The Approach Look For The Rare But Remember The Ordinary

Patients and family members often inquire about the heritability of common medical conditions. This chapter provides suggestions for directed family history questions related to many of the everyday medical diseases encountered in the "typical" family history. By supplementing general family history screening questions (as reviewed in Chapter 3) with a more targeted query, the clinician can probe deeper into the medical-family history and identify individuals who may benefit from a more extensive genetic evaluation and genetic counseling. To borrow from a common proverb, these screening questions are a method to distinguish the unusual trees from the vast forest. As with any "field guide," often it is best to look to the experts for final identification. Resources for making a patient referral for genetic services

4.1 THE APPROACH: LOOK FOR THE RARE BUT REMEMBER THE ORDINARY 69

can be found in Chapter 11. Some of the "red flags" in a medical-family history that suggest a genetic etiology of disease are reviewed in Table 4.1.

Instead of discussing the potential genetic disorders associated with every common medical condition, I shall focus on a selection of medical-family history signposts representative of medical conditions with a potential hereditary etiology. For example, leukemia, although a rare complication of Down syndrome, is not a useful "signpost" for recognizing this condition because an infant with Down syndrome is more readily diagnosed by other "signposts." In contrast, leukemia is a common cancer in children and adults in the familial cancer syndrome Li-Fraumeni (see Chapter 5). In this instance, knowing more about the family history can aid the clinician in deciding on genetic testing and health management strategies for relevant family members. The patient's answers to such targeted queries can be transposed into a medical pedigree and used as an investigative map to assist with diagnosis and risk appraisal.

In this chapter I provide suggestions for medical-family history queries for the following broad categories of disease: birth anomalies (Section 4.2), hearing loss (Section 4.3), visual impairment (Section 4.4), mental retardation (Section 4.5), autism (Section 4.6), neurological conditions (Section 4.7), seizures (Section 4.8), dementia (Section 4.9), mental illness (Section 4.10), cardiac disease (Section 4.11), chronic respiratory disease (Section 4.12), renal disorders (Section 4.13), short stature (Section 4.14), diabetes (Section 4.15), reproductive loss and infertility (Section 4.16), and sudden infant death (Section 4.17). Family history markers for identifying individuals with an inherited susceptibility to cancer are discussed in Chapter 5. The decision to include these general groupings of disease in this chapter is based on my experience with some of the questions people have asked me most frequently about disorders in their family.

I do not provide information on the diagnostic tests and the clinical signs and symptoms of the many genetic disorders mentioned in this chapter, nor do I discuss the essential genetic counseling and psychosocial issues for each condition. I do mention several situations where obtaining a medical-family history poses special challenges (such as obtaining a history from a person with profound hearing loss, or from an individual with severe learning disabilities). There are many excellent and comprehensive tomes delving into the medical and psychosocial intricacies of hereditary disease (see Appendix A.5: The Genetics Library).

The key to teasing out potential genetic variables in a patient's family history is to look for unusual and infrequent features against a background of common diseases and normal physical variation. Male infertility is common, but a man with infertility, small testes (hypogonadism), and absence of the sense of smell (anosmia), may have a rare inherited condition called Kallman syndrome. Diabetes mellitus is a common chronic disorder, but a person with diabetes, seizures, hearing loss, and an unsteady gait may have a mitochondrial myopathy.

As clinicians, when we recognize a set of "peculiarities" as a "genetic case" (paraphrasing Dr. Rubinstein in the introductory quote to this chapter), it is natural to swell with a peacock's pride at our diagnostic prowess. It is easy for us to lose sight of the person behind the "peculiar" signs and symptoms. Observes a parent of

TABLE 4.1 The Red Flags in a Medical-Family History Suggestive of a Genetic Condition or an Inherited Susceptibility to a Common Disease

• Multiple closely related individuals affected with the same condition, particularly if the condition is rare

• Common disorders with earlier age of onset than typical (especially if onset is early in multiple family members). For example:

Breast cancer < age 45-50 years (premenopausal)

Colon cancer < age 45-50 years

Prostate cancer < age 50-60 years

Vision loss < age 55 years

Hearing loss < age 50-60 years

Dementia < age 60 years

Heart disease < age 40-50 years

• Bilateral disease in paired organs (e.g., eyes, kidneys, lungs, breasts)

• Sudden cardiac death in a person who seemed healthy

• Individual or couple with three or more pregnancy losses (e.g., miscarriages, stillbirths)

• Medical problems in the offspring of parents who are consanguineous (first cousins or more closely related)

A person with:

• Two or more medical conditions (e.g., hearing loss and renal disease, diabetes and muscle disease)

• A medical condition and dysmorphic features

• Developmental delay with dysmorphic features and/or physical birth anomalies

• Developmental delay associated with other medical conditions

• Progressive mental retardation, loss of developmental milestones

• Progressive behavioral problems

• Unexplained hypotonia

• A movement disorder

• Unexplained seizures

• Unexplained ataxia

• Two or more major birth anomalies (see Table 4.3)

• Three or more minor birth anomalies (see Table 4.3)

• One major birth defect with two minor anomalies

• A cleft palate, or cleft lip with or without cleft palate

• Unusual birthmarks (particularly if associated with seizures, learning disabilities, or dysmorphic features)

• Hair anomalies (hirsute, brittle, coarse, kinky, sparse or absent)

• Congenital or juvenile deafness

• Congenital or juvenile blindness

Cataracts at a young age

• Primary amenorrhea

• Ambiguous genitalia

• Proportionate short stature with dysmorphic features and/or delayed or arrested puberty

• Disproportionate short stature

Premature ovarian failure

• Proportionate short stature and primary amenorrhea

• Males with hypogonadism and/or significant gynecomastia

• Congenital absence of the vas deferens

• Oligozoospermia/azoospermia

A fetus with:

• a major structural anomaly

• significant growth retardation

• or multiple minor anomalies

a child with a "rare" condition, "A condition is only rare when it happens in someone else's family." Carolyn, a woman with multiple birth anomalies who wept after her astute genetic counselor remarked on her beautiful feet, touchingly recalls the profound impact of constantly having clinicians point only to her peculiarities:

Over the years I've seen a lot of doctors. Every one of them has described in excruciating detail what was wrong with me. After a while, I began to feel like no part of me was normal. But deep down inside, I always felt I had beautiful feet. I knew my arm was misshapen, and I knew I didn't have periods like other women, and even my kidneys, which worked fine and people couldn't see, were abnormal. But my feet.. . from the knees down, I thought I looked like every woman. As odd as it sounds, having that little bit of security has helped me get through some tough days. Then, 5 years ago, a doctor casually mentioned that my feet look abnormal. His words were not said cruelly, but they crushed me. The last part of me which I had clung to as normal had been destroyed by what that doctor said. When you just told me now that my feet look normal, it brought back the memory of that day when my whole self-image collapsed (Resta, 1997).

Behind each "genetic case" is a person and family with normal dreams, thoughts, and feelings.

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