30 0 Med Genet 1992; 29: 30-35

The cyclops and the mermaid: an

epidemiological study of two types of rare J Med Genet: first published as 10.1136/jmg.29.1.30 on 1 January 1992. Downloaded from malformation*

Bengt Kallen, Eduardo E Castilla, Paul A L Lancaster, Osvaldo Mutchinick, Lisbeth B Knudsen, Maria Luisa Martinez-Frias, Pierpaolo Mastroiacovo, Elisabeth Robert

Abstract complex depends on which forms are in- Infants with or are cluded, and also on the frequency with which born at an approximate rate of 1 in necropsy is performed on infants dying in the 100 000 births. Eight malformation moni- neonatal period. However, the two extreme toring systems around the world jointly forms, cyclopia and sirenomelia, are easily Department of studied the epidemiology of these rare recognised and usually clearly defined, but Embryology, University of Lund, malformations: 102 infants with cyclopia, both forms are very rare and it is therefore Biskopsgatan 7, S-223 96 with sirenomelia, and one with both difficult to collect material large enough to 62 Lund, Sweden. conditions were identified among nearly permit detailed epidemiological studies. B Kalln 10-1 million births. Maternal age is some- We have collected such material by using ECLAMC/Genetica/ what increased for cyclopia, indicating data from eight malformation monitoring sys- Fiocruz, Rio de Janeiro, Brazil, and the likely inclusion of some chromoso- tems around the world, all members of the IMBICE, Casilla 403, mally abnormal infants which were not International Clearinghouse for Birth Defects 1900 La Plata, identified. About half of the infants are Monitoring Systems,7 and we report some Argentina. E E Castilla stillborn. There is a female excess among findings on the prevalence at birth, other epi- infants with cyclopia. Excess twinning demiological features, and associated malfor- AIHf National Perinatal Statistics occurred for cyclopia and possibly also mations. Unit, Building A27, for sirenomelia. An analysis ofassociated University of Sydney, malformations indicates the similarity Sydney, NSW 2006, Australia. between the two conditions, which is in agreement with recent embryological Material and methods P A L Lancaster Data were collected from the following eight RYVEMCE, analysis. Departamento de malformation monitoring systems which will be described a GenCtica, Instituto very briefly. Australia: national, http://jmg.bmj.com/ Nacional de Nutrici6n A recent paper' reported an interpretation of population based monitoring system covering Salvador Zubiran, some 240 000 Vasco de Quiroga 15, cyclopia and symmelia, based on a detailed annual births.8 Denmark: a Tlalpan, 14000 Mexico embryological study of human embryos and national, population based registry of congen- DF, Mexico. ital malformations covering approximately 0 published reports. The authors pointed out a Mutchinick number of similarities in the development of 55 000 annual births.9 France, Rhone-Alps- National Board of Auvergne (RAA): a regional, population based Health, Amaliegade these two lethal conditions. They both arise by a failure of lateralisation of rudiments, the monitoring system based on nearly 90 000 13, PO Box 2020, on September 28, 2021 by guest. Protected copyright. DK-1012 Copenhagen, early brain rudiment, which gets its laterality annual births.'0 Italy, IPIMC: a hospital based Denmark. monitoring system including reports from 147 L B Knudsen from the influence of the prechordal meso- derm,2 and the 'caudal eminence', the caudal hospitals and covering approximately 130 000 Hospital Universitario annual births (about 25% of all Italian San Carlos, continuation of the primitive node and there- INSALUD, ECEMC, fore also a basic structure in the development births)." Mexico: a hospital based monitoring Facultad de Medicina, of axial .' system including 21 hospitals in 11 cities with Universidad an annual birth rate of approximately 50000.12 Complutense, 280 40 Cyclopia is an extreme form of holoprosen- Madrid, Spain. cephaly, which covers a broad spectrum of South America, ECLAMC: a hospital based M L Martinez-Frias conditions from cyclopia to infants who are monitoring system including approximately 70 IPIMC, Servizio externally normal but have more or less pro- hospitals in all South American countries and Epidemiologia e nounced disturbance ofthe pairing of the brain covering a total number of annual births of Clinica Difetti about 215 000."3 Spain, ECEMC: a hospital Congeniti, Policlinico hemispheres.4 Similarly, symmelia or sireno- Universitario A melia is an extreme form of a spectrum of based monitoring system including reports Gemelli, Largo malformations which have been summarised from 45 hospitals, covering nearly 60 000 Gemelli 8, 00168 annual births (about 15% of all Spanish Rome, Italy. as the caudal regression malformation complex that spans sirenomelia to agenesis or births).'4 Sweden: a national, population based P Mastroiacovo registry of congenital malformations covering Institut Europeen des even anal atresia.56 The delimitation of holo- G6nomutations, 86 prosencephaly is difficult4 which is reflected in approximately 100 000 annual births.'5 Rue Edmond Locard, the fact that data on its prevalence at birth vary From each registry, data were extracted for F-69005 Lyon, France. the two conditions according to the following E Robert considerably. Similarly, the actual prevalence at birth of the caudal regression malformation definitions. Cyclopia: infants born with one Correspondence to orbit in the middle of the face and with one or Dr Kallen. two eyes. Known chromosome anomalies are Received 18 February 1991. *The malformation monitoring programmes that participated Revised version accepted in this study are all members of the International Clearinghouse not included (because in some programmes 15 April 1991. for Birth Defects Monitoring Systems. they are often registered only as such), but a The cyclops and the mermaid 31 Table 1 Number of cases and number of births recorded in each programme (rates per 100 000 births). Cyclopia Sirenomelia No of Programme Years births No Rate No Rate J Med Genet: first published as 10.1136/jmg.29.1.30 on 1 January 1992. Downloaded from Australia 1982-1989 1 945 888 23 1-2 22 1-1 Denmark 1983-1988 328 254 0 - 2 0-6 France, RAA 1976-1987 943 579 5 0 5 7 0-7 Italy, IPIMC 1983-1988 824478 11 1-3 5 0-6 Mexico 1978-1988 358 590 8 2-2 3 0-8 South America 1967-1989 2 278 771 30 1-3 32 1-4 Spain 1976-1989 728368 6* 0-8 7* 1 0 Sweden 1965-1988 2 258 613 20 0 9 19 0-8 Total 10 097 383 103 1.03 97 0-96 *One infant had both cyclopia and sirenomelia.

special study was made of trisomy 13. Sireno- rate is probably higher (estimated to be 0 99 melia: complete or partial fusion of the lower per 100 000 births). limbs. Fig 1 compares the recorded numbers of In general the conditions under study are cyclopia and sirenomelia in the different pro- easily defined and clear cut. Two infants with a grammes. It can be seen that the recorded proboscis and without eyes were reported but differences in rate (table 1) may well be not included because they did not fulfil the explained by random fluctuations. working definition, even though they actually Table 2 shows the recorded number of in- may represent the most severe forms. Simi- fants with trisomy 13, how many of them were larly, an infant with rotated lower limbs, and described with respect to the malformations therefore with feet facing backwards, was not present, and how many of these had cyclopia. included. These few borderline cases do not It can be seen that cyclopia occurred in 2-7% affect the registered rates much. Fewer than of all trisomy 13 infants where malformations 10% of the cases of each type of malformation were described. As the rate of recorded tri- were karyotyped (nine with cyclopia, six with somy 13 is about 1 in 17200, it can be esti- sirenomelia). mated that to the rate of cyclopia described For each infant information was given above can be added 0 15 per 100 000 of cyclo- (when available) on date of birth, matemal and pia recorded as trisomy 13, giving a total of paternal age at birth, parity, sex, birth weight, 1-20 per 100 000. survival (stillborn, liveborn dying in the peri- Fig 2 shows the time trend: for both malfor- natal period, liveborn surviving the perinatal mations the rates up to 1974 were higher than period), necropsy, whether cytogenetic invest- igation was performed, and multiple birth, in ® Cyclopia which case sex and status of co-twin or co- 401

triplets. Population data (when available) were http://jmg.bmj.com/ also given for these variables. *Sam were not included in the Spanish material until 1980 and in the South American / Aus I,- 0 material until 1978. definition var- * Swe - ied: in Australia, all stillbirths are registered after the 20th completed week, in Denmark, France, and Sweden after the 28th week, in Italy after 180 days, while in Mexico, Spain, on September 28, 2021 by guest. Protected copyright. and South America the definition is a birth weight of 500 g or more.

40' Sirenomelia Results PREVALENCE AT BIRTH 30' The total number of births which represents the denominator is given in table 1 for each No programme. A total of 103 infants with cyclo- 20- pia was identified. This gives a crude rate of * Swe 1-03 per 100000 births, but as roughly one- third of the identified cases were stillbirths and 10' these were not included in part of the South Spai *FFran, - American and Spanish programmes (a total of . Mex oItal 873 897 births before inclusion of stillbirths), /Dk - the rate will be somewhat underestimated. By 0 1 2 3 adding 1/3 of cases for those programmes for Million births Figure 1 Diagrams showing number of births in each that period, the true rate can be estimated to be programme and number of malformed infants recorded. 1-05 per 100 000. Aus = Australia, Dk = Denmark, Fran = France, RAA, Similarly, there were 97 infants reported Ital= Italy, IPIMC, Mex = Mexico, R YVEMCE, with sirenomelia, which gives a crude rate of Sam = South America, ECLAMC, Spa = Spain, ECEMC, Swe = Sweden. The unbroken line marks the 0-96 per 100 000 births, but because about average rate of the malformation and the broken lines one-third of the cases were stillbirths, the true the 95% confidence interval. 32 Kallen et al

Table 2 Registered infants with trisomy 13 in the programme (not all cases were karyotyped) (rates per 100 000 births). No No of No with No with

Programme Years of births trisomy 13 Rate malformations cyclopia J Med Genet: first published as 10.1136/jmg.29.1.30 on 1 January 1992. Downloaded from Australia 1981-1988 1 798 728 161 9 0 144 3 Denmark 1983-1987 328 254 15 4 0 13 0 France, RAA 1976-1988 1 033 600 50 4 8 40 3 Italy, IPIMC 1983-1988 824478 54 6-5 54 1 Mexico 1978-1988 358 590 13 3-6 13 0 South America 1967-1989 2 278 771 81 3-6 81 0 Spain 1976-1989 728 368 28 4-1 28 1 Sweden 1973-1988 1 079 683 88 8 2 63 0 Total 8 430 472 490 5-8 436 8

during the period 1975 to 1983 and then the with cyclopia was not known and the co-twin rate increases again. The temporal graph will was a microcephalic male. In one pair with a be sensitive to the periods of participation of female infant with cyclopia, the sex of the co- the different programmes. twin was not known but it had a congenital hip subluxation. There were two unlike sexed and one like sexed (female) pair with a normal co- SURVIVAL, NECROPSY, AND CYTOGENETICS twin. In two pairs, no information was avail- As stressed above, the stillbirth rate is high. able on the co-twin. There was one twin with Among infants with cyclopia, 28 were still- sirenomelia of unknown sex and with a normal births and 75 were born alive but died shortly female co-twin and a further two twin pairs after birth. The corresponding numbers for without information on the co-twin. sirenomelia were 35 stillbirths and 62 live- births that died shortly after birth. Necropsy was performed in 68 cases of cyclopia and 57 of sirenomelia. Gytogenetic investigations were MATERNAL AGE performed in only nine cases of cyclopia and Fig 3 shows that there is an apparently six of sirenomelia. It is therefore possible that increased risk for cyclopia with high maternal infants with chromosome anomalies were age. In sirenomelia, deviations from the inadvertently included. expected maternal age distribution are small, but there is an indication of increased risk in

SEX There is an excess of female births among 3, infants with cyclopia, 38 male and 62 female Cyclopia

infants, and in three cases (one with sirenome- http://jmg.bmj.com/ lia) the sex was unknown. There are 15 males and 17 females among the cases of sirenomelia; however, in the majority of cases (65), the sex 2- QL was unknown. Assigning sex in sirenomelic X -0 infants was based on chromosomal or gonadal Q sex. Among karyotyped trisomy 13 infants 1 -

with known sex, 158 were males and 160 on September 28, 2021 by guest. Protected copyright. females. The sex ratio for trisomy 13 is thus close to 1 0 in our material.

0 3. TWINNING Sirenomelia There were seven twin pairs among the infants with cyclopia. In one pair, the sex of the infant

2 C1 x

(a 20 -0 Figure 2 Rate of cyclopia (unbroken line) 1- and sirenomelia (broken 1-5. A IA'% line) each year during the II % I %V. observation period, based on moving three year '/A A~~~~~/% "a 1-0 / o L averages. The ratio .0 between the observed and 0 i ~ " 15 20 25 30 35 40 45 expected number is Maternal age plotted, the latter calculatedfrom the 0-5' Figure 3 Observed over expected ratio for each average rate of the maternal age class for (A) cyclopia and (B) malformation during the sirenomelia. The expected numbers are calculatedfor whole period in each each maternal age class from the age distribution of the programme and the background population after stratification for number of births each year 65 67 69 71 73 75 77 79 81 83 85 87 89 programme and year of birth (95% confidence intervals in that programme. Year of birth are marked with vertical bars). The cyclops and the mermaid 33 young and old women. There were 14 women Table 3 Associated malformations found in infants aged above 35 with cyclopean infants against with cyclopia or sirenomelia. 8 8 expected (X2=3.4, 0l10>p>0 05). The No of cases with

corresponding figures for mothers of sireno- Type of malformations Cyclopia Sirenomelia J Med Genet: first published as 10.1136/jmg.29.1.30 on 1 January 1992. Downloaded from melic infants was 10 against 8-4 (X2 = 075, Central nervous system NS). Mean matemal age is 30 5 years for Neural tube defects 10 7 cyclopean and 30 4 years for sirenomelic in- 1 0 Hydrocephalus - 2 fants. Cyclopia - 1 Head and neck Cleft lip/palate 4 3 - 1 Choanal atresia 1 1 ASSOCIATED MALFORMATIONS Gastrointestinal system Both conditions studied had associated malfor- Oesophageal atresia 2 8 Tracheal agenesis/atresia 1 1 mations which are direct consequences of the Anal atresia 5 - primary developmental defect. Cyclopia is Malrotation of gut 2 4 Gall bladder agenesis 1 2 obligatorily associated with Omphalomesenteric duct 0 1 (and therefore often with microcephaly) Heart defects Septal defects (VSD, ASD) 7 3 because it originates in deficient lateralisation Hypoplastic left heart 2 0 of the early rudiment of the brain. Other Truncus communis 1 3 Single ventricle 0 1 median defects in the development of the face Single atrium 1 0 may also arise, like median facial clefts or Tricuspid atresia/single atrium 0 1 Unspecified 1 0 otocephaly. Sirenomelia is obligatorily associ- Body wall defects ated with other severe caudal defects in the 2 0 Celosomia 0 1 spine, absent or malformed kidneys, anal atre- Diaphragmatic hernia 2 3 sia, and absence of external genital organs. Prune belly 0 1 Urogenital system and Potter facial anom- Kidney malformations 6 - alies usually occur, related to the kidney mal- Double - 3 2 Hypoplastic genital organs 5 - formations. Limb defects Postaxial polydactyly is a feature of the most Polydactyly 7 1 Syndactyly 1 0 common chromosomal anomaly found with Talipes 3 - cyclopia, trisomy 13.4 Among the 103 cases of Radial defects 3 6 Probable radial defect 0 1 cyclopia in the present material, 15 had pos- Transverse arm reduction 1 2 taxial polydactyly and in eight of them this was Unspecified arm malformation 1 1 Genu recurvatum 1 - the only malformation outside the cyclopean Absent 5th toe bilaterally 1 complex. Among the 14 cases with polydactyly Sirenomelia 1 Other defects and with known maternal age, seven were over Simian creases 1 1 35 years (50%); among the 86 cases without Thoracic vertebral anomalies 0 2 Fusion of ribs 0 1 polydactyly and with known maternal age, Absent lung lobe 0 1 eight (9%) were aged over 35. This supports Brachydactyly 1 0 the idea that most cases with cyclopia and - = obligatory or impossible malformations. http://jmg.bmj.com/ polydactyly have an undetected trisomy. In one infant with a normal karyotype Meckel syndrome was suspected, and other syndromes like pseudotrisomy 13,16 18p-, 7q-, or intersti- MALFORMATION IN SIBS tial 2p deletion may be included. We identified 65 sibs born before a proband Excluding polydactyly, there were 50 cyclo- with cyclopia, one of whom had hydrocepha-

pean infants with associated malformations. lus. Of 11 sibs born after a proband with on September 28, 2021 by guest. Protected copyright. The malformations involved are shown in cyclopia, none was malformed. We identified table 3. In 10 of them, neural tube defects 41 sibs born before a proband with sirenome- occurred (six , three , lia, one of whom had a persistent . Of 10 one encephalocele). Among the 98 sirenomelic sibs born after the sirenomelia probands, none infants, 55 were 'isolated', in that there were had a major malformation. no associated malformations. Table 3 shows the malformations recorded among the other 43 cases. Among the seven neural tube defects, Discussion six were low spina bifida and one was a cervical Both conditions studied in this paper are ex- spina bifida. tremely rare. We found an approximate pre- It should be noted that one infant had both valence at birth of 1 in 100 000 for each malfor- cyclopia and sirenomelia and has been tabu- mation. In order to study the epidemiology of lated under both headings. This infant had such rare conditions, data were pooled from a sirenomelia with an , cyclopia number of malformation monitoring pro- with microcephaly, and radial agenesis on the grammes representing more than 10 million right side (fig 4). Table 3 shows that some of births. the malformations which are directly associ- Infants with a known chromosome anomaly ated with one condition also occur with the were excluded, but most were not studied other, for example, otocephaly and sirenome- cytogenetically. It has been estimated that lia, and anal atresia or kidney malformations about 50% of all infants with holoprosence- and cyclopia. Some relatively rare malforma- phaly have a chromosome anomaly,'7 18 but it tions seem to occur at a high rate in both has been suggested that this percentage is in groups of infants, for example, oesophageal fact lower.4 The most common chromosome atresia and radial defects. anomaly associated with holoprosencephaly is 34 Kallen et al with such rare conditions, moderate changes with time are difficult to quantify. Unusually, many of the cyclopean infants

were twins; given 103 such infants, the J Med Genet: first published as 10.1136/jmg.29.1.30 on 1 January 1992. Downloaded from expected number of twins would be one or two but we found seven pairs. Among 98 sireno- melic infants three pairs of twins were found. Cyclopia also occurred in dizygotic (unlike sexed) twin pairs and the co-twin was normal except for one pair where it had microcephaly. In a review of published reports, four such pairs were found; in three the co-twin was malformed and only one was normal, but this may be a result of reporting bias.4 As the disturbance leading to cyclopia oc- curs in early embryonic life, some other effects are inevitable, like a severe holoprosencephalic brain and disturbances of the midface. These are therefore direct consequences of the cyclo- pean state. Similarly, sirenomelia is (nearly always) associated with malformations of the kid- Figure 4 Photograph of spine or pelvis, absence of or malformed infant with both cyclopia neys (with pulmonary hypoplasia and Potter and sirenomelia (courtesy face as a sequence), absence of external genital of Spanish Collaborative Study of Congenital organs, and anal atresia. Malformations The presence of neural tube defects with (ECEMC), Dr A Garcia both conditions is expected. The association Garcia (Residencia and cyclopia is well Sanitaria de la S S between anencephaly Guadalajara). MI known and has been regarded as an expression of the same basic disturbance in the induction of the neural plate.'9 As the most caudal part of from the caudal eminence, trisomy 13 with an overall prevalence at birth the spine develops between low spina bifida and in our material of 1 in 17200, but although the association holoprosencephaly is common in trisomy 13, sirenomelia is understandable. fewer than 3% of these infants had cyclopia. If Included in our material is one infant with chromosomally abnormal cyclopean infants both cyclopia and sirenomelia. In another sire- was present, a feature are included, the prevalence at birth may nomelic case, otocephaly also found that increase to 1 2 per 100 000. often seen with cyclopia. We also We found indirect evidence that undetected malformations which are an obligatory or com- http://jmg.bmj.com/ the malformation trisomy 13 cases were included in our material: mon consequence of one of in cyclopean infants with postaxial polydac- types were often also present with the other we an association tyly, a feature of trisomy 13, maternal age was type. Furthermore, found and two more often above 35 years than in cyclopean between both types of malformation infants without polydactyly. Inclusion of relatively rare defects: oesophageal atresia and unidentified trisomy 13 cases can hardly radial reduction defects. The association explain the female excess among cyclopean between vertebral, anal, oesophagotracheal, on September 28, 2021 by guest. Protected copyright. the infants, as the sex ratio of trisomy 13 in our and renal/radial defects has been given heart and study was close to 10. The problem with acronym VATER20 or (including is some inclusion or exclusion of chromosome anomal- limb defects) VACTERL.21 There ies is of less significance in relation to sireno- evidence22 that cardiac defects do not occur in in melia as these infants are usually chromoso- this complex more often than they occur any mally normal. multimalformed infant. It has also been sug- Another source of variation in the recorded gested23 that the VATER-like infants and rate of cyclopean or sirenomelic infants is the those with the syndrome of caudal regression inclusion/exclusion of stillbirths in the study (where sirenomelia is the extreme form) and the definition of stillbirths when included. actually form a continuum. It is therefore of About one-third of all these infants are still- special interest that both radial defects and not born and when stillbirths are not included in tracheo-oesophageal defects are common the material, the prevalence at birth will be only with sirenomelia but also with cyclopia. It underestimated. We estimated that the preval- should also be noted that the presence of in- ence at birth of cyclopia is about 1-2 in 100 000 oesophageal atresia and radial defects may and of sirenomelia 1 05 per 100 000. We found dicate that undetected cases of trisomy 18 are no convincing variation in the recorded rates included in the group studied. between the programmes, which probably in- This circumstantial epidemiological evid- dicates that a variable inclusion of chromoso- ence supports the notion of O'Rahilly and mally abnormal cases does not affect the esti- Muller' that cyclopia and sirenomelia actually mates much. have a similar mode of formation, and one We found some, but not convincing, evid- could speculate that aetiological or pathogene- ence of a change in the registered rate with tic factors could be similar for the two con- year of birth; however it should be noted that ditions. In both conditions there are reasons to The cyclops and the mermaid 35 limites de la teratovigilance. Onze annees d'experience believe that the basic disturbance is in induc- (1976-1986). J Gynecol Obstet Biol Reprod 1988;17:601-7. tion processes where central mesoderm is 11 Mastroiacovo P. The Italian birth defects monitoring sys- involved and it is possible that other induction tem: baseline rates based on 283 453 births and compari- son with other registries. In: Prevention of physical and

processes can also be disturbed in other parts mental congenital defects, Part B. Epidemiology, early detec- J Med Genet: first published as 10.1136/jmg.29.1.30 on 1 January 1992. Downloaded from of the body (for example, during limb bud tion and therapy, and environmental factors. New York: Alan R Liss, 1985:17-21. formation). There is actually one teratogenic 12 Mutchinick 0, Lisker R, Babinsky V. Programa Mexicano condition, maternal , which has been de 'Registro y vigilancia epidemi6logica de malforma- ciones congentias extemas'. Salud Publica Mex shown to be associated both with the holopro- 1988;30:88-100. sencephaly-cyclopia complex24 and the caudal 13 Castilla EE, Orioli IM. El estudio colaborativa Latinoamer- regression complex.25 Among the cyclopic in- icano de malformaciones congenitas: ECLAMC/MONI- TOR. Interciencia 1983;8:271-8. fants studied in this paper, maternal diabetes 14 Martinez-Frias ML, Salvador J, Prieto L, Zaplana J. was noted in four instances. Epidemiological study of gastroschisis and omphalocele in Spain. 1984;29:377-82. 1 O'Rahilly R, Muiller F. Interpretation of some median 15 Kallen B, Winberg J. A Swedish register of congenital anomalies as illustrated by cyclopia and symmelia. Tera- malformations. Experience with continuous registration tology 1989;40:409-21. during 2 years with special reference to multiple malfor- 2 Adelmann HB. A study of cyclopia in Amblystoma puncta- mations. Pediatrics 1968;41:765-76. tum with special reference to the mesoderm. J Exp Zool 16 Atkin JP. A new syndrome with cyclopia and trisomy 13 1937;67:219-8 1. features. Am J Hum Genet 1988; suppl 43:A143. 3 Holmdahl D. Die erste Entwicklung des K6rpers bei den 17 Laurence KM, Ishmael J. Arrhinencephaly and 13-15(D) Vogeln und Saugetieren, inkl dem Menschen, besonders trisomy. Oxford Chromosome Conference. Chromosomes mit Rucksicht auf die Bildung des Ruickenmarks, des Today. 1969: proc 2,86-9, (quoted from Cohen 1989). Zoloms unter der entodermalen Kloake, nebst einen Exkurs uber die Enstehung der Spina bifida in der Lum- 18 Ming PM, Goodner DM, Park TS. Cytogenetic variants in bosakralregionen. Morphol Jb 1925;54:333-84,55:112- holoprosencephaly. Am J Dis Child 1976;130:864-7. 208. 19 Kallen B. Errors in the differentiation ofthe central nervous 4 Cohen MM Jr. Perspectives on holoprosencephaly. Part I. system. In: Handbook of clinical neurology. Vol 6. Malfor- Epidemiology, genetics and syndromology. Teratology mations. Amsterdam: Elsevier, 1987:19-47. 1989;40:21 1-35. 20 Quan L, Smith DW. The VATER association: vertebral 5 Duhamel B. From the mermaid to anal imperforation: the defect, anal atresia, T-E fistula with , syndrome of caudal regression. Arch Dis Child radial and renal dysplasia: a spectrum of associated de- 1961;36:152-5. fects. J Pediatr 1973;82:104-7. 6 Kallen B, Winberg J. Caudal mesoderm pattern of anomal- 21 Nora AH, Nora JJ. A syndrome of multiple congenital ies: from renal agenesis to sirenomelia. Teratology anomalies associated with teratogenic exposure: the VAC- 1974;9:99-1 12. TERL syndrome. Arch Environ Health 1975;30:17-21. 7 Congenital Malformations Worldwise. A report from the 22 Kallen B. Population surveillance of multimalformed in- International Clearinghouse for Birth Defects Monitor- fants. Experience with the Swedish registry of congenital ing Systems. Amsterdam: Elsevier, 1991. Second part. J Genet Hum 1987;35:321- 8 Lancaster PAL. Health registers for congenital malforma- malformations. tions and in vitro fertilization. Clin Reprod Fertil 38. 1986;4:27-37. 23 Kallen B. Caudal aplasia. In: Handbook ofclinical neurology. 9 National Board of Health. Registry on Congenital Malfor- Vol 6. Malformations. Amsterdam: Elsevier, 1987;509-18. mations 1984-1985. In: Vitalstatistik. I:18. Copenhagen: 24 Barr M, Hanson JW, Currey K, et al. Holoprosencephaly in Sundhedsstyrelsen, 1986 (in Danish with English subti- infants of diabetic mothers. J Pediatr 1983;102:565-8. tles and summary). 25 Passarge E, Lenz W. Syndrome of caudal regression in 10 Robert E, Francannet C, Robert JM. Le registre de malfor- infants of diabetic mothers. Observations of further cases. mations de la region Rhone-Alps/Auvergne. Interet et Pediatrics 1966;37:672-5. http://jmg.bmj.com/ on September 28, 2021 by guest. Protected copyright.