Hemihyperplasia–Multiple Lipomatosis Syndrome

Hemihyperplasia–multiple lipomatosis syndromes (HHML) is a rare congenital disorder characterized by asymmetrical overgrowth of one side of the body and multiple benign fatty tumors (lipomas) in various tissues. The condition is caused by a genetic mutation and presents with physical, as well as cosmetic abnormalities.

Definition: Hemihyperplasia-multiple lipomatosis syndrome (HHML) is a congenital disorder characterized by asymmetrical overgrowth of one side of the body and multiple lipomas, which are benign tumors composed of adipose (fat) tissue. Overgrowth affects the bones, muscles, and other tissues of the body, leading to physical and cosmetic abnormalities.

Types: There are two types of HHML, depending on the extent of the overgrowth and the presence of other associated anomalies:

1. Classic HHML: This is the more severe form of the condition, characterized by asymmetrical overgrowth that affects one side of the face, neck, torso, and extremities. The overgrowth may also be accompanied by other anomalies, such as intellectual disability, skin abnormalities, and structural abnormalities of the heart, lungs, and other organs.
2. Mild HHML: This is a less severe form of the condition, characterized by milder asymmetrical overgrowth, fewer lipomas, and a lower incidence of associated anomalies. The overgrowth is usually limited to the limbs and may not affect the face or other parts of the body.

Causes

The exact cause of HHML is not well understood, but several genetic and environmental factors have been suggested to play a role in its development.

1. Genetic mutations: The most common cause of HHML is a genetic mutation in the GNAS gene. The GNAS gene provides instructions for making a protein called G protein-stimulated adenylyl cyclase, which plays a role in regulating cell growth and division. Mutations in this gene can result in overactive signaling, leading to the uncontrolled growth of cells and the development of HHML.
2. Mosaicism: HHML can also result from a phenomenon known as mosaicism, in which some cells in the body have a genetic mutation while others do not. This can occur when the mutation occurs after the initial cell division that occurs during embryonic development. Mosaic HHML is often less severe than inherited HHML, as the affected cells are limited to specific areas of the body.
3. Environmental factors: Environmental factors such as radiation exposure, infections, and certain chemicals have also been suggested as possible causes of HHML. However, the role of these factors in the development of the disorder is not well understood and requires further investigation.
4. Epigenetic changes: Epigenetic changes, which refer to modifications to the DNA molecule that do not involve changes to the underlying genetic code, have also been implicated in the development of HHML. For example, alterations in DNA methylation or histone modification patterns could result in changes to gene expression and contribute to the development of the disorder.
5. Interaction of genetic and environmental factors: It is possible that a combination of genetic and environmental factors may contribute to the development of HHML. For example, a person with a genetic susceptibility to the disorder may be more likely to develop HHML if they are exposed to certain environmental triggers.
6. Inheritance pattern: HHML is an autosomal dominant condition, which means that an affected person has a 50% chance of passing the condition on to each of their children. This means that if one parent has the condition, there is a high likelihood that their children will also inherit the condition.
7. Chromosomal abnormalities: In some cases, HHML may be caused by chromosomal abnormalities such as duplications or deletions of specific genetic material. These abnormalities can disrupt the normal functioning of the GNAS1 gene, leading to the development of HHML.
8. Other genetic factors: In addition to mutations in the GNAS1 gene, there may be other genetic factors that contribute to the development of HHML. For example, some studies have suggested that mutations in other genes may interact with the GNAS1 gene to increase the risk of developing HHML.

Symptoms

The condition is caused by a genetic mutation that affects the function of the GLI3 gene, which plays a crucial role in regulating cell growth and differentiation.

Here is a list of symptoms commonly associated with HHML:

1. Hemihyperplasia: The most prominent symptom of HHML is hemihyperplasia, which refers to the overgrowth of one side of the body. This can manifest as an enlarged arm, leg, or other body part on one side of the body compared to the other. The degree of hemihyperplasia can vary, and in some cases, it may be more pronounced in certain parts of the body than others.
2. Lipomas: Lipomas are fatty tumors that can form anywhere in the body, but are most commonly found in the subcutaneous tissue (just under the skin). They are typically soft and round, and can range in size from a few millimeters to several centimeters in diameter. People with HHML may develop multiple lipomas in various parts of the body, including the arms, legs, torso, and neck.
3. Skeletal abnormalities: Some individuals with HHML may also have skeletal abnormalities, such as scoliosis (curvature of the spine), asymmetry of the pelvis, or a shortening of one limb. These abnormalities can lead to difficulties with balance, gait, and mobility, and may require surgical intervention to correct.
4. Intellectual disability: Some individuals with HHML may have an intellectual disability, which can range from mild to severe. This can affect their ability to learn, communicate, and perform everyday tasks, and may require special education and support services.
5. Craniofacial anomalies: Some individuals with HHML may have craniofacial anomalies, such as an enlarged forehead, a small jaw, or a cleft palate. These anomalies can impact speech, hearing, and overall facial appearance, and may require surgical intervention to correct.
6. Cardiac anomalies: Some individuals with HHML may have cardiac anomalies, such as an enlarged heart, a heart murmur, or an abnormal heart rhythm. These anomalies can impact overall health and may require medical intervention to manage.
7. Genital anomalies: Some individuals with HHML may have genital anomalies, such as undescended testicles, hypospadias (a condition in which the urethral opening is located on the underside of the penis), or a small penis. These anomalies can impact fertility and sexual function, and may require surgical intervention to correct.
8. Vision and hearing problems: Some individuals with HHML may have vision and hearing problems, such as strabismus (crossed eyes), nystagmus (involuntary eye movements), or hearing loss. These problems can impact overall quality of life and may require medical or surgical intervention to manage.
9. Skin abnormalities: Some individuals with HHML may have skin abnormalities, such as hyperpigmentation (dark patches of skin), café-au-lait spots (light-brown patches of skin), or nevi (moles). These abnormalities can impact overall appearance and may require medical or surgical intervention to manage.
10. Behavioral and emotional problems: Some individuals with HHML may have behavioral and emotional problems, such as attention deficit hyperactivity disorder

Diagnosis

Diagnostic tests used to diagnose HHML.

1. Physical examination

The first step in diagnosing HHML is a thorough physical examination by a healthcare provider. During the physical exam, the healthcare provider will look for signs of asymmetrical overgrowth and the presence of lipomas. The overgrowth may affect one side of the face, trunk, limb, or any combination of these. The lipomas may be located anywhere on the body, but are typically found on the trunk, neck, and extremities. The healthcare provider may also perform a neurological examination to assess for any nerve or muscle involvement.

2. Imaging studies

Imaging studies such as X-rays, CT scans, and MRI scans can help to confirm the diagnosis of HHML and provide a better understanding of the extent of the overgrowth and the number and size of the lipomas. X-rays can provide information about the bone structure and can help to identify any skeletal abnormalities. CT scans and MRI scans can provide detailed images of the soft tissue, including the fatty tumors, and can help to determine their location and size.

3. Genetic testing

Genetic testing is the most definitive way to diagnose HHML. The most common genetic cause of HHML is a mutation in the PIK3CA gene. This gene provides instructions for making a protein that is involved in regulating cell growth and division. Mutations in the PIK3CA gene can result in uncontrolled cell growth and division, leading to the development of the overgrowth and fatty tumors characteristic of HHML.

There are several different types of genetic testing that can be used to diagnose HHML, including:

• Sanger sequencing: This is the most common type of genetic testing used to diagnose HHML. It involves sequencing a specific portion of the PIK3CA gene to look for mutations.
• Multiplex ligation-dependent probe amplification (MLPA): This test is used to look for large deletions or duplications in the PIK3CA gene.
• Array comparative genomic hybridization (aCGH): This test is used to detect changes in the number of copies of specific genes, including the PIK3CA gene.

4. Biopsy

In some cases, a biopsy of a lipoma may be necessary to confirm the diagnosis of HHML. A biopsy involves removing a small sample of tissue from the lipoma and examining it under a microscope. The biopsy can help to confirm the presence of fatty tissue and can also be used to rule out other types of tumors, such as liposarcoma, which are a type of cancer that can develop in fatty tissue.

5. Other tests

In some cases, other tests may be necessary to diagnose HHML. For example, a nerve conduction study may be performed to assess for any nerve involvement. An electrocardiogram (ECG) may be performed to evaluate the heart function. These tests can help to determine the extent of the overgrowth and the presence of any associated complications.

Treatment

There is currently no cure for HHML, but there are several treatments that can help manage the symptoms and improve quality of life. These treatments may include:

1. Surgery: In some cases, surgical removal of lipomas may be recommended to alleviate discomfort or improve function. The decision to perform surgery is usually based on the size, location, and number of lipomas, as well as the patient’s overall health and medical history.
2. Surgical removal of lipomas: Lipomas are the most commonly occurring tumors in HHML and can cause discomfort, pain, and functional limitations. Surgical removal is the primary treatment option for lipomas, and the procedure is usually performed under general anesthesia. The goal of surgery is to remove the lipoma completely, while minimizing scarring and preserving the surrounding tissue. In some cases, lipomas may recur, and multiple surgeries may be necessary.
3. Orthopedic devices: Orthopedic devices, such as braces or prosthetics, can be used to help correct limb length discrepancies, improve balance, and reduce pain.
4. Pain management: Pain management is an important part of treatment for HHML, as many patients experience discomfort due to the asymmetrical overgrowth and the development of lipomas. Pain management may include medication, physical therapy, and other treatments as appropriate.
5. Psychological support: Living with a rare genetic condition can be challenging, and many patients with HHML may benefit from psychological support. Talking to a mental health professional can help individuals cope with the emotional and psychological impact of their condition.
6. Physical therapy and rehabilitation: Physical therapy and rehabilitation can help improve range of motion, muscle strength, and functional abilities for individuals with HHML. Physical therapy can also help manage pain and prevent joint contractures. Occupational therapy may also be recommended to help individuals with HHML improve their daily living skills and independence.
7. Pain management: Individuals with HHML may experience discomfort and pain due to the growth of lipomas and asymmetrical overgrowth. Pain management strategies may include medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), muscle relaxants, and pain relievers. In some cases, interventional procedures such as nerve blocks, epidural injections, or trigger point injections may be recommended to manage pain.
8. Orthopedic devices: Orthopedic devices such as braces, splints, and orthotics can help support and stabilize joints and limbs affected by asymmetrical overgrowth. These devices can help reduce pain and prevent further joint deformities.
9. Psychological support: Living with a rare genetic disorder like HHML can be emotionally challenging, and individuals may benefit from psychological support and counseling. Support groups and online resources can provide individuals with a sense of community and a means to connect with others who are facing similar challenges.
10. Monitoring for potential complications: Regular monitoring and follow-up care are important for individuals with HHML to detect and manage any potential complications that may arise. This may include monitoring for joint problems, skin ulcerations, and changes in the growth of lipomas.
11. Genetic counseling: HHML is a genetic disorder, and individuals who have the condition or have a family history of the condition may benefit from genetic counseling. Genetic counseling can help individuals understand their risk of passing the condition on to their children and can provide guidance on family planning and reproductive options.

In conclusion, the management of HHML requires a multidisciplinary approach, including surgical removal of lipomas, physical therapy and rehabilitation, pain management, orthopedic devices, psychological support, monitoring for potential complications, and genetic counseling. The goal of treatment is to improve the quality of life and manage the symptoms and complications associated with the condition. It’s important to work closely with a healthcare provider to develop an individualized treatment plan that meets the specific needs and goals of each person with HHML.

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