Journal of Perinatology (2014) 34, 873–874 © 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp
PERINATAL/NEONATAL CASE PRESENTATION
Limb hypoplasia resulting from intrauterine infection with herpes simplex virus: a case report D Carola1, M Skibo1, S Cannon2, KM Cam2, P Hyde2,3 and ZH Aghai1 Intrauterine infection with herpes simplex virus, although very rare, has devastating effects on multiple organ systems in the fetus and can lead to in utero fetal demise. Neonates born following intrauterine herpes simplex virus infection commonly manifest with cutaneous lesions, ocular damage and/or brain abnormalities. We describe the case of a dichorionic, diamniotic twin gestation complicated by intrauterine herpes simplex virus infection. This infection led to the fetal demise of twin A and a very uncommon presentation of limb hypoplasia in twin B. Journal of Perinatology (2014) 34, 873–874; doi:10.1038/jp.2014.121
INTRODUCTION Neonatal herpes simplex virus (nHSV) infection can have devastating effects on multiple organ systems and has wide symptom overlap with other newborn diseases, thereby making it difficult to diagnose and treat in a timely fashion.1 We report an unusual case of intrauterine HSV (iuHSV) infection that presented at birth with left arm hypoplasia as opposed to the classic skin, eye and brain anomalies. CASE A 19-year-old African American female presented to the hospital at 26 weeks gestation in preterm labor with dichorionic–diamniotic twins. There was discordance noted early in the pregnancy, and the growth restricted twin A died in utero a few days before mom’s arrival. The pregnancy was otherwise without complications or known maternal illnesses. She had negative standard prenatal infection labs in addition to negative varicella, cytomegalovirus, Toxoplasma and parvovirus titers. She was never tested for HSV but had no known clinical history of herpes infection. Mom was admitted and twin A was stillborn shortly after. A week after admission, now at 26 and 6/7 weeks gestation, mom again had spontaneous labor and delivered twin B vaginally. The delivery was complicated by chorioamnionitis. At delivery, the 818-g average for gestational age female had Apgars of 4 and 7, but required intubation for apnea. She was noted to have a hypoplastic, shiny appearing left arm with patches of ‘sloughing’ skin (Figure 1). She was extubated by the following day and remained clinically stable, but her laboratory workup showed persistent neutropenia with a lymphocyte predominance, so she ultimately finished a 7 day course of ampicillin and gentamicin for culture negative sepsis and her cell count improved. Dermatology was consulted on the day of birth. They described her left arm as ‘hypoplastic with syndactyly of fingers 3–5 with hypoplastic nail formation and linearly eroded, yellow skin showing re-epithelialization from the distal left arm up to the shoulder, chest, neck, back and scalp’. Initial evaluation of the arm
included a Doppler ultrasound that was normal, and X-ray imaging of the left hand showed normal bony structures with five separate digits. Dermatology felt that this initial presentation was most consistent with cutis aplasia or an infectious etiology; however, the differential diagnosis also included epidermolysis bullosa, Addams–Oliver syndrome (cutis aplasia of the scalp along with limb defects), focal dermal hypoplasia and incontinentia pigmenti. On the third day of life, after initiation of phototherapy for hyperbilirubinemia, the infant developed a vesicular rash on an erythematous base contralateral to her hypoplastic limb. A Tzanck smear of the vesicular fluid showed multinucleated giant cells concerning for herpes or varicella infection. Surface HSV cultures, serum and cerebrospinal HSV PCR, and varicella titers were sent, and she was started on high-dose IV acyclovir (60 mg kg − 1 per day). Varicella titers were negative but surface cultures were positive for HSV within 24 h. Her serum PCR was also positive for herpes simplex 2, however, her cerebrospinal was negative. Ophthalmology found no evidence of chorioretinitis, and cranial ultrasound and later magnetic resonance imaging showed no evidence of central nervous system infection. Also, there were no laboratory signs of disseminated disease. Placental pathology showed evidence of chorioamnionitis and tested positive for HSV 2. Upon review, the stillborn twin A and placenta were never tested for HSV. The infant’s skin healed well, but she had restricted movement of her left arm at the elbow and wrist. She completed a 21-day course of high-dose acyclovir, and then was started on an oral acyclovir prophylactic regimen of 300 mg m −2 every 8 h to continue for 6 months. The remainder of her course was relatively unremarkable, and she was discharged with no artificial respiratory or feeding support. DISCUSSION nHSV infection remains relatively rare with an overall incidence in 2006 of just 9.6 cases per 100 000 births2 with intrauterine infection representing only 5% of those cases.3 There are three time periods for transmission of nHSV including intrauterine,
1 Division of Neonatology, Nemours at Thomas Jefferson University, Philadelphia, PA, USA; 2Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA and 3Department of Pediatric Dermatology, Nemours/A.I. Dupont Hospital for Children, Wilmington, DE, USA. Correspondence: Dr D Carola, Department of Neonatology, Thomas Jefferson University, 833 Chestnut St, Suite 1210, Philadelphia, PA 19107, USA. E-mail: [email protected] Received 24 April 2014; accepted 6 May 2014
Neonatal limb hypoplasia from intrauterine herpes D Carola et al
874
Johansson et. al.6 With no other common sequelae of congenital varicella (microcephaly, seizures and chorioretinitis6) and no serological evidence of varicella infection, we concluded that our patient’s limb hypoplasia was likely due to iuHSV infection. There have been many attempts to create a list of diagnostic criteria for determining whether a patient has iuHSV infection. Most of these have included (1) evidence of infection within 48 h of life and (2) virologic confirmation of infection. Some have required evidence of effect on embryogenesis and evidence of viral placentitis.3 All four of these were seen in our patient. Also, in congenital varicella syndrome, limb hypoplasia is believed to result from abnormal growth after viral injury to the limb’s nervous supply.10 HSV is also a neurotropic virus and we question whether it may cause limb hypoplasia by a similar mechanism. In order to treat nHSV infection, we have to be able to diagnose it promptly, so we hope that our case presentation demonstrates that limb hypoplasia should be considered as a presenting symptom for nHSV infection to avoid any delay in the timely diagnosis and treatment of this potentially deadly infection. CONFLICT OF INTEREST The authors declare no conflicts of interest.
Figure 1. A photograph showing a comparison of the normal, proportionally sized right arm with the hypoplastic left arm. Also, note the abnormal appearance of the skin of the left arm and chest.
perinatal and post partum.1 Alarmingly, 70% of all women who give birth to a baby afflicted by nHSV have no clinical history of HSV infection themselves.4 Generally, nHSV infection presents as one of three typical presentations: (1) skin, eye and mucous membrane type; (2) central nervous system type; or (3) disseminated disease.5 iuHSV commonly shares features of multiple types,1 and infection by this mode is usually evident at birth or by 2 days of age.6 Disseminated disease is, by far, the most devastating and resembles sepsis.7 Overall, nHSV carries a fatality rate of 4.1% (ref. 2) with a fourfold greater relative risk of death in preterm vs term infants.8 Further complicating the diagnosis of nHSV infection is the wide overlap with the clinical findings in other newborn diseases. nHSV shares similar skin findings with congenital varicella, enterovirus or cytomegalovirus infection, scalded skin syndrome, cutis aplasia, epidermolysis bullosa and incontinentia pigmenti.4,6,9 Limb hypoplasia, however, is classically only described in congenital varicella syndrome with only one previous description in nHSV by
Journal of Perinatology (2014), 873 – 874
REFERENCES 1 Kimberlin DW. Neonatal herpes simplex infection. Clin Microbiol Rev 2004; 17: 1–13. 2 Flagg E, Weinstock H. Incidence of Neonatal herpes simplex virus infections in the United States, 2006. Pediatrics 2011; 127: e1–e8. 3 Marquez L, Levy M, Munoz F, Palazzi D. A report of three cases and review of intrauterine herpes simplex virus infection. Pediatr Infect Dis J 2011; 30: 153–157. 4 Koch L, Fisher R, Chen C, Foster M, Bass WT, Williams J. Congenital herpes simplex virus infection: two unique cutaneous presentations associated with probable intrauterine transmission. J Am Acad Dermatol 2008; 60: 312–315. 5 Corey L, Wald A. Maternal and neonatal herpes simplex virus infections. N Engl J Med 2009; 361: 1376–1385. 6 Johansson A, Rassart A, Blum D, Van Beers D, Liesnard C. Lower-limb hypoplasia due to intrauterine infection with herpes simplex virus type 2: possible confusion with intrauterine varicella-zoster syndrome. Clin Infect Dis 2004; 38: e57–e62. 7 Thompson C, Whitley R. Neonatal herpes simplex virus infections: where are we now? Adv Exp Med Biol 2011; 697: 221–230. 8 O’Riordan D, Golden WC, Aucott S. Herpes simplex virus infections in preterm infants. Pediatrics 2006; 118: e1612. 9 Low L, Carton J, Walker M, Tudor-Williams G, Hardman C. Intrauterine herpes simplex virus infection presenting with hypopigmented lesions. Pediatr Dermatol 2012; 29: 515–517. 10 Smith C, Arvin A. Varicella in the fetus and newborn. Semin Fetal Neonatal Med 2009; 14: 211.
© 2014 Nature America, Inc.
PERINATAL/NEONATAL CASE PRESENTATION
Limb hypoplasia resulting from intrauterine infection with herpes simplex virus: a case report D Carola1, M Skibo1, S Cannon2, KM Cam2, P Hyde2,3 and ZH Aghai1 Intrauterine infection with herpes simplex virus, although very rare, has devastating effects on multiple organ systems in the fetus and can lead to in utero fetal demise. Neonates born following intrauterine herpes simplex virus infection commonly manifest with cutaneous lesions, ocular damage and/or brain abnormalities. We describe the case of a dichorionic, diamniotic twin gestation complicated by intrauterine herpes simplex virus infection. This infection led to the fetal demise of twin A and a very uncommon presentation of limb hypoplasia in twin B. Journal of Perinatology (2014) 34, 873–874; doi:10.1038/jp.2014.121
INTRODUCTION Neonatal herpes simplex virus (nHSV) infection can have devastating effects on multiple organ systems and has wide symptom overlap with other newborn diseases, thereby making it difficult to diagnose and treat in a timely fashion.1 We report an unusual case of intrauterine HSV (iuHSV) infection that presented at birth with left arm hypoplasia as opposed to the classic skin, eye and brain anomalies. CASE A 19-year-old African American female presented to the hospital at 26 weeks gestation in preterm labor with dichorionic–diamniotic twins. There was discordance noted early in the pregnancy, and the growth restricted twin A died in utero a few days before mom’s arrival. The pregnancy was otherwise without complications or known maternal illnesses. She had negative standard prenatal infection labs in addition to negative varicella, cytomegalovirus, Toxoplasma and parvovirus titers. She was never tested for HSV but had no known clinical history of herpes infection. Mom was admitted and twin A was stillborn shortly after. A week after admission, now at 26 and 6/7 weeks gestation, mom again had spontaneous labor and delivered twin B vaginally. The delivery was complicated by chorioamnionitis. At delivery, the 818-g average for gestational age female had Apgars of 4 and 7, but required intubation for apnea. She was noted to have a hypoplastic, shiny appearing left arm with patches of ‘sloughing’ skin (Figure 1). She was extubated by the following day and remained clinically stable, but her laboratory workup showed persistent neutropenia with a lymphocyte predominance, so she ultimately finished a 7 day course of ampicillin and gentamicin for culture negative sepsis and her cell count improved. Dermatology was consulted on the day of birth. They described her left arm as ‘hypoplastic with syndactyly of fingers 3–5 with hypoplastic nail formation and linearly eroded, yellow skin showing re-epithelialization from the distal left arm up to the shoulder, chest, neck, back and scalp’. Initial evaluation of the arm
included a Doppler ultrasound that was normal, and X-ray imaging of the left hand showed normal bony structures with five separate digits. Dermatology felt that this initial presentation was most consistent with cutis aplasia or an infectious etiology; however, the differential diagnosis also included epidermolysis bullosa, Addams–Oliver syndrome (cutis aplasia of the scalp along with limb defects), focal dermal hypoplasia and incontinentia pigmenti. On the third day of life, after initiation of phototherapy for hyperbilirubinemia, the infant developed a vesicular rash on an erythematous base contralateral to her hypoplastic limb. A Tzanck smear of the vesicular fluid showed multinucleated giant cells concerning for herpes or varicella infection. Surface HSV cultures, serum and cerebrospinal HSV PCR, and varicella titers were sent, and she was started on high-dose IV acyclovir (60 mg kg − 1 per day). Varicella titers were negative but surface cultures were positive for HSV within 24 h. Her serum PCR was also positive for herpes simplex 2, however, her cerebrospinal was negative. Ophthalmology found no evidence of chorioretinitis, and cranial ultrasound and later magnetic resonance imaging showed no evidence of central nervous system infection. Also, there were no laboratory signs of disseminated disease. Placental pathology showed evidence of chorioamnionitis and tested positive for HSV 2. Upon review, the stillborn twin A and placenta were never tested for HSV. The infant’s skin healed well, but she had restricted movement of her left arm at the elbow and wrist. She completed a 21-day course of high-dose acyclovir, and then was started on an oral acyclovir prophylactic regimen of 300 mg m −2 every 8 h to continue for 6 months. The remainder of her course was relatively unremarkable, and she was discharged with no artificial respiratory or feeding support. DISCUSSION nHSV infection remains relatively rare with an overall incidence in 2006 of just 9.6 cases per 100 000 births2 with intrauterine infection representing only 5% of those cases.3 There are three time periods for transmission of nHSV including intrauterine,
1 Division of Neonatology, Nemours at Thomas Jefferson University, Philadelphia, PA, USA; 2Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA and 3Department of Pediatric Dermatology, Nemours/A.I. Dupont Hospital for Children, Wilmington, DE, USA. Correspondence: Dr D Carola, Department of Neonatology, Thomas Jefferson University, 833 Chestnut St, Suite 1210, Philadelphia, PA 19107, USA. E-mail: [email protected] Received 24 April 2014; accepted 6 May 2014
Neonatal limb hypoplasia from intrauterine herpes D Carola et al
874
Johansson et. al.6 With no other common sequelae of congenital varicella (microcephaly, seizures and chorioretinitis6) and no serological evidence of varicella infection, we concluded that our patient’s limb hypoplasia was likely due to iuHSV infection. There have been many attempts to create a list of diagnostic criteria for determining whether a patient has iuHSV infection. Most of these have included (1) evidence of infection within 48 h of life and (2) virologic confirmation of infection. Some have required evidence of effect on embryogenesis and evidence of viral placentitis.3 All four of these were seen in our patient. Also, in congenital varicella syndrome, limb hypoplasia is believed to result from abnormal growth after viral injury to the limb’s nervous supply.10 HSV is also a neurotropic virus and we question whether it may cause limb hypoplasia by a similar mechanism. In order to treat nHSV infection, we have to be able to diagnose it promptly, so we hope that our case presentation demonstrates that limb hypoplasia should be considered as a presenting symptom for nHSV infection to avoid any delay in the timely diagnosis and treatment of this potentially deadly infection. CONFLICT OF INTEREST The authors declare no conflicts of interest.
Figure 1. A photograph showing a comparison of the normal, proportionally sized right arm with the hypoplastic left arm. Also, note the abnormal appearance of the skin of the left arm and chest.
perinatal and post partum.1 Alarmingly, 70% of all women who give birth to a baby afflicted by nHSV have no clinical history of HSV infection themselves.4 Generally, nHSV infection presents as one of three typical presentations: (1) skin, eye and mucous membrane type; (2) central nervous system type; or (3) disseminated disease.5 iuHSV commonly shares features of multiple types,1 and infection by this mode is usually evident at birth or by 2 days of age.6 Disseminated disease is, by far, the most devastating and resembles sepsis.7 Overall, nHSV carries a fatality rate of 4.1% (ref. 2) with a fourfold greater relative risk of death in preterm vs term infants.8 Further complicating the diagnosis of nHSV infection is the wide overlap with the clinical findings in other newborn diseases. nHSV shares similar skin findings with congenital varicella, enterovirus or cytomegalovirus infection, scalded skin syndrome, cutis aplasia, epidermolysis bullosa and incontinentia pigmenti.4,6,9 Limb hypoplasia, however, is classically only described in congenital varicella syndrome with only one previous description in nHSV by
Journal of Perinatology (2014), 873 – 874
REFERENCES 1 Kimberlin DW. Neonatal herpes simplex infection. Clin Microbiol Rev 2004; 17: 1–13. 2 Flagg E, Weinstock H. Incidence of Neonatal herpes simplex virus infections in the United States, 2006. Pediatrics 2011; 127: e1–e8. 3 Marquez L, Levy M, Munoz F, Palazzi D. A report of three cases and review of intrauterine herpes simplex virus infection. Pediatr Infect Dis J 2011; 30: 153–157. 4 Koch L, Fisher R, Chen C, Foster M, Bass WT, Williams J. Congenital herpes simplex virus infection: two unique cutaneous presentations associated with probable intrauterine transmission. J Am Acad Dermatol 2008; 60: 312–315. 5 Corey L, Wald A. Maternal and neonatal herpes simplex virus infections. N Engl J Med 2009; 361: 1376–1385. 6 Johansson A, Rassart A, Blum D, Van Beers D, Liesnard C. Lower-limb hypoplasia due to intrauterine infection with herpes simplex virus type 2: possible confusion with intrauterine varicella-zoster syndrome. Clin Infect Dis 2004; 38: e57–e62. 7 Thompson C, Whitley R. Neonatal herpes simplex virus infections: where are we now? Adv Exp Med Biol 2011; 697: 221–230. 8 O’Riordan D, Golden WC, Aucott S. Herpes simplex virus infections in preterm infants. Pediatrics 2006; 118: e1612. 9 Low L, Carton J, Walker M, Tudor-Williams G, Hardman C. Intrauterine herpes simplex virus infection presenting with hypopigmented lesions. Pediatr Dermatol 2012; 29: 515–517. 10 Smith C, Arvin A. Varicella in the fetus and newborn. Semin Fetal Neonatal Med 2009; 14: 211.
© 2014 Nature America, Inc.
