Multiple malformation syndrome

    Last updated date: 14-Jun-2023

    Originally Written in English

    Multiple Malformation Syndrome

    Multiple Malformation Syndrome

    Three to five percent of live-born newborns have significant congenital abnormalities, while a further three percent have mild abnormalities. The central nervous system and the heart are often involved in 15-20% of the major congenital anomalies in liveborn infants.

    The proportion of clinical issues attributable to congenital malformations has increased with the advancement of antenatal, intrapartum, postnatal, and infant care, and about 20% of pediatric admissions are brought on by genetic disorders, including single gene disorders, chromosomal abnormalities, exposures to teratogens, and multifactorial genetic disorders.

    Congenital defects now account for almost as many deaths in the US as premature birth does. Congenital abnormalities will soon overtake other causes of neonatal death as a result of the ongoing advancements in perinatal care.

    Multiple congenital abnormalities (MCAs) in a newborn pose challenging diagnostic and therapeutic challenges. The seemingly limitless lists of illnesses with perplexing eponyms and complex jumbles of traits may be overwhelming, not to mention a lack of experience with syndromes. This is made worse by the intensely emotional context in which decisions must be made.

    By offering a list of differential diagnoses, directing the choice of testing, and offering the most correct information for parental counseling, developing a practical approach to numerous congenital abnormality syndromes can help to resolve many of these issues.


    What is Multiple Malformation Syndrome

    Malformation Syndrome

    A structural abnormality that is evident at birth and out of the ordinary is referred to as a congenital malformation.  These malformations can be further divided into major malformations that require both medical and surgical attention (such as congenital heart problems, cleft palate, and meningomyelocele) and minor malformations with little bearing on health (e.g., single palmar crease, epicanthal folds, fifth digit clinodactyly). According to the developmental process involved in their development, abnormalities themselves can be categorized. Malformations, deformations, disruptions, dysplasias, syndromes, relationships, and sequences are examples of well-defined categories of anomalies. It's crucial to realize that these might not fully be mutually exclusive. An underlying cause that can be environmental (teratogenic), genetic (e.g., single-nucleotide variant), or chromosomal causes the primary developmental abnormalities of two or more systems, resulting in multiple malformation syndrome.


    Multiple Malformation Syndrome Causes

    Multiple Malformation Syndrome Causes

    According to estimates, around one-fourth of all congenital abnormalities could be genetic in origin. Recent estimates, however, indicate that the percentage may be greater because cytogenetic and molecular procedures have improved significantly over the past 20 years, making it possible to detect previously undetectable chromosomal abnormalities, gene mutations, and genetic polymorphisms. Single-gene defects and chromosomal abnormalities are the two most frequent genetic causes of congenital malformations.

    Gene structure modifications (mutations) result in single-gene defects. A little over 15% of congenital abnormalities are caused by them. One or both parents may pass on single-gene abnormalities to their offspring, or a random (new) mutation may be to blame. Single-gene defects that result in isolated malformation, such as cleft lip with or without cleft palate and some types of congenital heart defects, are growingly being discovered by new research. However, single-gene defects seem to be more frequently associated with multiple malformation syndrome that is syndromic than with isolated malformations.

    About 10% of children with congenital malformations have chromosomal abnormalities found, which may involve the autosomes or the sex chromosomes. Changes include chromosomal structural abnormalities such as deletions (e.g., deletion of the proximal region in the long arm of chromosome 22 associated with the DiGeorge and velocardiofacial syndromes) and duplications (e.g., duplication of the short arm of chromosome 9), as well as numerical abnormalities including having an additional chromosome (e.g., trisomies such as Down syndrome or trisomy 21, trisomy 13 and trisomy 18) or missing a chromosome. Patterns of several congenital defects are nearly always associated with chromosomal abnormalities. An estimated 5-10% of congenital abnormalities have known environmental and maternal origins. Examples comprise:

    • Nutritional status of the mother
    • Chemical exposure, and perhaps the use of illegal drugs
    • Infections in mothers (e.g., rubella)
    • Physical elements like heat and ionizing radiation
    • Chronic maternal disorders (e.g., diabetes).
    • Exposure to teratogenic prescription drugs (such as valproic acid and retinoic acid).

    The etiology of about 66% of congenital abnormalities is still unclear. Congenital abnormalities that are thought to have environmental origins or be multifactorial are included in this category. Multifactorial refers to the interaction of numerous unidentified gene variations with environmental variables to produce a particular abnormality.

    Concerning various congenital malformations, a variety of potential gene-environment interactions have been investigated. For instance, it has been investigated to what extent the mutations and polymorphisms of several genes, such as TGFA, TGFB3, CYP1A1, NAT1, NAT2, and GSTT1, are associated with an elevated risk for oral clefts in the kids of cigarette-smoking mothers. Prenatal exposure to the anticonvulsant medication phenytoin is another instance of how genes and the environment interact. In 4-10% of newborns exposed to phenytoin in utero, structural congenital abnormalities are linked to the drug. Epoxide hydrolase, a microsomal enzyme that typically detoxifies phenytoin metabolites, has been reported to have decreased activity in these infants, which has been demonstrated to be correlated with the occurrence of congenital abnormalities. Some intermediate teratogenic metabolites are not removed when epoxide hydrolase is not functioning effectively. The developing fetus may develop a congenital abnormality as a result of this.


    Multiple Malformation Syndrome Screening

    medical genetic testing

    Preconception and peri-conceptional healthcare comprise standard reproductive health procedures as well as medical genetic testing and counseling. Screening is possible during the following three times:


    Preconception Screening

    This can help identify those who are at risk for developing certain disorders or passing a disorder on to their offspring. In countries where consanguineous marriage is widespread, screening is especially beneficial and includes collecting family histories and carrier screening.


    Peri-Conception Screening

    Maternal characteristics might make a woman more at risk; thus, screening results should be utilized to determine the right level of care to provide. This may involve checking for early or advanced maternal age, checking for alcohol or tobacco use, or checking for other concerns. During the first trimester, ultrasound can be used to check for Down syndrome and significant structural abnormalities, and during the second trimester, it can check for severe fetal malformations. To predict the likelihood of developing chromosomal abnormalities or neural tube defects, maternal blood can be tested for placental markers or free fetal DNA, which can detect a variety of chromosomal abnormalities. Chromosome abnormalities and infections in high-risk pregnant women can be identified via diagnostic procedures including chorionic villus sampling and amniocentesis.


    Neonatal Screening

    Newborn screening is a crucial step in the detection process. Earlier referral and the start of medical or surgical therapy help to lower mortality and morbidity from birth abnormalities. Early detection of hearing loss offers the chance for early treatment and the chance to improve language, speech, and communication abilities. Early detection of congenital cataracts in infants allows for early referral and surgical repair, increasing the possibility that the child will survive with his sight. It is possible to screen newborns for a variety of metabolic, hematologic, and endocrine abnormalities, many of which may not show symptoms immediately. Depending on prevalence and cost, different conditions are checked for in different countries. Even in low-income and middle-income countries, newborn screening is becoming more common.


    Multiple Malformation Syndrome Diagnosis

    Multiple Malformation Syndrome

    A wide range of diagnostic abilities is required for the neonatologist to address multiple malformation syndrome (MMS), which involves significant clinical concerns. Without a proper MMS diagnosis, many therapeutic options go unutilized and others might be tried, though they would be comparatively ineffective. Furthermore, advice regarding the prognosis and danger of recurrence could be given unrealistically. Only a small number of prevalent MMS symptoms are fatal in newborns. But it's important to remember that during this critical stage of development, abnormalities are the leading cause of death. The clinician should be made aware of the likelihood of cryptogenic malformations or diseases by the symptoms and signs. An MMS syndrome will be identified if overt abnormalities are present, and diagnostic attempts will start right away. However, if the disorder's external symptoms are nonspecific or modest and routine neonatal support procedures have already begun, early findings may go unnoticed. The prevalence of each symptom described is higher in newborns with MMS syndromes. Chromosome abnormalities, monogenic illnesses, multifactorial disorders, and unknown conditions can all be the cause of MMS syndromes. Neonatal MMS syndromes are diagnosed using the same methods as older children. Detailed physical evaluation of these kids can be difficult because so many of them are intubated with numerous lines and tubes. When a clinical geneticist is not around, clinical photographs are very important. If experts in these subjects are not readily available, calling a university medical institution for advice is frequently helpful. Searching for other major malformations is crucial (echocardiography, renal/abdominal ultrasound, brain imaging, etc.) if the newborn is extremely unwell and there is a suspicion that the MMS syndrome is present. A combination of describing the physical symptoms and genetic testing is the basis for the diagnosis of an MMS syndrome in a neonate. Additionally, because initial attempts frequently prioritize therapy, diagnostic issues can arise. However, a diagnosis will frequently help or better direct therapy.


    Multiple Malformation Syndrome Treatment

    Multiple Malformation Syndrome Treatment

    Most birth abnormalities are irreversible. The goal of treatment is to control the symptoms. There are, however, some situations where certain congenital abnormalities can be treated.

    • Gene therapy. Genes that are either absent or damaged are replaced by gene therapy. Gene therapy has been utilized to treat a group of extremely rare disorders known as severe combined immunodeficiency diseases (SCID).
    • Enzyme replacement therapy. Genes encode proteins called enzymes. Therefore, an enzyme is lacking or damaged when a gene is altered and does not create the gene product. The enzyme that the gene is not making can be replaced as a treatment for this kind of genetic abnormality. Gaucher disease is an illustration of an illness for which enzyme replacement therapy has been produced.
    • Prenatal treatment. Before birth, some birth abnormalities can be identified and treated. For example, prenatal surgery can cure infants with rare lung tumors and obstructions of the urinary tract.


    Multiple Malformation Syndrome Prevention

    Multiple Malformation Syndrome Prevention

    The likelihood of a woman giving birth to a child with a congenital anomaly can be decreased in various ways, including by maintaining good health before conception. This is because a woman frequently has no idea she is pregnant during the first few weeks, which can be extremely important for the baby's health and growth. You can also do the following throughout your pregnancy:

    • Stop smoking. In addition to secondhand smoke exposure potentially harming the baby, babies born to smoker moms typically have lower birthweights.
    • Adopt a healthy diet. In addition to being beneficial for the mother's general health, consuming a well-balanced diet before and during pregnancy is crucial for giving the growing fetus the nutrients it needs for healthy growth and development.
    • Maintain a healthy weight. Women who are underweight run the risk of giving birth to babies who are underweight, and overweight women run the risk of developing health issues including high blood pressure and diabetes.
    • Medical management of preexisting conditions. Manage any existing or prior medical conditions, such as high blood pressure or diabetes.
    • Folic acid. Birth malformations of the brain and spinal cord, or neural tube defects, can be prevented by consuming 400 micrograms of folic acid daily. Some green leafy vegetables, almonds, legumes, citrus fruits, and fortified breakfast cereals also contain vitamins.
    • Avoid using drugs and alcohol while pregnant. If you use any prescription drugs or herbal supplements, be sure to let your doctor know because they all have the potential to harm an unborn child.
    • Stay away from dangerous substances. These include lead, pesticides, and radiation (such as x-rays), all of which could be harmful to the fetus as it develops.
    • Reduce your risk for infection. In addition to avoiding all contact and exposure to cat feces and cat litter, which may contain the parasite toxoplasma gondii, which causes toxoplasmosis, pregnant women should also avoid eating undercooked meat and raw eggs. Insects that have come into contact with cat waste are other potential causes of infection.
    • Daily vitamin intake. To ensure that your body receives all the vitamins and nutrients required to sustain a healthy baby, start taking a daily prenatal vitamin as directed by your doctor.
    • Addressing domestic violence. Pregnant women who have experienced abuse may experience more abuse later on. You can access community, social, and legal options to deal with domestic violence with the support of your doctor.



    The World Health Organization (WHO) asserts that the term congenital malformations should only refer to structural problems. Congenital anomalies are those that are present at birth and are either structural or functional, including metabolic diseases. A significant contributor to infant mortality is congenital abnormalities. It is a significant factor in fetal death, premature birth, and childhood and adult morbidity, as well as having a large negative impact on mothers and their families. Parents with children with birth defects experience particular difficulties, want to improve their children's lives, and express concern about the risk to their plans for having children. Communication with healthcare providers, issues with the quality of life, and locating resources and assistance are a few of the difficulties parent encounter. Frequent communication with the parents, reassuring them that nothing they did or did not do contributed to the abnormalities found, and assisting them in planning for their upcoming pregnancies by identifying the etiology and giving them prenatal/preimplantation genetic diagnosis, all significantly reduce anxiety and decision-making about the treatment of their child and the treatment of their family as a whole.