pediatrics
Male Hypogonadism in Children
Classification of Male Hypogonadism in Children
There are 3 types of hypogonadism: primary, secondary, and a type caused by defective androgen action, primarily due to defective androgen receptor activity. In primary (hypergonadotropic) hypogonadism, damage to the Leydig cells impairstestosteroneproduction, damages the seminiferous tubules, or does both; oligospermia or azoospermia and elevated gonadotropins result. Themost common causeis Klinefelter Syndrome (47,XXY) None Other causes are disorders of sexual development such as gonadal dysgenesis (rare), Cryptorchidism , bilateral anorchia, Leydig cell aplasia, Noonan syndrome, and Rare causes include orchitis due to mumps, testicular torsion, chemotherapy with alkylating drugs, and trauma. Klinefelter Syndrome (47,XXY) None Errors of sex determination and gonadal development,such as gonadal dysgenesis (46,XX or 46,XY) and testicular and ovotesticular disorders of sex development, represent rare forms of male hypogonadism. They may result in a male or undervirilized male phenotype, ambiguous genitals at birth, and some degree of testicular and spermatogenic failure. Cryptorchidism , Inbilateral anorchia (vanishing testes syndrome),the testes were presumably present but were resorbed before or after birth. External genitals and wolffian structures are normal, but müllerian duct structures are lacking. Thus, testicular tissue must have been present during the first 12 weeks of embryogenesis because testicular differentiation occurred andtestosteroneand müllerian-inhibiting factor were produced. Leydig cell aplasiaoccurs when congenital absence of Leydig cells causes partially developed or ambiguous external genitals. Although wolffian ducts develop to some extent,testosteroneproduction is insufficient to induce normal male differentiation of the external genitals. Müllerian ducts are absent because of normal production of müllerian-inhibiting hormone by Sertoli cells. Gonadotropin levels are high with lowtestosteronelevels. Noonan syndromemay occur sporadically or as an autosomal dominant disorder. Phenotypic abnormalities include hyperelasticity of the skin, hypertelorism, ptosis, low-set ears, short stature, shortened 4th metacarpals, high-arched palate, and primarily right-sided cardiovascular abnormalities (eg, pulmonic valve stenosis, atrial septal defect). Testes are often small or cryptorchid.Testosteronelevels may be low with high gonadotropin levels. is caused by enzyme defects that impair androgen synthesis, which may occur in any of the pathways leading from cholesterol to dihydrotestosterone. These congenital problems may occur in Overview of Congenital Adrenal Hyperplasia (eg, steroidogenic acute regulatory [StAR] protein deficiency, 17alpha-hydroxylase deficiency, 3beta-hydroxysteroid dehydrogenase deficiency) when the same enzyme defect occurs in the adrenal glands and the testes, resulting in defective androgen activity and ambiguous external genitals of varying degrees. Causes of secondary hypogonadism include panhypopituitarism, hypothalamic or pituitary tumors, isolated gonadotropin deficiency, Kallmann syndrome, Laurence-Moon syndrome, isolated luteinizing hormone deficiency, Prader-Willi syndrome, and functional and acquired disorders of the central nervous system (eg, trauma, infection, infiltrative disease such as Langerhans cell histiocytosis). Causes of secondary hypogonadism must be differentiated from constitutional delay of puberty, which is a functional form of secondary hypogonadism. Several acute disorders and chronic systemic disorders (eg, chronic renal insufficiency, anorexia nervosa) may lead to hypogonadotropic hypogonadism, which resolves after recovery from the underlying disorder. Hypogonadism is also more common among long-term survivors of childhood cancers treated with craniospinal irradiation. Panhypopituitarismmay occur congenitally or anatomically (eg, in septo-optic dysplasia or Dandy-Walker malformation), causing deficiency of hypothalamic-releasing factors or pituitary hormones. Acquired hypopituitarism may result from tumors, neoplasia, or their treatment, vascular disorders, infiltrative disorders (eg, sarcoidosis, Langerhans cell histiocytosis), infections (eg, encephalitis, meningitis), or trauma. Hypopituitarism in childhood may cause delayed growth, hypothyroidism, diabetes insipidus, hypoadrenalism, and lack of sexual development when puberty is expected. Hormone deficiencies, whether originating in the anterior or posterior pituitary, may be varied and multiple. Kallmann syndromecauses about 60% of congenital forms of hypogonadism. It is characterized by anosmia due to aplasia or hypoplasia of the olfactory lobes and by hypogonadism due to deficiency of hypothalamic gonadotropin-releasing hormone (GnRH). It occurs when fetal GnRH neurosecretory neurons do not migrate from the olfactory placode to the hypothalamus. The genetic defect is known; inheritance is classically X-linked but can also be autosomal dominant or autosomal recessive. Other manifestations include microphallus, cryptorchidism, midline defects, and unilateral kidney agenesis. Presentation is clinically heterogeneous, and some patients have a normal ability to detect odors. Isolated luteinizing hormone (LH) deficiency(fertile eunuch syndrome) is a rare cause of hypogonadism due to monotropic loss of LH secretion in boys; follicle-stimulating hormone (FSH) levels are normal. At puberty, growth of the testes is normal because most testicular volume consists of seminiferous tubules, which respond to FSH. Spermatogenesis may occur as tubular development proceeds. However, absence of LH results in Leydig cell atrophy andtestosteronedeficiency. Therefore, patients do not develop normal secondary sexual characteristics, but they continue to grow, reaching eunuchoidal proportions (arm span exceeds height by 5 cm; pubic to floor length exceeds crown to pubic length by>5 cm) because the epiphyses do not close. Prader-Willi syndromeis characterized by diminished fetal activity, muscular hypotonia, and failure to thrive during early childhood followed later by obesity, intellectual disability, and hypogonadotropic hypogonadism. The syndrome is caused by deletion or disruption of a gene or genes on the proximal long arm of paternal chromosome 15 or by uniparental disomy of maternal chromosome 15. Failure to thrive due to hypotonia and feeding difficulties during infancy usually resolves after age 6 to 12 months. From 12 to 18 months onward, uncontrollable hyperphagia causes excessive weight gain and psychologic problems; plethoric obesity becomes the most striking feature. Rapid weight gain continues into adulthood; stature remains short and may be caused by growth hormone deficiency. Features include emotional lability, poor gross motor skills, facial abnormalities (eg, a narrow bitemporal dimension, almond-shaped eyes, a mouth with thin upper lips and down-turned corners), and skeletal abnormalities (eg, scoliosis, kyphosis, osteopenia). Hands and feet are small. Other features include cryptorchidism and a hypoplastic penis and scrotum. Constitutional delay of pubertyis absence of pubertal development before age 14 years; it is more common among boys. By definition, children with constitutional delay show evidence of sexual maturation by age 18 years, but pubertal delay and short stature may generate anxiety in adolescents and their families. Many children have a family history of delayed sexual development in a parent or sibling. Typically, stature is usually short during childhood, adolescence, or both but ultimately reaches the normal range. Growth velocity is nearly normal, and growth pattern parallels the lower percentile curves of the growth chart. The pubertal growth spurt is delayed, and at the expected time of puberty, height percentile begins to drop, which may contribute to psychosocial difficulties for some children. Skeletal age is delayed and is most consistent with the child's height age (age at which a child's height is at the 50th percentile) rather than chronologic age. Diagnosis is by exclusion of growth hormone deficiency, hypothyroidism, systemic conditions that may interfere with puberty (eg, inflammatory bowel disease, eating disorders), and hypogonadism (whether primary or due to gonadotropin deficiency). 