American Journal of Medical Genetics 43:732-736 (1992)
Craniorachischisis Totalis and Sirenomelia Jose Ignacio Rodriguez and Jose Palacios Department of Pathology, La Paz Hospital, Madrid, Spain
We report on a male infant with craniorachischisis totalis and sirenomelia, an association that seems to have been observed only 5 times before. In addition to these anomalies, the patient had hypoplasia of the phalanges of the right thumb. The pattern of associated malformations in infants with anencephaly and sirenomelia is reviewed. This condition, which combines cephalic and caudal defects of the embryo, could be considered an example of the “axial mesodermal dysplasia spectrum” and may be related to the midline developmental field concept. Q 1992 Wiley-Liss, Inc. KEY WORDS: anencephaly,sirenomelia, mesodermal dysplasia, midline abnormalities
anus, and a single “fused” lower limb, ending in a single foot with 8 toes (Figs. 1,2). The right thumb was proximally implanted (Fig. 3). Postmortem radiographs (Figs. 4,5) demonstrated absence of the cranial vault, complete rachischisis with multiple errors of the spinal segmentation, and no sacrum. The single lower limb contained 2 femora and tibiae, and 8 metatarsals and phalanges. The right thumb had hypoplastic phalanges (Fig. 6). Internal examination demonstrated malrotation of the large bowel, absence of the rectum, right adrenal gland, both kidneys and ureters, bladder, urethra, and internal genitalia; testicular parenchyma was identified by histology into 2 fibrous bands, which were macroscopically found adjacent to the inguinal orifices. Tissue culture from the kidney and lung failed to generate cell growth for chromosomal analysis. Table I shows the main clinical and autopsy findings of this stillborn infant compared with all 5 previously reported patients.
INTRODUCTION Anencephaly and sirenomelia are well-defined congenital malformations that usually occur independently. Battaglia and Fraccaro [19541 first reported a stillborn fetus with craniorachischisis totalis and sirenomelia. Subsequently, 4 additional patients with anencephaly and sirenomelia have been observed [Opitz and Gilbert, 1982; Schwaibold et al., 1986; Pfeiffer and Becker, 1988; Rodriguez et al., 19911. Here we report on a further patient and review the clinicopathological findings observed in all 6 known patients with this unusual association of defects. CLINICAL REPORT A 31-year-old woman, with an unremarkable past medical and family history, was first seen a t 30 weeks of her first gestation. Ultrasonography demonstrated anencephaly, and delivery was induced 1 week later. The propositus was a 460 g macerated stillborn fetus of unidentifiable sex with a total length of 22 cm. External examination showed anencephaly with complete rachischisis, absence of external genitalia, imperforate
Received for publication June 6,1991; revision received September 18, 1991. Address reprint requests to Dr. Jose Ignacio Rodriguez, Departamento de Anatomia Patobgica, Hospital La Paz, Paseo de la Castellana 261, E-28046 Madrid, Spain.
0 1992 Wiley-Liss, Inc.
Fig. 1. Frontal view of the patient. Note the “fusion”of the lower limbs.
Craniorachischisis Totalis and Sirenomelia
Fig. 4. Radiograph of the stillborn fetus. Fig. 2. Posterior view of the stillborn fetus. Note the craniorachischisis totalis.
Fig. 3. Proximally implanted right thumb.
Fig. 5. Multiple errors of the spinal segmentation.
733
734
Rodriguez and Palacios
Fig. 6. Hypoplastic phalanges of the right thumb.
The macroscopicallyand histologicallynormal placenta weighed 126 g. The umbilical cord contained a single umbilical artery and had a velamentous insertion.
DISCUSSION Anencephaly is the most common major congenital anomaly among stillborn infants, comprising 18.8/1.000of cases in the Spanish Birth Defects Register [Martinez-F'rias et al., 19861. However, its association with caudal defects typical of sirenomelia is unusual. In a review of 2 autopsy series of anencephaly and associated congenital anomalies [David et al., 1983; Melnick and Myrianthopoulos, 19871, none of the 206 reported patients lacked external genitalia, and imperforate anus and sacral agenesis were found in 0-0.6% and 01.2%of the patients, respectively. Moreover, although 5.2-15% of the infants had aplastic, hypoplastic, or dysplastic kidneys, no patient showed other changes typical of sirenomelia such as complete absence of the ureters, urinary bladder, and urethra, or severe internal genital abnormalities. Central nervous system anomalies, such as atelencephaly and Arnold-Chiari malformation, may be present in about 5% of patients with sirenomelia [Stevenson et al., 1986; Young et al., 1986; Duncan and Shapiro, 19881. However, to the best of our knowledge, only 5 previous patients have been reported with both anencephaly and sirenomelia. Table I shows that anencephaly in patients with sirenomelia may be the only
neural tube defect (NTD)or it may be associated with an exposed area of spinal cord of variable extent. The extent of the NTD seems to be inversely correlated with the extent of lower limb abnormalities. Three of the 6 reported anencephalic infants with sirenomelia were one of a pair of twins, 2 were monozygotic twins (MZ) (patients 2 and 41, and one was a dizygotic twin (patient 31, although monozygosity was not completely excluded in the last case [for comments see Rodriguez et al., 19911. Sirenomelia and anencephaly are 2 of the early types of defects that have been considered to be in excess frequency in MZ twins [Jones, 19881. MZ twinning is seen in about 2.5% of cases of anencephaly and 7% of sirenomelia [Schinzel et al., 19791. In patients with anencephaly and sirenomelia, associated congenital defects were more frequently observed in twins than in singletons. The associated congenital anomalies, other than vertebral defects, described in these patients were lung hypoplasia, upper limb deficiencies, and cleft lip and/or palate. Lung hypoplasia has been reported in 44.5%of sirenomelic infants [de Jonge et al., 19841, and in 34%of anencephalic infants [Melnick and Myrianthopoulos, 19871. Whereas polyhydramnios is a frequent finding during gestation of anencephalic infants, oligohydramnios is observed in most cases of sirenomelia. Although abnormal data on the amount of amniotic fluid were not recorded in 5 anencephalic patients with sirenomelia, polyhydramnios has been reported in patient 2 [Opitz and Gilbert, 19821; 3 of the 6 patients showed lung hypoplasia, which may be related both to abnormal intrauterine swallowing in anencephaly or to bilateral renal agenesis. Various upper limb deficiencies existed in 3 of the 6 anencephalic patients with sirenomelia. In all 3 infants the common finding was the involvement of the preaxial ray, and the radius and/or the thumb bones were the most frequently affected. Upper limb reduction defects are unusual in patients with anencephaly. They have been recorded in only 4 instances among 662 anencephalic infants (0.6%)[David et al., 1983; Sadovnick and Baird, 1985; Melnick and Myrianthopoulos, 19871. Radial aplasia or hypoplasia have been described in 2 patients with sirenomelia. In these infants other typical manifestations of VATER association were also present [ K a l l h and Winberg, 1974; Young et al., 19861. Cleft lip and/or palate are present in about 2 to 6%of anencephalic patients [David et al., 1983; Melnick and Myrianthopoulos, 19871, whereas the incidence of this facial defect in sirenomelia has not been established. The incidence of cleft lip and/or palate was higher than expected in anencephalic patients with sirenomelia; 4 of the 6 patients had it, and the 3 were the twins. The association of anencephaly or craniorachischisis totalis with sirenomelia indicates the existence of a malformation process acting in early embryogenesis.Fusion of the neural tube first occurs on day 22 a t the level of somite 3; early fusion also occurs in the area of the optic primordia. Fusion proceeds rostrally and caudally from both points, respectively, and the anterior neuropore is closed by day 23-26. It has also been estimated that the teratogenic termination period for sirenomelia is 3%
31w
6. Present case
Anencephaly Cervicothoracal meningomyelocele
Anencephaly
CRT
M SB?
F SB
M SB
Anencephaly
CRT
us SB F SB
CRT
NTD
-~
Sex M SB
Lung hypoplasia Cleft palate
Phalangeal hypoplasia of right thumb
Sympus monopus (2 femora and tibiae, 8 metatarsals and. digits)
-
Midface and Diaphagmatic defects Lung hypoplasia Agenesis left thumb and right 5th finger Hypoplasia of the left radius and ulna Bilateral CLP Acrenesis of both radii
Associated malformations Lung hypoplasia
Sympus apus (2 femora and tibiae)
Sirenomelia (not specified)
Sympus apus (single femur and tibia)
Lower limb abnormalities Sympus dipus (no skeletal anomalies) Sympus apus
No
Yes
Yes
Yes
No
Twinning No
-
Anencephaly Cervicothoracal meningomyelocele Left CLP Agenesis of the left radius and two fingers Anal atresia Duplication of the cervix, uterus, and vagina Ambiguous external genitalia Right ovary teratoma
No
-
-
Twin’s malformations
SeX.
* All 6 patients presented absence of external genitalia, kidneys,ureters,bladder, and urethra;severe internal genitalia abnormalitieswere also present in all but patient 3 (not specified).G.A.:gestational age; CRT craniorachischisistotalis; CLP: cleft lip and palate;SB: stillborn;NTD: neural tube defect; US: undetermined
32w
?
38w
27w
5. Rodriguez et al. [19911
Becker 119881
4. Pfeiffer and
2. Opitz and Gilbert [19821 3. Schwaibold et al. [1986]
1. Battaglia and Fraccaro [19541
G.A. 7th
TABLE I. Clinical and Autopsy Findings in Infants With Both Anencephalia and Sirenomelia*
736
Rodriguez and Palacios
weeks; lower limb buds are recognized in the embryo during Stage 13 [O’Rahilly and Muller, 19891, which corresponds to approximately 28-32 days of development. From an embryological point of view, conditions that combine cephalic and caudal defects, as in these patients, are considered by some authors to be examples of the axial mesodermal dysplasia spectrum. MarinPadilla [19781 has proposed that impaired formation, elevation, and approximation of the neural folds is probably due to a primary disturbance of the axial chondromesodermal system and would result in a deficiency of the indispensable underlying nonsegmented mesoderm. ORahilly and Muller [ 19891 have suggested that sirenomelia would occur by a failure in lateralization of lower limbs secondary to a mesenchymal deficiency of the caudal eminence. The caudal eminence is an active seat of cell proliferation, which contributes to the formation of the notochord, vertebrae, lower limb buds, perineum, neural plate, neural cord, hindgut, and blood vessels. Although an extensive disturbance of the axial mesoderm is likely to occur in patients with NTDs, a concomitant alteration of the neural ectoderm cannot be excluded in this very vulnerable period of embryogenesis in which complex and coordinated processes of cell proliferation, migration, and cell-cell adhesion take place so that neural tube closure is achieved. The association of anencephaly with sirenomelia in these infants may be related through the midline developmental field concept, as proposed by Opitz and Gilbert [19821. Occurrence of multiple midline defects in the same individuals is seen more often than what would be expected by chance [Czeizel, 1981; Khoury et al., 19891. In early embryogenesis, the midline is a field characterized by generalized weakness. It has been suggested that midline vulnerability involves the early process of determination and that difficulties with this process may cause both duplication and deficiencies [Lubinsky, 19871. Twinning may be the cause of the association of anencephaly and sirenomelia in 3 patients. In one sense, twins could be considered the ultimate midline anomaly: a complete duplication. Twinning may predispose the midline to further problems and could account for the anomalies seen in these 3 patients and in their twins [Rodriguez et al., 19911. By definition, developmental field defects are causally nonspecific heterogeneous entities. The existence of either autosomal [Carmi et al., 19901 or X-linked [Toriello and Higgins, 19851 oligogenes with a major effect on several midline morphogenetic processes has been suggested. It has also been suggested that X-linked mutations may be the explanation for the excess of males observed in several midline defects [Norio et al., 19841. In this sense, an excess of males has been reported in sirenomelia, and 2 of the 3 singleton anencephalic patients with sirenomelia were also males, being the third one of undetermined sex.
REFERENCES Battaglia S, Fraccaro M (1954): Anencefalia in sirenide. Fol Hered PatholIIIl97-204. Carmi R, Meizner I, Katz M (1990): Familial congenital diaphragmatic defect and associated midline anomalies: Further evidence for an X-linked midline gene? Am J Med Genet 36:313-315. Czeizel A (1981): Schisis-association. Am J Med Genet 10:25-35. David TJ, McCrae FC, Bound J P (1983): Congenital malformations associated with anencephaly in the Fylde peninsula of Lancashire. J Med Genet 20:338-341. de Jonge HJM, Los JA, Knipscheer RJJL, Frensdorf EL (1984): Sirenomelia (“mermaid). Europ J Gynec Reprod Biol 18:85-93. Duncan PA, Shapiro LR (1988): Sirenomelia and VATER association: Possible interrelated disorders with common embryonic pathogenesis. Dysmorph Clin Genet 2:96-103. Jones KL (1988): “Smith’s Recognizable Patterns of Human Malformation.” Philadelphia: W B Saunders, pp 574. Kallkn B, Winberg J (1974): Caudal mesoderm pattern of anomalies: From renal agenesis to sirenomelia. Teratology 9:99-112. Khoury MJ, Corder0 JM, Mulinare JM, Opitz J M (1989):Association of selected midline defects: A population study. Pediatrics 84:266272. Lubinsky MS (1987): Midline developmental “weakness” as a consequence of determinative field properties. Am J Med Genet [suppll 3:23-28. Marin-Padilla M (1978): Clinical and experimental rachischisis. In Vinken PJ, Bruyn GW, Myrianthopoulos C (eds.): “Handbook of Clinical Neurology, Vol32, Congenital Malformations of the Spine and Spinal Cord.” Amsterdam: Elsevier, pp 159-191. Martinez-Frias ML, Salvador J , Frias J L (1986): Frecuencia de 10s defectos congknitos en Espana: 1976-1983. An Esp Pediatr 25145153. Melnick M, Myrianthopoulos NC (1987): Studies in neural tube defects 11. Pathologic findings in a prospectively collected series of anencephalics. Am J Med Genet 26:797-810. Norio R, Kaariainen H, Rapola J , Herva R, Kekomaki M (1984): Familial congenital diaphragmatic defects: Aspects of etiology, prenatal diagnosis, and treatment. Am J Med Genet 17:471-483. ORahilly R, Muller F (1989): Interpretation of some median anomalies as illustrated by cyclopia and symmelia. Teratology 40:409-421. Opitz JM, Gilbert EF (1982):Editorial comment: CNS anomalies and the midline as a “developmental field.” Am J Med Genet 12:443455. Pfeiffer RA, Becker V (1988): Comments on Schwaibolds “Sirenomelia and anencephaly in one of dizygotic twins.” Teratology 38:497-498. Rodriguez JI, Palacios J , Razquin S (1991): Sirenomelia and anencephaly. Am J Med Genet 39:25-27. Sadovnick AD, Baird PA (1985): Congenital malformations associated with anencephaly in liveborn and stillborn infants. Teratology 32:355-361. Schinzel AAGL, Smith DW, Miller J R (1979): Monozygotic twinning and structural defects. J Pediatr 95921-930. Schwaibold H, Oehler U, Helpap R, Bohm N (1986): Sirenomelia and anencephaly in one of dizygotic twins. Teratology 34:243-247. Stevenson RE, Jones KL, Phelan MC, Jones MC, Barr MJr, Clericuzio C, Russell AH, Benirschke K (1986): Vascular steal: The pathogenetic mechanism producing sirenomelia and associated defects of the viscera and soft tissues. Pediatrics 78:451-457. Toriello HV, Higgins J V (1985): X-linked midline defects. Am J Med Genet 21:143-146. Young ID, O’Reilly KM, Kendall CH (1986): Etiological heterogeneity in sirenomelia. Pediatr Path01 5:31-43.
Craniorachischisis Totalis and Sirenomelia Jose Ignacio Rodriguez and Jose Palacios Department of Pathology, La Paz Hospital, Madrid, Spain
We report on a male infant with craniorachischisis totalis and sirenomelia, an association that seems to have been observed only 5 times before. In addition to these anomalies, the patient had hypoplasia of the phalanges of the right thumb. The pattern of associated malformations in infants with anencephaly and sirenomelia is reviewed. This condition, which combines cephalic and caudal defects of the embryo, could be considered an example of the “axial mesodermal dysplasia spectrum” and may be related to the midline developmental field concept. Q 1992 Wiley-Liss, Inc. KEY WORDS: anencephaly,sirenomelia, mesodermal dysplasia, midline abnormalities
anus, and a single “fused” lower limb, ending in a single foot with 8 toes (Figs. 1,2). The right thumb was proximally implanted (Fig. 3). Postmortem radiographs (Figs. 4,5) demonstrated absence of the cranial vault, complete rachischisis with multiple errors of the spinal segmentation, and no sacrum. The single lower limb contained 2 femora and tibiae, and 8 metatarsals and phalanges. The right thumb had hypoplastic phalanges (Fig. 6). Internal examination demonstrated malrotation of the large bowel, absence of the rectum, right adrenal gland, both kidneys and ureters, bladder, urethra, and internal genitalia; testicular parenchyma was identified by histology into 2 fibrous bands, which were macroscopically found adjacent to the inguinal orifices. Tissue culture from the kidney and lung failed to generate cell growth for chromosomal analysis. Table I shows the main clinical and autopsy findings of this stillborn infant compared with all 5 previously reported patients.
INTRODUCTION Anencephaly and sirenomelia are well-defined congenital malformations that usually occur independently. Battaglia and Fraccaro [19541 first reported a stillborn fetus with craniorachischisis totalis and sirenomelia. Subsequently, 4 additional patients with anencephaly and sirenomelia have been observed [Opitz and Gilbert, 1982; Schwaibold et al., 1986; Pfeiffer and Becker, 1988; Rodriguez et al., 19911. Here we report on a further patient and review the clinicopathological findings observed in all 6 known patients with this unusual association of defects. CLINICAL REPORT A 31-year-old woman, with an unremarkable past medical and family history, was first seen a t 30 weeks of her first gestation. Ultrasonography demonstrated anencephaly, and delivery was induced 1 week later. The propositus was a 460 g macerated stillborn fetus of unidentifiable sex with a total length of 22 cm. External examination showed anencephaly with complete rachischisis, absence of external genitalia, imperforate
Received for publication June 6,1991; revision received September 18, 1991. Address reprint requests to Dr. Jose Ignacio Rodriguez, Departamento de Anatomia Patobgica, Hospital La Paz, Paseo de la Castellana 261, E-28046 Madrid, Spain.
0 1992 Wiley-Liss, Inc.
Fig. 1. Frontal view of the patient. Note the “fusion”of the lower limbs.
Craniorachischisis Totalis and Sirenomelia
Fig. 4. Radiograph of the stillborn fetus. Fig. 2. Posterior view of the stillborn fetus. Note the craniorachischisis totalis.
Fig. 3. Proximally implanted right thumb.
Fig. 5. Multiple errors of the spinal segmentation.
733
734
Rodriguez and Palacios
Fig. 6. Hypoplastic phalanges of the right thumb.
The macroscopicallyand histologicallynormal placenta weighed 126 g. The umbilical cord contained a single umbilical artery and had a velamentous insertion.
DISCUSSION Anencephaly is the most common major congenital anomaly among stillborn infants, comprising 18.8/1.000of cases in the Spanish Birth Defects Register [Martinez-F'rias et al., 19861. However, its association with caudal defects typical of sirenomelia is unusual. In a review of 2 autopsy series of anencephaly and associated congenital anomalies [David et al., 1983; Melnick and Myrianthopoulos, 19871, none of the 206 reported patients lacked external genitalia, and imperforate anus and sacral agenesis were found in 0-0.6% and 01.2%of the patients, respectively. Moreover, although 5.2-15% of the infants had aplastic, hypoplastic, or dysplastic kidneys, no patient showed other changes typical of sirenomelia such as complete absence of the ureters, urinary bladder, and urethra, or severe internal genital abnormalities. Central nervous system anomalies, such as atelencephaly and Arnold-Chiari malformation, may be present in about 5% of patients with sirenomelia [Stevenson et al., 1986; Young et al., 1986; Duncan and Shapiro, 19881. However, to the best of our knowledge, only 5 previous patients have been reported with both anencephaly and sirenomelia. Table I shows that anencephaly in patients with sirenomelia may be the only
neural tube defect (NTD)or it may be associated with an exposed area of spinal cord of variable extent. The extent of the NTD seems to be inversely correlated with the extent of lower limb abnormalities. Three of the 6 reported anencephalic infants with sirenomelia were one of a pair of twins, 2 were monozygotic twins (MZ) (patients 2 and 41, and one was a dizygotic twin (patient 31, although monozygosity was not completely excluded in the last case [for comments see Rodriguez et al., 19911. Sirenomelia and anencephaly are 2 of the early types of defects that have been considered to be in excess frequency in MZ twins [Jones, 19881. MZ twinning is seen in about 2.5% of cases of anencephaly and 7% of sirenomelia [Schinzel et al., 19791. In patients with anencephaly and sirenomelia, associated congenital defects were more frequently observed in twins than in singletons. The associated congenital anomalies, other than vertebral defects, described in these patients were lung hypoplasia, upper limb deficiencies, and cleft lip and/or palate. Lung hypoplasia has been reported in 44.5%of sirenomelic infants [de Jonge et al., 19841, and in 34%of anencephalic infants [Melnick and Myrianthopoulos, 19871. Whereas polyhydramnios is a frequent finding during gestation of anencephalic infants, oligohydramnios is observed in most cases of sirenomelia. Although abnormal data on the amount of amniotic fluid were not recorded in 5 anencephalic patients with sirenomelia, polyhydramnios has been reported in patient 2 [Opitz and Gilbert, 19821; 3 of the 6 patients showed lung hypoplasia, which may be related both to abnormal intrauterine swallowing in anencephaly or to bilateral renal agenesis. Various upper limb deficiencies existed in 3 of the 6 anencephalic patients with sirenomelia. In all 3 infants the common finding was the involvement of the preaxial ray, and the radius and/or the thumb bones were the most frequently affected. Upper limb reduction defects are unusual in patients with anencephaly. They have been recorded in only 4 instances among 662 anencephalic infants (0.6%)[David et al., 1983; Sadovnick and Baird, 1985; Melnick and Myrianthopoulos, 19871. Radial aplasia or hypoplasia have been described in 2 patients with sirenomelia. In these infants other typical manifestations of VATER association were also present [ K a l l h and Winberg, 1974; Young et al., 19861. Cleft lip and/or palate are present in about 2 to 6%of anencephalic patients [David et al., 1983; Melnick and Myrianthopoulos, 19871, whereas the incidence of this facial defect in sirenomelia has not been established. The incidence of cleft lip and/or palate was higher than expected in anencephalic patients with sirenomelia; 4 of the 6 patients had it, and the 3 were the twins. The association of anencephaly or craniorachischisis totalis with sirenomelia indicates the existence of a malformation process acting in early embryogenesis.Fusion of the neural tube first occurs on day 22 a t the level of somite 3; early fusion also occurs in the area of the optic primordia. Fusion proceeds rostrally and caudally from both points, respectively, and the anterior neuropore is closed by day 23-26. It has also been estimated that the teratogenic termination period for sirenomelia is 3%
31w
6. Present case
Anencephaly Cervicothoracal meningomyelocele
Anencephaly
CRT
M SB?
F SB
M SB
Anencephaly
CRT
us SB F SB
CRT
NTD
-~
Sex M SB
Lung hypoplasia Cleft palate
Phalangeal hypoplasia of right thumb
Sympus monopus (2 femora and tibiae, 8 metatarsals and. digits)
-
Midface and Diaphagmatic defects Lung hypoplasia Agenesis left thumb and right 5th finger Hypoplasia of the left radius and ulna Bilateral CLP Acrenesis of both radii
Associated malformations Lung hypoplasia
Sympus apus (2 femora and tibiae)
Sirenomelia (not specified)
Sympus apus (single femur and tibia)
Lower limb abnormalities Sympus dipus (no skeletal anomalies) Sympus apus
No
Yes
Yes
Yes
No
Twinning No
-
Anencephaly Cervicothoracal meningomyelocele Left CLP Agenesis of the left radius and two fingers Anal atresia Duplication of the cervix, uterus, and vagina Ambiguous external genitalia Right ovary teratoma
No
-
-
Twin’s malformations
SeX.
* All 6 patients presented absence of external genitalia, kidneys,ureters,bladder, and urethra;severe internal genitalia abnormalitieswere also present in all but patient 3 (not specified).G.A.:gestational age; CRT craniorachischisistotalis; CLP: cleft lip and palate;SB: stillborn;NTD: neural tube defect; US: undetermined
32w
?
38w
27w
5. Rodriguez et al. [19911
Becker 119881
4. Pfeiffer and
2. Opitz and Gilbert [19821 3. Schwaibold et al. [1986]
1. Battaglia and Fraccaro [19541
G.A. 7th
TABLE I. Clinical and Autopsy Findings in Infants With Both Anencephalia and Sirenomelia*
736
Rodriguez and Palacios
weeks; lower limb buds are recognized in the embryo during Stage 13 [O’Rahilly and Muller, 19891, which corresponds to approximately 28-32 days of development. From an embryological point of view, conditions that combine cephalic and caudal defects, as in these patients, are considered by some authors to be examples of the axial mesodermal dysplasia spectrum. MarinPadilla [19781 has proposed that impaired formation, elevation, and approximation of the neural folds is probably due to a primary disturbance of the axial chondromesodermal system and would result in a deficiency of the indispensable underlying nonsegmented mesoderm. ORahilly and Muller [ 19891 have suggested that sirenomelia would occur by a failure in lateralization of lower limbs secondary to a mesenchymal deficiency of the caudal eminence. The caudal eminence is an active seat of cell proliferation, which contributes to the formation of the notochord, vertebrae, lower limb buds, perineum, neural plate, neural cord, hindgut, and blood vessels. Although an extensive disturbance of the axial mesoderm is likely to occur in patients with NTDs, a concomitant alteration of the neural ectoderm cannot be excluded in this very vulnerable period of embryogenesis in which complex and coordinated processes of cell proliferation, migration, and cell-cell adhesion take place so that neural tube closure is achieved. The association of anencephaly with sirenomelia in these infants may be related through the midline developmental field concept, as proposed by Opitz and Gilbert [19821. Occurrence of multiple midline defects in the same individuals is seen more often than what would be expected by chance [Czeizel, 1981; Khoury et al., 19891. In early embryogenesis, the midline is a field characterized by generalized weakness. It has been suggested that midline vulnerability involves the early process of determination and that difficulties with this process may cause both duplication and deficiencies [Lubinsky, 19871. Twinning may be the cause of the association of anencephaly and sirenomelia in 3 patients. In one sense, twins could be considered the ultimate midline anomaly: a complete duplication. Twinning may predispose the midline to further problems and could account for the anomalies seen in these 3 patients and in their twins [Rodriguez et al., 19911. By definition, developmental field defects are causally nonspecific heterogeneous entities. The existence of either autosomal [Carmi et al., 19901 or X-linked [Toriello and Higgins, 19851 oligogenes with a major effect on several midline morphogenetic processes has been suggested. It has also been suggested that X-linked mutations may be the explanation for the excess of males observed in several midline defects [Norio et al., 19841. In this sense, an excess of males has been reported in sirenomelia, and 2 of the 3 singleton anencephalic patients with sirenomelia were also males, being the third one of undetermined sex.
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