Prenatal information, beginning with conception, must be specifically sought from both the mother and her obstetric records. The nature and timing of maternal illnesses, such as rubella or cytomegalovirus infections, including febrile episodes, can suggest a direct infectious disruption. Maternal use of alcohol, drugs, medications, or tobacco—degree, gestational timing, and duration—should be documented. Quickening, the date at which there is maternal sensation of fetal movement, and the subsequent vigor and frequency of fetal activity, reflects central nervous system integrity and peripheral muscular function. Prenatal ultrasonography, especially if performed serially and in detail, may yield critical information regarding the amount of amniotic fluid and malformations of the kidneys, brain, heart, skeleton, and gastrointestinal system. Recent reports have suggested an association between in vitro fertilization and several genetic conditions, such as Angelman syndrome (11), retinoblastoma (12) and Beckwith-Wiedemann syndrome (13). Chorionic villus sampling has previously been suspected to cause limb-reduction deformities, but recent studies by the World Health Organization affirm its safety for first-trimester prenatal diagnosis (14). A review of the ultrasound studies and the obstetric record, and a discussion with the attending obstetrician or perinatologist, can save valu-able time and effort. Maternal serum and amniotic fluid αfetoprotein levels and prenatal chromosome studies should be verified and documented in the infant’s medical record. Late trimester problems with fetal position, such as transverse or breech lie, potentially indicate neuromuscular or structural abnormalities of the fetus. Fetuses with significant neuromuscular problems often encounter perinatal distress and have a poor transition to extrauterine life. Finally, it often is useful to inquire about any prenatal event or factors that the parents suspect, even remotely, may have caused their infant’s problems. Concerns about witnessing a solar or lunar eclipse, for example, are best made explicit, if only for the purpose of assuaging guilt.

A systematic and detailed inquiry into the age, health, development, and congenital anomalies of all members of the immediate family comprises the core of an adequate family history. All second-degree relatives, such as grandparents, aunts, uncles, nieces, and nephews, should be considered, and more distant relatives may contribute valuable data. A three-generation pedigree provides a concise picture of patterns of inheritance. One must specifically clarify the biologic parentage for each individual. Spontaneous abortions, miscarriages, stillbirths, and infant deaths clearly are germane, but parents typically omit this information unless the interviewer specifically inquires. Consanguinity also should be directly but tactfully questioned. A “quick pedigree” is an
oxymoron; routinely the entire process requires patience and time. With this in mind, the interviewer will be sympathetic, on the day of delivery, to parents who are understandably terrified, exhausted, and disoriented. After rest, time, and a chance to speak with relatives, they may be more prepared to help refine and expand on their complete family history.

It is axiomatic that a proper newborn physical examination is detailed and complete. The careful observer, especially one who repeats the examination several times, will recognize departures from the norm. Several points are worth keeping in mind when examining infants with a malformation or a generalized dysmorphic appearance.

The emerging clinical picture will dictate imaging studies and consultations with pediatric subspecialists. For example, a newborn with Down syndrome, even when a cardiac murmur is absent, merits the attention of a pediatric cardiologist, because significant structural defects of the heart are present in 50% but may be missed on clinical examination. A newborn girl with puffy hands and feet, a webbed neck, and coarctation of the aorta also should receive a renal ultrasound, because kidney malformations commonly are associated with Turner syndrome. When the diagnosis is unclear and several malformations are present, occult anomalies of the central nervous system, heart, kidneys, vertebrae, and eyes are reasonable to pursue, especially when the known birth defects are multiple and severe. Renal ultrasounds are often ordered when the neonate has a single umbilical artery or an ear malformation, such as a preauricular pit. In the absence of supporting findings, such as other malformations, a family history of deafness or renal anomalies, or maternal diabetes, this investigation is unlikely to be useful (17). Skeletal films, to include hands, feet, long bones, pelvis, vertebrae, chest, and cranium, are helpful when length is less then the 5th percentile for gestational age or when the limbs are disproportionately short. These studies often require interpretation by a pediatric radiologist skilled in this area.

Forty-six chromosomes are present in most normal human cells. Formation of ova and sperm, however, is a surprisingly error-prone process: nearly two-thirds of all fertilizations result in aneuploidy or abnormal chromosomal number or structure, with subsequent reproductive loss. Some of this prenatal loss occurs late enough to be recognized as a miscarriage or spontaneous abortion, but most wastage is occult. Ninety-eight percent of these chromosomal defects are lethal (13).

An abnormal karyotype occurs in one of 170 liveborn infants. Among chromosomally abnormal neonates, one-third have an extra sex chromosome with mild or no phenotypic manifestations in the newborn period, one-fourth have trisomy of an autosome, such as trisomy 21 or trisomy 18, and 40% have a variation of chromosomal structure, such as a deleted or duplicated segment or a translocation. Of the latter, most (79%) are balanced and generally do not cause birth defects. Approximately 10% of infants who die in the perinatal period secondary to multiple congenital malformations have abnormal cytogenetic studies (13).

Which infants deserve chromosomal studies? Truly isolated malformations are very infrequently caused by a cytogenetic defect. On the other hand, neonates with multiple major malformations or a generalized dysmorphic appearance, and stillborn infants, with or without malformations, should have cytogenetic testing. Between these extremes lies a sizable gray area. Factors in favor of chromosomal testing include intrauterine growth retardation, an abnormal neurologic exam, a major malformation accompanied by several minor malformations, and a history
of multiple pregnancy losses for the mother or in close relatives.

Peripheral blood lymphocytes are the tissue of choice for most cytogenetic analysis, but many other tissues can be used, including skin fibroblasts, bone marrow, placenta, and pericardium, usually harvested postmortem. Two to three milliliters of venous or arterial blood, collected in a sodium heparin (green top) tube, are generally sufficient and should be kept at room temperature or refrigerated, never frozen, in transit. The cells usually will remain viable for 1 or 2 days, but the shortest possible transit time increases the chances for useful results. If the sample is shipped, an overnight courier is recommended. The lymphocytes are separated, incubated in the presence of a mitogen to stimulate cell division, which is then abruptly halted with colchicine, and the cell membranes are disrupted gently while being placed on a glass slide. After enzymatic preparation and staining, the “spread” of chromosomes is analyzed in approximately 20 cells. Generally, 550 or more bands are visible with Giemsa staining of 46 chromosomes at metaphase. Several cells are photographed and arranged in standard groupings, a karyotype. Turnaround time for cytogenetic analysis is typically three to four days, although some laboratories are able to provide results in slightly less time. Because of the high percentage of dividing cells in bone marrow, karyotypes from this tissue may be obtained in a matter of hours, although the quality of the banding frequently is inadequate for high-resolution analysis of small or subtle abnormalities. To achieve the latter, a special request for prometaphase analysis should accompany a peripheral blood sample.

In the past several years, an increasing number of syndromic conditions have been found to be caused by very small chromosomal deletions that are not visible by routine karyotyping, even at pro-metaphase levels of detail. Molecular probes that will hybridize at these loci with great specificity have been developed. These DNA probes are complexed with a fluorescent marker and become powerful tools for detecting submicroscopic chromosomal deletions. This technique, termed fluorescent in situ hybridization (FISH), has also been adapted for whole, entire chromosomes and can identify the nature of many chromosomal anomalies, such as translocations. A metaphase spread can, in essence, be painted with several single-locus or whole-chromosome FISH probes simultaneously, providing a highly specific, and colorful, picture of genomic structure.

Among children with mental retardation of unknown etiology, in whom extensive investigations, including standard cytogenetic studies, are normal, approximately 5% harbor very small, occult chromosomal deletions or unbalanced translocations. A recently developed technique—subtelomeric probe analysis—uses FISH and/or other molecular tools to ascertain whether the regions just proximal to the tips of each of the 46 chromosomes are present in their normal locations. Although initially designed to investigate subnormal intelligence in older children, subtelomeric analysis appears to also be useful for some infants with congenital anomalies in whom standard investigations have not been fruitful. This technology seems to have better diagnostic success for individuals with intrauterine growth retardation, microcephaly, and a positive family history (19).

Inborn errors of metabolism are often assumed to have a purely biochemical or neurologic phenotype, but metabolic disease is well recognized as an occasional cause of dysmorphic facial features and congenital malformations (20). For instance, ambiguous genitalia are seen in some cases of 21-hydroxylase deficiency and other types of congenital adrenal hyperplasia, and infants with pyruvate dehydrogenase deficiency may have agenesis of the corpus callosum and facial features that resemble fetal alcohol syndrome. A number of the congenital disorders of glycosylation feature congenital malformations of the heart, limbs, and central nervous system (21). Many peroxisomal conditions result in distinctive phenotypes: Zellweger syndrome, also known as cerebro-hepato-renal syndrome, and rhizomelic chondrodysplasia punctata (RCDP) exemplify this class of disease. For the Zellweger spectrum of peroxisomal abnormalities, serum levels of very long chain fatty acids will be elevated; in RCDP the very long chain fatty acids are normal but phytanic acid is elevated.

Every clinician develops a unique, individual strategy of diagnosis. Acquiring a deep and broad fund of knowledge is arguably fundamental and, oftentimes, sufficient in itself. Unfortunately, the sheer numbers of conditions and syndromes impose some limits on the “brute force” approach; the London Dysmorphology Database, for instance, contains over 3,000 multiple congenital anomaly syndromes (22).

Precise diagnosis is neither possible nor necessary in the immediate newborn period for many neonates with a multiple congenital anomaly syndrome. More than half of all individuals with congenital anomalies never receive a firm diagnosis, even after the most definitive of workups, and remain an “unknown.” Categorization of an anomaly as a malformation, disruption, or deformation, however, is a feasible and useful first step. These terms have been defined and discussed previously. An isolated major anomaly in the absence of any similarly affected relative would suggest a multifactoral etiology. If there are multiple malformations, one of the following strategies may be useful:

Once a preliminary analysis has generated a differential diagnosis, all reasonable efforts are made to test each competing hypothesis. Often, a clinical finding can corroborate a possibility. For instance, a lateral radiograph of the knee may allow confirmation of chondrodysplasia punctata by demonstrating the typical stippled, punctate mineralization of the epiphyses. Although many diagnoses are purely clinical, molecular tools are becoming extremely helpful. An electronic literature search or querying an internet resource, such as Online Mendelian Inheritance in Man, can help determine whether a novel approach using direct deoxyribonucleic acid (DNA) sequence analysis, FISH, or linkage analysis has been developed for the disease in question.

More often than not, the diagnostician will not be able to establish an etiology. When this is the case, there is a temptation to “force” a diagnosis, analogous to hammering a somewhat square peg into a slightly round hole. This may not be in the best interests of the patient so that, in these situations, there is honor in admitting ignorance. Certain characteristics of many syndromic conditions, such as the so-called “elfin” facies of Williams syndrome, are not apparent in the newborn period. The most useful diagnostic decision may be to wait and start afresh at a later time, recollecting data, recombining features into new patterns, and researching the literature. The assistance of a clinical geneticist or dysmorphologist during all phases of evaluation frequently optimizes the diagnostic process. If such services are not immediately available via direct consultation, telephonic or telemedicine consultation may be highly effective.

Communication with the parents of a child with congenital anomalies requires a compassionate, timely, and honest presentation of the facts. One’s choice of terminology is important but often challenging. Many parents find it quite helpful for the principal caregiver to examine the infant in their presence, pointing out the features that seem to be unusual, and delineating those that are normal. Parents naturally feel responsible for the birth defect, which they might interpret as a reflection of their own shortcomings, real or imagined. Guilt is as common for the parents of a malformed child as pride is for the parents of a normal newborn. Although it is not always possible to convince parents to set aside unreasonable guilt, they can at least be reassured that they had no control over the events causing the abnormality and that they have permission to not feel guilty.

Expect the full spectrum of grief from both parents. They have experienced the loss of a much-anticipated “normal” child. Shock, denial, bargaining, and acceptance will all occur, even when their child does not have a lethal condition. The physicians and nursing personnel involved in the care of the malformed infant work as a team to keep track of this process and be alert for dysfunctional grief. Social work services, clergy, and support groups are important adjuncts. The National Organization for Rare Disorders, the Alliance of Genetic Support Groups, and specific support groups can provide up-to-date information and lay contacts for interested parents.

Not uncommonly, parents and relatives seek and find extensive information about birth defects, syndromes, chromosomal anomalies, and teratogenic conditions on the internet. In some cases, this information is more detailed and current than that available to a busy clinician who relies on brief textbook entries. Based on this information, parents may become firm, even strident and argumentative, demanding specific tests and management. This situation requires judgment, tact, and an open mind on the part of the attending physician, because this information may be quite useful, and parents who remain your allies will positively influence the entire spectrum of medical management. As correct and cutting edge as this information may be, parents will appreciate your pointing out that the clinical acumen and experience of the neonatal team is essential to assess the extent to which generic recommendations may be helpful for any particular patient. An imperative component of this process will be to verify the reliability of the information and ascertain whether it is based on credible scientific data.

If the malformed infant dies and there is any question regarding the precise diagnosis, a full, unrestricted autopsy can prove extremely useful. Visceral, central nervous system, and skeletal anomalies frequently come to light at postmortem examination. Clinical photography and cytogenetic analysis of fibroblasts obtained from sterile skin biopsy, fascia, or pericardium also may yield important insights. Tissue, cells in culture, and extracted DNA can be stored in a long-term repository and later reanalyzed in light of new research or collaboration.

Families often are reluctant to grant permission for an autopsy. In many instances, however, this procedure has profound implications for the parents’ reproductive options and even those of distant relatives. Cultural and social beliefs and practices must, of course, be carefully respected regarding the care of the child’s body after death. Nevertheless, an autopsy can be recast in the light of a final gift of the child to his family, perhaps even to the world, if in fact a diagnosis is thereby established or medical science advanced.

A teratogen, from the Greek root teras, meaning monster or marvel, is any environmental factor that causes a structural or functional abnormality in the developing fetus or embryo. These environmental agents include infections, medications, drugs, chemicals, and maternal metabolites, such as phenylalanine (Table 38-3). By their very nature, teratogens induce a disruption or sequence of disruptions of inherently normal tissue. Extensive compendia of these agents have been studied in humans and laboratory animals, and several excellent resources are available for the clinician. Additionally, both professionals and patients can access regional teratogen hot lines.

Ethanol, the most common human teratogen, is estimated to affect as many as 1 in 300 newborns, primarily as a neurotoxin, with consequences ranging from cerebral palsy to learning disability. Up to one-fifth of mental retardation (usually mild) is attributable to fetal alcohol syndrome (FAS), but numerous structural anomalies have also been reported (Table 38-4). Although the syndrome has been recognized for over 30 years, the dysmorphisms and other clinical signs of FAS are still often overlooked in the newborn nursery (23).

The multifactoral model of inheritance, as previously discussed, provides a conceptual basis for understanding the pathogenesis and recurrence risks of isolated, nonsyndromic congenital malformations. The central concept of this model is that multiple genes and environmental factors influence whether a particular anatomic structure may develop abnormally. The susceptibility, or genetic liability, of a malformation in a population is described in terms of
a continuous distribution of susceptibility factors in which there is a point, or threshold, beyond which, in an all-or-none fashion, a structural defect will occur. Table 38-5 lists some common multifactoral disorders and their recurrence risks. This type of multifactoral heritability is postulated to account for most isolated malformations.