One article collation: "McCune-Albright syndrome" of rare endocrine diseases

McCune-Albright syndrome (MAS) is an endocrine disorder (such as non-gonadotropin-releasing hormone-dependent precocious puberty, hyperprolactinemia, hypersecretion of growth hormone, hyperthyroidism, Cushing’s syndrome, thyroid Hyperparathyroidism, etc.
), fibrous bone dysplasia, and skin milk coffee spots are typical clinical syndromes.

It was first reported by McCune and Albright in different magazines in 1936 and 1937, respectively.

 Etiology and epidemiology MAS is caused by mutations in the gene encoding the G protein-coupled receptor-stimulated alpha subunit (GNAS) in somatic cells.

The GNAS gene is located on chromosome 20, q13.
3.

Mutations in this gene increase the activity of adenylate cyclase, leading to the accumulation of cAMP, resulting in the activation of a variety of cAMP-dependent receptors in the body, including parathyroid hormone (PTH), adrenocorticotropic hormone (ACTH), and thyroid stimulating hormone (TSH).
), Follicle-forming Hormone (FSH), Luteinizing Hormone (LH), etc.
are activated, causing bone disease and the corresponding endocrine target organ hyperfunction.

 The disease is very rare.

The prevalence rate reported abroad is about 1/1000 000 to 1/100,000, which can occur in people of different races and genders.
The prevalence of women is higher than that of men.

The prevalence of this disease in the Chinese population is unclear.

The disease is self-limiting, it progresses quickly before puberty, and most of the lesions tend to be stable after adulthood.

MAS rarely undergoes malignant transformation, and malignant transformation mainly occurs in the bones, accounting for about 1%.

 Clinical manifestations of MAS 1.
Skin manifestations MAS patients generally have milk coffee spots at birth, often located on the same side of the bone lesions and bounded by the midline, which are one or more spots of brown or yellow-brown patches of varying sizes Shaped pigmentation with irregular borders.

 2.
Skeletal system Approximately 98% of MAS patients have single-bone type or multi-bone type bone fibrous heteroplasia, and multi-bone type is more common.

It is characterized by an increase in aberrant osteoblasts and abnormal differentiation, causing extensive proliferation and differentiation of fibroblasts in the bone marrow, forming immature woven bones, prone to pathological fractures and skeletal deformities, and causing bone pain, which can almost affect the whole body bones, especially Craniofacial bones and long bones are more commonly involved.
Local bones swell and bulge, causing facial structural changes and compression symptoms.

Severe orbital involvement can compress the optic nerve and cause visual impairment.

Auditory nerve involvement can cause hearing loss.

Involvement of the spine can cause compression fractures of the vertebral body, causing scoliosis or kyphosis.

The peak age of pathological fracture caused by fibrous dysplasia is mostly 6 to 10 years old.

The imaging showed that the bones showed swelling, osteolytic changes or ground glass-like changes.

 3.
Performance of endocrine gland involvement MAS can involve a variety of endocrine glands, leading to hyperfunction or tumors of the involved glands, and the level of serum secretagogues is normal or decreased.

Among them, precocious puberty is more common, and it can occur in both men and women, but it is more common in female patients, and it is often earlier than bone disease.

Female children may manifest as early development of secondary sexual signs, premature vaginal bleeding, uterus and ovaries larger than normal children of the same age, or ovarian cysts, early healing of epiphyses, etc.

Precocious puberty is relatively rare in male children, and testicular lesions (Leydig cell hyperplasia, microlithia, focal calcification, etc.
) can be seen on ultrasound.

Goiter and hyperfunction are also common, and hyperparathyroidism has also been reported.

Other endocrine diseases have also been reported, such as hypercortisolism, gigantism/acromegaly, hyperprolactinemia, etc.
, but they are relatively rare.

 4.
Hypophosphatemia According to reports, about 4.
0% to 38.
5% of MAS patients are combined with hypophosphatemia, showing hypophosphatemia rickets.

This is due to the increased level of FGF23 in the diseased bone tissue, which increases renal phosphorus excretion.

Patients with hypophosphatemia are usually bony fibrous dysplasia.

 5.
Other patients with MAS may also have rare clinical symptoms such as jaundice, hepatitis, arrhythmia, and intestinal polyps due to mutations involving peripheral blood leukocytes, liver, heart, thymus and gastrointestinal tract.

 Auxiliary examination 1.
Laboratory examination Endocrine hormone detection: including serum ACTH, blood cortisol, LH, FSH, E2, T, P, thyroid function, GH, IGF-1, etc.
; bone metabolism indicators: blood calcium, phosphorus, alkalinity Phosphatase, β-CTX, PTH, urinary calcium, phosphorus, etc.

 2.
Imaging examination: X-ray film of the skull and other parts of the body; bone scan; head MRI; ovarian or testicular ultrasound, breast ultrasound, thyroid ultrasound, etc.

 3.
Molecular biological examination The mutation detection of GNAS gene can be carried out for local diseased tissues.

The detection rate of mutations in peripheral blood DNA is usually low.

 Diagnosis McCune-Albright syndrome is a sporadic syndrome characterized by the triad of bone fibrous dysplasia, milk coffee spots, and endocrine gland hyperfunction.

Two of the triad can be used to diagnose MAS.

Endocrine dysfunction can include precocious puberty, hyperthyroidism, Cushing’s syndrome, hyperparathyroidism, hyperprolactinemia, and excessive growth hormone secretion.

MAS patients often seek medical treatment for precocious puberty or pathological fractures.
For these patients, detailed physical examination should be performed to observe skin pigmentation and screen endocrine gland involvement and bone disease.

When necessary, GNAS gene mutation detection for diseased tissues can help confirm the diagnosis.

 The differential diagnosis should be compared with other diseases similar to skin pigmentation (such as neurofibromatosis), endocrine gland hyperfunction or neoplastic diseases (such as pituitary somatotropoma, Graves’ disease, central precocious puberty, etc.
), involving bones Different diseases (such as acute leukemia extramedullary involvement, Paget's disease of bone, other diseases that cause hypophosphatemic rickets, malignant tumor bone metastasis, osteosarcoma, etc.
) for differential diagnosis.

 Neurofibromatosis can also be manifested as milk coffee spots, and can also be accompanied by hypophosphatemia.
Patients with typical neurofibromatous skin lesions can be seen, but there is usually no obvious skeletal malformations, precocious puberty, hyperthyroidism and other endocrine gland involvement.

 In terms of endocrine diseases, pituitary growth hormone tumors can manifest as gigantism/acromegaly, with characteristic facial changes, thickening of bone and soft tissues, but usually without milk coffee spots and pathological fractures.

Patients with Graves' disease have typical hyperthyroidism, without milk coffee spots and bone involvement, and often have TSH receptor antibody positive.

 In other diseases involving bones, acute leukemia extramedullary involvement should have peripheral blood changes, which can be confirmed by bone marrow aspiration and biopsy.

Paget’s disease of bone can also be manifested as skeletal deformities and pathological fractures.
Patients may have enlarged skulls and deformed limbs, which are difficult to distinguish from the changes in the skull caused by MAS.
However, patients with Paget’s disease of bone are often middle-aged and elderly.
The endocrine glands are affected, and the response to bisphosphonate therapy is better than that of MAS patients.

Other hypophosphatemic rickets can be manifested as hypophosphatemia, skeletal deformities, bone pain, and pathological fractures.
Patients usually have typical signs of rickets and imaging findings without other endocrine gland involvement.

Malignant tumors, bone metastases, osteosarcoma, etc.
are usually late onset and have corresponding manifestations of the original disease.
Medical history and imaging examinations can assist in the identification.

 Treatment of MAS The treatment of MAS is mainly symptomatic treatment, and there is no effective cure.

 1.
Targeting peripheral precocious puberty Currently commonly used treatment drugs include: high-efficiency progesterone (such as medroxyprogesterone), gonadotropin releasing hormone analogs, aromatase inhibitors (such as letrozole, etc.
).

In recent years, studies have found that selective estrogen receptor modulators (such as tamoxifen) can compete with estradiol to bind to estrogen receptors, reduce vaginal bleeding, control the sexual development of MAS patients, delay the progression of bone age, and promote high lifelong growth .

 2.
Other endocrine diseases caused by MAS can be treated with corresponding drugs, such as methimazole, propylthiouracil, etc.
for the treatment of hyperthyroidism, but drug treatments are often difficult to achieve satisfactory results, and most of them recur after stopping the drug.
Surgery or surgery is recommended.
Radioactive 131I treatment.

For MAS patients with excessive secretion of growth hormone, long-acting somatostatin analogs (octreotide microspheres) have a certain effect.
If pituitary tumors require surgery, the timing of surgery should be grasped to prevent thickening of the skull and maxillofacial bones And increase the difficulty of the operation.

Radiotherapy cannot be used as the first choice for the treatment of growth hormone adenomas.
Because of the possibility of causing bone fibrous dysplasia to become osteosarcoma, it should be avoided as much as possible.

For patients with Cushing’s syndrome, there are reports of the use of metyrapone abroad.
When complications such as heart and liver diseases occur, it indicates a poor prognosis, and the adrenal glands should be removed as soon as possible.

Cushing syndrome in patients with MAS is often associated with cholestatic hepatitis, so hepatotoxic drugs (such as ketoconazole) should be avoided as much as possible.

 3.
For skeletal abnormalities.
There is no need for special treatment for single, asymptomatic bone fibrous dysplasia, but it is necessary to prevent the development of pathological fractures and bone deformities.

For bony or severe bone lesions, the currently commonly used drugs are bisphosphonates.
If hypophosphatemia is also combined, neutral phosphorus solution can be supplemented.

Curettage of bone lesions and bone graft surgery are only suitable for adults with localized and symptomatic bone fibrous dysplasia.

If the disease occurs in long bones such as limbs, the functional exercise of the muscles surrounding the bone disease should be strengthened.

If there are severe compression symptoms or multiple pathological fractures causing severe skeletal deformities, affecting normal life, surgical treatment can be selected.
The surgical methods include resection, decompression, bone reconstruction, and repair.

 4.
Milk coffee spots For milk coffee spots, there is no need for treatment if there is no special discomfort, and can be concealed by beauty.

Some scholars once reported using Q-switched ruby ​​laser to remove skin pigmentation, but the exact effect still needs long-term follow-up observation.

 Figure 1 McCune-Albright syndrome diagnosis process The above content is extracted from: National Health Commission of the People's Republic of China.
Guidelines for the diagnosis and treatment of rare diseases (2019 edition) [J].
Official website of the National Health Commission of the People's Republic of China.