What Is Kallmann Syndrome?

Kallmann Syndrome (KS) is a low gonadotropin hypogonadism with loss of or loss of smell. It is a disease with clinical and genetic heterogeneity. KS can be familial or sporadic, and there are three ways of heredity: X-linked recessive inheritance, autosomal dominant inheritance, and autosomal recessive inheritance.

Wu Xueying	(Chief physician)	Department of Endocrinology, Peking Union Medical College Hospital
Mao Jiangfeng	(Attending physician)	Department of Endocrinology, Peking Union Medical College Hospital
Huang Bingkun	(Resident)	Department of Endocrinology, Peking Union Medical College Hospital

On May 11, 2018, the National Health Commission and other five departments jointly formulated the "First Batch of Rare Diseases", and Kalman Syndrome was included. ^[1]

Western Medicine Name: Kalman syndrome
English name: Kallmann Syndrome, KS
Affiliated Department: Internal Medicine-Endocrinology

The main symptoms: Hypogonadism, loss of smell or loss
Main cause: Hereditary diseases
Contagious: Non-contagious

About Kalman Syndrome

In 1856, the Spanish pathologist Maestre de San Juan reported for the first time in the world the absence of an olfactory bulb in the brain and the appearance of a small testicle in the same person. In 1944, the American medical geneticist Kallmann conducted a study of 3 families with hypogonadism and olfactory loss, and found that in all affected patients, the olfactory loss and hypogonadism appear as a co-segregation of linkage imbalance. , Identified the disease as a genetic disease. In the 1950s, Swiss anatomist de Morsier reported that some men with hypogonadism were accompanied by dysplasia or loss of the olfactory bulb and olfactory tract. A few years later, this hypogonadism was due to a defect in GnRH secretion. The epidemiological characteristics of KS are unclear. Roughly, the incidence of boys is 1/8000, and the incidence of girls is about 1/5 of boys.

Kalman syndrome etiology and pathogenesis

The pathogenesis of KS is not very clear. At present, it is thought that the GnRH neurons originating from the olfactory substrate can not normally migrate for a variety of reasons and localize in the hypothalamus, resulting in a complete or partial loss of the ability to synthesize and secrete GnRH, resulting in hypothalamic-pituitary-gonadal axis inability to start Puberty is manifested by delayed pubertal development. With the deepening of KS genetics research, some genes related to the pathogenesis of KS have been discovered, such as KAL1 gene, fibroblast growth factor receptor 1 gene (FGFRI), fibroblast growth factor 8 gene (FGF8), prokinetics Protein 2 gene receptor (PROKR2) and prokinin 2 gene (PROK2). The functions of these genes may be closely related to the normal migration of GnRH neurons, the development of olfactory bulbs, and the projection process of GnRH neuron axons to the midline uplift. But only 30% of the onset of Kallmann syndrome is related to the above genes, suggesting that there are other KS-related genes that have not been found.

Clinical manifestations of Kalman syndrome

1. Hypogonadism: Most male patients have a lower amount than an upper amount, showing a corpus-like shape, a juvenile external genitalia, a short penis, small testis or cryptorchidism, and lack of secondary sexual characteristics during adolescence (no beard, axillary hair, and pubic hair growth , No sound change) ,. Female patients with internal and external genital dysplasia, no breast development during puberty, no axillary and pubic hair growth, no menstrual cramps.

2. Loss or loss of smell: Patients may show complete lack of smell and cannot distinguish odor, but some patients may only show loss of smell.

3. Related physical abnormalities: In addition to GnRH deficiency and lack of smell, KS can be accompanied by a variety of physical abnormalities, including developmental defects such as cleft lip and palate, short metacarpals, and abnormal kidney development. Nervous system manifestations include sensory hearing loss, mirror movement (associated movement), abnormal eye movements, and cerebellar ataxia. So far, kidney dysplasia and mirror movement have been found only in X-linked KS.

Kalman syndrome diagnosis

GnRH levels in peripheral blood are currently unavailable in the laboratory. Routine laboratory tests include: LH, FSH, and T levels. The diagnosis of KS is based on: 1) males> 18 years of age (selecting 18 years of age can exclude some cases when they reach puberty at the age of 14-18), 2) clinical manifestations of hypogonadism, 3) LH, FSH, T T <100ng / dl) low level, 4) thyroid axis function, adrenal axis function, growth hormone axis function and prolactin are normal, 5) no abnormalities in hypothalamus and pituitary organs in MRI of saddle area, 6) olfactory bulb / Olfactory beam MRI: The olfactory bulb and olfactory beam are underdeveloped or undeveloped, 7) the bone age is backward, 8) the GnRH excitation test shows delayed response, and 9) the chromosome karyotype is normal.

Differential diagnosis of Kalman syndrome

1. Idiopathic hypogonadotropin hypogonadism

At present, hypogonadism with a normal sense of smell and no clear cause in clinical practice is generally referred to as idiopathic hypogonadotropin hypogonadism (nIHH). Because KS has different degrees of olfactory decline, sometimes it is not easy to distinguish between KS and nIHH, especially patients with hypogonadism often do not have a careful evaluation of olfactory function. There is genetic evidence that the genes encoding GnRH and Kisspeptin receptors are related to nIHH, but not related to the migration of GnRH neuroendocrine cells (the KS patients may have abnormal migration of GnRH neuroendocrine cells), suggesting that KS and nIHH may have different genetic Background and pathogenesis.

2. Delayed constitutional puberty

Due to the delayed activity of the GnRH pulse dispenser, puberty started later than normal in children, and there is a family history of delayed growth and development. The clinical manifestations are: short stature and hypogonadism. Normal puberty starts before the age of 18, and the puberty process is normal, and normal sexual maturity can be obtained eventually. Patients with KS do not have normal adolescence onset.

Klinefelter syndrome

The disease is a chromosomal abnormality, with a typical karyotype of 47, XXY. Patients present with congenital testicular seminiferous dysplasia, hyaline degeneration, and sexual development during puberty to a certain extent, but the testicular volume is generally less than 4ml. Because the patient's gonadotropins are not effective in stimulating testes to produce testosterone, secondary sexual characteristics are hypoplastic. However, due to normal hypothalamus-pituitary function and insufficient testosterone secretion, the negative feedback inhibition on LH and FSH cells produced by the pituitary gland is weakened, so it is manifested as high gonadotropin hypogonadism, with significant blood LH and FSH levels Elevated, testosterone levels are below normal or the lower limit of normal.

4.Turner syndrome

Female KS patients with primary amenorrhea need to be distinguished from Turner syndrome. Turner syndrome is a disease with abnormal number of chromosomes, with a common karyotype of 45, X0. Clinical manifestations include primary amenorrhea, short stature, naive sex, neck web, elbow Eversion, shortening of the fourth and fifth metacarpals, etc. The karyotype can be identified.

5, CHARGE syndrome

The incidence of CHARGE syndrome is estimated to be about 1 / 8500-12000. The name of the disease is composed of the initials of the following clinical manifestations: coloboma, heart anomalies, choanal atresia, retardation of growth and / or development , Genital anomalies and ear anomalies. Since most patients with CHARGE syndrome also have olfactory bulb hypoplasia / hypoplasia and hypogonadism, and this is the clinical feature of KS, it is necessary to consider whether CHARGE syndrome may be clinically diagnosed. Studies have found that CHARGE syndrome is associated with the CHD7 gene. CHARGE's diagnosis is as follows: eye defects and posterior nostril atresia are the main diagnostic criteria, and the remaining 4 are secondary diagnostic criteria, which can be diagnosed if they meet 4 diagnostic criteria (at least 1 major diagnostic criterion).

Kalman syndrome disease treatment

At present, the main treatment options for male KS patients are:

1. Androgen: For patients with no fertility needs, androgen treatment 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 help maintain normal mood And cognition, but androgen treatment cannot restore fertility. During the use of androgen, it is necessary to monitor the bone age to prevent premature closure of the epiphysis, which affects the patient's life height in adulthood; it is necessary to remind that after 6 months of androgen treatment, the drug can be discontinued and the hypothalamus-pituitary- The function of the gonad axis, such as the unilateral testicular volume significantly increased to more than 4ml, the endogenous testosterone level increased significantly, you should continue to stop the drug follow-up, consider the possibility of reversion to normal gonadal function.

2. Gonadotropin: Gonadotropin treatment may restore fertility in patients. The administration method is HCG 2,000-5,000U, intramuscular injection twice a week. Adjust the medication according to testosterone levels and testicular growth. When testosterone levels reach the median value of normal adult men, add HMG / FSH 75-150U to intramuscular injections 2-3 times a week. Studies have shown that the median time to sperm production is 7 months. Gynecomastia is a common adverse reaction to HCG treatment. If the HCG dose is adjusted to maintain the serum testosterone at the lower limit of normal values to avoid excessive estrogen production, breast growth can be avoided.

3. GnRH pulse therapy: When the anterior pituitary function is normal, GnRH pulse therapy can be considered. Using a portable infusion pump, GnRH is infused subcutaneously every 1.5h-2h, simulating the physiological secretion pattern of GnRH, promoting the synthesis and release of gonadotropin in the anterior pituitary gland, and then promoting testicular growth and development, secreting testosterone and producing sperm. It is reported that the spermatogenesis rate of patients treated with GnRH pulse for 12 months is as high as 77%. ^[2-4]