Facing the Challenge: Hormonal hurdles, Olfaction Obstacles in Kallmann Syndrome

 

Gayatri Made¹*, Jyothi Swapna Raparthi¹, Vinod Kumar Mugada¹, Srinivasa Rao Yarguntla²

¹Department of Pharmacy Practice, Vignan Institute of Pharmaceutical Technology, Duvvada, AP, India.

²Department of Pharmaceutics, Vignan Institute of Pharmaceutical Technology, Duvvada, AP, India.

 

ABSTRACT:

Kallmann syndrome (KS) is an uncommon disorder that was first defined in 1856 and designed by Kallmann in 1944. It is also referred to as olfactogenital dysplasia and is characterized by hypogonadism and the agenesis of the olfactory bulb. The prevalence of KS is not well understood, with the incidence in males ranging from 1 in 8000 to 1 in 10,000 and being less common in females. Kallmann syndrome exhibits genetic heterogeneity, with the inheritance of the trait occurring in an autosomal recessive, autosomal dominant, or X-linked manner. Over 24 genes have been determined to be responsible for Kallmann syndrome, which is thought to be caused by mutations that inhibit the formation of cell markers necessary for the migration of olfactory and GnRH (gonadotropin-releasing hormone) neurons to the forebrain during foetal development. Kallmann syndrome is characterised by hypogonadotropic hypogonadism and hyposmia or anosmia. Other less common symptoms include osteoporosis, cleft lip and palate, cryptorchidism, unilateral renal agenesis, and cardiovascular problems. Magnetic resonance imaging (MRI) can help detect anomalies in the olfactory system and other forebrain regions, as well as pituitary disorders. The treatment for Kallmann syndrome typically involves hormone replacement therapy (HRT) with both testosterone and gonadotropin-releasing hormone (GnRH) analogues to stimulate puberty and promote secondary sexual characteristics.

 

 

 

INTRODUCTION:

Hypogonadotropic hypogonadism with anosmia is commonly referred to as Kallmann Syndrome (KS), which can manifest as either a genetic or sporadic disorder. KS is a relatively uncommon disorder that affects sexual development and is characterized by a combination of hypogonadism (a condition where the gonads produce insufficient sex hormones) and the agenesis (absence or underdevelopment) of the olfactory bulb, leading to a reduced or complete loss of the sense of smell (hyposmia or anosmia).

 

This may be concomitant with normal olfaction or by an aberrant sense of smell¹. In its normosmic variation, it is designated as normosmic idiopathic hypogonadotropic hypogonadism (nIHH) or it can be Idiopathic hypogonadotropic hypogonadism (IHH)^2,3. If it is genetic it is known as Congenital hypogonadotropic hypogonadism (CHH). KS leads to a lack of sexual development in adolescence, with symptoms like amenorrhea in women and underdeveloped testes in men. Other symptoms include underdeveloped secondary sexual traits and a micropenis in males. These symptoms are caused by low levels of follicle-stimulating hormone and luteinizing hormone, which reduce oestrogen and progesterone in females and testosterone in males⁴. It was first linked in 1856 and classified by Franz Josef Kallmann in 1944. Several genes have been linked to KS, with KAL1 being the primary causative gene. Mutations in this gene, as well as FGFR1(Fibroblast growth factor receptor 1) and GNRHR (gonadotropin releasing hormone receptor), can restrict the migration of GnRH cells and olfactory nerves throughout embryonic development, leading to the majority of genetic causes of IHH. KAL1 mutations are inherited through X-linked variation². X-linked Kallmann syndrome affects males due to KAL1 mutation, while females are usually unaffected. Anosmin 1, a protein encoded by the KAL1 gene, plays a crucial role in neural development and migration, and mutations in this gene account for approximately 10-15% of KS cases. FGFR1 is the second genetic factor linked to KS and causes an autosomal dominant form of the condition. FGFR1 regulates GnRH neuron migration during embryonic development, and mutations in this gene impair GnRH neuron migration, leading to hypogonadism.

 

SIGNS AND SYMPTOMS:

Anosmia, Hyposmia, Microcephalus, Cryptorchidism, Amenorrhea, Small penis and testicles, No pubertal erection, Congenital sensorineural deafness, Abnormal pigmentation of the hair, skin and iris. Gynecomastia, physical anomalies such as cleft palate, hypodontia, cleft hand or foot, and renal agenesis may also occur⁶. Other possible anomalies include midline defects, craniofacial anomalies, agenesis of the corpus callosum, and brachy-or syndactyly, along with ptosis, as well as anaemia. The presence of symptoms such as lack of body hair growth, hoarse or absent deepening of voice, ichthyosis, synkinesia, pituitary defects, hypothalamic dysfunction, delayed puberty, and bilateral small testes may indicate underlying medical conditions^2,3.

 

EPIDEMIOLOGY:

Kallmann syndrome, an uncommon hereditary endocrine disorder, is commonly transmitted through the X chromosome and has an estimated incidence of 1 in 8,000 to 1 in 10,000 males, with a male-to-female ratio of five to one. According to Finnish studies, the prevalence of this congenital disorder is 1 in 48,000 individuals. Although the incidence rate of this condition is relatively low in women, affecting approximately 1 in 125,000 women, it is possible that the number of female cases is underestimated^7. Research reported that about 1 in 30,000 men are affected by the syndrome. However, a 2022 study implies that the actual number of cases could be higher than the current estimates⁴.

 

ETIOLOGY:

Kallmann Syndrome (KS) is primarily caused by abnormal development of the hypothalamic GnRH neurons during embryonic development. ANOS1 and FGFR1 gene deficits are the most common causes of KS, but there are 40 different genes with mutations linked to HH disorders, including KS⁸. One such example is KISS1 gene, which encodes the kisspeptin signaling molecule, which is a effective stimulator of GnRH synthesis in the hypothalamus and influenced by environmental factors. KAL1 gene mutations are linked to X-linked forms, while FGF8, FGFR1, SOX10, HS6ST1, WDR11, CHD7, IL17RD and SEMA3A are associated with autosomal dominant forms of Kallmann Syndrome. FEZF1, PROK2, and PROKR2 are associated with autosomal recessive and oligogenic forms of the disorder. Mutations in the KAL-1 gene can affect the migration of olfactory neurons, and GnRH-secreting neurons leading to KS patients losing or having problems with their sense of smell. The KAL adhesion protein cannot be generated in patients with KS, which impedes the migration of the olfactory bulb and GnRH nerve cells¹⁰. Insufficient hypothalamic GnRH release during the development of olfactory bundles can cause luteinizing hormone (LH) and follicle-stimulating hormone (FSH) insufficiency, leading to immature testicular or ovarian tissue in male and female patients, respectively. This can prevent secondary sexual maturation and result in sterility during reproductive           age ⁵.

 

PATHOGENESIS:

The KISS1/Kiss1 gene produces kisspeptin hormone, which regulates puberty and reproduction by controlling the GnRH pathway. Mutations in the KISS1R gene can cause some types of hypogonadotropic hypogonadism (HH). HH and Kallmann syndrome are caused by disruptions in genes and signaling pathways that control the migration and activity of GnRH. The FGFR1 receptor plays an imperative role in the development of the forebrain, skeleton, and neuroendocrine systems. Disruptions in the fibroblast growth factor (FGF) signaling pathway have shown to play a significant aspect in the pathophysiology of CHH and KS. The first mutated gene detected in patients with KS is an extracellular matrix protein termed anosmin-1¹⁰. Anosmin-1 has shown to bind to FGFR1 and regulate the signaling activity of the receptor¹¹. According to¹² anosmin-1 may play a role in heparan sulfate-mediated avotation of certain cell types to the FGFR1/FGF8 signaling complex^13. During puberty, the tachykinin and kisspeptin signaling systems substantially affect the generation and release of GnRH. Kisspeptin-producing neurons are the primary afferents to GnRH neurons and balance the feedback regulation of GnRH and gonadotropin production, as well as the preovulatory surge¹⁴. Within the arcuate and infundibular regions of the hypothalamus, certain subpopulations of neurons are known to co-express neurokinin-Band kisspeptin¹⁵. GnRH neuronal migration may not be necessary for the activation of signaling pathways mediated by kisspeptin and its receptor G protein-coupled receptor-54 (GPR54) during developmental stages^16,14. In animal models, the leptin and insulin signaling pathways exert significant control over GnRH neuronal activity, in addition to their crucial role in the reproductive endocrine system¹⁷.

 

DIAGNOSIS:

The diagnosis of Kallmann syndrome is often diagnosed during adolescence due to insufficient sexual maturation, with symptoms such as primary amenorrhea in females or small testes and a lack of virilization in males. The diagnosis is confirmed by reduced levels of blood gonadotropins and gonadal steroids, as well as impaired olfactory function. Physical assessment typically reveals deficient sexual development and a eunuchoid body habitus¹⁸.

 

The physical examination results, determined using the Tanner staging table.

 

Table 1: Tanner staging table

Stage	Pubic hair	Male genitalia	Female breast development
1	None	The physical characteristics of scrotum, testes and penis during childhood.	No noticeable growth of breast tissue, their areola are small, and their nipples are slightly raised.
2	The hair is thin, lengthy, and has a light pigment.	The testicles have become bigger and the scrotum has a reddish color.	There is the development of breast tissue and the areola have become larger.
3	The hair is now darker, rougher, and has a curled shape.	The testicles continue to grow and the penis is getting longer.	The breast tissue continues to develop and the areola are growing larger, eventually merging with the breast tissue.
4	There is now hair covering the pubic area, which is typical for adults.	The testes continue to enlarge, the penis is widening, the glans is growing, and the scrotum is darkening in color.	The breast tissue is still developing, and the areola and nipples are becoming more prominent, forming a secondary mound above the main contour of the breast.
5	Hair that is typical of an adult, and is distributed across the sides of the body.	Developed adult genitalia.	The nipple is the only part of the breast that protrudes, while the areola and breast tissue blend together smoothly. This indicates a fully developed breast.

Source: Balasubramanian, 2022 ²⁵.

 

In males, testosterone levels should be over 100ng/dL, while females should have estradiol levels over 50 pg/mL. Low levels of FSH and LH combined with lower sex steroid concentrations can indicate hypogonadism. Clinical assessments can confirm the lack of sexual characteristics and a eunuchoid physique. It also highlights the importance of recognizing that the growth of pubic hair may appear natural in both genders due to the production of androgens from the adrenal glands^3,19. It is also important to evaluate olfactory function in individuals with hypogonadotropic hypogonadism to differentiate between Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Even if a small percentage of KS patients have normal olfactory bulb images, forebrain MRI is still essential for infants who are not suitable for extensive olfactory or hypothalamic-pituitary-gonadal axis testing^20,18. The diagnostic evaluation for congenital hypogonadotropic hypogonadism (CHH) involves cranial MRI, bone age assessment, abdominal and/or pelvic ultrasonography, and dual-energy X-ray absorptiometry. The cranial MRI is used to visualize the olfactory and inner ear structures and to detect tumors or space-occupying lesions. Bone age assessment and pelvic/abdominal ultrasonography are important diagnostic tools used to assess bone development and reproductive health in individuals. Bone age assessment compares the level of an individual's bone development with their chronological age by evaluating the degree of epiphyseal closure, while pelvic and/or abdominal ultrasonography is used to detect conditions such as unilateral renal agenesis and examine the internal reproductive organs. These non-invasive imaging techniques allow healthcare professionals to identify potential growth disorders, hormone imbalances, or other underlying medical conditions early on, enabling prompt and effective treatment^20,18.

 

GENETIC TESTING:

Genetic testing is crucial for the diagnosis, prognosis, and genetic counseling of Kallmann syndrome. X-linked inheritance is typical for this syndrome, and determining the inheritance pattern is necessary before undergoing genetic testing for CHH^21,22. The observation indicates that the KAL1 (ANOS1) mutations accountable for Kallmann syndrome possess a characteristic property²³. A thorough analysis of two different modes of inheritance patterns, specifically the autosomal dominant, vertical patterns. The vertical transmission pattern is identified by the transfer of the inherited trait across one or more generations, while the autosomal dominant pattern is recognized by its equal expression in both males and females, with noticeable transmission between males¹⁸. CHH's genetic foundation is intricate, with variable penetrance and expression. Researchers have identified autosomal recessive and autosomal dominant, and X-linked inheritance patterns. The attainment of precise diagnosis, prognosis, and genetic counseling mandates the undertaking of genetic testing. IL17RD, CHD7 and SOX10 are considered potential candidates for genetic screening for CHH owing to their correlation with hearing loss²⁴. Recognizing the early onset of morbid obesity and specific accompanying symptoms may aid in the identification of causal mutations. Moreover, it is important to note that the co-occurrence of CHH with other medical ailments may be indicative of contiguous gene syndrome. A comprehensive examination of comparative genomic hybridization or karyotype array holds the promise of revealing chromosomal aberrations²⁴.

 

TREATMENT:

Kallmann pattern, an inheritable complaint that occurs rarely, can be well-managed through proper medical intervention. The remedial approaches for this condition include administering steroid relief remedies and gonadotropin-based medicinals, which enhance fertility. Likewise, surgical intervention is necessary for males with the condition to correct cryptorchidism, a complaint where the testes fail to descend into the scrotum. To stimulate penile growth in affected males, low-dose testosterone is also administered, and treatment plans are customized based on the case's age and medical history⁶. These curatives grease typical pubertal development, height, and psychosexual development and lower the liability of unseasonable sexual exertion. Also, cerebral comforting may be helpful to address the emotional and social enterprises that individuals with the Kallmann pattern may encounter due to delayed puberty and sexual development. It's important to note that the efficacy of these treatments may differ depending on the condition's inflexibility and individual patient response^6,4.

 

Injectables and transdermal testosterone are the most extensively used forms, while mortal chorionic gonadotropin injections are a voluntary procedure that can also promote testicular growth and regulate testosterone levels. When considering the Human chorionic gonadotropin (HCG) remedy, the implicit threat of gynecomastia should be balanced against the benefits, and gradually reducing the HCG lozenge can help alleviate the threat⁷. For ladies Hormone relief medication is important to maintain secondary coitus characteristics and induce puberty. The estrogen relief remedy for ladies aims to replicate physiological puberty, starting with low boluses and gradually adding Treatment generally begins at age 10 or later and aims to replicate estrogen situations during gonadal development ²⁵. Estradiol is used to treat endometrial hyperplasia in adults and can be taken orally or transdermally. Transdermal operations are preferred over oral administration⁶. During the first two times of treatment, low doses of estrogen are given, and native treatment should only be used when pullout hemorrhage begins and no earlier than two times after estrogen administration²⁶. Ovulation induction drugs are an extensively used strategy to manage gravidity in woman cases with CHH. The primary goal of this approach is to stimulate the growth and release of a single mature egg, while minimizing the threat of multiple gravities. There are several treatment options available, including pulsatile GnRH treatment or an FSH remedy followed by HCG or LH to stimulate ovulation. These specifics work by bluffing the hormonal changes that do during a natural menstrual cycle, thereby promoting the development and release of a mature follicle²⁷.

 

It's worth noting that normal estradiol release is essential for cervical mucus creation and endometrial development, which are necessary for successful embryo implantation and sperm conveyance. Thus, hormone situations are precisely covered throughout the treatment process to ensure optimal outcomes. Subcutaneous FSH boluses of 75- 150IU per day are generally used, although tablets may be acclimated grounded on individual case response. Furthermore, the development of a mature follicle generally takes roughly 12 days, after which ovulation may do. Ultrasound monitoring may be used to track follicular growth and determine the optimal time for ovulation induction^6,27. In some cases clomiphene citrate or letrozole may be used to enhance the response to ovulation induction therapy. It's important to note that the effectiveness of ovulation induction drug may vary depending on a variety of factors, including the inflexibility of CHH and individual patient response. Overall, the administration of ovulation induction drugs is a precious approach to managing gravidity in womanish cases with CHh and can ameliorate the chances of successful gestation and parturition²⁷.

 

Progesterone supplementation may be given to enhance progesterone synthesis after ovulation until embryonic endogenous HCG production takes over during the postovulatory phase. Different pulse frequencies may be used throughout the cycle to provide GnRH and mimic natural ovarian stimulation Fixed-frequency pulsatile GnRH stimulates ovarian follicle growth, leading to an LH peak, and is dosed through subcutaneous injections of 3-10g every 90 minutes gonadotropin therapy poses a higher risk of multiple pregnancies and ovarian hyperstimulation syndrome in comparison to using GnRH for ovulation induction⁶. Both pulsed gonadotropin therapy and GnRH can induce ovulation in females and boost sperm production in males. However, males with the ANOS1 (KAL1) pathogenic mutation may respond differently to treatment²¹. IVF can be considered for couples who are unable to achieve fertility despite efficient spermatogenesis or ovulation induction²⁵. As with any medical treatment, close monitoring and follow- up evaluations are necessary to insure applicable tablets and optimal issues²⁷.

 

COMPLICATIONS:

Disorders that affect hypogonadism, such as Kallmann syndrome, may cause dry skin as a side effect. There may also be signs of neurological abnormalities, such as central hearing loss, mirror motions of the hands (synkinesis), ataxia, and reports of colorblindness and ocular window abnormalities⁴. A double ureter, and horseshoe kidneys are also reported as potential complications of Kallmann syndrome²⁸. A minute proportion of Kallmann syndrome patients, such as those with osteoporosis or porous bones (a disease characterized by low bone mass and structural deterioration of bone tissue)^28,29. Kidney rotation, hydronephrosi (Hydronephrosis describes a urinary tract abnormality where hydrostatic dilatation of the renal pelvis and calyces exists)³⁰. Bone deformities, such as a cleft palate or cleft lip, are one of the most common congenital deformities, might develop gradually and manifest at birth³¹.

 

CONCLUSION:

Kallmann syndrome (KS) is a kind of hypogonadotropic hypogonadism (HH) characterized by a deficiency of sex hormone production and anosmia, which can also affect various organs. KS is an inherited condition. Statistically, the condition is seen in 1 out of every 120,000 females and 1 out of every 30,000 males. Gene mutations associated with KS impair the olfactory nerve cells, resulting in a loss of sense of smell. Diagnostic tests, including hormone evaluation, olfactory function testing, MRIs, and genetic testing, are conducted by healthcare providers if KS is suspected. Hormone replacement therapy is the typical treatment for KS and may include oestrogen and progesterone pills or skin patches for females and testosterone injections or skin patches for males. GnRH injections prompt ovulation in females with irregular cycles, and HCG injections boost fertility in females and sperm count in males.

 

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Received on 21.06.2023         Modified on 19.08.2023

Accepted on 09.10.2023       ©A&V Publications All right reserved