American Journal of Medical Genetics 3899-102 (1991)
Polyasplenia, Caudal Deficiency, and Agenesis of the Corpus Callosum ~~
~~
Jose Ignacio Rodriguez, Jose Palacios, Felix Omenaca, and Marien Lorente Departamento de Anatomia Patologica (J.I.R., JP.) and Servicio de Neonatologia (F.O., M.L.), Hospital L a Paz, Madrid, Spain
Fullana et al. [Am J Med Genet (suppl. 2): 23-29, 19861 reported on 2 sibs with an autosoma1 recessive syndrome of caudal deficiency and polyasplenia anomalies. We report on a similar patient in which agenesis of the corpus callosum (ACC) was also found. Such an association has not been reported previously. This finding of ACC is to be interpreted as another midline anomaly rather than as a causally independent malformation.
KEY WORDS: caudal deficiency sequence, laterality sequence, polysplenia, agenesis corpus callosum, midline defects INTRODUCTION F’ullana et al. [1986] reported on 2 sibs with a syndrome of caudal deficiency and asplenia. Five similar cases with caudal deficiency and polysplenia anomalies have been found in the literature [Waldemar et al., 1982; Salvador e t al., 1983; Peoples et al., 1983; Mathias et al., 19871. We present a new patient in which manifestations of caudal deficiency sequence and laterality sequence (polyasplenia or bilateral left-sidedness sequence) have been observed. In addition, the patient had agenesis of the corpus callosum (ACC), an anomaly not previously documented in this syndrome. CLINICAL REPORT The patient, a 37 week gestation female infant, was the product of the second gestation of a 29-year-old healthy woman. The parents were non-consanguineous and the family history was unremarkable, except for the existence of 4 cases of diabetes mellitus in the mother’s family. There was no known teratogenic exposure dur-
Received for publication March 1,1990;revision received May 7, 1990.
Address reprint requests to Dr. Jose Ignacio Rodriguez, Departamento de Anatomia Patologica, Hospital La Paz, Paseo de la Castellana 261, E-28046 Madrid, Spain.
0 1991 Wiley-Liss, Inc.
ing pregnancy, and maternal blood and urinary glucose levels were normal. Ultrasound scan showed a single atrium and short femora. Delivery was spontaneous with vertex presentation; the amount of amniotic fluid was normal; and there was a single umbilical artery. At birth, the infant weighed 2,730 g and her total length was 34 cm. Apgar score a t 5 min was 5. Physical examination showed round face with apparently low-set and malformed ears, short neck, trunk, and femora, imperforate anus, ambiguous external genitalia, and multiple contractures of the lower limbs (Figs. 1,2).Radiographs showed cardiomegaly, 11 pairs of ribs, and agenesis of the sacrum and lumbar vertebrae (Fig. 3). The patient developed respiratory distress 2 hours after birth and died 2 days later. Autopsy disclosed a complex congenital heart malformation of aortic atresia, hypoplasia of the ascending aorta, hypoplasia of the left ventricle, a single atrium, and persistent atrioventricular canal with dysplastic leaflets of mitral and tricuspid valves. The ductus arteriosus was patent (13 mm of perimeter). Examination of the abdominal cavity demonstrated polysplenia and right abdominal situs of the spleens, stomach, duodenum, and pancreas; a symmetric liver; and malrotation of the bowel, with small bowel located on the right and large bowel totally on the left (Figs. 43).Microscopically, portal fibrosis in the liver and islet cell hyperplasia in the pancreas were also observed. The genitourinary system showed agenesis of the right kidney and ureter, a rounded left kidney with multiple glomerular cysts on histological study, a duplication of the uterus and vagina, and a recto-vaginal fistula. The ovaries and tubes were normal. CNS examination demonstrated ACC (Fig. 6 ) and on histological study neuronal heterotopia in the occipital white matter, glial heterotopia of meninges, and anomalies in cerebral cortical structure.
DISCUSSION Laterality sequences (bilateral left-sidedness sequence or asplenia syndrome, and bilateral right-sidedness sequence or polysplenia syndrome) are pathogenetically similar [Jones, 19881 and both represent a midline developmental field complex with variable expression of altered laterality [Opitz and Gilbert, 19821. Sporadic occurrence, autosomal dominant, autosomal
Rodriguez et al.
100
Fig. 2. Dorsal view of the patient. Note the imperforate anus
recessive, X-linked recessive inheritance, and in aneuploidy, e.g., trisomy 13, have all been documented [Opitz, 1986; Mathias et al., 19871. Fullana et al. [1986] suggested that the association of a laterality sequence with caudal deficiency represents a new syndrome with autosomal recessive inheritance. These authors described 2 sibs with asplenia and caudal deficiency. We know of 4 other sporadic cases of caudal deficiency, sacral agenesis [Waldemar et al., 19821, or imperforate anus [Salvador et al., 1983; Peoples et al., 19831 in combination with polysplenia. An additional patient with an X-linked laterality sequence showed
Fig. 1. The patient. Note facial and limb anomalies.
TABLE I. Anomalies in Patients With Polyasplenia and Caudal Deficiency* Patients
1
2
-
+ ? ? ?
-
+ ++ + +-
-
3
4
5
~~
~
Pol yasplenia Polysplenia Asplenia Bilobed lungs Trilobed lungs Situs inversus Symmetric liver Heart defect Caudal deficiency Imperforate anus Unilat. renal agenesis Renal fusion Ureter-hydronephrosis Lumbo-sacral agenesis Lower limbs anomalies Genital system defects Central nervous system Myelomeningocele Hydrocephalus Corpus callosum agenesis
-
+ + + + + + -
+ + +
+ +
6
7
+
? ? ? ?
+ +
-
++
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
+ +-
-
-
+ +
+ + +
8
~~~
+ +a -
-
-
-
-
-
-
-
-
+ ++ + +-
+ ? +
+
-
+ + +
-
+ +-
-
-
fa -
+ +-
+ + + -
-
-
+ + -
-
-
-
-
+-
-
-
-
-
-
-
-
-
-
+
*Patient 1and 2: Fullana et al. [1986]. Patient 3: Waldemar et al. [1982]. Patient 4 and 5: Peoples et al. [19831. Patient 6: Salvador et al. [19831. Patient 7: Mathias et al. [19871. Patient 8: present patient. "Anal stenosis.
Polyasplenia and Caudal Deficiency
Fig. 3. Anteroposterior roentgenogram shows agenesis of sacral and lumbar vertebrae.
101
Fig. 4. Internal view of the thoracic and abdominal viscera.
Fig. 6. Agenesis of the corpus callosum.
Fig. 5. Polysplenia.
abdominal and heart situs inversus and agenesis of the sacrum [Mathias e t al., 19871 (Table I). The present patient’s anomalies affected the genitourinary and intestinal system, lumbosacral spine, and lower limbs and
fit into the caudal deficiency sequence; other anomalies encountered in the cardiovascular system and abdominal viscera are included within the polysplenia sequence. In addition, ACC, a n anomaly not previously found in the those patients, was noted (Table I).ACC is a relatively common malformation that may occur in isolation, in combination with other malformations, or as a
102
Rodriguez et al.
part of several syndromes, e.g., FG, Aicardi, Anderson and Menkes, and G syndromes [Friede, 1989; Neri e t al., 19871. However, as far as we know, ACC has not been reported in combination with laterality or caudal deficiency sequences. The reported CNS malformations in these 2 sequences are, in the former, arteriovenous malformation of midbrain, meningocele, hydrocephalus, and cerebellar hypoplasia [Rose et al., 1975; Mathias et al., 19871, and in the latter, hydrocephalus, myelomeningocele, microcephaly, and absence of the pituitary gland [Fullana et al., 1986; Anderton and Owen, 19831. Laterality sequence, caudal deficiency sequence, and ACC are considered developmental field defects affecting the midline ofthe embryo [Opitz, 19861.The association of ACC to laterality sequence and caudal deficiency sequence in the same patient, in our opinion, should not be regarded as a fortuitous event. In this pattern of anomalies, ACC probably represents a n extension of the association described by Fullana et al. [1986]. Most midline defects tend to be statistically associated with other midline defects, and combinations occur together more than would be expected on the basis of the chance alone [Khoury et al., 19891.Therefore, the developmental field concept may explain the combination of the malformations affecting 3 different portions of the midline found in present patient.
REFERENCES Anderton JM, Owen R (1983):Absence of the pituitary gland in a case of congenital sacral agenesis. J Bone Joint Surg 65-B:182-183. Friede RL (1989): “Developmental Neuropathology.” New York: Springer-Verlag, pp 317-321. Fullana A, Garcia-Frias E, Martinez-Frias ML, Razquin S, Quero J (1986):Caudal deficiency and asplenia anomalies in sibs. Am J Med Genet (Suppl 2):23-29. Jones KL (1988):“Smith’s Recognizable Patterns of Human Malformation.” Philadelphia: WB Saunders Company, p 543. Khoury MJ, Corder0 JF, Mulinare J , Opitz JM (1989):Selected midline defects associations: A population study. Pediatrics 84:266-272. Mathias RS, Lacro VL, Lyons KL (1987): X-linked laterality sequence: Situs inversus, complex cardiac defects, splenic defects. Am J Med Genet 28:lll-116. Neri G, Genuardi M, Natoli G, Costa P, Maggioni G (1987):A girl with G syndrome and agenesis of the corpus callosum. Am J Med Genet 28:287-291. Opitz JM, Gilbert EF (1982):Editorial comment: CNS anomalies and the midline as a “developmental field.” Am J Med Genet 12443-445. Opitz JM (1986): “The Developmental Field Concept.” Alan R. Liss, Inc., New York. Peoples WM, Moller JH, Edwards J E (1983): Polysplenia: A review of 146 cases. Pediatr Cardiol 4:129-137. Rose V, Izukawa T, Moes CAF (1975): Syndromes of asplenia and polysplenia. A review of cardiac and non-cardiac malformations in 60 cases with special reference to diagnosis and prognosis. Br Heart J 37:840-852. Salvador J , Sanchez de Le6n L, Felix V, Frias J , Martinez-Frias ML (1983): Caso Clinico. Bol ECEMC, serie 11 no.2:15-19. Waldemar AC, Kliegman RM, Dixon MS, Fletcher BD, Fanaroff AA (1982): Vertebral agenesis. Am J Dis Child 136533-537,
Polyasplenia, Caudal Deficiency, and Agenesis of the Corpus Callosum ~~
~~
Jose Ignacio Rodriguez, Jose Palacios, Felix Omenaca, and Marien Lorente Departamento de Anatomia Patologica (J.I.R., JP.) and Servicio de Neonatologia (F.O., M.L.), Hospital L a Paz, Madrid, Spain
Fullana et al. [Am J Med Genet (suppl. 2): 23-29, 19861 reported on 2 sibs with an autosoma1 recessive syndrome of caudal deficiency and polyasplenia anomalies. We report on a similar patient in which agenesis of the corpus callosum (ACC) was also found. Such an association has not been reported previously. This finding of ACC is to be interpreted as another midline anomaly rather than as a causally independent malformation.
KEY WORDS: caudal deficiency sequence, laterality sequence, polysplenia, agenesis corpus callosum, midline defects INTRODUCTION F’ullana et al. [1986] reported on 2 sibs with a syndrome of caudal deficiency and asplenia. Five similar cases with caudal deficiency and polysplenia anomalies have been found in the literature [Waldemar et al., 1982; Salvador e t al., 1983; Peoples et al., 1983; Mathias et al., 19871. We present a new patient in which manifestations of caudal deficiency sequence and laterality sequence (polyasplenia or bilateral left-sidedness sequence) have been observed. In addition, the patient had agenesis of the corpus callosum (ACC), an anomaly not previously documented in this syndrome. CLINICAL REPORT The patient, a 37 week gestation female infant, was the product of the second gestation of a 29-year-old healthy woman. The parents were non-consanguineous and the family history was unremarkable, except for the existence of 4 cases of diabetes mellitus in the mother’s family. There was no known teratogenic exposure dur-
Received for publication March 1,1990;revision received May 7, 1990.
Address reprint requests to Dr. Jose Ignacio Rodriguez, Departamento de Anatomia Patologica, Hospital La Paz, Paseo de la Castellana 261, E-28046 Madrid, Spain.
0 1991 Wiley-Liss, Inc.
ing pregnancy, and maternal blood and urinary glucose levels were normal. Ultrasound scan showed a single atrium and short femora. Delivery was spontaneous with vertex presentation; the amount of amniotic fluid was normal; and there was a single umbilical artery. At birth, the infant weighed 2,730 g and her total length was 34 cm. Apgar score a t 5 min was 5. Physical examination showed round face with apparently low-set and malformed ears, short neck, trunk, and femora, imperforate anus, ambiguous external genitalia, and multiple contractures of the lower limbs (Figs. 1,2).Radiographs showed cardiomegaly, 11 pairs of ribs, and agenesis of the sacrum and lumbar vertebrae (Fig. 3). The patient developed respiratory distress 2 hours after birth and died 2 days later. Autopsy disclosed a complex congenital heart malformation of aortic atresia, hypoplasia of the ascending aorta, hypoplasia of the left ventricle, a single atrium, and persistent atrioventricular canal with dysplastic leaflets of mitral and tricuspid valves. The ductus arteriosus was patent (13 mm of perimeter). Examination of the abdominal cavity demonstrated polysplenia and right abdominal situs of the spleens, stomach, duodenum, and pancreas; a symmetric liver; and malrotation of the bowel, with small bowel located on the right and large bowel totally on the left (Figs. 43).Microscopically, portal fibrosis in the liver and islet cell hyperplasia in the pancreas were also observed. The genitourinary system showed agenesis of the right kidney and ureter, a rounded left kidney with multiple glomerular cysts on histological study, a duplication of the uterus and vagina, and a recto-vaginal fistula. The ovaries and tubes were normal. CNS examination demonstrated ACC (Fig. 6 ) and on histological study neuronal heterotopia in the occipital white matter, glial heterotopia of meninges, and anomalies in cerebral cortical structure.
DISCUSSION Laterality sequences (bilateral left-sidedness sequence or asplenia syndrome, and bilateral right-sidedness sequence or polysplenia syndrome) are pathogenetically similar [Jones, 19881 and both represent a midline developmental field complex with variable expression of altered laterality [Opitz and Gilbert, 19821. Sporadic occurrence, autosomal dominant, autosomal
Rodriguez et al.
100
Fig. 2. Dorsal view of the patient. Note the imperforate anus
recessive, X-linked recessive inheritance, and in aneuploidy, e.g., trisomy 13, have all been documented [Opitz, 1986; Mathias et al., 19871. Fullana et al. [1986] suggested that the association of a laterality sequence with caudal deficiency represents a new syndrome with autosomal recessive inheritance. These authors described 2 sibs with asplenia and caudal deficiency. We know of 4 other sporadic cases of caudal deficiency, sacral agenesis [Waldemar et al., 19821, or imperforate anus [Salvador et al., 1983; Peoples et al., 19831 in combination with polysplenia. An additional patient with an X-linked laterality sequence showed
Fig. 1. The patient. Note facial and limb anomalies.
TABLE I. Anomalies in Patients With Polyasplenia and Caudal Deficiency* Patients
1
2
-
+ ? ? ?
-
+ ++ + +-
-
3
4
5
~~
~
Pol yasplenia Polysplenia Asplenia Bilobed lungs Trilobed lungs Situs inversus Symmetric liver Heart defect Caudal deficiency Imperforate anus Unilat. renal agenesis Renal fusion Ureter-hydronephrosis Lumbo-sacral agenesis Lower limbs anomalies Genital system defects Central nervous system Myelomeningocele Hydrocephalus Corpus callosum agenesis
-
+ + + + + + -
+ + +
+ +
6
7
+
? ? ? ?
+ +
-
++
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
+ +-
-
-
+ +
+ + +
8
~~~
+ +a -
-
-
-
-
-
-
-
-
+ ++ + +-
+ ? +
+
-
+ + +
-
+ +-
-
-
fa -
+ +-
+ + + -
-
-
+ + -
-
-
-
-
+-
-
-
-
-
-
-
-
-
-
+
*Patient 1and 2: Fullana et al. [1986]. Patient 3: Waldemar et al. [1982]. Patient 4 and 5: Peoples et al. [19831. Patient 6: Salvador et al. [19831. Patient 7: Mathias et al. [19871. Patient 8: present patient. "Anal stenosis.
Polyasplenia and Caudal Deficiency
Fig. 3. Anteroposterior roentgenogram shows agenesis of sacral and lumbar vertebrae.
101
Fig. 4. Internal view of the thoracic and abdominal viscera.
Fig. 6. Agenesis of the corpus callosum.
Fig. 5. Polysplenia.
abdominal and heart situs inversus and agenesis of the sacrum [Mathias e t al., 19871 (Table I). The present patient’s anomalies affected the genitourinary and intestinal system, lumbosacral spine, and lower limbs and
fit into the caudal deficiency sequence; other anomalies encountered in the cardiovascular system and abdominal viscera are included within the polysplenia sequence. In addition, ACC, a n anomaly not previously found in the those patients, was noted (Table I).ACC is a relatively common malformation that may occur in isolation, in combination with other malformations, or as a
102
Rodriguez et al.
part of several syndromes, e.g., FG, Aicardi, Anderson and Menkes, and G syndromes [Friede, 1989; Neri e t al., 19871. However, as far as we know, ACC has not been reported in combination with laterality or caudal deficiency sequences. The reported CNS malformations in these 2 sequences are, in the former, arteriovenous malformation of midbrain, meningocele, hydrocephalus, and cerebellar hypoplasia [Rose et al., 1975; Mathias et al., 19871, and in the latter, hydrocephalus, myelomeningocele, microcephaly, and absence of the pituitary gland [Fullana et al., 1986; Anderton and Owen, 19831. Laterality sequence, caudal deficiency sequence, and ACC are considered developmental field defects affecting the midline ofthe embryo [Opitz, 19861.The association of ACC to laterality sequence and caudal deficiency sequence in the same patient, in our opinion, should not be regarded as a fortuitous event. In this pattern of anomalies, ACC probably represents a n extension of the association described by Fullana et al. [1986]. Most midline defects tend to be statistically associated with other midline defects, and combinations occur together more than would be expected on the basis of the chance alone [Khoury et al., 19891.Therefore, the developmental field concept may explain the combination of the malformations affecting 3 different portions of the midline found in present patient.
REFERENCES Anderton JM, Owen R (1983):Absence of the pituitary gland in a case of congenital sacral agenesis. J Bone Joint Surg 65-B:182-183. Friede RL (1989): “Developmental Neuropathology.” New York: Springer-Verlag, pp 317-321. Fullana A, Garcia-Frias E, Martinez-Frias ML, Razquin S, Quero J (1986):Caudal deficiency and asplenia anomalies in sibs. Am J Med Genet (Suppl 2):23-29. Jones KL (1988):“Smith’s Recognizable Patterns of Human Malformation.” Philadelphia: WB Saunders Company, p 543. Khoury MJ, Corder0 JF, Mulinare J , Opitz JM (1989):Selected midline defects associations: A population study. Pediatrics 84:266-272. Mathias RS, Lacro VL, Lyons KL (1987): X-linked laterality sequence: Situs inversus, complex cardiac defects, splenic defects. Am J Med Genet 28:lll-116. Neri G, Genuardi M, Natoli G, Costa P, Maggioni G (1987):A girl with G syndrome and agenesis of the corpus callosum. Am J Med Genet 28:287-291. Opitz JM, Gilbert EF (1982):Editorial comment: CNS anomalies and the midline as a “developmental field.” Am J Med Genet 12443-445. Opitz JM (1986): “The Developmental Field Concept.” Alan R. Liss, Inc., New York. Peoples WM, Moller JH, Edwards J E (1983): Polysplenia: A review of 146 cases. Pediatr Cardiol 4:129-137. Rose V, Izukawa T, Moes CAF (1975): Syndromes of asplenia and polysplenia. A review of cardiac and non-cardiac malformations in 60 cases with special reference to diagnosis and prognosis. Br Heart J 37:840-852. Salvador J , Sanchez de Le6n L, Felix V, Frias J , Martinez-Frias ML (1983): Caso Clinico. Bol ECEMC, serie 11 no.2:15-19. Waldemar AC, Kliegman RM, Dixon MS, Fletcher BD, Fanaroff AA (1982): Vertebral agenesis. Am J Dis Child 136533-537,
