kallmann syndrome, also known as loss of smell-hypogonadism syndrome. Disease description: Kallmann syndrome (KS) is a hypogonadotropic hypogonadism with olfactory deficiency or hypoesthesia. KS can be familial or sporadic and is inherited in three ways: X-linked recessive, autosomal dominant, and autosomal recessive. 1856, the Spanish pathologist Maestre de San Juan reported for the first time in the world the presence of olfactory bulb deficiency and small testes in the brain in the same individual. 1944. Kallmann, an American medical geneticist, studied three families with hypogonadism with olfactory loss and found that in all affected patients, olfactory loss and hypogonadism showed a chain of unbalanced “co-segregation”, which identified the disease as a genetic disorder. In the 1950s, the Swiss anatomist de Morsier reported that some men with hypogonadism had hypogonadism with an underdeveloped or absent olfactory bulb and bundle. Some years later, this hypogonadism was attributed to a defect in the secretion of GnRH. The epidemiological features of KS are not known, and a rough estimate of the incidence is 1/8000 in boys and about 1/5 in girls. Etiology and pathogenesis: The pathogenesis of KS is not well understood. At present, it is thought that the GnRH neurons originating from the olfactory substrate may not be able to migrate and localize normally in the hypothalamus for various reasons, resulting in complete or partial loss of the ability to synthesize and secrete GnRH, causing hypothalamic-pituitary-gonadal axis hypofunction and failure to initiate puberty, which is manifested as delayed pubertal development. With the in-depth study of KS genetics, some genes related to KS pathogenesis have been identified one after another, such as KAL1 gene, fibroblast growth factor receptor 1 gene (FGFRI), fibroblast growth factor 8 gene (FGF8), prokinetic protein 2 gene receptor (PROKR2), and prokinetic protein 2 gene (PROK2), the functions of which may be related to GnRH neurons’ normal migration, the development of the olfactory bulb and the projection process of GnRH neurons’ axons to the median bulge are closely related. However, only 30% of Kallmann syndrome cases are associated with these genes, suggesting that there are other genes associated with the development of KS that have not yet been identified. Clinical manifestations: 1. Hypogonadism: most male patients have a lower volume greater than the upper volume, eunuch-like body shape, infantile state of external genitalia, short penis, small testes or cryptorchid, lack of secondary sexual characteristics development at puberty (no beard, axillary hair, pubic hair growth, no voice change),. In female patients, there is no internal or external genitalia development, no breast development, no axillary hair, no pubic hair growth, no menstruation. 2. Absence or hyposmia of smell: Patients may show complete absence of smell, unable to distinguish fragrance and odor, but some patients may only show hyposmia of smell. 3.Related somatic abnormalities: In addition to GnRH deficiency and olfactory deficiency, KS can be accompanied by various somatic abnormalities, including facial midline developmental defects such as cleft lip and cleft palate, short metacarpals and abnormal kidney development. Neurological manifestations include sensory hearing loss, mirroring movements (association band movements), eye movement abnormalities and cerebellar ataxia. To date, abnormal renal development and mirror movements have only been found in X-linked KS. Diagnosis Laboratory tests for peripheral blood GnRH levels are not currently available. The diagnosis of KS is based on: 1) males >18 years of age (selected 18 years of age excludes some cases of puberty at 14-18 years of age); 2) clinical manifestations of hypogonadism; 3) low levels of LH, FSH, and T (T <100ng/dl); 4) thyroid axis function, adrenal axis function 4) normal thyroid axis function, adrenal axis function, growth hormone axis function and lactogen; 5) no organic abnormalities of hypothalamus and pituitary gland on MRI of saddle area; 6) MRI of olfactory bulb/olfactory bundle: olfactory bulb and olfactory bundle were hypoplastic or undeveloped; 7) backward bone age; 8) GnRH excitation test showed delayed response; 9) normal karyotype of chromosome. Differential diagnosis 1. Idiopathic hypogonadotropic hypogonadism At present, hypogonadism with normal olfaction and no clear clinical cause can be found is generally referred to as idiopathic hypogonadotropic hypogonadism (nIHH). Because hyposmia in KS can manifest itself in different degrees, it is sometimes not easy to distinguish clearly between KS and nIHH, especially since patients with hypogonadism often do not have a careful assessment of olfactory function. There is genetic evidence that the genes encoding GnRH and Kisspeptin receptors are associated with nIHH, but not with the migration of GnRH neuroendocrine cells (KS patients may have abnormal migration of GnRH neuroendocrine cells), suggesting that KS and nIHH may have different genetic background and pathogenesis. 2. Somatic delayed pubertal development Due to delayed activity of GnRH pulse-issuing apparatus, resulting in later than normal initiation of puberty in children, there is mostly a family history of delayed growth and development, with clinical manifestations of short stature and concomitant hypogonadism. They often have normal puberty initiation before the age of 18, with a normal pubertal process, and eventually achieve normal sexual maturity. Patients with KS will not have normal puberty initiation. Disease treatment: Currently, the main treatment options for male KS patients are: 1. Androgens: For patients with no need for fertility, androgen therapy can be given after the age of 14 to promote the development of male secondary sexual characteristics, maintain normal sexual function, body fat composition, bone density, and also help maintain normal mood and cognition, but androgen therapy cannot restore fertility. During the use of androgens, bone age should be monitored to avoid premature epiphyseal closure, which may affect the lifelong height of patients in adulthood; it should be reminded that: after 6 months of androgen therapy, the drug can be discontinued for observation and the function of hypothalamic-pituitary-gonadal axis can be re-evaluated. If the unilateral testicular volume increases significantly to more than 4 ml and the endogenous testosterone level increases significantly, the drug should be continued to be discontinued for follow-up, and the reversal of gonadal function should be considered The possibility of returning to normal. 2.Gonadotropin: Gonadotropin treatment has the potential to restore the patient's fertility, and is administered as HCG 2,000-5,000U by intramuscular injection twice a week. After testosterone levels reach the median value for normal adult males, HMG/FSH 75-150 U is added 2-3 times a week. Studies have shown that the median time to sperm production is 7 months. Gynecomastia is a common adverse effect of HCG treatment. Breast development can be avoided if HCG dose is adjusted to maintain serum testosterone at the lower limit of normal value to avoid excessive estrogen production. GnRH pulse therapy: When the anterior pituitary function is normal, GnRH pulse therapy can be considered: a portable infusion pump is used to infuse GnRH subcutaneously in a pulse-like manner every 1.5h-2h to simulate the physiological secretion pattern of GnRH and promote the synthesis and release of anterior pituitary gonadotropin, which in turn promotes testicular growth and development, secretion of testosterone and sperm production. It has been reported that the sperm production rate of patients with GnRH pulse treatment for 12 months is as high as 77%.