CLL in the Family

About 5% of CLL is familial. In 95% of people there is no risk of passing
the disease on to the next generation, but if there is a family history of the
disease, then the risk is increased. If more than one generation is involved
the surer we can be that the disease is in the family.

We do not know about how it is inherited. It is nothing to do with the
common chromosomal abnormalities in CLL such s trisomy 12. Nor do we know how
likely it is that any children will develop the disease. In my experience, if it
is the mild form in one family member, it is mild in other family members.

Patients with CLL who have CLL in the family should contact one of the
specialists who are investigating this phenomenon because we hope to be able to
study them to establish how the disease is inherited. At the moment the only way
we know whether CLL is of the familial type is by knowing that it is present
in more than one member of the family. However, there are many families with
only two people with the disease.

When we look at families with CLL, with very sensitive tests, we can detect
a population of cells that resemble CLL cells, but don't necessarily
proliferate into CLL in about 13% of family members over the age of 40.
 

Familial CLL is well recognized but quite uncommon. Probably, less than 5% of cases are familial. It has been suggested that familial cases are commoner amongst Jews, but that is by no means proven. In my series of 320 patients who have had their VH genes done, there are three sets of brothers. One set of identical twins, one set of non-identical twins and one set of ordinary brothers. I haven't got a detailed breakdown of other relatives. I'm not saying my series is typical, but it gives you an order of magnitude.

There is a large kindred from Denmark who were first reported in 1947, and even today new cases who are related to that family keep turning up. There are several doctors around the world who are making collections of family cases.

We know absolutely nothing about what genes may be involved in inherited cases, though it does not seem to be anything to do with the common chromosomal abnormalities seen in CLL.

Concerning these: deletions of 13q, 11q, and 17p, and trisomy 12; these are all aquired abnormalities, occuring because something has gone wrong in the leukemic clone. they are not present in any other cells in the body, and they haven't been with us all our lives.

One characteristic of familial cases is the phenomenon of 'anticipation', this means that in each succeeding generation the leukemia occurs at an earlier age. It is not certain that this is a real effect because everybody gets diagnosed earlier these days because the tests are more sensitive and doctors more alert to the diagnosis.

The only other genetic thing that can be said about CLL is that it is astonishingly rare among oriental people, even when they reside and live like Americans.

Familial CLL is very rare, but there is no way of telling whether you have
the familial type, other than by looking at your family. If there is no family
history then you probably haven't. If there is one other member of your
family who has it, then you might have it, if there is more than one other family
member who has it then it probably is the familial type, especially if there
are other types of lymphoma also in the family.

I have been prompted to look again at the question of whether CLL is common
in people of Jewish origin. We do know that some diseases are commoner in
Jews, probably because of a tendency to marry distant (and sometimes not so
distant) relatives. An example would be Tay-Sachs disease. So it would not be
unlikely that diseases that have a hereditary element should be commoner in Jews.
A recent epidemiological study convincingly suggested that colorectal cancer
was commoner in Jews and less convincingly also suggested that a number of
other cancers, including lymphoid tumors might be.

The original suggestion that Jews had more CLL was in a 1957 paper in Blood
which suggested that it was twice as common (not three times, my memory
failed me). However, this has not been confirmed or denied by larger studies and
CLL in 1957 was not the disease that we know now. More recently there has been
a small study of familial CLL from New York. Here is the abstract:

Cancer Invest. 1992;10(2):103-9.

Increased incidence of hematologic malignancies in first-degree relatives of
patients with chronic lymphocytic leukemia.

Cuttner J.

Department of Medicine, Mount Sinai School of Medicine, New York, New York
10029.

Cases of leukemia in more than one family member occur rarely. Family
members of patients with chronic lymphocytic leukemia (CLL) may, however, be at
increased risk of hematologic malignancy. The charts of all patients with CLL
(29) seen by the author from 1987 through 1989 were reviewed and living
patients specifically questioned about family history of malignancy. Ten of the 29
(34%) had a first-degree relative with a hematologic malignancy. Three
patients had a first-degree relative with CLL including a pair of identical twins.
Two additional patients had a spouse with a lymphoid malignancy. No
differences were found in serum immunoglobulin levels between those patients with a
family history of hematologic neoplasia and those without. The lymphocytes of
the majority of patients with a family history of hematologic neoplasia (60%)
expressed kappa light chains as did those without (70%). An increased
incidence of lymphoid malignancy has been reported in western Ashkenazi Jews and in
particular those of Russian descent. The majority of our cases were of Jewish
origin and came from Eastern Europe. Seven of 10 patients with a family
history of hematologic neoplasia were from Eastern Europe. In contrast only one of
three patients with CLL who had a first-degree relative with CLL was of
Jewish origin.

Note that the author was practising from Mount Sinai Hospital in New York.
His experience that 34% of his CLL patients had a relative with a hematologic
malignancy is wildly greater than most people would find. It may be because
so many of his patients were Jewish that he found this.

So the jury is still out on whether CLL is commoner in those with Jewish
origins. In my own practice I have seen a set of identical twins whose severe
and fatal CLL was almost identical - they were Jewish. I have seen a set of
non-identical twins whose CLL was equally benign - they are Jewish. I have seen
two brothers, both with fairly benign CLL, who as far as I know are
non-Jewish. And I have seen another 800+ patients, most of whom have have no relative
with CLL; some are Jewish; some are not; but most of whom I never asked.