鄒冬華，邵　煜，張建華，萬(wàn)　雷，秦志強(qiáng)，劉寧國(guó)，黃　平，陳憶九（司法部司法鑒定科學(xué)技術(shù)研究所上海市法醫(yī)學(xué)重點(diǎn)實(shí)驗(yàn)室，上海200063）

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新生兒成骨不全Ⅱ型的尸檢和MSCT鑒定1例（英文）

鄒冬華，邵煜，張建華，萬(wàn)雷，秦志強(qiáng)，劉寧國(guó)，黃平，陳憶九
（司法部司法鑒定科學(xué)技術(shù)研究所上海市法醫(yī)學(xué)重點(diǎn)實(shí)驗(yàn)室，上海200063）

摘要：本文報(bào)道了1例成骨不全（osteogenesis imperfecta，OI）Ⅱ型死胎案例。在妊娠期間胎兒即有顱骨骨折和顱腦損傷。法醫(yī)尸體檢驗(yàn)后，隨即進(jìn)行尸體多層螺旋CT（multi-sliced computed tomography，MSCT）掃描和三維重建。尸檢結(jié)果顯示了OIⅡ型的典型特征，包括顱骨變軟、四肢畸形、髖關(guān)節(jié)彎曲和外展及一些異常特征如白色鞏膜、髖內(nèi)翻、部分骨骼和器官缺失、唇裂和兩耳不對(duì)稱。CT檢測(cè)到的異常變化有腭裂、下頜發(fā)育異常、脊柱裂、頸肋、肋骨和椎骨融合，這些都是在常規(guī)尸檢中難以檢測(cè)到的。本文闡述了OI的分類、致病性基因突變、死亡原因以及OI與兒童受虐的鑒別，更強(qiáng)調(diào)了OI學(xué)科知識(shí)對(duì)法醫(yī)病理學(xué)工作者的重要性和MSCT在法醫(yī)病理學(xué)尸體檢驗(yàn)中的價(jià)值。

關(guān)鍵詞：法醫(yī)病理學(xué)；成骨不全；致死性發(fā)育不良；體層攝影術(shù)，螺旋計(jì)算機(jī)；尸體檢驗(yàn)

Author: ZOU Dong-hua（1981—）, M.S. major in forensic pathology; E-mail: zoudh@ssfjd.cn

Introduction

Osteogenesis imperfecta（OI）, a genetic disorder of increased bone fragility and low bone mass, is generally classified into 4 types[1]. The lethal perinatal typeⅡOI being the most severe form. The clinical features of patients with the condition are characterized by such skeletal manifestations as multiple rib and long bone fractures at birth, soft calvarial bones, a narrow thorax, deformed extremities with a typical frog-like position, and extra-skeletal manifestations as dark or blue sclera. Usually, the patients die during the perinatal period because of respiratory failure resulting from multiple rib fractures, and they rarely survive beyond 1 year[2]. The origin of this lethal form is mainly associated with mutations in COL1A1 or COL1A2, or some other genes which could result in the absence of cartilage-associated protein（CRTAP）[3-6]. The prevalence of typeⅡOI is between 1:20000 and 1:60000[7]. When compared with other types, lethal typeⅡOI has been docu-mented by few reports from the perspective of forensic pathology. We herein report a case of a newborn with lethal perinatal typeⅡOI. The infant was confirmed to be a stillbirth. The conventional autopsy revealed special skeletal and organic anomalies in addition to typical features, while MSCT and 3D-reconstruction demonstrated other skeletal malformations which were difficult to observe at autopsy, thus indicating the advantages of MSCT and 3D-reconstruction in detecting lesions and deformation of bone.

Case report

A 30-year-old female had a natural delivery of a stillbirth with the assistance of an unlicensed midwife. The mother had neither medical record nor radiologic or genetic prenatal testing during pregnancy. According to the police investigation, family history of OI and other common genetic diseases and congenital malformations were disclaimed.

The male infant weighed 2 140 g, at a length of 50 cm and a head circumference of 36 cm. He had a small thoracic cage with a chest circumference of 28.5 cm, and an abdominal circumference of 23.5 cm（Fig. 1）. The estimated gestational age was approximately 39 weeks, as the mother reported.

The infant had a right cleft lip extending 2 cm up to the right side of the nose and 1.5 cm down to the palatum durum, forming a deformed right apertura narium. The infant was observed to have prominent asymmetric ears, with a lower right ear lateral to the mandibular angle（Fig. 2）.

At further external examination was visible a deformed craniofacial structure, including a relatively large cranium, a small, triangular face, and a broad forehead, and bulging occiput. On the right side the deformed extremities were characterized by the abducted, flexed and varus hip which formed a typical frog-like position（Fig. 3）. Beneath a 14 cm× 7 cm laceration in the parietal region of the head, the skull was noted to be fractured with thin, delicate margins. The sclera were white（Fig. 2）. A contusion on the asymmetric hip indicated a deformed pelvis and probable fractures. Moreover, the malformation of the upper and lower limbs on the right side was featured by a right wrist deformity, an absent right thumb and right hand thenar, together with dysplasia of the lower part of the right leg （the left leg much more thinner than the right leg）and right ankle joint hypermobility（Fig. 4）.

With such malformations revealed, we performed a whole body MSCT scan and 3D-reconstruction. The images confirmed a soft and fractured calvarium, a cleft palate on the right side, the absence of the right radial bone, first metacarpal bone of the right hand, and phalanx of the right thumb（Fig. 2 & 4）. No fracture was identified in the pelvis. The 3D-reconstruction also illustrated dysplasia of the mandible, with a cleft in the middle of the mandibular body, and several other anomalies such as the missing left 12th rib, but an additional left 7th costa cervicalis, and fusion of the right 2nd and 3rd ribs as well as the right 4th and 5th thoracic vertebrae. Additionally, the images detected spina bifida in the lumbar spine（Fig. 2 & 5）. All of the abnormalities would have been difficult to be demonstrated during conventional autopsy.

At the internal examination, no lesions were observed on or below the scalp, with no presentation of epidural or subdural hemorrhage. Severe calvarial dysplasia existed, as indicated by an extremely soft and non-mineralized membranous portion of the skull and multiple oval, worm-eaten defects in the right side of the frontal bone. Such defects were also observed on the right side of the parietal bone in association with the bone fractures with collapsed margins（Fig. 3）. The brain weighed 350g, with areas of autolysis: a 4 cm×2 cm cerebral hemorrhage in the left occipital lobe, and no structure but a mushy consistency in the right parietal lobe. A wrist bone malformation and an absent radial bone were noted under the soft tissue of the right forearm（Fig. 4）. Since the abnormalities of the facial bones and spine were clearly demonstrated by the MSCT images, as required by the mother, the torso’s face and back were not invasively examined.

The heart weighed 13g, the cavities filled with non-clotted blood. The existence was demonstrated of a patent ductus arteriosus, and membranous closure of the foramen ovale with small cracks. No detection was made of septal defect, and the right lung, pulmonary artery and kidney. As indicated by the hydrostatic test, also known as Raygat’s test, the left lung（Fig. 3C）, stomach, and bowel were confirmed to be negative.

At the histologic examination, the sections of the left lung demonstrated undulated alveoli, and unexpanded and partially collapsed bronchi.

In view of which, the cause of death was determined as lethal typeⅡOI. Unfortunately, no blood or tissue was persevered during autopsy and formalin-soaked tissue was failed in genetic testing.

Discussion

In the current case of lethal typeⅡOI, the proband exhibited typical characteristics of typeⅡOI, including bone fragility with intrauterine fractures, an extremely soft calvarium, micrognathia, a small chest, deformed extremities, flexed and abducted hips, and death at the time of birth. In addition to the typical clinical features, the infant presented such uncommon features as white sclera,coxa vara, together with absence of the radial bone, right thumb and right hand thenar. The right lung, pulmonary artery, and kidney were absent. Furthermore, the infant exhibited other malformations such as cleft lip and palate, mandibular dysplasia, asymmetric ears, and several anomalies and variations of the vertebrae and ribs, as in the case of spina bifida and bone fusion.

OI is a genetic disorder characterized by bone fragility and other connective tissue manifestations. The original Sillence classification of OI described 4 types; agenesis and disorder were considered to be caused by mutations in COL1A1 or COL1A2, with an autosomal dominant mode of transmission. In 2006, Barnes et al.[3]reported that mutations resulting in severe deficiency of CRTAP could cause recessive lethal typeⅡOI, and the study revealed that CRTAP acted as part of a collagen 3-hydroxylation complex and prolyl 3-hydroxylation of typeⅠcollagen, which was crucial for normal bone formation. A lack of prolyl 3-hydroxylation in other collagen types may affect the development of multiple organs, including the heart, kidney, and lung, in spite of few reports, which fits the features of the patient in the current case. Infants with CRTAP deficiency could present other distinct presentations as white sclera and coxa vara[5], which also matches the features of the current case. Regarding the patient’s malformations and variations of the lip, palate, nose, ears, mandible, ribs, and vertebrae, no direct linkage was demonstrated between the deformation and lethal typeⅡOI in the literature, but several reports have mentioned cleft palate or spina bifida in OI patients or in parents of the proband[8-10]. We theorize that patients with such genetic disorders as OI are probably susceptible to other types of dysplasia or malformations caused by genetic mutations. Unfortunately, no further genetic testing evidence is available to confirm whether the victim suffered from other genetic diseases.

The generally acknowledged mechanism of death in probands with lethal typeⅡOI is primarily respiratory failure due to multiple rib fractures at birth, followed by pulmonary insufficiency, congestive heart failure, or infection[2,11]. In the current case, the infant had a small chest, but with no rib fractures. Indeed, the case demonstrated an extremely soft, defective, and collapsed calvarium, which may have been caused by the crush injury during gestation and birth, resulting in craniocerebral injury and death. And the lacerations found during autopsy could also be consistent with maceration due to death in uterus before delivery.

The current case report deals with a stillbirth with OI. In reality, many such patients are born alive, but die in their early ages. Child abuse is another frequent cause of fractures, with the highest incidence in the first year of life[1]. For forensic pathologists, it can be difficult but crucial to distinguish OI from child abuse. It has proposed to help in the differential diagnosis to use the family history, clinical and pathological features, bone-mineral density examinations with X-ray or CT. In addition, genetic analysis can be of great help.

Postmortem MSCT is increasingly utilized for the diagnosis of trauma-based injuries and certain diseases in forensic medicine. The advantage of digital images from CT scans lies in two- and three-dimensional documentation and analysis of autopsy findings including fracture systems, pathologic gas collections, and gross tissue injury[12]. In the previous case report, we succeeded in detecting the acute pericardial tamponade caused by blunt trauma to the chest in a motor-vehicle collision using postmortem MSCT[13].

In conclusion, OI, a disorder of bone formation with several classification types and causative genetic mutations, is characterized by increased bone fragility with fractures and clinical features present in the calvarium, chest, hip, and extremities. Of the types, lethal typeⅡOI is the most severe form, which has been seldom reported based on forensic pathology. Thus, the current case report can provide forensic pathologists with a better understanding of lethal typeⅡOI. Infants with typeⅡOI not only manifest typical features such as soft calvarium with fractures, a small chest, short and curved extremities, and flexed and abducted hips, but also exhibit atypical and novel features as white sclera, coax vara, and the absence of organs. Patients with OI can also have other genetic disorders such as cleft palate and spina bifida, and variations as fusion of ribs and vertebrae. As a rare but relatively lethal disease, OI is of great significance for forensic pathologists to notice that its manifestations should not be mistaken with bone fractures due to child abuse. Postmortem MSCT and 3D-reconstruction can be more effective than the conventional autopsy in detecting skeletal anomalies in special locations, which are difficult to examine during autopsy; therefore they can be a promising technique in forensic pathologic examinations.

Acknowledgements

This study was funded by the 12th Five-year National Plan for Science and Technology （2012BAK16B02）, the Council of National Science Foundation of China（81571851, 81401559）, the Scientific and Technological Key Project of Shanghai Municipality（14231202500, 14DZ2271500）, and the Central Research Institute Public Project （GY2013Z-3, GY2014Z-1）.

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（Received date: 2015-01-08）

（Editor: LIANG Lu）

Determination of a Newborn with Lethal TypeⅡOsteogenesis Imperfecta and Other Anomalies Using Autopsy and Postmortem MSCT--A Case Report

ZOU Dong-hua, SHAO Yu, ZHANG Jian-hua, WAN Lei, QIN Zhi-qiang, LIU Ning-guo, HUANG Ping, CHEN Yi-jiu
（Shanghai Key Laboratory of Forensic Medicine, Institute of Forensic Science, Ministry of Justice, P.R.China, Shanghai 200063, China）

Abstract:A case of a stillbirth with lethal typeⅡosteogenesis imperfecta（OI）was reported. The fetus had skull fractures and craniocerebral injuries during pregnancy. Postmortem multi-sliced computed tomography（MSCT）and 3D-reconstruction were performed, followed by a medico-legal autopsy. The autopsic findings showed the typical features of typeⅡOI, including a soft calvarium, deformed extremities, flexed and abducted hips, and uncommon features, such as white sclera, coxa vara, absence of several bones and organs, a cleft lip, and asymmetric ears. The radiologic images revealed such anomalies and variations as a cleft palate, mandibular dysplasia, spina bifida, costa cervicalis, and fusion of the ribs and vertebrae, which were difficult to detect during conventional autopsy. The paper investigated the classification, causative mutation, cause of death, and the differentiation of OI from child abuse, coming to a conclusion that OI knowledge can be of great importance to forensic pathologists and that the merits of postmortem MSCT should be emphasized in forensic pathologic examinations.

Key words:forensic pathology; osteogenesis imperfecta; thanatophoric dysplasia; tomography, spiral computed; postmortem examination

Corresponding author:CHEN Yi-jiu, professor, major in forensic pathology; E-mail: chenyj@ssfjd.cn

文章編號(hào)：1004-5619（2016）01-0069-04

中圖分類號(hào)：DF795.4

文獻(xiàn)標(biāo)志碼：B

doi：10.3969/j.issn.1004-5619.2016.01.018