Dermatoglyphics and Acute Lymphocytic Leukemia in Children Joan Edelstein, RN, DrPH, Michael Amylon, MD, and Jo Anne Berkman Walsh, RN, MA
Cellular features of acute lymphocytic leukemia (ALL) in children suggest that it originates in abnormal embryogenesis. Because palmar flexion creases develop in the embryo at the same time as the blood-forming cells, and because both arise from mesodermal tissue, insults to the embryo that may lead to leukemic changes in the blood-forming cells may also result in aberrant palmar crease patterns. This study investigated the relationship between aberrant palmar creases and ALL in children who developed leukemia at age 6 years or younger. Odds ratios and chi squares demonstrated significant differences in bilateral aberrant palmar creases between ALL children and relatives (P < .025). Differences were not explained by familial clustering of aberrant creases. These results support the theory that the insult occurred during pregnancy, probably in the first trimester. There were no significant differences in either bilateral or unilateral aberrant palmar creases between ALL children and their siblings. All children with bilateral aberrant creases had a higher incidence of central nervous system involvement (50%) than those without bilateral aberrant creases (6%). This may reflect a preleukemic change in utero before the time the blood-brain barrier has been established. © 1991 by Association of Pediatric Oncology Nurses.
LEUKEMIAS comprise approximately 15% to 40% of major malignancies in children under 10 years of age. Of these, acute lymphocytic leukemia (ALL} accounts for 60% to 70% of cases. Treatment of the leukemias has improved, but their etiology remains unclear. In adults, tumors seem to develop through dedifferentiation of cells in mature tissue. Cellular features of childhood tumors suggest that they originated in abnormal embryogenesis.1 Palmar creases are determined during the same period of embryological development as the’blood-forming cells; both arise from meso-
THE
From the Department of Nursing, San Jose State University, San Jose, CA and Children’s Hospital at Stanford, Palo Alto, CA Address reprint
to Joan Edelstein, RN, DrPH, San Jose State University, San Jose, CA 95192-0057. ©1991 by Association of Pediatric Oncology Nurses.
requests
Department of Nursing,
1043-4542/91/0801-0005$03.00/0
dermal tissue. It is possible that abnormal growth-regulating factors may be reflected in palmar creases as well as_ in those bloodforming cells that become malignant.
Dermatoglyphics
and Disease
Dermatoglyphics refer to the epidermal ridge patterns of the palms, fingers, soles, and toes. The transverse flexion creases of the palm were not originally included in the definition of dermatoglyphics, but over time fell under the category of dermatoglyphics and are so included in this study. Development of the transverse flexion creases of the palm are the target of this study. Palmar creases are formed by a combination of fetal volar pad placement and growth of the fetal hand. Volar pads are mounds of mesodermal tissue on the fingertips, between the fingers on the distal palm, and on the hypothenar area of the palm. They may be clearly seen in the fetus during the first trimester as cherry-
30
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31
shaped &dquo;lumps&dquo; distributed over the fingers and palm. Abnormal palmar crease patterns have been identified in those suffering from a number of chromosomal abnormalities as well as those with nongenetic diseases. These include Down’s syndrome (trisomy 21), trisomy 18, and trisomy 13? Dar and Jaffe3 identified aberrant bilateral palmar crease patterns in 15% of patients with mental retardation of congenital origin and aberrant unilateral crease patterns in 57% of those patients (n 200). In the same study, 1.2% of normal, healthy school-age controls had bilateral aberrant creases, and 8.2% had unilateral aberrant creases (n 500). They conclude that =
=
Dermatoglyphic and palmar-crease patterns develop during the first trimester. Events causing fetal insult during this period may results in unusual dermatoglyphic or palmar-crease patterns?
-
in retinoblastoma and Wilms’ tumor.’ Acto Altman ~ Schwartz,~ patients with bilateral forms of Wilms’ tumors and retinoblastoma are considered to have the hereditary form of the disease while those with unilateral tumors are, for the most part, considered to have the case
cording
disease
as
the result of spontaneous, ie, nonhe-
reditary mutations. If laterality of palmar crease patterns is a reflection of the significance of a prenatal phenomenon, there should be a significant difference in the incidence of bilateral palmar creases cases versus controls and that difference should be greater than the difference in unilateral aberrant creases. . The purpose of this study is to determine whether there is an increased incidence of bilateral aberrant palmar flexion creases in children with early onset ALL compared with a control group of their parents and other relatives.
in
Studies of the incidence of abnormal der-
matoglyphic patterns in various cancers have reported conflicting results. 4-12- Most studies have not separated populations by age, diagnosis, or whether creases were bilateral or unilateral. Only one studylo addressed dermatoglyphic alterations, specifically fingertip patterns, as prognostic indicators. It is appropriate to expect that if the initial insult predisposing to or resulting in a leukemic change occurred in utero, the leukemia would be expressed within the first 6 years of life. 13 Consequently, if expression of a clinical marker associated with leukemic changes in utero is examined, it would most likely be evidenced in the first 6 years of life. Data from Oorthuys et al12 reflect this assumption. Of the children diagnosed with ALL in the first 5 years, 60% had aberrant creases (both unilateral and bilateral creases) compared with 26% of con~ trols. Of children diagnosed with ALL after 5 years of age, the frequency of aberrant creases was 21 % , a proportion comparable to the control group. The lack of segregation of age groups in other studies may well have influenced the findings. The presence of unilateral versus bilateral creases may also be significant in research on leukemia and palmar creases. In nature, bilateral expression of a trait may indicate hereditary rather than spontaneous abnormalities, as is the ’
Methods
..
Children diagnosed with ALL at or before age 6 years (cases) were compared to their unaffected relatives (controls). Cases were chosen from all surviving patients at the Children’s Hospital at. Stanford Leukemia Clinic who were diagnosed with ALL at age 6 years or younger between 1973 and 1983. A total of 71 children were diagnosed and/or treated with ALL at Children’s Hospital at Stanford who were 6 years of age or younger in this period. All diagnoses were established by bone marrow morphology. There were no children with Down’s syndrome, Bloom’s syndrome, Fanconi’s anemia, or any other known chromosomal, genetic, or congenital abnormality. Survival time, number of relapses, current state of the disease, sex, and race were not criteria for inclusion or exclusion. Controls consisted of the cancer-free siblings, half-siblings, parents, aunts, uncles, and first cousins of the cases. Relatives were grouped into three subsets: (a) siblings and half-siblings, (b) parents, and (c) parents and siblings. For those children who were followed on a regular basis, or who were recently diagnosed,’ each family was contacted in the clinic at the time of the patient’s appointment Contacts were , made by mail for those families whose children were no
longer
seen on a
Downloaded from jpo.sagepub.com at INDIANA UNIV on May 9, 2015
frequent
or
regular
32
basis. Written information on the study was provided to the family at the time of the first contact in the form of a letter that described the nature of the study as well as the risks and benefits. Written informed consent, including a request for access to patient medical records, was ob-
sample included 25 families of 26 children diagnosed with ALL at age 6 years or less. The sample included 13 males and 13 females. There was one pair of siblings with ALL. The sample also included 20 whites, four Hispanics,
tained. Code numbers were assigned to assure confidentiality. Families were given a copy of the Research Subject’s Bill of Rights separately from the consent form and were advised of their right to drop out of the study at any time for any
were
reason.
Appointments were scheduled at the families’ convenience, either in their homes
or at the the nature of the During appointment, were reviewed discussed. and study objectives All family members were encouraged to ask
clinic.
the
questions. Prints of the palms and fingers of both hands of all participating patients and relatives were obtained using a rotary slab and card holder. The ink method was used for clarity of impressions. A waterless, nontoxic hand cleaner was used to immediately remove the ink. Dermal patterns of both hands were analyzed according to standard procedures using the classifcations developed by Wertelecki 14 (Fig 1). Handprints were then double-coded and rearranged so that all children’s handprints were together and all adults’ handprints were together. The 200 handprints (two prints for each subject) were read separately by one of the researchers and by a doctoral student who had no prior knowledge as to which prints were those of affected children, parents, siblings, or other relatives. Results were compared and there was agreement for 187 of 200 prints. The 13 in question had been borderline prints. These were closely examined by both readers to determine whether the proximal palmar flexion crease extended beyond the imaginary axis of the fifth digit. Agreement was reached after close examination in all of the cases.
Results Of the original sample of 71 patients identified appropriate to this study, seven moved out of the area or were followed in other hospitals. A total of 29 families agreed to participate. Of these, three dropped out of the study and one child died before data could be obtained. The as
final
two Asians, and no blacks. Three of the children
born out of the United States (one in Iraq, in the Philippines, and one in Vietnam). One of the three children diagnosed at 1 year of age had bilateral aberrant creases. Two of the three children diagnosed at 2 years of age had bilateral aberrant creases and one had unilateral aberrant creases. All three children diagnosed at 3 years of age had bilateral aberrant creases. One of the three children diagnosed at 4 years of age had unilateral aberrant creases. None of the four children diagnosed at 5 years of age had aberrant creases. One of the four children diagnosed at 6 years of age had bilateral aberrant creases, and one had unilateral aberrant one
creases.
Of the six children with ALL and bilateral abwith bilateral aberrant creases. No other relatives of these children demonstrated aberrant creases. Of the three children with ALL and unilateral aberrant creases, one had a mother with unilateral aberrant creases-and one had two younger siblings with unilateral aberrant creases. Of the 15 children with ALL and no aberrant creases, three had older siblings with bilateral aberrant creases, one had a paternal aunt with bilateral aberrant creases, three had mothers with unilateral aberrant creases, and one had a paternal aunt with unilateral aberrant creases. errant creases, one had a father
Relationships
of Aberrant Creases to ALL
It was
hypothesized that children with ALL onor younger would have significantly more bilateral and unilateral aberrant palmar creases than their parents, siblings, and firstdegree relatives. set 6 years
Presence or absence of aberrant creases in ALL children and their family members is shown in Table 1. Aberrant creases do not appear to cluster in families, ie, ALL children with aberrant creases are not more likely to have relatives with aberrant creases than are ALL children with normal handprints. Findings summarized in Table 2 support the
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33
FIGURE 1. Schematic representation of palmar flexion crease patterns. (Reprinted with permission from Wertelecki W: The Simian and Sydney Crease, in Wertelecki W, Plato CC (eds): The National Foundation-IHarch of Dimes, Birth Defects: Original Article Series: Vol 1(6): Dermatoglyphics-Fifty Years Later. Copyright @ by Wiley-Uss.
1979.)
hypothesis that children with ALL age 6 years or younger are significantly more likely to have bilateral or unilateral aberrant creases than their parents and first-degree relatives. They do not
more aberrant creases than their siblings. Estimates of the relative risk using the odds ratio and chi squares tested at the .05 level of significance were computed comparing groups.
have
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34
TABLE 1 Aberrant Creases in Relatives of ALL Children
TABLE 3 Types of Aberrant Creases in ALL Cases and Controls ’
Both
contribute and ALL. The distribution of Sydney and Simian creases among patients and controls with aberrant creases is shown in Table 3. The relative frequency of Sydney versus Simian creases is similar for cases and controls: about 75% of subjects with aberrant creases have Sydney creases. Thus, the association between each type of crease and ALL will be similar, but the power to detect the elevated risk will be’lower.
Sydney
and Simian
creases
to the association of aberrant
creases
(CNS) involvement in their disease. Each of the following children had ALL and bilateral aberrant creases.
’
of Aberrant Creases to Central Nervous System Involvement Among ALL Patients
Relationships
1. One child was diagnosed at 2 years of age. He had a CNS relapse and died during the course of the study. He had one younger
sibling and his mother had a spontaneous abortion at 6 weeks in 1978, 1 year after the affected child’s birth. There was no family history of cancer. 2. One child was diagnosed at 1.5 years of age. He had a CNS relapse and is surviv-
ing.
’ The six children with ALL and bilateral aber- . rant creases were compared with ALL children without bilateral aberrant creases with respect to age at diagnosis and central nervous system
3.
’
’
TABLE 2 Relative Risks and Chi Squares for Association Between ALL and Aberrant Creases
4.
5.
6.
Abbreviations: RR, relative risks; lYS, not
significant.
He has two older maternal half-sisters
who were not available for the study. His maternal grandfather died of cancer of the pancreas. No other family members have a history of cancer One child was born in Vietnam and diagnosed in the Philippines in a refugee camp at age 6 years. He had no CNS ivolvement. He was the only ALL child with bilateral aberrant creases whose parent (father) also has bilateral aberrant creases. There is no known family history of cancer. One child was diagnosed during the course of the study at age 2.5 years. She is currently in first remission with no known CNS involvement Family history of cancer is not available. One child was born in Iraq and diagnosed at 1.5 years of age while the family was visiting in the United States. He had CNS involvement and died during the course of the study. There is no known family history of cancer. One child was 3 years old at time of diagnosis. She remained in remission after initial therapy and had no CNS involvement. She is doing well after therapy. Her maternal grandmother died of breast cancer, a
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35
maternal aunt has stomach cancer, and a maternal uncle has cancer of the rectum. Her paternal grandfather died of lung canand a paternal aunt died of cancer, type unknown. She has a sibling 2 years younger who is healthy. Her mother was given drugs to help prolong both pregnancies from the second or third months for 3-4 months during the pregnancies. cer
Of the 18 children with ALL without bilateral only one child had CNS involvement. The child is from the only family with two affected children. The child with CNS involvement is the oldest of four siblings. He was diagnosed at 6 years of age and had his first CNS relapse at age 9. He is currently doing well on therapy. His youngest sibling was diagnosed 2 years afterward and has had no CNS involvement to date. While neither of the two affected children had aberrant creases, one healthy sibling did have bilateral aberrant creases. The family lives in a rural area in northern California. They are particularly health oriented, ie, they grow their own vegetables, fruits, etc, and moved to an isolated area years before their children were diagnosed in order to avoid harmful carcinogens such as pollutants, pesticides, and chemically treated foods. Conversely, both parents have a long history of hallucinogenic drug use. The mother’s paternal aunt has had breast cancer, a maternal great aunt died at 81 years of age due to a lymphoma, and a maternal aunt died of leukemia in 1960 at age 12 years. Analysis of the data supports the hypothesis that children with ALL, onset 6 years or younger, will have a significantly greater incidence of bilateral aberrant creases than their parents, relatives, and all controls as a group. However, when compared with their siblings alone, the data showed no significant difference in bilateral crease frequency. This is consistent with previous research in relation to siblings.t2 Cancer is a complex phenomenon and characteristics of the immune system influencing resistance to malignancy are unclear. An interaction between the immune system and the insult leading to cell susceptibility to malignancy may be necessary to create a malignancy. If the insult alone occurs, it may effectively alter palmar crease patterns without a resultant cancer. In
aberrant creases,
this case, siblings might be expected to experience similar events (viral insults, chemical carcinogens, etc, in utero), but differences in their immune systems would avert the development of leukemia. Only 19 siblings were available for study. The incidence of bilateral aberrant creases as well as unilateral aberrant creases in siblings was intermediate between cases and all other relative controls. Although this is not an adequate sample from which to draw inferences, it is of note that none of the cousins of the cases demonstrated any aberrant creases. The aberrant creases demonstrated did not seem to be accounted for by differences in parental palmar crease patterns. Of the children with ALL who demonstrated bilateral aberrant creases, one parent (father) had bilateral aberrant creases and none had unilateral aberrant creases. Of the children with ALL who demonstrated unilateral aberrant creases, no parents had bilateral aberrant creases and only one parent (mother) had a unilateral aberrant crease (Table 2). Thus aberrant creases do not appear to be inherited in this sample. The significant differences in bilateral aberrant creases in ALL children compared with controls support the theory that an insult occurred during pregnancy to alter palmar creases. The crucial interval is probably the first trimester of pregnancy. This finding is in keeping with the two-hit hypothesis described byAltman and SCDwartz13 as &dquo;a mutation model of childhood cancer which is dependent upon two discrete mutational events to induce carcinogenesis.&dquo; This hypothesis includes a two-step progression: -
’
.
1. In step one, the initiator phase, cells become precancerous, or susceptible to becoming cancerous. This may occur through inheritance (eg, autosomal dominant disease such as retinoblastoma), or somatically by radiation, viral carcinogens, or chemical carcinogens.1f this first mutation is in the germ line, it will be present in all somatic cells that are still capable of normal differentiation. If, for these ALL patients, the event is somatic but during early embryonic development, all daughter cells of the altered cell will be altered similarly. In
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36
this work, mutations that are known to alter palmar creases were excluded from the
centage of males would be expected (up to two thirds of cases), whereas the study sample consisted of 50% males and 50% females. Six males (46%) and three females (25%) demonstrated aberrant creases. In comparison, four male controls (13%) and six female controls ( 3% ) demonstrated aberrant creases. The reason for the higher percentage of affected males with aberrant creases is not clear, but the differ-
study. 2. In step two, the promoter phase, cells become cancerous. This is somatic and may be random for ALL in these children. If this mutation arises before fertilization or during embryologic development, it may influence the formation of palmar volar pads, with a resultant increase in the incidence of aberrant palmar creases in children with early onset ALL.
Hypothesis
ences are not
2 stated that children with ALL,
onset 6 years or younger, would be more likely to have unilateral aberrant creases than their
parents, siblings, and relatives. There
significant increase Limitations of the
in unilateral
creases
was no
alone.
Study
The fact that the cases in this study are relatively long-term ALL survivors is a major limiting factor. Characteristics of nonsurvivors may have affected the results. Their disease may have included CNS involvement or may have for other unknown reasons been more virulent. One of the factors contributing to poor prognosis is the age of the child at onset. Children diagnosed under age 2 years do not tend to do as well as those children diagnosed between ages 2 and 1 D years. Children with very early onset may be those whose leukemia developed during the embryonic stage, a period of rapid cell proliferation. If this were the case, a higher incidence of aberrant creases among ALL cases might be expected due to the increased likelihood that fetal volar pads would be affected during embryonic development. The underrepresehtation of very long-term survivors may also have had bearing on the results of the study. Long-term survivor families, who did not attend the clinic on a regular basis, were contacted by mail. The response rate was low in this group. It is not clear in which direction the results may have been influenced by the underrepresentation of this sample. The study sample was not representative of the total leukemia population of children diagnosed at age 6 years or younger. A higher per-
significant.
No black families participated in the study, although there were black families in the clinic population. This factor and the fact that cases followed at Children’s Hospital at Stanford may be different from cases followed at other oncology clinics may further limit the ability to draw general conclusions from these findings. As Plato and Wertelecki 15 point out, there are presently no available formal means of teaching in dermatoglyphic techniques. While interrater reliability was high (.94), it would have been useful to have had more clearly established guidelines and practice in the reading of palmar crease patterns. This would have added to the reliability and validity of findings. ’
Relationships of Aberrant Creases to CNS Involvement in ALL Patients The percentage of ALL patients with bilateral aberrant creases and CNS involvement (50%), compared with ALL patients without aberrant creases who had CNS involvement (5% ), was an unexpected outcome of the study. One possible explanation of this finding derives from the embryological development of palmar creases. If the initial insult occurs during early development of the volar pads, the time frame would include the first 6 to 8 weeks of intrauterine life. During these first weeks, the CNS is particularly vulnerable to teratogenic agents. 16 If the leukemic , change has occurred by that time, leukemic or preleukemic cells may enter the CNS because the blood-brain barrier may not yet be adequate to protect the CNS from leukemic infiltration. A second possibility is that the insult also results in a defect in the blood-brain barrier. This question further suggests that embryonic development of leukemia might be associated with an increased incidence of CNS involvement and poor prog-
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37
nosis. This portion of the population would be expected also to demonstrate an increased incidence of aberrant creases. As this population would include the nonsurvivors, the question is of particular interest.
Implications
for
Nursing
outcomes.
a study to determine any increased risk of CNS complications in children with aberrant creases could be carried out by obtaining handprints of children diagnosed with ALL at age 6 or before. Children with and without aberrant creases would be followed throughout the course of their illness to assess the incidence of CNS involvement. ’
for
Nursing Practice
Increased risk for many disorders are associated with physical characteristics not immediately identified as related (urinary tract problems with earlobe shape, breast cancer with type of
’
like an art project to the child. Only child in the study refused to participate, in spite of encouragement from his family. The authors immediately accepted his refusal and advised the parents that it seemed important to allow him to feel some measure of control over what happened to his body during the clinic visit As he was not able to refuse blood work, chemotherapy, bone marrow sampling, or spinal taps, here was one area where he actually could make a choice that would be respected by all those in control. Most children and families eagerly made several sets of prints to hang up at home. Several parents took extra sets to include in their identification files on their children (set up by many local authorities where fingerprinting of children is available). Children and their families also.enjoyed comparing prints to see whose matched and where differences were. Many children took copies of their prints to school for show-and-tell to share their experience with their peers. In general, children and their families actually enjoyed this part of the clinic visit and had something tangible and positive to bring home with them. one
Additionally,
Implications
families, often find their visits traumatic and painful. Obtaining prints is not painful and seems more
Research
A prospective study using handprints obtained at birth from a large sample of infants and their families would be useful in helping to determine the relationship between ALL and aberrant creases. Children would be followed through their sixth year in order to accurately assess
for
establishing a relationship with a newly diagnosed child and family as well as an enjoyable time in the visit. Children involved in the study, as well as their means
cerumen and with body shape). Until it is determined whether a substantial correlation exists between type of palmar creases and risk of ALL, and/or risk of CNS involvement, nurses in the pediatric oncology setting continue to make a significant contribution to the treatment plan through their assessments. Nurses have the opportunity to obtain handprints from the affected child and his or her family in both the clinic and acute care settings. Not only may this noninvasive part of the assessment provide useful information about children with ALL, it provides a
-
’
Summary
.
of handprints to determine dermal patterns is a noninvasive means of obtaining potentially significant information. Substantiation of the relationship of dermal patterns and cancer outcomes through further research could provide a simple, inexpensive means of screening children for possible risk and to provide for earlier intervention and, ultimately, better out-
The
comes.
use
-
References 1. Altman AJ, Schwartz AD:
Malignant Diseases of
In-
fancy, Childhood and Adolescence. Philadelphia, PA, Saunders, 1978 2. Thompson JS, Thompson MW: Genetics in Medicine. Philadelphia, PA, Saunders, 1980 3. Dar H, Jaffe M: Dermatoglyphic and palmar-crease al-
as indicators of early intra-uterine insult in mental retardation. Dev Med Child Neurol 25:53-59, 1983 4. Menser MA, Purvis-Smith SG: Dermatoglyphic defects in children with leukemia. Lancet 1:1076-1078, 1969
terations
5. Rosner F: Dermatoglyphics in leukaemic children. Lan2:272-273, 1969
cet
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38
6. Wertelecki W, Plato CC, Fraumeni JF: Dermatoglyphics of leukaemia. Lancet 2:806-807, 1969 7. Nora AH, Nora YY, Fembach DJ: Dermatoglyphics and leukemia. Lancet 2:905-906, 1969 8. Verbov JL: Dermatoglyphs in leukaemia. J Med Genet
7:125-130, 1970 9. Purvis-Smith SG, Menser MA: Dermatoglyphics in children with acute leukaemia. Br Med J 4:646-648, 1973 10. Till M, Larrauri S, Smith PG: Dermatoglyphics in childhood leukaemia: A guide to prognosis and aetiology? Br J Cancer 37:1063-1073, 1978 11. Oorthuys AM, De Vaan GA, Behrend H, et al: Dermatoglyphics in childhood leukemia, in Wertelecki W, Plato CC (eds): The National Foundation—March of Dimes, Birth Defects : Original Article Series: Vol 1(6): Dermatoglyphics— Fifty Years Later. New York, NY, Uss, 1979, pp 721-735
12. Oorthuys AM, De Vaan GA, Behrendt H, et al: Palmar flexion creases in childhood neoplasia. Cancer 43:749-759, 1979 13. Stewart A: Aetiology of childhood malignancies: Congenitally determined leukaemias. Br Med J 1:452-560, 1961 14. Wertelecki W: The Simian and Sydney crease, in Wertelecki W, Plato CC (eds): The National Foundation— March of Dimes, Birth Defects: Original Article Series: Vol 1(6): Dermatoglyphics—Fifty Years Later. New York, NY, Wiley-Liss, 1979, pp 455-471 15. Plato CC, Wertelecki W: Changing trends in dermatoglyphic research, in Bartsocas CS (ed): Progress in Clinical and Biological Research. Vol 84: Progress in Dermatoglyphic Research. New York, NY, Liss, 1982, pp 1-11 16. Jensen M, Benson R, Bobak I: Maternity Care: The Nurse and the Family (ed 2). St. Louis, MO, Mosby, 1981
Downloaded from jpo.sagepub.com at INDIANA UNIV on May 9, 2015
Cellular features of acute lymphocytic leukemia (ALL) in children suggest that it originates in abnormal embryogenesis. Because palmar flexion creases develop in the embryo at the same time as the blood-forming cells, and because both arise from mesodermal tissue, insults to the embryo that may lead to leukemic changes in the blood-forming cells may also result in aberrant palmar crease patterns. This study investigated the relationship between aberrant palmar creases and ALL in children who developed leukemia at age 6 years or younger. Odds ratios and chi squares demonstrated significant differences in bilateral aberrant palmar creases between ALL children and relatives (P < .025). Differences were not explained by familial clustering of aberrant creases. These results support the theory that the insult occurred during pregnancy, probably in the first trimester. There were no significant differences in either bilateral or unilateral aberrant palmar creases between ALL children and their siblings. All children with bilateral aberrant creases had a higher incidence of central nervous system involvement (50%) than those without bilateral aberrant creases (6%). This may reflect a preleukemic change in utero before the time the blood-brain barrier has been established. © 1991 by Association of Pediatric Oncology Nurses.
LEUKEMIAS comprise approximately 15% to 40% of major malignancies in children under 10 years of age. Of these, acute lymphocytic leukemia (ALL} accounts for 60% to 70% of cases. Treatment of the leukemias has improved, but their etiology remains unclear. In adults, tumors seem to develop through dedifferentiation of cells in mature tissue. Cellular features of childhood tumors suggest that they originated in abnormal embryogenesis.1 Palmar creases are determined during the same period of embryological development as the’blood-forming cells; both arise from meso-
THE
From the Department of Nursing, San Jose State University, San Jose, CA and Children’s Hospital at Stanford, Palo Alto, CA Address reprint
to Joan Edelstein, RN, DrPH, San Jose State University, San Jose, CA 95192-0057. ©1991 by Association of Pediatric Oncology Nurses.
requests
Department of Nursing,
1043-4542/91/0801-0005$03.00/0
dermal tissue. It is possible that abnormal growth-regulating factors may be reflected in palmar creases as well as_ in those bloodforming cells that become malignant.
Dermatoglyphics
and Disease
Dermatoglyphics refer to the epidermal ridge patterns of the palms, fingers, soles, and toes. The transverse flexion creases of the palm were not originally included in the definition of dermatoglyphics, but over time fell under the category of dermatoglyphics and are so included in this study. Development of the transverse flexion creases of the palm are the target of this study. Palmar creases are formed by a combination of fetal volar pad placement and growth of the fetal hand. Volar pads are mounds of mesodermal tissue on the fingertips, between the fingers on the distal palm, and on the hypothenar area of the palm. They may be clearly seen in the fetus during the first trimester as cherry-
30
Downloaded from jpo.sagepub.com at INDIANA UNIV on May 9, 2015
31
shaped &dquo;lumps&dquo; distributed over the fingers and palm. Abnormal palmar crease patterns have been identified in those suffering from a number of chromosomal abnormalities as well as those with nongenetic diseases. These include Down’s syndrome (trisomy 21), trisomy 18, and trisomy 13? Dar and Jaffe3 identified aberrant bilateral palmar crease patterns in 15% of patients with mental retardation of congenital origin and aberrant unilateral crease patterns in 57% of those patients (n 200). In the same study, 1.2% of normal, healthy school-age controls had bilateral aberrant creases, and 8.2% had unilateral aberrant creases (n 500). They conclude that =
=
Dermatoglyphic and palmar-crease patterns develop during the first trimester. Events causing fetal insult during this period may results in unusual dermatoglyphic or palmar-crease patterns?
-
in retinoblastoma and Wilms’ tumor.’ Acto Altman ~ Schwartz,~ patients with bilateral forms of Wilms’ tumors and retinoblastoma are considered to have the hereditary form of the disease while those with unilateral tumors are, for the most part, considered to have the case
cording
disease
as
the result of spontaneous, ie, nonhe-
reditary mutations. If laterality of palmar crease patterns is a reflection of the significance of a prenatal phenomenon, there should be a significant difference in the incidence of bilateral palmar creases cases versus controls and that difference should be greater than the difference in unilateral aberrant creases. . The purpose of this study is to determine whether there is an increased incidence of bilateral aberrant palmar flexion creases in children with early onset ALL compared with a control group of their parents and other relatives.
in
Studies of the incidence of abnormal der-
matoglyphic patterns in various cancers have reported conflicting results. 4-12- Most studies have not separated populations by age, diagnosis, or whether creases were bilateral or unilateral. Only one studylo addressed dermatoglyphic alterations, specifically fingertip patterns, as prognostic indicators. It is appropriate to expect that if the initial insult predisposing to or resulting in a leukemic change occurred in utero, the leukemia would be expressed within the first 6 years of life. 13 Consequently, if expression of a clinical marker associated with leukemic changes in utero is examined, it would most likely be evidenced in the first 6 years of life. Data from Oorthuys et al12 reflect this assumption. Of the children diagnosed with ALL in the first 5 years, 60% had aberrant creases (both unilateral and bilateral creases) compared with 26% of con~ trols. Of children diagnosed with ALL after 5 years of age, the frequency of aberrant creases was 21 % , a proportion comparable to the control group. The lack of segregation of age groups in other studies may well have influenced the findings. The presence of unilateral versus bilateral creases may also be significant in research on leukemia and palmar creases. In nature, bilateral expression of a trait may indicate hereditary rather than spontaneous abnormalities, as is the ’
Methods
..
Children diagnosed with ALL at or before age 6 years (cases) were compared to their unaffected relatives (controls). Cases were chosen from all surviving patients at the Children’s Hospital at. Stanford Leukemia Clinic who were diagnosed with ALL at age 6 years or younger between 1973 and 1983. A total of 71 children were diagnosed and/or treated with ALL at Children’s Hospital at Stanford who were 6 years of age or younger in this period. All diagnoses were established by bone marrow morphology. There were no children with Down’s syndrome, Bloom’s syndrome, Fanconi’s anemia, or any other known chromosomal, genetic, or congenital abnormality. Survival time, number of relapses, current state of the disease, sex, and race were not criteria for inclusion or exclusion. Controls consisted of the cancer-free siblings, half-siblings, parents, aunts, uncles, and first cousins of the cases. Relatives were grouped into three subsets: (a) siblings and half-siblings, (b) parents, and (c) parents and siblings. For those children who were followed on a regular basis, or who were recently diagnosed,’ each family was contacted in the clinic at the time of the patient’s appointment Contacts were , made by mail for those families whose children were no
longer
seen on a
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frequent
or
regular
32
basis. Written information on the study was provided to the family at the time of the first contact in the form of a letter that described the nature of the study as well as the risks and benefits. Written informed consent, including a request for access to patient medical records, was ob-
sample included 25 families of 26 children diagnosed with ALL at age 6 years or less. The sample included 13 males and 13 females. There was one pair of siblings with ALL. The sample also included 20 whites, four Hispanics,
tained. Code numbers were assigned to assure confidentiality. Families were given a copy of the Research Subject’s Bill of Rights separately from the consent form and were advised of their right to drop out of the study at any time for any
were
reason.
Appointments were scheduled at the families’ convenience, either in their homes
or at the the nature of the During appointment, were reviewed discussed. and study objectives All family members were encouraged to ask
clinic.
the
questions. Prints of the palms and fingers of both hands of all participating patients and relatives were obtained using a rotary slab and card holder. The ink method was used for clarity of impressions. A waterless, nontoxic hand cleaner was used to immediately remove the ink. Dermal patterns of both hands were analyzed according to standard procedures using the classifcations developed by Wertelecki 14 (Fig 1). Handprints were then double-coded and rearranged so that all children’s handprints were together and all adults’ handprints were together. The 200 handprints (two prints for each subject) were read separately by one of the researchers and by a doctoral student who had no prior knowledge as to which prints were those of affected children, parents, siblings, or other relatives. Results were compared and there was agreement for 187 of 200 prints. The 13 in question had been borderline prints. These were closely examined by both readers to determine whether the proximal palmar flexion crease extended beyond the imaginary axis of the fifth digit. Agreement was reached after close examination in all of the cases.
Results Of the original sample of 71 patients identified appropriate to this study, seven moved out of the area or were followed in other hospitals. A total of 29 families agreed to participate. Of these, three dropped out of the study and one child died before data could be obtained. The as
final
two Asians, and no blacks. Three of the children
born out of the United States (one in Iraq, in the Philippines, and one in Vietnam). One of the three children diagnosed at 1 year of age had bilateral aberrant creases. Two of the three children diagnosed at 2 years of age had bilateral aberrant creases and one had unilateral aberrant creases. All three children diagnosed at 3 years of age had bilateral aberrant creases. One of the three children diagnosed at 4 years of age had unilateral aberrant creases. None of the four children diagnosed at 5 years of age had aberrant creases. One of the four children diagnosed at 6 years of age had bilateral aberrant creases, and one had unilateral aberrant one
creases.
Of the six children with ALL and bilateral abwith bilateral aberrant creases. No other relatives of these children demonstrated aberrant creases. Of the three children with ALL and unilateral aberrant creases, one had a mother with unilateral aberrant creases-and one had two younger siblings with unilateral aberrant creases. Of the 15 children with ALL and no aberrant creases, three had older siblings with bilateral aberrant creases, one had a paternal aunt with bilateral aberrant creases, three had mothers with unilateral aberrant creases, and one had a paternal aunt with unilateral aberrant creases. errant creases, one had a father
Relationships
of Aberrant Creases to ALL
It was
hypothesized that children with ALL onor younger would have significantly more bilateral and unilateral aberrant palmar creases than their parents, siblings, and firstdegree relatives. set 6 years
Presence or absence of aberrant creases in ALL children and their family members is shown in Table 1. Aberrant creases do not appear to cluster in families, ie, ALL children with aberrant creases are not more likely to have relatives with aberrant creases than are ALL children with normal handprints. Findings summarized in Table 2 support the
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33
FIGURE 1. Schematic representation of palmar flexion crease patterns. (Reprinted with permission from Wertelecki W: The Simian and Sydney Crease, in Wertelecki W, Plato CC (eds): The National Foundation-IHarch of Dimes, Birth Defects: Original Article Series: Vol 1(6): Dermatoglyphics-Fifty Years Later. Copyright @ by Wiley-Uss.
1979.)
hypothesis that children with ALL age 6 years or younger are significantly more likely to have bilateral or unilateral aberrant creases than their parents and first-degree relatives. They do not
more aberrant creases than their siblings. Estimates of the relative risk using the odds ratio and chi squares tested at the .05 level of significance were computed comparing groups.
have
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34
TABLE 1 Aberrant Creases in Relatives of ALL Children
TABLE 3 Types of Aberrant Creases in ALL Cases and Controls ’
Both
contribute and ALL. The distribution of Sydney and Simian creases among patients and controls with aberrant creases is shown in Table 3. The relative frequency of Sydney versus Simian creases is similar for cases and controls: about 75% of subjects with aberrant creases have Sydney creases. Thus, the association between each type of crease and ALL will be similar, but the power to detect the elevated risk will be’lower.
Sydney
and Simian
creases
to the association of aberrant
creases
(CNS) involvement in their disease. Each of the following children had ALL and bilateral aberrant creases.
’
of Aberrant Creases to Central Nervous System Involvement Among ALL Patients
Relationships
1. One child was diagnosed at 2 years of age. He had a CNS relapse and died during the course of the study. He had one younger
sibling and his mother had a spontaneous abortion at 6 weeks in 1978, 1 year after the affected child’s birth. There was no family history of cancer. 2. One child was diagnosed at 1.5 years of age. He had a CNS relapse and is surviv-
ing.
’ The six children with ALL and bilateral aber- . rant creases were compared with ALL children without bilateral aberrant creases with respect to age at diagnosis and central nervous system
3.
’
’
TABLE 2 Relative Risks and Chi Squares for Association Between ALL and Aberrant Creases
4.
5.
6.
Abbreviations: RR, relative risks; lYS, not
significant.
He has two older maternal half-sisters
who were not available for the study. His maternal grandfather died of cancer of the pancreas. No other family members have a history of cancer One child was born in Vietnam and diagnosed in the Philippines in a refugee camp at age 6 years. He had no CNS ivolvement. He was the only ALL child with bilateral aberrant creases whose parent (father) also has bilateral aberrant creases. There is no known family history of cancer. One child was diagnosed during the course of the study at age 2.5 years. She is currently in first remission with no known CNS involvement Family history of cancer is not available. One child was born in Iraq and diagnosed at 1.5 years of age while the family was visiting in the United States. He had CNS involvement and died during the course of the study. There is no known family history of cancer. One child was 3 years old at time of diagnosis. She remained in remission after initial therapy and had no CNS involvement. She is doing well after therapy. Her maternal grandmother died of breast cancer, a
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35
maternal aunt has stomach cancer, and a maternal uncle has cancer of the rectum. Her paternal grandfather died of lung canand a paternal aunt died of cancer, type unknown. She has a sibling 2 years younger who is healthy. Her mother was given drugs to help prolong both pregnancies from the second or third months for 3-4 months during the pregnancies. cer
Of the 18 children with ALL without bilateral only one child had CNS involvement. The child is from the only family with two affected children. The child with CNS involvement is the oldest of four siblings. He was diagnosed at 6 years of age and had his first CNS relapse at age 9. He is currently doing well on therapy. His youngest sibling was diagnosed 2 years afterward and has had no CNS involvement to date. While neither of the two affected children had aberrant creases, one healthy sibling did have bilateral aberrant creases. The family lives in a rural area in northern California. They are particularly health oriented, ie, they grow their own vegetables, fruits, etc, and moved to an isolated area years before their children were diagnosed in order to avoid harmful carcinogens such as pollutants, pesticides, and chemically treated foods. Conversely, both parents have a long history of hallucinogenic drug use. The mother’s paternal aunt has had breast cancer, a maternal great aunt died at 81 years of age due to a lymphoma, and a maternal aunt died of leukemia in 1960 at age 12 years. Analysis of the data supports the hypothesis that children with ALL, onset 6 years or younger, will have a significantly greater incidence of bilateral aberrant creases than their parents, relatives, and all controls as a group. However, when compared with their siblings alone, the data showed no significant difference in bilateral crease frequency. This is consistent with previous research in relation to siblings.t2 Cancer is a complex phenomenon and characteristics of the immune system influencing resistance to malignancy are unclear. An interaction between the immune system and the insult leading to cell susceptibility to malignancy may be necessary to create a malignancy. If the insult alone occurs, it may effectively alter palmar crease patterns without a resultant cancer. In
aberrant creases,
this case, siblings might be expected to experience similar events (viral insults, chemical carcinogens, etc, in utero), but differences in their immune systems would avert the development of leukemia. Only 19 siblings were available for study. The incidence of bilateral aberrant creases as well as unilateral aberrant creases in siblings was intermediate between cases and all other relative controls. Although this is not an adequate sample from which to draw inferences, it is of note that none of the cousins of the cases demonstrated any aberrant creases. The aberrant creases demonstrated did not seem to be accounted for by differences in parental palmar crease patterns. Of the children with ALL who demonstrated bilateral aberrant creases, one parent (father) had bilateral aberrant creases and none had unilateral aberrant creases. Of the children with ALL who demonstrated unilateral aberrant creases, no parents had bilateral aberrant creases and only one parent (mother) had a unilateral aberrant crease (Table 2). Thus aberrant creases do not appear to be inherited in this sample. The significant differences in bilateral aberrant creases in ALL children compared with controls support the theory that an insult occurred during pregnancy to alter palmar creases. The crucial interval is probably the first trimester of pregnancy. This finding is in keeping with the two-hit hypothesis described byAltman and SCDwartz13 as &dquo;a mutation model of childhood cancer which is dependent upon two discrete mutational events to induce carcinogenesis.&dquo; This hypothesis includes a two-step progression: -
’
.
1. In step one, the initiator phase, cells become precancerous, or susceptible to becoming cancerous. This may occur through inheritance (eg, autosomal dominant disease such as retinoblastoma), or somatically by radiation, viral carcinogens, or chemical carcinogens.1f this first mutation is in the germ line, it will be present in all somatic cells that are still capable of normal differentiation. If, for these ALL patients, the event is somatic but during early embryonic development, all daughter cells of the altered cell will be altered similarly. In
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36
this work, mutations that are known to alter palmar creases were excluded from the
centage of males would be expected (up to two thirds of cases), whereas the study sample consisted of 50% males and 50% females. Six males (46%) and three females (25%) demonstrated aberrant creases. In comparison, four male controls (13%) and six female controls ( 3% ) demonstrated aberrant creases. The reason for the higher percentage of affected males with aberrant creases is not clear, but the differ-
study. 2. In step two, the promoter phase, cells become cancerous. This is somatic and may be random for ALL in these children. If this mutation arises before fertilization or during embryologic development, it may influence the formation of palmar volar pads, with a resultant increase in the incidence of aberrant palmar creases in children with early onset ALL.
Hypothesis
ences are not
2 stated that children with ALL,
onset 6 years or younger, would be more likely to have unilateral aberrant creases than their
parents, siblings, and relatives. There
significant increase Limitations of the
in unilateral
creases
was no
alone.
Study
The fact that the cases in this study are relatively long-term ALL survivors is a major limiting factor. Characteristics of nonsurvivors may have affected the results. Their disease may have included CNS involvement or may have for other unknown reasons been more virulent. One of the factors contributing to poor prognosis is the age of the child at onset. Children diagnosed under age 2 years do not tend to do as well as those children diagnosed between ages 2 and 1 D years. Children with very early onset may be those whose leukemia developed during the embryonic stage, a period of rapid cell proliferation. If this were the case, a higher incidence of aberrant creases among ALL cases might be expected due to the increased likelihood that fetal volar pads would be affected during embryonic development. The underrepresehtation of very long-term survivors may also have had bearing on the results of the study. Long-term survivor families, who did not attend the clinic on a regular basis, were contacted by mail. The response rate was low in this group. It is not clear in which direction the results may have been influenced by the underrepresentation of this sample. The study sample was not representative of the total leukemia population of children diagnosed at age 6 years or younger. A higher per-
significant.
No black families participated in the study, although there were black families in the clinic population. This factor and the fact that cases followed at Children’s Hospital at Stanford may be different from cases followed at other oncology clinics may further limit the ability to draw general conclusions from these findings. As Plato and Wertelecki 15 point out, there are presently no available formal means of teaching in dermatoglyphic techniques. While interrater reliability was high (.94), it would have been useful to have had more clearly established guidelines and practice in the reading of palmar crease patterns. This would have added to the reliability and validity of findings. ’
Relationships of Aberrant Creases to CNS Involvement in ALL Patients The percentage of ALL patients with bilateral aberrant creases and CNS involvement (50%), compared with ALL patients without aberrant creases who had CNS involvement (5% ), was an unexpected outcome of the study. One possible explanation of this finding derives from the embryological development of palmar creases. If the initial insult occurs during early development of the volar pads, the time frame would include the first 6 to 8 weeks of intrauterine life. During these first weeks, the CNS is particularly vulnerable to teratogenic agents. 16 If the leukemic , change has occurred by that time, leukemic or preleukemic cells may enter the CNS because the blood-brain barrier may not yet be adequate to protect the CNS from leukemic infiltration. A second possibility is that the insult also results in a defect in the blood-brain barrier. This question further suggests that embryonic development of leukemia might be associated with an increased incidence of CNS involvement and poor prog-
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37
nosis. This portion of the population would be expected also to demonstrate an increased incidence of aberrant creases. As this population would include the nonsurvivors, the question is of particular interest.
Implications
for
Nursing
outcomes.
a study to determine any increased risk of CNS complications in children with aberrant creases could be carried out by obtaining handprints of children diagnosed with ALL at age 6 or before. Children with and without aberrant creases would be followed throughout the course of their illness to assess the incidence of CNS involvement. ’
for
Nursing Practice
Increased risk for many disorders are associated with physical characteristics not immediately identified as related (urinary tract problems with earlobe shape, breast cancer with type of
’
like an art project to the child. Only child in the study refused to participate, in spite of encouragement from his family. The authors immediately accepted his refusal and advised the parents that it seemed important to allow him to feel some measure of control over what happened to his body during the clinic visit As he was not able to refuse blood work, chemotherapy, bone marrow sampling, or spinal taps, here was one area where he actually could make a choice that would be respected by all those in control. Most children and families eagerly made several sets of prints to hang up at home. Several parents took extra sets to include in their identification files on their children (set up by many local authorities where fingerprinting of children is available). Children and their families also.enjoyed comparing prints to see whose matched and where differences were. Many children took copies of their prints to school for show-and-tell to share their experience with their peers. In general, children and their families actually enjoyed this part of the clinic visit and had something tangible and positive to bring home with them. one
Additionally,
Implications
families, often find their visits traumatic and painful. Obtaining prints is not painful and seems more
Research
A prospective study using handprints obtained at birth from a large sample of infants and their families would be useful in helping to determine the relationship between ALL and aberrant creases. Children would be followed through their sixth year in order to accurately assess
for
establishing a relationship with a newly diagnosed child and family as well as an enjoyable time in the visit. Children involved in the study, as well as their means
cerumen and with body shape). Until it is determined whether a substantial correlation exists between type of palmar creases and risk of ALL, and/or risk of CNS involvement, nurses in the pediatric oncology setting continue to make a significant contribution to the treatment plan through their assessments. Nurses have the opportunity to obtain handprints from the affected child and his or her family in both the clinic and acute care settings. Not only may this noninvasive part of the assessment provide useful information about children with ALL, it provides a
-
’
Summary
.
of handprints to determine dermal patterns is a noninvasive means of obtaining potentially significant information. Substantiation of the relationship of dermal patterns and cancer outcomes through further research could provide a simple, inexpensive means of screening children for possible risk and to provide for earlier intervention and, ultimately, better out-
The
comes.
use
-
References 1. Altman AJ, Schwartz AD:
Malignant Diseases of
In-
fancy, Childhood and Adolescence. Philadelphia, PA, Saunders, 1978 2. Thompson JS, Thompson MW: Genetics in Medicine. Philadelphia, PA, Saunders, 1980 3. Dar H, Jaffe M: Dermatoglyphic and palmar-crease al-
as indicators of early intra-uterine insult in mental retardation. Dev Med Child Neurol 25:53-59, 1983 4. Menser MA, Purvis-Smith SG: Dermatoglyphic defects in children with leukemia. Lancet 1:1076-1078, 1969
terations
5. Rosner F: Dermatoglyphics in leukaemic children. Lan2:272-273, 1969
cet
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38
6. Wertelecki W, Plato CC, Fraumeni JF: Dermatoglyphics of leukaemia. Lancet 2:806-807, 1969 7. Nora AH, Nora YY, Fembach DJ: Dermatoglyphics and leukemia. Lancet 2:905-906, 1969 8. Verbov JL: Dermatoglyphs in leukaemia. J Med Genet
7:125-130, 1970 9. Purvis-Smith SG, Menser MA: Dermatoglyphics in children with acute leukaemia. Br Med J 4:646-648, 1973 10. Till M, Larrauri S, Smith PG: Dermatoglyphics in childhood leukaemia: A guide to prognosis and aetiology? Br J Cancer 37:1063-1073, 1978 11. Oorthuys AM, De Vaan GA, Behrend H, et al: Dermatoglyphics in childhood leukemia, in Wertelecki W, Plato CC (eds): The National Foundation—March of Dimes, Birth Defects : Original Article Series: Vol 1(6): Dermatoglyphics— Fifty Years Later. New York, NY, Uss, 1979, pp 721-735
12. Oorthuys AM, De Vaan GA, Behrendt H, et al: Palmar flexion creases in childhood neoplasia. Cancer 43:749-759, 1979 13. Stewart A: Aetiology of childhood malignancies: Congenitally determined leukaemias. Br Med J 1:452-560, 1961 14. Wertelecki W: The Simian and Sydney crease, in Wertelecki W, Plato CC (eds): The National Foundation— March of Dimes, Birth Defects: Original Article Series: Vol 1(6): Dermatoglyphics—Fifty Years Later. New York, NY, Wiley-Liss, 1979, pp 455-471 15. Plato CC, Wertelecki W: Changing trends in dermatoglyphic research, in Bartsocas CS (ed): Progress in Clinical and Biological Research. Vol 84: Progress in Dermatoglyphic Research. New York, NY, Liss, 1982, pp 1-11 16. Jensen M, Benson R, Bobak I: Maternity Care: The Nurse and the Family (ed 2). St. Louis, MO, Mosby, 1981
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