Introduction
Polyostotic fibrous dysplasia, also known as Albright syndrome orMcCune-Albright Syndrome (MAS). The disease was first described by McCune (1936) and Albright (1937). It is a disease of bone growth and development, which is characterized by bone damage, precocious puberty and skin pigmentation. A small number of patients also have other abnormalities in endocrine function.
Cause
(1) Causes of the disease
The cause has not been fully elucidated. However, there have been breakthroughs in recent years. Intrinsic patients have extensive mutations in the excitatory alpha subunit (Gs) gene of the avian nucleotide binding protein (G protein), which leads to pro-osteoblast proliferation and bone fiber dysplasia. The Gs mutation is mostly located in the RaolC or RaolH site encoded by the gene.
(two) pathogenesis
Since 1994, the etiology of the disease has made a breakthrough. Malchoff and Shenker et al. first discovered the stimulatory G protein (Gs) alpha in the guanine nucleotide binding protein (G protein) in patients' cells by detecting tissue and cell molecular biology of MAS patients. The base gene is mutated (Gs consists of 3 subunits of α, β, γ). When the function of Gs is impaired, cAMP accumulation in the cells → intracellular cAMP increases. As a result, 1 receptors that stimulate cAMP-dependent receptors (such as ACTH, TSH, FSH, and LH receptors) are activated, allowing related hormones to act directly on certain target organs, and target cells are enhanced in function. For example, melanocytes secrete increased melanin → skin pigmentation; 2 the body is resistant to a variety of hormones, such as resistance to PTH leading to bone softening and rickets; 3 activated Gs down-regulates osteocalcin levels, increasing pre-osteoblasts Proliferation, inhibition of differentiation, leading to bone fiber dysplasia, formation of bone tissue conformational deformity.
Recently, some scholars have detected the mutation of the α subunit of Gs by the reverse transcription polymerase chain reaction technique with specific allele primers, specific allelic nucleotide hybridization and DNA sequencing, and located at the R201C or R201H site of the gene coding. The cause of the mutation is due to the increased activity of the GTPase, which impairs the activity of the mediated receptor.
symptom
1. Skeletal damage Bone damage is mainly caused by focal lesions. The focal lesion consists of fibrous connective tissue and scattered immature interwoven bone and cartilage nodules. Bone damage often swells to the cortical bone in the bone marrow cavity, resulting in thinning of the cortical bone. Some localized lesions with multiple fibrous dysplasia may have liquefaction, cystic changes, hemorrhage and ossification in the cartilage nodules to form focal malformations, which may lead to lameness and even pathological fractures.
The above lesions can be involved in the bones and bones of the whole body. According to the nature of the lesions, they can be divided into single hair style and multiple hair style. The single-shot is most common with the femur, tibia and ribs, and the spine and pelvis are relatively rare. 30% involved the craniofacial bone, but mainly involved the upper and lower jaw and the top of the skull. Cranial base hyperosteogeny often compresses the cranial nerve, leading to optic atrophy. Hyperplasia of the facial bone, making the face asymmetrical, sinus occlusion. Spinal, pelvic, and long bone lesions of the extremities lead to bone deformities and pathological fractures and bone pain. Multiple people are involved in the bilateral or side of the body, lower limbs, femur, tibia and pelvis are more common, less involved in the ribs and skull invasion, can involve the skull base.
2. Skin pigmentation Skin pigmentation occurs on the same side of the bone lesions, with localized dark brown flat spots. Typical pigment spots are called Cafe-au-lait spots, irregular in shape, often in the form of small patches; skin pigmentation More common in the back, more common in the lips, neck back, hips and thighs. At birth, pigment spots are not obvious, but they become markedly deeper and deeper with age or sun exposure. The shape of the pigmentation is related to the amount of bone lesions. If the pigmentation edge is clear, generally only a single bone is involved; if the edge is unclear, it is a map-like shape, usually involving multiple sites of bone.
3. Precocious puberty More common in women, precocious puberty is more than 6 years old, the average developmental age is 3 years old. There are reports of sexual precocity in the first month after birth. Women's menstrual cramps are the primary symptom of precocious puberty. Before the development of the mammary gland, plasma estrogen levels fluctuate between normal or significantly elevated (>900pg/ml), often periodic. LH and FSH levels were inhibited in young women and did not respond to GnRH stimulation (except for adult patients), indicating that girls' precocious puberty did not depend on gonadotropins. Female precocious puberty is consistent with bone age. The long-acting GnRH analogue cyproheptadine is ineffective in the treatment of prepubertal patients. The aromatase inhibitor testosterone has a significant therapeutic effect on girls.
Boys have much less precociousness than girls. Testicular enlargement is symmetrical, followed by penis enlargement and pubic hair, which is equal to normal puberty. Histological examination of the testes confirmed the enlargement of the seminiferous tubules with no or a small amount of interstitial cells.
In girls and boys, when the bone age reaches pubertal age, gonadotropin secretion begins, and the response to GnRt becomes puberty, when gonadotropin-dependent precocious puberty overlaps with earlier non-gonadotropin-dependent precocious puberty. In men, menstruation has become more regular. In the adult stage, female patients have normal puberty and normal reproductive function.
4. Multiple endocrine abnormalities and other organ diseases In addition to the two or one of the above three major signs of abnormalities, some patients also have endocrine or non-endocrine abnormalities.
(1) Thyroid abnormalities: can occur at any age of MAS, even shortly after birth. Hyperthyroidism with this disease is different from Graves' disease. It has the same distribution in men and women, and its goiter tends to multiple nodules. The nodules are often benign, indicating an increase in radioactive iodine uptake. In most cases, nodules are often complicated by hyperthyroidism, but thyroid hormone is often measured at the upper limit. TRH stimulation test showed that TSH release was suppressed, thyroid pathology showed no lymphocytic infiltration, and no thyroid antibody. These can be distinguished from clinical severe hyperthyroidism. If hyperthyroidism is clinically obvious, antithyroid drugs, isotope or surgery can also be used.
(2) Cortisol: not common in hyperthyroidism and precocious puberty in MAS. Children with hypercortisolism show a decrease in growth rate, and the age at which MAS develops hypercortisolism may be early and severe. Low ACTH levels, high doses of dexamethasone do not inhibit adrenal function.
(3) Hyperphosphatemia and hypophosphatemia rickets or osteomalacia can be combined with MAS: urinary cAMP increases in patients with MAS, and is associated with increased filtration of glomerular cAMP. If the urinary phosphorus response is normal, urinary cAMP is slow to respond to the input of exogenous PTH. Treatment with vitamin D and oral phosphate, rickets and rickets can usually be corrected, but most are resistant to treatment.
(4) Others: Abnormal livers include severe neonatal jaundice, increased enzyme activity in the liver, and cholestasis and bile duct abnormalities during liver biopsy. Cardiac abnormalities include enlarged heart, sustained tachycardia, and sudden death in young patients. Atypical cardiomyocyte hypertrophy also shows histologically the role of endocrine abnormalities. The etiology of restrictive lung disease, arteriovenous shunt or primary cardiac abnormalities and abnormal cardiac conduction remains unclear. Other MAS-related anomalies have not been reported.
With the following item 1 or item 2, the diagnosis can be established. If item 3 is considered, the possibility of MAS diagnosis should be highly considered.
1. It has three major signs of bone damage, skin pigmentation and precocious puberty.
2. X-ray manifestations of poor bone fiber structure, skin Cafe-au-lait point, age below 30 years old, accompanied by endocrine or non-endocrine abnormalities.
3. Young patients with either or both of the first items plus endocrine or non-endocrine abnormalities.
diagnosis
Mainly with osteoarthritis andNeurofibromatosis(von Recklinghausen disease) identification.
1. Deformative osteitis MAS bone disease is easily confused with osteoarthritis, but osteoarthritis is vegetatively premature, and there is no pigmentation of Cafe-au-lait spots, while blood ALP is significantly elevated. Identification.
2. Neurofibromatosis involves bones, often combined with skin coffee spots, without endocrine abnormalities, similar to MAS. Neurofibromatosis has subcutaneous nodules or soft color block changes and multiple neurofibromatosis, as well as asexual precocity.
complication
AcromegalyAnd hyperprolactinemia: can occur in a small number of MAS patients. Patients with acromegaly in MAS are similar to those with acromegaly caused by pituitary growth tumors. After applying TRH, GHRH and GH levels were increased without glucose inhibition. Adolescent acromegaly promotes bone growth and fibrous dysplasia of the skull surface is similar to acromegaly. Because the course of MAS is slowly progressive, MAS cases should be scanned regularly for the skull. Acromegaly of MAS is often associated with hyperprolactinemia, but may have hypogonadism and galactorrhea. The most common pathological reports are pituitary adenomas and nodular hyperplasia. Treatment includes surgery, radiation therapy, bromocriptine, and long-acting somatostatin analogues. If fibrosis occurs, surgery at the base of the sella is difficult. Radiation therapy has the risk of increasing the deterioration around the bone, and drug treatment can be considered.
treatment
(a) treatment
The disease has a self-limiting tendency, and the following measures can improve some clinical symptoms, including:
1. Medical treatment of bone damage
(1) Calcitonin: Calcitonin 50～100U or Yishenning 40U every other day or 2 times a week, intramuscular injection, some people think that the drug has obvious limitations on bone deformity caused by bone swelling and fracture stimulation of nerve endings. Analgesic effect, no obvious side effects, long-term medication due to high price.
(2) Diphosphate preparations: The efficacy of each report is different, commonly used are:
1EHDP (disodium edetate): 20mg/kg per day, oral treatment for 6 months to 1 year.
2 pamidronate (pamidronate): 60mg / d, intravenous infusion for 3 days, repeated every 6 months.
The patient did not have spontaneous fracture during the treatment. After 2 to 3 courses of treatment, the bone pain and gait disappeared abnormally, the length of the limb did not change, the blood ALP and urinary hydroxyproline decreased, but the radiology of bone damage was not cured. And confirmation of scintillation photography.
The use of the above two drugs also showed no obvious side effects (may be related to too little case observation), and the mechanism of action is not yet clear.
2. Surgical treatment of bone deformity For patients with severe MAS malformation, osteotomy orthopedic surgery is feasible. Scraping the bone of the lesion, using bone grafting and internal fixation, may recur after surgery. If the lesion grows rapidly, it is necessary to be vigilant and become osteofibrosarcoma, followed by osteosarcoma. At this time, it is not suitable for radiation therapy to avoid malignant transformation.
3. Treatment of precocious puberty
(1) hydroxyprogesterone (MPV): 5 ~ 10mg / d, can inhibit FSH, LH secretion, breast retraction, menstruation stopped, or the penis and testicles shrink, vaginal hair reduction, the effect is certain. A small number of patients have side effects such as nausea, vomiting, fatigue, and lethargy. Those with liver and kidney dysfunction should be used with caution.
(2) megestrol acetate (danazol, danacrin, danazol): can inhibit the secretion of gonadotropin, does not inhibit the normal level of FSH, LH in normal body, the same effect as above, the usual amount of 50mg / time, 1 ~ 2 Dosage /d or adjust the dose as appropriate. The side effect is elevated liver transaminase. Long-term application requires regular examination of liver function, and patients with liver dysfunction are prohibited from large doses.
(3) medroxyprogesterone (depoprovera): 100 ~ 200mg each time, intramuscular injection, once every 2 to 3 weeks, the effect, efficacy and MPA similar.
(4) Ketoconazole: has the effect of inhibiting the synthesis of adrenal and gonadal steroids. A recent report from Syed and Chalew from the Maryland Medical Center in the United States showed that they used ketoconazole 200 mg three times a day to treat two women with MAS who had precocious puberty, and that precocious puberty was suppressed 1 year later. The side effect is itchy skin and rash, but it does not affect the use. The liver function can be recovered after stopping the drug.
(5) Testosterone: It can inhibit the secretion of estrogen and promote the maturation of the girl's mammary gland. It also promotes the linear growth of bone and the maturation of bones. The effect on non-gonadotropin-dependent precocious puberty is positive. The dosage is 20-40 mg/(kg·d).
(6) Tamoxifen: It is currently considered to be the best anti-non-gonadotropin-dependent precocious puberty drug, which can compete with estradiol for estrogen receptors and deplete estrogen. After this treatment, puberty slowed down, linear growth decreased, and GnRH analogues were given during central puberty development, and growth rate and skeletal maturity remained stable. The dosage is 10-20 mg twice daily.
(two) prognosis
The prognosis of this disease depends mainly on the combination of endocrine abnormalities. When the bone deformity caused by poor bone fiber structure is serious, it can affect the daily activities of the patient. There are no reports of malignant changes in this disease in the literature.
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