(Y) chromosome, ranging from infertile men, hypospadias, ambiguous genitalia, and Turner syndrome to sex reversal. In this article we present 5 cases of patients with idic(Y) referred for suspected disorder of sex development (DSD), 3 with a male assignment and 2 with a female assignment. All cases have variable clinical characteristics, which were assessed by the transdisciplinary group of Disorders of Sex Development of the Hospital Universitario San Ignacio, Bogotá, Colombia. Patients were analyzed by conventional and molecular cytogenetics using high-resolution G-band and FISH techniques. Our findings highlight the importance of cytogenetic studies in the diagnosis of DSD patients.