GeNeViSTA Fetal Dysmorphology: An Indispensable Tool for Synthesis of Perinatal Diagnosis Shagun Aggarwal Department of Medical Genetics, Nizam’s Institute of Medical Sciences, Hyderabad & Centre for DNA Fingerprinting and Diagnostics, Hyderabad Email: [email protected] Introduction for pregnancy management as it aids in accurate prognostication and communicating the possibility of intellectual disability and other co-morbidities in Dysmorphology is the science (and art!) of studying such children, helps in decision-making regarding abnormal form, with special emphasis on subtle termination or continuation of pregnancy, facili- ndings which provide clue to an underlying diag- tates appropriate postnatal management and also nosis, mostly a genetic syndrome. It has been the provides recurrence risk estimates for subsequent prime tool of the geneticist enabling a syndromic conceptions. In the postnatal scenario, such a diag- diagnosis on basis of patient’s gestalt with ndings nosis facilitates emotional closure, recurrence risk like a white forelock, heterochromia iridis, broad counseling and early, denitive prenatal diagnosis thumb, asymmetric crying facies and many other in subsequent pregnancies. subtle features acting as decisive tools in the ge- Any morphological or growth abnormality in the netics clinic. Most individuals with dysmorphism fetal life can be an isolated abnormality of multi- are affected with genetic syndromes, which can factorial origin, the consequence of environmental be due to chromosomal abnormalities, copy num- etiologies like a teratogenic insult, intrauterine fac- ber variations or single gene defects. However, tors, maternal illness, etc. or a component of a various environmental factors can also lead to genetic syndrome. In such a scenario, it is impor- dysmorphism, many times mimicking specic ge- tant to be aware of these possibilities, and perform netic syndromes due to involvement of a common a complete dysmorphological evaluation with an biological pathway. A dysmorphological evaluation aim to distinguish between these different situa- typically involves a head to toe examination look- tions with varied prognosis and recurrence risks. ing for malformations, and minor features showing Figure 1 shows some common fetal abnormalities deviation from the expected norm as per sex, and respective etiologies. age, family background and ethnicity. This often forms the rst and most crucial step in establishing a genetic diagnosis and is subsequently followed Setting of fetal dysmorphology by relevant genetic testing for conrmation. In There are two main settings where syndromic di- the era of next generation sequencing when the agnosis in the fetus is a possibility and should be rate of gene discovery has surpassed the clini- actively looked for: cal recognition of a new genetic syndrome and reverse phenotyping has become commonplace, a. Abnormal antenatal ultrasound. dysmorphology still remains an important tool in the hands of an experienced geneticist. b. Postmortem evaluation of an unexplained fetal demise or morphologically abnormal fetus. Although as a discipline dysmorphology evolved in the paediatrics setting, it can be extended to Abnormal antenatal ultrasound: Abnormal- the fetal life to enable the diagnosis of a genetic ities• on antenatal ultrasound can be found in syndrome in the fetus. The recognition of a genetic 5-10% of pregnancies. These can vary from growth syndrome in particular, has important implications abnormalities, major or minor malformations, soft Genetic Clinics 2017 | April - June | Vol 10 | Issue 2 11 GeNeViSTA Fetal abnormality Acquired etiologies Genetic etiologies Naso-maxillary • Fetal warfarin syndrome • Brachytelephalangic hypoplasia/Binder • Vitamin K deficiency chondrodysplasia punctata facies • Keutel syndrome • Vitamin K metabolism defects Talipes- • Oligohydramnios • Chromosomal disorders: sex equinovarus • Uterine malformations chromosome aneuploidy • Multiple pregnancy • Neuromuscular disorders • Skeletal dysplasias Cleft lip • Multifactorial • Isolated Mendelian* • Fetal hydantoin syndrome • Syndromic- chromosomal disorders, copy number abnormalities or Mendelian disorders# Ventriculomegaly • Fetal infections • Isolated Mendelian* • Intracranial hemorrhage • Syndromic- Chromosomal disorders • Associated with neural • Copy number abnormalities tube defect (multifactorial) • Mendelian disorders# Hydrops fetalis • Blood group antigen • Chromosomal disorders: Turner isoimmunisation syndrome, Down syndrome • Fetal infections esp. • Mendelian disorders#: Noonan Parvovirus syndrome, primary lymphatic • Hypothyroidism dysplasias, alpha thalassemia, • Congenital heart block, lysosomal storage disorders, others fetal arrhythmias • Cardiac defects Neural tube defect • Maternal diabetes • Isolated Mendelian* • Maternal hyperthermia • Syndromic- Chromosomal, • Folate deficiency Mendelian# eg. Meckel-Gruber syndrome, Spondylocostal dysostosis *Isolated Mendelian: Isolated defect due to mutation in single gene #Syndromic Mendelian disorder: A spectrum of multiple defects arising due to mutation in single gene Figure 1 Common fetal abnormalities and their etiologies. markers and liquor or placental abnormalities. along with relevant images to enable recognition of At least 10-30% of prenatally detected malforma- dysmorphic facies, recognize the pattern of abnor- tions are due to a genetic etiology (Beke et al., malities and elicit a detailed family history, which 2005). This gure is much higher for specic ab- would help in synthesis of a syndromic diagnosis. normalities like omphalocele, holoprosencephaly The advent of 3D ultrasound technology provides and cystic hygroma where 50-90% cases can be opportunity for facial dysmorphism recognition, attributed to genetic abnormalities involving the and can be used as an adjunct to the conventional chromosomes. In each of these scenarios, the 2D ultrasonography. antenatal ultrasonography should be performed by a fetal medicine specialist with a dysmorphol- Postmortem evaluation/ Fetal autopsy: ogy or clinical genetics knowledge. Alternatively, Post-mortem• evaluation is an important modal- a clinical geneticist consultation should be sought, ity for establishing the cause of unexplained fetal Genetic Clinics 2017 | April - June | Vol 10 | Issue 2 12 GeNeViSTA deaths as well as a medically terminated mor- opment. Maternal drug use especially antiepileptic phologically abnormal fetus. At least 15-30% of drugs, coumarin derivatives, ACE inhibitors and stillbirths are reported to be due to genetic causes some rarer drugs like retinoic acid derivatives, (fleddy et al., 2012). Besides the histopatholog- thalidomide, etc. needs to be ascertained as these ical examination of the placenta which provides are known to be potent fetal teratogens. Some evidence of acquired insults like utero-placental of these can result in fetal malformations which insufficiency and perinatal infections, dysmorpho- mimic genetic disorders involving defects in the logical evaluation by a geneticist or perinatal common biological pathway. An example is fetal pathologist with expertise in dysmorphology is es- warfarin syndrome, arising due to exposure to war- sential for syndrome recognition. Various studies farin in the rst half of pregnancy. Warfarin inhibits indicate that autopsy provides additional ndings the activity of Vitamin K, and its fetal effects are or modies the antenatal diagnosis in 20-50% cases similar to a genetic disorder brachytelephalangic (flodriguez et al., 2014). Antenatal series have also chondrodysplasia punctata which is caused by a shown that at least 50% syndromic diagnoses are mutation in the ARSE gene, important for Vitamin K possible only after an autopsy (Stoll et al., 2003). metabolism in the body. Hence, all cases with abnormal ultrasound ndings Family history: A three-generation family should undergo a post-mortem evaluation. pedigree• forms the cornerstone of the family his- tory ascertainment. This can provide important Practical approach to fetal information like consanguinity, which increases the dysmorphology risk of autosomal recessive disorders; previous fetus or child with similar or overlapping pheno- The evaluation of the fetus in-utero and/or post- type; other family members with pregnancy losses, mortem for syndrome recognition involves the infertility or abnormal offspring indicating possi- following steps (depicted in gure 2): bility of a chromosomal rearrangement or single gene etiology; and at times a parent with milder Antenatal and medical history manifestation of the same condition as the fetus. • Family history Ultrasonographic ndings: Various ultra- • Ultrasonographic ndings sonographic ndings may be a manifestation • fleports of serum aneuploidy screen • of an underlying genetic syndrome in the fetus • Postmortem evaluation and a high degree of suspicion as well as careful • Genetic testing search for associated abnormality(ies) is important • Antenatal history: The woman should be to recognise these. asked• about history of potential teratogenic ex- a. Structural/ morphological abnormality: These posure in the form of prescription drugs, high most commonly are malformations i.e. intrinsic grade fever, exposure to environmental toxins and defects in the formation of a structure, but can infection with teratogenic pathogens like rubella, also be deformations due to compressive effects cytomegalovirus, etc. History of decreased fe- on a normally formed structure e.g. varus de- tal movement perception and