Clinical Features

Progeria, illustrated in Figure 1, is a rare genetic disease with striking clinical features that resemble premature aging (1-3). It has a reported birth incidence of about 1 in 8 million (1). Patients with this condition generally appear normal at birth, but by about 1 year of age, severe growth retardation is usually seen. Balding occurs, and loss of eyebrows and eyelashes is common in the first few years of life. Widespread loss of subcutaneous tissue occurs. As a result, the veins over the scalp become prominent. The skin appears old, and pigmented age spots appear. The patients are very short and thin. They average about 40 inches in height, but they usually weigh no more than 25 or 30 pounds even as teenagers. The weight-to-height ratio is thus very low. The voice is thin and high-pitched. Sexual maturation usually does not occur. They have a characteristic facial appearance with prominent eyes, a beaked nose, a "plucked-bird" appearance, and facial disproportion resulting from a small jaw and large cranium. The large balding head and small face give them an extremely aged appearance. The bones show distinctive changes, with frequent resorption of the clavicles and replacement by fibrous tissue. Resorption of the terminal finger bones (acro-osteolysis), stiffening of finger joints, elbow and knee joint enlargement, coxa valga, and a resulting "horse-riding" stance are all seen. Aseptic necrosis of the head of the femur and hip dislocation is common (18-19).

Individuals with progeria have a normal to above-average intelligence. The median age of death is 12 years. Over 80% of deaths are due to heart attacks or

Figure 1 A 10-year-old girl with Hutchinson-Gilford progeria. She had mild strokes and bilateral hip dislocations. She died at age 13 years of atherosclerotic heart disease.

congestive heart failure. Widespread atherosclerosis, with interstitial fibrosis of the heart, is usually seen at postmortem examination (20). Occasionally, marked enlargement of the thymus gland is noted. However, some features often associated with normal aging such as tumors, cataracts, diabetes, and hyperlipidemia, although occasionally reported (21-23), are not usually present.

Consideration of the mode of inheritance in progeria is important for genetic counseling and may help to understand the nature of the underlying mutation. Recessive diseases often appear to be caused by enzymatic deficiencies that lead to metabolic abnormalities. Dominant diseases often involve structural proteins. However, they may be due to partial deficiencies of rate-limiting enzymes (i.e., porphyria) or cell surface receptors (i.e., familial hypercholesterolemia) where half the normal level of the gene product can lead to a disease.

Several genetic considerations suggest progeria is most likely a sporadic dominant mutation. First, high rates of consanguinity (i.e., first-cousin marriages) are expected in rare recessive diseases. High consanguinity is not seen in proge-ria. Debusk (1) has noted that consanguinity was present in only 3 of 19 families in which it was specifically discussed. Some of these cases had come from areas of the world with high background population levels of consanguinity, and the diagnosis in some may be in doubt. In addition, it was not reported to be present in 41 other families in the literature. A family history of consanguinity was not present in any of some 50 progeria cases that we have seen since then. Thus, we estimate the frequency of babies with progeria born to consanguineous marriages to be less than 3%. For rare recessive diseases, an estimate of the expected frequency of consanguinity can be derived using the Dahlberg formula (24). Assuming a birth incidence of progeria to be 1 per 8 million, and a background population consanguinity frequency of 1%, this leads to an estimate of expected consanguinity of 64% in families in which progeria occurs. Thus, the 3.6% observed consanguinity frequency in progeria is much lower than the high level that would be expected for such a rare recessive disease.

Although the reported incidence of progeria in the United States is about 1 in 8 million births (1), the true population incidence may be somewhat higher, as not all cases are reported. Based on our experience, we estimate that about 50% of all cases in the United States are reported, which leads to an estimate of incidence of 1 in 4 million. This would still lead to a much higher expected consanguinity frequency (45%) than the low frequency that is seen in families in which progeria occurs. This lack of consanguinity suggests progeria is unlikely to be a rare recessive condition.

Second, a paternal age effect is seen in progeria that is also observed in some other genetic conditions caused by sporadic dominant mutations. Jones and coworkers (25) have reported that among 18 progeria cases, the fathers were older than expected by an average of 2.56 years when controlled for maternal age, a difference that was highly significant (P = .005). In addition to progeria, they reported a paternal age effect in seven other disorders involving new mutations for which autosomal dominant inheritance had been clearly established (basal cell nevus syndrome, Waardenburg syndrome, Crouzon syndrome, cleidocranial dysostosis, Oculo-dental-digital syndrome, Treacher-Collins syndrome, and multiple exostoses), and in four disorders (achondroplasia, Apert syndrome, fibrodysplasia ossicans progressiva, and Marfan syndrome) in which older paternal age in the setting of a new mutation previously has been shown.

We observed a paternal age effect in 24 cases of progeria that we examined where parental ages were available (2). The fathers were older than the mothers by an average of 4.5 years, which is higher than the expected control value of 2.8 years (25). The paternal age effect observed in these 24 cases confirms the previously reported paternal age effect in 18 earlier cases (25) and also suggests dominant inheritance. The paternal age effect appears to be due to the fact that about 20% of fathers are about 20 years older than the mothers, as illustrated in Figure 2. A similar secondary paternal age peak has been reported in new cases of neu-rofibromatosis, another dominant disease (26).

Third, for a recessive condition, the proportion of affected siblings is ex-

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