Overview

Frohlich Syndrome is a rare metabolic disorder named after the neurologist who first described its common signs, also known as adiposogenital dystrophy. It affects children and causes hormone deficiencies that can lead to obesity, poor vision, growth disturbances, delayed puberty, short stature, and underdeveloped genital organs.^1,2 Frohlich Syndrome is not inherited but acquired. It is believed to manifest after damage to the hypothalamus, a brain region closely linked to hormone release stimuli. Such damage is often attributed to tumors and can affect hormones responsible for appetite, body temperature maintenance, sleep regulation and metabolism.¹ It is more common in males than females, and the treatment consists of managing the cause of the lesion to the hypothalamus, which is usually involves removing a tumor in that region.² 

Overview of pathophysiological mechanisms

Interaction between hypothalamic dysfunction and obesity 

The hypothalamus acts as a connection between the endocrine system and brain responses, and vice versa. By sensing blood content, it manages the release and action of specific substances sending signals to the neurons. These signals aim for regulatory responses. Feelings of hunger or satiety are triggered by hypothalamic actions, crucial in the process of regulating body weight and growth. For example, if the hypothalamus detects high insulin or leptin levels in the blood, it might release substances that stimulate the brain into feeling hungry, encouraging food intake.⁴

Hormonal dysregulation 

Hormones regulate and connect the organism, allowing this to function in harmony and to detect alterations to recruit proper responses. Frohlich Syndrome mainly affects children and adolescents, people in the process of maturing and experiencing constant development, growth and changes. The endocrine system plays a crucial role in such processes, especially once puberty starts. During this phase, the body is flourishing and molding to the environment, aiming to evolve to adulthood. The impact of hormonal dysregulations caused by the syndrome during this life phase causes, mainly, impairments in growth, puberty, and metabolism.¹ 

Secondary effects 

The previously mentioned characteristics and mechanisms of Frohlich Syndrome have a strong impact in the development of obesity-related complications (cardiac disorders, diabetes, arthritis, sleep apnea, fatty liver diseases) and delayed or abnormal sexual development (infertility, poorly developed sexual organs).¹

Causes of Frohlich syndrome

Hypothalamic dysfunction 

Among the imbalances triggered by a malfunction of the hypothalamus, the most characteristic to Frohlich Syndrome is the complex net that regulates stimuli for hunger and satiety, sleep cycle, body temperature, and growth development, which are a series of essential actions required to keep the body functional. By stimulating the right organs, to produce and release hormones, it manages the whole organism.³

Dysfunctions of the hypothalamus can affect the patient in a systematic order, causing a cascade of deregulations that can impact the body in a negative way. Such dysfunctions most commonly happen due to physical lesions in the hypothalamic area. Among the causes of these damages, the most common are tumors. A mass of cells growing uncontrollably in this region can affect the balance of the endocrine system. Therefore, tumors account for a large number of cases of hypothalamic damage, and are one of the main causes of Frohlich Syndrome.³ 

Endocrine disorders 

Pituitary gland involvement

The hypothalamus also interacts with other organs to articulate proper and complete responses to the body’s needs. The pituitary gland has a significant role in the balance of the endocrine system. It is stimulated by the hypothalamus to produce and secrete essential hormones involved with a variety of other organs (thyroid, adenohypophysis, ovaries, adrenal glands, kidneys,...) and functions (growth development, ovulation and menstrual cycle, reproduction, blood pressure).⁵ 

• Hypopituitarism: a deficiency in one or more of the pituitary hormones. It can cause a series of imbalances within the net of organs that depend on pituitary hormones to properly function. Hypopituitarism is related to a risk of cardiovascular and respiratory diseases⁵ 
• Growth hormone deficiency: one of the main pituitary hormones, the growth hormone (GH) is responsible for a wide range of body regulations. When deficient, symptoms such as mood disturbances, reduced bone remodeling, altered body fat distribution, hyperlipidemia, and cardiac risk can arise⁶ 

Hormonal imbalances

Some cases of Frohlich Syndrome have its roots in the deficiency of hormones affected by hypothalamus activity. For example, low gonadotropins, also called hypothalamic hypogonadism. Gonadotropins are precursors to sexual hormones, which when in low levels can cause decreased bone and muscle mass, fertility problems and secondary sexual characteristics.⁷ 

Infectious diseases

Studies have shown a correlation between severe infections, like tuberculosis, and posterior development of hypothalamic and pituitary disorders. The infectious mechanisms and the inflammatory responses to them interfere in the production and release of hormones managed in those regions of the brain. The correlation is not yet established, as it needs further investigation, but observations show this tendency.⁸

Environmental and prenatal factors 

Evidence suggests that stressful experiences during pregnancy can impact the baby. Due to the closeness and connection, the fetus can be affected by the mother's reactions to both external and internal stimuli. These can make the fetus susceptible to a number of postpartum problems, including a tendency to develop Frohlich syndrome. Among the possibilities of stressants to the mother are:⁹

• Exposure to radiation or toxins during pregnancy
• Maternal health issues during pregnancy

Genetic factors 

Genetic factors are not established as a direct contribution to the development of Frohlich Syndrome¹. Genetic mutations or syndromes linked to hypothalamic-pituitary or other endocrine dysfunctions may be indirectly associated. 

Risk factors associated with Frohlich syndrome

Age

• Commonly occurs in childhood and adolescence²
• Onset during critical growth periods

Gender

• Higher prevalence in males¹

Tumor

• Craniopharyngioma¹
• Other hypothalamic/pituitary tumors¹

History of radiation exposure

• Therapeutic radiation for other conditions may cause damage to the hypothalamus or the pituitary gland¹⁰ 

Family history

• Inherited predisposition to endocrine disorders

Summary

Frohlich Syndrome is a complex and wide metabolic disorder that happens in children and teenagers. It usually manifests after a lesion to the hypothalamus or the pituitary gland, often being related to a tumor in these areas. The consequences appear as a dysregulation in the endocrine system. Under the impairments to their regulator, essential hormones are not properly supporting the body in its needs, often being deficient. As the syndrome affects people during a significant phase of body development, a variety of processes related to that can be impaired and become a problem through the patient’s life. One of its main characteristics is obesity, once hormones related to the feeling of hunger and satiety are disbalanced, but other symptoms are common as well like, short stature, delayed puberty, vision impairments and drowsiness. It is not an inherited condition, so its main causes are related to lesions to the hypothalamic region and, therefore, its treatment is to treat and manage the damage to this area of the brain (tumoral removal, for example).