Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ogechukwu Hannah Nnabude, MD

Harvey Williams Cushing named the condition Fröhlich syndrome after Alfred Fröhlich. French nationals Dr. Jean Camus (1872–1924) and Dr. Gustave Roussy (1874–1948) first undertook systematic and controlled observations of the effects of localized injuries to the basal hypothalamus in dogs and cats. Their observations led them to claim that both permanent polyuria and adiposogenital dystrophy are symptoms caused by damage to the ITR.

There is no established system for the classification of adiposogenital dystrophy.

The pathogenesis of adiposogenital dystrophy is believed to result from damage to the hypothalamus which links the nervous system to the endocrine system through the pituitary gland. This leads to a disruption of hormone production.

There are various types of lesion that can lead to adiposogenital dystrophy, most of which result from an injury of a part of the arcuate nucleus and ventromedial nuclei of the hypothalamus. Deep brain stimulation has also been seen to produce similar symptoms in patients with Parkinson’s disease.

Other diseases such as Prader-Willi syndrome, Bardet-Biedl syndrome, Klinefelter’s syndrome and Borjeson syndrome can cause polyphagia, obesity, and a delayed puberty. Proper testing can be used to differentiate these diseases from adiposogenital dystrophy.

The prevalence of adiposogenital dystrophy is currently unknown, however, it is more commonly seen in males.

Common risk factors in the development of adiposogenital dystrophy are male sex, hypothalamic tumors, infectious, autoimmune, chemical, traumatic, and radiation insults to the brain.

There is currently no recommended screening for adiposogenital dystrophy.

The symptoms of adiposogenital dystrophy are due to deficiency of hypothalamic and pituitary hormones. Some complications of adiposogenital dystrophy includeobesity, mental retardation, and diabetes insipidus. The condition will not improve without treatment and often worsens over time.

Imaging, laboratory tests, hormonal assay, molecular and genetic test are useful in the diagnosis of adiposogenital dystrophy.

The history and symptoms of adiposogenital dystrophy are related to the loss of hypothalamic and pituitary hormones. Examples include a history of traumatic brain injury, a history of radiation treatment, a headaches, a vision disturbances, prepubertal obesity, polyphagia.

Patients with adiposogenital duystrophy may show the following physical findings associated with hypothalamic and pituitary dysfunction including short stature, obesity, delayed puberty, small testes.

Laboratory findings are crucial in the diagnosis of adiposogenital dystrophy. Pituitary hormones are low and there may also be downstream hormonal deficiencies such as estrogen deficiency, testosterone deficiency, and hypothyroidism. Electrolyte imbalance may also be seen.

There are no ECG findings associated with adiposogenital dystrophy.

There are no head X-ray findings associated with adiposogenital dystrophy. However, on skeletal X-ray, delayed ossification may be revealed.

CT scan is not the imaging study of choice for patients with adiposogenital dystrophy, however, it may be used in emergencies. It may reveal tumors, suprasellar calcifications, or pituitary destruction.

MRI is better than CT scan for diagnostic imaging the pituitary gland, hence it is considered to be the gold standard imaging modality for adiposogenital dystrophy. It may reveal tumors, suprasellar calcifications, or pituitary destruction.

Patients with adiposogenital dystrophy may suffer from vision impairments such as bitemporal hemianopsia and color vision impairment. It may be severe enough to render the patient legally blind.

There are no other imaging modalities used for [[adiposogenital dystrophy besides X-ray, CT scan, and MRI.

Molecular and genetic testing for DNA methylation to rule out other diseases that are similar to adiposogenital dystrophy.

Treatment modalities include hormone replacement, surgery and appetite suppressants. Diet and exercise are also helpful.

Hormonal supplementation can be used for treating hormone deficiencies, if present. Appetite suppressants, diet, and exercise are also used to manage obesity.

Patients with tumors may benefit from biopsy and surgery.

There is no primary prevention available for adiposogential dystrophy.

There is no Secondary prevention available for adiposogential dystrophy.

Treatment of adiposogenital dystrophy can very expensive, with hormone replacement and surgery costing tens of thousands of dollars per year.

Information on current clinical trials can be found at https://clinicaltrials.gov/. Some current clinical trials also are posted on https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/ Clinical trials sponsored by private sources http://www.centerwatch.com/ For information about clinical trials conducted in Europe https://www.clinicaltrialsregister.eu/“Froelich Syndrome – NORD (National Organization for Rare Disorders)”.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ogechukwu Hannah Nnabude, MD

Harvey Williams Cushing named the condition Fröhlich syndrome after Alfred Fröhlich. French nationals Dr. Jean Camus (1872–1924) and Dr. Gustave Roussy (1874–1948) first undertook systematic and controlled observations of the effects of localized injuries to the basal hypothalamus in dogs and cats by pricking on their infundibulo-tuberal region (ITR) with a heated needle. This series of surgical procedures, performed from 1913 and 1922, led them to claim that both permanent polyuria and adiposogenital dystrophy are symptoms caused by damage to the ITR.

In 1901, Harvey Williams Cushing named the condition Frohlich syndrome after Alfred Fröhlich, the first person to publish an article regarding an adiposogential syndrome seen in a young boy with a pituitary cyst. He realized that the symptoms described by Frohlich were similar to those of a female patient named Mary D he had who had a similar tumor ^[1]. In 1902, Harvey Williams Cushing attempted to remove the tumor but failed. The tumor was found at autopsy ^[1]. The French nationals Dr. Jean Camus (1872–1924) and Dr. Gustave Roussy (1874–1948) first undertook systematic and controlled observations of the effects of localized injuries to the basal hypothalamus in dogs and cats by pricking on their infundibulo-tuberal region (ITR) with a heated needle. This series of surgical procedures, performed from 1913 and 1922, led them to claim that both permanent polyuria and adiposogenital dystrophy are symptoms caused by damage to the ITR.^[2]

Adiposogenital dystrophy has several other names:^[3]

• Babinski-Fröhlich syndrome^[4] (named after Joseph Babinski^[5] and Alfred Fröhlich,^[6] but probably first described by Giovanni Battista Morgagni|Morgagni). It was given its name by Harvey Cushing.^[7]
• Froelich’s syndrome
• Frölich’s Syndrome
• Hypothalamic Infantilism-Obesity
• Launois-Cleret Syndrome
• Sexual Infantilism

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ogechukwu Hannah Nnabude, MD

There is no established system for the classification of adiposogenital dystrophy.

There is no established system for the classification of adiposogenital dystrophy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ogechukwu Hannah Nnabude, MD

The pathogenesis of adiposogenital dystrophy is believed to result from damage to the hypothalamus which links the nervous system to the endocrine system through the pituitary gland. This leads to a disruption of hormone production. This occurs regardless of the cause of adiposogenital dystrophy.

Adiposogenital dystrophy is an acquired disorder that result from lesions that damage the infundibulo-tuberal region in the floor of the third ventricle. Such lesions affect the hypothalamus. Possible causes include tumors such as craniopharyngioma, encephalitis, Friedreich Ataxia or demyelinating diseases. If a tumor is involved, symptoms such as vision impairment and headache can occur. Regardless of the cause, hypothalamic dysfunction and hypopituitarism is observed and majorly affects the somatotropic hormones and the gonadotropins leading delayed puberty and hypogonadism. ^[1]. It has also been postulated that leptin and insulin disruption due to hypothalamic injury may be a possible factor in the development of hypothalamic obesity. ^[2]. However, the levels of ghrelin, an appetite stimulating hormone produced in the gut, is at similar levels to those seen in individuals with common obesity ^{[3] [4]}. Also, patients with adiposogenital dystrophy have a lower postprandial ghrelin response in comparison to healthy patients of similar body mass index and total body fat ^[5].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ogechukwu Hannah Nnabude, MD

There are various types of lesion that can lead to adiposogenital dystrophy, most of which result from an injury of a part of the arcuate nucleus and ventromedial nuclei of the hypothalamus. Deep brain stimulation has also been seen to produce similar symptoms in patients with Parkinson’s disease.

• The most common cause of adiposogenital dystrophy are tumors affecting the hypothalamus or pituitary. In children, the most common tumor that would cause adiposogenital dystrophy is a craniopharyngioma, a tumor arising from the Ratke’s pouch^[1].
• Inflammation due to infections such as tuberculosis, and encephalitis ^{[2] [3]}

• Neurosarcoidosis ^{[4] [5]}

• Deep brain stimulation ^{[6] [7]}. Some patients were observed to have an increase in weight of up to 20kg^[8].

• Chemotherapy ^{[9] [10]}

• Traumatic brain injuries ^{[11] [12]}

• Radiation ^{[13] [14]}

• Other causes of adiposogenital dystrophy include Friedreich ataxia, demyelinating diseases, and microcephaly^{[15] [16]}

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ogechukwu Hannah Nnabude, MD

Adiposogenital dystrophy must be differentiated from other diseases that cause polyphagia, obesity, and a delayed puberty such as Prader-Willi syndrome, Bardet-Biedl syndrome, Klinefelter’s syndrome and Borjeson syndrome.

Disease/Condition	Clinical presentation	Demographics/History	Diagnosis	Treatment
Adiposogenital Dystrophy	Partial destruction of hypothalamic nuclei resulting in hormonal dysfunction with obesity, growth retardation, and hypogonadism. Deep brain stimulation may also cause symptoms similar to adiposogenital syndrome [1] [2].	Prevalence is unknown, but it is more common in males [3] [4]	Diagnosis is based on visual field tests, hormonal assays, CT, MRI, autoimmune assays	Diet and exercise Radiation Surgery, thermoablation, radiosurgery Hormone replacement[5]
Prader-Willi Syndrome	It presents with hyperphagia, hypogonadism, truncal obesity, intellectual disability, growth delay, hypotonia, almond-shaped palpebral fissures, narrow frontal diameter, thin upper vermilion with downturned corners of the mouth behavioral problems such as anxiety and temper outbursts [6]	Prader Willi Syndrome has a prevalence of 1 in every 1 in 20000 to 1 in 30000 births[7]. Females and males can be equally affected, and there is no difference between races and ethnicities[8]. Most cases of Prader Willi syndrome are sporadic, but familial cases can present when the paternal genes carry a microdeletion in the imprinting center inherited from his mother[9].	Molecular testing for DNA methylation Fluorescence In Situ Hybridization to investigate 15q11-q13 Chromosomal microarray to determine presence of maternal disomy[9].	Hormone replacement[10] Cognitive and behavioral therapy[11]
Bardet-Biedl Syndrome	Visual impairment Polydactyly, brachydactyly or syndactyly Obesity Renal and genital abnormalities Neurological and mental deficits such as learning difficulties developmental delay, speech deficit, ataxia Diabetes mellitus Congenital heart disease	It is a rare autosomal recessive genetic disorder. [12]. Males and females are affected equally[13]. Increased in the Arab population of Kuwait at a prevalence of approximately 1:13500[14]	Bardet–Biedl syndrome mutations can be diagnosed by genomic sequencing which would show the coding regions of the genes implicated in causing the disease[15].	Treatment is symptomatic with focus on managing co=morbidities especially diabetes, hypertension, and obesity [16].
Klinefelter Syndrome	Gynecomastia Azoospermia and infertility Dyslipidemia Obesity Increased risk for osteoporosis, autoimmune diseases and neoplasia Impaired social skills Insulin resistance	It is the most common chromosomal disorder in males with about 1:500 to 1:650 affected. [17] [18].	Klinefelter syndrome can be definitively diagnosed by chromosomal karyotyping [17]	It is treated by testosterone replacement therapy[17].
Börjeson-Forssman-Lehmann syndrome	Visual impairment Intellectual disability Polyneuropathy Epilepsy Cleft palate Obesity Gynecomastia	It is a rare X-linked recessive genetic disorder. Females rarely show symptoms or have mild symptom	Diagnosis is confirmed by the identification of a PHF6 mutation[19].	Surgery for cleft palate and cryptorchidism Medication can help with epilepsy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ogechukwu Hannah Nnabude, MD

The prevalence of adiposogenital dystrophy is unknown.

The prevalence of adiposogenital dystrophy is currently unknown, however, it is more commonly seen in males^[1].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ogechukwu Hannah Nnabude, MD

Common risk factors in the development of adiposogenital dystrophy are male sex, hypothalamic tumors, infectious, autoimmune, chemical, traumatic, and radiation insults to the brain.

Risk factors for adiposogenital genital dystrophy include:

• Tumors of the hypothalamus and pituitary^[1]
• Male sex ^[2]
• Radiation ^{[3] [4]}
• Autoimmune disease ^{[5] [6]}
• Traumatic brain injuries ^{[7] [8]}
• Infections^{[9] [10]}
• Chemotherapy ^{[11] [12]}
• Deep brain stimulation ^{[13] [14]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ogechukwu Hannah Nnabude, MD

There is currently no recommended screening for adiposogenital dystrophy

There is currently no recommended screening for adiposogenital dystrophy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ogechukwu Hannah Nnabude, MD

The symptoms of adiposogenital dystrophy are due to deficiency of hypothalamic and pituitary hormones. The condition will not improve without treatment and often worsens over time.

Patients develop prepubertal obesity with fat deposition at the breasts, hips, femoral regions, and abdomen, Dehydration and hypernatremia can occur as a result of antidiuretic hormone deficiency. Mental retardation may also be seen^[1]. Radiologic findings include delayed bone ossification. If a pituitary tumor is involved, there may also be visual disturbances, which may be seen with or without compression of the optic chiasm ^{[2] [3]}.

Complications of adiposogenital syndrome include^[4][5]:

• Obesity which can further lead to a variety of health conditions
• Mental retardation which has socioeconomic impact on the patient, the patient’s family, and the society
• Diabetes insipidus which may lead to dehydration, electrolyte imbalance, organ dysfunction and death
• Short stature
• Infertility
• Osteoporosis and an increased risk of fractures

Prognosis depends on the underlying cause. Without treatment, there is no improvement in the condition. Radiation and surgical removal of tumors may aid in treatment. Hormone replacement for the hormones that are underproduced as well as diet and exercise are important in the management of the condition^[6].

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