Monogenic inherited dermatoses are a large group of diseases with varying phenotypes and severity, totaling about 1000 diseases. With the advances in molecular biology techniques and the Human Genome Project, many major breakthroughs have been made in the field of genetic dermatoses. From the 1980s to the present, the molecular genetic basis of most monogenic inherited skin diseases has been elucidated, which has laid the foundation for widespread genetic diagnosis and prenatal diagnosis. Some severe hereditary skin diseases, such as junctional and dystrophic epidermolysis bullosa (EB), staining dry skin disease, congenital dyskeratosis, and lamellar ichthyosis, seriously affect the quality of life of patients and even threaten their lives, and it is necessary to interrupt the inheritance of diseases through prenatal diagnosis to improve the quality of the population and reduce the family and social It is necessary to stop the inheritance of diseases through prenatal diagnosis, improve the quality of population, and reduce the burden of family and society. 1. Prenatal diagnosis methods 1.1 Fetal skin biopsy combined with histological testing Prenatal diagnosis of severe hereditary skin diseases started in 1980, and two groups of scholars have successfully implemented prenatal diagnosis in families with junctional EB [1] and congenital ichthyosis vulgaris-like erythroderma [2] by applying fetal skin biopsy combined with histopathological and electron microscopic techniques. Fetal skin biopsy can be performed by fetoscopy or in combination with ultrasound guidance. Some pigmentary abnormalities such as albinism as well as keratotic dermatoses such as ugly fetal ichthyosis can be detected abnormally by fetoscopy. The specimens obtained can be examined morphologically with light and electron microscopy. With the advances in monoclonal antibodies and immunohistochemistry, fetal skin specimens can also be detected at the protein level, increasing the reliability of the diagnosis. Fetal skin biopsy can be performed in the mid-15-22 weeks of pregnancy. Its biggest drawback is that it can only be performed when morphological changes in the disease are present and is relatively invasive. One of the more internationally performed such techniques is the St John’s Institute of Dermatology in the United Kingdom, where 191 cases were performed [3]. With the advances in molecular biology, prenatal diagnosis based on DNA testing has largely replaced the above methods since 1994. 1.2 Prenatal diagnosis based on DNA testing Since the 1990s, thanks to the rapid progress of molecular biology techniques, the molecular genetic basis of most monogenic inherited skin diseases has been elucidated. In 1995, several groups of scholars [4-7] reported the implementation of DNA-based prenatal diagnosis in families with dystrophic or junctional EB, and in 2002, the Department of Dermatology at Peking University First Hospital was the first in China to do so [8]. To date, the group has successfully implemented prenatal diagnosis in more than 10 families with dystrophic EB, pigmented dry skin disease, and lamellar ichthyosis. In recent years, some units in China have also started to carry out similar work [9, 10]. It is believed that with the gradual popularization of molecular biology techniques, more and more units will carry out this work in China. 1.2.1 Chorionic villus sampling Chorionic villus sampling refers to obtaining a small amount of chorionic tissue from the pregnant woman’s uterus, which has the same DNA as that of the fetus and can be used for genetic testing. The most commonly used method nowadays is transabdominal puncture chorionic villus biopsy under ultrasound guidance. The greatest advantage of this method is that the specimen can be obtained early in pregnancy, usually at 10-12 weeks of gestation, so DNA testing can be performed earlier. However, the disadvantages are that it is technically more demanding, has a higher risk of maternal tissue contamination, and may have a higher incidence of miscarriage and risk of fetal development than amniocentesis, although these aspects also depend on the skill and proficiency of the obstetrician. The St John’s Institute of Dermatology in the UK has used this method in recent years and has performed nearly 100 cases to date [3]. 1.2.2 Amniocentesis Amniocentesis is the most commonly used invasive prenatal diagnostic technique and is now widely used for prenatal diagnosis of fetal chromosomal disorders and congenital metabolic disorders. Amniocentesis is mostly performed in the middle of pregnancy (12-20 weeks of gestation) and is a relatively mature technique with low risk. 10-20 ml of amniotic fluid can be extracted at one time and enough cells are obtained for DNA testing. The amniotic fluid contains mainly fetal kidney cells and fetal epithelial cells, which can be used for amniotic fluid cell culture. Unless there is a condition such as placenta praevia, it is generally unlikely that the amniotic fluid is contaminated with maternal cells. This method is basically used in China because it is relatively convenient because it can be performed at the same time as amniotic fluid cell culture to detect chromosomal diseases. 1.2.3 Preimplantation genetic diagnosis means that after in vitro fertilization, when the embryo has reached the stage of 8-12 cells, one or two cells are taken for DNA testing by microscopic operation to make sure that the embryo is free of disease before transferring into the uterus. The embryos are then transferred into the uterus. The technical difficulty is the single-cell PCR, which has a relatively high rate of misdiagnosis and often requires further confirmation by subsequent chorionic villus sampling or amniotic cavity puncture sampling. The technical requirements of this method are high and the cost is much higher. The disease in which this method is now more frequently used abroad is cystic fibrosis [11]; in the field of dermatology, this technique has been implemented in the UK in families with fragile-epidermal dysplasia syndrome of the skin [12]. 1.2.4 Non-invasive prenatal testing The discovery of free fetal cells in maternal blood in the 1950s has made non-invasive prenatal testing possible. One of the most practical is the fetal nucleated red blood cells, which can be detected at 8-12 weeks of gestation. The key to this method is how to enrich and purify the fetal cells, excluding contamination of maternal blood. Some progress has been made in this technique in recent years [13], but further exploration is needed in clinical application, such as the optimal time for enrichment of fetal cells, influencing factors, establishing a specific and sensitive analytical method, and overcoming the problem of false negatives and false positives. Only if these problems are solved, this method can become an ideal non-invasive prenatal diagnosis method. Today this method is not yet carried out in hereditary skin diseases, but it may become the future development direction. 2, the indications of prenatal diagnosis Not all hereditary skin diseases are necessary for prenatal diagnosis, the main reason is not technical problems, but ethical issues. In recent years, prenatal diagnosis is mostly carried out for severe hereditary skin diseases, such as heavy EB (mainly dystrophic and junctional), pigmented dry skin disease (mainly type A and C), laminar ichthyosis and heavy ectodermal dysplasia. These diseases are a serious health risk for patients and can have a serious impact on their quality of life and psychological well-being, and can place a great burden on their families and society. For some mild genetic diseases, such as ichthyosis vulgaris, hereditary symmetrical pigmentation disorder and woolly hair, there is no serious impact on the health of patients, and some of them only represent some rare traits, reflecting biological diversity, so there is no need to perform prenatal diagnosis. In recent years, the best choices for prenatal diagnosis in China and abroad include: heavy EB, heavy ichthyosis, pigmented dry skin disease, heavy ectodermal dysplasia, etc.; the next best choices include: albinism, Hailey-Hailey disease, etc. In contrast, mild EB, mild ichthyosis, pigmentary anomalies and hair anomalous disorders should not be the better choice for prenatal diagnosis because they involve possible abortions and are not quite in line with modern ethical principles. In fact, the prenatal diagnosis implemented in China and abroad also focuses on a few diseases such as heavy EB and heavy ichthyosis. After continuous exploration in recent years, the Department of Dermatology of Peking University First Hospital can now routinely perform prenatal diagnosis for the above diseases. 3. Problems faced by prenatal diagnosis 3.1 Ethical issues: The main ethical issues involved in prenatal diagnosis include: 3.1.1 Abortion can also have psychological effects on parents and families. 3.1.2 Gender identification: For some X-linked genetic diseases, such as X-linked hypohidrotic ectodermal dysplasia and X-linked ichthyosis, generally only male fetuses may have the disease, so the correct prenatal diagnosis can be basically made through gender identification. This also involves some ethical issues. 3.1.3 Overmedication: Prenatal diagnosis of mild genetic diseases has been highly controversial and can be considered by many to be overmedicated, although there may be a strong demand from the patient’s family. For controversial diseases, it is recommended to discuss with ethics experts before implementation. Given the high number of ethical issues involved in prenatal diagnosis, it is essential to obtain approval from the local ethics committee before implementation. 3.2 Legal issues: Since prenatal diagnosis is a new technology developed only in recent years, the relevant domestic laws and regulations are being gradually improved. The State enacted the Law of the People’s Republic of China on Maternal and Infant Health Care in 1994, and the Ministry of Health also enacted the Administrative Measures for Prenatal Diagnosis and some supporting documents, and local governments have also issued corresponding regulations. It is important for institutions to fully study and master the relevant contents before carrying out prenatal diagnosis. In addition, for possible false-negative and false-positive problems, patients and doctors should fully communicate and there must be adequate risk communication during the informed consent process to avoid possible legal disputes. It is necessary for dermatologists to consult with relevant legal experts if they encounter some issues that may involve the law when performing such work. 3.3 Qualification issues: At present, the institutions qualified for prenatal diagnosis are mostly obstetrics and gynecology, and doctors need to attend the corresponding legal and technical training, and obtain the corresponding certificates to be qualified for implementation. The prenatal diagnosis of hereditary skin diseases obviously requires the joint participation of dermatologists and obstetricians and gynecologists. Few doctors outside of obstetrics and gynecology have obtained this qualification. The Department of Dermatology of Peking University First Hospital has passed the training and examination in Beijing and obtained the qualification of prenatal diagnosis. 3.4 Cost issue: There is no domestic fee standard for prenatal diagnosis of DNA testing for hereditary skin diseases. The cost of prenatal diagnosis can be several thousand to several tens of thousands of yuan for different types of diseases. The first few cases of prenatal diagnosis performed by the author’s research group were carried out with research grants applied for, but with the increasing number of cases performed, the funding sources have been stretched to the limit. Most patients are now volunteering for voluntary donations for prenatal diagnosis of their family lineage. As the economic level and moral culture continue to improve, it is believed that the state or relevant health departments will set clear fees and increase support for such work, and various non-governmental organizations such as genetic skin disease foundations will emerge one after another in China to promote and fund such research and clinical work. 4.Problems and Prospects Prenatal diagnosis of hereditary skin diseases is a technology that has been developed and matured gradually in the past 30 years, but now in China, through amniocentesis and DNA testing, this work can be carried out routinely for a variety of serious hereditary skin diseases. This is a successful example of modern medicine benefiting human health, which is of great significance in improving the quality of the birth population, reducing the incidence of such diseases, and alleviating the burden of patients’ families and society. With the wide spread of molecular biology technology in domestic dermatology, how to develop and standardize DNA testing prenatal diagnosis technology in order to serve patients’ families more safely and effectively will be a topic to be faced in the future. It is believed that with the gradual improvement of relevant laws and regulations, and with the continuous progress of laboratory regulation and quality control, the above problems should be effectively solved. Looking ahead, with the continuous progress of science and technology, non-invasive prenatal testing and prenatal genetic testing should be the future development trend of prenatal diagnosis. China has reached the international advanced level in this field, and it is believed that in the near future, these safer and more efficient technologies will be widely used in China. [References] [1] Rodeck CH, Eady RA, Gosden CM. Prenatal diagnosis of epidermolysis bullosa letalis[J]. Lancet, 1980, 1(8175):949-952. [2] Golbus MS, Sagebiel RW, Filly RA et al. Prenatal diagnosis of congenital bullous ichthyosiform erythroderma ( epidermolytic hyperkeratosis) by fetal skin biopsy[J]. N Engl J Med, 1980,302(2):93-95. [3] Fassihi H, Eady RA, Mellerio JE, et al. Prenatal diagnosis for severe inherited skin disorders: 25 years’ experience [J].Br J Dermatol, 2006, 154(1):106-113. [4] Hovnanian A, Hilal L,Blanchet-Bardon C et al. DNA-based prenatal diagnosis of generalized recessive dystrophic epidermolysis bullosa in six pregnancies at risk for recurrence[J]. J Invest Dermatol, 1995, 104(4):456C461. [5] Vailly J, Pulkkinen L, Miquel C et al. Identification of a homozygous one-basepair deletion in exon 14 of the LAMB3 gene in a patient with Herlitz junctional epidermolysis bullosa and prenatal diagnosis in a family at risk for recurrence[J]. J Invest Dermatol, 1995,104(4):462C466. [6] Dunnill MG, Rodeck CH, Richards AJ et al. Use of type VII collagen gene (COL7A1) markers in prenatal diagnosis of recessive dystrophic epidermolysis bullosa [J]. J Med Genet, 1995,32(9):749C750. [7] McGrath JA, Dunnill MG, Christiano AM et al. First trimester DNAbased exclusion of recessive dystrophic epidermolysis bullosa from chorionic villus sampling[J]. Br J Dermatol, 1996,134(4):734C739. [8] Yang Y, Ding B, Wang K, et al. DNA-based prenatal diagnosis in a Chinese family with Xeroderma Pigmentosum group A [J]. BrJ Dermatol, 2004, 150(6): 1190-1093. [9] Li W, Gao B Di, Li Luyun, et al. Detection of Cx30 mutation in a family with sweaty ectodermal dysplasia and prenatal diagnosis [J]. Chinese Journal of Medical Genetics, 2006;23(6):618-621. [10] Liang K-Y, Tao J, Zhang D-G, et al. Successful implementation of a prenatal diagnosis of herpetic epidermolysis bullosa with removal of maternal cell contamination[J]. Chinese Journal of Dermatology, 2009, 42 (7): 448-450. [11] Handyside AH, Lesko JG, Tarín JJ, et al. Birth of a normal girl after in vitro fertilization and preimplantation diagnostic testing for cystic fibrosis[J]. N Engl J Med, 1992, 327 (13): 905C909. [12] Fassihi H,Grace J, Lashwood A, et al. Preimplantation genetic diagnosis of skin fragility-ectodermal dysplasia syndrome[J]. Br J Dermatol, 2006, 154(3): 546-550. [13] Sekizawa A, Kimura T, Sasaki M, et al. Prenatal diagnosis of Duchenne muscular dystrophy using a single fetal nucleated erythrocyte in maternal blood [J]. Neurology, 1996, 46(5): 1350C1353.