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CME ARTICLE
Year : 2021  |  Volume : 22  |  Issue : 4  |  Page : 293-300

Prenatal diagnosis in dermatology


Department of Dermatology, Dr. D Y Patil Medical College, Navi Mumbai, Maharashtra, India

Date of Submission02-Aug-2020
Date of Decision04-Apr-2021
Date of Acceptance01-May-2021
Date of Web Publication01-Oct-2021

Correspondence Address:
Faaria Ali
Address: 51 Gulmohar Cross Road No. 4, JVPD Scheme, Mumbai - 400 049, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpd.IJPD_127_20

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  Abstract 


Prenatal diagnosis (PND) of inherited skin disorders comprises all the diagnostic modalities carried out in utero for couples who are at high risk of producing a child with congenital abnormalities. With the constant research being carried out in the field of molecular diagnosis and genetics, it is of utmost importance for dermatologists to be abreast about all the available means of genetic testing in utero. This will enable us to provide the best of options to the couples who are at risk of having children with inheritable skin disorders so that they can get the tests done at the appropriate time during gestation and the pregnancy can be continued safely till term. This article talks about all the invasive and noninvasive methods of PND practised at present and the ones that may gain popularity in the near future.

Keywords: Cell-free fetal DNA, DNA-based methods, fetal skin biopsy, preimplantation genetic testing, prenatal diagnosis


How to cite this article:
Gautam M, Ali F. Prenatal diagnosis in dermatology. Indian J Paediatr Dermatol 2021;22:293-300

How to cite this URL:
Gautam M, Ali F. Prenatal diagnosis in dermatology. Indian J Paediatr Dermatol [serial online] 2021 [cited 2021 Dec 5];22:293-300. Available from: https://www.ijpd.in/text.asp?2021/22/4/293/327442




  Introduction Top


Genetic skin diseases or genodermatoses refer to the disorders of the skin and its appendages caused by single-gene mutation. Currently, there are more than 500 genodermatoses with identified gene or chromosomal abnormality. Most of the genodermatoses do not have a cure at present.[1] They may be associated with significant mortality and long-term morbidity. Prenatal diagnosis (PND) of genodermatoses forms an integral part of medical care. It can help the parents to prepare themselves emotionally and financially should the results be positive for the genetic disease in question. Likewise, one can anticipate the medical problems during pregnancy and labor and offer timely medical assistance. The parents also have a therapeutic option of medical termination of affected pregnancy in cases where the genetic disease is severe and life threatening or may result in a severely disabled child with a very poor quality of life.[2]

The past few decades have witnessed enormous development in the field of prenatal screening and PND. Recent advances in molecular genetics and DNA sequencing have revolutionized the techniques of PND in terms of accuracy as well as the range of testing for genetic abnormalities.


  Prenatal Screening versus Prenatal Diagnosis Top


  • Prenatal screening is routinely offered to all pregnant women to assess any abnormality in the fetus. It is performed in the first or second trimester of pregnancy and includes ultrasound of the fetus and maternal blood tests. Being noninvasive, it is not associated with complications like miscarriage
  • On the other hand, PND comprises all diagnostic modalities aimed at identifying any genetic abnormalities in the embryo or fetus before birth. It is offered only to those parents who have a history of genetic disorder in the family. It is used to diagnose medical conditions specific to the family. It can be associated with medical complications since it involves invasive procedures.



  Evolution of Prenatal Diagnosis in Dermatology Top


  • PND for inherited skin diseases was introduced in the 1980s using fetal skin biopsy (FSB) techniques based on ultrastructural and immunohistochemical abnormalities of the fetal skin[2]
  • FSB was first performed for gravis type of junctional epidermolysis bullosa (JEB) of Herlitz (gravis JEB) in 1980 and recessive dystrophic EB (RDEB) in 1981[3]
  • Initially, biopsies were performed through direct visualization of the fetus using a fetoscope, under sedation and local anesthesia until the advent of ultrasound-guided FSB.[4],[5],[6] These biopsy samples were initially analyzed for light and electron microscopy. Later, immunohistochemical tests were performed on these samples with the development of specific antibodies
  • As the molecular biology advanced, specific gene mutations responsible for a number of inherited skin diseases were identified. This led to the development of DNA-based testing like amniocentesis and chorionic villus sampling (CVS)
  • As the in vitro fertilization (IVF) and embryo manipulation technologies advanced, preimplantation genetic diagnosis was introduced and it gained popularity during the 1990s to identify genetic defects in embryos created through IVF, thereby allowing transfer of genetically normal embryos to the uterus for implantation
  • All invasive methods for PND carry some risk for the fetus and the mother. Therefore, there was a need to develop noninvasive tests
  • The discovery of circulating fetal nucleic acids (DNA and RNA) in the maternal blood in 1997 resulted in the development of noninvasive methods of PND to determine the fetal risk for genetic disorders without incurring the risk of abortion.



  Indications for Prenatal Diagnosis Top


PND of inherited skin disorders should be carried out in any patient:

  • With a history of a previously affected pregnancy
  • With a family history of an inherited skin disorder
  • Who is a known carrier of a genetic skin disease
  • Who has shown abnormal signs during her regular prenatal screening.



  Significance of Prenatal Diagnosis Top


PND is important in couples with a history of genetic or chromosomal disorders in the family which can be transmitted to the offspring. It gives them the choice to terminate the pregnancy if the test results are positive for the suspected disease. However, it is indicated only for those conditions which are associated with significant morbidity and/or mortality.


  Different Methods of Prenatal Diagnosis Used in Dermatology Top


There are various methods of PND which can be classified as invasive or non-invasive. The different invasive and non-invasive methods are shown in [Table 1]:
Table 1: Methods of prenatal diagnosis

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Invasive methods of prenatal diagnosis

A summary of all the techniques of PND in dermatology is given in [Table 2]. These methods involve direct investigation of fetal cells or tissue which is obtained by insertion of forceps or needle into the fetus. They include the following:
Table 2: Summary of different techniques of Prenatal diagnosis[3]

Click here to view


Fetal skin biopsy

Although the most commonly performed invasive techniques for PND include amniocentesis and CVS, there is still a need to obtain fetal skin for the diagnosis of a small number of genodermatoses in some circumstances.[7]

Procedure

  • It is an invasive prenatal diagnostic test which involves removal of 1–2 mm of fetal skin tissue with the help of a biopsy forceps under ultrasonography (USG) guidance
  • Routinely, four full-thickness FSBs are taken, two for electron microscopy and two for immunohistochemistry[8]
  • The sites most commonly biopsied are the buttocks, back, or thorax.[9]


Indications for fetal skin biopsy

Nowadays, due to the introduction of newer, less invasive molecular diagnostic procedures, FSB is gradually being superseded by gene analysis.

It is, however, useful:

  • When the causative gene is unknown
  • When the causative gene is known but the specific genetic mutation cannot be identified in the family[3],[8] or the informative DNA markers are not available (example: if the affected child died before the DNA samples could be obtained)[8]
  • FSB also might be useful in de novo cases, where there is a suspicion of a genodermatosis[10]
  • Finally, if the results of DNA-based PND have been equivocal or unsatisfactory.[8]


Appropriate time for performing fetal skin biopsy

FSB is usually performed relatively late in pregnancy between 15 and 22 weeks of gestation when the fetal skin is morphologically and biochemically developed.[4]

The appropriate period of gestation at which FSB should be performed for the particular skin disorders is listed below:

  • Harlequin ichthyosis – 22 weeks (as the structural abnormalities begin to appear at this stage)[11]
  • Bullous ichthyosiform erythroderma, lamellar ichthyosis, and Sjogren–Larsson syndrome – Between 20 and 22 weeks
  • Epidermolysis bullosa – 16–17 weeks[11]
  • Ectodermal dysplasias – X-linked hypohidrotic ectodermal dysplasia – 20 weeks
  • Albinism – Tyrosinase-negative oculocutaneous albinism – 18–20 weeks.[4]


Disadvantages of fetal skin biopsy

  • FSB can be performed only in the second trimester of pregnancy and requires a long waiting period for test results. This could delay the process of abortion if the biopsy results confirm genetic abnormalities in the fetus.[4] The delay also adds to the parents' anxiety about the status of their babies
  • It is an invasive procedure with the risk of fetal loss being 1%–3%[10]
  • It may be associated with amniotic fluid leakage and fetal scarring[3]
  • The number of centers with the experience and expertise to perform FSB is becoming increasingly low.[10]


Amniocentesis and chorionic villus sampling

The identification of the molecular basis of most of the inherited skin disorders has resulted in the practice of DNA-based PND over non-DNA-based methods.[3] Amniocentesis and CVS are DNA-based methods used to obtain fetal cells for analysis of any genetic or structural abnormalities. In contrast to amniocentesis which aspirates amniotic fluid, CVS aspirates placental tissue.

Indications for amniocentesis and chorionic villus sampling

  • These tests are done when the causative genetic mutation has been identified in the family
  • A couple who has had a child affected with an inherited skin disorder and wants to plan another child.[3]


Prerequisites

  • Knowledge of the diagnosis and inheritance pattern of the previously affected pregnancy in order to determine the genetic risk[8]
  • DNA samples of both parents and affected family members (usually extracted from peripheral blood samples) are required to characterize the pathogenic mutation and exclude situations such as de novo mutations, uniparental disomy, nonpaternity, and germline mosaicism.[3],[5]


Procedure of amniocentesis

  • Amniotic fluid contains amniotic cells obtained from various fetal epithelia such as the fetal epidermis, alimentary and genitourinary mucosa, and the amnion[8]
  • Amniocentesis is performed between 15 and 17 weeks of gestation
  • The fetal cells are obtained by aspirating about 15 ml of amniotic fluid by a needle inserted transabdominally under ultrasound guidance
  • The fetal DNA is investigated for a known genetic mutation
  • Risk of miscarriage – 0.5%–1%.


Procedure of chorionic villus sampling

  • Chorionic villi are of fetal origin and hence can be used as a source of fetal cells
  • It is performed in the 11th or 12th week of gestation. It is not advisable to do it before the 11th week as the risk of limb abnormalities is higher[6]
  • Depending on the site of the placenta, CVS can be done either transcervically or transabdominally under ultrasound guidance
  • Fetal DNA is then extracted from the specimen and investigated for genetic mutation[9]
  • Risk of miscarriage – ~1%
  • The actual analysis of fetal DNA can be completed between 48 and 72 h after its receipt in the laboratory.[2]


Chorionic villus sampling versus amniocentesis

  • The main advantage of CVS over amniocentesis is the ability to perform this test earlier in pregnancy[10]
  • The risk for fetal loss is almost the same for both procedures[3]
  • Common risk factors include cramping, vaginal bleeding, infection, and amniotic fluid leakage.[3]


Currently, it is possible to carry out the genetic diagnosis of more than 300 genodermatoses through the analysis of fetal DNA, but it is mainly carried out for the serious ones.[12]


  Some Disorders for Which DNA-Based Prenatal Testing Has Been Performed Top


  • Epidermolysis bullosa and its variants
  • Bullous congenital ichthyosiform erythroderma
  • Pachyonychia congenita
  • Netherton's syndrome
  • Lamellar ichthyosis
  • Harlequin ichthyosis
  • Congenital erythropoietic porphyria
  • Oculocutaneous albinism
  • Xeroderma pigmentosum Group A
  • Sjögren–Larsson syndrome
  • Wiskott–Aldrich syndrome
  • Chediak–Higashi syndrome
  • Ehlers–Danlos syndrome Type IV.[12]


Preimplantation genetic diagnosis

  • Preimplantation genetic diagnosis (PGD) is an alternative to postconception diagnostic procedures, which allows a study of DNA of the early embryo prior to its implantation or of an oocyte prior to its fertilization to identify those with genetic defects. The embryo or the oocyte is obtained through IVF
  • It helps to minimize the chances of transfer of genetically abnormal embryo by selecting disease-free embryos for transfer into the uterus for implantation[10]
  • PGD helps families who are at risk of transmitting genetic disorders conceive a normal child
  • It is a highly specialized procedure and is available in relatively few centers worldwide
  • Since the test is done before pregnancy has begun, it removes the stress of undergoing an abortion for couples following unfavorable PND.[2]



  Stage at Which the Embryo Can Be Biopsied Top


The embryo can be biopsied at various stages of development:

Cleavage stage biopsy

  • Most common method of embryo biopsy
  • Performed at the 8- to 12-cell stage (about 72 h after IVF).


Blastocyst stage biopsy/trophectoderm biopsy

  • This technique involves biopsy of trophectoderm (outer cell mass of embryo which develops into placenta) from a hatching blastocyst on day 5 of IVF
  • Shows better results compared to the cleavage stage biopsy.


Once the sample is obtained, its DNA is amplified using the appropriate single-cell polymerase chain reaction (PCR) protocol and then tested for genetic disease.[5],[9],[13]

If the genetic disorder is ruled out, a maximum of two disease-free embryos can be implanted into the uterus on day 4 or day 6 of development.[2],[9]

Risks and limitations

  • The risk for transferring an affected fetus which was mistakenly identified as normal is approximately 2% in autosomal recessive conditions and 11% in autosomal dominant diseases.[3] Thus, PGD reduces but does not completely eliminate the risk of conceiving a child with a genetic disorder
  • Misdiagnoses have also occurred from contamination, failure to amplify, and allele dropout[3]
  • The small amount of DNA that is available for analysis in a single cell also makes it difficult in obtaining results
  • Due to these difficulties, it is recommended that CVS or amniocentesis should be performed ultimately to confirm the genetic diagnosis
  • Some of the other limitations include the high cost of the procedure, limited access, and lower pregnancy rates[10]
  • The overall clinical pregnancy rate after PGD for monogenic disorders is about 25% per embryo transfer[5]
  • The interval between biopsy and implantation of the embryo is 2–3 days, so the tests need to be performed within this limited time frame only.



  Preimplantation genetic diagnosis in dermatology Top


PGD should be a viable means to prevent the development of severe genodermatoses since most of these disorders follow Mendelian inheritance. However, PGDs have been performed successfully in a limited number of genodermatoses. It has been performed for Herlitz JEB, and although pregnancy was not established in one case, an unaffected child was born in another family.[10] It has also been done for two cases of ectodermal dysplasia–skin fragility syndrome, resulting in delivery of a healthy child.[10]

Monogenic genodermatoses and diseases with skin manifestations for which preimplantation genetic diagnosis has been performed are as follows: [3]

Autosomal dominant genodermatoses

  • Neurofibromatosis Type 1
  • Tuberous sclerosis Type 1 and 2
  • Noonan syndrome
  • Glomuvenous malformation
  • Marfan syndrome
  • Rapp–Hodgkin syndrome
  • Osteogenesis imperfecta Type 1A
  • Ectrodactyly–ectodermal dysplasia–cleft lip or palate syndrome
  • Pseudohypoparathyroidism Type 1A ( Albright hereditary osteodystrophy More Details).


Autosomal recessive genodermatoses

  • Cystic fibrosis
  • Oculocutaneous albinism Type 1
  • Hallopeau–Siemens RDEB
  • Herlitz JEB
  • Ectodermal dysplasia–skin fragility syndrome
  • Severe combined immunodeficiency disorder
  • Wiskott–Aldrich syndrome.


X-linked genodermatoses

  • X-linked dominant incontinentia pigmenti
  • X-linked recessive Fabry disease.


Preimplantation genetic haplotyping

  • Recent advances in detection of EB involve amplification of the template DNA by whole–genome amplification before any disease markers are assessed
  • It results in approximately 1 million-fold amplification, thus increasing the template DNA from a single cell to approximately 6 mg. This is known as preimplantation genetic haplotyping (PGH)[5],[8]
  • The main advantage of PGH is that only the implicated gene and mode of inheritance are required to be known and the precise details of the mutation are not required
  • This helps in faster and more accurate diagnosis from a single-cell biopsy.


Non-invasive methods of prenatal diagnosis

All invasive methods for PND carry some risk for the fetus and the mother. PCR and DNA analysis of single cells has helped in the development of noninvasive prenatal genetic tests.

Fetal cells in maternal blood

  • In the 1960s, it was found that nucleated fetal cells could be isolated from maternal circulation[8]
  • The different fetal cell types that have been recovered in maternal circulation include nucleated erythrocytes, trophoblast, mesenchymal stem cells, and hematopoietic stem cells expressing the antigen CD34[3]
  • However, studies have found that only 2–6 fetal cells are present per ml of maternal blood in mid-gestation, which makes the isolation of these cells very difficult
  • Furthermore, the final purity of the fetal cells is low as they are often contaminated with maternal cells[10]
  • These cells may persist in the maternal blood for months to years, thus their value in prenatal testing remains doubtful.[8]


Cell-free fetal DNA and mRNA in maternal blood

  • The presence of fetal DNA in maternal blood was discovered in 1997 whereas fetal mRNA was detected in maternal blood 3 years later[10]
  • The main source of the fetal DNA is the syncytiotrophoblast cells from the placenta, which undergo apoptosis and release nucleic acids. The hematopoietic stem cells and direct fetal–maternal transfer contribute a smaller fraction[8],[10]
  • It constitutes about 3%–6% of DNA in the maternal plasma and consists mostly of short fragments (<200 base pairs)
  • It is detectable after 4 weeks of gestation, after which its concentration increases with increasing gestational age[8]
  • It is ideally done between 4 and 10 weeks
  • Mean half-life of this cell-free genetic material is 16 min, thus they do not persist for long in maternal plasma.


Challenges faced

  • As cell-free fetal DNA (cffDNA) makes up a very small proportion of the total free DNA in the maternal plasma, it is very challenging to isolate it
  • It is very difficult to distinguish between the fetal and maternal DNA. Therefore, this method is mostly useful for diagnosis of mutations that are inherited from the father[10],[14]
  • PCR amplification of Y-sequences in maternal circulation helps to detect male fetuses at risk for severe X-linked genetic disorders. Although not yet used in the diagnosis of genodermatoses, this may be applied to severe X-linked genodermatoses.[2]


The main source of fetal RNA is the maternal placenta. This could be used for PND in the future.[8]

Ultrasonography

  • USG has no direct role in the PND of genetic skin diseases as it cannot detect morphological abnormalities associated with fetal skin diseases because these are microscopic
  • Ultrasound imaging of the fetus as well as uterine contents can mainly provide information about the structural and internal organ abnormalities related to the inherited skin disorders
  • The major advantage of ultrasound is that abnormalities can be detected in the absence of any family history, thus proving to be useful for de novo cases[3]
  • USG is also useful as a guide for fetoscopy, fetal blood sampling, tissue sampling, amniocentesis, and CVS.


Dermatological conditions in which USG can be used

  • Epidermolysis bullosa – The presence of pyloric atresia, ureteral stenosis, arthrogryposis, and nose or ear deformities is suggestive of EB.[10] Snowflake sign in the amniotic cavity might be a marker of fetal skin sloughing in JEB with pyloric atresia as well as in harlequin ichthyosis[2]
  • Harlequin ichthyosis – Routine prenatal two-dimensional (2D) USG might reveal echogenic amniotic fluid, large joint contractures, digital contractures, and facial dysmorphism like flat face and wide mouth with thickened lips.[3] If these findings are seen, the patient is referred for a 3D USG in which facial dysmorphism can be seen more clearly along with the rest of the findings[10]
  • Noonan syndrome – It is characterized by short stature, congenital heart defects, and characteristic faces with webbed neck[3],[10]
  • Tuberous sclerosis complex (TSC) – The presence of cardiac rhabdomyomas is the earliest and most common (66%) marker of tuberous sclerosis.[3],[10] The lesions can be visualized as early as 22–27 weeks of gestation. Multiple tumors are highly predictive of TSC[3]
  • Other heritable skin syndromes associated with anomalous development which can be seen on USG include hypohidrotic ectodermal dysplasia, chondroectodermal dysplasia, linear nevus sebaceous, and cutis verticis gyrata.[3],[8]


Currently, this method can be used only after around 18 weeks of gestation, thus playing a limited role in PND.

Maternal serum screening

  • The maternal triple-marker screen, which consists of alpha-fetoprotein, human chorionic gonadotropin, and estriol, is a part of the standard clinical obstetric practice and is commonly used to diagnose Down syndrome, trisomy 18, and open neural tube defects. It can also be useful in the diagnosis of X-linked ichthyosis
  • Steroid sulfatase deficiency, the molecular basis of X-linked ichthyosis, is the commonest cause for extremely low levels of unconjugated estradiol. This occurs due to the placental insufficiency of steroid sulfatase due to which there is defective steroidogenesis
  • Amniocentesis or CVS must be performed to confirm its suspicion.[10]


Prenatal diagnosis in dermatology – The Indian scenario

FSB, CVS and amniocentesis, maternal serum screening, and USG are performed in various laboratories based in all the metropolitan cities. The approximate cost of these tests is around Rs. 20,000/- per test.

PGD, being an integral part of assisted reproductive technology procedures, is also performed in all the metropolitan cities with IVF setup.[15] The cost of this test ranges from Rs 2.5 to 5 lakhs.

Noninvasive prenatal tests like cffDNA in maternal serum are carried out for screening of genetic conditions such as Down syndrome, Turner syndrome, and Klinefelter syndrome in Mumbai, Delhi, and few other cities at a cost of approximately Rs. 10,000/-. They are not currently carried out for any genodermatoses in our country.

Genetic counseling in prenatal diagnosis

Genetic counseling is an integral part of PND. It is a process in which a patient and/or the parents are advised about the course, treatment and prognosis of the genetically inherited disease present in the family, the risk of inheritance of that disease during each pregnancy, and ways to have a normal child. For this purpose, accurate diagnosis of the disease, family history, physical examinations, and evaluation of inheritance patterns are essential. Estimating the risk of a fetus being affected by a genetic disease is one of the most important parts of genetic counseling. Apart from this, it consists of appropriate counseling of the couple before investigations and taking informed consent of parents. It is important to ensure non-directive counseling, and the counselor should facilitate informed decision-making. The option for terminating the pregnancy should be left with the parents if the test results are positive for a genetic disease.

Ethical concerns related to prenatal diagnosis

Prenatal genetic testing has significant medical, social, and ethical implications on patients and their families. The decision to perform a PND is influenced by many factors such as religion, ethics, intellectual values, and the disease itself.[10] There are various aspects related to PND that can pose an ethical challenge. The two most important questions that pose an ethical issue are what should be the severity of the genetic disorder to recommend a PND and if a genetic disorder has been diagnosed, what is the indication that can be defined as severe enough to give an option for medical termination of pregnancy.[8] There are some genodermatoses such as harlequin ichthyosis, variants of epidermolysis bullosa which could be life threatening or may result in significant morbidity, some like neurofibromatosis, tuberous sclerosis which are associated with severe cosmetically disfigurement and systemic involvement, whereas many other genodermatoses are mild with no effect on life expectancy. Many health care personnel may feel that aborting a fetus which is detected as having one of the milder forms of a genetic disorder is not justified as it does not affect the life expectancy significantly. Some societies might feel that any couple at risk has the right to know about the available options with the intention of terminating the affected pregnancy. Thus, informed choices are valued in certain countries.

The development of PGD further complicates ethical intricacies. PGD involves very tight regulatory controls and licensing since it involves analysis of a 3-dayold embryo.

Thus, since there are no clear guidelines, each case should be carefully considered individually and the decision to conduct PND should be carefully justified by hospital ethics committee.


  Conclusion Top


PND in dermatology has evolved immensely from more invasive procedures like FSB to more sophisticated non-invasive prenatal tests. Although currently the number of genetic skin conditions that can be diagnosed by non-invasive prenatal tests is limited, they will increase in the coming years. A thorough knowledge regarding the various tests that are available along with their specific indications will enable us to give proper guidance to the parents.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Ma Y, Gong H, Wen Y. Nucleic acid-based non-invasive prenatal diagnosis of genetic skin diseases: Are we ready? Exp Dermatol 2013;22:392-5.  Back to cited text no. 1
    
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Fassihi H, McGrath JA. Prenatal diagnosis of epidermolysis bullosa. Dermatol Clin 2010;28:231-7.  Back to cited text no. 2
    
3.
Luu M, Cantatore-Francis JL, Glick SA. Prenatal diagnosis of genodermatoses: Current scope and future capabilities. Int J Dermatol 2010;49:353-61.  Back to cited text no. 3
    
4.
Soothill PW. Prenatal diagnosis of skin diseases. Arch Dis Child 1988;63:1175-8.  Back to cited text no. 4
    
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Ashton GH, Eady RA, McGrath JA. Prenatal diagnosis for inherited skin diseases. Clin Dermatol 2000;18:643-8.  Back to cited text no. 5
    
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Wieacker P, Steinhard J. The prenatal diagnosis of genetic diseases. Dtsch Arztebl Int 2010;107:857-62.  Back to cited text no. 6
    
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Elias S, Emerson DS, Simpson JL, Shulman LP, Holbrook KA. Ultrasound-guided fetal skin sampling for prenatal diagnosis of genodermatoses. Obstet Gynecol 1994;83:337-41.  Back to cited text no. 7
    
8.
McGrath JA. Prenatal diagnosis of genetic skin disease. In: Tony Burns, Stephen Breathnach, Neil Cox and Christopher Griffiths. Rook's Textbook of Dermatology. 8th ed. U.K: Blackwell Publishing Ltd; 2010. p. 16.1-6.11.  Back to cited text no. 8
    
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Fassihi H, Eady RA, Mellerio JE, Ashton GH, Dopping-Hepenstal PJ, Denyer JE, et al. Prenatal diagnosis for severe inherited skin disorders: 25 years' experience. Br J Dermatol 2006;154:106-13.  Back to cited text no. 9
    
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Ramot Y. Intrauterine diagnosis of genodermatoses. Curr Dermatol Rep 2013;2:243-8.  Back to cited text no. 10
    
11.
McGrath JA. Genetics and the skin. In: Christopher Griffiths, Jonathan Barker, Tanya Bleiker, Robert Chalmers and Creamer Daniel. Rook's Textbook of Dermatology. 9th ed. U.K: Wiley Blackwell; 2016. p. 7.1-7.11.  Back to cited text no. 11
    
12.
de Abreu SM, Prado de OZ, Javier M. Prenatal diagnosis of genodermatoses. An Bras Dermatol 2007;82:353-8.  Back to cited text no. 12
    
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Sanders KD, Griffin DK. Chromosomal preimplantation genetic diagnosis: 25 years and counting. J Fetal Med 2017;4:51-6.  Back to cited text no. 13
    
14.
McGrath JA. The molecular revolution in cutaneous biology: Era of molecular diagnostics for inherited skin diseases. J Invest Dermatol 2017;137:e83-6.  Back to cited text no. 14
    
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Parikh FR, Athalye AS, Naik NJ, Naik DJ, Sanap RR, Madon PF. Preimplantation genetic testing: Its evolution, where are we today? J Hum Reprod Sci 2018;11:306-14.  Back to cited text no. 15
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Introduction
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