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Congenital anomalies: Approach to evaluation

Congenital anomalies: Approach to evaluation
Literature review current through: Jan 2024.
This topic last updated: Aug 11, 2023.

INTRODUCTION — A congenital anomaly refers to an anatomic structural anomaly present at birth that may interfere with function depending upon the organ or body system involved (eg, meningomyelocele and ambulation, or cleft palate and feeding and speech). These anomalies can be caused by genetic abnormalities and/or environmental exposures, although the underlying etiology is often unknown. Congenital anomalies can be isolated or present in a characteristic combination or pattern that may affect one or more organ systems.

Evaluation of a child with a congenital anomaly includes a comprehensive history and physical examination. This is followed by further testing, as indicated. A general approach to evaluation is presented here. More detailed descriptions are included in the topic reviews of specific disorders. The types, patterns, and causes of congenital anomalies are also discussed separately. (See "Congenital anomalies: Epidemiology, types, and patterns" and "Congenital anomalies: Causes".)

REFERRAL FOR INITIAL EVALUATION — Referral to a genetic specialist is suggested for any child that presents with a single major congenital anomaly or a combination of multiple anomalies, whether those are major or minor, since the risk for having a syndrome increases with the number of defects and many syndromes have clear genetic etiologies. In addition, any family history of a specific congenital anomaly or history of miscarriages and/or stillbirths should prompt referral to a geneticist. Other referrals may include plastic surgery for correction of structural limb anomalies (polydactyly, syndactyly) or for craniosynostoses, orthopedics for clubfoot deformities, ophthalmology for microphthalmia, and neurology for microcephaly.

HISTORY — The prenatal history may uncover specific exposures and etiologic factors. The history taken should include medical and obstetric history, such as the duration of gestation, prenatal care, and maternal exposures (eg, alcohol, prescribed or illicit drugs, cigarettes, fevers, illnesses, chemicals, radiation). A history of stillbirths and miscarriages could be related to a balanced chromosomal rearrangement in one of the parents. Results of noninvasive and invasive prenatal testing, including ultrasound examinations, should be obtained. (See "Assessment of the newborn infant", section on 'History' and "Congenital anomalies: Causes".)

A complete family history and pedigree (ideally four generations) should be obtained to identify medical conditions related to the congenital anomaly or other medical issues that can impact the family's health (ie, multiple cancers, susceptibility to infections, neurodegenerative disorders). The age of the parents is important because the incidence of chromosome aneuploidies is increased in older mothers, and new autosomal dominant pathogenic variants (eg, achondroplasia, neurofibromatosis type 1) are more commonly seen with older fathers due to advanced paternal age. The family should be asked about consanguinity, which may suggest the possibility of autosomal recessive disorders. (See "Congenital cytogenetic abnormalities", section on 'Numeric abnormalities' and "Achondroplasia" and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

Determining ethnic/racial origin may be helpful because some diseases are more prevalent in certain ethnic/racial groups. As an example, postaxial polydactyly is more frequent in Black people, with a prevalence of 1.3 percent [1,2]. This congenital anomaly can result from an autosomal dominant trait. Polydactyly is linked to a determined set of homeobox genes, transcription factors, and Wnt signaling. A careful family history should be obtained when evaluating a child with polydactyly since penetrance for this trait can be incomplete.

PHYSICAL EXAMINATION — A thorough physical examination should be performed. In addition to standard measurements of weight, length, and head circumference, measurements of specific body structures may be helpful. They can be compared with age-, sex-, and population-matched standard measurements [3]. (See "Assessment of the newborn infant", section on 'Physical examination' and "The pediatric physical examination: General principles and standard measurements", section on 'Physical examination' and "The pediatric physical examination: General principles and standard measurements", section on 'Standard measurements'.)

The standard measurements used in clinical genetics include the commonly used head circumference (occipital frontal circumference), height/length, and weight. Arm span and lower segment/upper segment are often obtained in children with short stature and/or suspected skeletal dysplasias and are also used for assessment of persons with connective tissue disorders such as Marfan syndrome. (See "Skeletal dysplasias: Approach to evaluation", section on 'Physical examination'.)

Measurements of craniofacial structures can be valuable to confirm suspected clinical findings and help delineation of syndromes. They are often performed by clinical geneticists and can be useful in the same way growth charts are for the pediatrician. In addition, to confirm findings, measurements are done when there is uncertainty about a clinical diagnostic decision. These measurements include ear length, inner canthal distance, outer canthal distance, interpupillary distance, palpebral fissures length, and philtrum length (extends from the nasal septum to the upper vermilion border). Other frequently used measurements include hands, feet, and digits length to assess for brachydactyly or arachnodactyly.

In newborns and fetuses, the placenta and umbilical cord should also be examined. Two-vessel cord is often associated with structural congenital heart defects. Intrauterine growth retardation can result from a diseased placenta (chromosomal mosaicism in the placenta, vascular abnormalities like thrombi or infarction) that interferes with growth. (See "Assessment of the newborn infant", section on 'Umbilical cord' and "The pediatric physical examination: General principles and standard measurements" and "Gross examination of the placenta".)

Examination of family members may assist with the evaluation of some abnormalities. One example is the child with holoprosencephaly. One of the parents may have a single incisor or hypotelorism, representing a mild manifestation of the same disorder. Another example is Treacher-Collins syndrome, an autosomal dominant disorder in which a parent can have minimal microtia or mild underdevelopment of malar facial structures that may have been missed on previous examinations. (See "Overview of craniofacial clefts and holoprosencephaly", section on 'Holoprosencephaly' and "Syndromes with craniofacial abnormalities", section on 'Treacher Collins syndrome'.)

The physical exam is a powerful tool for geneticists and clinicians. The following list highlights some of the most important dysmorphic features assessed by the exam in the genetics clinic, which is not all that different than any regular pediatrics exam. Some of the abnormalities listed are paired with examples of common genetic disorders in which those features are encountered.

Cranium size and appearance (see "The pediatric physical examination: HEENT", section on 'Head')

Microcephaly (chromosomal anomalies and many single gene disorders, fetal exposures to infections [eg, toxoplasmosis, rubella, Zika virus]) (see "Congenital anomalies: Causes", section on 'Genetic abnormalities' and "Congenital anomalies: Causes", section on 'Infectious agents' and "Microcephaly in infants and children: Etiology and evaluation" and "Microcephaly: A clinical genetics approach")

Macrocephaly (fragile X syndrome, phosphatase and tensin homolog [PTEN] pathogenic variants, neurofibromatosis type 1, achondroplasia) (see "Macrocephaly in infants and children: Etiology and evaluation" and "Fragile X syndrome: Clinical features and diagnosis in children and adolescents", section on 'Physical features' and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Macrocephaly' and "Achondroplasia", section on 'Clinical manifestations')

Brachycephaly (craniosynostosis syndromes such as Crouzon syndrome) (see "Craniosynostosis syndromes", section on 'Crouzon syndrome')

Plagiocephaly (craniosynostosis and/or deformations) (see "Craniosynostosis syndromes")

Craniofacial profile (see "The pediatric physical examination: HEENT", section on 'Face')

Midface retrusion or hypoplasia (chromosomal anomalies [eg, Down syndrome], type II collagen disorders [eg, Stickler syndrome]) (see "Down syndrome: Clinical features and diagnosis", section on 'Head and neck' and "Syndromes with craniofacial abnormalities")

Prognathism (Angelman syndrome) (see "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion syndrome (Angelman syndrome)')

Asymmetry (hemifacial or craniofacial microsomia [Goldenhar syndrome], CHARGE [coloboma, heart defects, atresia choanae, retarded growth and development, genitourinary anomalies, ear abnormalities] syndrome due to cranial nerve involvement) (see "Syndromes with craniofacial abnormalities")

Eyes (see "The pediatric physical examination: HEENT", section on 'Eyes')

Hypertelorism (cri-du-chat syndrome, Wolf-Hirschhorn syndrome) (see "Congenital cytogenetic abnormalities", section on '5p deletion syndrome (cri-du-chat syndrome)' and "Syndromic immunodeficiencies", section on 'Partial deletions of chromosome 4p (Wolf-Hirschhorn syndrome)')

Hypotelorism (holoprosencephaly, trisomy 13) (see "Overview of craniofacial clefts and holoprosencephaly" and "Congenital cytogenetic abnormalities", section on 'Trisomy 13 syndrome')

Extraocular movement abnormalities (myopathic processes, neurologic abnormalities)

-Ophthalmoplegia in mitochondrial disorders (Kearns-Sayre syndrome, mitochondrial depletion syndromes)

-Esotropia (Angelman syndrome, Down syndrome) (see "Causes of horizontal strabismus in children", section on 'Esodeviations')

-Exotropia (Angelman syndrome, Down syndrome) (see "Causes of horizontal strabismus in children", section on 'Exodeviations')

-Nystagmus (Septo-optic dysplasia) (see "Overview of nystagmus")

-Ptosis (Smith-Lemli-Opitz syndrome, Kearns-Sayre syndrome)

Ears (see "The pediatric physical examination: HEENT", section on 'Ears')

Shape and rotation (short, long, anteriorly or posteriorly rotated) (see "Congenital anomalies of the ear"). Malformed and posteriorly rotated ears, which are often also low set, can be seen in multiple genetic disorders, such as trisomy 18, triploidy, and Smith-Lemli Opitz syndrome. Posteriorly rotated ears alone can be seen in children with congenital hydrocephalus.

Microtia (hemifacial or craniofacial microsomia [Goldenhar syndrome], Treacher Collins syndrome, retinoic acid fetal exposure). (See "Syndromes with craniofacial abnormalities" and "Congenital anomalies of the ear".)

Nose (see "The pediatric physical examination: HEENT", section on 'Nose')

Prominent, bulbous tip (22q11.2 microdeletions) (see "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis")

Split appearance (frontonasal dysplasia) (see "Congenital anomalies of the nose", section on 'Frontonasal dysplasia')

Anteverted nares (Cornelia de Lange syndrome, Smith-Lemli-Opitz syndrome)

Philtrum

-Length (long philtrum in Williams syndrome) (see "Williams syndrome")

-Smooth (fetal alcohol syndrome) (see "Fetal alcohol spectrum disorder: Clinical features and diagnosis")

Mouth and throat (see "The pediatric physical examination: HEENT", section on 'Mouth and throat')

Macrostomia (oculo-auriculo-vertebral spectrum, Angelman syndrome) (see "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion syndrome (Angelman syndrome)')

Microstomia (trisomy 18)

High arched palate (Marfan syndrome) (see "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders")

Cleft uvula (22q11.2 microdeletion, Loeys-Dietz syndrome) (see "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis" and "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'TGFBR1 or TGFBR2 mutation: Loeys-Dietz syndrome')

Dentition

-Widely spaced teeth (Angelman syndrome) (see "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion syndrome (Angelman syndrome)')

-Dental decay, enamel hypoplasia (dentinogenesis imperfecta, osteogenesis imperfecta) (see "Developmental defects of the teeth", section on 'Dentinogenesis imperfecta' and "Osteogenesis imperfecta: An overview")

Tongue

-Protrusion (due to macroglossia in disorders such as Beckwith-Wiedemann syndrome and Pompe disease) (see "Beckwith-Wiedemann syndrome" and "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)")

-Thrusting (Down syndrome or other conditions with poor orofacial muscular tone) (see "Down syndrome: Clinical features and diagnosis")

Neck (see "The pediatric physical examination: HEENT", section on 'Neck')

Wide neck (Turner syndrome, Noonan syndrome) (see "Clinical manifestations and diagnosis of Turner syndrome" and "Noonan syndrome")

Short neck with excessive nuchal folds (Down syndrome) (see "Down syndrome: Clinical features and diagnosis")

Webbing (Turner syndrome, Noonan syndrome) (see "Clinical manifestations and diagnosis of Turner syndrome" and "Noonan syndrome")

Chest (see "The pediatric physical examination: Chest and abdomen", section on 'Chest')

Pectus excavatum (Noonan syndrome) (see "Noonan syndrome")

Pectus carinatum (Marfan syndrome) (see "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders")

Wide-spaced nipples (Down syndrome, Turner syndrome, Noonan syndrome) (see "Down syndrome: Clinical features and diagnosis" and "Clinical manifestations and diagnosis of Turner syndrome" and "Noonan syndrome")

Cardiovascular (see "The pediatric physical examination: Chest and abdomen", section on 'Heart')

Cardiomyopathies (Noonan syndrome, Duchenne muscular dystrophy, Pompe disease)

Arrhythmias (myotonic dystrophy, multiple lentigines syndrome)

Conotruncal defects (22q11.2 deletion syndrome, retinoic acid embryopathy)

Structural heart defects – Atrial septal defect (Holt-Oram syndrome), atrioventricular canal or ventricular septal defect (trisomy 21), ventricular septal defect (CHARGE association)

Aortic hypoplasia (Turner syndrome), supravalvular aortic stenosis (Williams syndrome)

Aortic dilatation (Marfan syndrome, Loeys-Dietz syndrome)

Abdomen (see "The pediatric physical examination: Chest and abdomen", section on 'Abdomen')

Hepatomegaly with or without splenomegaly (glycogen storage disorders, Gaucher disease, Niemann-Pick syndrome) (see "Overview of inherited disorders of glucose and glycogen metabolism" and "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis" and "Overview of Niemann-Pick disease")

Genitourinary (see "The pediatric physical examination: The perineum")

Examination includes evaluation of external genitalia, breast development, and Tanner staging. Genitourinary anomalies are common in genetic syndromes. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)

-Ambiguous genitalia (WAGR association [Wilms tumor, aniridia, genitourinary anomalies, and developmental delay], Robinow syndrome, Smith-Lemli-Opitz syndrome)

-Sex reversal (campomelic dysplasia; 46,XY patients with campomelic dysplasia commonly have female genitalia development with failure of male differentiation)

-Micropenis (Robinow syndrome, Prader-Willi syndrome)

-Cryptorchidism (Prader-Willi syndrome, Rubinstein-Taybi syndrome, trisomy 13, trisomy 18, trisomy 9 mosaic)

-Hypoplasia of labia majora (Prader-Willi syndrome; Brachmann de Lange, also known as Cornelia de Lange, syndrome)

-Bicornuate uterus with or without double vagina (exstrophy of cloaca sequence, Fraser syndrome)

-Vaginal atresia (Müllerian duct aplasia, unilateral renal agenesis, and cervicothoracic somite [MURCS] association; sirenomelia)

Spine (see "The pediatric physical examination: Back, extremities, nervous system, skin, and lymph nodes", section on 'Back' and "Adolescent idiopathic scoliosis: Clinical features, evaluation, and diagnosis", section on 'Scoliosis examination' and "Adolescent idiopathic scoliosis: Clinical features, evaluation, and diagnosis", section on 'Radiographic evaluation')

Thoracolumbar scoliosis (neurofibromatosis type 1, Marfan syndrome, skeletal dysplasias) (see "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders" and "Skeletal dysplasias: Specific disorders")

Vertebral segmentation defects (Alagille syndrome [hemivertebrae], MURCS association [cervicothoracic defects], VACTERL association [vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities])

Deep sacral dimple, sacral hair tufting, sacral tag (cord tethering)

Sirenomelia (anomalies of the lumbosacral spine and partial to complete fusion of the lower extremities)

Extremities (see "The pediatric physical examination: Back, extremities, nervous system, skin, and lymph nodes", section on 'Extremities')

Limited range of motion (arthrogryposis, storage disorders [such as Hurler or Hurler-Scheie syndrome], contractures [disorders affecting neuromuscular function like myotonic dystrophy or affecting muscular development: amyoplasia congenital, arthrogryposes multiplex congenita]) (see "Overview of peripheral nerve and muscle disorders causing hypotonia in the newborn", section on 'Arthrogryposis multiplex congenita')

Hands and feet

-Polydactyly (single gene defects [Carpenter syndrome, Bardet-Biedl syndrome], chromosome abnormalities [trisomy 13]) (see "Congenital cytogenetic abnormalities", section on 'Trisomy 13 syndrome')

-Syndactyly (Smith-Lemli Opitz syndrome, Apert syndrome, Greig cephalopolysyndactyly syndrome) (see "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Smith-Lemli-Opitz syndrome')

-Brachydactyly (2q37 deletion syndrome) (see "Microdeletion syndromes (chromosomes 1 to 11)", section on '2q37 deletion syndrome')

-Arachnodactyly (Marfan syndrome) (see "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders")

-Broad thumbs and toes (Rubinstein-Taybi syndrome, Saethre-Chotzen syndrome)

-Clubfoot (Potter syndrome, deformation sequence, distal arthrogryposes)

Skin, hair, and nails (see "The pediatric physical examination: Back, extremities, nervous system, skin, and lymph nodes", section on 'Skin')

Sparse hair (ectodermal dysplasias) (see "The genodermatoses: An overview", section on 'Ectodermal dysplasias')

Hair color lighter than expected (albinism, Chediak-Higashi syndrome) (see "The genodermatoses: An overview", section on 'Oculocutaneous albinism' and "Chediak-Higashi syndrome", section on 'Clinical manifestations')

Skin pigmentation

-Hyperpigmentation (may suggest somatic mosaicism depending upon the distribution)

-Hypopigmentation (tuberous sclerosis) (see "Tuberous sclerosis complex: Clinical features", section on 'Dermatologic manifestations')

-Skin color lighter than expected (albinism, full/partial) (see "The genodermatoses: An overview", section on 'Oculocutaneous albinism')

Nail dystrophy (ectodermal dysplasias) (see "The genodermatoses: An overview", section on 'Ectodermal dysplasias')

LABORATORY STUDIES — Laboratory evaluation depends in part upon the results of the history and physical examination. Testing is performed for specific infectious agents (eg, TORCH infections [toxoplasmosis, other, rubella, cytomegalovirus, and herpes virus], Zika virus) or maternal autoimmune disorders, for example, if findings suggest one of these causes. Diagnostic genetic testing is performed if a specific genetic defect is suspected based upon the initial evaluation. A broader genetic screening tool is used if no specific diagnoses are identified with the history and physical examination. (See "Congenital anomalies: Causes".)

When to order laboratory studies — Laboratory studies are guided by the clinical presentation. The majority of children that present with a single or multiple congenital anomalies are studied first for the presence of chromosome abnormalities. Specialized testing is performed if a neurologic presentation includes hypotonia or suspicion of visceromegaly (eg, peroxisomal studies for Zellweger syndrome, serum cholesterol precursors for Smith-Lemli-Opitz, organic acids in urine for glutaric acidemia type I). Exome sequencing has aided significantly in the identification of rare single gene disorders. Exome sequencing, ideally a trio sequencing (patient and both parents), should be used in cases with multiple congenital anomalies with or without intellectual disabilities where there is no identified genetic defect and chromosome microarray studies were normal. Genome sequencing is increasingly used in the clinical setting. This technique allows the sequencing of exons, introns, and regulatory regions and may be suitable to determine copy number variation changes as well. Genome sequencing can therefore provide information obtained by both exome sequencing and chromosome microarray studies. (See "Genomic disorders: An overview".)

Chromosome studies — Molecular-based chromosome microarray studies (array comparative genomic hybridization [aCGH]) are widely used to diagnose conditions that are difficult to recognize clinically and/or cytogenetically (eg, microdeletions of the short arm of chromosome 16 [4] or microdeletions of 22q11.2 [5]). aCGH is the first line of testing in children with multiple anomalies and intellectual disabilities and has displaced the use of conventional cytogenetic studies such as Giemsa banding karyotype (G-banding) and fluorescent in situ hybridization (FISH) studies. aCGH is preferred because it can identify small chromosome abnormalities that cannot be detected by traditional chromosome studies such as G-banding (eg, duplications of the 22q11.2 critical region for velocardiofacial syndrome [6,7]) and does not require a presumptive clinical diagnosis and prior knowledge of which specific chromosomal region to examine, as is needed with the older, molecular-based techniques such as FISH. Use of aCGH has increased the detection yield to 12 to 15 percent compared with conventional chromosome studies that have a detection yield of approximately 5 to 7 percent [8-11]. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics".)

FISH studies were often used as confirmatory studies after an abnormality (particularly a microdeletion or microduplication) was detected by aCGH. They are widely used in prenatal screening performed on amniotic fluid samples. Traditional chromosome studies are often performed as a second-tier evaluation when an abnormality is detected by aCGH but the specific cause cannot be determined. As an example, aCGH can identify a loss or gain of material. However, in the case of a gain, it may not identify where the gain of material is localized. A gain may be the result of chromosome region duplication, a translocation, an insertion of an extra chromosome piece in a different chromosome, or a marker chromosome (a structurally abnormal chromosome results in a partial trisomy).

Indications for aCGH include:

One or more major anomalies (eg, congenital heart disease)

Three or more minor anomalies

Unexplained intellectual disability with or without dysmorphic features or other anomalies, autism spectrum disorders (see "Intellectual disability in children: Evaluation for a cause")

Unexplained growth retardation or failure to thrive (see "Diagnostic approach to children and adolescents with short stature" and "Poor weight gain in children younger than two years in resource-abundant settings: Etiology and evaluation")

Any congenital anomaly and a family history of congenital anomalies and/or multiple miscarriages

Some arrays used in clinical medicine include single nucleotide polymorphisms (SNPs). There are 10 million SNPs in the genome, and they are helpful in determining areas where there is absence of heterozygosity. This can be seen in situations of consanguinity (increasing concerns of autosomal recessive disorders) or in uniparental disomy (UPD), where areas of chromosome material are only contributed by a single parent instead of both. (See "Genomic disorders: An overview".)

Indications for chromosome studies include:

Clinical findings suggestive of Down syndrome. A chromosome study is preferable to aCGH in the case of suspected Down syndrome because it can distinguish between trisomy 21 (the most common form of Down syndrome) and a translocation. Both types of genetic defects are abnormal with aCGH but are indistinguishable. Patients with trisomy 13 that can be the result of a chromosomal translocation can often be seen to have involvement of acrocentric chromosomes (chromosomes 13, 14, 15, 21, and 22). (See "Down syndrome: Clinical features and diagnosis".)

Large gains of chromosome material, in order to determine the nature of the rearrangement (ie, duplications, insertions, translocations, marker chromosome).

Unexplained intellectual disability with or without dysmorphic features or other anomalies. (See "Intellectual disability in children: Evaluation for a cause".)

Ambiguous genitalia. In some of these cases, a combination of chromosome studies and aCGH is needed to make the diagnosis if there is mosaicism involving the sex chromosomes. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)

Suspicion of a sex chromosome anomaly (sex chromosome mosaicism can be difficult to detect by aCGH alone).

Couples with multiple first trimester miscarriages (more than three) as they may be the result of balanced chromosome translocations that cannot be detected by aCGH.

Specialized metabolic genetics studies — Depending upon the clinical presentation, the presence of dysmorphic features, and physical exam clues, other specialized metabolic genetics studies may be requested. The following studies mentioned are not an exhaustive list but are perhaps some of the most frequently used tests in clinical genetics:

Urine organic acids to rule out organic acidemias (eg, glutaric acidemia type I). Typical presentation for organic acidemias includes unexplained metabolic acidosis, episodic vomiting, seizures, failure to thrive, frequent infections, neutropenia, and developmental delay, and, in some rare cases, dysmorphic features as are seen in glutaric acidemia type I (hypotonia, macrocephaly, dysmorphic features, brain atrophy, and basal ganglia abnormalities). (See "Organic acidemias: An overview and specific defects", section on 'Initial evaluation'.)

Peroxisomal studies (eg, Zellweger syndrome presenting with macrocephaly, a large and wide anterior fontanel, hypotonia, seizures, retinitis pigmentosa, cataracts, hepatomegaly, renal cysts, and psychomotor delay). (See "Peroxisomal disorders", section on 'Zellweger spectrum disorders'.)

Serum cholesterol precursors (7-dehydrocholesterol). Smith-Lemli-Opitz syndrome is caused by a defect in cholesterol biosynthesis and presents with microcephaly, ptosis, anteverted nares, cleft palate, congenital heart disease, limb anomalies (ie, polydactyly, 2/3 toe syndactyly), and ambiguous genitalia in males. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Smith-Lemli-Opitz syndrome'.)

Lactic acid and pyruvic acid may be indicated in patients with suspected mitochondrial disorders presenting with severe hypotonia, seizures, ptosis, external ophthalmoplegia, and sensorineural hearing loss. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)

Metabolomics uses mass spectrometry to detect and quantify hundreds of small molecules (approximately 900) in plasma for the detection of inborn errors of metabolism [12]. It is often superior to conventional metabolic testing and may replace the multiple metabolic studies that are currently used. (See "Personalized medicine", section on 'Other personalized medicine platforms'.)

Whole exome and whole genome sequencing — Whole exome sequencing (WES) is powerful genetic technology that is used for the diagnosis of children with multiple anomalies, intellectual disability, and/or seizures. WES analyzes the exons or coding regions of approximately 20,000 genes simultaneously using next-generation sequencing techniques. This test is extremely valuable for uncovering changes in Mendelian genes (single genes) responsible for medical disorders. By sequencing the exome of a patient and comparing it with the normal reference sequence, variations in an individual's deoxyribonucleic acid (DNA) sequence can be identified and related back to the individual's medical concerns in an effort to discover the cause of the medical disorder.

The analysis and interpretation of WES are rapidly improving. Several factors have played a role in the rapid evolution of WES and the changing capacities of this genetic technology. The ability to identify variants of clinical significance depends upon two modifying variables: the current state of the art of the sequencing technology used as far as the depth of the sequencing (the number of times a region is repetitively sequenced to assure the entire region is examined) and the robustness of the "standard reference." As an example, WES detected causative pathogenic variants in 25 to 27 percent of children with complex malformations and and/or severe developmental disorders in two initial studies [13,14]. A WES reanalysis of the second study of 1133 children with severe undiagnosed neurodevelopmental disorders and/or congenital anomalies, dysmorphic features, abnormal growth, or unusual behavioral phenotypes using improved data and methodologies identified additional causal monogenic defects in a further 182 individuals, bringing the overall diagnostic yield to 40 percent [15]. By comparison, in a study of WES in 278 infants in the intensive care unit (ICU) with congenital anomalies, hypotonia, seizures, abnormal growth, feeding difficulties, respiratory failure, and/or metabolic acidosis, a molecular diagnosis was identified in 37 percent [16]. In this study, 32 out of 63 cases were correctly diagnosed using trio WES (patient and parents sequencing at the same time) with a 51 percent yield. In 52 to 72 percent of the cases, depending upon the group selected, the care was redirected secondary to the diagnosis.

An underlying genetic pathogenic variant is still possible, even if nothing is detected on WES. WES is not suitable for the detection of microdeletions or microduplications that can be detected by chromosome microarrays. Whole genome sequencing (WGS), in contrast to WES, may detect larger deletions or duplications, triple repeat expansions, and pathogenic variants in deep intronic regions; regulatory regions that are outside of the coding regions; and untranslated gene regions. However, WGS is a more costly screening tool that has its own limitations. Testing technologies that are mostly used in clinical research include long read sequencing [17]. This technique allows detection of complex structural variants not accessible to other sequencing methods. (See "Genomic disorders: An overview" and "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

IMAGING — Imaging studies, such as brain computed tomography (CT) and magnetic resonance imaging (MRI) scans, echocardiogram, and appropriate radiographs, should be performed to help define abnormalities not apparent on physical examination. As examples, brain MRI or CT scans are indicated in children with microcephaly, macrocephaly, holoprosencephaly, seizures, or developmental regression. MRI is best suited to examining brain structures to determine myelination, white matter development, structural anomalies, and migration defects. Head CT scans can be useful for craniosynostosis where enhanced viewing with bone windows can accurately determine premature suture fusion or closing. Radiographs of the entire body, also known as skeletal surveys, are indicated when limb anomalies are present or dwarfism is suspected due to prenatal or postnatal growth restriction. If an infant dies, postmortem pathology studies can be extremely important to establish a diagnosis and provide appropriate counseling. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)

Ultrasound evaluations are often used to delineate renal, genitourinary, and internal genitalia anatomy, particularly in patients who present with ambiguous genitalia or suspected congenital anomalies of the kidneys and genitourinary tract (CAKUT). Size and position of the kidneys can be assessed, along with an evaluation for abnormalities of the ureters, uterine malformations (which may require MRI studies), and testicular position.

ADDITIONAL SUBSPECIALTY REFERRAL — Further subspecialty referrals may be required to evaluate the patient with a genetic defect. One important referral is to ophthalmology to ascertain a number of features that can be seen in multiple genetic disorders, including colobomas of the irides and/or optic nerve (CHARGE association [coloboma, heart defects, atresia choanae, retarded growth and development, genitourinary anomalies, ear abnormalities]), optic nerve atrophy, retinitis pigmentosa (Cockayne syndrome), cataracts (storage disorders such as the mucopolysaccharidoses), lens dislocations (Marfan syndrome), and optic gliomas (neurofibromatosis type 1). (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis", section on 'CHARGE syndrome' and "Neuropathies associated with hereditary disorders", section on 'Cockayne syndrome' and "Mucopolysaccharidoses: Complications" and "Management of Marfan syndrome and related disorders" and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Newborn appearance (The Basics)")

SUMMARY

Terminology and etiology – A congenital anomaly refers to an anatomic structural anomaly present at birth. These defects can be caused by genetic abnormalities and/or environmental exposures (teratogens), although the underlying etiology is often unknown. Specific terms are used to describe congenital anomalies (table 1). In addition, multiple malformations are often grouped in a recognizable pattern (table 2). (See 'Introduction' above and "Congenital anomalies: Causes" and "Congenital anomalies: Epidemiology, types, and patterns".)

Evaluation – Evaluation of a child with a congenital anomaly includes a comprehensive history and physical examination. This is followed by further testing as indicated. (See 'History' above and 'Physical examination' above.)

History – The prenatal history may uncover specific exposures and etiologic factors. A complete family history (including parental age and consanguinity) and pedigree (four generations, if possible) should be obtained to help uncover genetic causes. Determining ethnic/racial origin may be helpful because some diseases are more prevalent in certain ethnic/racial groups. (See 'History' above.)

Physical examination – A thorough physical examination should be performed. In addition to standard measurements of weight, length, and head circumference, measurements of specific structures may be helpful depending upon the presenting features. The patient is also examined for dysmorphic features. (See 'Physical examination' above.)

Laboratory evaluation – Laboratory evaluation depends in part upon the results of the history and physical examination. Testing is performed for specific infectious agents (eg, TORCH infections [toxoplasmosis, other, rubella, cytomegalovirus, and herpes virus], Zika virus) or maternal autoimmune disorders, for example, if findings suggest one of these causes. Diagnostic genetic testing is performed if a specific genetic defect is suspected based upon the initial evaluation. A broader genetic screening tool (array comparative genomic hybridization [aCGH]) is used followed by whole exome sequencing (WES) or whole genome sequencing (WGS) as needed if no specific diagnoses are identified with the history and physical examination. (See 'Laboratory studies' above.)

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Topic 2940 Version 23.0

References

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