Limb-mammary syndrome (LMS) is a rare genetic disorder that affects the development of limbs and mammary glands. It is caused by mutations in the TP63 gene, which provides instructions for making a protein called p63. This protein is involved in the development and maintenance of epithelial tissues, which are the thin layers of cells that cover and line various parts of the body. LMS is also known as split hand/split foot malformation with long bone deficiency, cleft lip/palate, and/or hypopigmentation.

There are several different types of LMS, each with its own set of characteristic symptoms. The most common types include:

1. Split hand/split foot malformation with long bone deficiency (SHFLD) This type of LMS is characterized by the partial or complete absence of the central digits of the hands and feet, giving the hands and feet a split appearance. The condition also affects the long bones of the arms and legs, resulting in shortened or missing bones. Other features of SHFLD include cleft lip and/or palate, abnormal teeth, and hypopigmentation of the skin and hair.
2. Adermatoglyphia Adermatoglyphia is a rare condition that causes the absence of fingerprints and other skin ridges on the palms of the hands and the soles of the feet. It is often seen in individuals with LMS and is caused by mutations in the same TP63 gene. Adermatoglyphia may occur as an isolated condition or as part of LMS.
3. Ectodermal dysplasia with cleft lip/palate (EEC) EEC syndrome is characterized by the abnormal development of several tissues derived from the ectoderm, including the skin, hair, nails, teeth, and sweat glands. People with EEC often have cleft lip and/or palate, which can cause feeding difficulties and speech problems. They may also have hypopigmentation, abnormal teeth, and other features of LMS.
4. Limb-mammary syndrome with leukonychia and hair abnormalities (LMS-L) LMS-L is a rare subtype of LMS that is characterized by hypopigmentation of the skin and hair, leukonychia (white spots or lines on the nails), and abnormal hair growth. Individuals with LMS-L may also have split hand/foot malformation and cleft lip/palate.
5. Isolated cleft lip/palate Isolated cleft lip/palate is a common birth defect that can occur on its own or as part of other genetic syndromes, including LMS. In LMS, cleft lip/palate may be accompanied by other features such as limb abnormalities and hypopigmentation.

Causes

Causes for Limb-mammary syndrome:

1. Autosomal dominant inheritance: Most cases of LMS are inherited in an autosomal dominant pattern, which means that a person only needs to inherit one copy of the mutated TP63 gene from one parent to develop the condition. The other copy of the gene is typically normal and able to produce enough functional protein to maintain normal development.
2. De novo mutations: In some cases, LMS may be caused by de novo mutations in the TP63 gene, which means that the mutation occurs spontaneously during embryonic development and is not inherited from either parent.
3. Missense mutations: Missense mutations in the TP63 gene can change a single amino acid in the resulting protein, which can affect its function and lead to LMS.
4. Nonsense mutations: Nonsense mutations in the TP63 gene can introduce a premature stop codon that truncates the resulting protein, leading to a non-functional or partially functional protein that can cause LMS.
5. Frameshift mutations: Frameshift mutations in the TP63 gene can alter the reading frame of the DNA sequence, leading to an abnormal protein that can cause LMS.
6. Splice site mutations: Splice site mutations in the TP63 gene can disrupt the process of splicing, which is necessary for producing a functional protein, leading to LMS.
7. Duplication mutations: Duplication mutations in the TP63 gene can cause an extra copy of the gene to be produced, leading to an overexpression of the TP63 protein and LMS.
8. Inversion mutations: Inversion mutations in the TP63 gene can reverse the orientation of the gene, leading to abnormal expression of the protein and LMS.
9. Point mutations: Point mutations in the TP63 gene can alter a single nucleotide in the DNA sequence, leading to an abnormal protein that can cause LMS.
10. Insertion mutations: Insertion mutations in the TP63 gene can introduce extra nucleotides into the DNA sequence, leading to an abnormal protein that can cause LMS.
11. Deletion mutations: Deletion mutations in the TP63 gene can remove one or more nucleotides from the DNA sequence, leading to an abnormal protein that can cause LMS.
12. Missense mutations affecting the SAM domain: The SAM domain of the TP63 protein is important for protein-protein interactions and is frequently affected by missense mutations that can cause LMS.
13. Missense mutations affecting the transactivation domain: The transactivation domain of the TP63 protein is important for gene expression and is frequently affected by missense mutations that can cause LMS.
14. Missense mutations affecting the DNA binding domain: The DNA binding domain of the TP63 protein is important for recognizing and binding to specific DNA sequences and is frequently affected by missense mutations that can cause LMS.
15. Missense mutations affecting the oligomerization domain: The oligomerization domain of the TP63 protein is important for forming dimers and tetramers, and is frequently affected by missense mutations that can cause LMS.
16. Missense mutations affecting the sterile alpha motif (SAM) domain: The SAM domain of the TP63 protein is important for protein-protein interactions and is frequently affected by missense mutations that can cause LMS.

Symptoms

The symptoms of LMS can vary widely among affected individuals, even within the same family. However, there are some common signs that can help diagnose this condition. Here are the symptoms of Limb-mammary syndrome:

1. Abnormalities of the hands and feet: Individuals with LMS may have missing or underdeveloped fingers or toes. This can range from mild to severe, with some individuals having only minor abnormalities while others may have significant limb defects.
2. Hypoplastic nails: The nails on the fingers and toes may be small and underdeveloped in individuals with LMS.
3. Syndactyly: This refers to webbing between the fingers or toes, which can occur in individuals with LMS.
4. Camptodactyly: This is a condition where the fingers are permanently bent in a flexed position, which can also be seen in LMS.
5. Split hand/foot malformation: This is a condition where the hand or foot has a cleft in the middle, resulting in a split appearance. This can also occur in LMS.
6. Absent mammary glands: In some cases, individuals with LMS may be born without mammary glands, which can lead to breastfeeding difficulties later in life.
7. Hypoplastic mammary glands: The mammary glands may be underdeveloped in individuals with LMS, leading to reduced milk production during breastfeeding.
8. Abnormal hair growth: Individuals with LMS may have sparse hair growth or bald patches on the scalp, as well as abnormal hair growth in other areas of the body.
9. Hyperpigmentation: Some individuals with LMS may have patches of darker skin on the face or other parts of the body.
10. Hypopigmentation: Others may have areas of lighter skin, or patches of skin that lack pigmentation altogether.
11. Cleft lip and/or palate: This is a condition where the lip and/or palate does not fuse properly during fetal development, resulting in a gap or cleft in the lip or roof of the mouth. This can also occur in individuals with LMS.
12. Dental abnormalities: Individuals with LMS may have missing teeth, abnormal tooth shape, or other dental abnormalities.
13. Eye abnormalities: Some individuals with LMS may have cataracts, glaucoma, or other eye problems.
14. Hearing loss: Individuals with LMS may have hearing loss, which can range from mild to severe.
15. Skin abnormalities: Individuals with LMS may have dry, scaly skin, or skin that is prone to infections.
16. Genital abnormalities: In some cases, individuals with LMS may have genital abnormalities, such as a small penis or undescended testicles in males.
17. Urogenital abnormalities: Some individuals with LMS may have abnormalities of the urinary system, such as a small bladder or urinary incontinence.
18. Respiratory abnormalities: Individuals with LMS may have a higher risk of respiratory infections, due to abnormalities of the respiratory system.
19. Limb asymmetry: The limbs may be different sizes or shapes in individuals with LMS, which can lead to difficulties with movement or balance.
20. Intellectual disability: In some cases, individuals with LMS may have intellectual disability or developmental delays.

Diagnosis

Diagnosis of LMS is based on clinical findings and genetic testing. Here are diagnoses and tests for LMS:

1. Physical examination: A doctor will perform a physical exam to look for abnormalities in the limbs and mammary glands, as well as other features of LMS, such as skin and nail abnormalities.
2. Medical history: The doctor will ask about the patient’s medical history, including any family history of limb or mammary gland abnormalities.
3. Radiography: X-rays of the limbs can show missing or malformed bones in the fingers or toes.
4. CT scan: A CT scan can provide a detailed image of the bones, muscles, and other tissues in the affected limbs.
5. MRI: An MRI can provide detailed images of soft tissues, such as muscles and tendons, in the affected limbs.
6. Ultrasonography: Ultrasonography can be used to examine the mammary glands and detect any abnormalities.
7. Mammography: Mammography is a type of X-ray that can detect abnormalities in the breast tissue.
8. Genetic testing: Genetic testing can identify mutations in the TP63 gene that cause LMS.
9. Chromosomal microarray analysis: Chromosomal microarray analysis can detect chromosomal abnormalities that may be associated with LMS.
10. Whole-exome sequencing: Whole-exome sequencing can identify mutations in genes other than TP63 that may be responsible for the patient’s symptoms.
11. Targeted gene panel testing: Targeted gene panel testing can identify mutations in a specific set of genes that are associated with LMS.
12. TP63 mutation analysis: TP63 mutation analysis can identify specific mutations in the TP63 gene that are associated with LMS.
13. Protein expression analysis: Protein expression analysis can determine whether the patient’s p63 protein is being produced and functioning properly.
14. Western blot: Western blot is a type of protein expression analysis that can detect abnormalities in the p63 protein.
15. Immunohistochemistry: Immunohistochemistry can be used to examine tissue samples from the affected limbs or mammary glands for abnormalities in the p63 protein.
16. Skin biopsy: A skin biopsy can provide a sample of skin tissue for examination under a microscope to look for abnormalities.
17. Nail biopsy: A nail biopsy can provide a sample of nail tissue for examination under a microscope to look for abnormalities.
18. Electromyography (EMG): Electromyography can be used to test the function of the muscles in the affected limbs.
19. Nerve conduction studies: Nerve conduction studies can be used to test the function of the nerves in the affected limbs.
20. Physical therapy evaluation: A physical therapy evaluation can assess the patient’s functional abilities and identify areas of weakness or impairment.

In conclusion, diagnosis of LMS requires a combination of clinical evaluation and genetic testing. The physical examination should focus on abnormalities in the limbs and mammary glands, as well as other features of the syndrome. Radiography, CT scan, MRI, ultrasonography, mammography, and biopsy can provide detailed images

Treatment

There is no cure for LMS, but various treatments can help manage the symptoms and improve quality of life. Here are treatments that may be used for LMS:

1. Physical therapy: Physical therapy can help individuals with LMS improve their mobility, strength, and flexibility. It can also help prevent complications such as joint contractures.
2. Occupational therapy: Occupational therapy can help individuals with LMS learn new skills and techniques to perform daily activities, such as dressing and grooming, with greater ease.
3. Speech therapy: Some individuals with LMS may have speech difficulties due to abnormal development of the mouth and throat. Speech therapy can help improve speech and language skills.
4. Surgery for limb abnormalities: Surgery may be recommended to correct limb abnormalities such as missing fingers or toes, extra fingers or toes, or clubfoot.
5. Prosthetics: For individuals with limb abnormalities that cannot be corrected surgically, prosthetics such as artificial limbs or fingers may be recommended to improve mobility and function.
6. Breast implants: In cases where mammary glands are underdeveloped or absent, breast implants may be an option to improve the appearance of the chest.
7. Hormone replacement therapy: Hormone replacement therapy may be recommended to help stimulate breast development in females with LMS.
8. Skin grafts: Skin grafts may be used to repair skin abnormalities such as cleft lip and palate or missing skin on the fingers or toes.
9. Pain management: Individuals with LMS may experience pain due to limb abnormalities or other complications. Pain management strategies such as medications or physical therapy may be recommended.
10. Genetic counseling: Genetic counseling can help individuals with LMS and their families understand the genetic basis of the condition and make informed decisions about family planning.
11. Assistive devices: Assistive devices such as wheelchairs, crutches, or braces may be recommended to help individuals with LMS improve their mobility and independence.
12. Education and support: Education and support can help individuals with LMS and their families cope with the challenges of the condition and improve quality of life.
13. Psychological counseling: Some individuals with LMS may experience psychological difficulties such as depression or anxiety due to the challenges of living with the condition. Psychological counseling can help individuals cope with these challenges and improve mental health.
14. Adaptive equipment: Adaptive equipment such as modified utensils or clothing may be recommended to help individuals with LMS perform daily activities with greater ease.
15. Speech-generating devices: For individuals with severe speech difficulties, speech-generating devices such as computerized voice synthesizers may be recommended to improve communication.
16. Augmentative and alternative communication (AAC): AAC refers to various methods of communication that can be used to supplement or replace speech. AAC may be recommended for individuals with severe speech difficulties due to LMS.
17. Nutritional support: Individuals with LMS may have difficulty feeding or swallowing due to abnormalities of the mouth and throat. Nutritional support such as tube feeding or specialized diets may be recommended to ensure adequate nutrition.
18. Dental care: Individuals with LMS may have dental abnormalities such as missing teeth or misaligned jaws. Regular dental care and orthodontic treatment may be recommended to improve oral health and function.
19. Social support: Social support from family, friends, and community can help individuals with LMS cope with the challenges of the condition and improve their quality of life.