Int J Gynecol Qbstet, 1992, 39: 321-332 International Federation of Gynecology and Obstetrics
321
Prenatal diagnosis of recurrent Meckel Syndrome H.M. Ramadani
and H.A. Nasrat
Department of Obsterics and Gynaecology. King Abdulaziz University, College of Medicine, Jeaiiah (Saudi Arabia)
(Received April 13th, 1992) (Revised and accepted July 29th, 1992)
frame of the currently accepted ethical guidelines in our society are being discussed.
Abstract We report a rare case of Me&e/-Gruber syndrome in a woman who had three affected offsprings in the past with similar condition. Ante-natal ultrasonographic diagnosis and management are presented.
Keywords Ante-natal; Ultrasound Meckel-Gruber syndrome.
diagnosis;
Introduction The Meckel-Gruber Syndrome is a condition of multiple congenital abnormalities with an occipital encephalocele, polydactyly and polycystic kidney disease with some other variable features [4,9,11,1 S]. The condition is considered invariably fatal with an autosomal recessive pattern of transmission, a 25% recurrence risk and no recognized expression in the presumed carriers of the gene. Prenatally, the diagnosis is entertained in the presence’of an elevated alpha-fetoprotein level with an encephalocele and/or a sonographic delineation of the polycystic enlarged kidneys. Here we report a case with four recurrences of Meckel-Gruber Syndrome in one Saudi family. The indications for prenatal diagnosis and the approach for management, within the 0020-7292l92605.00 0 1992 International
Federation of Gynecology and Obstetrics Printed and Published in Ireland
Case report A 37-year-old Saudi female, was referred from another hospital following an ultrasound diagnosis of severe hydrocephalus. She had no relevent medical history and her husband was a first cousin. She was G9, P6, A2 and in three of her previous pregnancies, she gave birth to babies with almost similar malformations. The first two pregnancies, ended by spontaneous full term home deliveries of healthy girls who are alive and well. She then had a spontaneous miscarriage at 12 weeks. The following three pregnancies continued to the third trimesters and ended by vaginal deliveries, at home, of congenitally malformed babies. Chacteristically, they were all described as having features of encephalocele, polydactyly plus other nonspecific limb anomalies. The fourth pregnancy was a stillborn, the fifth was an early neonatal death (lived for a few minutes) and the sixth was a girl who lived for about 2 months before she died. The mother then had another spontaneous miscarriage at 12 weeks. In the eighth pregnancy she was followed antenatally at a local hospital, was diagnosed as having gestational diabetes. The male fetus had severe hydrocephaly and was delivered at Case Report
328
Ram&i
and Nasrat
37 weeks of gestation by an elective lower segment cesarean section weighing 3.4 kg. At delivery, the baby exhibited multiple anomalies, namely: hydrocephaly, occipital encephalocele, short neck and post axial and feet. polydactyly in both hands Encephalocele and hydrocephaly were corrected surgically, but he only lived for 1 month. The case was diagnosed as MeckelGruber Syndrome. In the last, index pregnancy, when the patient was referred to this unit, she was at approximately 28 weeks gestation according to her last menstrual period and an early ultrasound. However, the uterine fundal height corresponded to 36 weeks gestation with polyhydramnios. Serum cr-fetoprotein was 127.2 IU/ml. A level II ultrasound scan showed a fetus with
biparietal diameter equivalemt to 32 weeks gestation, other measurements including abdominal circumference, femur length and humerus were less than the 10th percentile for the estimated gestational age of 28 weeks. There was severe polyhydramnios; large occipital encephalocoele (measuring 5 x 6 cm) was confirmed. The lateral and fourth ventricles were extensively dilated and communicating together, the cerebellum was hypoplastic with a minimum amount of brain matter seen (Fig. 1). The vertebral spines looked intact, the heart, lungs, kidneys, stomach, bladder and abdominal wall were seen as normal. The parents were counselled regarding the findings and prognosis. After discussion they expressed their preference not to continue with the pregnancy, if at all possible.
Fig. 1. Ultrasound showing posterior occipital encephalocele and dilated ventricles. Int J Gynecol Obstet 39
Dtiagnosis of Meckel Syndrome
Fig. 2.
329
Newborn with occipital encephalocele.
The case was further discussed in the hospital ethical committee and eventually it was agreed to induce labor at around 32 weeks gestation. Labor was induced by prostin E 3.0 mg vaginal tablets. After a total of 8 h, she spontaneously delivered a girl with an apgar score of 3, 6 and 8 at 1, 5 and 10 min, respectively, with birth weight of 2410 g and she had a large occipital encephalocele (Fig. 2), extremely small low set ears, depressed nasal bridge, maxillary hypoplasia, hypertelorism, micrognathia, short web neck, lobulated fragmented tongue (Fig. 3), extra digit on both hands and feet (Figs. 4 and 5). All extremities were short and trunk examination showed no nipples. The placenta
weighed 350 g with 3 vessels in the cord. A cord blood sample was sent from the newborn for karyotyping which later revealed a normal female (46 XX). The baby’s length was 43 cm, head circumference 34 cm and chest circumference 26 cm. It survived for 36 h before it expired. A post-mortem limited necropsy, performed on the chest and abdominal organs, showed normal heart and great vessels, hypoplastic lung, normal liver, kidney and stomach and the rest of the abdominal organs were normal. Disclussion Meckel-Gruber Syndrome (MGS) was first Case Report
330
Ramadani and Nasrat
Fig. 5.
Fig. 3.
Labulated gragmental tongue.
Fig. 4.
Left hand with extra digit.
Int J Gynecol Obstet 39
Left foot with polydactyly.
described more than 170 years ago [9]. Commonly referred to as the Meckel Syndrome (MS), it refers to the polytropic combination of occipital meningoencephalocele, polydactyly and polycystic kidneys. However, two of the three main manifestations are enough to establish the diagnosis [lo]. Hasia et al. [5] have proposed that other frequently seen anomalies such as cleft lip and/or palate, microcephaly, microphthalmia, small or ambiguous genitalia are frequently seen with Meckel Syndrome. The incidence of Meckel syndrome diagnosed at birth, varies from 1:140 000 to I:13 250 births [14]. In the case presented, encephalocele and poldactyly were the main present anomalies, mentioned earlier. plus others These anomalies, added to the positive history of similar malformations strongly suggest Meckel Syndrome. In a typical case, the earliest clinical and sonographic finding is oligohydramnios, which is usually a result of nonfunctioning kidneys. Two components of the triad of microcephaly, hydrocephaly or encephalocoele, polydactyly and bilateral cystic kidneys should strongly suggest the diagnosis of MS [2,6,16]. However, the ultrasonographic picture of the autosomal dominant polycystic kidney disease (ADPKD) has to be differen-
Diagnosis of Meckel
tiated from that of Meckel Syndrome [ 181. A high amniotic fluid AFP would suggest the diagnosis [2,7] and fetal cell karyotyping would rule out trisomies. Antenatal sonographic diagnosis of MS should include prompt cardiac evaluation by fetal echocardiography [3]. Opitz [l l] reported 13.8% congenital heart disease (5 out of 36 patients) in association with MS. The earliest prenatal diagnosis of MS was at 13 weeks gestation by ultrasound in a patient with a 25% recurrent risk [lo]. Recently, magnetic resonance imaging has been reported as a helpful tool in confirming the diagnosis of MS where the fetal subcutaneous tissues, CNS, spinal cord and abdominal organs are particularly well visualized [ 171, In our case there was consanguinity factor, 3 neonates affected in the family and ultrasound confirmed the diagnosis in the current case. MS had an autosomal recessive form of inheritance. The parents were not karotyped, but as in the previous reports karyotyping of parents has not been considered necessary for making the diagnosis. The survival of MS infants depends largely on the spectrum of anomalies and severity. The majority are either stillborn or die immediately after delivery. Lowry [8] reported two affected siblings where one survived for nearly 28 months without mention about the quality of life. Although not all patients die immediately after birth and the phenotype may not be severely abnormal, the quality of life is extremely poor. This information should be considered when parents are counselled. In this case there was a large encephalocele with ventriculomegally and hardly any cerebral brain matter together with hypoplasia of the cerebellum. Therefore the option of termination of pregnancy by induction of labor was offered to the couple. The issue of termination of pregnancy has been a subject of much debate and discussion among scholars and physicians. The present ‘Fatwa’ prohibits termination of pregnancy (TOP) after 134 days from the first day of the last
Syndrome
331
menstrual period (before this date TOP can only be performed for very strong indications). After this age i.e. 134 days, the fetus is an independent life, who deserves all respect and rights that any born individual would have [l]. Therefore it was only possible to induce labor at this gestational age when the case of fetal survival outweighed the risk of death from prematurity, taking into account the facilities of the hospital’s newborn intensive care unit. In this case, induction of labor at 32 weeks avoid maternal risks of a longer period of full term pregnancy and possible repeat cesarean section. With the present technology of high resolution ultrasonography, and transvaginal probes, first trimester diagnosis is possible. For their future pregancies, the couple were advised to attend for medical care as early as possible whenever pregnancy is suspected. In summary this case describes perhaps for the first time, a recurrent MS syndrome in a Saudi family, explaining its main features. It also demostrates the management options for care of fetal anomalies presently acceptable in local society. References Albar M: The Malformed Fetus: Etiology, Diagnosis and Islamic Jurispendence view (Arabic). p 439, Al Manara Publishing House, Jeddah, 1991. Aula P, Karjalainen 0, Rapola J, Lindgren J, Seppala M: Prenatal diagnosis of the Meckel syndrome. Am J Obstet Gynecol 129: 700, 1977. Cope.1JA, Pilu G, ICleimnan CS: Congenital heart disease and extra cardiac anomalies: associations and indications for fetal echocardiography. Am J Obstet Gynecol 154: 1121, 1986. Gruber GB: Beitrage Zur Frage ‘gekoppelter’ missbildungen (Akrocephalosyndactylie und Dysencephalia splanchnocystica). Beiter. Path01 Anat 93: 459, 1934. Hsia YE, Bratu M, Herbordt A: Genetics of the Meckel syndrome (dysencephalia splanchnocystica). Pediatrics 48: 237, 1971. Johnson VP, Holzwarth DR: Prenatal Diagnosis of Meckel syndrome: Case reports and literature review. Am J Med Genet 18: 699, 1984. Karjalainen 0. Aula P, Seppala M, Hartikainen-sorri AL, Article
332
8
9
10
11
12
13
14
Ramaahi and Nasrat Ryynanen N: Prenatal Diagnosis of the Meckel Syndrome. Obstet Gynecol 57: 13S, 1981. Lowry RB, Hill RH, Tischler B: Survival and spectrum of anomalies in the Meckel Syndrome. Am J Med Genet 14: 417, 1983. Meckel, JR: Beschreibung Zweier durch sehr ahnliche Bildungsabweichung en&teller Geschwister. Dtsch. Arch Physiol 7: 99, 1822. Meckle S, Passarge E: Encephalocele, polycystic kidneys and polydactyly as an autosomal recessive trait simulating certain other disorders: The Meckel syndrome: Ann Genet (Paris) 14: 97, 1971. Opitz JM, Howe JJ. The Meckel Syndrome (dysencephalia splanchnocystica the Gruber syndrome) Birth defects 5: 167, 1969. Pachi A, Gioancotti A, Torcia F, Deprosperi V, Maggi E: Meckel-Gruber Syndrome: Ultrasonographic diagnosis at 13 weeks gestational age in at risk case. Prenat Diagn Mar 9: 87, 1989. Salonen R, Norio R: The Meckel syndrome in Finland: epidemiologic and genetic aspects: Am J Med Genet 18: 691, 1984. Salonen R: The Meckel syndrome: Clinicopathological findings in 67 patients. Am J Med Genet 18: 671, 1984.
Int J Gynecol Obstet 39
Smith DW, Jones KL: Recongnizable pattern of human malformation genetic, embroyological and clinical aspects, p 140, W.B. Saunders Company, Philadelphia, 1982. Wapner RJ, Kurtz AB, Ross RD, Jackson LG: Ultraasonographic parameters in the pre-natal diagnosis of Meckel syndrome. Obstet Gynecol57: 388, 1981. Williamson RA, Weiner CP, Yuh WT, Ahu-Yousef MM: Magnetic resonance imaging of anomalous fetuses. Obstet Gynecol 73: 952, 1989. Zerres K, Hansmann M, Knopfle G, Stephen M: Prenatal diagnosis of genetically determined early manifestation of autosomal dominant polycystic kidney disease? Human Genet 71: 368, 1985.
Address for reprin& H. Ramadani Department of Obstetrics and Gpcology P.O. Box 6615 Jeddab 21452 !hdie Arabia
321
Prenatal diagnosis of recurrent Meckel Syndrome H.M. Ramadani
and H.A. Nasrat
Department of Obsterics and Gynaecology. King Abdulaziz University, College of Medicine, Jeaiiah (Saudi Arabia)
(Received April 13th, 1992) (Revised and accepted July 29th, 1992)
frame of the currently accepted ethical guidelines in our society are being discussed.
Abstract We report a rare case of Me&e/-Gruber syndrome in a woman who had three affected offsprings in the past with similar condition. Ante-natal ultrasonographic diagnosis and management are presented.
Keywords Ante-natal; Ultrasound Meckel-Gruber syndrome.
diagnosis;
Introduction The Meckel-Gruber Syndrome is a condition of multiple congenital abnormalities with an occipital encephalocele, polydactyly and polycystic kidney disease with some other variable features [4,9,11,1 S]. The condition is considered invariably fatal with an autosomal recessive pattern of transmission, a 25% recurrence risk and no recognized expression in the presumed carriers of the gene. Prenatally, the diagnosis is entertained in the presence’of an elevated alpha-fetoprotein level with an encephalocele and/or a sonographic delineation of the polycystic enlarged kidneys. Here we report a case with four recurrences of Meckel-Gruber Syndrome in one Saudi family. The indications for prenatal diagnosis and the approach for management, within the 0020-7292l92605.00 0 1992 International
Federation of Gynecology and Obstetrics Printed and Published in Ireland
Case report A 37-year-old Saudi female, was referred from another hospital following an ultrasound diagnosis of severe hydrocephalus. She had no relevent medical history and her husband was a first cousin. She was G9, P6, A2 and in three of her previous pregnancies, she gave birth to babies with almost similar malformations. The first two pregnancies, ended by spontaneous full term home deliveries of healthy girls who are alive and well. She then had a spontaneous miscarriage at 12 weeks. The following three pregnancies continued to the third trimesters and ended by vaginal deliveries, at home, of congenitally malformed babies. Chacteristically, they were all described as having features of encephalocele, polydactyly plus other nonspecific limb anomalies. The fourth pregnancy was a stillborn, the fifth was an early neonatal death (lived for a few minutes) and the sixth was a girl who lived for about 2 months before she died. The mother then had another spontaneous miscarriage at 12 weeks. In the eighth pregnancy she was followed antenatally at a local hospital, was diagnosed as having gestational diabetes. The male fetus had severe hydrocephaly and was delivered at Case Report
328
Ram&i
and Nasrat
37 weeks of gestation by an elective lower segment cesarean section weighing 3.4 kg. At delivery, the baby exhibited multiple anomalies, namely: hydrocephaly, occipital encephalocele, short neck and post axial and feet. polydactyly in both hands Encephalocele and hydrocephaly were corrected surgically, but he only lived for 1 month. The case was diagnosed as MeckelGruber Syndrome. In the last, index pregnancy, when the patient was referred to this unit, she was at approximately 28 weeks gestation according to her last menstrual period and an early ultrasound. However, the uterine fundal height corresponded to 36 weeks gestation with polyhydramnios. Serum cr-fetoprotein was 127.2 IU/ml. A level II ultrasound scan showed a fetus with
biparietal diameter equivalemt to 32 weeks gestation, other measurements including abdominal circumference, femur length and humerus were less than the 10th percentile for the estimated gestational age of 28 weeks. There was severe polyhydramnios; large occipital encephalocoele (measuring 5 x 6 cm) was confirmed. The lateral and fourth ventricles were extensively dilated and communicating together, the cerebellum was hypoplastic with a minimum amount of brain matter seen (Fig. 1). The vertebral spines looked intact, the heart, lungs, kidneys, stomach, bladder and abdominal wall were seen as normal. The parents were counselled regarding the findings and prognosis. After discussion they expressed their preference not to continue with the pregnancy, if at all possible.
Fig. 1. Ultrasound showing posterior occipital encephalocele and dilated ventricles. Int J Gynecol Obstet 39
Dtiagnosis of Meckel Syndrome
Fig. 2.
329
Newborn with occipital encephalocele.
The case was further discussed in the hospital ethical committee and eventually it was agreed to induce labor at around 32 weeks gestation. Labor was induced by prostin E 3.0 mg vaginal tablets. After a total of 8 h, she spontaneously delivered a girl with an apgar score of 3, 6 and 8 at 1, 5 and 10 min, respectively, with birth weight of 2410 g and she had a large occipital encephalocele (Fig. 2), extremely small low set ears, depressed nasal bridge, maxillary hypoplasia, hypertelorism, micrognathia, short web neck, lobulated fragmented tongue (Fig. 3), extra digit on both hands and feet (Figs. 4 and 5). All extremities were short and trunk examination showed no nipples. The placenta
weighed 350 g with 3 vessels in the cord. A cord blood sample was sent from the newborn for karyotyping which later revealed a normal female (46 XX). The baby’s length was 43 cm, head circumference 34 cm and chest circumference 26 cm. It survived for 36 h before it expired. A post-mortem limited necropsy, performed on the chest and abdominal organs, showed normal heart and great vessels, hypoplastic lung, normal liver, kidney and stomach and the rest of the abdominal organs were normal. Disclussion Meckel-Gruber Syndrome (MGS) was first Case Report
330
Ramadani and Nasrat
Fig. 5.
Fig. 3.
Labulated gragmental tongue.
Fig. 4.
Left hand with extra digit.
Int J Gynecol Obstet 39
Left foot with polydactyly.
described more than 170 years ago [9]. Commonly referred to as the Meckel Syndrome (MS), it refers to the polytropic combination of occipital meningoencephalocele, polydactyly and polycystic kidneys. However, two of the three main manifestations are enough to establish the diagnosis [lo]. Hasia et al. [5] have proposed that other frequently seen anomalies such as cleft lip and/or palate, microcephaly, microphthalmia, small or ambiguous genitalia are frequently seen with Meckel Syndrome. The incidence of Meckel syndrome diagnosed at birth, varies from 1:140 000 to I:13 250 births [14]. In the case presented, encephalocele and poldactyly were the main present anomalies, mentioned earlier. plus others These anomalies, added to the positive history of similar malformations strongly suggest Meckel Syndrome. In a typical case, the earliest clinical and sonographic finding is oligohydramnios, which is usually a result of nonfunctioning kidneys. Two components of the triad of microcephaly, hydrocephaly or encephalocoele, polydactyly and bilateral cystic kidneys should strongly suggest the diagnosis of MS [2,6,16]. However, the ultrasonographic picture of the autosomal dominant polycystic kidney disease (ADPKD) has to be differen-
Diagnosis of Meckel
tiated from that of Meckel Syndrome [ 181. A high amniotic fluid AFP would suggest the diagnosis [2,7] and fetal cell karyotyping would rule out trisomies. Antenatal sonographic diagnosis of MS should include prompt cardiac evaluation by fetal echocardiography [3]. Opitz [l l] reported 13.8% congenital heart disease (5 out of 36 patients) in association with MS. The earliest prenatal diagnosis of MS was at 13 weeks gestation by ultrasound in a patient with a 25% recurrent risk [lo]. Recently, magnetic resonance imaging has been reported as a helpful tool in confirming the diagnosis of MS where the fetal subcutaneous tissues, CNS, spinal cord and abdominal organs are particularly well visualized [ 171, In our case there was consanguinity factor, 3 neonates affected in the family and ultrasound confirmed the diagnosis in the current case. MS had an autosomal recessive form of inheritance. The parents were not karotyped, but as in the previous reports karyotyping of parents has not been considered necessary for making the diagnosis. The survival of MS infants depends largely on the spectrum of anomalies and severity. The majority are either stillborn or die immediately after delivery. Lowry [8] reported two affected siblings where one survived for nearly 28 months without mention about the quality of life. Although not all patients die immediately after birth and the phenotype may not be severely abnormal, the quality of life is extremely poor. This information should be considered when parents are counselled. In this case there was a large encephalocele with ventriculomegally and hardly any cerebral brain matter together with hypoplasia of the cerebellum. Therefore the option of termination of pregnancy by induction of labor was offered to the couple. The issue of termination of pregnancy has been a subject of much debate and discussion among scholars and physicians. The present ‘Fatwa’ prohibits termination of pregnancy (TOP) after 134 days from the first day of the last
Syndrome
331
menstrual period (before this date TOP can only be performed for very strong indications). After this age i.e. 134 days, the fetus is an independent life, who deserves all respect and rights that any born individual would have [l]. Therefore it was only possible to induce labor at this gestational age when the case of fetal survival outweighed the risk of death from prematurity, taking into account the facilities of the hospital’s newborn intensive care unit. In this case, induction of labor at 32 weeks avoid maternal risks of a longer period of full term pregnancy and possible repeat cesarean section. With the present technology of high resolution ultrasonography, and transvaginal probes, first trimester diagnosis is possible. For their future pregancies, the couple were advised to attend for medical care as early as possible whenever pregnancy is suspected. In summary this case describes perhaps for the first time, a recurrent MS syndrome in a Saudi family, explaining its main features. It also demostrates the management options for care of fetal anomalies presently acceptable in local society. References Albar M: The Malformed Fetus: Etiology, Diagnosis and Islamic Jurispendence view (Arabic). p 439, Al Manara Publishing House, Jeddah, 1991. Aula P, Karjalainen 0, Rapola J, Lindgren J, Seppala M: Prenatal diagnosis of the Meckel syndrome. Am J Obstet Gynecol 129: 700, 1977. Cope.1JA, Pilu G, ICleimnan CS: Congenital heart disease and extra cardiac anomalies: associations and indications for fetal echocardiography. Am J Obstet Gynecol 154: 1121, 1986. Gruber GB: Beitrage Zur Frage ‘gekoppelter’ missbildungen (Akrocephalosyndactylie und Dysencephalia splanchnocystica). Beiter. Path01 Anat 93: 459, 1934. Hsia YE, Bratu M, Herbordt A: Genetics of the Meckel syndrome (dysencephalia splanchnocystica). Pediatrics 48: 237, 1971. Johnson VP, Holzwarth DR: Prenatal Diagnosis of Meckel syndrome: Case reports and literature review. Am J Med Genet 18: 699, 1984. Karjalainen 0. Aula P, Seppala M, Hartikainen-sorri AL, Article
332
8
9
10
11
12
13
14
Ramaahi and Nasrat Ryynanen N: Prenatal Diagnosis of the Meckel Syndrome. Obstet Gynecol 57: 13S, 1981. Lowry RB, Hill RH, Tischler B: Survival and spectrum of anomalies in the Meckel Syndrome. Am J Med Genet 14: 417, 1983. Meckel, JR: Beschreibung Zweier durch sehr ahnliche Bildungsabweichung en&teller Geschwister. Dtsch. Arch Physiol 7: 99, 1822. Meckle S, Passarge E: Encephalocele, polycystic kidneys and polydactyly as an autosomal recessive trait simulating certain other disorders: The Meckel syndrome: Ann Genet (Paris) 14: 97, 1971. Opitz JM, Howe JJ. The Meckel Syndrome (dysencephalia splanchnocystica the Gruber syndrome) Birth defects 5: 167, 1969. Pachi A, Gioancotti A, Torcia F, Deprosperi V, Maggi E: Meckel-Gruber Syndrome: Ultrasonographic diagnosis at 13 weeks gestational age in at risk case. Prenat Diagn Mar 9: 87, 1989. Salonen R, Norio R: The Meckel syndrome in Finland: epidemiologic and genetic aspects: Am J Med Genet 18: 691, 1984. Salonen R: The Meckel syndrome: Clinicopathological findings in 67 patients. Am J Med Genet 18: 671, 1984.
Int J Gynecol Obstet 39
Smith DW, Jones KL: Recongnizable pattern of human malformation genetic, embroyological and clinical aspects, p 140, W.B. Saunders Company, Philadelphia, 1982. Wapner RJ, Kurtz AB, Ross RD, Jackson LG: Ultraasonographic parameters in the pre-natal diagnosis of Meckel syndrome. Obstet Gynecol57: 388, 1981. Williamson RA, Weiner CP, Yuh WT, Ahu-Yousef MM: Magnetic resonance imaging of anomalous fetuses. Obstet Gynecol 73: 952, 1989. Zerres K, Hansmann M, Knopfle G, Stephen M: Prenatal diagnosis of genetically determined early manifestation of autosomal dominant polycystic kidney disease? Human Genet 71: 368, 1985.
Address for reprin& H. Ramadani Department of Obstetrics and Gpcology P.O. Box 6615 Jeddab 21452 !hdie Arabia
