When to suspect a genetic syndrome

Abstract

Family physicians should be able to recognize findings on physical examination and history that suggest the presence of a genetic syndrome to aid in the diagnosis and treatment of potentially affected patients, as well as subspecialty referral. General themes that can alert family physicians to the presence of genetic conditions include dysmorphic features that are evident on physical examination; multiple anomalies in one patient; unexplained neurocognitive impairment; and a family history that is suggestive of a hereditary disease. The presence of one obvious malformation should not limit the full evaluation, because additional, subtler findings will often be important in the differential diagnosis. Taking an accurate three-generation family history is invaluable when considering a genetic syndrome. Important elements include the age and sex of family members; when family members were affected by disease or when they died; the ethnic background; and if there is consanguinity. Genetic subspecialists can assist family physicians in diagnosis, suggest additional testing and referrals if warranted, help direct medical care, and provide counseling for affected patients and their families.

Figure 1

Examples of dysmorphic features that can be found on physical examination that may be helpful in the diagnosis of genetic syndromes. (A) A black infant presents with pigmentary anomalies in the context of a genetic condition; notice the hypopigmented tips of the hair. (B) An iris coloboma can be associated with many genetic syndromes, or can occur as an isolated feature. (C) A single maxillary central incisor can occur in conditions that include midline deficits, and can be a clue to the presence of accompanying brain malformations. (D) A small ear with an overfolded helix can be a familial variant or can occur as part of a genetic syndrome. (E) Fifth-finger clinodactyly (incurving of the fifth finger) occurs in many genetic conditions, and is classically seen in persons with Down syndrome. (F) An unusual shape of the digits, such as tapered digits, can occur in many conditions; this patient has Coffin-Lowry syndrome. (G) Various types of syndactyly (fusion) of the fingers or toes may be seen; second- and third-toe syndactyly, which occurs in Smith-Lemli-Opitz syndrome, is shown here. (H) Examination of the skin is an important part of the physical examination; this child with neurofibromatosis 1 has multiple café au lait macules. (I) This lesion, visible with a Wood lamp, has irregular borders and is typical of sporadic café au lait macules.

Figure 2

Example pedigree for a (relatively small) family that may be affected with a hypothetical genetic syndrome showing history of first-, second-, and third-degree relatives of the proband. In this situation, a 14-week fetus of unknown sex (marked with a “P” for “proband” or “propositus,” and indicated with an arrow; the “P” inside the diamond [for “pregnancy”] indicates the fetal status) has been prenatally identified as possibly being affected by a genetic condition because of the presence of congenital heart disease. The proband has a healthy sister two years of age. The mother, who is 23 years of age, is affected by attention-deficit/hyperactivity disorder and major depressive disorder. The proband’s mother has a dizygotic twin brother with asthma who also had congenital heart disease in the form of a ventricular septal defect that was repaired in infancy (his symbol is shown in solid black to indicate that he, like the proband, had a congenital cardiac malformation). The maternal grandfather is healthy at 52 years of age. The maternal grandfather is separated from the maternal grandmother (almost no medical history, including her current age, is known about the maternal grandmother, who was adopted). With another partner, about whom few details are known, the maternal grandmother had a spontaneous abortion at less than 10 weeks’ gestation; the sex was not known. A maternal great-aunt, who is 56 years of age, has hypertension and non–insulin-dependent diabetes mellitus. She did not have children (by choice). The maternal great-grandparents are both deceased; the maternal great-grandmother is described as dying of “old age” at 79 years of age, and the maternal great-grandfather died of “cancer” (more specifics unknown) at 65 years of age. The father is 22 years of age and has insulin-dependent diabetes. The paternal grandmother is 49 years of age and has hypercholesterolemia. The paternal grandfather died in a motor vehicle crash at 48 years of age; details of his family history are not known. The paternal great-uncle is healthy at 54 years of age, but is infertile (for unknown reasons). The paternal great-grandmother is 77 years of age and has breast cancer and a history of hypertension. The paternal great-grandfather died at 70 years of age of a myocardial infarction. Other details not shown here could include the ethnicity of the family, which could have a bearing on the frequency of certain conditions, as well as the age at which the previously mentioned conditions were diagnosed (such as the age at which the paternal great-grandmother received the breast cancer diagnosis). In taking the family history, it would also be important to ascertain the presence of conditions possibly related to that of the proband, including the presence of consanguinity, any type of congenital malformations, and cognitive impairment manifesting in childhood. Pedigree symbols are reviewed in reference .