CONGENITAL
VARICELLA
SYNDROME
GENITOURINARY
ANOMALIES
GEORGE
M.D.
T. KLAUBER,
FREDERICK
WITH
J. FLYNN, JR., M.D.
BRIAN D. ALTMAN, M.D. From the Departments of Surgery (Urology) and Pediatrics, University of Connecticut Health Center, Farmington, and Newington Children’s Hospital, Newington, Connecticut
ABSTRACT -A female child, born at term to a mother who contracted varicella in early pregnancy, presented with multiple congenital defects. These included mental retardation, numerous skeletal anomalies, and absent uterus and vagina. Urologic anomalies included bilateral chronic pyelonephritis secondary to vesicoureteric reflux. This pattern of congenital abnormalities has not been reported areviouslu.
Multiple congenital malformations have been described in 6 neonates exposed in utero to maternal varicella infection. l-5 Srabstein et al5 reported 5 cases describing similar features, including exposure to varicella during the first trimester, low birth weight, eye abnormalities, disorders of the central nervous system, and skeletal and skin lesions. This suggested the possibility of a varicella syndrome. We report a case of a child with multiple defects of a pattern as yet unreported in the literature, born to a mother who contracted herpes zoster during the second month of pregnancy. Case Report A fifteen-year-old white female was admitted to the urology service at Newington Children’s Hospital in May, 1973. During the second month of pregnancy with the patient, her mother, a thirty-three-year-old, white, gravida 5, para 4, had contracted herpes zoster simultaneously with chicken pox in her four living children. No serology was available at that time. There was no known exposure to mutagens or other infections. The father was a thirty-five-year-old white male. There was no known consanguinity. Subsequent to the patient, a normal female sibling
UROLOGY
/ AUGUST 1976 / VOLUME
VIII,
NUMBER 2
was born. Family history for congenital anomalies was negative. The patient was a full-term, breech delivery. Birth weight was 2,645 Gm. Neonatal feeding difficulties were experienced, in addition to a respiratory infection which required oxygen therapy for the first ten days of life. A second episode of respiratory infection required hospitalization at two years of age. Developmental milestones were severely delayed; she walked at age thirty-six months. She had postvoid urinary incontinence and infections, and recurrent pyelonephritis. Three years prior to admission she was found radiologically to have changes of chronic cystitis, bilateral vesicoureteric reflux, and bilateral pyelonephritis. Physical examination revealed a small, stooped, thin, nonverbal, white female (Fig. 1). Height was 130 cm., weight 24.5 Kg., and head circumference 47.4 cm., all below the third percentile for her age. Facial appearance was abnormal. Eyes were in normal position with right hypertropia, slight exotropia, and bilateral ptosis. There was no chorioretinitis. Funduscopic examination was normal. The nose was severely beaked. Examination of the ears revealed retroverted pinnae, but normal tympanic membranes. The palate was
153
very high-arched, with a submucosal cleft and bifid uvula. The mandible was hypoplastic. Teeth were formed normally, but supernumerary incisors and malocclusion were present. Mild pectus excavatum was noted, with very early breast development. Pulse and blood pressure were normal. Breath sounds were normal. Heart sounds, which were in normal sinus rhythm, were normal. A grade II-III/VI short, high-pitched blowing systolic murmur was present. This is consistent with mitral insufficiency or papillary muscle dysfunction. The abdomen was unremarkable. The genitalia revealed moderate development of pubic hair. Labia, clitoris, and urethral location were all normal. Vagina was absent, being represented by a suburethral dimple; uterus could not be palpated by rectal examination. Musculoskeletal examination revealed a thoracic scoliosis, short clavicles with the suggestion of neck webbing, and generalized atrophic musculature. There were normal carrying angles of both upper extremities. The right thumb was proximally placed with respect to the first
metacarpal. Malformation of both great toes was noted with a left hallux valgus and a proximally placed right hallux (Fig. 2A). Urinalysis revealed white blood cells in clumps and masses, and significant bacteriuria. Urine culture grew Escherichia coli, with more than 100,000 colonies per cubic centimeter. Further laboratory examination revealed a buccal smear with normal female pattern; chromosome analysis was normal. Blood urea nitrogen was 20 mg. and serum creatinine 1 mg. per 100 ml. Urinary amino acids were normal. Radiologic studies indicated a bone age of thirteen years, compared with a chronologic age of fifteen. Abnormal fusion of the second and third cervical vertebrae, bilaterally enlarged and abnormal first metatarsals (Fig. 2B), and fusion of the left index finger were demonstrated by roentgenogram. Intravenous urogram revealed bilaterally shrunken pyelonephritic kidneys. Voiding cystourethrogram demonstrated bilateral low-pressure reflux to both upper collecting systems (Fig. 3). Electroencephalogram was abnormal with a generalized slowing of the tracing. Cystoscopy revealed poor trigonal development, and gaping ureteral orifices with later& ectopia. Laparotomy performed coincident with bilateral Leadbetter-Politano ureterovesicoplasties confirmed the absence of vagina and uterus. Two normal ovaries were identified; cordlike structures emanated from the medial aspects of both and joined with the contralateral ones in the midline. Histologic examination of both ovarian biopsies was normal. Comment
---.-FIGURE 1. General appearance demonstrates parent webbing of neck due to small clavicles.
154
ap-
Several prenatal, maternally contracted viral diseases, including rubella, measles, mumps, small pox, vaccinia, poliomyelitis, cytomegalic inclusion disease, Coxsackie, and Western equinus encephalitis, are transmitted to the fetus. Of these, rubella is the only viral disease known to cause congenital malformations in the fetus. Of previously reported cases, 5 had sequential antibody titers, which confirmed an intrauterine varicella infection. Attempts to isolate virus particles from spinal fluid, sputum,2 skin lesions,6 and autopsy specimens5 were all unsuccessful. Siegel’ suggested the possibility that the varicella infection was coincidental and not causative in cases of multiple anomalies. He studied the incidence of major malformations after prenatal maternal chicken pox, mumps, measles, and viral hepatitis, in a controlled cohort study of offspring followed up to five years of age. Major congenital
UROLOGY
/ AUGUST 1976 / VOLUME
VIII,
NUMBER
2
defects occurred in each viral group, but the malformations were equal in frequency and often similar in type to those observed among comparable controls for the respective viral groups. Consequently, the malformations which occurred could not be attributed directly to the associated diseases under study. However, the similarity of clinical features in the cases reviewed by Srabstein and co-workers suggest that the return of maternal varicella in early pregnancy and low birth weight, eye abnormalities, micrognathia, hypotrophic limbs, cortical atrophy, and skin lesions is more than coincidental. 5 Our own case presents without chorioretinitis and skin lesions, and without any immunologic or viral data. However, gross mental retardation with electroencephalogram changes were present, which could be consistent with the cortical atrophy found in the cases reviewed by Srabstein.5 The thumb and great toe changes are similar to those in the previously reported hypotrophic limb, especially with the presence of the short clavicles. Genitourinary abnormalities have been reported;1*3*5 however, the absence of uterus and vagina has not been noted previously. The kidney changes in our patient must be considered secondary to the congenital abnormality of the ureterovesical junction. Successful reconstructive urologic surgery has facilitated the general management of this severely retarded child. She has remained free of infection for twenty-four months and her urinary incontinence is markedly improved.
UROLOGY
/ AUGUST 1976 / VOLUME
VIII,
NUMBER 2
FIGURE
3.
C
ystogram
demonstrates
vesicouretetic
rejlux.
155
Whether the antecedent herpes zoster infection in our case is causative or coincidental remains a matter for speculation. Reactivation of a latent virus in the mother, who must have had previous exposure to the varicella-zoster virus, would be necessary to explain such a causative relationship. 181 East Cedar Street Newington, Connecticut 06111 (DR. KLAUBER) References
1. LAFORET, E. G., and LYNCH, C. L., JR.: Multiple congenital defects following maternal varicella. Report of
156
a case, N. Engl. J. Med. 236: 534 (1947). 2. RINVIK, R.: Congenital varicella encephalomyelitis in surviving newborn, Am. J. Dis. Child. 117: 231 (1969). 3. MCKENDRY, J. B. J., and BAILEY, J. D.: Congenital varicella associated with multiple defects, Can. Med. Assoc. J. 108: 66 (1973). 4. SAVAGE,M. O., MOOSA,A., and GORDON,R. R.: Maternal varicella infection as a cause of fetal malformations, Lancet 1: 352 (1973). Is there a congenital varicella 5. SRABSTEIN,J. C., et al.: syndrome? J. Pediatr. 84: 239 (1974). 6. DODION-FRANSEN, J., DEKEGEL, D., and THIRTY, L.: Congenital varicella-zoster infection related to maternal disease in early pregnancy, &and. J. Infec. Dis. 5: 149 (1973). 7. SIEGEL, M.: Congenital malformations following chickenpox, measles, mumps, and hepatitis, J.A.M.A. 226: 1521 (1973).
UROLOGY i
AUGUST 1976 /
VOLUME VIII. NUMBER 2
VARICELLA
SYNDROME
GENITOURINARY
ANOMALIES
GEORGE
M.D.
T. KLAUBER,
FREDERICK
WITH
J. FLYNN, JR., M.D.
BRIAN D. ALTMAN, M.D. From the Departments of Surgery (Urology) and Pediatrics, University of Connecticut Health Center, Farmington, and Newington Children’s Hospital, Newington, Connecticut
ABSTRACT -A female child, born at term to a mother who contracted varicella in early pregnancy, presented with multiple congenital defects. These included mental retardation, numerous skeletal anomalies, and absent uterus and vagina. Urologic anomalies included bilateral chronic pyelonephritis secondary to vesicoureteric reflux. This pattern of congenital abnormalities has not been reported areviouslu.
Multiple congenital malformations have been described in 6 neonates exposed in utero to maternal varicella infection. l-5 Srabstein et al5 reported 5 cases describing similar features, including exposure to varicella during the first trimester, low birth weight, eye abnormalities, disorders of the central nervous system, and skeletal and skin lesions. This suggested the possibility of a varicella syndrome. We report a case of a child with multiple defects of a pattern as yet unreported in the literature, born to a mother who contracted herpes zoster during the second month of pregnancy. Case Report A fifteen-year-old white female was admitted to the urology service at Newington Children’s Hospital in May, 1973. During the second month of pregnancy with the patient, her mother, a thirty-three-year-old, white, gravida 5, para 4, had contracted herpes zoster simultaneously with chicken pox in her four living children. No serology was available at that time. There was no known exposure to mutagens or other infections. The father was a thirty-five-year-old white male. There was no known consanguinity. Subsequent to the patient, a normal female sibling
UROLOGY
/ AUGUST 1976 / VOLUME
VIII,
NUMBER 2
was born. Family history for congenital anomalies was negative. The patient was a full-term, breech delivery. Birth weight was 2,645 Gm. Neonatal feeding difficulties were experienced, in addition to a respiratory infection which required oxygen therapy for the first ten days of life. A second episode of respiratory infection required hospitalization at two years of age. Developmental milestones were severely delayed; she walked at age thirty-six months. She had postvoid urinary incontinence and infections, and recurrent pyelonephritis. Three years prior to admission she was found radiologically to have changes of chronic cystitis, bilateral vesicoureteric reflux, and bilateral pyelonephritis. Physical examination revealed a small, stooped, thin, nonverbal, white female (Fig. 1). Height was 130 cm., weight 24.5 Kg., and head circumference 47.4 cm., all below the third percentile for her age. Facial appearance was abnormal. Eyes were in normal position with right hypertropia, slight exotropia, and bilateral ptosis. There was no chorioretinitis. Funduscopic examination was normal. The nose was severely beaked. Examination of the ears revealed retroverted pinnae, but normal tympanic membranes. The palate was
153
very high-arched, with a submucosal cleft and bifid uvula. The mandible was hypoplastic. Teeth were formed normally, but supernumerary incisors and malocclusion were present. Mild pectus excavatum was noted, with very early breast development. Pulse and blood pressure were normal. Breath sounds were normal. Heart sounds, which were in normal sinus rhythm, were normal. A grade II-III/VI short, high-pitched blowing systolic murmur was present. This is consistent with mitral insufficiency or papillary muscle dysfunction. The abdomen was unremarkable. The genitalia revealed moderate development of pubic hair. Labia, clitoris, and urethral location were all normal. Vagina was absent, being represented by a suburethral dimple; uterus could not be palpated by rectal examination. Musculoskeletal examination revealed a thoracic scoliosis, short clavicles with the suggestion of neck webbing, and generalized atrophic musculature. There were normal carrying angles of both upper extremities. The right thumb was proximally placed with respect to the first
metacarpal. Malformation of both great toes was noted with a left hallux valgus and a proximally placed right hallux (Fig. 2A). Urinalysis revealed white blood cells in clumps and masses, and significant bacteriuria. Urine culture grew Escherichia coli, with more than 100,000 colonies per cubic centimeter. Further laboratory examination revealed a buccal smear with normal female pattern; chromosome analysis was normal. Blood urea nitrogen was 20 mg. and serum creatinine 1 mg. per 100 ml. Urinary amino acids were normal. Radiologic studies indicated a bone age of thirteen years, compared with a chronologic age of fifteen. Abnormal fusion of the second and third cervical vertebrae, bilaterally enlarged and abnormal first metatarsals (Fig. 2B), and fusion of the left index finger were demonstrated by roentgenogram. Intravenous urogram revealed bilaterally shrunken pyelonephritic kidneys. Voiding cystourethrogram demonstrated bilateral low-pressure reflux to both upper collecting systems (Fig. 3). Electroencephalogram was abnormal with a generalized slowing of the tracing. Cystoscopy revealed poor trigonal development, and gaping ureteral orifices with later& ectopia. Laparotomy performed coincident with bilateral Leadbetter-Politano ureterovesicoplasties confirmed the absence of vagina and uterus. Two normal ovaries were identified; cordlike structures emanated from the medial aspects of both and joined with the contralateral ones in the midline. Histologic examination of both ovarian biopsies was normal. Comment
---.-FIGURE 1. General appearance demonstrates parent webbing of neck due to small clavicles.
154
ap-
Several prenatal, maternally contracted viral diseases, including rubella, measles, mumps, small pox, vaccinia, poliomyelitis, cytomegalic inclusion disease, Coxsackie, and Western equinus encephalitis, are transmitted to the fetus. Of these, rubella is the only viral disease known to cause congenital malformations in the fetus. Of previously reported cases, 5 had sequential antibody titers, which confirmed an intrauterine varicella infection. Attempts to isolate virus particles from spinal fluid, sputum,2 skin lesions,6 and autopsy specimens5 were all unsuccessful. Siegel’ suggested the possibility that the varicella infection was coincidental and not causative in cases of multiple anomalies. He studied the incidence of major malformations after prenatal maternal chicken pox, mumps, measles, and viral hepatitis, in a controlled cohort study of offspring followed up to five years of age. Major congenital
UROLOGY
/ AUGUST 1976 / VOLUME
VIII,
NUMBER
2
defects occurred in each viral group, but the malformations were equal in frequency and often similar in type to those observed among comparable controls for the respective viral groups. Consequently, the malformations which occurred could not be attributed directly to the associated diseases under study. However, the similarity of clinical features in the cases reviewed by Srabstein and co-workers suggest that the return of maternal varicella in early pregnancy and low birth weight, eye abnormalities, micrognathia, hypotrophic limbs, cortical atrophy, and skin lesions is more than coincidental. 5 Our own case presents without chorioretinitis and skin lesions, and without any immunologic or viral data. However, gross mental retardation with electroencephalogram changes were present, which could be consistent with the cortical atrophy found in the cases reviewed by Srabstein.5 The thumb and great toe changes are similar to those in the previously reported hypotrophic limb, especially with the presence of the short clavicles. Genitourinary abnormalities have been reported;1*3*5 however, the absence of uterus and vagina has not been noted previously. The kidney changes in our patient must be considered secondary to the congenital abnormality of the ureterovesical junction. Successful reconstructive urologic surgery has facilitated the general management of this severely retarded child. She has remained free of infection for twenty-four months and her urinary incontinence is markedly improved.
UROLOGY
/ AUGUST 1976 / VOLUME
VIII,
NUMBER 2
FIGURE
3.
C
ystogram
demonstrates
vesicouretetic
rejlux.
155
Whether the antecedent herpes zoster infection in our case is causative or coincidental remains a matter for speculation. Reactivation of a latent virus in the mother, who must have had previous exposure to the varicella-zoster virus, would be necessary to explain such a causative relationship. 181 East Cedar Street Newington, Connecticut 06111 (DR. KLAUBER) References
1. LAFORET, E. G., and LYNCH, C. L., JR.: Multiple congenital defects following maternal varicella. Report of
156
a case, N. Engl. J. Med. 236: 534 (1947). 2. RINVIK, R.: Congenital varicella encephalomyelitis in surviving newborn, Am. J. Dis. Child. 117: 231 (1969). 3. MCKENDRY, J. B. J., and BAILEY, J. D.: Congenital varicella associated with multiple defects, Can. Med. Assoc. J. 108: 66 (1973). 4. SAVAGE,M. O., MOOSA,A., and GORDON,R. R.: Maternal varicella infection as a cause of fetal malformations, Lancet 1: 352 (1973). Is there a congenital varicella 5. SRABSTEIN,J. C., et al.: syndrome? J. Pediatr. 84: 239 (1974). 6. DODION-FRANSEN, J., DEKEGEL, D., and THIRTY, L.: Congenital varicella-zoster infection related to maternal disease in early pregnancy, &and. J. Infec. Dis. 5: 149 (1973). 7. SIEGEL, M.: Congenital malformations following chickenpox, measles, mumps, and hepatitis, J.A.M.A. 226: 1521 (1973).
UROLOGY i
AUGUST 1976 /
VOLUME VIII. NUMBER 2
