Sirenomelia: an Epidemiologic Study in a Large Dataset from the International Clearinghouse of Birth Defects Surveillance and Research, and Literature Review IEˆ DA M

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provided by PUblication MAnagement American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 157:358–373 (2011) ARTICLE

Sirenomelia: An Epidemiologic Study in a Large Dataset From the International Clearinghouse of Birth Defects Surveillance and Research, and Literature Review IEˆ DA M. ORIOLI,1,2 EMMANUELLE AMAR,3 JAZMIN ARTEAGA-VAZQUEZ,4 MARIAN K. BAKKER,5 SEBASTIANO BIANCA,6 LORENZO D. BOTTO,7,8 MAURIZIO CLEMENTI,9 ADOLFO CORREA,10 MELINDA CSAKY-SZUNYOGH,11 EMANUELE LEONCINI,12 ZHU LI,13 JORGE S. LO´ PEZ-CAMELO,2,14 R. BRIAN LOWRY,15 LISA MARENGO,16 MARIÁ-LUISA MARTIŃEZ-FRIÁS,17,18,19 PIERPAOLO MASTROIACOVO,12 MARGERY MORGAN,20 ANNA PIERINI,21 ANNUKKA RITVANEN,22 GIOACCHINO SCARANO,23 24 2,14,25 ELENA SZABOVA, AND EDUARDO E. CASTILLA, 1ECLAMC (Estudo Colaborativo Latino Americano de Malformaço˜es Congeˆnitas) at Departamento de Gene´tica, Instituto de Biologia, Rio de Janeiro, Brazil 2INAGEMP (Instituto Nacional de Gene´tica Me´dica Populacional), Rio de Janeiro, Brazil 3Rhone-Alps Registry of Birth Defects REMERA, Lyon, France 4Departamento de Gene´tica, RYVEMCE (Registro y Vigilancia Epidemiolo´gica de Malformaciones Congeńitas), Instituto Nacional de Ciencias Me´dicas y Nutricioń ‘‘Salvador Zubirań’’, Me´xico City, Mexico 5Eurocat Northern Netherlands, Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands 6Dipartimento Materno Infantile, Centro di Consulenza Genetica e di Teratologia della Riproduzione, Laboratorio di Citogenetica, P.O. Garibaldi, Nesima, Catania, Italy 7Division of Medical Genetics, Department of Pediatrics, University of Utah Health Sciences Center, Salt Lake City, Utah 8Utah Birth Defect Network, Utah Department of Health, Salt Lake City, Utah 9Department of Pediatrics, University of Padua, Clinical Genetics Unit, Padua, Italy 10Metropolitan Atlanta Congenital Defects Program, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia 11Department of Hungarian Congenital Abnormality Registry and Surveillance, National Center for Healthcare Audit and Inspection, Budapest, Hungary 12Centre of the International Clearinghouse for Birth Defects Surveillance and Research, Rome, Italy 13National Center for Maternal and Infant Health, Peking University Health Science Center, Beijing, People’s Republic of China 14ECLAMC at CEMIC (Centro de EducaciońMe´dica e InvestigaciońClıńica), Buenos Aires, Argentina 15Alberta Congenital Anomalies Surveillance System, Alberta Health & Wellness, Calgary, Alberta, Canada 16Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Texas 17ECEMC (Spanish Collaborative Study of Congenital Malformations), Centro de Investigacioń sobre Anomalıás Congeńitas (CIAC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain 18CIBER de Enfermedades Raras (CIBERER) (Centre for Biomedical Research on Rare Diseases), Madrid, Spain 19Department of Pharmacology, Faculty of Medicine, Universidad Complutense de Madrid, Spain 20CARIS, the Congenital Anomaly and Register for Wales, Singleton Hospital, Swansea, United Kingdom 21Tuscany Registry of Congenital Defects (RTDC), Epidemiology Unit, IFC-CNR, Pisa, Italy 22The Finnish Register of Congenital Malformations, National Institute for Health and Welfare, THL, Helsinki, Finland 23Birth Defects Campania Registry, Medical Genetics Dept, General Hospital ‘‘G. Rummo’’ Benevento, Italy 24Slovak Teratologic Information Centre, Slovak Medical University, Bratislava, Slovak Republic 25ECLAMC at Laborato´rio de Epidemiologia de Malformaço˜es Congeˆnitas, Instituto Oswaldo Cruz, Fundaçaõ Oswaldo Cruz, Rio de Janeiro, Brazil

Sirenomelia is a very rare limb anomaly in which the normally paired lower limbs are replaced by a single midline limb. This study describes the prevalence, associated malformations, and maternal characteristics among cases with sirenomelia. Data originated from 19 birth defect surveillance system members of the International Clearinghouse for Birth Defects Surveillance and Research, and were reported according to a single pre- established protocol. Cases were clinically evaluated locally and reviewed centrally. A total of 249 cases with sirenomelia were identiﬁed among 25,290,172 births, for a prevalence of 0.98 per 100,000, with higher prevalence in the Mexican registry. An increase of sirenomelia prevalence with maternal age less than 20 years was statistically signiﬁcant. The proportion of twinning was 9%, higher than the 1% expected. Sex was ambiguous in 47% of cases, and no different from expectation in the rest. The proportion of cases born alive,

Disclaimer: The ﬁndings and conclusions in this report are those of the authors and do not necessarily represent the ofﬁcial position of the Centers for Disease Control and Prevention. Grant sponsor: MCT/CNPq, Brazil; Grant numbers: 573993/2008-4, 476978/2008-4, 554755/2009-2, 306750/2009-0, 402045/2010-6; Grant sponsor: FAPERJ, Brazil; Grant numbers: E-26/102.748/2008, E-26/170.007/2008; Grant sponsor: CAPES, Brazil; Grant numbers: 1957/2009, 2799/ 2010; Grant sponsor: Center for Disease Control and Prevention; Grant number: 1U50DD000524-02. *Correspondence to: Ieˆ da M. Orioli, Departamento de Gene´ tica, Universidade Federal do Rio de Janeiro, Caixa Postal 68.011, 21944-970 Rio de Janeiro, Brazil. E-mail: [email protected] DOI 10.1002/ajmg.c.30324 Published online 14 October 2011 in Wiley Online Library (wileyonlinelibrary.com).

ß 2011 Wiley Periodicals, Inc. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 359

premature, and weighting less than 2,500 g were 47%, 71.2%, and 88.2%, respectively. Half of the cases with sirenomelia also presented with genital, large bowel, and urinary defects. About 10–15% of the cases had lower spinal column defects, single or anomalous umbilical artery, upper limb, cardiac, and central nervous system defects. There was a greater than expected association of sirenomelia with other very rare defects such as bladder exstrophy, cyclopia/holoprosencephaly, and acardia-acephalus. The application of the new biological network analysis approach, including molecular results, to these associated very rare diseases is suggested for future studies. ß 2011 Wiley Periodicals, Inc.

KEY WORDS: sirenomelia; caudal regression spectrum; twinning; maternal age; world prevalence; caudal dysgenesis How to cite this article: Orioli IM, Amar E, Arteaga-Vazquez J, Bakker MK, Bianca S, Botto LD, Clementi M, Correa A, Csaky-Szunyogh M, Leoncini E, Lo´ pez-Camelo JS, Li Z, Lowry RB, Marengo L, Martı´nez-Frı´as ML, Mastroiacovo P, Morgan M, Pierini A, Ritvanen A, Scarano G, Szabova E, Castilla EE. 2011. Sirenomelia: An epidemiologic study in a large dataset from the International Clearinghouse of Birth Defects Surveillance and Research, and literature review. Am J Med Genet Part C Semin Med Genet 157:358–373.

INTRODUCTION type [Aslan et al., 2000], OMIM 263650 Prenatal diagnosis of sirenomelia by and 605203, respectively. However, ultrasound is impaired by the coexisting According to Stevenson [2006] ‘‘Sire- popliteal pterygia associated with caudal oligohydramnion resulting from the nomelia is a limb anomaly in which the regression spectrum (CRS; caudal dys- frequently associated bilateral renal a/ normally paired lower limbs are replaced genesis) were described in a child born dysgenesis [Wasnik and Lalchandani, by a single midline limb.’’ This from a diabetic mother [Al Kaissi et al., 2010]. However, there is a narrow is probably the best definition in the 2008]. window, between weeks 8 and 16 of literature because it does not use the ICD-10 lacks a specific code for gestation, that is, when the limb struc- term ‘‘fusion.’’ Other definitions char- sirenomelia, which must be coded as tures are visible to ultrasound, and the acterize sirenomelia as different degrees Q87.2 ‘‘congenital malformation syn- amniotic fluid still depends mainly from of fusion between the lower limbs. dromes predominantly affecting limbs.’’ maternal production, whenvisualization However, the term ‘‘fusion,’’ derived This is a serious limitation for the of sirenomelia is possible [Valenzano from Latin fundere, should be avoided study of time-space clusters, as reported et al., 1999; Schiesser et al., 2003]. because, as a noun derived from Latin from South America [Castilla et al., Nevertheless, first trimester ultrasono- fundere, it implies the uniting of separated graphic examinations are infrequent parts, in this case the para-medial limb and only a few cases of early diagnos- buds, which is an unproven mechanism ICD-10 lacks a specific code for ed sirenomelia have been reported of production for sirenomelia. sirenomelia, which must be [Blaicher et al., 2001; Carbillon et al., coded as Q87.2 ‘‘congenital 2001; Akbayir et al., 2008]. Patel and Definition and Diagnostic Suchet [2004] applied color and power Challenges malformation syndromes Doppler ultrasound to diagnose second and third trimester fetuses with sireno- Even when sirenomelia seems to be a predominantlyaffecting limbs.’’ melia mainly based on fetal vascular discrete and well-defined anomaly,some This is a serious limitation images. difficulties can be encountered in its for the study of time-space delineation. On one hand, if its definition as the presence of an axial clusters, as reported from South Classification positioned single lower limb is accepted, America, as well as for statutory the first three of the seven types in Sirenomelia was first classified into three Stocker and Heifetz [1987] classification birth defects registries that only types according to the number of feet (see next section on Classification) use ICD-10 as the basis for and named sympus apus, monopus, and cannot be included as sirenomelias since dipus, for none, one, or two feet, they do not present an axial single lower their coding system for respectively [Foerster, 1861–1865]. A limb. On the other hand, extended congenital anomalies. more adequate classification of sireno- crural or multiple crural-popliteal-talus melia is that of Stocker and Heifetz pterygia can overlap with Type-I sire- [1987] in which seven types are defined: nomelia from the clinical and radio- 2008; Orioli et al., 2009], as well as for I, all thigh and leg bones present; logical standpoints. Furthermore, when statutory birth defects registries that only II, single fibula; III, absent fibulae; associated with other unrelated anoma- use ICD-10 as the basis for their coding IV, partially fused femurs, fused lies such as craniofacial, sirenomelia system for congenital anomalies. The fibulae; V, partially fused femurs, absent may overlap with multiple pterygium pediatric extension of ICD10 (BPA) has fibulae; VI, single femur, single tibia; syndromes of the Bartsocas–Papas a specific code for ‘‘sirenomelia syn- VII, single femur, absent tibiae. How- [Bartsocas and Papas, 1972], or Aslan drome’’ which is Q87.24. ever, none of these classifications follow 360 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

strosities. Sirenomelia is referred as Opitz et al., 2002; Kjaer et al., 2003; Sirenomelia was first classified ‘‘mermaid’’ in mythology, that is: as a Garrido-Allepuz et al., 2011], while the into three types according to the female, more frequently than as the male latter is based on an abnormal develop- counterpart ‘‘merman,’’ or Triton type ment of the umbilical vessels resulting in number of feet and named sirenomelia, probably due to the more a deficient blood supply of the caudal sympus apus, monopus, and attractive and esthetic sensual attributes, part of the embryo [Kampmeier, 1927; as bosom, eyes, and hair in the female Hentschel et al., 2006]. This latter dipus, for none, one, or two feet, gender when external genitalia was hypothesis is supported by observations respectively. A more adequate omitted. of caudal ‘‘vascular steal’’ through a classification of sirenomelia is persistent vitelline artery [Stevenson et al., 1986; Bianchi et al., 2000; Patel Embryology that of Stocker and Heifetz in and Suchet, 2004]. There have been several case reports supporting the which seven types are defined. Normal development: Morphology. In the vascular hypothesis [Hentschel et al., mouse, each lower limb derives from a 2006; Duesterhoeft et al., 2007] as well different para-medial developmental as some rejecting it [Jaiyesimi et al., field determined at gastrulation due to a dysmorphogenetic rationale, propos- 1998]. Since these hypotheses are ex- the expression of Pitx1-dependent Tbx4 ing nothing more than discrete group- tended to the whole CRS, as well as to [Ouimette et al., 2010]. This process ings of a continuous spectrum. other associated defects, it is feasible that occurs over 25 days, beginning at week 4 both hypotheses are valid, even allowing after fertilization, and by the end of for additional possible pathogenetic me- Historical Aspects the eighth week, the limb is perfectly chanisms to be proposed in the future. formed. Lower limbs are delayed 2 days Very rare congenital defects (VRDs), in comparison to forelimbs. The trigger having an expected occurrence rate of 1 Sirenomelia and caudal regression spectrum for limb bud initiation is unknown, even per 100,000 or lower, were expected to (CRS). The concept of sirenomelia as though fibroblast growth factors 8 and happen only once every several gener- the most severe extreme of CRS was 10 are hypothesized as being involved ations in most ancient populations at advanced by Duhamel [1961], fitting [Agarwal et al., 2003]. the time of polytheist religions, when within the general concept of very rare Limb development is a continuous several VRDs became mythological defects being extremes of dysmorpho- process that encompasses meso- and figures. Early human populations were logic spectra [Castilla and Mastroiacovo, ectodermal components and is divided mostly rural, and urban areas seldom 2011]. While sirenomelia and CRS into four stages: the bud (outgrowth), passed over 1,000 inhabitants, except for without sirenomelic share some com- the paddle (dorso-ventral flattening), classical Athens, one of the first known mon characteristics as male sex prefer- the plate (relative expansion of the distal city-state, with about 100,000 residents ence, maternal diabetes, and absent end), and the rotation (around the in the late 5th and 4th century BC sacrum [Duesterhoeft et al., 2007], proximo-distal axis). In the latter stage, [Scheidel, 2008]. Thus, even with a associated defects as single umbilical the position of the limb buds relative to natality rate as high as 50 per thousand artery, lethal renal a/dysgenesis, and the trunk change due to the differentiate per year, no more than one case of a oligohydramnios-related deformities growth of the cartilage model that given VRD every 20 years or more was are much more frequent in the former continues to elongate the limb, with to be expected (i.e., approximately one than in the latter [Ka¨lleń and Winberg, different parts growing at different rates. case per generation, assuming 25 years 1974; Martıńez-Frıás et al., 2008]. Thus, Lower limbs twist around their proxi- per generation). Pictured or written the concept of sirenomelia and caudal mo-distal axis medially (internally) descriptions probably facilitated the dysgenesis being at the severest end of bringing the great toe to the midline recording and/or historical recognition the same CRS, proposed by Thottungal from its initial postaxial position [Larsen, of a given VRD. Nevertheless, et al. [2010] makes sense and incorpo- 1993]. the large time-lapse between occur- rates most observations made until now rences in ancient populations probably [Goodlow et al., 1988; Guidera et al., allowed for magical or mythological Abnormal development: Dysmorphology. 1991; Das et al., 2002]. thinking about such defects [Stahl and Two main non-mutually exclusive hy- Tourame, 2010]. potheses were advanced to explain the Genetics and Clinical Genetics Sirenomelia, cyclopia, and, to a abnormal development of the lower lesser degree, conjoined twins received limbs leading to sirenomelia: blastoge- As is the case with most, if not all special attention in most fantasies, my- netic and vascular. The former hypoth- congenital anomalies, sirenomelia is thologies, and religions, in which these esis postulates a primary anomaly in the etiologically heterogeneous. No in- defects seem to have been taken more development of the caudal axial meso- stances of familial recurrence of sireno- as caprice of nature than as real mon- derm [Ka¨lleń and Winberg, 1974; melia have been reported. However, ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 361 under the pathogenetic concept of currence of both conditions, sirenomelia Maternal age. An international study sirenomelia as part of the CRS, familial and holoprosencephaly, in the same showed an U-shaped curve with in- cases are known. A pair of sirenomelic human newborn [Martıńez-Frıás et al., creased risk for sirenomelia at young concordant identical twins was reported 1998b]. and old maternal ages: under 20, and by Di Lorenzo et al. [1991]. Four siblings A so-called ‘‘mermaid (merm) over 40 years old [Ka¨lleń et al., 1992]. with renal defects, one of them with mutant’’ (Nup133merm mutation) was However this observation has not been sirenomelia [Selig et al., 1993], are described disrupting mouse (mus muscu- investigated further. considered to have renal adysplasia lus) gastrulation which is a functional (OMIM 191830), The renal adysplasia null allele of nucleoporin Nup133, a Maternal diabetes. One-fifth of pub- patients can have mutations in the RET constituent of the conserved Nup107- lished sirenomelia cases were delivered gene (OMIM 164761) located at 160 complex [Garcıá-Garcıá et al., to diabetic mothers, the offspring of 10q11.2 or in the uroplakin IIIA gene 2005]. The phenotype in mice includes whom are reported to have a prevalence (UPK3A; OMIM 611559) located at exencephaly, shortened trunk, irregu- of one in 200 births for a sirenomelia/ 22q13.31. Sirenomelia was reported in larly segmented somites, and a minimal caudal regression (CRS) infant one case with an extra small bisatellit- tail bud. [Gurakan et al., 1996; Martıńez-Frıás ed marker chromosome identified as et al., 1998a; Al-Haggar et al., 2010]. the proximal part of the long arm of Epidemiology: Prevalence, However, in a 15-year pathology series chromosome 22 [Jensen and Hansen, Risk Factors Bruce et al. [2009] found a history of 1981]; probably this case was an earlier maternal diabetes in three out of nine example of UPK3A gene deletion. Prevalence. The birth prevalence of CRS cases, but in none of six cases of Molecular studies in CRS show a sirenomelia varies from 1 to 2 per sirenomelia. variety of specific anomalies: mutations 100,000, depending on the denomina- Some associations with sirenomelia in the VANGL1 gene mapped at 1p13 tor definition and case ascertainment and/or CRS such as VATER association for CRS [Kibar et al., 2007], a homeo- since one-third of the cases of sireno- [Castori et al., 2010], pterygia [Al Kaissi box gene on chromosome 7q36 for melia are stillborn [Ka¨lleń et al., 1992; et al., 2008], and twinning [Zaw and anorectal atresia [Lowry et al., 2007], Castilla and Orioli, 2004]. From 10% to Stone, 2002] present with a history of and mutations in HLXB9 gene for the 15% of occurrences are in twin births, maternal diabetes providing clues for a Currarino syndrome reported by Ko¨ch- mostly monozygous [Valenzano et al., common risk factor. Castori et al. [2010] ling et al. [2001]. No gene mutations 1999]. report a diabetic mother having had have been reported in sirenomelia Due to the absence of external infants with sirenomelia and VATER patients. No SHH mutations were found genitalia and infrequent information on association from two out of her three by Vargas et al. [1998] in sacral agenesis/ gonadal or chromosomal sex, data on sex pregnancies, indicating a possible causal sirenomelia cases. Sirenomelia can occur distribution are very scarce. Nonethe- relationship between maternal diabetes in crosses between specific mice strains less, the limited information available and these two early blastogenic defects. and as consequence of mutations that indicates male sex preference [Duester- Beside this observation, these authors increase retinoic acid, as observed in hoeft et al., 2007], or does not indicate also speculate on the pathogenetic gene-knockouts of Cyp26 that codifies any substantial sex preference [Ka¨lleń identity of both anomalies belonging to for a retinoic acid degrading enzyme et al., 1992]. the same dysmorphogenic spectrum. (CYP26), recently revised by Pennim- These conclusions were based not pede et al. [2010]. Clusters. A time-space cluster of sir- only on the reported case but also on Zakin et al. [2005] have shown that enomelia in 2005 in the city of Cali two previously published observations the lack of bone morphogenetic protein (Colombia) was reported by ECLAMC [Valenzano et al., 1999; Castori et al., 7(Bmp 7) in combination with half a (Spanish acronym for the Latin Ameri- 2008]. dose or complete loss of twisted gastru- can Collaborative Study of Congenital lation (Tsg) protein cause sirenomelia in Malformations) [Castilla et al., 2008; Environmental risk factors. Several mice. Tsg is one of several regulators of Orioli et al., 2009]. As with most chemicals have been reported to induce Bmp, whose gradient determines the reported epidemics of congenital anom- sirenomelia/CRS in experimental dorso-vertebral patterning in vertebrate alies, except for phocomelia due to mammals, including retinoic acid in and invertebrate embryos. The same maternal thalidomide exposure this mice [Padmanabhan, 1998], cadmium team has earlier described that in the cluster ended spontaneously, without and lead in golden hamsters [Hilbelink absence of Tsg, the loss of one copy of identification of its cause. The most and Kaplan, 1986], and ochratoxin A in Bmp4 results in holoprosencephaly and interesting aspect of this cluster is the chick embryos [Wei and Sulik, 1996]. branchial arc defects [Zakin and De nearly simultaneous rise and fall in the Human reports on prenatal exposures Robertis, 2004]. Then, Tsg and Bmp birth prevalence rates of sirenomelia and include cocaine [Sarpong and Headings, interaction seems doubly interesting to cyclopia, supporting the concept of 1992], and an undefined ‘‘snuff’’ the VRD studies, considering the oc- shared causal factors. [Taghavi et al., 2009]. A thorough 362 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE review by Holmes [2002] found no (NTD), mainly with spina bifida, is to period, hampering any intent of treat- plausible teratogens associated with sir- be expected since the lower spine is ment. In a large set of consecutive birth enomelia. affected in this anomaly [Ka¨lleń et al., series (10.1 million births), 97 cases of 1992]. A more extended NTD in a sirenomelia were identified, 35 of them fetus with sirenomelia and acardia in stillbirths, and 62 in live births who Associated and Combined was reported by Halder et al. [2001]. died shortly after birth [Ka¨lleń et al., Anomalies Sirenomelia and popliteal or multiple 1992]. Since sirenomelia is not well delineated, pterygia were reported in some cases In sirenomelia, the prognosis for relative to the CRS, it is difficult to [Aslan et al., 2000], and a common morbidity, survival, and quality of life specify which congenital anomalies are causality due to maternal diabetes was depends almost exclusively on the pres- pathogenetically associated with sireno- proposed [Al Kaissi et al., 2008]. ence or not of congenital anomalies melia. Association of sirenomelia/CRS affecting vital organs, such as renal with component anomalies of the Potter Combined VRD. We are here naming a/dysgenesis [Messineo et al., 2006]. sequence is obviously expected due to as ‘‘combined’’ VRD the concurrence There is documentation of one individ- the an/oligohydramnios produced by of two or more of the eight defects ual with sirenomelia born in the early the usually associated severe and lethal (acardia, amelia, phocomelia, conjoined 1990s that was claimed to be the second renal a/dysgenesis [Savader et al., 1989; twins, cyclopia, sirenomelia, bladder, surviving case of sirenomelia known Al-Haggar et al., 2010]. An association and cloaca esxtrophies) reported in this [Murphy et al., 1992], additionally,there between sirenomelia/CRS and VATER series of articles with material from is documentation in 2003 of a 4-year-old association could be explained by both ICBDSR [2009]. This is to distinguish patient reported to be the fifth surviving deriving from an early blastogenic insult, them from the commonly named ‘‘asso- patient [Stanton et al., 2003]. when the potential embryo exists in a ciated’’ for the coexistence of sirenome- Only about 1% of cases survive the single developmental field [Opitz et al., lia with other unrelated congenital first week of life. Among these, three 2002]. Epidemiological data supporting anomalies. The occasional coincidence cases with Stocker and Heifetz [1987] this were provided by Duncan and of more than one VRD in the same types I to III of sirenomelia were widely Shapiro [1993], Duncan et al. [1991], individual is difficult to accept as chance publicized through the lay press. One and Schu¨ler and Salzano [1994]. Further occurrence, and a common etiopatho- of them was born in August 1999 in support came from clinical observations, genic mechanism is more likely to Kennebunkport, Maine, USA, having a in which maternal diabetes provided an explain it since most of them are small remnant of a kidney, 15 cm of large etiological ground for both anomalies presumably early blastogenic defects intestine, one ovary, and absent uterus [Kalter, 1993; Valenzano et al., 1999; [Opitz et al., 2002]. and external genitalia. She underwent Castori et al., 2010], as well as from more two kidney transplants, dying at the age Sirenomelia–Cyclopia. There is evid- recent experimental studies with adria- of 10 years from pneumonia. The other ence for concurrence of sirenomelia mycin in rats and mice [Abu-Hijleh two cases still are still alive at present (in and cyclopia in the same patient et al., 2000; Dawrant et al., 2007]. The 2011), both of them, apparently having [Martıńez-Frıás et al., 1998b], being alternative approach of searching for no other major anomalies, and who un- associated with similar epidemiological sirenomelia/CRS in association with derwent successful surgery for leg sepa- risk factors [Ka¨lleń et al., 1992]; being VATER in the same patient also pro- ration. However, as mentioned above, observed in the same clusters [Castilla vided support to this preferential associ- these milder types could not be true et al., 2008], and for potentially sharing ation [Botto et al., 1997; Rittler et al., sirenomelias, but pterygia involving just a similar pathogenetic mechanisms 1996]. the soft tissues of lower limbs. [O’Railly and Mu¨ller, 1989]. Another potential similarity of There is room for the primary sirenomelia/CRS with VATER associ- Sirenomelia–Acardia. Concurrence in prevention of sirenomelia through the ation is imperforate anus, the A in the same case was documented by appropriate pre-conceptional diagnosis VATER acronym, which Duhamel Zanforlin Filho et al. [2007], as well as and treatment of all types of diabetes [1961] proposed as the mildest end of by Halder et al. [2001]. that can lead to an exposure of the the CRS. However, during the survey Sirenomelia/CRS and situs inversus in early embryo to high levels of maternal of the epidemic of sirenomelia in the the same case were reported by Langer glycemia. In theory,as many as 20% of all city of Cali, variations in the birth et al. [1999] and Rougemont et al. cases of sirenomelia could be avoided prevalence of imperforate anus was [2008]. [Kadian et al., 2008; Delissaint and analyzed as a sentinel phenotype for McKyer, 2011]. minor forms of CRS, and no concomi- In order to expand on the limited Prognosis, Treatment, Survival, tant rise in frequency was detected epidemiologic information on sireno- and Prevention [Castilla et al., 2008]. melia, we conducted a descriptive anal- The reported association of sireno- Except for very rare instances, sireno- ysis of prevalence data collected on melia/CRS with neural tube defects melia is a lethal condition in the perinatal sirenomelia by 19 program members ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 363 of the International Clearinghouse for each of them subdivided into different 29 years group as the reference group. Birth Defects Surveillance and Research sub-sets under different ad hoc codes. Pearson correlation was used as a (hereafter referred to as ‘‘the Clearing- The cases with sirenomelia were also measure of correlation between the house’’). In this analysis, we examined separated into isolated cases (i.e., cases prevalence of sirenomelia and two the variation in prevalence by program, with no other defect outside the sireno- variables: the number of births and the over time, and by selected maternal and melia spectrum reported in the same proportion of ETOPFA in each registry. infant characteristics. case); and MCA (multiple congenital The 95% CI were computed using the anomalies) cases (i.e., cases with associ- Poisson distribution. Statistical test sig- ated non-sirenomelia-spectrum defects nificance was set to P < 0.05. Statistical METHODS reported). analyses were done with Stata software, The Clearinghouse collects data from Programs were asked to provide version 10.0 [StataCorp, 2007]. 46 member birth defect surveillance de-identified case records following a programs around the world, sampling common protocol, with information on RESULTS out data from 37 countries. Six countries phenotype, genetic testing, and selected have two or more participating pro- demographic and prenatal information. Prevalence grams, and one (ECLAMC: Estudo Further details can be found in Castilla Colaborativo Latino Americano de and Mastroiacovo [2011] in this issue. The total number of births and of Malformaço˜es Congeˆnitas) including sirenomelia cases is given in Table I for hospitals from 10 different South Case Review each of the 19 surveillance programs American countries. Each program members of the International Clearing- submits data in the same format to the All records were reviewed by two house for Birth Defects Surveillance and Clearinghouse for the annual report, experienced dysmorphologists (PM, Research (ICBDSR). A total of 249 which includes detailed descriptions of IMO). When information was unclear cases with sirenomelia were identified each member registry [ICBDSR, 2009]. or missing, clarification and further data among 25,290,172 births, for a birth were requested from the participating prevalence of 1 per 100,758 births or program. All cases were reported verba- 0.98 per 100,000 (95% CI 0.87–1.11). Study Design and Cohorts tim and centrally classified. The proportion of ETOPFA was This was a retrospective cohort study 24.5% considering all reported cases. from population-based and hospital- Inclusions and Exclusions ETOPFA was not permitted in two sur- based birth defect surveillance programs. Included were cases of sirenomelia, as veillance programs (Mexico RYVEMCE: Nineteen programs from North and identified by the participating programs. Registro y Vigilancia Epidemiolo´gica South America, Europe, China, and Cases with extended crural pterygium, de Malformaciones Congeńitas; and Australia provided data on sirenomelia, and non-medial single lower limb, South America ECLAMC), and was ascertained from a total birth population suggestive of lower limb amelia were not recorded in another two (Spain of almost 25.3 million births. Birth years excluded. Spontaneous abortions (less ECEMC: Spanish Collaborative Study included in the study ranged from 1968 500 g, or 20 weeks gestation) were ex- of Congenital Malformations; and to 2006, and varied by program. Births cluded among cases and denominators. China, Beijing). Excluding these four included live births, stillbirths, and, for programs the proportion of ETOPFA some but not all programs, elective was 49.5%. There was no correlation Statistical Methods pregnancy terminations for fetal anoma- between the proportion of cases of lies (ETOPFA). Occurrence was expressed as total prev- sirenomelia submitted to ETOPFA and Cases with sirenomelia were classi- alence (number of live births, stillbirths the sirenomelia prevalence (r ¼ 0.25; fied according to the number of defects and ETOPFA with sirenomelia per P ¼ 0.37). unrelated to the CRS [Orioli et al., 100,000 births) with its 95% confidence Figure 1 shows the sirenomelia 2009]. Defects considered as related intervals (CI). For each program the prevalence with their 95% CI in the dif- to sirenomelia include urinary, genital, expected number of cases was calculated ferent surveillance programs. Hungary large bowel, low spinal column, single under the hypothesis of a homogeneous (0.33 per 100,000; 95% CI 0.16–0.61; umbilical artery, and oligohydramnion prevalence among all programs. Using P < 0.0001) as well as Italy Campania derived defects. Other types of defects the expected values, we calculated the (0.16 per 100,000; 95% CI 0.00–0.87; were grouped into 17 sets: other spinal exact Poisson probabilities of observing P < 0.013) show statistically significant column or rib, small intestine, esophagus N or more cases (P (N X)) in each lower prevalence, suggesting under- or diaphragmatic, cardiac, upper limb, registry. Maternal age-specific preva- ascertainment. Five programs show a abdominal or thoracic wall, ear, eye, oral lence ratios were calculated using the statistically significant higher sirenome- cleft, other facial, holoprosencephaly, number of total cases and all births (live lia prevalence: Mexico RYVEMCE: skin tag, situs inversus, hydrocephalus, births and stillbirths) data by 5 years 2.36 (95% CI 1.53–3.49; P < 0.0001), CNS, other artery,and other defects; and maternal age groups and using the 25– South America ECLAMC: 1.36 364 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

TABLE I. Total Prevalence (per 100,000 Births) of Sirenomelia in 19 Surveillance Programs Members of the International Clearinghouse for Birth Defects Surveillance and Research

Total %of Prevalence 95% Conﬁdence Surveillance program Period Births cases ETOPFA cases (per 100,000 births) intervals (CI) Canada Alberta 1980–2005 1,062,483 17 35.3 1.60 0.93–2.56 USA Utah 1997–2004 380,706 2 50.0 0.53 0.06–1.90 USA Atlanta 1968–2004 1,283,999 11 36.4 0.86 0.43–1.53 USA Texas 1996–2002 2,054,788 17 23.5 0.83 0.48–1.32 Mexico RYVEMCE 1978–2005 1,058,885 25 NP 2.36 1.53–3.49 South America ECLAMC 1982–2006 4,556,173 62 NP 1.36 1.04–1.74 Finland 1993–2004 713,494 5 60.0 0.70 0.23–1.64 Wales 1998–2004 222,309 5 80.0 2.25 0.73–5.25 Northern Netherlands 1981–2003 369,658 2 50.0 0.54 0.07–1.95 Slovak Republic 2000–2005 318,257 1 0 0.31 0.01–1.75 Hungary 1980–2005 3,022,194 10 10.0 0.33 0.16–0.61 France Central East 1979–2004 2,500,214 26 88.5 1.04 0.68–1.52 Italy North East 1981–2004 1,186,497 20 35.0 1.69 1.03–2.60 Italy Tuscany 1992–2004 336,744 4 50.0 1.19 0.32–3.04 Italy Campania 1992–2004 643,962 1 100 0.16 0.00–0.87 Italy Sicily 1991–2002 216,257 1 0 0.46 0.01–2.58 Spain ECEMC 1980–2004 2,045,751 13 NR 0.64 0.34–1.09 China Beijing 1992–2005 1,927,622 16 NR 0.83 0.47–1.35 Australia Victoria 1983–2004 1,390,179 11 36.4 0.79 0.39–1.42 25,290,172 249 24.5a 0.98 0.87–1.11

RYVEMCE,Registroy Vigilancia Epidemiolo´gica de Malformaciones Conge´nitas; ECLAMC, Estudo Colaborativo Latino Americano de Malformac¸o˜es Congeˆnitas; ECEMC, Spanish Collaborative Study of Congenital Malformations; ETOPFA, elective termination of pregnancy for fetal anomaly; NP, not permitted; NR, not reported. aThe percentage computed on the 15 surveillance programs registering ETOPFA is 49.5% (n ¼ 61/133).

(95% CI 1.04–1.74; P < 0.006), Italy 19 programs. However, there were no increased significantly (1.71; 95% CI North-East 1.69 (95% CI 1.03–2.60; evident secular trends. 1.13–2.59). When the cases were sepa- P < 0.009), Canada Alberta (1.6 per rated into isolated or MCA (multiple 100,000; 95% CI 0.93–2.56; P < congenital anomalies) groups (TableIII), Maternal Age 0.021), and Wales (2.25 per 100,000; the same prevalence trend and signifi- 95% CI 0.73–5.25; P < 0.024). If we For the maternal age analyses we cant prevalence ratio remained only for discard the two registries with under- excluded sirenomelia cases and births the MCA group. ascertainment only the Mexican registry from China (before 1997 and after had a higher prevalence than the other 2003), Italy North-East, and Italy Sicily Sex registries. because the number of births by mater- There was no correlation between nal age was not available. Maternal age The sirenomelia spectrum of defects the sirenomelia prevalence and number was analyzed in six groups: less than includes external and internal genital of births in each surveillance program 20 years, 20–24, 25–29, 30–34, 35–39, defects; thus making sex determination (r ¼ 0.03; P ¼ 0.92). More than half and 40 years or older. In Table II the difficult. Autopsy findings were more (53.4%) of the sirenomelia cases in this sirenomelia prevalence for each mater- helpful in the sex determination since study were provided by four reporting nal age group and the prevalence ratios only 12 patients (8 females and 4 males) surveillance programs: South America for maternal age groups relative to the had a karyotype result. In 11% of cases ECLAMC, France Central East, Mexico reference age group of 25–29 years the sex was unknown and 47.0% were RYVEMCE, and Italy North East. with corresponding 95% CI are shown. described as having ambiguous genitalia. There was a clear gradient (Fig. 2) in The proportion of males (49%) did not the sirenomelia prevalence from differ from the 51% expected in the Secular Variation younger to older maternal age groups sample of 105 patients with determined There is variation in the annual frequen- (P < 0.01), with the prevalence ratio sex. When grouping patients into iso- cies of sirenomelia within each of the for maternal age less than 20 years lated and associated defects, the propor- ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 365

neous abortion, plurality, maternal age, parental age difference, and maternal education between isolated and MCA sirenomelia cases. The associations with maternal age and sex were already described above. Pregnancy outcomes among sirenomelia cases were: liveborn 47%, stillbirths 28.5%, and ETOPFA 24.5%. The proportion of ETOPFA was slightly higher in MCA cases (28.6%) than in the isolated cases (20.3%), but the difference did not reach statistical significance (P ¼ 0.13). For other pregnancy outcomes, the isolated and MCA cases had similar distributions. Only 11.1% of the sirenomelia births weighed more than 2,500 g. The proportion of cases who were low birth weight did not differ between isolated and MCA cases. Prematurity was found in 71.2% of the cases, with 25.6% below 32 weeks, and 37.6% between 33 and 36 weeks of gestation, and no difference between isolated and MCA cases. The proportions of first births, previous spontaneous abortion, years of parental age difference and of maternal education did not differ between the isolated and MCA groups of sirenomelia cases, and were similar to those expected in the general population. However, the proportion of multiple births among sirenomelia cases was 8% versus an expected rate of 1% or slightly more in the general population. Figure 1. Total prevalence per 100,000 births (bar) and 95% confidence interval (line) by surveillance program and overall (dotted line) of sirenomelia in 19 surveillance Related and Unrelated Defects in programs members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). Sirenomelia Single midline lower limb, reno-urinary, genital, large bowel, low spinal column, tion of unspecified sex was smaller in diabetes. Misoprostol first trimester single or anomalous umbilical artery,and the MCA (7.1%) than in the isolated exposure was found in one case, and oligohydramnios-derived defects were group (14.6%). The ETOPFA cases fever in six cases (4.5%). in this work considered as part of the had 47% of males among the small None of the 249 sirenomelia cases sirenomelia sequence. Cases with sire- sample of 43 patients with determined had any indication of other family nomelia that had other different defects sex; information on sex was missing members being affected by this or CRS. were classified as MCA cases. Cases with in only 3%, and not determined in 18%. inadequately described or minor defects were not considered. The isolated group Descriptive Analysis of (I) comprised of 123 infants (49%), and Other Risk Factors Sirenomelia Patients the remaining 126 (51%) were divided in Information on risk factors (i.e., mainly There were 123 isolated cases (49%), groups having 1 (28%), 2 (16%), and 3 or maternal exposures during pregnancy) and 126 (51%) with other non-related more unrelated defects (7%), The unre- was not available for most of the defects. In Table IV we present the com- lated defects formed 17 groups of defects registries. Among 133 informative cases, parison of sex, outcome, birth weight, coded ad hoc as explained in the there were seven (5%) with maternal gestational age, parity, previous sponta- Methods Section. Since the description 366 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

TABLE II. Number of Births, Number of Cases Crude Prevalence Estimates, and Prevalence Ratios for Maternal Age Groups Relative to the Reference Age Group of 25–29 Years for Sirenomelia

Prevalence Prevalence Maternal age group Birthsa Casesa (per 100.000 births) 95% CI ratio 95% CI <20 2,334,023 35 1.50 1.04–2.09 1.71 1.13–2.59 20–24 5,922,300 56 0.95 0.71–1.23 1.08 0.75–1.55 25–29 7,079,853 62 0.88 0.67–1.12 1.00 (Reference) 30–34 4,966,752 43 0.87 0.63–1.17 0.99 0.67–1.46 35–39 2,024,166 12 0.59 0.31–1.04 0.68 0.36–1.26 40 or older 426,799 2 0.47 0.06–1.69 0.54 0.13–2.19

aCases and births excluded: China before 1997 and after 2003, Italy North East, Italy Sicily because no births by maternal age were available.

of the specific defects is higher in 12.9%, horseshoe kidney (including defect being present in 16% of all MCA groups with 812 specific defects horseshoe cystic kidney) in 5.2%, and cases. Sacral or sacrococcygeal absence described in 126 patients (6.44 defects hydronephrosis in 4.3% of the cases. was present in 59.9% of the 40 informa- by patient) than in the isolated group tive cases, and the sacral or sacrococcy- with 346 specific defects in 123 Related Genital Defects geal defects described in 25.4% of these patients (2.81 defects by patient), we cases. Genital defects were described in 59.5% show the frequency of related defects of MCA and in 57% of all patients. only in MCA group or in the total Related Large Bowel Defects Absence of total genitalia absence was sample. reported in 59.9%, and ambiguous Defects of the large intestine were genitalia in 25.4% of all 142 informative described in 62.7% of MCA cases, being Related Reno-Urinary Defects patients. present in 53.4% of all cases. Anal atresia Urinary defects were mentioned in was the most frequent defect, present in 57.1% of MCA cases and in 46.6% of 91.0% of 133 informative cases. Anal and Related Lower Spinal Column all cases. Total absence of the reno- intestinal duplication were described in Defects urinary tree was described in 73.3% of three cases. informative cases. Unilateral kidney Most of the sirenomelia cases (80.2% in agenesis or bilateral hypoplasia was seen MCA groups) had no lower spinal in 9.5%, cystic or dysplastic kidneys in column defects described, with this Other Related Defects Single or anomalous umbilical artery was present in 16.5% and oligohydramnion related defects in 24.9% of all cases. Among the 62 cases with these defects, 12.4% were described as Potter anomalies and 7.2% as lung hypoplasia.

Unrelated Defects The 17 groups of unrelated defects observed in the 126 MCA sirenomelia patients were deﬁned in the Methods Section. Below they are summarized in the limb, trunk, and head regions.

Limbs Figure 2. Prevalence ratios for maternal age groups relative to the reference age The commonest non-related defects group of 25–29 years with corresponding 95% conﬁdence intervals for sirenomelia in 19 surveillance program members of the International Clearinghouse for Birth Defects (30.2%) among the MCA group were Surveillance and Research (ICBDSR). those in the upper limb group. These latter defects included: 14.3% of radial ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 367

TABLE III. Number of Births, Number of Cases, Crude Prevalence Estimates, and Prevalence Ratios for Maternal Age Groups Relative to the Reference Age Group of 25–29 Years for Isolated and MCA Sirenomelia

Prevalence Prevalence Maternal age group Birthsa Casesa (per 100,000 births) 95% CI ratio 95% CI Isolated <20 2,334,023 15 0.64 0.36–1.06 1.26 0.69–2.31 20–24 5,922,300 24 0.41 0.26–0.60 0.80 0.48–1.34 25–29 7,079,853 36 0.51 0.36–0.70 1.00 (Reference) 30–34 4,966,752 24 0.48 0.31–0.72 0.95 0.57–1.59 35–39 2,024,166 5 0.25 0.08–0.58 0.49 0.19–1.24 40 or older 426,799 2 0.47 0.06–1.69 0.92 0.22–3.83 MCA <20 2,334,023 20 0.86 0.52–1.32 2.33 1.30–4.18 20–24 5,922,300 32 0.54 0.37–0.76 1.47 0.88–2.47 25–29 7,079,853 26 0.37 0.24–0.54 1.00 (Reference) 30–34 4,966,752 19 0.38 0.23–0.60 1.04 0.58–1.88 35–39 2,024,166 7 0.35 0.14–0.71 0.94 0.41–2.17 40 or older 426,799 0 0.00 0.00–0.86 0.00 NC

MCA, multiple congenital anomalies; NC, not computable. aCases and births excluded: China before 1997 and after 2003, Italy North East, Italy Sicily because no births by maternal age were available.

aplasia/hypoplasia, 7.9% described as cordis, bladder exstrophy, bladder exs- taxic defects such as dextrocardia, spleen upper limb reduction, and 3.2% as poly- trophy with cephalic celosomia, and agenesis or defect, and lung lobation dactyly or pre-axial polydactyly; lobster gastroschisis (one case for each of these anomalies. claw hands were described in three associations). (2.4%) sirenomelia cases; postaxial limb Syndromes or Associations reduction, webbed upper limbs and Head upper limb joint contractures, with one Chromosomal syndromes are not com- case each. Hydrocephalus was present in 8.7% of mon among the sirenomelia cases. Only MCA cases. Microtia was described in 12 cases of sirenomelia had karyotype 6.3% of MCA cases, and oral clefts in results and all such results were normal. Trunk 5.1% of MCA cases. Eye defects were Monogenic syndromes were not Other or unspecified defects of spinal reported in 5.6% of MCA cases, with described in any cases. Considering the column and of ribs were described in 4.0% being microphthalmia. Several association with other VRD there were 21.4% of MCA cases of sirenomelia. cases (11.9%) had other facial defects, three cases combining sirenomelia and Cardiac defects were present in 20.6% of including ocular hypertelorism seen in bladder exstrophy, one from Mexico MCA cases, with 4.8% presenting as 3.2% of the MCA cases. registry and two, a twin pair, from tetralogy of Fallot, 3.2% as single ven- South America. Acardia-acephalus were tricle, and 2.4% as left heart hypoplasia. described in two cases with sirenomelia, Other Defects of central nervous system were one from Spain [Martıńez-Frıás, 2009] described in 19.0% of MCA cases, with Arterial defects different from single or and one from South America. This last spina bifida (mainly lower spina bifida) anomalous umbilical artery were des- case presented also with cyclopia and reported in 10.3%, and microcephaly in cribed in 9.5% of MCA cases, with 4.0% was a case with acardia-acephalus, cyclo- 2.4% of the cases. Esophageal atresia/ being persistent superior vena cava. pia, and sirenomelia. Also from South fistula was described in 12.7% of MCA Duodenal atresia (4.8%), skin tag America there were one case with cases, defects of the diaphragm in 3.2% (2.4%), and holoprosencephaly (one sirenomelia and conjoined twin and of such cases. In decreasing prevalence case), were also described among the other probable case of sirenomelia– order, the following defects were also unrelated defects. Since hydrocephalus cyclopia, described as sirenomelia, described: omphaloceles (5.6%) and was frequent and could sometimes be medial cleft lip, and ocular hypotelorism. other abdominal wall defects (4.0%). considered as a heterotaxic defect, it is Another case from France presented Other cases were reported as having important to note that 5.6% of MCA with sirenomelia and holoprosence- abdominal wall defect and ectopia patients presented with other hetero- phaly. TABLE IV. Characteristics of the Infants With Sirenomelia

Cases with associated Total cases (n ¼ 249) Isolated cases (n ¼ 123) malformations (n ¼ 126)

n%n%n% Sex Male 51 20.5 22 17.9 29 23.0 Female 54 21.7 22 17.9 32 25.4 Indeterminate 117 47.0 61 49.6 56 44.4 Missing data 27 10.8 18 14.6 9 7.1 Outcome Livebirths 117 47.0 60 48.8 57 45.2 Stillbirths 71 28.5 38 30.9 33 26.2 ETOPFA 61 24.5 25 20.3 36 28.6 Missing data 0 0.0 0 0.0 0 0.0 Birth weight (g)a <1,500 46 39.3 21 35.0 25 43.9 1,500–2,500 51 43.6 31 51.7 20 35.1 >2,500 13 11.1 5 8.3 8 14.0 Missing data 7 6.0 3 5.0 4 7.0 Gestational age (week)a <32 30 25.6 14 23.3 16 28.1 33–36 44 37.6 22 36.7 22 38.6 37 30 25.6 18 30.0 12 21.1 Missing data 13 11.1 6 10.0 7 12.3 Parity 0 39 15.7 16 13.0 23 18.3 1 87 34.9 49 39.8 38 30.2 2 or more 35 14.1 17 13.8 18 14.3 Missing data 88 35.3 41 33.3 47 37.3 Previous spontaneous abortions 0 74 29.7 40 32.5 34 27.0 1 16 6.4 7 5.7 9 7.1 Missing data 159 63.9 76 61.8 83 65.9 Plurality Single 204 81.9 101 82.1 103 81.7 Twin 20 8.0 11 8.9 9 7.1 Triplet 1 0.4 0 0.0 1 0.8 Missing data 24 9.6 11 8.9 13 10.3 Maternal age <20 35 14.1 15 12.2 20 15.9 20–24 62 24.9 27 22.0 35 27.8 25–29 64 25.7 37 30.1 27 21.4 30–34 44 17.7 25 20.3 19 15.1 35 14 5.6 7 5.7 7 5.6 Missing data 30 12.0 12 9.8 18 14.3 Parental age difference Mother same age or older 25 10.0 12 9.8 13 10.3 Mother 1–2 years younger 20 8.0 8 6.5 12 9.5 Mother 3–4 years younger 13 5.2 8 6.5 5 4.0 Mother >4 years younger 19 7.6 11 8.9 8 6.3 Missing data 172 69.1 84 68.3 88 69.8 Maternal education (years) <9 21 8.4 15 12.2 6 4.8 9 or more 37 14.9 17 13.8 20 15.9 Missing data 191 76.7 91 74.0 100 79.4 aBirth weight, gestational age: the data are for livebirths only. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 369

DISCUSSION diabetes in our data to examine the Sex possible association of maternal pre- Prevalence The sex in sirenomelia was generally gestational diabetes and sirenomelia. based on gonadal or, rarely, on chromo- The sirenomelia prevalence observed in There is a reasonable level of somal examination, which explains why this population of more than 25 million confidence in the certainty of the almost half of the cases had undeter- births of 0.98 per 100,000 births did not sirenomelia diagnosis in the 249 studied mined sex. However, the cases with differ from previous estimates [Ka¨lleń cases. However, unilateral lower limb determined sex did not show a higher et al., 1992; Castilla and Orioli, 2004]. amelia can sometimes be confounded prevalence of males as suggested pre- The lower prevalence observed in the with sirenomelia when the only lower viously [Duesterhoeft et al., 2007]. In a Hungary registry could reflect some limb has a median position. Since 40 small sample of sirenomelia cases under-ascertainment since only 10% of cases (16%) were described only by the (n ¼ 32) studied by Ka¨lleń et al. [1992], the identified sirenomelias came from word sirenomelia, it is possible that there were more females than males. ETOPFA, a proportion lower than the diagnostic misclassification occurred in However, this difference was not statisti- percentage estimated from the 15 sur- a few instances. cally different from the expected male- veillance programs registering ETOPFA to-female sex ratio. (49.5%). We observed statistically sig- Maternal Age nificant higher sirenomelia prevalence in the Mexican, South American, Italy The higher prevalence of sirenomelia Other Risk Factors observed in the younger maternal age North-East, and Canada Alberta regis- Due to a lack of systematically collected group (less than 20) is a new finding tries, and also a lower than expected data on maternal conditions, we were in the epidemiology of sirenomelia. prevalence in the Italy Campania regis- unable to confirm previous reports that Since twinning and maternal diabetes try. However, if we exclude the data one-fifth of mothers of sirenomelic are usually associated with sirenomelia, from Hungary and Italy Campania, infants have diabetes [Gurakan et al., and both conditions are more likely only the Mexican registry had a higher 1996; Martıńez-Frıás et al., 1998a; Al- to occur with older maternal age, the sirenomelia prevalence than the other Haggar et al., 2010]. Our results, how- registries. ever, were more consistent with those of The higher prevalence observed in The higher prevalence of other authors [Stocker and Heifetz, the Mexican registry has no direct 1987; Duncan and Shapiro, 1993; Lynch explanation. Other registries with limit- sirenomelia observed in ed or no recording of ETOPFA (e.g., the younger maternal South America, Spain, and China) did Due to a lack of systematically not have a high prevalence of sirenome- age group (less than 20) is collected data on maternal lia, so lack of ETOPFA does not seem to a new finding in be a likely explanation. The Mexican conditions, we were unable the epidemiology population could be ethnically different to confirm previous reports from the other studied populations, of sirenomelia. having a higher proportion of Amer- that one fifth of mothers of indians [Collins-Schramm et al., 2004]; sirenomelic infants have however, it is unclear whether this higher prevalence of sirenomelia we characteristic is likely to account for found in younger mothers was unex- diabetes. Our results, however, the higher prevalence of sirenomelia. pected. Ka¨lleń et al. [1992] suggested an were more consistent with those Only specific case–control studies can increased risk of sirenomelia in offspring test this suggestion of an association of young and older mothers, but such of other authors that reported a of sirenomelia with ethnicity. A more findings were not statistically significant. lower prevalence of maternal specific hypothesis is that pre-gestational The higher sirenomelia prevalence we diabetes (i.e., less than 4%) diabetes (e.g., diagnosed and undiag- observed in younger mothers was evi- nosed type 2 diabetes), which may be dent in the MCA case group but not in among cases of sirenomelia. more prevalent in the population cov- the isolated case group. Since there was a ered by the Mexican registry than the similar prevalence gradient in the total populations of other registries since the data set, this lack of significance for the and Wright, 1997; Duesterhoeft et al., prevalence of pre-gestational diabetes is isolated case group could reflect low 2007] that reported a lower prevalence reported to be higher among pregnant power of small sample sizes or, alter- of maternal diabetes (i.e., less than 4%) Hispanic women than among pregnant natively, indicate some etiologic differ- among cases of sirenomelia. The 5% of non-Hispanic white women [Lawrence ence between the isolated and the MCA diabetic mothers in our sample of 133 et al., 2008]. However, we did not case groups (e.g., difference in pre- informative cases coincide with the have adequate data on pre-gestational gestational diabetes). suggestion that diabetes could be a main 370 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE factor in CRS but not in sirenomelia that some defects of this spectrum with some registries, the frequency we found [Bruce et al., 2009]. This does not wide phenotypic variability were pref- could very well represent an underesti- exclude the possibility that a few cases erentially described in some registries. mate. Garrido-Allepuz et al. [2011] have of sirenomelia may have a pathogenesis Other defects were described in updated the discussion about the two linked to maternal diabetes that is similar sirenomelia with a frequency similar to hypotheses about sirenomelia etiology, or identical to that of some CRS cases. that of the lower spinal column defects and pointed that both theories were not or single or anomalous umbilical artery mutually exclusive although the defi- frequency. Upper limb defects, mainly cient blastogenesis hypothesis explains Descriptive Analysis pre-axial reduction, congenital heart both the vascular and the organs defects. The infants with sirenomelia were born defect, and central nervous system, The frequency of the associations of alive in almost half of the cases which did mainly spina bifida, occurred in 14.9%, VRD as those described here, involving not undergo ETOPFA, and presented a 10.8%, and 10.4% of all cases, respec- sirenomelia with bladder exstrophy, higher proportion of prematurity and of tively, and could be also accepted as holoprosencephaly/cyclopia, or acar- twinning than expected. These charac- part of the sirenomelia/CRS spectrum. dia-acephalus in the same infant is teristics were the same in both the Since only cases of sirenomelia were greater than expected considering isolated and MCA case groups. studied here, we cannot assess the the prevalence of each one of these prevalence of the abovementioned defects. Also the association in the same defects in non-sirenomelic CRS case- infant of three VRD as sirenomelia, Associated Defects series. Therefore, for future work, the acardia-acephalus, and cyclopia is never The division of infants with sirenomelia observations here reported could only expected to occur under random expec- into isolated and MCA case groups did suggest which defects to be included in tations. These associations, the high not show any epidemiological difference the sirenomelia spectrum, and which frequency of twinning, and the overlap between these two groups other than an considered as associated defects, that is, of defects with other early conditions as association with younger maternal age in not as part of the spectrum. VATER and CRS indicate a common the MCA group. The proportion of each Several other early defects, such as pathway for them. They could be the defect considered part of the sirenome- VATER and twinning, have been linked result of early insults in blastogenesis lia/CRS spectrum was always higher, to sirenomelia/CRS through common caused by the primary gene mutation or although not statistically significantly, in risk factors such as maternal diabetes by environmental determinants or by the MCA than in the isolated group, [Zaw and Stone, 2002; Castori et al., interaction of both, and the final pheno- suggesting that in the former group the 2010] or through the overlapping of type will depend on the disease modify- cases were described in more detail. the specific defects in each condition ing genes, divided in those uniquely Since only 16% of patients had the [Ka¨lleń and Winberg, 1974]. From the affected by the primary mutation, and limited descriptor of ‘‘sirenomelia,’’ the five defects included in the VATER those whose actions reflect generic studied sample of 84% of cases seems acronym (Vertebral, Anal atresia, responses to organism stress evoked by appropriate for evaluating the extension Tracheo-Esophageal, Renal and Radial the principal mutation (intermediate of the sirenomelia/CRS spectrum. anomalies), three (VAR) are already part phenotypes). Since each path involves Single umbilical artery, lethal of the accepted sirenomelia/CRS spec- concatenated networks, the application renal a/dysgenesis, and oligohydram- trum. Even if we described among our of biological network analysis [Loscalzo nios, were described much more fre- sirenomelia cases 28 with radial defects et al., 2007], together with molecular quently in sirenomelia than in CRS and 16 with tracheo-esophageal anoma- results, could help us to understand this non-sirenomelic [Ka¨lleń and Winberg, lies, only 3 cases presented exclusively class of complex diseases. 1974; Martıńez-Frıás et al., 2008]. defects of the VATER association. Thus Nonetheless, only the urinary defects, the proposition of a unique spectrum for CONCLUSIONS as well as the genital, and large bowel sirenomelia/CRS and VATER [Castori defects, were described in approximately et al., 2010] was not supported by our Sirenomelia prevalence was noted to half of the cases with sirenomelia in our findings. be higher in the Mexican registry (2.36 sample. Single or anomalous umbilical Some authors [Heifetz, 1984; Ste- per 100,000) than in others registries, artery, as well as defects of the lower venson et al., 1986] which support the with no plausible explanation identified spinal column, were described in only vascular ‘‘steal’’ theory for sirenomelia based on the available data. Prevalence 16% of the cases, while oligohydramn- etiology have proposed that single um- estimates of sirenomelia around the ion derived defects in 24.9% of the case. bilical artery or anomalous umbilical world were similar otherwise (0.98 per The differences in diagnostic methods artery were always present in sirenome- 100,000), with exception of Hungary (clinical examination with or without lia. However, we could not confirm this and Campania-Italy registries where a imaging studies or autopsy) does not hypothesis with our findings. Because low prevalence suggests that under- explain the observed differences of fre- single umbilical artery is considered ascertainment could be occurring. The quency. However, we could not discard a minor defect and not reported by proportion of twinning among cases of ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 371 sirenomelia was higher than the 1 or 2% Akbayir O, Gungorduk K, Sudolmus S, Gulkilik Knowler WC, Silva G, Belmont JW, Seldin expected in the general population. The A, Ark C. 2008. First trimester diagnosis of MF. 2004. Mexican American ancestry- sirenomelia: A case report and review of the informative markers: Examination of pop- sirenomelia prevalence was also higher literature. Arch Gynecol Obstet 278:589– ulation structure and marker characteristics in younger age mothers among all cases 592. in European Americans, Mexican Ameri- and those with MCA, but not among the Al Kaissi A, Klaushofer K, Grill F. 2008. Caudal cans, Amerindians and Asians. Hum Genet regression syndrome and popliteal webbing 114:263–271. isolated case. Half of the cases with in connection with maternal diabetes Das BB, Rajegowda BK, Bainbridge R, Giam- sirenomelia presented also with genital, mellitus: A case report and literature review. pietro PF.2002. Caudal regression syndrome large bowel, and urinary defects. About Cases J 1/407:1–4. versus sirenomelia: A case report. J Perinatol Al-Haggar M, Yahia S, Abdel-Hadi D, Grill F, Al 22:168–170. 10–15% of sirenomelia cases had lower Kaissi A. 2010. Sirenomelia (symelia apus) Dawrant MJ, Giles S, Bannigan J, Puri P. 2007. spinal column defects, single or anom- with Potter’s syndrome in connection with Adriamycin produces a reproducible terato- alous umbilical artery, upper limb, gestational diabetes mellitus: A case report genic model of vertebral, anal, cardiovascu- and literature review. Afr Health Sci lar, tracheal, esophageal, renal, and limb cardiac, and central nervous system 10:395–399. anomalies in the mouse. J Pediatr Surg 42: defects. There was a higher than Aslan Y, Erduran E, Kutlu N. 2000. Autosomal 1652–1658. expected association of sirenomelia with recessive multiple pterygium syndrome: A Delissaint D, McKyer ELJ. 2011. A systematic new variant? Am J Med Genet 93:194–197. review of factors utilized in preconception other VRD such as bladder exstrophy, Bartsocas CS, Papas CV. 1972. Popliteal ptery- health behavior research. Health Educ cyclopia/holoprosencephaly, and acar- gium syndrome: Evidence for a severe Behav Apr 21 [Epub ahead of print]. DOI: dia-acephalus. The biological network autosomal recessive form. J Med Genet 9: 10.1177/1090198110389709. 222–226. Di Lorenzo M, Brandt ML, Veilleux A. 1991. analysis approach of these related com- Bianchi DW, Crombleholme TM, Alton ME. Sirenomelia in an identical twin. J Pediatr plex conditions was suggested for future 2000. Sirenomelia. In: Medina M, editor. Surg 26:1334–1336. work. Fetology. New York: McGraw Hill. pp Duesterhoeft SM, Ernst LM, Siebert JR, Kapur 649–655. RP. 2007. Five cases of caudal regression Blaicher W, Lee A, Deutinger J, Bernaschek G. with an aberrant abdominal umbilical artery: ACKNOWLEDGMENTS 2001. Sirenomelia: Early prenatal diagnosis Further support for a caudal regression- with combined two- and three-dimensional sirenomelia spectrum. Am J Med Genet Part This study was supported by the MCT/ sonography. Ultrasound Obstet Gynecol A 143A:3175–3184. CNPq, Brazil (grant nos. 573993/2008- 17:542–545. Duhamel B. 1961. From the mermaid to the anal Botto LD, Khoury MJ, Mastroiacovo P, Castilla imperforation: The syndrome of caudal 4, 476978/2008-4, 554755/2009-2, EE, Moore CA, Skjaerven R, Mutchinick regression. Arch Dis Child 36:152–155. 306750/2009-0, 402045/2010-6), OM, Borman B, Cocchi G, Czeizel AE, Duncan PA, Shapiro LR. 1993. Sirenomelia and FAPERJ, Brazil (grant nos. E-26/ Goujard J, Irgens LM, Lancaster PAL, VATER association: Possible interrelated Martinez-Frias ML, Merlob P, Ruusinen disorders with common embryologic 102.748/2008, E-26/170.007/2008), A, Stoll C, Sumiyoshi Y. 1997. The pathogenesis. Dysmorph Clin Genet 2:96– and CAPES, Brazil (grant nos. 1957/ spectrum of congenital anomalies of the 103. 2009, 2799/2010). Work conducted at VATER association: An international study. Duncan PA, Shapiro LR, Klein RM. 1991. Am J Med Genet 71:8–15. Sacrococcygeal dysgenesis association. Am the Centre of the International Clear- Bruce JH, Romaguera RL, Rodriguez MM, J Med Genet 41:153–161. inghouse for Birth Defects Surveillance Gonza´lez-Quintero VH, Azouz EM. 2009. Foerster A. 1861–1865. Die Missbildungen des and Research was supported by the Caudal dysplasia syndrome and sirenomelia: Menschen, nebst einem Atlas (German). Are they part of a spectrum? Fetal Pediatr Manke: Jena Friedrich. Center for Disease Control and Preven- Pathol 28:109–131. Garcıá-Garcıá MJ, Eggenschwiler JT, Caspary T, tion (1U50DD000524-02). This work Carbillon L, Seince N, Largilliere C, Bucourt M, Alcorn HL, Wyler MR, Huangfu D, Rake- was in part supported by Instituto de Uzan M. 2001. First trimester diagnosis of man AS, Lee JD, Feinberg EH, Timmer JR, sirenomelia: A case report. Fetal Diagn Ther Anderson KV. 2005. Analysis of mouse Salud Carlos III (ISCIII, Ministry of 16:284–288. embryonic patterning and morphogenesis Science and Innovation) of Spain, and Castilla EE, Mastroiacovo P. 2011. Very rare by forward genetics. Proc Natl Acad Sci the Fundacioń 1000 sobre Defectos defects: What can we learn? Am J Med USA 102:5913–5919. Genet Part C (this issue). Garrido-Allepuz C, Haro E, Gonza´lez-Lamunõ Congeńitos, of Spain. CIBERER is an Castilla EE, Orioli IM. 2004. ECLAMC: The D, Martıńez-Frıás ML, Bertocchini F, Ros initiative of ISCIII. CIBERER is an Latin American Collaborative Study of MA. 2011. A clinical and experimental initiative of ISCIII. Components of Congenital Malformations. Community overview of sirenomelia: Insight into the Genet 7:76–94. mechanisms of congenital limb malforma- ECEMC’s Peripheral Group are grate- Castilla EE, Mastroiacovo P, Lo´pez-Camelo JS, tions. Dis Models Mech 4:289–299. fully acknowledged. Saldarriaga W, Isaza C, Orioli IM. 2008. Goodlow OG, McCoy Sibley RI, Allen BG, Sirenomelia and cyclopia cluster in Cali, Kamanda WS, Gullattee AC, Rayfield WC. Colombia. Am J Med Genet Part A 146A: 1988. Sirenomelia: Mermaid syndrome. J REFERENCES 2626–2636. Natl Med Assoc 80:343–346. Castori M, Rinaldi R, Capocaccia P, Roggini M, Guidera KJ, Raney E, Ogden JA, Highhouse M, Abu-Hijleh G, Qi BQ, Williams AK, Beasley SW. Grammatico P. 2008. VACTERL associa- Habal M. 1991. Caudal regression: A review 2000. Development of the bones and tion and maternal diabetes: A possible causal of seven cases, including the mermaid synovial joints in the rat model of the relationship? Birth Defects Res A Clin Mol syndrome. J Pediatr Orthop 11:743–747. VATER association. J Orthop Sci 5:390– Teratol 82:169–172. Gurakan B, Karaaslan E, Balci S. 1996. Sireno- 396. Castori M, Silvestri E, Cappellacci S, Binni F, melia in an infant of a diabetic mother: A Agarwal P, Wylie JN, Galceran J, Arkhitko O, Li Sforzolini GS, Grammatico P. 2010. Sire- case report. Turk J Pediatr 38:393–397. C, Deng C, Grosschedl R, Bruneau BG. nomelia and VACTERL association in the Halder A, Pahi J, Chaddha V, Agarwal SS. 2001. 2003. Tbx5 is essential for forelimb bud offspring of a woman with diabetes. Am J Sirenomelia sequence associated with cra- initiation following patterning of the limb Med Genet Part A 152A:1803–1807. niorachischisis totalis, limb reduction and filed in the mouse embryo. Development Collins-Schramm HE, Chima B, Morii T, Wah K, primitive heart. Indian Pediatr 38:1041– 130:623–633. Figueroa Y, Criswell LA, Hanson RL, 1045. 372 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

Heifetz SA. 1984. Single umbilical artery. A tion of pregnant women, 1999–2005. Rittler M, Paz JE, Castilla EE. 1996. VACTERL statistical analysis of 237 autopsy cases and Diabetes Care 31:899–904. association, epidemiologic definition and review of the literature. Perspect Pediatr Loscalzo J, Kohane I, Barabasi AL. 2007. Human delineation. Am J Med Genet 63:529–536. Pathol 8:345–378. disease classification in the postgenomic era: Rougemont AL, Bouron-Dal Soglio D, De´silets Hentschel J, Stierkorb E, Schneider G, Goedde S, a complex systems approach to human V,Jovanovic M, Perreault G, Laurier Oligny Siemer S, Gortner L. 2006. Caudal regres- pathobiology. Mol Syst Biol 3:124. L, Fournet JC. 2008. Caudal dysgenesis, sion sequence: Vascular origin? J Perinatol Lowry RB, Sibbalda B, Bedarda T. 2007. Stability sirenomelia, and situs inversus totalis: A 26:445–447. of prevalence rates of anorectal malforma- primitive defect in blastogenesis. Am J Med Hilbelink DR, Kaplan S. 1986. Sirenomelia: tions in the Alberta Congenital Anomalies Genet Part A 146A:1470–1476. Analysis in the cadmium- and lead-treated Surveillance System 1990–2004. J Pediatr Sarpong S, Headings V. 1992. Sirenomelia golden hamster. Teratog Carcinog Mutagen Surg 42:1417–1421. accompanying exposure of the embryo to 6:431–440. Lynch SA, Wright C. 1997. Sirenomelia, limb cocaine. South Med J 85:545–547. Holmes LB. 2002. Teratogen-induced limb reduction defects, cardiovascular malforma- Savader SJ, Savader BL, Clark RA. 1989. defects. Am J Med Genet 112:297–303. tion, renal agenesis in an infant born to a Sirenomelia without Potter syndrome: MR ICBDSR International Clearinghouse for Birth diabetic mother. Clin Dysmorphol 6: characteristics. J Comput Assist Tomogr Defects Surveillance and Research. 2009. 75–80. 13:689–691. Annual Report 2007. Roma and website: Martıńez-Frıás ML. 2009. Epidemiology of Scheidel W. 2008. Demography of the ancient http://www.icbdsr.org, Nov 27, 2009. acephalus/acardius monozygotic twins: world. In: Durlauf SN, Blume LE, editors. Jaiyesimi F, Gomathinayagam T, Dixit A, Amer New insights into an epigenetic causal The new Palgrave dictionary of economics M. 1998. Sirenomelia without vitelline hypothesis. Am J Med Genet Part A online. Palgrave Macmillan. DOI:10.1057/ artery steal. Ann Saudi Med 18:542– 149A:640–649. 9780230226203.1875. 544. Martıńez-Frıás ML, Bermejo E, Rodriguez- Schiesser M, Holzgreve W, Lapaire O, Willi N, Jensen PKA, Hansen P.1981. A bisatellited marker Pinilla E, Prieto L, Frias JL. 1998a. Epi- Lu¨thi H, Lopez R, Tercanli S. 2003. Sireno- chromosome in an infant with the caudal demiological analysis of outcomes of preg- melia, the mermaid syndrome—Detection in regression anomalad. Clin Genet 19:126– nancy in gestational diabetic mothers. Am J the first trimester. Prenatl Diagn 23:493–495. 129. Med Genet 78:140–145. Schu¨ler L, Salzano FM. 1994. Patterns in multi- Kadian YS, Duhan N, Rattan KN, Rawal M. Martıńez-Frıás ML, Garcia A, Bermejo E. 1998b. malformed babies and the question of the 2008. Sirenomelia (mermaid syndrome): A Cyclopia and sirenomelia in a liveborn relationship between sirenomelia and VAC- rare anomaly. Afr J Paediatr Surg 5:105– infant [letter]. J Med Genet 35:263–264. TERL. Am J Med Genet 49:29–35. 106. Martıńez-Frıás ML, Bermejo E, Rodriguez- Selig AM, Benacerraf B, Greene MF,Garber M-F, Ka¨lleń B, Winberg J. 1974. Caudal mesoderm Pinilla E, Prieto L, ECEMC Working Genest DR. 1993. Renal dysplasia, mega- pattern of anomalies: From renal agenesis to Group. 2008. Does Single Umbilical Artery locystis, and sirenomelia in four siblings. sirenomelia. Teratology 9:99–112. (SUA) Predict Any Type of Congenital Teratology 47:65–71. Ka¨lleń B, Castilla EE, Lancaster PAL, Mutchinick Defect? Clinical–Epidemiological Analysis Stahl A, Tourame P. 2010. De la te´ratologie aux O, Knudsen L, Martinez-Frias ML, Mas- of a Large Consecutive Series of Malformed monstres de la mythologie et des le gendes troiacovo P, Robert E. 1992. The cyclops Infants. Am J Med Genet Part A 146A:15– antiques (From teratology to mythology: and the mermaid. An epidemiological study 25. Ancient legends). Arch Pe´diatr 17:1716– of two types of rare malformations. J Med Messineo A, Innocenti M, Gelli R, Pancani S, Lo 1724. [French] Genet 29:30–35. Piccolo R, Martin A. 2006. Multidiscipli- Stanton MP, Penington EC, Hutson JM. 2003. A Kalter H. 1993. Case reports of malformations nary surgical approach to a surviving infant surviving infant with sirenomelia (Mermaid associated with maternal diabetes: History with sirenomelia. Pediatrics 118:e220– syndrome) associated with absent bladder. J and critique. Clin Genet 43:174–179. e223. Pediatr Surg 38:1266–1268. Kampmeier OF. 1927. On sireniform monsters, Murphy JJ, Fraser GC, Blair GK. 1992. Sireno- StataCorp. 2007. Stata Statistical Software: Release with a consideration of the causation and the melia: Case of the surviving mermaid. J 10. College Station, TX: StataCorp LP. predominance of the male sex among them. Pediatr Surg 27:1265–1268. Stevenson RE. 2006. Limbs. In: Stevenson RE, Anat Rec 34:365–389. O’Railly R, Mu¨ller F. 1989. Interpretation of Hall JG, editors. Human malformations and Kibar Z, Torban E, McDearmid JR, Reynolds A, some median anomalies as illustrated by related anomalies, 2nd edition. New York: Berghout J, Mathieu M, Kirillova I, De cyclopia and symmelia. Teratology 40:409– Oxford University Press. Marco P, Merello E, Hayes JM, Wallingford 421. Stevenson RE, Jones KL, Phelan MC, Jones MC, JB, Drapeau P, Capra V, Gros P. 2007. Opitz JM, Zanni G, Reynolds JF Jr, Gilbert- Barr M Jr, Clericuzio C, Harley RA, Mutations in VANGL1 associated with Barness E. 2002. Defects of blastogenesis. Benirschke K. 1986. Vascular steal: The neural-tube defects. N Engl J Med 356: Am J Med Genet 115:269–286. pathogenetic mechanism producing sireno- 1432–1437. Orioli IM, Mastroiacovo P, Lo´pez-Camelo JS, melia and associated defects of the viscera Kjaer KW,Keeling JW,Opitz JM, Gilbert-Barness Saldarriaga W, Isaza C, Aiello H, Zarante I, and soft tissues. Pediatrics 78:451–457. E, Hartling U, Hansen BF, Kjær I. 2003. Castilla EE. 2009. Clusters of sirenomelia in Stocker J, Heifetz S. 1987. Sirenomelia, a Sirenomelia sequence according to the South America. Birth Defect Res A 85: morphological study of 33 cases and review distance between the first sacral vertebra 112–118. of the literature. Perspect Pediatr Pathol and the ilia. Am J Med Genet Part A Ouimette JF, Jolin ML, L’honore´ A, Gifuni A, 10:7–50. 120A:503–508. Drouin J. 2010. Divergent transcriptional Taghavi MM, Jafari Naveh HR, Shariati M, Ko¨chling J, Karbasiyan M, Reis A. 2001. activities determine limb identity. Nat Morteza Zade F. 2009. Sirenomelia (mer- Spectrum of mutations and genotype-phe- Commun 1:35–43. maid syndrome): An infant from parents who notype analysis in Currarino syndrome. Eur Padmanabhan R. 1998. Retinoic acid-induced used a special form of snuff. Pak J Biol Sci J Hum Genet 9:599–605. caudal regression syndrome in the mouse 12:722–725. Langer B, Stoll C, Nicolav R, Gasser B, Schlaedr fetus. Reprod Toxicol 12:139–151. Thottungal AD, Charles AK, Dickinson JE, G. 1999. Sirenomelia and situs inversus: Patel S, Suchet I. 2004. The role of color and Bower C. 2010. Caudal dysgenesis and Case report and review of the literature. power Doppler ultrasound in the prenatal sirenomelia-single centre experience sug- Fetal Diagn Ther 11:79–84. diagnosis of sirenomelia. Ultrasound Obstet gests common pathogenic basis. Am J Med Larsen WJ. 1993. Human embryology. Chapter Gynecol 24:684–691. Genet Part A 152A:2578–2587. 11: Development of the limbs. New York: Pennimpede T, Cameron DA, MacLean GA, Li Valenzano M, Paoletti R, Rossi A, Farinini D, Churchill Livingstone. pp 281–307. H, Abu-Abed S, Petkovich M. 2010. The Garslaschi G, Fulcheri E. 1999. Sirenomelia. Lawrence JM, Contreras R, Chen W, Sacks DA. role of CYP26 enzymes in defining appro- Pathological features, antenatal ultrasono- 2008. Trends in the prevalence of preexist- priate retinoic acid exposure during graphic clues, and a review of current ing diabetes and gestational diabetes mellitus embryogenesis. Birth Defects Res A Clin embryogenic theories. Hum Reprod among a racially/ethnically diverse popula- Mol Teratol 88:883–894. Update 5:82–88. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 373

Vargas FR, Roessler E, Gaudenz K, Belloni E, Wei X, Sulik KK. 1996. Pathogenesis of caudal the development of ventral posterior Whitehead AS, Kirke PN, Mills JL, Hooper dysgenesis/sirenomelia induced by ochra- mesoderm. Development 132:2489– G, Stevenson RE, Cordeiro I, Correia P, toxin A in chick embryos. Teratology 2499. Felix T, Gereige R, Cunningham ML, 53:378–391. Zanforlin Filho SM, Guimara˜es Filho HA, Canu´n S, Antonarakis SE, Strachan T, Tsui Zakin L, De Robertis EM. 2004. Inactivation Araujo E Jr, Pires CR, Mattar R, LC, Scherer SW,Muenke M. 1998. Analysis of mouse twisted gastrulation reveals its role Nardozza LM. 2007. Sirenomelia sequence: of the human Sonic Hedgehog coding and in promoting Bmp4 activity during Early prenatal diagnosis of one rare promoter regions in sacral agenesis, tripha- forebrain development. Development 131: case associated with acardiac malforma- langeal thumb, and mirror polydactyly. 413–424. tion. Arch Gynecol Obstet 275:315– Hum Genet 102:387–392. Zakin L, Reversade B, Kuroda H, Lyons KM, 316. Wasnik A, Lalchandani UR. 2010. Sirenomelia— De Robertis EM. 2005. Sirenomelia Zaw W, Stone DG. 2002. Caudal regression Sympus uni pus (mermaid deformity). in Bmp7 and Tsg compound mutant syndrome in twin pregnancy with type II Pediatr Radiol 40:S14. mice: Requirement for Bmp signaling in diabetes. J Perinatol 22:171–174.