191CHAPTER 7

Assessing Patients With a Genetic “Eye”: Family History and Physical Assessment

Kendra L. Schaa

The initial recognition of the need for a genetics referral may arise when a nurse suspects a genetic contribution to disease because of personal or family medical history and/or findings from a physical assessment. For example, the nurse may notice very high low-density lipoprotein (LDL) cholesterol levels in a 34-year-old patient. Upon collection of a three-generation family history, the nurse discovers that the patient’s mother passed away in her early 40s from a heart attack. During physical examination, tendon xanthomas are noted in the patient (caused by cholesterol buildup). Discussion of these findings with the health care team leads to a diagnosis of familial hypercholesterolemia, the leading cause of inherited high cholesterol and an autosomal dominant genetic condition. This diagnosis has important implications for the care of other at-risk family members.

FAMILY HISTORY

Family history is a valuable and cost-effective tool that is often underutilized in clinical practice. Gathering an accurate three-generation family medical history can be critical to the identification of an individual and/or family member(s) at risk for a genetic contribution to disease and can be helpful in developing a personalized management and treatment plan for a patient. A family history can be collected through a face-to-face interview or over the telephone. Information provided by the patient is then used to draw a pedigree, a visual representation of the family medical history. It is important to recognize that gathering this information takes time and depends on the size and health of a patient’s family. However, once collected, family history can be easily updated during future clinic visits and used by the entire health care team to assess the patient’s risk for disease. My Family Health Portrait, an online tool from the Surgeon General, guides individuals in the collection and organization of personal and family health history (https://familyhistory.hhs.gov). This tool includes a printing feature to facilitate sharing this information 192during a patient’s health care visit. Several other tools are available for collecting family history and can be found on the following websites: the National Coalition for Health Professional Education in Genetics (www.nchpeg.org) and the American Medical Association (www.ama-assn.org).

Collecting Family History

Family history should span at least three generations of relatives, including children, brothers and sisters, parents, aunts and uncles, nieces and nephews, grandparents, and cousins. Specific questions to ask while collecting family history depend on multiple factors, including the reason for the clinic visit, previously collected or observed personal or family medical history information, laboratory data or physical assessment, and a patient’s answers to previous questions. Collecting personal and family history can be a sensitive subject and necessitates asking questions in a culturally and socially sensitive manner. It is beneficial to explain to the patient why collecting this information is important (i.e., it helps to inform a more comprehensive picture of the patient’s health and facilitates the identification of risk factors).

The following is a list of essential information to collect as part of the personal and family history. This may require more than one visit to collect or may require that the patient speak with other family members to verify or collect missing information. When the patient is a child, each parent should ideally provide information about his or her respective side of the family.

Personal Medical History

       Age

       Medical diagnoses (current and previous; age at diagnosis)

       Medical conditions and age of onset, even if not formally diagnosed

       Medications (current and previous; adverse reactions)

       Allergies (e.g., food and medications)

       Occupation (current and previous—may indicate environmental exposures)

       Exposure to biological, chemical, or radiation hazards (at home, work, or during military service)

       Lifestyle practices that may affect health

       Substance use (including tobacco, alcohol, and recreational drugs—current and previous)

Family History

More specific questions will depend on the responses received during the interview and/or observations from the physical examination. When possible, all information should be confirmed by medical records, laboratory data, photographs, autopsy reports, and other objective methods. Changes in personal/family medical history and lifestyle choices should be expected. Therefore, periodic updating of this information is critical, as it can impact a patient’s risk assessment.

Identifying relatives in a patient’s family with the same or similar diagnosis or medical condition does not necessarily mean that the patient will develop that condition. Similarly, obtaining a negative family history does not rule out an underlying genetic condition or genetic component to a patient’s disease. Furthermore, a negative family history does not necessarily suggest that other family members are not at increased risk to develop the disease. There are many reasons that can explain a negative family history and may warrant additional questions or testing, including:

Family history is discussed further in this chapter in the “Pedigrees” section.

194Environmental and Occupational Histories

Many common genetic conditions result from complex interactions between genetic and environmental factors. These multifactorial conditions often cluster in families, given that family members share a fraction of their genes along with a similar environment. Therefore, it is critical to collect information about potential environmental exposures to help inform a patient’s risk assessment. Health care professionals should become familiar about toxic environmental agents that are common in their specific geographic location. They should recognize that a number of environmental factors that cause adverse health outcomes disproportionately affect vulnerable and underserved populations. These populations are more likely to be exposed to higher levels of air pollution and more toxic indoor agents, such as lead and pesticides.

Environmental exposures can result from an individual’s current or past occupations, residence location, volunteer activities (e.g., firefighting), recreational activities and hobbies, and, for children, anyplace where they spend a considerable amount of time (e.g., day care and a grandparent’s home). Information to be obtained regarding the place of residence should include location, composition of the household, source of drinking water or food (especially in rural areas), the proximity of any factories, knowledge of any chemical spills or waste exposure, noticeable air pollution, type of insulation and heating, insecticide or pesticide exposure, and other data as relevant. Sometimes, the job itself can alert the practitioner to possibilities of toxic exposure; for example, military service can be associated with exposure to Agent Orange. Information should be gathered for both the patient and the other individuals living in the household. For example, the individual doing the laundry may be exposed to fibers on the clothing of the worker. Inquire about the kinds of materials that the person may be exposed to, such as radiation, chemicals, fumes, dust, fibers, tobacco, gas, temperature extremes, microorganisms, and vibrations. If the person is unsure about specific substances, it may be necessary to collect this information from the employer, depending on how critical the information is to the problem at hand. Patients should also be asked about contact with domestic animals (e.g., cats and dogs) and farm animals on the job or at home. Any affirmative answers about exposure should be followed up to determine the duration of exposure/employment, the frequency, and the last time the person was exposed.

Toxic environmental agents, including cigarette smoke exposure, are known to have a harmful effect on reproductive health across the life course. Patients with identified toxic exposures should be asked whether there is a history of infertility, miscarriages, stillbirths, or abnormalities in reproductive function (e.g., puberty and menopause). Those with children should be asked whether there is a history of birth defects, developmental or intellectual disabilities, or childhood cancer. If a specific health concern appears to be job or environmentally related, the patient should be asked if anyone at work or with exposure to the same environment (e.g., neighborhood) has had similar health problems (see Chapter 12).

If an environmental exposure is identified, educating the patient on the possible consequences of such exposure and methods to reduce exposure is critical. For 195example, a pregnant woman who works at a pet boarding kennel can be advised on safe methods for disposing excreta and handling animals to minimize her own exposure without jeopardizing her employment.

Medication and Drug Use

It is helpful to ask the patient to bring a list of current medications to each clinical visit. Teaching and encouraging patients to keep an up-to-date list of medications will facilitate collection of this information. Patients should be asked about prescription drugs, over-the-counter medications, and home remedies. If the health care visit is after the birth of an affected child, document any medications taken a few months before pregnancy in both the male and female partner and during the pregnancy in the female. There are a number of drugs known to cause malformations in the fetus if taken during pregnancy, including many antiepileptic drugs and vitamin A analogues (e.g., Accutane). See Chapter 8 for more information on medications and drugs in pregnancy. Many individuals may overlook items that they do not consider to be drugs or medications. Therefore, asking broad questions about how a patient treats common ailments, such as headaches or stomachaches, may help to elicit this information. Use of recreational drugs, caffeine, alcohol, and tobacco should be explored in a sensitive manner. For any drug or medication taken, the dose, frequency of use, reason for use, duration, and approximate dates should be obtained.

The patient should be asked about any personal or family history of drug allergies, adverse drug reactions, or if she or he has received specific instructions to avoid certain medications or foods from a health care professional. In some cases, this information may suggest an underlying genetic variant in the patient that is affecting drug response and can often be confirmed by a pharmacogenetic test. A growing number of Food and Drug Administration (FDA) approved drugs have labeling that includes pharmacogenomic information, which can be used to optimize drug dosage and prevent adverse and life-threatening drug reactions in a patient or family member.

Reproductive History

There is some overlap between collecting the family history and collecting a complete reproductive history. All pregnancies, including miscarriages, abortions, stillbirths, infant deaths, and offspring, should be noted as part of the family history. Discussing pregnancy loss and infertility is particularly emotional for many individuals; therefore, it is important to acknowledge the sensitive nature of the information being requested. In the case of an affected infant or child, the following information should be obtained, if possible.

One primary reason for collecting this information is to help inform whether a condition, such as intellectual disability, may have been caused by environmental factors or whether an underlying genetic cause is more likely. Keep in mind that it is always worth asking the patient whether there is any other relevant information worth sharing that might be important to the presenting issue. Confirmation of relevant data through records may be necessary for accuracy.

If the woman is currently pregnant, the date of the last menstrual period and the expected date of delivery should be obtained. Some clinics have developed a short questionnaire that is a screening tool for potential genetic risks to the pregnancy. These questionnaires are usually set up in a simple yes/no format and are best administered in the native language of the patient. When a patient answers affirmatively to any of the specific questions, the chart is flagged for a consultation with a geneticist or a genetic counselor. A genetics consultation may need to happen immediately, depending on how far along the woman is in her pregnancy, given that information discussed during such a consultation may influence the direction of the pregnancy. Information that can be ascertained on such screening tools, which typically warrants a genetics consultation, includes:

Not infrequently, taking a reproductive history follows the birth of an affected child, recurrent pregnancy loss, or difficulty conceiving. Thus, retrospective information is likely to be influenced by feelings of guilt (real or imagined) as well as other emotions.

PEDIGREES

A pedigree is a graphic representation of the family history developed using a standard set of symbols described in Figures 7.1 through 7.3. Collecting and translating personal and family medical history into a pedigree makes it possible for the health care team to understand the patient from a holistic perspective and provides a permanent record of the genetic information in a family. Additional benefits of a pictorial representation of family history include:

Computer software programs are available specifically for pedigree construction. Many printable templates exist as well and hand-drawn pedigrees are also acceptable. All methods require that the nurse not only understand the purpose of a pedigree but can successfully construct one from a family history. It is helpful to document the family names or initials on the pedigree, along with the date the pedigree was collected and the name of the individual recording the information.

Once the pedigree is drawn, characteristic findings of common inheritance patterns should be noted, including male-to-male transmission, maternal pattern of inheritance, ratio of affected males to affected females, or other features of the typical inheritance patterns as discussed in Chapter 4. In some cases, the mode of inheritance cannot be determined from the pedigree due to small family size, reduced penetrance or variable expressivity of the disease, lack of accurate information, presence of a new genetic mutation in the affected individual, or environmental/gene interactions.

198

FIGURE 7.1. Common pedigree symbols.

Source: Bennett, French, Resta, and Doyle (2008).

DEVELOPMENTAL AND PHYSICAL ASSESSMENT

Information from the family history can suggest specific findings to look for during a physical assessment or in lab results. Clinical clues that suggest the need for further evaluation or testing depend on the individual’s age. The appearance of certain features may be considered normal at a certain age but deviant at another. High cholesterol levels in an overweight 60-year-old may be unremarkable; however, high levels in a young adult may suggest the possibility of familial hypercholesterolemia and should be investigated. A newborn girl who has lymphedema may require a karyotype because of the possibility of Turner syndrome (see Chapter 9); however, the lymphedema rapidly disappears, and the next time of suspicion may be when menstruation and the development of secondary sex characteristics are delayed. Likewise, Wilson disease (an autosomal recessive disorder of copper metabolism) should be considered in the child or adolescent who experiences acute liver failure. In an infant or child, certain odors are associated with specific biochemical abnormalities (see Chapter 9).

199

FIGURE 7.2. Pedigree line definitions.

Source: Bennett, French, Resta, and Doyle (2008).

Physical examinations of children and adolescents can provide an opportunity for detection of disorders making their appearance around puberty and can provide a forum for preconception counseling for adolescent girls. Sexual development in relation to age may be assessed by use of the Tanner criteria. For girls or women with significant menorrhagia, screening is recommended for von Willebrand disease (a hereditary bleeding disorder characterized by deficiency of von Willebrand factor needed for optimum platelet adhesiveness). It is important to screen before initiation of oral contraceptive therapy, since this may mask diagnosis. Sometimes, physical examination takes place in a sports physical setting, where screening is rushed and there is pressure to approve a child for sports. It is important, however, to assess the child’s personal and family medical history for heritable connective tissue disorders, such as Marfan syndrome (see Chapter 10), and for cardiomyopathies or other cardiac abnormalities.

200

FIGURE 7.3. Assisted reproductive technology symbols and definitions.

Source: Bennett, French, Resta, and Doyle (2008).

Measurements

Measurements should be taken to determine whether a specific anomaly found during the physical examination is truly abnormal. Normal measurement charts are widely available for reference. The purpose of this section is to identify measures and observations that are of particular importance when making a diagnosis of a genetic syndrome.

201The extent to which the nurse uses measurements depends on the area of practice. For the normal infant and child, standard measurements include height, weight, and head circumference. Other measurements, such as arm span, chest circumference, internipple distance, ear measurements, and craniofacial measures, should only be taken when indicated and by a trained clinician. Craniofacial examination is often evaluated by cephalometrics (three-dimensional craniofacial surface imaging from CT scans, MRI, and computer-driven techniques).

Any unusual physical findings should be compared to other family members to determine their relevance. The child’s birth weight and maturity should always be considered when evaluating unusual results. The occurrence of two and, especially, three minor malformations in an otherwise healthy infant should alert the practitioner to search carefully for one or more major anomalies and consider chromosome analysis (see Chapter 5). Keep in mind that major anomalies are not always visible (e.g., congenital heart defect).

Isolated measurements should be taken into consideration with other factors. One abnormal measurement should not cause immediate concern, but serial measurements should be kept so that growth velocity can be examined. When possible, sex and race/ethnic-specific growth charts should be used. If a growth disorder is present, determining the specific type is important for diagnosis, treatment, and genetic counseling. Failure to thrive (FTT) is a relatively common consultation in pediatric clinics. Failure to thrive may be organic (medical) or nonorganic (social and environmental). Determining the underlying cause of FTT is critical as it can be a feature of various inherited metabolic disorders that, in turn, may necessitate immediate, life-saving dietary restrictions. For all FTT cases, it is important to inquire about pregnancy history, feeding history, gastrointestinal symptoms, and food intolerance. Delayed or precocious puberty can be assessed through criteria for pubertal stage attainment. Hypogonadism and delayed puberty are frequent components of many genetic disorders and must be fully investigated. Other growth disorders should be noted. Macrosomia can be seen in the offspring of diabetic mothers. Truncal obesity, associated with hypotonia and FTT, is a feature of Prader–Willi syndrome (see Chapter 9).

Head circumference reflects brain development and should be measured over time. Given that brain growth completes around the age of 2, serial head circumference measurements should be obtained during each visit from infancy until 36 months. When measuring head circumference, a nonstretchable tape measure should be used. The child’s head must be still. The tape should measure the greatest circumference, starting at the forehead between the eyebrows and hairline, then passing to the rear of the head over the occipital prominence and coming around to the forehead for the final measurement. The average head circumference is approximately 35 cm in a full-term infant but can range from 32 to 38 cm. There is approximately a 5-cm increase in the first 4 months of life and an increase of 5 cm more by the first year. Head size should always be evaluated within the context of other factors, including body size, weight, chest circumference, and parental head circumference. Variation in head size can be caused by familial characteristics and racial/ethnic group differences, as well as by other reasons. An unusually small (microcephaly) or large (macrocephaly) head 202size warrants further investigation due to the association with genetic syndromes. Microcephaly is defined as approximately less than the second percentile. Conversely, macrocephaly is defined as approximately greater than the 98th percentile. Microcephaly can be caused by craniosynostosis, fetal alcohol syndrome, underlying structural abnormalities (diagnosed by MRI), congenital infection, metabolic disease, and chromosomal deletions/microdeletions. Macrocephaly is associated with hydrocephalus and other structural abnormalities of the brain, metabolic disease, overgrowth syndromes, Fragile X syndrome, and chromosomal abnormalities.

Appraisal and Assessment

When possible, unusual features discovered during the physical examination should be photographed for permanent documentation, to allow for interprofessional consultation and to permit later study and comparison. Photographs with the child’s parents may be helpful in assessing familial contributions to facial features. Attention should be given to any parental concerns about delayed development or unusual behavior in an infant or child. For example, children with xeroderma pigmentosum (an autosomal recessive disorder with extreme sensitivity to sunlight that leads to malignancies) often cry on sun exposure, an event that occurs before any other signs and symptoms. Parents’ recall of developmental milestones, except for walking, may not be reliable. Therefore, providing the parents with a book for recording important developmental milestones may be helpful. Developmental delay is a feature of many genetic conditions and an accurate assessment of the child’s delay can be helpful in determining a list of differential diagnoses.

Clinical findings seen in some genetic conditions are organized by region of the body in Table 7.1. Note that this is not an all-inclusive list. Indications suggestive of specific conditions and those that necessitate a genetics evaluation are also given throughout the book and at the end of this chapter. The frequency of syndromes associated with blindness, deafness, failure to thrive, and developmental disability precludes discussion here but mandates full evaluation.

Head, Neck, and Face

Assessment of the head and face can be challenging, given the wide variation in normal measurements. Any suspected abnormality should warrant further investigation or consultation with a specialist. Mild asymmetry may be present in the newborn because of intrauterine factors and birth. In those with microcephaly, a tapering is noted from the forehead to the vertex. Premature closure of the cranial sutures (craniosynostosis) can result in an abnormal head shape. Delayed fontanel closure or a large fontanel can result from achondroplasia and other skeletal disorders, congenital hypothyroidism, Down syndrome, rickets, and increased intracranial pressure, among other conditions. A small fontanel or early fontanel closure can be related to craniosynostosis or abnormal brain development that may or may not result in microcephaly. Note that craniosynostosis is associated with a number of genetic syndromes, along with hyperthyroidism, hypophosphatasia, rickets, and hyperparathyroidism. A third fontanel located between the anterior and posterior fontanels is found in 5% to 15% of normal infants, but is more common in infants with Down syndrome and hypothyroidism.

207Characteristic facies have been described as components of specific genetic syndromes. For example, coarse facies are associated with many lysosomal storage disorders and may be present at birth or develop with time. A smooth philtrum, the vertical groove in the median portion of the upper lip, is associated with fetal alcohol syndrome. Cleft lip and palate may occur as single defects or as a part of a syndrome (see Chapter 9). A bifid uvula may be dismissed by the practitioner but is frequently associated with submucous cleft palate and Loeys–Dietz syndrome (a connective tissue disorder).

Careful examination of the teeth can provide clues to an underlying ectodermal dysplasia or other genetic conditions. Missing teeth or abnormally shaped teeth should be noted. Teeth anomalies are often associated with unusual hair, skin, and/or nails, given that all of these tissues share a common origin.

Eyes and Ocular Region

Congenital cataracts occur in approximately 3 to 6 per 10,000 births; nearly 50% of congenital cataracts are genetic. Cataracts can be isolated, inherited, or occur as part of a syndrome and, therefore, be associated with other malformations. Both unilateral and bilateral cataracts can be present. In general, unilateral cataracts are not typically inherited. Approximately one fifth of children born with bilateral cataracts will be registered blind. Cataracts are often the first abnormality noticed in congenital and acquired infections and in various metabolic disorders (e.g., galactosemia). Prompt referral to an ophthalmologist is essential if cataracts are suspected.

Like cataracts, corneal clouding can be a clue to an underlying genetic disorder. In childhood, clouding of the cornea is often associated with inherited metabolic conditions. In adults, corneal dystrophy can be a sign of Fabry disease or cystinosis. Various pigmentation abnormalities of the iris are often seen in Waardenburg syndrome type I, including irides of different color or brilliant blue irides. Brushfield spots are speckled white areas in the iris that occur in normal children, but are more common among those with Down syndrome. Lens dislocation is frequent in individuals affected with Marfan syndrome or homocystinuria.

Hypertelorism represents an increased interpupillary distance and is a frequent component of many genetic syndromes. This distance can also appear wide because of a low nasal bridge, telecanthus, or short palpebral fissures. The palpebral fissure length is the distance from the inner to the outer corner of the eye. Short palpebral fissures are common in individuals affected with fetal alcohol syndrome, among other genetic conditions. The slant of the palpebral fissure varies based on ethnic origin. However, up- and down-slanted palpebral fissures, in addition to other dysmorphic facial features, can point toward an underlying genetic syndrome. Inner epicanthal folds are often present in children with Down syndrome and Turner syndrome.

Ears

Much variation exists in the external ear; as previously suggested, photographs provide the best documentation if ear anomalies are suspected. Ears should be examined 208for symmetry, position, and size. “Low-set ears” is a descriptor commonly used; however, ears can appear to be low-set because of other features, such as a short or extended neck, tilted ear, small chin, or high cranial vault, any of which can be present alone or in conjunction with another syndrome. Assessment of the position of the ear should ultimately be done by objective measurements, and a detailed investigation of craniofacial structures should follow.

Various degrees of malformation of the ear can occur and may be genetic or acquired. In some cases, ear malformations are associated with syndromes that include renal disease (e.g., branchio-oto-renal syndrome) and hearing loss (CHARGE syndrome) as primary components. For this reason, infants or children with a minor ear malformation may benefit from an audiogram and renal ultrasound scan. When collecting the family history of a patient suspected to have an ear anomaly, always inquire about hearing loss and renal problems in relatives. Note that hereditary hearing loss can be inherited in many different patterns, including mitochondrial, autosomal dominant, autosomal recessive, and X-linked recessive (see Chapter 4). The following list of red flags in the personal and family medical history may indicate an increased risk for hearing loss and warrant further investigation:

Genetic:

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