From the Guidelines
Kallmann syndrome is a genetic disorder characterized by delayed or absent puberty and an impaired sense of smell, and its treatment should prioritize hormone replacement therapy and fertility management to improve quality of life and minimize morbidity and mortality.
Definition and Pathophysiology
Kallmann syndrome occurs due to a defect in the migration of GnRH neurons during embryonic development, leading to hypogonadotropic hypogonadism, as noted in the context of hypogonadotropic hypogonadism treatment 1. The disorder is associated with an impaired sense of smell, which is a key diagnostic feature.
Treatment Approach
The treatment of Kallmann syndrome typically involves hormone replacement therapy to induce puberty and maintain secondary sexual characteristics. For males, testosterone replacement is not recommended for those interested in current or future fertility, as it can inhibit spermatogenesis 1. Instead, human chorionic gonadotropin (hCG) and FSH injections may be used to restore testosterone production and spermatogenesis.
Fertility Management
For fertility, both sexes may require gonadotropin therapy with FSH and LH or pulsatile GnRH, as suggested by the guidelines for male infertility treatment 1. Early diagnosis and treatment are crucial to prevent complications like osteoporosis and psychological issues related to delayed puberty.
Genetic Counseling
Genetic counseling is also important as Kallmann syndrome can be inherited in X-linked, autosomal dominant, or autosomal recessive patterns, with several genes potentially involved including KAL1, FGFR1, and PROKR2. The most recent guidelines emphasize the importance of individualized treatment approaches and careful consideration of the potential effects of hormone therapy on fertility 1.
From the Research
Definition and Characteristics of Kallmann Syndrome
- Kallmann syndrome (KS) is a genetic disorder characterized by hypogonadotropic hypogonadism and anosmia 2, 3, 4, 5, 6
- It is marked by a deficiency in the production of sex hormones, leading to delayed or absent puberty and a reduced or absent sense of smell 2, 3, 6
- The syndrome can also present with non-reproductive, non-olfactory symptoms, depending on the genetic form of the disease 2, 3
Genetic Basis of Kallmann Syndrome
- Kallmann syndrome is a genetically heterogeneous disorder, with six causal genes identified: KAL1, FGFR1, FGF8, CHD7, PROKR2, and PROK2 2
- The KAL1 gene is associated with X-linked recessive inheritance, while other forms can be autosomal dominant or recessive 6
- Germline mutations in the KAL1 gene can lead to a deficiency in GnRH hormone, resulting in low levels of circulating gonadotropin and testosterone 6
Clinical Manifestations and Diagnosis
- Cardinal features of patients with KS include hypogonadotropic hypogonadism and anosmia or hyposmia 2
- Other clinical manifestations can include midline cranial anomalies, dental agenesis, optic problems, and mirror movements of the upper limbs 2
- Diagnosis is based on clinical findings, as the sensitivity of molecular testing is only about 30% 2
- Plasma levels of luteinising hormone, follicle stimulating hormone, and estradiol can be very low in patients with KS 3
Treatment and Management
- The goal of treatment is to induce and maintain secondary sex characteristics, as well as enable fertility in some patients 2, 6
- Treatment options include hormone replacement therapy, gonadotropin, and gonadotropin-releasing hormone therapy 2, 3, 5
- Early diagnosis and treatment can prevent complications associated with KS, such as infertility and osteoporosis 6