Kallmann Syndrome (Kallmann Syndrome) of Rare Disease Series

PART 01.
Overview Kallmann Syndrome (Kallmann Syndrome, KS) is a disease characterized by hypogonadotropin function and hypoosmia or loss, and is the cause of idiopathic hypogonadotropic hypogonadism (IHH) A subtype, accounting for 60% of IHH
.
The levels of sex hormones such as testosterone, estradiol, luteinizing hormone (LH) and follicle stimulating hormone are low in patients, and the interaction between luteinizing hormone, follicle stimulating hormone and estradiol is also disturbed
.
As a genetic disease, there are multiple genes related to the syndrome
.
They are located on different chromosomes and have different inheritance patterns
.
The clinical manifestations are underdeveloped secondary sex characteristics and impaired gametogenesis, as well as olfactory disorders
.
Male patients may have small testes, azoospermia, poor development of male secondary sexual characteristics, beardless Adam's apple, and decreased testosterone secretion
.
Women may have early puberty development, such as pubic hair growth and breast development, but this situation will stop and menarche will not occur spontaneously[1]
.
In addition, it may be accompanied by other diseases such as mirror movement of the eye, cleft palate, and renal hypoplasia
.
Kalman syndrome mostly affects men.
The incidence rate is 1:10000 for men and 1/50000-1/60000 for women.
The ratio of male to female is roughly 5:1.
Most cases are sporadic [2]
.
On May 11, 2018, the National Health Commission and other five departments jointly formulated the "First Batch of Rare Disease Catalog", in which Kalman syndrome was included
.
PART 02.
Causes During fetal development, GnRH (gonadotropin-releasing hormone) neurons located in the olfactory epithelium need to pass through the olfactory tract to migrate to the hypothalamus and play a normal physiological role
.
Due to the developmental disorder of the olfactory bulb and olfactory tract, GnRH neurons cannot migrate to the hypothalamic area, resulting in a lack of GnRH neurons in the hypothalamic area and unable to activate the function of the gonadal axis
.
Kalman syndrome has strong clinical phenotypic heterogeneity and genetic heterogeneity
.
Except for gonadal dysplasia and congenital anosmia or hypoosmia, the corresponding phenotypes of different genotypes are not the same, even if the phenotypes caused by the same gene mutation may be different
.
Has a clear genetic mutations can lead to a variety of Kallmann syndrome, such as KAL1, FGFR1, FGF8, GNRHR, PROK2, PROKR2, CHD7 and so on
.
Among them, KAL1 mutations are mainly inherited by X chromosome recessively, while FGFR1 and PROKR2 mutations are mainly inherited by autosomal dominant
.
PART 03.
Treatment At present, patients with Kalman syndrome need long-term medication replacement therapy to maintain secondary sexual characteristics and hormone homeostasis in the body, and improve the quality of life
.
A clear diagnosis of the disease at an early stage is critical to correct treatment, and the older the patient, the worse the effect will be
.
For patients with complete or partial loss of smell, there is currently no effective treatment
.
Existing treatment methods are mainly targeted at hypogonadism
.
For male Kalman patients, the main treatment options include testosterone replacement, gonadotropin spermatogenesis and pulsed GnRH spermatogenesis
.
Androgen replacement therapy can promote virilization, allowing patients to complete normal sexual life and ejaculation, but can not produce sperm; gonadotropin therapy can promote the production of testosterone and sperm; pulse GnRH therapy promotes the testis by promoting the secretion of gonadotropins by the pituitary gland Development
.
For female Kalman patients, when there is no need for fertility, cyclic estrogen and progesterone replacement therapy is given to promote the development of secondary sexual characteristics
.
When there is a need for fertility, gonadotropin ovulation induction therapy or pulsed GnRH therapy is feasible
.
· Gonadorelin Gonadorelin is a synthetic gonadotropin releasing hormone, a decapeptide hormone GnRHR agonist
.
In 1996, China first approved Maanshan Fengyuan Pharmaceutical Co.
, Ltd.
's gonarelin for injection (H10960063, H10960064) for the differential diagnosis of fertility disorders caused by hypothalamus or hypopituitarism, and gonadal atrophic diseases in men or women.
Insufficient gonadal function, galactorrheic amenorrhea, primary and secondary amenorrhea, menopause and precocious menopause, pituitary tumors, pituitary organ damage and actual hypothalamic dysfunction, etc.
, have the function of releasing pituitary gonadotropin
.
According to Yaodu.
com, Maanshan Fengyuan Pharmaceutical Co.
, Ltd.
's gonarelin for injection is an exclusive product listed in the country, and there is no other registration for this product in China
.
· Chorionic gonadotropin for injection Chorionic gonadotropin for injection is a gonadotropin drug
.
For women, it can promote and maintain the function of the corpus luteum and make the corpus luteum synthesize progesterone
.
It can promote the formation and maturation of follicles.
It can simulate the peak of physiological luteinizing hormone to induce ovulation
.
For men, the testes of those with insufficient pituitary function can produce androgens, which can promote the decline of testes and the development of male secondary sexual characteristics
.
It is approved in China for the treatment of male infertility caused by hypopituitarism and female anovulatory infertility caused by insufficient pituitary gonadotropin
.
China currently has 14 pharmaceutical manufacturing companies including Livzon Group Livzon Pharmaceutical Factory, Maanshan Fengyuan Pharmaceutical, Shenyang Sunshine Pharmaceutical, Guangdong Xinghao Pharmaceutical, etc.
, with a total of 49 approval document numbers
.
· GnRH pulse therapy[4] According to the "2016 GnRH Pulse Therapy Expert Consensus (Draft)", GnRH pulse therapy is a miniature GnRH input device controlled by artificial intelligence, which uses pulsed subcutaneous injection of GnRH analogues , To simulate the hypothalamic GnRH physiological pulse secretion mode, so as to effectively stimulate the pituitary gland to secrete gonadotropin, and then promote the development of the gonads, secrete sex hormones and gametes, and obtain fertility
.
The GnRH pulse pump is composed of four parts: an artificial intelligence control system containing a microelectronic chip, a battery-driven mechanical pump system, a medicine reservoir, and a subcutaneous infusion device connected to it
.
The front end of the infusion tube can be buried under the patient's skin.
In the working state, the pump mechanical system receives instructions from the control system, drives the piston in the reservoir, and injects the GnRH analogue into the subcutaneous through the infusion tube according to a predetermined setting
.
The clinical application of GnRH pulse therapy began in 1982, mainly for the treatment of IHH
.
At the same time, the domestic GnRH pulse pump was developed and tested for clinical use
.
Limited by technical conditions, it cannot be promoted clinically
.
At the beginning of the 21st century, the new pulse pump with micro-motor technology and a specially developed artificial intelligence control system has been significantly reduced in size, and can be infused regularly and quantitatively; the frequency and dose can be adjusted; the pulse infusion is fast and accurate; it is easy to operate and has high safety
.
At present, China has approved three hormone injection pumps for the subcutaneous injection of gonadotropin releasing hormone (GnRH)
.
PART 04.
Summary Most rare diseases are life-threatening chronic, serious, and genetic diseases.
The most common genetic diseases at present are autosomal dominant, autosomal negative, and X-linked negative genetic diseases
.
Most rare diseases occur in the early stages of life and can be prevented through pre-marital, pre-pregnancy, and pre-natal screening
.
Most of the nearly 7,000 rare diseases in the world still lack effective treatments
.
The United States has approved more than 600 drugs for rare diseases, and the European Union has approved more than 100 drugs[5]
.
Compared with Europe and the United States, China has a huge population base and a relatively large number of rare diseases.
However, patients can choose fewer drugs than Europe and the United States, and treatment costs are higher
.
In May 2018, the National Health Commission and other five departments jointly announced China's "First Batch of Rare Disease Catalog".
The catalog included 121 rare diseases, of which more than 50 have been listed in China and have indications
.
From a market perspective, the rare disease drug market is still a big pie.
Especially in the context of the continuous implementation of favorable policies such as the country's encouragement of new drug innovation, there is still a lot of room for development in new drug research and development. .
References [1] Marie Aln?s, Knut Olav Melle.
Kallmann syndrome[J].
Tidsskr Nor Laegeforen.
2019: 139(17).
[2] Wang Lizhi
.
Kallmann syndrome-family report[J].
Chongqing Medicine, 2009, 38(16): 2134-2135.
[3] Liu Mengying
.
The genetic study of Kalman syndrome [D], 2013.
[4] Expert consensus on gonadotropin releasing hormone (GnRH) pulse therapy (draft), 2016
.
[5] Tang Yan, Li Jiantao, Maydan, et al
.
Research progress in analysis of the impact of rare disease drugs on budget[J].
Chinese Pharmaceutical Journal.
2020, 55(9):704-708.