Kallmann Syndrome

What is Kallmann syndrome?

Kallmann Syndrome (KS), otherwise known as anosmic hypogonadism, is a rare genetic condition whereby the body does not make enough gonadotropin-releasing hormone (GnRH), a hormone required for the production of sex hormones in both genders.^1,2 If left untreated, people with Kallmann Syndrome will remain sexually underdeveloped, and infertile.  

Gonadotropin-releasing hormone causes the pituitary gland in the brain to make and secrete the hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In men, these hormones cause the testicles to produce testosterone, and in women, they cause the ovaries to make oestrogen and progesterone.³

A deficiency in GnRH is associated with a normal sense of smell in approximately 40% of affected individuals and an impaired sense of smell in approximately 60%. Only when the sense of smell is affected can it be classified as Kallmann syndrome.⁴

Kallmann syndrome occurs more often in males than in females, with figures showing it affects around 1 in 30,000 males and 1 in 120,000 females.¹ It's important to differentiate Kallmann syndrome from a closely related condition, normosmic idiopathic hypogonadotropic hypogonadism (nIHH), which too causes problems during development and puberty, only without affecting the sense of smell.⁴

Symptoms of Kallmann syndrome

From birth, males may exhibit features such as micropenis or undescended testicles, signalling early signs of the condition. However, the most noticeable symptoms typically arise at puberty due to the lack of sexual maturation.^1,2,5

Symptoms in males:

• Little to no testicular growth.
• Decreased bone density.
• Reduced muscle mass.
• Erectile dysfunction.
• Low libido.
• Infertility.
• Micropenis.
• Undescended testes.

Symptoms in females:

• Amenorrhea (absence of menstrual periods).
• Insufficient breast development.
• Infertility.

Symptoms affecting both genders:

• Impaired or absent sense of smell (anosmia or hyposmia).
• Delayed or absent puberty signs.
• Decreased bone density (increasing the risk of osteoporosis).
• Non-reproductive features that may be present include:
  • Cleft lip or palate.
  • Hearing impairment.
  • Skeletal anomalies such as shortened digits.
  • Dental anomalies.
  • Ocular motor disturbances.
  • Renal anomalies.

Diagnosis of Kallmann syndrome

There are two distinct features of Kallmann syndrome that physicians look out for when prompting for diagnosis:

1. A lack of physical change / sexual development is associated with puberty.
2. An impaired or absent sense of smell. 

Due to the noticeable lack of sexual development, a diagnosis of Kallmann syndrome is typically made by an endocrinologist when examining a patient going through puberty. However, signs such as undescended testicles or a small penis in infancy can also prompt early investigation.^1,2

An endocrinologist can confirm a diagnosis through clinical examination, blood testing, imaging, and using the Tanner staging tool—an established diagnostic method used in the field of endocrinology to determine the development stage of certain sexual characteristics. In some cases, genetic testing may be requested to further assist in diagnosing various forms of this disease.⁵

What is known, however, is that these genetic alterations can be inherited through several mechanisms:

• Autosomal recessive inheritance occurs when a child inherits the faulty gene from both parents, who are carriers but typically do not show symptoms themselves.
  
• Autosomal dominant inheritance refers to inheriting the mutation from just one parent, either the mother or the father.
  
• X-Linked Inheritance is used to describe the condition when females are the carriers, but males may exhibit the symptoms. A mother can pass the condition to her sons, while either parent may have daughters who are carriers.
  
• And, there is a newer understanding of genetic inheritance called oligogenic inheritance that suggests mutations in multiple genes may combine to cause the condition, adding another layer of complexity to its genetic origins.

‍Treatment of Kallmann Syndrome

Currently there is no cure for Kallmann syndrome, but there are treatments that are effective at managing the disease.² Treatment is usually lifelong and involves hormone replacement therapy, with further options available for those seeking fertility. Without treatment, most affected men and women are unable to have biological children due to infertility.¹  

However, getting the right treatment for Kallmann Syndrome can at times be difficult, given the rather private nature of the disease. This has led to a cultural hesitancy among many UK doctors to initiate discussions about hypogonadism, which inadvertently causes delays in treatment. This reluctance can make it challenging for patients to seek help, with some individuals only receiving treatment to induce puberty in their 40s.⁷

On the contrary, Kallmann syndrome is considered a lifelong condition; about 10-15% of patients may experience spontaneous recovery of their hormonal system, though the reasons for this remain unclear.⁵

Kallmann syndrome is not associated with decreased life expectancy, and treated individuals have a normal appearance and function that is indistinguishable from individuals without the condition.⁶ Untreated, the condition can lead to various complications in adulthood, including decreased bone density, muscle mass, infertility, erectile dysfunction in males, and abnormal menstruation (amenorrhea) and insufficient breast development in females. 

Fertility Treatment

If fertility is affected, additional treatment with gonadotropins is necessary to stimulate the gonads.⁶ However, the effects can take up to two years to be apparent for men, whereas women may ovulate after just a week of treatment.⁷

Although fertility can often be achieved, access to treatment poses significant challenges. Patients and healthcare providers may not be aware of the potential for normal fertility, and expertise in inducing spermatogenesis in men is limited.⁷

Success rates for spontaneous impregnation are around 40%, with an additional 20–30% success rate with in vitro fertilisation (IVF).^7,8

‍Prognosis of Kallmann Syndrome

The prognosis for individuals with Kallmann syndrome is generally positive with the right management. While it is a lifelong condition, hormone replacement therapy can effectively address the associated low levels of testosteone, enabling the development of secondary sexual characteristics and improving fertility in many cases.

Early diagnosis and treatment are key to mitigating potential complications, such as reduced bone density or psychosocial challenges. With lifelong treatment, individuals with Kallmann syndrome can lead healthy and fulfilling lives.