THIEME 576 Case Report Fetal Skeletal Lethal Dysplasia: Case Report Displasia Esquelética Letal Fetal: Relato de Caso Alexandre Mello Savoldi1,2,3 Maria Auxiliadora Monteiro Villar1,2,3 Heloisa Novaes Machado2,4 Juan C. Llerena Júnior1,2,3,5,6 1 Center for Medical Genetics and Center for Rare Diseases, Instituto Address for correspondence Juan Clinton Llerena Jr., MD, PhD, Nacional Fernandes Figueira (IFF), Fundação Oswaldo Cruz (Fiocruz), Instituto Nacional Fernandes Figueira, IFF/Fiocruz, Av. Rui Barbosa, Rio de Janeiro, RJ, Brazil 716, 22.250-020 - Rio de Janeiro, RJ, Brasil 2 LatinAmericanCollaborativeStudy of Congenital Malformations (e-mail: llerena@iff.fiocruz.br). (ECLAMC), Hospital A05, Instituto Nacional Fernandes Figueira (IFF), Fiocruz, Rio de Janeiro, RJ, Brazil 3 Reference Center for Osteogenesis Imperfecta (CROI), Instituto Nacional Fernandes Figueira (IFF), Fiocruz, Rio de Janeiro, RJ, Brazil 4 Pathological Anatomy Service, Instituto Nacional Fernandes Figueira (IFF), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, RJ, Brasil 5 Instituto Nacional de Genética Médica Populacional (Inagemp), Rio de Janeiro, RJ, Brazil 6 Fundação Arthur Sá Erp, Faculdade de Medicina de Petrópolis, Rio de Janeiro, RJ, Brazil Rev Bras Ginecol Obstet 2017;39:576–582. Abstract The clinical management and decision-making in pregnancies in which there is Keywords suspicion of lethal fetal malformations during the prenatal period, such as lethal ► pregnancy skeletal dysplasia (SD), demand a multidisciplinary approach coordinated by an ► skeletal dysplasia experienced physician. Based on the presentation of a case of osteogenesis imperfecta ► osteogenesis type IIA, we offer and discuss recommendations with the intention of organizing imperfecta clinical and laboratory investigations aiming toward the clinical management, prog- ► prenatal period nosis, and etiological diagnosis of these malformations, as well as genetic counselling ► genetic syndromes topatientswhowishtobecomepregnant. Resumo O manejo clínico e a tomada de decisões médicas em gestantes com suspeita de Palavras-chave malformação letal em um feto no período pré-natal, tal qual uma displasia esquelética ► gravidez letal, demandam uma abordagem multidisciplinar coordenada por um médico experi- ► displasia esquelética ente. Baseado na apresentação de um caso de osteogênese imperfeita tipo IIA, ► osteogênese recomendações são apresentadas e discutidas com a intenção de organizar as imperfeita investigações clínicas e laboratoriais visando o manejo clínico, o prognóstico, e o ► período pré-natal diagnóstico etiológico dessas malformações, e o aconselhamento genético para as ► síndromes genéticas pacientes que desejam engravidar. Introduction heterogeneous characteristics. They affect the bone tissue and cartilage, resulting in changes in the growth, shape and Skeletal dysplasias (SDs), or osteochondrodysplasias (OCDs), development of the skeletal system. The OCDs can be very are a group of bone disorders with clinical and etiological rare; however, as a group, their prevalence is estimated at received DOI https://doi.org/ Copyright © 2017 by Thieme Revinter December 13, 2016 10.1055/s-0037-1603943. Publicações Ltda, Rio de Janeiro, Brazil accepted ISSN 0100-7203. April 4, 2017 published online August 7, 2017 FetalSkeletalLethalDysplasia:CaseReport Savoldi et al. 577 around 2.4 per 10,000 live births1,2, with the lethal SD forms physicians to define proper etiological diagnosis and clinical – corresponding to 0.95-1.5 per 10,000 births.1 3 It is known prognosis, as well as genetic counselling, once few of these that there are more than 456 entities classified into 40 genetic disorders may present with considerable recurrence categories by their cardinal features (radiological findings, risks. molecular etiology, inheritance), among which 40% can be This article aims, through the presentation of a clinical already detected in the perinatal period, representing 9 case of a lethal SD with radiological features (OI type IIA), to deaths per 1,000 births.1,4 review the most common lethal SDs in the perinatal period, Osteogenesis imperfecta type II (OI type II) comprises 14% highlight their clinical and radiologic features, and compare of lethal SDs, and is the second most common cause, among the reported case with the literature. Furthermore, recom- thanatophoric dysplasia (26%) and the achondrogenesis (9%) mendations for the clinical management of similar cases are – group, which represents 40–60% of all lethal SDs.1,5 7 Oste- discussed. ogenesis imperfecta type II is a genetic disorder of the connective tissue characterized by severe bone fragility, Clinical Case Description susceptibility to severe deformities, and the occurrence of several pathological fractures, with predominance of de novo A 33-year-old pregnant woman in her 6th pregnancy, with 5 autosomal dominant inheritance caused by mutations in previous vaginal deliveries, was referred to our outpatient genes COL1A1 and COL1A2.8 Multiple fractures are frequent prenatal clinic due to a malformation in her fetus detected by in utero, and perinatal death occurs in the majority of cases,9 an ultrasound in the Family Care Clinic. Her family history where most prenatal diagnosis are suspected primarily by was unremarkable. A prenatal ultrasound fetal biometry at early fetal ultrasound, and confirmed by skeletal radiogra- 23 weeks of pregnancy revealed an estimated fetal weight of phy, autopsy and, less frequently, by molecular tests. 505 g and shortening of the long bones, so the hypothesis of Due to the suspicion of a presumptive diagnosis of SD based an SD was considered. At 39 weeks of pregnancy, an ultra- on early gestational ultrasound findings, a range of clinical sound revealed an estimated fetal weight of 815 g and fetal diagnosis with different outcomes may be considered. Based malformations characterized by hypotelorism, short and on the severity of the condition, such considerations and saddled nose, micrognathia with redundancy of soft tissue observations can impose difficulties to an appropriate clinical in the face and neck, very short ribs, and narrow thoracic cage management of these fetuses, the pregnant women, and their (►Fig. 1a). Furthermore, it was possible to observe skeletal families regarding genetic counselling. abnormalities with shortening of the limbs more pro- In face of a medical emergency for the fetus with a nounced in the femora and humeri. Fetal hypocalcification presumed lethal SD, and the presence of a rather uniform of the skull was evident, and complete and normal visuali- gestational ultrasound phenotype among lethal SDs, clinical zation of the encephalon, cerebral hemispheres, ventricles management guidelines become crucial. They may assist and the posterior fossa was apparently present. A fetal Fig. 1 Obstetric ultrasound and fetal development quantile curves of OI type IIA – 38 weeks. Rev Bras Ginecol Obstet Vol. 39 No. 10/2017 578 FetalSkeletalLethalDysplasia:CaseReport Savoldi et al. echocardiography showed normal cardiac activity, with a humeri and femora, abnormally shaped ribs containing thoracic diameter well below the third percentile, in addition numerous fractures (“pearl appearance”), and a vertebral to the presence of a mild to moderate tricuspid regurgitation. column with flattened vertebrae (platyspondylia) (►Fig. 2). The small thoracic diameter suggested a high probability of Based on the clinical and radiological evidences, the severe pulmonary hypoplasia. patient was diagnosed as having OI type IIA (lethal form) A history of Zika virus infection was suspected when the (►Figs. 1, 2, 3). mother was 20 weeks and 4 days pregnant due to clinical manifestations described as arthralgia during 10 days, mod- Discussion erate fever, and erythematous exanthema spots on the body. Real-time polymerase chain reaction (PCR) for Zika virus The lethal forms of SD represent a group of genetic disorders could not be performed. that are clinically and genetically heterogeneous, and whose At 39 weeks and 3 days of gestational age, the patient cardinal manifestations are observed in the perinatal period delivered a singleton male live newborn with facial malforma- with severe and prominent phenotypic features. The major- tion and very short limbs. The Apgar score was 1 for the 1st ity of deaths result from respiratory insufficiency due to minute of life, and 0 for the 5th minute. The newborn died due to pulmonary hypoplasia, with 23% of stillbirths and 32% of cardiorespiratory arrest 15 minutes after birth. A post-mortem babies not surviving the first week of life.1,4 In a clinical examination of the baby was performed after we obtained the routine basis, the diagnosis of lethal SD occurs more fre- parents’ authorization, and it included skeletal X-ray scans. quently in the second trimester of gestation, through ultra- Genetic molecular tests were not performed (►Fig. 2). sound findings (85%) and changes related to bone mineral The anatomopathological study revealed a deformed ne- density, including pathological fractures, growth deficiency, onate boy measuring 38 cm (below the 3rd percentile) and rib abnormalities, bowing or shortening of the long bones, weighing 1,800 g (below the 3rd percentile), with extreme and abnormal skull ossification, can be observed.10 However, shortening of all members. The skull was very soft, with no the ultrasonography findings do not always point to a cranium ossification, and visualization of the meninges was specific SD, which may lead to an imprecise diagnosis, evident.