Introduction

Frohlich syndrome (Froh-lish), otherwise known as adiposogenital dystrophy, is a rare endocrine disorder that affects boys more than girls and is caused primarily by damage to the hypothalamus from lesions such as tumours. Named after Alfred Frohlich, a pharmacologist and neurologist from Austria who first described it in 1901, the disorder is characterised by numerous symptoms such as excessive eating that leads to obesity, delayed puberty, underdeveloped sexual features (hypogonadism) and short stature. Although initially the disorder was thought to be limited to childhood only, recent research has shown that it can also happen later in life with slightly different symptoms.

The main cause of Frohlich syndrome is often linked to hypothalamic tumours, primarily craniopharyngiomas, which are non-cancerous tumours that normally develop near the pituitary gland of the brain. These are not the only causes, as trauma, injuries during surgery, infections and inflammations can also contribute to the disorder. These conditions cause a change in the hormone levels of the individual, which affects their growth, sexual development, well-being and metabolism.

Recent studies have unveiled that symptoms are slightly different. As with any disorder that targets adults and children, it is important that extra care is given to ensure that help is provided, and symptoms in children can get worse as they get older, for which early diagnosis is crucial. This article aims to explore more about Frohlich syndrome and the differences in its manifestation among individuals of different age groups.

Cause and pathophysiology

Why does Frohlich syndrome occur? The main cause of this disorder is most commonly from problems in the hypothalamus, which is the region of the brain responsible for coordinating a range of tasks such as hunger, thirst, body temperature, mood and sleep. Therefore, any damage or dysfunction in this region due to tumours or inflammation can lead to disastrous results in a range of body functions. This can lead to symptoms such as delayed growth, hypogonadism and obesity. Dysfunction to the hypothalamus can create an impact in the function of the anterior pituitary gland; however, no direct damage happens to the gland. After the hypothalamus and/or anterior pituitary gland are affected, there are several hormonal imbalances that might occur.

The first hormone affected is the Growth Hormone (GH), which is secreted via Growth Hormone-Releasing Hormone (GHRH) and regulated by the hypothalamus. Its role is to primarily promote height in young people by stimulating the Insulin-like Growth Factor 1 hormone (IGF-1) in the liver.¹ In individuals who are affected by Frohlich syndrome, there is a decrease in the secretion of GHRH, which leads to less GH being produced in the pituitary. This leads to affected people having a short stature and increased body fat.

The second important hormone affected is Gonadotropin, which is released from the pituitary gland when Gonadotropin-releasing hormone (GnRH) is secreted from the hypothalamus. They have two main forms: Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH), which work together to perform sexual development; however, they have different tasks in males and females. In males, LH stimulates Leydig cells in the testes to produce testosterone, which is important in male growth and development. If this is inhibited, it can lead to a loss of libido, thereby resulting in poor masculine features such as improper hair growth and poor voice quality. In females, LH works by releasing an egg from the ovary by triggering ovulation and producing progesterone via the corpus luteum.²

FSH in males works predominantly to perform spermatogenesis, which is the process in which Sertoli cells are stimulated in the testes in order to produce sperm. When this is inhibited in Frohlich syndrome, individuals end up with a decreased quality and number of sperm. In females, FSH stimulates oestrogen production and helps follicles in the ovary to grow and prepare them for ovulation. A decreased FSH level in females can lead to problems such as infertility, irregular periods, a loss of libido and decreased oestrogen production.³

Symptoms and presentation

Frohlich syndrome generally shows more prominent symptoms in childhood due to its significant impact on development and growth. One of the main symptoms is disproportionate fat being accumulated around the torso and abdomen, which is made more obvious by no increase in height. Another important sign is a delayed or even absent puberty caused by Gonadotropin release inhibition by either hypothalamic or pituitary dysfunction, as mentioned before. There may also be behavioural and social issues, such as poor performance at school, low social interaction and lethargy.

In adults, the symptoms are more subtle and can be nonspecific, leading to a delayed or incorrect diagnosis. Obesity is still a key feature; however, there is no growth retardation that is usually seen in children. On the other hand, hypogonadism becomes a much more prominent marker in adults, with many individuals reporting a reduced libido, infertility and also physical and emotional disturbances such as fatigue, muscle weakness, depression and anxiety. Some individuals can also experience vision difficulties in cases where there is a specific hypothalamic tumour, such as craniopharyngioma.

Diagnosis

Diagnosis of Frohlich syndrome can be done as a mix of physical examinations, neuroimaging tests and hormonal evaluation. Physical and visual examination of the body, looking for growth retardation, obesity, hypogonadism and delayed puberty can be quickly identified by a medical professional and is very straightforward. Scans taken of the body, such as MRI or CT scans, can be used to identify any tumours or other abnormalities in the hypothalamus or pituitary, which are often considered the main cause of Frohlich syndrome. Hormonal tests can be performed, measuring the levels of the various hormones present in the body, such as LH and FSH.

There are some difficulties in diagnosing Frohlich syndrome in adults. Identifying symptoms in children is straightforward and easy due to the fact that the irregularities, such as a delayed puberty, an increase in body fat and an absent or delayed growth in height, can be very quickly identified. In adults, there can be a delay in diagnosis because symptoms such as obesity, reduced libido and fatigue can be attributed to lifestyle choices or misdiagnosed as another illness, so a professional clinical consultation may be needed.

Management of symptoms

In people affected by Frohlich syndrome, a multidisciplinary targeting route would most likely be needed. If a craniopharyngioma is present in the hypothalamus or pituitary gland, surgery might be necessary to remove it.⁴ If there is a considerable hormone inhibition, some individuals may have to go for hormone replacement therapy to increase levels of hormones such as testosterone for males and oestrogen for females.

Alongside medication and surgery, there may also be counselling sessions and interventions, where the person would be given advice and support to help with their body fat, including nutritional recommendations and exercises to do. If an individual’s social life and confidence are affected, psychological support may be provided to help with behaviour, self-esteem and also educational help with school and college.

Differences in treatment will arise from the age of the individual and their sex. In children, the primary focus will be to restore normal growth and development of the body, ensuring that there is no delay in puberty. This, in turn, will lead to a long-term improvement in physical and psychological health. In adults, the focus is more on fertility and quality of life, making sure that there is no misdiagnosis, but also that the individual is able to enjoy life. Since there is often a prolonged, untreated period in adults where symptoms can be misinterpreted, there can be a risk of a lower success rate in managing symptoms.

Conclusion

Frohlich syndrome shows differences in symptoms between children and adults and thus has different ways to manage and treat the disorder. In children, the main symptoms are generally growth retardation, delay in puberty and also unexplained obesity. In adults, the symptoms such as hypogonadism, fatigue and emotional problems can go undetected for longer, which can cause long-term issues. Management of these symptoms can also vary between childhood and adulthood. In children, the focus is mostly on restoring body development, ensuring puberty is unaffected, losing body weight and boosting confidence. In adults, managing the symptoms is not only medicinal, but can also be emotional and psychological, to make sure that the quality of life is improved. The important factor is to ensure that early intervention takes place to diagnose the illness and ensure that regular support is provided.