What Is Kobberling Dunnigan Syndrome?

Introduction

Familial partial lipodystrophy (FPL) is a rare genetic disorder characterized by the gradual and specific loss of body fat, known as adipose tissue, occurring in different body parts.  People with FPL typically experience a reduction in fat under the skin(subcutaneous fat) in their arms and legs, while fat loss in the head and trunk regions may vary or may not occur at all. Conversely, individuals affected by FPL may experience excessive accumulation of subcutaneous fat in other body areas, particularly the neck, face, and intra-abdominal regions. Subcutaneous fat refers to the layer of fatty or adipose tissue located directly beneath the skin. In most cases, the loss of adipose tissue typically begins during puberty. FPL is also known as Kobberling-Dunnigan syndrome or lipoatrophic diabetes. These terms are used interchangeably, referring to a rare genetic disorder characterized by the selective loss of adipose(fat) tissue in certain parts of the body, resulting in metabolic abnormalities and other health issues.^1,2

FPL can indeed be subdivided into several types:

• Autosomal recessive FPL
• FPL type 1 (Kobberling lipodystrophy)
• FPL type 2 (Dunnigan lipodystrophy)
• FLP type 3
• FLP type 4
• FLP type 5

Signs & symptoms

Familial Partial Lipodystrophy (FPL) comprises various subtypes differentiated by the underlying genetic mutations. The clinical presentation and outcome significantly differ among patients based on the particular FPL subtype and the presence and extent of related symptoms. Even among individuals with the same subtype or within the same family, the specific symptoms and severity can vary. Furthermore, some FPL subtypes have been documented in only a few individuals, making it challenging for physicians to establish a precise understanding of associated symptoms, severity, and prognosis. Therefore, it is crucial to understand that affected individuals may not experience all the symptoms detailed below. Those affected should consult with their physician and medical team to discuss their specific case, associated symptoms, and overall prognosis.²

Typical symptoms of FPL encompass the selective, progressive loss of subcutaneous fat in the arms, legs, chest, and trunk regions, as well as the abnormal accumulation of subcutaneous fat in other areas, along with various metabolic complications. Typically, women experience more pronounced metabolic complications compared to men in FPL. Additionally, there may be additional symptoms affecting the liver or heart.²

FPL type 2, dunnigan variant (FPL2)

This is the most common form of FPL. Individuals affected usually exhibit normal fat distribution during early childhood. However, around the onset of puberty, a gradual loss of fat occurs in the arms, legs, and trunk. In women, this fat loss can be particularly striking in the buttocks and hips. During this time, fat may accumulate in other parts of the body, such as the face (resulting in a double chin) and the neck and upper back between the shoulder blades (causing a hump). Those affected might have a round face resembling individuals with Cushing's syndrome. This distinct fat distribution pattern, coupled with an overall muscular appearance, makes it more recognizable in women than in men.

Insulin resistance is common and may be linked to a condition called acanthosis nigricans, characterized by abnormal skin colouration (hyperpigmentation) and thickening (hyperkeratosis) of the skin, especially in skin fold areas like the neck, groin, and underarms. An enlarged liver (hepatomegaly) is also prevalent, often due to fat buildup in the liver (fatty liver or steatosis). Over time, fat accumulation can lead to liver scarring and damage (cirrhosis), eventually resulting in liver dysfunction.

Other complications of insulin resistance may include glucose intolerance, high triglyceride levels (hypertriglyceridemia), and diabetes, which can be severe and challenging to manage. Women affected by FPL are at a higher risk of developing diabetes compared to affected men and often experience more severe metabolic complications. In some cases, extreme hypertriglyceridemia can lead to episodes of acute pancreatitis, characterized by abdominal pain, chills, jaundice, weakness, sweating, vomiting, and weight loss.

After puberty, some women with FPL may develop polycystic ovary syndrome (PCOS), a complex of symptoms characterized by hormonal imbalances, potentially leading to irregular menstrual periods or a lack of menstruation, acne-prone oily skin, ovarian cysts, failure to release eggs from the ovaries, and mild hirsutism (abnormal hair growth resembling a male pattern). Hair growth may occur on the upper lip, chin, and other body parts.

Individuals with FPL, the Dunnigan variant, have an increased predisposition to coronary artery disease and other types of atherosclerotic vascular diseases. In rare instances, individuals with specific mutations in the lamin A/C (LMNA) gene are at a heightened risk of developing heart muscle diseases (cardiomyopathy), potentially leading to congestive heart failure and irregular heart rhythms (cardiac arrhythmias) like heart block or atrial fibrillation. Some individuals may also develop muscular dystrophies, which are conditions characterized by muscle weakness and joint contractures.²

FPL type 1, kobberling variant (FPL1)

This form of FPL has only been documented in a few individuals. The symptoms resemble those seen in FPL2, the Dunnigan variant. However, fat loss typically affects only the arms and legs, with more pronounced loss in the lower (distal) parts of these limbs. Affected individuals may display normal or slightly increased fat distribution on the face, neck, and trunk. Additionally, some individuals may develop excess belly fat (central obesity). Metabolic abnormalities, including insulin resistance, high blood pressure (hypertension), and severe hypertriglyceridemia, have also been reported. This form of FPL has only been observed in women.²

FPL type 3, caused by PPARG mutations (FPL3)

This form of FPL has been reported in approximately 30 individuals and is generally milder than FPL2, Dunnigan variant. Consequently, many cases may go undiagnosed. Fat loss primarily affects the calves and forearms, with associated diabetes, hypertriglyceridemia, hypertension, fatty liver, pancreatitis, and hirsutism. Metabolic abnormalities tend to be more prominent than the lipodystrophy itself in this form of the disorder.²

FPL4, caused by PLIN1 mutations (FPL4)

This form of FPL has only been reported in a handful of individuals. Lipodystrophy is most prominent in the lower limbs and buttocks, with muscular hypertrophy sometimes noticeable in the calves. Insulin resistance, severe hypertriglyceridemia, and diabetes have also been documented.²

FPL5, caused by AKT2 mutations (FPL5)

This form of FPL has been observed in four members of a single family, who experienced hypertension, severe insulin resistance, and diabetes mellitus. Insulin resistance typically emerges between the ages of 20 and 30, with lipodystrophy primarily affecting the arms and legs.²

Autosomal recessive FPL (type 6, caused by CIDEC mutation)

This form of FPL has only been documented in one individual in medical literature. Reported symptoms include partial lipodystrophy, severe insulin resistance, fatty liver, acanthosis nigricans, and diabetes.²

Diagnosis

The diagnosis of FPL relies on the identification of characteristic symptoms, a comprehensive patient history review, and a thorough clinical assessment. Suspecting FPL is warranted in individuals who experience subcutaneous fat loss during puberty, resulting in a more muscular appearance. In general, lipodystrophy should be considered for individuals who maintain a lean or "non-obese" physique and exhibit early diabetes, severe hypertriglyceridemia, hepatic steatosis, hepatosplenomegaly, acanthosis nigricans, and/or polycystic ovarian syndrome.²

Clinical testing and evaluation

While the primary method of diagnosing lipodystrophy remains clinical evaluation, various tests can support the diagnosis or rule out other conditions. A blood chemical profile may be administered to assess glucose, lipid, liver enzyme, and uric acid levels.

Magnetic resonance imaging (MRI) can reveal the distinctive pattern of fat loss in the arms, legs, and trunk, accompanied by fat gain in muscular fasciae.

Molecular genetic testing is generally the most conclusive method to confirm an FPL diagnosis. This testing can identify mutations in specific genes responsible for FPL, although it is clinically available for only a few genes, such as LMNA.

Individuals with FPL may also undergo tests to detect or assess potential complications, particularly heart abnormalities. Holter monitoring, echocardiography, and stress tests are conducted on those suspected of having cardiomyopathy or coronary heart disease. Holter monitoring involves a portable device continuously tracking heart rhythms. Echocardiography employs reflected sound waves to generate images of the heart, while a stress test evaluates the heart's response to external stressors in a controlled setting.

Additionally, individuals with FPL may have their leptin levels assessed. Leptin is a hormone found in fat tissues known as adipocytes and some individuals with FPL exhibit low levels of this hormone.

Treatment

The management of Familial Partial Lipodystrophy (FPL) centres around managing the specific symptoms exhibited by each affected individual. This often necessitates the collaborative efforts of a multidisciplinary healthcare team, including paediatricians, plastic surgeons, cardiologists, endocrinologists, nutritionists, and other specialists, to develop a comprehensive treatment plan tailored to each child's needs.

Upon receiving a diagnosis, individuals with FPL and their families are encouraged to seek psychological counselling. The diagnosis can bring about anxiety, stress, and significant psychological distress, making professional counselling and participation in support groups invaluable sources of support. Genetic counselling may also prove beneficial for both affected individuals and their families.

While clinical trials are limited, individuals with FPL are advised to adopt a high-carbohydrate, low-fat diet to help mitigate chylomicronemia, a condition characterized by the accumulation of fatty droplets in the plasma, often associated with acute pancreatitis. However, it's important to note that such diets may elevate very low-density lipoprotein triglyceride levels.

Given the increased risk of coronary heart disease in individuals with FPL, limiting saturated and trans-unsaturated fats and dietary cholesterol intake is recommended. The long-term effectiveness of these measures in reducing fatty liver or serum triglyceride levels and improving glycemic control remains uncertain.

Regular physical activity and maintaining a healthy weight are encouraged to reduce the risk of developing diabetes. For individuals with FPL, exercise and calorie control are crucial to prevent excess fat deposition in areas such as the face, neck, and intra-abdominal region.

Extreme hypertriglyceridemia, in some cases, may necessitate treatment with fibric acid derivatives, statins, or n-3 polyunsaturated fatty acids.

It's essential to recognize that the loss of fat tissue characteristic of FPL cannot be reversed. Therefore, cosmetic surgery, including procedures like liposuction, may be considered to improve appearance and manage metabolic complications by removing excess fat in problematic areas (e.g., chin).

In severe cases, FPL-related liver disease may require a liver transplant.

Regular cardiac evaluations are recommended for individuals with FPL to detect potential symptoms associated with the disorder, such as coronary heart disease. Those with heart abnormalities, like heart block or atrial fibrillation, may require a pacemaker, and in some instances, a heart transplant might become necessary.

Additional therapies for FPL management are primarily treating symptoms and supportive care, following established guidelines. Diabetes is typically treated with standard therapies, including drugs like metformin. Individuals with FPL and diabetes may also require insulin therapy, often at high doses. High blood pressure may be managed with antihypertensive medications, although clinical trials are lacking in establishing optimal drug therapy for addressing metabolic complications in FPL individuals.

Summary

Familial Partial Lipodystrophy (FPL) is a rare genetic disorder characterized by the gradual loss of body fat in specific areas and abnormal fat accumulation in others. There are several subtypes of FPL, each with its unique symptoms and genetic mutations.

Common symptoms of FPL include the selective loss of subcutaneous fat in the arms, legs, chest, and trunk regions, along with abnormal fat buildup in areas like the face, neck, and intra-abdominal regions. Metabolic complications are also common, including insulin resistance, high triglyceride levels, and diabetes, which can be severe. Women with FPL often experience more severe metabolic issues.

FPL Type 2, known as the Dunnigan variant, is the most common form and typically manifests during puberty. It leads to fat loss in the arms, legs, and trunk, with fat accumulation in other areas like the face and neck. Liver problems and heart-related issues can also occur.

FPL Type 1, known as the Kobberling variant, is similar to FPL2 but primarily affects the arms and legs, with some individuals developing excess belly fat.

FPL Type 3, caused by PPARG mutations, is milder than FPL2 and leads to fat loss in the calves and forearms, along with metabolic issues.

FPL4, caused by PLIN1 mutations, is rare and primarily affects the lower limbs and buttocks.

FPL5, caused by AKT2 mutations, involves fat loss in the arms and legs and severe metabolic complications.

Autosomal Recessive FPL (Type 6, caused by CIDEC mutation) is extremely rare and leads to partial lipodystrophy, insulin resistance, fatty liver, and diabetes.

Diagnosis of FPL involves clinical evaluation, blood tests to assess metabolic markers, and imaging tests like MRI to confirm fat distribution patterns. Genetic testing can provide a conclusive diagnosis.

Treatment for FPL is tailored to each individual's specific symptoms and may involve psychological counselling, dietary changes, exercise, medications to manage metabolic complications, and, in severe cases, cosmetic surgery, liver transplants, or heart-related interventions. Regular cardiac evaluations are crucial for monitoring heart health in individuals with FPL.