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Bone dysplasias in 1.6 million births in Argentina
European Journal of Medical Genetics xxx (xxxx) xxx–xxx
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Bone dysplasias in 1.6 million births in Argentina Santiago Pablo Duarte, María Eugenia Rocha, María Paz Bidondo, Rosa Liascovich, Pablo Barbero, Boris Groisman∗ National Network of Congenital Anomalies in Argentina (RENAC), National Center of Medical Genetics, National Administration of Laboratories and Health Institutes, National Ministry of Health, Argentina
A R T I C LE I N FO
A B S T R A C T
Keywords: Osteochondrodysplasias Prevalence Epidemiology Achondroplasia Thanatophoric dysplasia Osteogenesis Imperfecta Argentina
Currently accepted birth prevalence for osteochondrodysplasias (OCDs) is about 2 per 10,000 births. Our main goal is to estimate the prevalence of OCDs in Argentina and compare it with other surveillance systems. We examined 1,663,610 births among 160 hospitals of RENAC (Red Nacional de Anomalías Congénitas - National Network of Congenital Anomalies) between November 2009 and December 2016. Cases were detected and registered according to a pre-established protocol, ranked in three diagnostic evidence levels according to available clinical documentation, and categorized according to the 9th edition of the nosology and classification of genetic skeletal disorders. Within our dataset, the most frequent groups were Group-1 (FGFR3, chondrodysplasia) and Group-25 (Osteogenesis Imperfecta and decreased bone density). Birth prevalence per 10,000 for the main OCD types, were: Achondroplasia 0.47 (95% CI: 0.38–0.59), Thanatophoric Dysplasia 0.37 (95% CI: 0.29–0.48), and the Osteogenesis Imperfecta group 0.34 (95% CI: 0.26–0.44). For total OCD, birth prevalence was 2.20 per 10.000 births (95% CI: 1.98–2.44). RENAC prevalence of total OCDs was found to be lower than that reported by the Latin-American Study of Congenital Malformations (ECLAMC) and Utah Birth Defect Network but higher than EUROCAT. Our investigation is the first study of OCD prevalence in Argentina using data from every jurisdiction of the country.
1. Introduction Skeletal dysplasias, also known as osteochondrodysplasias (OCDs) are a complex group of more than 400 clinically and molecularly heterogeneous conditions that affect the growth and development of both bone and cartilage, including skeletal dysplasias, metabolic bone disorders, dysostosis and skeletal malformation and/or reduction syndromes [Spranger et al., 2002]. Albeit individually rare, their birth prevalence as a group is estimated to range from 2.1 to 4.7/10,000 [Gustavson and Jorulf, 1975; Camera and Mastroiacovo, 1982; Orioli et al., 1986; Stoll et al., 1989; Rasmussen et al., 1996; Stevenson et al., 2012]. As a general rule, OCDs are monogenic disorders. A typical presentation of OCDs is short stature. Radiographic patterns may include any or all of the following: spondylo, epiphyseal, metaphyseal, and diaphyseal dysplasia. These patterns help narrow down the possible group of dysplasias. Due to the heterogeneity found in OCDs, musculoskeletal effects range in severity from premature arthritis to severe short stature with death in the perinatal period. About 40% of all OCD have clinical manifestations from birth (neonatal forms), the rest being usually diagnosed during childhood. Neonatal
∗
forms usually compromise the child's health in a severe way, some of them being lethal. In skeletal dysplasias, death is caused mainly by pulmonary hypoplasia secondary to thoracic involvement. The diagnosis of neonatal forms of OCD can be suspected prenatally (usually prompted by identification of long-bone shortening on sonography, some of them have also polyhydramnios); and is confirmed by X-rays at birth or when signs and symptoms of the syndrome occur. An important goal after detection of a fetal skeletal dysplasia is determining its severity; of special concern is whether the prognosis is lethal [Schramm et al., 2009]. Being a cause of infant mortality and morbidity, the impact that these pathologies have in the public healthcare system is very important. Prevalence of OCDs has been evaluated in various countries and results are heterogenous. The only information of prevalence of OCDs in Latin-America comes from the Latin-American Study of Congenital Malformations (ECLAMC, Spanish acronym), which aggregates data from different hospitals in the region. We did not find previous reports of OCDs frequency in Argentina. The main goal of this work is to present the descriptive epidemiology of OCD in Argentina and compare its prevalence with other
Corresponding author. Av. Las Heras 2670, 3er floor, City of Buenos Aires, 1425, Argentina. E-mail address: [email protected] (B. Groisman).
https://doi.org/10.1016/j.ejmg.2018.12.008 Received 3 August 2018; Received in revised form 5 November 2018; Accepted 15 December 2018 1769-7212/ © 2018 Published by Elsevier Masson SAS.
Please cite this article as: Duarte, S.P., European Journal of Medical Genetics, https://doi.org/10.1016/j.ejmg.2018.12.008
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Table 1 Evidence Level of diagnosis and prevalence according OCD Diagnostic Groups from International Skeletal Dysplasia Society (ISDS), National Network of Congenital Anomalies of Argentina, 2009–2016. Diagnostic groups
1. FGFR3 chondrodysplasia group Achondroplasia Thanatophoric Dysplasia (type 1 and 2 included) 2. Type 2 collagen group Spondyloepiphyseal dysplasia congenital (SEDC) Kniest Dysplasia 3. Type 11 collagen group Fibrochondrogenesis 4. Sulfation disorders group Diastrophic Dysplasia 8. TRPV4 group Metatropic dysplasia 9. Ciliopathies with major skeletal involvement Chondroectodermal dysplasia (Ellis van creveld) Short rib–polydactyly syndrome (SRPS) type 1/3 - Asphyxiating thoracic dysplasia 18. Campomelic dysplasia and related disorders Campomelic Dysplasia 21. Chondrodysplasia punctata group Chondrodysplasia punctata 23. Osteopetrosis and related disorders Osteopetrosis 25. Osteogenesis Imperfecta and decreased bone density group Osteogenesis Imperfecta (type II and II) 26. Abnormal mineralization group Hypophosphatasia Achondrogenesisa Total a
Evidence level 1
Evidence level 2
Total
Prevalence (CI 95%)
n
%
n
%
33 36
41.8 58.1
46 26
58.2 41.9
79 62
4.75(3.76–5.92) 3.73(2.86–4.78)
0 2
0.0 100.0
1 0
100.0 0.0
1 2
0.06(0–0.33) 0.12(0.01–0.43)
0
0.0
1
100.0
1
0.06(0–0.33)
3
100.0
0
0.0
3
0.18(0.04–0.53)
1
100.0
0
0.0
1
0.06(0–0.33)
5 9
83.3 81.8
1 2
16.7 18.2
6 11
0.36(0.13–0.79) 0.66(0.33–1.18)
8
66.7
4
33.3
12
0.72(0.37–1.26)
8
80.0
2
20.0
10
0.60(0.29–1.11)
1
100.0
0
0.0
1
0.06(0–0.33)
43
75.4
14
24.6
57
3.43(2.6–4.44)
1 4 154
100.0 66.7 60.9
0 2 99
0.0 33.3 39.1
1 6 253
0.06(0–0.33) 0.36(0.13–0.79) 15.21(13.39–17.2)
Achondrogenesis without specific type classification.
● Evidence level 1: Cases with confirmatory X-rays or diagnosis performed by a medical geneticist. ● Evidence level 2: Cases with satisfactory clinical description or clinical photos sufficient to establish a probable diagnosis or familiar history of specific OCD. ● Evidence level 3: Cases described as “skeletal dysplasia” or as having features compatible with skeletal dysplasia (i.e.: short stature and short limbs), but without a specified OCD type.
surveillance programs.
2. Methods We used data from the National Network of Congenital Anomalies of Argentina (RENAC), collected from November 1st 2009 to December 31st, 2016. RENAC is a hospital-based surveillance program of major structural congenital anomalies, operating since 2009 in maternity hospitals distributed in the 24 jurisdictions of Argentina. At present it covers around 300,000 births per year, 40% of annual births in the country. The birth outcomes included are live births and stillbirths (weighting more than 500 g), with major structural congenital anomalies detected from birth until hospital discharge. Neonatologists in each hospital send reports to the RENAC coordination. The reporting neonatologists follow a common methodology standardized in a manual of operations, an atlas of congenital anomalies, and reinforced through on-line and in person trainings. The reports include a verbatim description of the affected cases and a core set of variables. The reporting neonatologists can send photographs of x-rays, clinical photos or results of additional studies that contribute to the diagnostic accuracy. These reports are sent through an on-line forum that allows review and discussion of cases [Groisman et al., 2013]. Each case is coded using the ICD-10 with the Royal College of Pediatrics and Child Health modification. The working definition used in this study for OCD was: ‘‘a clinically defined growth deficiency of prenatal onset, associated or not with body disproportion’’ (ICD-10 codes: Q77-Q78). All available information about OCD cases, including clinical records, skeletal X-rays, and clinical photos were reviewed. Cases were classified according to the International Classification provided by International Skeletal Dysplasia Society (ISDS) [Bonafe et al., 2015]. In order to evaluate the diagnostic accuracy of OCD type, cases were assorted into three different diagnostic evidence levels as follows:
We calculated the prevalence for total OCD and for the most frequent specific types as the proportion of cases over the total numbers of births (live births and stillbirths) with 95% confidence intervals calculated using the Poisson distribution with the STATA software 12. We present the proportion of cases with prenatal diagnosis for the period 2013–2016 because this variable was not initially included in RENAC reports. We compared birth weight, gestational age, proportion of preterms and maternal age between cases and total births from Argentina; population data came from the Information Health Department (DEIS). We compared our results with data from ECLAMC [Barbosa-Buck et al., 2012], the Utah Birth Defect Network (UBDN) [Stevenson et al., 2012], and the European Surveillance of Congenital Anomalies (EUROCAT) [Boyd et al., 2011]. ECLAMC is a hospital based, voluntary network of South American maternity centers with a case control design that monitors the occurrence of congenital anomalies in South American countries since the late 1960s [Castilla and Orioli, 2004]. UBDN collects population-based data for Utah on births from all resident women in the state. EUROCAT is a network of population-based registries of congenital anomalies in Europe. In the comparison between RENAC, ECLAMC, UBDN, and EUROCAT, a “Z” value was obtained using the RENAC prevalence of each OCD as the reference (expected value), and the ECLAMC (Z1), EUROCAT (Z2) and UBDN (Z3) prevalences as comparator values (observed values) [Z= (observed valueexpected value)/root(expected value)]. The statistical significance was 2
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births is consistent with previous reports [Barbosa-Buck et al., 2012]. The relative frequency of the different OCDs may vary according to particular characteristics of the population under study. For example, a high birth prevalence (9.5/10,000) was reported in United Arab Emirates [Al-Gazali et al., 2003]. In this population the proportion of consanguineous couples may reach 50%, and it is common for men with advanced age to father children. Both factors increase the risk of Mendelian disorders: consanguinity increases the risk of autosomal recessive disorders, and advanced paternal age increases the risk of autosomal dominant disorders due to an increase in the probability of spontaneous mutations. Besides, in the United Arab Emirates study, about half of the OCD cases were autosomal recessive entities, fibrochondrogenesis being the most common with a prevalence of 1.05/ 10,000. In our study, we detected only one case with fibrochondrogenesis, whereas Barbosa-Buck et al. (2012) did not report any case in over 1,000,000 births. These results show the heterogeneity of prevalence according to different regions. In relation to previous studies performed in our region, the birth prevalence observed in our study is similar to the one reported by ECLAMC in 1986 [Orioli et al., 1986], but is lower than the prevalence reported more recently by the same surveillance program [BarbosaBuck et al., 2012]. Stevenson (Stevenson et al., 2012) in Utah established a prevalence of 3.0 per 10,000 liveborns (95% CI: 2.53–3.48), statistically significant higher than the prevalence reported by RENAC. These could be related to the ascertainment window for each system: the UBDN has no maximum age of diagnosis, whereas RENAC includes cases detected until hospital discharge. UBDN also includes multiple sources (delivery units, paediatric departments, laboratories, etc), and RENAC only includes maternity hospitals. RENAC prevalence of total OCDs was statistically significant higher than EUROCAT. Although EUROCAT programs have also multiple sources and most extend the ascertainment window until 1 year of age, in most of them prenatal diagnosis and elective terminations are a common practice. The lower prevalence could be related with underascertainment of elective terminations. Despite being illegal, terminations of pregnancy are performed in Argentina, and thus not routinely accounted for in official statistics. The ratio of prevalence in stillbirths over the prevalence in live births in RENAC was 6.98 and perinatal death occurred in more than 50% of cases. The high perinatal lethality is possibly due to the inclusion of severe OCD and perhaps to a sub-registration of cases with milder forms. Approximately one-quarter of OCD are considered lethal in the perinatal period (Lachman, 2008; Parnell and Phillips, 2012). Mortality in skeletal dysplasias is determined largely by the degree of pulmonary hypoplasia. In our study, 150 of 253 cases with specific diagnosis (59.3%) were lethal dysplasias (Thanatophoric, Fibrochondrogenesis, Short rib polydactyly, Campomelic, lethal type of Osteogenesis Imperfecta, Achondrogenesis and Hypophosphatasia). Lethal skeletal dysplasias can be diagnosed by prenatal ultrasound using several sonographic parameters. Fetal lung volumes (i.e.: < 5th percentile for gestational age), femur length to abdominal circumference ratio (i.e.: < 0.16 and polyhydramnios is present), and thoracic circumference to abdominal circumference ratio (i.e.: < 0.6), are the three
established using Bonferroni's correction for multiple comparisons, in Z = ± 2.60865, corresponding to a p value of 0.0045. The Stata statistical software was used. 3. Results In the period from November 2009 to December 2016: 1,663,610 births were examined, 366 of whom had OCDs. Thus, overall birth prevalence of OCDs was 2.20 per 10.000 births (95% CI: 1.98–2.44). In live births, the prevalence was 2.09 per 10,000 births (95% CI: 1.88–2.32), and in stillbirths was 14.58 per 10,000 births (CI 95%: 9.13–22.07). Out of the 366 cases reported, 253 (69.1%) had a specific diagnosis (Evidence levels 1 and 2) (Table 1); 113 cases (30.9%) did not have an accurate diagnosis of OCD (Evidence level 3). The main diagnoses were Achondroplasia, Osteogenesis Imperfecta, and Thanatophoric Dysplasia, together representing 78.3% of the cases distributed between the highest evidence levels (evidence levels 1 and 2). Birth prevalence per 100,000 for the main OCD types, were: Achondroplasia 4.8 (95% CI: 3.8–5.9), Thanatophoric Dysplasia 3.7 (95% CI: 2.9–4.8), and the Osteogenesis Imperfecta group 3.4 (95% CI: 2.6–4.4). Data concerning prenatal diagnosis was available in 274 cases. Out of these patients, 184 (67.2%) were detected by the finding of short limbs on an ultrasound scan. Perinatal lethality (stillbirths plus early neonatal deaths) occurred in 56.8% of cases. Prenatal diagnosis was more frequent in cases resulting in perinatal death (80.6%) than in cases alive at hospital discharge (56.0%) (p < 0.01). Sex ratio was 1.06 (186 males, 175 females), 3 cases had undetermined sex and in 2 sex was not specified. Means of birth weight, gestational age, and proportion of premature births for cases and total births are shown in Table 2. Cases had lower birth weight; lower gestational age; and were more preterm. There was no statistically significant differences in maternal age. RENAC showed a statistically significant lower prevalence than ECLAMC in total OCD prevalence, and osteogenesis Imperfecta. RENAC showed a statistically significant higher prevalence than EUROCAT of total OCD and Achondroplasia; Osteogenesis Imperfecta could not be compared because that specific data was not reported. RENAC presented a statistically lower prevalence than UBDN in total OCD and Osteogenesis Imperfecta (Table 3). 4. Discussion The OCD birth prevalence observed in our study was similar to previous reports [Orioli et al., 1986; Stoll et al., 1989; Rasmussen et al., 1996]. However, some epidemiological studies have shown higher prevalences, like the study made by Gustavson and Jorulf (1975) in Sweden (4.7/10,000) and the one made by Andersen and Hauge (1989) in Denmark (7.6/10,000). The first one was conducted in a single hospital with a sample of less than 15,000 births. The prevalence in a single high complexity hospital could be spuriously elevated due to referral bias. In the Danish study, OCDs cases diagnosed later in life were included and, as referred, a high proportion of OCDs are diagnosed during childhood. The lower means of weight, gestational age, and proportion of preterm births observed in cases with OCDs when compared to the total
Table 2 Distribution of cases and total births in the Argentinean population by birth weight, gestational age, proportion of preterms and maternal age. Osteochondrodysplasias cases Birth weight (mean; SD) Gestational age (mean; SD) Proportion of preterms (%) Maternal age (mean; SD) a
Total birthsa
2550 g (SD: 836)
P-value < 0.01
3220 (SD: 681) 39.4 (SD 7.2) 8.35 26.7 years
36.2 weeks (SD: 3.6) 38.40 27.1 years
Statistics and Information Health Department (DEIS), 2016 3
< 0.01 < 0.01 0.18
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NA: data not available. a RENAC prevalence was calculated over 1,663,610 births. b Prevalence was calculated over 1,544,496 births. Barbosa-Buck et al. (2012) c “Z” values were obtained using the RENAC prevalence of each OCD as the reference (expected value), and the ECLAMC (Z1), EUROCAT (Z2) and UBDN (Z3) prevalences as comparator values (observed values) [Z= (observed value-expected value)/root(expected value)]. d Prevalence was calculated over 4,791,349 births. Data was extracted from the EUROCAT network website. e Boyd et al.(2011). f Prevalence was calculated over 509,283 births. Stevenson et al. (2012) g Statistically significant. The statistical significance was established using Bonferroni's correction for multiple comparisons, in Z = ± 2.60865, corresponding to a p value of 0.0045.
6.99g 1.25 −2.27 9.76g (2.54–3.52) (0.27–0.65) (0.21–0.56) (0.56–1.07) 3.00 0.43 0.35 0.78 153 22 18 40 −4.09g −1.88 −3.36g NA 829 100 104 NA 366 62 79 57 Total Dysplasias Tanatophoric Dysplasia Achondroplasia Osteogenesis Imperfecta
2.20 0.37 0.47 0.34
(1.98–2.44) (0.29–0.48) (0.38–0.59) (0.26–0.44)
492 73 68 115
3.20 0.47 0.44 0.74
(2.90–3.50) (0.36–0.59) (0.33–0.55) (0.61–0.89)
8.57g 2.11 −0.65 8.86g
1.73 (1.61–1.85)d 0.34 (0.28–0.41)e 0.35 (0.29–0.43)e NA
UBDN Cases Z2c Eurocat prevalence per 10,000 (CI 95%) EUROCAT Cases Z1c ECLAMC prevalence per 10,000 (CI 95%)b ECLAMC Cases RENAC prevalence per 10,000 (CI 95%)a RENAC Cases Skeletal dysplasia
Table 3 Prevalence of total skeletal dysplasias, Tanatophoric dysplasia, Achondroplasia and Osteogenesis Imperfecta, in RENAC, ECLAMC, Eurocat and UBDN.
UBDN prevalence per 10,000 (CI 95%)f
Z3c
S.P. Duarte et al.
most accurate predictors of a lethal skeletal dysplasia. Also, fractures in uterus and severely bowed limbs are ominous signs of a lethal skeletal dysplasia (Milks et al., 2017). In our study, we analyzed the total number of cases detected prenatally. However, we did not have access to the exact description of the signs detected, or at what time of pregnancy the detection occurred. In RENAC, prenatal detection rate was in the range previously reported by other programs, but lower than ECLAMC rate (Barbosa-Buck et al., 2012), in which most reported cases (93%) had at least one prenatal ultrasound examination, with 73% suggesting an OCD. Maternity hospitals reporting to ECLAMC generally have greater complexity than those reporting to RENAC. Prenatal detection followed by referral to higher complexity establishments could explain the higher prevalence in the ECLAMC. When a newborn is diagnosed with a known lethal disorder in the fetal period, treating physicians should offer comfort care for the newborn, pain treatment but not aggressive management. For all newborns that die of complications from skeletal disorders, radiographs and a source of DNA should be obtained, and families should be offered autopsy. Collection of postmortem material aids in final diagnosis, which helps to provide parents emotional closure and determine recurrence risk for families through clinical molecular diagnosis or research participation (Krakow, 2015). As previously reported, we observed a lower mean weight, mean gestational age, and higher proportion of preterm in cases with OCD when compared with total births. There were no differences for maternal age. Paternal age, a well known risk factor for autosomal dominant OCD, was not available in our dataset. The latest available nosologic classification of OCD types [Bonafe et al., 2015] applied well to the material found in this study. We allocated most cases into specific slots, which will allow a better comparison of rates in future studies. The most frequent types of OCD were Achondroplasia, Thanatophoric Dysplasia, and the whole group of Osteogenesis Imperfecta. The results were lower for Osteogenesis Imperfecta, Thanatophoric Dysplasia and total dysplasias than those reported by the ECLAMC study in 2012 and the UBDN in 2012. On the other hand, our results were similar for Thanatophoric Dysplasia and higher for total dysplasias than the reports of EUROCAT in 2011. Our study had some limitations. According to the current classification of OCD [Bonafe et al., 2015] there are almost 250 conditions described. Among these, at least 110 are evident in the perinatal period. Although we used a large sample, we had few cases of the currently known OCDs of which diagnosis can be made in the perinatal period. This could be explained by under-ascertainment. Many OCD are very rare conditions and physicians who receive cases are most often neonatologists without sufficient knowledge about OCD. We believe it would be useful to disseminate information about OCDs among RENAC neonatologists in order to increase ascertainment. Also there are difficulties in the examination of stillborns, therefore, given that some of this conditions are lethal we could have an under-registration of them. Another limitation is that most cases with evidence level 3 are described as skeletal dysplasia vaguely. We stress the importance of documentation of cases with X-rays, even post-mortem, in order to arrive to a diagnosis. Moreover, molecular diagnosis was not made in any case due to the unavailability of such studies for patients in Argentina. RENAC covers 40% of births in the country, occurring in 160 hospitals. Most of this hospitals (n = 136) are from the public health subsector. Therefore, in the RENAC sample there is an overrepresentation of the population who seeks attention in this subsector, with lower socioeconomic level and mean lower maternal and paternal age than the non public sector. Since advanced paternal age is a risk factor for autosomal dominant conditions, the prevalence seen in the study may underestimate the true prevalence in Argentina. Our investigation is the first study of OCD prevalence in Argentina using data from every jurisdiction of the country. The prevalence we 4
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observed was lower than the prevalence of the last study by ECLAMC which used data from different high complexity hospitals in South America. Some cases may be under-ascertained because of the lack of knowledge about OCD, and difficulty in the clinical and radiological evaluation of stillborns. This study stresses the importance of training the reporting physicians about OCDs. Also, it is very important to have a system for sending photos (clinics and x-rays) in the monitoring programs of congenital defects. After clinical evaluation, it is critical to obtain complete anterior/posterior and lateral radiographs. This includes images photos of x-rays of the skull, extremities (including hands and feet) and the spine. Clinical photos of the baby are also important. This is useful to achieve a higher evidence level of diagnosis and improve detection, and hence, the opportunity for counseling and treatment. An accurate and specific description in a surveillance system means that cases are thoroughly examined, which facilitates diagnosis and care.
pattern of osteochondrodysplasias in an inbred high risk population. Birth Defects Res. Part A 67, 125–132. Andersen Jr., P.E., Hauge, M., 1989. Congenital generalized bone dysplasias: a clinical, radiological, and epidemiological survey. J. Med. Genet. 27, 37–44. Barbosa-Buck, C., Orioli, I., Dutra, M., Camelo, J., Castilla, E., Cavalcanti, D., 2012. Clinical epidemiology of skeletal dysplasias in South America. Am. J. Med. Genet. 158A, 1038–1045. Bonafe, L., Cormier-Daire, V., Hall, C., Lachman, R., Mortier, G., Mundlos, S., Nishimura, G., Sangiorgi, L., Savarirayan, R., Sillence, D., Spranger, J., Superti-Furga, A., Warman, M., Unger, S., 2015. Nosology and classification of genetic skeletal disorders: 2015 revision. Am. J. Med. Genet. 167A, 2869–2892. Boyd, P., Haeusler, M., Barisic, I., Loane, M., Garne, E., Dolk, H., 2011. Paper 1: the EUROCAT network—organization and processes. Birth Defects Res. Part A: Clin. Mol. Teratol. 91, S2S15. Camera, G., Mastroiacovo, P., 1982. Birth prevalence of skeletal dysplasias in the Italian Multicentric Monitoring System for Birth Defects. Prog Clin Biol Res. 104, 441–449. Castilla, E.E., Orioli, I.M., 2004. ECLAMC: the Latin-American collaborative study of congenital malformations. Community Genet. 7, 76–94. Groisman, B., Bidondo, M.P., Barbero, P., Gili, J.A., Liascovich, R., RENAC Task Force, 2013. RENAC: national registry of congenital anomalies of Argentina. Arch. Argent. Pediatr. 111 (6), 484–494 Dec. Gustavson, K.H., Jorulf, H., 1975. Different types of osteochondrodysplasia in a consecutive series of newborns. Helv. Pediat. Acta 30, 307–314. Krakow, D., 2015. Skeletal dysplasias. Clin. Perinatol. 42 (2), 301–319. https://doi.org/ 10.1016/j.clp.2015.03.003. Lachman, R.S., 2008. Skeletal dysplasias. In: Slovis, T. (Ed.), Caffey's Pediatric Diagnostic Imaging, eleventh ed. Mosby Elsevier, Philadelphia, pp. 2613. Milks, K.S., Hill, L.M., Hosseinzadeh, K., 2017. Evaluating skeletal dysplasias on prenatal ultrasound: an emphasis on predicting lethality. Pediatr. Radiol. 47 (2), 134–145 Feb. Orioli, I.M., Castilla, E.E., Barbosa-Neto, J.G., 1986. The birth prevalence rates for the skeletal dysplasias. J. Med. Genet. 23, 328–332. Parnell, S.E., Phillips, G.S., 2012. Neonatal skeletal dysplasias. Pediatr. Radiol. (42 Suppl. 1), S150–S157 Jan. Rasmussen, S.A., Bieber, B.R., Benacerraf, B.R., Lachman, R.S., Rimoin, D.L., Holmes, L.B., 1996. Epidemiology of osteochondrodysplasias: changing trends due to advances in prenatal diagnosis. Am. J. Med. Genet. 61, 49–58. Schramm, T., et al., 2009. Prenatal sonographic diagnosis of skeletal dysplasias. Ultrasound Obstet. Gynecol. 34, 160–170. Spranger, J.W., Brill, P.W., Poznanski, A., 2002. Bone Dysplasias, second ed. Oxford University Press, New York. Stevenson, D.A., Carey, J.C., Byrne, J.L.B., Srisukhumbowornchai, S., Feldkamp, M., 2012. Analysis of skeletal dysplasias in the Utah population. Am. J. Med. Genet. 158A, 1046–1054. Stoll, C., Dott, B., Roth, M.P., Alembik, Y., 1989. Birth prevalence rates of skeletal dysplasias. Clin. Genet. 35, 88–92.
Funding sources RENAC was supported in-part by UNICEF Argentina; the National Ministry of Health; the National Agency for Science and Technology. Conflicts of interest Authors declare that they have no conflict of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ejmg.2018.12.008. References Al-Gazali, L.I., Bakir, M., Hamid, Z., Varady, E., Varghes, M., Haas, D., Bener, A., Padmanabhan, R., Abdulrrazzaq, Y.M., Dawadu, A.K., 2003. Birth prevalence and
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Bone dysplasias in 1.6 million births in Argentina Santiago Pablo Duarte, María Eugenia Rocha, María Paz Bidondo, Rosa Liascovich, Pablo Barbero, Boris Groisman∗ National Network of Congenital Anomalies in Argentina (RENAC), National Center of Medical Genetics, National Administration of Laboratories and Health Institutes, National Ministry of Health, Argentina
A R T I C LE I N FO
A B S T R A C T
Keywords: Osteochondrodysplasias Prevalence Epidemiology Achondroplasia Thanatophoric dysplasia Osteogenesis Imperfecta Argentina
Currently accepted birth prevalence for osteochondrodysplasias (OCDs) is about 2 per 10,000 births. Our main goal is to estimate the prevalence of OCDs in Argentina and compare it with other surveillance systems. We examined 1,663,610 births among 160 hospitals of RENAC (Red Nacional de Anomalías Congénitas - National Network of Congenital Anomalies) between November 2009 and December 2016. Cases were detected and registered according to a pre-established protocol, ranked in three diagnostic evidence levels according to available clinical documentation, and categorized according to the 9th edition of the nosology and classification of genetic skeletal disorders. Within our dataset, the most frequent groups were Group-1 (FGFR3, chondrodysplasia) and Group-25 (Osteogenesis Imperfecta and decreased bone density). Birth prevalence per 10,000 for the main OCD types, were: Achondroplasia 0.47 (95% CI: 0.38–0.59), Thanatophoric Dysplasia 0.37 (95% CI: 0.29–0.48), and the Osteogenesis Imperfecta group 0.34 (95% CI: 0.26–0.44). For total OCD, birth prevalence was 2.20 per 10.000 births (95% CI: 1.98–2.44). RENAC prevalence of total OCDs was found to be lower than that reported by the Latin-American Study of Congenital Malformations (ECLAMC) and Utah Birth Defect Network but higher than EUROCAT. Our investigation is the first study of OCD prevalence in Argentina using data from every jurisdiction of the country.
1. Introduction Skeletal dysplasias, also known as osteochondrodysplasias (OCDs) are a complex group of more than 400 clinically and molecularly heterogeneous conditions that affect the growth and development of both bone and cartilage, including skeletal dysplasias, metabolic bone disorders, dysostosis and skeletal malformation and/or reduction syndromes [Spranger et al., 2002]. Albeit individually rare, their birth prevalence as a group is estimated to range from 2.1 to 4.7/10,000 [Gustavson and Jorulf, 1975; Camera and Mastroiacovo, 1982; Orioli et al., 1986; Stoll et al., 1989; Rasmussen et al., 1996; Stevenson et al., 2012]. As a general rule, OCDs are monogenic disorders. A typical presentation of OCDs is short stature. Radiographic patterns may include any or all of the following: spondylo, epiphyseal, metaphyseal, and diaphyseal dysplasia. These patterns help narrow down the possible group of dysplasias. Due to the heterogeneity found in OCDs, musculoskeletal effects range in severity from premature arthritis to severe short stature with death in the perinatal period. About 40% of all OCD have clinical manifestations from birth (neonatal forms), the rest being usually diagnosed during childhood. Neonatal
∗
forms usually compromise the child's health in a severe way, some of them being lethal. In skeletal dysplasias, death is caused mainly by pulmonary hypoplasia secondary to thoracic involvement. The diagnosis of neonatal forms of OCD can be suspected prenatally (usually prompted by identification of long-bone shortening on sonography, some of them have also polyhydramnios); and is confirmed by X-rays at birth or when signs and symptoms of the syndrome occur. An important goal after detection of a fetal skeletal dysplasia is determining its severity; of special concern is whether the prognosis is lethal [Schramm et al., 2009]. Being a cause of infant mortality and morbidity, the impact that these pathologies have in the public healthcare system is very important. Prevalence of OCDs has been evaluated in various countries and results are heterogenous. The only information of prevalence of OCDs in Latin-America comes from the Latin-American Study of Congenital Malformations (ECLAMC, Spanish acronym), which aggregates data from different hospitals in the region. We did not find previous reports of OCDs frequency in Argentina. The main goal of this work is to present the descriptive epidemiology of OCD in Argentina and compare its prevalence with other
Corresponding author. Av. Las Heras 2670, 3er floor, City of Buenos Aires, 1425, Argentina. E-mail address: [email protected] (B. Groisman).
https://doi.org/10.1016/j.ejmg.2018.12.008 Received 3 August 2018; Received in revised form 5 November 2018; Accepted 15 December 2018 1769-7212/ © 2018 Published by Elsevier Masson SAS.
Please cite this article as: Duarte, S.P., European Journal of Medical Genetics, https://doi.org/10.1016/j.ejmg.2018.12.008
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Table 1 Evidence Level of diagnosis and prevalence according OCD Diagnostic Groups from International Skeletal Dysplasia Society (ISDS), National Network of Congenital Anomalies of Argentina, 2009–2016. Diagnostic groups
1. FGFR3 chondrodysplasia group Achondroplasia Thanatophoric Dysplasia (type 1 and 2 included) 2. Type 2 collagen group Spondyloepiphyseal dysplasia congenital (SEDC) Kniest Dysplasia 3. Type 11 collagen group Fibrochondrogenesis 4. Sulfation disorders group Diastrophic Dysplasia 8. TRPV4 group Metatropic dysplasia 9. Ciliopathies with major skeletal involvement Chondroectodermal dysplasia (Ellis van creveld) Short rib–polydactyly syndrome (SRPS) type 1/3 - Asphyxiating thoracic dysplasia 18. Campomelic dysplasia and related disorders Campomelic Dysplasia 21. Chondrodysplasia punctata group Chondrodysplasia punctata 23. Osteopetrosis and related disorders Osteopetrosis 25. Osteogenesis Imperfecta and decreased bone density group Osteogenesis Imperfecta (type II and II) 26. Abnormal mineralization group Hypophosphatasia Achondrogenesisa Total a
Evidence level 1
Evidence level 2
Total
Prevalence (CI 95%)
n
%
n
%
33 36
41.8 58.1
46 26
58.2 41.9
79 62
4.75(3.76–5.92) 3.73(2.86–4.78)
0 2
0.0 100.0
1 0
100.0 0.0
1 2
0.06(0–0.33) 0.12(0.01–0.43)
0
0.0
1
100.0
1
0.06(0–0.33)
3
100.0
0
0.0
3
0.18(0.04–0.53)
1
100.0
0
0.0
1
0.06(0–0.33)
5 9
83.3 81.8
1 2
16.7 18.2
6 11
0.36(0.13–0.79) 0.66(0.33–1.18)
8
66.7
4
33.3
12
0.72(0.37–1.26)
8
80.0
2
20.0
10
0.60(0.29–1.11)
1
100.0
0
0.0
1
0.06(0–0.33)
43
75.4
14
24.6
57
3.43(2.6–4.44)
1 4 154
100.0 66.7 60.9
0 2 99
0.0 33.3 39.1
1 6 253
0.06(0–0.33) 0.36(0.13–0.79) 15.21(13.39–17.2)
Achondrogenesis without specific type classification.
● Evidence level 1: Cases with confirmatory X-rays or diagnosis performed by a medical geneticist. ● Evidence level 2: Cases with satisfactory clinical description or clinical photos sufficient to establish a probable diagnosis or familiar history of specific OCD. ● Evidence level 3: Cases described as “skeletal dysplasia” or as having features compatible with skeletal dysplasia (i.e.: short stature and short limbs), but without a specified OCD type.
surveillance programs.
2. Methods We used data from the National Network of Congenital Anomalies of Argentina (RENAC), collected from November 1st 2009 to December 31st, 2016. RENAC is a hospital-based surveillance program of major structural congenital anomalies, operating since 2009 in maternity hospitals distributed in the 24 jurisdictions of Argentina. At present it covers around 300,000 births per year, 40% of annual births in the country. The birth outcomes included are live births and stillbirths (weighting more than 500 g), with major structural congenital anomalies detected from birth until hospital discharge. Neonatologists in each hospital send reports to the RENAC coordination. The reporting neonatologists follow a common methodology standardized in a manual of operations, an atlas of congenital anomalies, and reinforced through on-line and in person trainings. The reports include a verbatim description of the affected cases and a core set of variables. The reporting neonatologists can send photographs of x-rays, clinical photos or results of additional studies that contribute to the diagnostic accuracy. These reports are sent through an on-line forum that allows review and discussion of cases [Groisman et al., 2013]. Each case is coded using the ICD-10 with the Royal College of Pediatrics and Child Health modification. The working definition used in this study for OCD was: ‘‘a clinically defined growth deficiency of prenatal onset, associated or not with body disproportion’’ (ICD-10 codes: Q77-Q78). All available information about OCD cases, including clinical records, skeletal X-rays, and clinical photos were reviewed. Cases were classified according to the International Classification provided by International Skeletal Dysplasia Society (ISDS) [Bonafe et al., 2015]. In order to evaluate the diagnostic accuracy of OCD type, cases were assorted into three different diagnostic evidence levels as follows:
We calculated the prevalence for total OCD and for the most frequent specific types as the proportion of cases over the total numbers of births (live births and stillbirths) with 95% confidence intervals calculated using the Poisson distribution with the STATA software 12. We present the proportion of cases with prenatal diagnosis for the period 2013–2016 because this variable was not initially included in RENAC reports. We compared birth weight, gestational age, proportion of preterms and maternal age between cases and total births from Argentina; population data came from the Information Health Department (DEIS). We compared our results with data from ECLAMC [Barbosa-Buck et al., 2012], the Utah Birth Defect Network (UBDN) [Stevenson et al., 2012], and the European Surveillance of Congenital Anomalies (EUROCAT) [Boyd et al., 2011]. ECLAMC is a hospital based, voluntary network of South American maternity centers with a case control design that monitors the occurrence of congenital anomalies in South American countries since the late 1960s [Castilla and Orioli, 2004]. UBDN collects population-based data for Utah on births from all resident women in the state. EUROCAT is a network of population-based registries of congenital anomalies in Europe. In the comparison between RENAC, ECLAMC, UBDN, and EUROCAT, a “Z” value was obtained using the RENAC prevalence of each OCD as the reference (expected value), and the ECLAMC (Z1), EUROCAT (Z2) and UBDN (Z3) prevalences as comparator values (observed values) [Z= (observed valueexpected value)/root(expected value)]. The statistical significance was 2
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births is consistent with previous reports [Barbosa-Buck et al., 2012]. The relative frequency of the different OCDs may vary according to particular characteristics of the population under study. For example, a high birth prevalence (9.5/10,000) was reported in United Arab Emirates [Al-Gazali et al., 2003]. In this population the proportion of consanguineous couples may reach 50%, and it is common for men with advanced age to father children. Both factors increase the risk of Mendelian disorders: consanguinity increases the risk of autosomal recessive disorders, and advanced paternal age increases the risk of autosomal dominant disorders due to an increase in the probability of spontaneous mutations. Besides, in the United Arab Emirates study, about half of the OCD cases were autosomal recessive entities, fibrochondrogenesis being the most common with a prevalence of 1.05/ 10,000. In our study, we detected only one case with fibrochondrogenesis, whereas Barbosa-Buck et al. (2012) did not report any case in over 1,000,000 births. These results show the heterogeneity of prevalence according to different regions. In relation to previous studies performed in our region, the birth prevalence observed in our study is similar to the one reported by ECLAMC in 1986 [Orioli et al., 1986], but is lower than the prevalence reported more recently by the same surveillance program [BarbosaBuck et al., 2012]. Stevenson (Stevenson et al., 2012) in Utah established a prevalence of 3.0 per 10,000 liveborns (95% CI: 2.53–3.48), statistically significant higher than the prevalence reported by RENAC. These could be related to the ascertainment window for each system: the UBDN has no maximum age of diagnosis, whereas RENAC includes cases detected until hospital discharge. UBDN also includes multiple sources (delivery units, paediatric departments, laboratories, etc), and RENAC only includes maternity hospitals. RENAC prevalence of total OCDs was statistically significant higher than EUROCAT. Although EUROCAT programs have also multiple sources and most extend the ascertainment window until 1 year of age, in most of them prenatal diagnosis and elective terminations are a common practice. The lower prevalence could be related with underascertainment of elective terminations. Despite being illegal, terminations of pregnancy are performed in Argentina, and thus not routinely accounted for in official statistics. The ratio of prevalence in stillbirths over the prevalence in live births in RENAC was 6.98 and perinatal death occurred in more than 50% of cases. The high perinatal lethality is possibly due to the inclusion of severe OCD and perhaps to a sub-registration of cases with milder forms. Approximately one-quarter of OCD are considered lethal in the perinatal period (Lachman, 2008; Parnell and Phillips, 2012). Mortality in skeletal dysplasias is determined largely by the degree of pulmonary hypoplasia. In our study, 150 of 253 cases with specific diagnosis (59.3%) were lethal dysplasias (Thanatophoric, Fibrochondrogenesis, Short rib polydactyly, Campomelic, lethal type of Osteogenesis Imperfecta, Achondrogenesis and Hypophosphatasia). Lethal skeletal dysplasias can be diagnosed by prenatal ultrasound using several sonographic parameters. Fetal lung volumes (i.e.: < 5th percentile for gestational age), femur length to abdominal circumference ratio (i.e.: < 0.16 and polyhydramnios is present), and thoracic circumference to abdominal circumference ratio (i.e.: < 0.6), are the three
established using Bonferroni's correction for multiple comparisons, in Z = ± 2.60865, corresponding to a p value of 0.0045. The Stata statistical software was used. 3. Results In the period from November 2009 to December 2016: 1,663,610 births were examined, 366 of whom had OCDs. Thus, overall birth prevalence of OCDs was 2.20 per 10.000 births (95% CI: 1.98–2.44). In live births, the prevalence was 2.09 per 10,000 births (95% CI: 1.88–2.32), and in stillbirths was 14.58 per 10,000 births (CI 95%: 9.13–22.07). Out of the 366 cases reported, 253 (69.1%) had a specific diagnosis (Evidence levels 1 and 2) (Table 1); 113 cases (30.9%) did not have an accurate diagnosis of OCD (Evidence level 3). The main diagnoses were Achondroplasia, Osteogenesis Imperfecta, and Thanatophoric Dysplasia, together representing 78.3% of the cases distributed between the highest evidence levels (evidence levels 1 and 2). Birth prevalence per 100,000 for the main OCD types, were: Achondroplasia 4.8 (95% CI: 3.8–5.9), Thanatophoric Dysplasia 3.7 (95% CI: 2.9–4.8), and the Osteogenesis Imperfecta group 3.4 (95% CI: 2.6–4.4). Data concerning prenatal diagnosis was available in 274 cases. Out of these patients, 184 (67.2%) were detected by the finding of short limbs on an ultrasound scan. Perinatal lethality (stillbirths plus early neonatal deaths) occurred in 56.8% of cases. Prenatal diagnosis was more frequent in cases resulting in perinatal death (80.6%) than in cases alive at hospital discharge (56.0%) (p < 0.01). Sex ratio was 1.06 (186 males, 175 females), 3 cases had undetermined sex and in 2 sex was not specified. Means of birth weight, gestational age, and proportion of premature births for cases and total births are shown in Table 2. Cases had lower birth weight; lower gestational age; and were more preterm. There was no statistically significant differences in maternal age. RENAC showed a statistically significant lower prevalence than ECLAMC in total OCD prevalence, and osteogenesis Imperfecta. RENAC showed a statistically significant higher prevalence than EUROCAT of total OCD and Achondroplasia; Osteogenesis Imperfecta could not be compared because that specific data was not reported. RENAC presented a statistically lower prevalence than UBDN in total OCD and Osteogenesis Imperfecta (Table 3). 4. Discussion The OCD birth prevalence observed in our study was similar to previous reports [Orioli et al., 1986; Stoll et al., 1989; Rasmussen et al., 1996]. However, some epidemiological studies have shown higher prevalences, like the study made by Gustavson and Jorulf (1975) in Sweden (4.7/10,000) and the one made by Andersen and Hauge (1989) in Denmark (7.6/10,000). The first one was conducted in a single hospital with a sample of less than 15,000 births. The prevalence in a single high complexity hospital could be spuriously elevated due to referral bias. In the Danish study, OCDs cases diagnosed later in life were included and, as referred, a high proportion of OCDs are diagnosed during childhood. The lower means of weight, gestational age, and proportion of preterm births observed in cases with OCDs when compared to the total
Table 2 Distribution of cases and total births in the Argentinean population by birth weight, gestational age, proportion of preterms and maternal age. Osteochondrodysplasias cases Birth weight (mean; SD) Gestational age (mean; SD) Proportion of preterms (%) Maternal age (mean; SD) a
Total birthsa
2550 g (SD: 836)
P-value < 0.01
3220 (SD: 681) 39.4 (SD 7.2) 8.35 26.7 years
36.2 weeks (SD: 3.6) 38.40 27.1 years
Statistics and Information Health Department (DEIS), 2016 3
< 0.01 < 0.01 0.18
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NA: data not available. a RENAC prevalence was calculated over 1,663,610 births. b Prevalence was calculated over 1,544,496 births. Barbosa-Buck et al. (2012) c “Z” values were obtained using the RENAC prevalence of each OCD as the reference (expected value), and the ECLAMC (Z1), EUROCAT (Z2) and UBDN (Z3) prevalences as comparator values (observed values) [Z= (observed value-expected value)/root(expected value)]. d Prevalence was calculated over 4,791,349 births. Data was extracted from the EUROCAT network website. e Boyd et al.(2011). f Prevalence was calculated over 509,283 births. Stevenson et al. (2012) g Statistically significant. The statistical significance was established using Bonferroni's correction for multiple comparisons, in Z = ± 2.60865, corresponding to a p value of 0.0045.
6.99g 1.25 −2.27 9.76g (2.54–3.52) (0.27–0.65) (0.21–0.56) (0.56–1.07) 3.00 0.43 0.35 0.78 153 22 18 40 −4.09g −1.88 −3.36g NA 829 100 104 NA 366 62 79 57 Total Dysplasias Tanatophoric Dysplasia Achondroplasia Osteogenesis Imperfecta
2.20 0.37 0.47 0.34
(1.98–2.44) (0.29–0.48) (0.38–0.59) (0.26–0.44)
492 73 68 115
3.20 0.47 0.44 0.74
(2.90–3.50) (0.36–0.59) (0.33–0.55) (0.61–0.89)
8.57g 2.11 −0.65 8.86g
1.73 (1.61–1.85)d 0.34 (0.28–0.41)e 0.35 (0.29–0.43)e NA
UBDN Cases Z2c Eurocat prevalence per 10,000 (CI 95%) EUROCAT Cases Z1c ECLAMC prevalence per 10,000 (CI 95%)b ECLAMC Cases RENAC prevalence per 10,000 (CI 95%)a RENAC Cases Skeletal dysplasia
Table 3 Prevalence of total skeletal dysplasias, Tanatophoric dysplasia, Achondroplasia and Osteogenesis Imperfecta, in RENAC, ECLAMC, Eurocat and UBDN.
UBDN prevalence per 10,000 (CI 95%)f
Z3c
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most accurate predictors of a lethal skeletal dysplasia. Also, fractures in uterus and severely bowed limbs are ominous signs of a lethal skeletal dysplasia (Milks et al., 2017). In our study, we analyzed the total number of cases detected prenatally. However, we did not have access to the exact description of the signs detected, or at what time of pregnancy the detection occurred. In RENAC, prenatal detection rate was in the range previously reported by other programs, but lower than ECLAMC rate (Barbosa-Buck et al., 2012), in which most reported cases (93%) had at least one prenatal ultrasound examination, with 73% suggesting an OCD. Maternity hospitals reporting to ECLAMC generally have greater complexity than those reporting to RENAC. Prenatal detection followed by referral to higher complexity establishments could explain the higher prevalence in the ECLAMC. When a newborn is diagnosed with a known lethal disorder in the fetal period, treating physicians should offer comfort care for the newborn, pain treatment but not aggressive management. For all newborns that die of complications from skeletal disorders, radiographs and a source of DNA should be obtained, and families should be offered autopsy. Collection of postmortem material aids in final diagnosis, which helps to provide parents emotional closure and determine recurrence risk for families through clinical molecular diagnosis or research participation (Krakow, 2015). As previously reported, we observed a lower mean weight, mean gestational age, and higher proportion of preterm in cases with OCD when compared with total births. There were no differences for maternal age. Paternal age, a well known risk factor for autosomal dominant OCD, was not available in our dataset. The latest available nosologic classification of OCD types [Bonafe et al., 2015] applied well to the material found in this study. We allocated most cases into specific slots, which will allow a better comparison of rates in future studies. The most frequent types of OCD were Achondroplasia, Thanatophoric Dysplasia, and the whole group of Osteogenesis Imperfecta. The results were lower for Osteogenesis Imperfecta, Thanatophoric Dysplasia and total dysplasias than those reported by the ECLAMC study in 2012 and the UBDN in 2012. On the other hand, our results were similar for Thanatophoric Dysplasia and higher for total dysplasias than the reports of EUROCAT in 2011. Our study had some limitations. According to the current classification of OCD [Bonafe et al., 2015] there are almost 250 conditions described. Among these, at least 110 are evident in the perinatal period. Although we used a large sample, we had few cases of the currently known OCDs of which diagnosis can be made in the perinatal period. This could be explained by under-ascertainment. Many OCD are very rare conditions and physicians who receive cases are most often neonatologists without sufficient knowledge about OCD. We believe it would be useful to disseminate information about OCDs among RENAC neonatologists in order to increase ascertainment. Also there are difficulties in the examination of stillborns, therefore, given that some of this conditions are lethal we could have an under-registration of them. Another limitation is that most cases with evidence level 3 are described as skeletal dysplasia vaguely. We stress the importance of documentation of cases with X-rays, even post-mortem, in order to arrive to a diagnosis. Moreover, molecular diagnosis was not made in any case due to the unavailability of such studies for patients in Argentina. RENAC covers 40% of births in the country, occurring in 160 hospitals. Most of this hospitals (n = 136) are from the public health subsector. Therefore, in the RENAC sample there is an overrepresentation of the population who seeks attention in this subsector, with lower socioeconomic level and mean lower maternal and paternal age than the non public sector. Since advanced paternal age is a risk factor for autosomal dominant conditions, the prevalence seen in the study may underestimate the true prevalence in Argentina. Our investigation is the first study of OCD prevalence in Argentina using data from every jurisdiction of the country. The prevalence we 4
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observed was lower than the prevalence of the last study by ECLAMC which used data from different high complexity hospitals in South America. Some cases may be under-ascertained because of the lack of knowledge about OCD, and difficulty in the clinical and radiological evaluation of stillborns. This study stresses the importance of training the reporting physicians about OCDs. Also, it is very important to have a system for sending photos (clinics and x-rays) in the monitoring programs of congenital defects. After clinical evaluation, it is critical to obtain complete anterior/posterior and lateral radiographs. This includes images photos of x-rays of the skull, extremities (including hands and feet) and the spine. Clinical photos of the baby are also important. This is useful to achieve a higher evidence level of diagnosis and improve detection, and hence, the opportunity for counseling and treatment. An accurate and specific description in a surveillance system means that cases are thoroughly examined, which facilitates diagnosis and care.
pattern of osteochondrodysplasias in an inbred high risk population. Birth Defects Res. Part A 67, 125–132. Andersen Jr., P.E., Hauge, M., 1989. Congenital generalized bone dysplasias: a clinical, radiological, and epidemiological survey. J. Med. Genet. 27, 37–44. Barbosa-Buck, C., Orioli, I., Dutra, M., Camelo, J., Castilla, E., Cavalcanti, D., 2012. Clinical epidemiology of skeletal dysplasias in South America. Am. J. Med. Genet. 158A, 1038–1045. Bonafe, L., Cormier-Daire, V., Hall, C., Lachman, R., Mortier, G., Mundlos, S., Nishimura, G., Sangiorgi, L., Savarirayan, R., Sillence, D., Spranger, J., Superti-Furga, A., Warman, M., Unger, S., 2015. Nosology and classification of genetic skeletal disorders: 2015 revision. Am. J. Med. Genet. 167A, 2869–2892. Boyd, P., Haeusler, M., Barisic, I., Loane, M., Garne, E., Dolk, H., 2011. Paper 1: the EUROCAT network—organization and processes. Birth Defects Res. Part A: Clin. Mol. Teratol. 91, S2S15. Camera, G., Mastroiacovo, P., 1982. Birth prevalence of skeletal dysplasias in the Italian Multicentric Monitoring System for Birth Defects. Prog Clin Biol Res. 104, 441–449. Castilla, E.E., Orioli, I.M., 2004. ECLAMC: the Latin-American collaborative study of congenital malformations. Community Genet. 7, 76–94. Groisman, B., Bidondo, M.P., Barbero, P., Gili, J.A., Liascovich, R., RENAC Task Force, 2013. RENAC: national registry of congenital anomalies of Argentina. Arch. Argent. Pediatr. 111 (6), 484–494 Dec. Gustavson, K.H., Jorulf, H., 1975. Different types of osteochondrodysplasia in a consecutive series of newborns. Helv. Pediat. Acta 30, 307–314. Krakow, D., 2015. Skeletal dysplasias. Clin. Perinatol. 42 (2), 301–319. https://doi.org/ 10.1016/j.clp.2015.03.003. Lachman, R.S., 2008. Skeletal dysplasias. In: Slovis, T. (Ed.), Caffey's Pediatric Diagnostic Imaging, eleventh ed. Mosby Elsevier, Philadelphia, pp. 2613. Milks, K.S., Hill, L.M., Hosseinzadeh, K., 2017. Evaluating skeletal dysplasias on prenatal ultrasound: an emphasis on predicting lethality. Pediatr. Radiol. 47 (2), 134–145 Feb. Orioli, I.M., Castilla, E.E., Barbosa-Neto, J.G., 1986. The birth prevalence rates for the skeletal dysplasias. J. Med. Genet. 23, 328–332. Parnell, S.E., Phillips, G.S., 2012. Neonatal skeletal dysplasias. Pediatr. Radiol. (42 Suppl. 1), S150–S157 Jan. Rasmussen, S.A., Bieber, B.R., Benacerraf, B.R., Lachman, R.S., Rimoin, D.L., Holmes, L.B., 1996. Epidemiology of osteochondrodysplasias: changing trends due to advances in prenatal diagnosis. Am. J. Med. Genet. 61, 49–58. Schramm, T., et al., 2009. Prenatal sonographic diagnosis of skeletal dysplasias. Ultrasound Obstet. Gynecol. 34, 160–170. Spranger, J.W., Brill, P.W., Poznanski, A., 2002. Bone Dysplasias, second ed. Oxford University Press, New York. Stevenson, D.A., Carey, J.C., Byrne, J.L.B., Srisukhumbowornchai, S., Feldkamp, M., 2012. Analysis of skeletal dysplasias in the Utah population. Am. J. Med. Genet. 158A, 1046–1054. Stoll, C., Dott, B., Roth, M.P., Alembik, Y., 1989. Birth prevalence rates of skeletal dysplasias. Clin. Genet. 35, 88–92.
Funding sources RENAC was supported in-part by UNICEF Argentina; the National Ministry of Health; the National Agency for Science and Technology. Conflicts of interest Authors declare that they have no conflict of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ejmg.2018.12.008. References Al-Gazali, L.I., Bakir, M., Hamid, Z., Varady, E., Varghes, M., Haas, D., Bener, A., Padmanabhan, R., Abdulrrazzaq, Y.M., Dawadu, A.K., 2003. Birth prevalence and
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