In the management of multiple congenital anomaly (MCA) syndromes, the neonatologist must deal with complex clinical issues calling for a wide range of diagnostic skills. Without a correct diagnosis of MCA syndrome, many available forms of therapy go underused and others may be tried, although they will be relatively ineffective. Furthermore, unrealistic counseling may be given about prognosis and recurrence risk. Only a few common MCA syndromes are life-threatening in the neonatal period. It is important to note, however, that malformations are the most common cause of death at this critical point in the life span. Table 88–2 lists symptoms and signs that should alert the clinician to the possibility of cryptogenic malformations or disorders. Obviously, if overt malformations are present, an MCA syndrome will be immediately recognized and diagnostic efforts will shortly follow. However, if external features of the disorder are subtle or nonspecific and the usual procedures associated with intensive newborn support have been started, findings may go unrecognized early. Each manifestation listed in Table 88–2 is more common in infants with MCA syndromes. Underlying etiologies for MCA syndromes include chromosomal abnormalities, monogenic disorders, multifactorial disorders, and unknown. The diagnostic approach to MCA syndromes in neonates is no different from that in older children. Because so many of these children are intubated with multiple lines and tubes, detailed assessment of physical characteristics can be challenging. Clinical photographs are essential, especially when a clinical geneticist is not available locally. If specialists in these fields are not available, a telephone call to a university medical center for expert advice is often useful. If the infant is critically ill and suspicion for a MCA syndrome is present, looking for other major malformations is important (eg, echocardiogram, renal/abdominal ultrasound, brain imaging). The basis for diagnosis of an MCA syndrome in a neonate involves a combination of defining the physical manifestations and diagnostic genetic testing. Diagnostic problems can also occur because immediate efforts tend to emphasize therapy. Nevertheless, diagnosis will often facilitate or guide therapy more efficiently.