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Familial occurrence of pruritic urticarial papules and plaques of pregnancy
Familial occurrence of pruritic urticarial papules and plaques of pregnancy Robert Weiss, MBBCh, FF Derm SA,a and Peter Hull, PhD, FF Derm SAb Johannesburg, South Africa
Background: The occurrence of pruritic urticarial papules and plaques of pregnancy (PUPPP) was noted in four women with unusual family relationships.
Ohjective: The purpose of the study was to document the occurrence of PUPPP in these fam-
ilies and to make observations on their possible relevance. Methods: Case reports of the four patients are detailed. Histologic and HLA studies are recorded. Results: In both families, sisters were married to brothers. A common paternal influence is suggested. Conclusion: We postulate that PUPPP may be a maternal response to a circulating paternal factor for which tolerance develops in subsequent pregnancies. (J AM ACAD DERMATOL 1992;26:715-7.) Pruritic urticarial papules and plaques of pregnancy (PUPPP) or polymorphic eruption of pregnancy develops late in pregnancy. It usually appears first in abdominal striae before spreading to other areas. The eruption clears soon after delivery. A familial predisposition has not been previously recorded. We report two families in which the familial relationships are unusual. In the first family, two sisters were married to brothers while in the second, twin sisters were married to twin brothers. The occurrence ofPUPPP in these families may reveal an important facet of this cQndition. CASE REPORTS
Family 1 The patients, two sisters, 16 and 20 years of age, were married to brothers. The families were not consanguineous, nor was there a family history suggestive ofPUPPP. The pregnancies had been uneventful and neither patient had taken medication. The sisters lived in different homes in the same suburb. Delivery of the babies took place two days apart. Case 1. One week before delivery the younger sister developed an itchy eruption in the abdominal striae and
From the University of the Witwatersrand Medical School,· and the University of Pretoria.b Accepted for publication Nov. 12, 1991. Reprint requests: Robert Weiss, P.O. Box 84634, Greenside, 2034 Johannesburg, South Africa,
16/1/34925
this subsequently spread to her arms and legs. The lesions consisted of 2 to 3 mm erythematous papules, some of which had an urticarial halo. Vesicles were present in some areas. Although striae were present on both the abdomen and breasts, the eruption involved only the abdominal striae. The eruption resolved within 10 days of the birth of a normal female infant. Case 2. The older sister also had prominent striae on the abdomen and breasts. She developed an itchy eruption in only her abdominal striae 1 day before the delivery of a healthy male infant by vacuum extraction. The eruption was similar to but more severe than that of her sister. Lesions were scattered symmetrically on the legs and on the outer aspects of her arms. They consisted of urticarial papules, some of which were vesiculated. The eruption started to fade 1 week after delivery but was still evident 14 days later, although no longer pruritic.
Family 2 In this family twin sisters were married to twin brothers, Both sets of twins were monozygous. The families were not related and the sisters were not living together during their pregnancies. Case 3. An 18-year-old primigravida had had an uneventful pregnancy until she developed a pruritic eruption 3 weeks before delivery. The lesions were initially confined to the abdominal striae but spread to her abdomen, thighs, arms, and palms. Erythematous papules were densely concentrated in the striae and less so on the flanks. She was delivered of the infant at term and the baby was normal. She subsequently had three normal pregnancies without recurrence of the eruption. Case 4. Her twin sister developed intense itching in the
715
Journal of the American Academy of Dermatology
716 Weiss and Hull A24 Cw4 835
A28 839
2
A28 Cw2 818
Cw3 862
A24 Cw4 835
A1 Case 3 A28 A28 Cw2 839 818
A24 A1 Cw4 835 88
14
A1 A2 Cw3 88 862
A24 A1 A28 A2 A28 A1 Cw4 Cw2 Cw3 835 B8 818 862 839 88
A28 A28 Cw2 839 819
A28 A1 Cw2 818 88
88
814
A1
A2 Cw3 88 862
A28 A1 Cw2 818 88
A28 A1 839 B8
.Fig. 1. Pedigree for family 2 showing HLA antigens. _, Pregnancies affected by PUPPP.
abdominal striae during the last week of her first pregnancy at the age of 19 years. A papular erythematous eruption was noted on the day after a normal delivery. The eruption extended with the development of large confluent erythematous plaques. It cleared in 3 weeks. There was no recurrence during her second pregnancy. A third pregnancy aborted at 9 weeks. During the third month of her fourth pregnancy, she again developed a pruritic eruption in the abdominal striae that spread to her arms and legs. The eruption was milder than that during the first pregnancy, persisted for 3 weeks, and resolved spontaneously. This episode was not observed by us. There was no recurrence of the eruption later in the pregnancy. A sister of the husbands, married to a brother of the wives, has had two pregnancies without developing PUPPP.
Histologic findings Biopsies were done of the papules on the legs and abdomen in cases 1 and 2 and from the abdomen only in cases 3 and 4. Direct and indirect immunofluorescence studies on perilesional skin were performed in cases 1 and
2. The histologic findings were similar in all specimens. In case 1 eosinophilic exocytosis of the epidermis was present. In the other cases the epidermis was normal. All biopsy specimens showed a perivascular lymphohistiocytic infiltrate that contained many eosinophils in the mid and reticular dermis. Van Gieson stain in the first two cases showed a decrease in number but no obvious fragmentation of elastic fibers in the papules in the abdominal striae, although this abnormality was not seen in specimens from the legs. Direct and indirect immunofluorescence studies were performed on cases 1 and 2. They were negative for IgG, IgA, IgM, C3, and fibrin.
HLA studies These were performed on the second family only (Fig. 1).
DISCUSSION
The origin of PUPPP is unknown. It occurs only in association with pregnancy either during the third trimester or immediately postpartum. Spontaneous clearing occurs after delivery and the infant is almost never affected. The condition occurs most frequently in primigravidas and usually does not recur in subsequent pregnancies. When this happens the condition is less severe and often develops during the first or second trimesters, The frequency of twin pregnancies is slightly increased in puppp.1-4 In contrast to herpes gestationis there is little evidence to suggest that PUPPP is an autoimmune disease. Direct immunofluorescence studies have generally been negative but vascular deposits of IgM, IgA, and C3 have been demonstrated in some patients. 5, 6 There is no HLA association in women with puppp.4, 7 Our data show identical HLA types in both affected and normal infants suggest that PUPPP is not an HLA-class I-related condition. Because the abdominal striae are the first sites to be involved in PUPPP, attention has recently focused on the development of striae as the trigger for the development of PUPPP. Striae are often worse in the first pregnancy, with multiple pregnancies and with hydramnios. A relation between maternal-fetal weight gain has been proposed but this has been challenged by others. 2,3 Striae acquired in situations other than pregnancy have never triggered PUPPP-
Volume 26 Number 5, Part 1 May 1992
like eruptions and it is possible that striae only serve to localize the eruption. Although the cases of PUPPP that we have described might be explicable on the basis of chance or perhaps even be the result of some environmental agent, we believe that they suggest a hitherto unrecognized genetic factor. This recognition was only possible only because of the unusual family relationships with brothers marrying sisters and twin brothers marrying twin sisters. The occurrence of PUPPP in the four primigravidas suggests a maternal response to a paternal influence. An alternative explanation is that the mothers shared a genetic susceptibility to develop PUPPP. This might be related to the development of striae that "trigger" the rash. The lack of other familial cases weakens the case for a sole maternal predisposition and strengthens the alternative of a shared maternal reaction to a common paternal influence. The nature ofthe paternal influence remains to be determined, but it is presumably expressed in the form of paternal antigens present in the fetal component of the placenta. This paternal antigen ex-
Familial PUPPP
pression might occur late in pregnancy or be released into the maternal circulation with placental degeneration near term or even at birth. The immune reaction that follows does not harm the fetus, which remains protected by the profound immune tolerance that surrounds the fetal allograft. REFERENCES 1. LawleyTJ, Hertz KC, Wade TR, et al. Pruritic urticarial
papules and plaques ofpregnancy. JAMA 1979;241:1696-9. 2. Cohen LM, Capeless EL, Krusinski PA, et al. Pruritic urticarial papules and plaques of pregnancy and its relationship to maternal-fetal weight gain and twin pregnancy. Arch DermatoI1989;125:1534-6. 3. Roger D, Vaillant L, Lorette G. Pruritic urticarial papules and plaques of pregnancy are not related to maternal or fetal weight gain [Letter]. Arch DermatoI1990;126:l5l7. 4. Yancey KB, Hall RP, Lawley TJ. Pruritic urticarial papules and plaques of pregnancy. J AM ACAD DERMATOL 1984;10:473-80. 5. Faber WR, van Joost TH, Hausman R, et al. Late prurigo of pregnancy. Br J DermatoI1982;106:511-6. 6. Aronson IK, Vomvouras S, Fiedler ve, et al. Immunopathology of pruritic urticarial papules and plaques of pregnancy [Abstract]. J Invest DermatoI1990;94:504. 7. Holmes Re. Polymorphic eruption of pregnancy. Semin Dermatol 1989;8:18-22.
HLA-DRI is not a sign of poor prognosis for the development of multiple basal cell carcinomas D. Czarnecki, MBBS,a A. Lewis, MBBS,b Ian Nicholson, BSc,c Brian Tait, PhD,c and C. Nash, PhDb Heidelberg, Fitzroy, and Parkville, Victoria, Australia Background: HLA-DRI is associated with the development of multiple basal cell carcinomas (BCC). However, the association is weak. Objective: The purpose of our study was to determine whether HLA-DR1 is a marker for susceptibility to the development of many BCCs during a lifetime. Methods: Persons with multiple BCCs were placed into two groups: those with less than 10 and those with 20 or more. In addition, the HLA-DRI frequencies were analyzed. Results: HLA-DRI was associated with multiple BeCs in the group with less than 10 BCCs but not with the other group. These patients were significantly younger on average than those with 20 or more BCCs. Conclusion: HLA-DRI is associated with the development of multiple BCCs at an early age but it is not associated with development of large numbers of BCCs. The amount of UV light a person receives appears to be more important. (J AM ACAD DERMATOL 1992;26:717-9.) From the Repatriation General Hospital, Heidelberg"; the Skin and Cancer Foundation, Fitzroyb; and the Tissue Typing Laboratory, Royal Melbourne Hospital, Parkville.c Supported by grants from the Skin and Psoriasis Foundation and Schering-Plough Pty., Ltd.
Accepted for publication Nov. 21, 1991. Reprint requests: D. Czarnecki, Dermatologist, Suite I, 12 Floriston Rd., Boronia, 3155, Australia. 16/1/35126
717
Background: The occurrence of pruritic urticarial papules and plaques of pregnancy (PUPPP) was noted in four women with unusual family relationships.
Ohjective: The purpose of the study was to document the occurrence of PUPPP in these fam-
ilies and to make observations on their possible relevance. Methods: Case reports of the four patients are detailed. Histologic and HLA studies are recorded. Results: In both families, sisters were married to brothers. A common paternal influence is suggested. Conclusion: We postulate that PUPPP may be a maternal response to a circulating paternal factor for which tolerance develops in subsequent pregnancies. (J AM ACAD DERMATOL 1992;26:715-7.) Pruritic urticarial papules and plaques of pregnancy (PUPPP) or polymorphic eruption of pregnancy develops late in pregnancy. It usually appears first in abdominal striae before spreading to other areas. The eruption clears soon after delivery. A familial predisposition has not been previously recorded. We report two families in which the familial relationships are unusual. In the first family, two sisters were married to brothers while in the second, twin sisters were married to twin brothers. The occurrence ofPUPPP in these families may reveal an important facet of this cQndition. CASE REPORTS
Family 1 The patients, two sisters, 16 and 20 years of age, were married to brothers. The families were not consanguineous, nor was there a family history suggestive ofPUPPP. The pregnancies had been uneventful and neither patient had taken medication. The sisters lived in different homes in the same suburb. Delivery of the babies took place two days apart. Case 1. One week before delivery the younger sister developed an itchy eruption in the abdominal striae and
From the University of the Witwatersrand Medical School,· and the University of Pretoria.b Accepted for publication Nov. 12, 1991. Reprint requests: Robert Weiss, P.O. Box 84634, Greenside, 2034 Johannesburg, South Africa,
16/1/34925
this subsequently spread to her arms and legs. The lesions consisted of 2 to 3 mm erythematous papules, some of which had an urticarial halo. Vesicles were present in some areas. Although striae were present on both the abdomen and breasts, the eruption involved only the abdominal striae. The eruption resolved within 10 days of the birth of a normal female infant. Case 2. The older sister also had prominent striae on the abdomen and breasts. She developed an itchy eruption in only her abdominal striae 1 day before the delivery of a healthy male infant by vacuum extraction. The eruption was similar to but more severe than that of her sister. Lesions were scattered symmetrically on the legs and on the outer aspects of her arms. They consisted of urticarial papules, some of which were vesiculated. The eruption started to fade 1 week after delivery but was still evident 14 days later, although no longer pruritic.
Family 2 In this family twin sisters were married to twin brothers, Both sets of twins were monozygous. The families were not related and the sisters were not living together during their pregnancies. Case 3. An 18-year-old primigravida had had an uneventful pregnancy until she developed a pruritic eruption 3 weeks before delivery. The lesions were initially confined to the abdominal striae but spread to her abdomen, thighs, arms, and palms. Erythematous papules were densely concentrated in the striae and less so on the flanks. She was delivered of the infant at term and the baby was normal. She subsequently had three normal pregnancies without recurrence of the eruption. Case 4. Her twin sister developed intense itching in the
715
Journal of the American Academy of Dermatology
716 Weiss and Hull A24 Cw4 835
A28 839
2
A28 Cw2 818
Cw3 862
A24 Cw4 835
A1 Case 3 A28 A28 Cw2 839 818
A24 A1 Cw4 835 88
14
A1 A2 Cw3 88 862
A24 A1 A28 A2 A28 A1 Cw4 Cw2 Cw3 835 B8 818 862 839 88
A28 A28 Cw2 839 819
A28 A1 Cw2 818 88
88
814
A1
A2 Cw3 88 862
A28 A1 Cw2 818 88
A28 A1 839 B8
.Fig. 1. Pedigree for family 2 showing HLA antigens. _, Pregnancies affected by PUPPP.
abdominal striae during the last week of her first pregnancy at the age of 19 years. A papular erythematous eruption was noted on the day after a normal delivery. The eruption extended with the development of large confluent erythematous plaques. It cleared in 3 weeks. There was no recurrence during her second pregnancy. A third pregnancy aborted at 9 weeks. During the third month of her fourth pregnancy, she again developed a pruritic eruption in the abdominal striae that spread to her arms and legs. The eruption was milder than that during the first pregnancy, persisted for 3 weeks, and resolved spontaneously. This episode was not observed by us. There was no recurrence of the eruption later in the pregnancy. A sister of the husbands, married to a brother of the wives, has had two pregnancies without developing PUPPP.
Histologic findings Biopsies were done of the papules on the legs and abdomen in cases 1 and 2 and from the abdomen only in cases 3 and 4. Direct and indirect immunofluorescence studies on perilesional skin were performed in cases 1 and
2. The histologic findings were similar in all specimens. In case 1 eosinophilic exocytosis of the epidermis was present. In the other cases the epidermis was normal. All biopsy specimens showed a perivascular lymphohistiocytic infiltrate that contained many eosinophils in the mid and reticular dermis. Van Gieson stain in the first two cases showed a decrease in number but no obvious fragmentation of elastic fibers in the papules in the abdominal striae, although this abnormality was not seen in specimens from the legs. Direct and indirect immunofluorescence studies were performed on cases 1 and 2. They were negative for IgG, IgA, IgM, C3, and fibrin.
HLA studies These were performed on the second family only (Fig. 1).
DISCUSSION
The origin of PUPPP is unknown. It occurs only in association with pregnancy either during the third trimester or immediately postpartum. Spontaneous clearing occurs after delivery and the infant is almost never affected. The condition occurs most frequently in primigravidas and usually does not recur in subsequent pregnancies. When this happens the condition is less severe and often develops during the first or second trimesters, The frequency of twin pregnancies is slightly increased in puppp.1-4 In contrast to herpes gestationis there is little evidence to suggest that PUPPP is an autoimmune disease. Direct immunofluorescence studies have generally been negative but vascular deposits of IgM, IgA, and C3 have been demonstrated in some patients. 5, 6 There is no HLA association in women with puppp.4, 7 Our data show identical HLA types in both affected and normal infants suggest that PUPPP is not an HLA-class I-related condition. Because the abdominal striae are the first sites to be involved in PUPPP, attention has recently focused on the development of striae as the trigger for the development of PUPPP. Striae are often worse in the first pregnancy, with multiple pregnancies and with hydramnios. A relation between maternal-fetal weight gain has been proposed but this has been challenged by others. 2,3 Striae acquired in situations other than pregnancy have never triggered PUPPP-
Volume 26 Number 5, Part 1 May 1992
like eruptions and it is possible that striae only serve to localize the eruption. Although the cases of PUPPP that we have described might be explicable on the basis of chance or perhaps even be the result of some environmental agent, we believe that they suggest a hitherto unrecognized genetic factor. This recognition was only possible only because of the unusual family relationships with brothers marrying sisters and twin brothers marrying twin sisters. The occurrence of PUPPP in the four primigravidas suggests a maternal response to a paternal influence. An alternative explanation is that the mothers shared a genetic susceptibility to develop PUPPP. This might be related to the development of striae that "trigger" the rash. The lack of other familial cases weakens the case for a sole maternal predisposition and strengthens the alternative of a shared maternal reaction to a common paternal influence. The nature ofthe paternal influence remains to be determined, but it is presumably expressed in the form of paternal antigens present in the fetal component of the placenta. This paternal antigen ex-
Familial PUPPP
pression might occur late in pregnancy or be released into the maternal circulation with placental degeneration near term or even at birth. The immune reaction that follows does not harm the fetus, which remains protected by the profound immune tolerance that surrounds the fetal allograft. REFERENCES 1. LawleyTJ, Hertz KC, Wade TR, et al. Pruritic urticarial
papules and plaques ofpregnancy. JAMA 1979;241:1696-9. 2. Cohen LM, Capeless EL, Krusinski PA, et al. Pruritic urticarial papules and plaques of pregnancy and its relationship to maternal-fetal weight gain and twin pregnancy. Arch DermatoI1989;125:1534-6. 3. Roger D, Vaillant L, Lorette G. Pruritic urticarial papules and plaques of pregnancy are not related to maternal or fetal weight gain [Letter]. Arch DermatoI1990;126:l5l7. 4. Yancey KB, Hall RP, Lawley TJ. Pruritic urticarial papules and plaques of pregnancy. J AM ACAD DERMATOL 1984;10:473-80. 5. Faber WR, van Joost TH, Hausman R, et al. Late prurigo of pregnancy. Br J DermatoI1982;106:511-6. 6. Aronson IK, Vomvouras S, Fiedler ve, et al. Immunopathology of pruritic urticarial papules and plaques of pregnancy [Abstract]. J Invest DermatoI1990;94:504. 7. Holmes Re. Polymorphic eruption of pregnancy. Semin Dermatol 1989;8:18-22.
HLA-DRI is not a sign of poor prognosis for the development of multiple basal cell carcinomas D. Czarnecki, MBBS,a A. Lewis, MBBS,b Ian Nicholson, BSc,c Brian Tait, PhD,c and C. Nash, PhDb Heidelberg, Fitzroy, and Parkville, Victoria, Australia Background: HLA-DRI is associated with the development of multiple basal cell carcinomas (BCC). However, the association is weak. Objective: The purpose of our study was to determine whether HLA-DR1 is a marker for susceptibility to the development of many BCCs during a lifetime. Methods: Persons with multiple BCCs were placed into two groups: those with less than 10 and those with 20 or more. In addition, the HLA-DRI frequencies were analyzed. Results: HLA-DRI was associated with multiple BeCs in the group with less than 10 BCCs but not with the other group. These patients were significantly younger on average than those with 20 or more BCCs. Conclusion: HLA-DRI is associated with the development of multiple BCCs at an early age but it is not associated with development of large numbers of BCCs. The amount of UV light a person receives appears to be more important. (J AM ACAD DERMATOL 1992;26:717-9.) From the Repatriation General Hospital, Heidelberg"; the Skin and Cancer Foundation, Fitzroyb; and the Tissue Typing Laboratory, Royal Melbourne Hospital, Parkville.c Supported by grants from the Skin and Psoriasis Foundation and Schering-Plough Pty., Ltd.
Accepted for publication Nov. 21, 1991. Reprint requests: D. Czarnecki, Dermatologist, Suite I, 12 Floriston Rd., Boronia, 3155, Australia. 16/1/35126
717