王若光教授专题之［出生缺陷］（28）Johanson-Blizzard综合征

病例来源：

2017-3-27

湖南生殖内分泌与产前诊断（三）群

谌根香 宜春市上高县人民医院：

下图为一男婴，第二胎，出生的时候评10分，约十分钟后评分就只有7-8分，不哭，肌张力稍差，儿科医生会诊后也建议到上级医院诊治，但患儿父母拒绝，出生24小时不到即死亡。母亲23岁，新疆少数民族，非近亲结婚，孕期未行任何产检。其第一胎为女婴，外观没有畸形，断脐后不久即死亡。请问各位老师，这种应该考虑是什么疾病？

王若光 若光医学中心

从这个图片看，胎儿鼻翼发育不良，小颌，其他资料不足。

鼻翼发育不良涉及近二十种综合征和几种序列征。通过分析，能够最大符合这个胎儿表型的考虑为：Johanson-Blizzard综合征。

这个病例建议取材胎儿组织进行基因检查确认为妥，对未来生育有帮助。

Johanson-Blizzard综合征

1

概述

Johanson-Blizzard综合征（JBS）属于消化系统的先天罕见疾病，有时会是致命的，属常染色体隐性遗传多系统疾病。其具有异常发育的胰腺，鼻畸形，鼻翼缺失，部分头皮缺损，智力发育迟滞，听力缺失，生长发育迟缓。有时被描述为外胚层发育不良。特别值得注意的是，严重胰腺发育异常和外分泌功能障碍，被认为是遗传性胰腺疾病。

2

特征

外分泌系

JBS最突出的影响是胰腺外分泌功能不全。脂肪酶分泌不同程度的减少，胰液如胰蛋白酶、胰蛋白酶原等，以及脂肪吸收不良，胰高血糖素分泌的中断以及其影响胰岛素活性引起的低血糖是诊断JBS的主要依据。主要与产前胰腺发育异常，受损细胞凋亡，慢性炎症损伤，胰腺腺泡的坏死和纤维化（胰腺外分泌腺组织，胰液分泌和相关酶发生）有关。已有报道JBS中的胰腺外分泌功能可以通过脂肪组织等替代。这是一个进步，但有些病例呈致命性结果。

内分泌系

JBS患者胰腺的内分泌功能不全不如外分泌功能不全普遍和影响明显。胰腺的内分泌功能包括释放胰高血糖素、生长抑素和胰岛素。胰腺的内分泌功能障碍常导致胰岛素抵抗及糖尿病，糖尿病被视为JBS的并发症。

JBS患者也存在一些其他的内分泌异常，如甲状腺功能减退，生长激素缺乏症和垂体机能减退。一些JBS患者发生垂体功能异常，包括发生神经胶质错构瘤，先天性垂体前叶发育不全。JBS患者生长迟缓及身材矮小（侏儒）可归因于垂体前叶功能下降引起的生长激素缺乏，脂肪吸收不良。

鼻

JBS患者的主要畸形是鼻腔发育不全（不发达）或“鼻翼”不发育（100%），即鼻子这一区域的结构性软骨和组织发育不全（部分或完全不存在）以及其下层的肌肉缺失，是疾病的主要特征。这些畸形使鼻子和鼻孔呈现出奇怪的形状和外观。鼻泪管表皮瘘（66%）。

Typical facial appearance of this patient with Johanson-Blizzard syndrome, showing aplasia of nasal alae, scalp defect, and sparse hair.（JBS患者典型的面部表现为鼻翼发育不全，头皮缺损，稀疏头发）

World J Gastroenterol. 2011 Oct 7; 17(37): 4247–4250.

神经系

大多数JBS患者存在从轻度到严重的智力发育迟滞（极严重者占67%），这与已知的涉及该疾病的诱变剂对发育过程中的中枢神经系统的影响有关。

听力

JBS患者存在内耳结构异常及双侧感觉神经性听力缺失。在耳蜗和前庭中形成囊性组织，导致这些微妙结构的扩张和畸形。颞骨先天性变形，对内耳的神经支配和发育产生了不良影响，也导致了这种类型的听力损失。

颅面

JBS患者可能会发生影响头皮、头部、脸部、颌骨和牙齿的其他异常。包括：外胚层中线头皮缺陷（后部更典型），头发稀疏，奇怪图案的毛发生长，前额部头发稀少并向上卷曲（96%），前部或头顶部头皮发育不全（不发达，非常薄的皮肤）（87%），大囟，突出的额头，眉毛和睫毛少，轻到中度小头畸形（50%），乳牙发育不良，恒齿缺如（90%）。

其他器官系统

肛门闭锁，膀胱输尿管返流，双子宫、阴道；新生儿胆汁淤积，肝硬化和门静脉高压；扩张型心肌病，右位心，房间隔和室间隔缺损；低出生体重；产后死亡；肌张力减退，骶骨间隙（骶椎结构缺陷）；先天性白内障；牛奶咖啡斑；第5指弯曲，通贯掌。

3

遗传

Johanson-Blizzard综合征，位于人15号染色体的UBR1基因突变引起的常染色体隐性遗传病。遗传模式：

4

病理生理

JBS是由UBR1基因突变引起的，UBR1基因编码N端规则通路的几种泛素连接酶之一。UBR1基因突变，破坏或阻止泛素连接酶的合成。在胰腺腺泡细胞，UBR1更高度比身体其他地方表达，是导致渐进炎性损伤，脂肪组织替代，结缔组织增生等的原因。这也适用于受到有害UBR1表达影响的其他区域，如颅面、肌肉骨骼和神经系统、牙列和器官。

错义、无义突变和剪接位点突变的UBR1在父母双方的基因已被发现与JBS关联。

5

治疗

有关胎儿抢救和治疗，主要是胰酶替代补充和手术矫形治疗。

可以参阅如下检索和文献：

World J Gastroenterol.2011 Oct 7;17(37):4247-50. doi: 10.3748/wjg.v17.i37.4247.（上文图片引自该文献）

Johanson–Blizzard syndrome

Congenital disorder of digestive system

（先天性消化系统病症）

The pancreas, and its location within the digestive system.

Classification and external resources

Specialty

medical genetics

ICD-10

Q45.0

ICD-9-CM

751.7

OMIM

243800

DiseasesDB

31914

Johanson–Blizzard syndrome (JBS) is a rare, sometimes fatal autosomalrecessive multisystem congenital disorder featuring abnormal development of the pancreas, nose and scalp, with mental retardation, hearing loss and growth failure.[1] It is sometimes described as a form of ectodermal dysplasia.[2]

The disorder is especially noted for causing profound developmental errors and exocrine dysfunction of the pancreas, and it is considered to be an inherited pancreatic disease.[3]

Characteristics

Exocrine

The most prominent effect of JBS is pancreatic exocrine insufficiency.[1][4][5][6][7] Varying degrees of decreased secretion of lipases, pancreatic juices such as trypsin, trypsinogen and others, as well as malabsorption of fats and disruptions of glucagon secretion and its response to hypoglycemia caused by insulin activity are major concerns when JBS is diagnosed.[1][3][8] Associated with developmental errors, impaired apoptosis, and both prenatal and chronic inflammatory damage, necrosis and fibrosis of the pancreatic acini (clusters of pancreatic exocrine gland tissue, where secretion of pancreatic juice and related enzymes occurs), pancreatic exocrine insufficiency in JBS can additionally stem from congenital replacement of the acini with fatty tissue.[1][3][8][9][10] Near total replacement of the entire pancreas with fatty tissue has also been reported. This is a progressive, sometimes fatal consequence of the disorder.[9]

Endocrine

Endocrine insufficiency of the pancreas occurs with JBS, though it is sometimes less common and less pronounced than the more prominent effects on exocrine function.[1] The islets of Langerhans are ducts in the pancreas where endocrine activity such as the release of hormones glucagon, somatostatin and insulin takes place. Pancreatic endocrine insufficiency in JBS can be associated with either a buildup of connective tissue in the islet regions, congenital replacement of the islets with fatty tissue, or improper nerve signalling to the islets.[1][5][8][11][12] Endocrine dysfunction of the pancreas often results in diabetes mellitus. Both insulin resistance and diabetes have been observed with JBS, and it is suggested that diabetes should be considered as a complication of JBS and its course.[5][11]

Ductular output of fluids and electrolytes is preserved in the pancreas of many with JBS, as well as moderate to normal levels of functioning bicarbonate.[1]

Endocrine abnormalities in other areas have also been present with the disorder. These include hypothyroidism,[2] growth hormone deficiency[1][8] and hypopituitarism.[1] Findings affecting pituitary function in some JBS patients have included such anomalies as the formation of a glial hamartoma (a neoplasm, or tumor composed of glial cells) on a lobe of the pituitary gland, as well congenital underdevelopment of the anterior pituitary.[13] Growth failure and associated short stature (dwarfism) in JBS can be attributed to growth hormone deficiency caused by diminished anterior pituitary function, with malabsorption of fats playing a subsequent role.[1][4][14]

Nasal

The primary malformation apparent with JBS is hypoplasia (underdevelopment) of the nasal alae, or "wing of the nose".[1][2][7]Both hypoplasia and aplasia (partial or complete absence) of structural cartilage and tissue in this area of the nose, along with the underlying alae nasi muscle, are prevailing features of the disorder. Together, these malformations give the nose and nostrils an odd shape and appearance.[7][15]

Neurological

Mental retardation ranging from mild to severe is present in the majority of JBS patients, and is related to the deleterious nature of the known mutagen responsible for the disorder and its effects on the developing central nervous system.[1][6][16]Normal intelligence and age appropriate social development, however, have been reported in a few instances of JBS.[12][16]

Auditory

Findings with the inner ear in JBS give explanation to the presence of bilateral sensorineural hearing loss in most patients affected by the disorder. The formation of cystic tissue in both the cochlea and vestibule, with resulting dilation (widening) and malformation of these delicate structures has been implicated.[7][9][17] Congenital deformations of the temporal bone and associated adverse anatomical effects on innervation and development of the inner ear also contribute to this type of hearing loss.[17][18]

Craniofacial

Other abnormalities, affecting the scalp, head, face, jaw and teeth may be found with JBS. These include: ectodermal mid-line scalp defects with sparse, oddly-patterned hair growth;[2][9] aplasia cutis (underdeveloped, very thin skin) over the head,[19] an enlarged fontanelle ("soft spot" on the head of young infants),[14] microcephaly (undersized skull),[19] prominentforehead,[14] absence of eyebrows and eyelashes,[14] mongoloidal eye shape,[17] nasolacrimo-cutaneous fistulae (this refers to the formation of an abnormal secondary passageway from either the tear duct or lacrimal sac to the facial skin surface, possibly discharging fluid),[9] flattened ears,[14] micrognathism of the maxilla and mandible (underdevelopment of the upper and lower jaw, respectively), with the maxilla more prominently affected in some cases;[14][20][21] congenital clefting of bonessurrounding the optical orbit (eye socket), such as the frontal and lacrimal bone;[20] and maldeveloped deciduous teeth ("baby teeth"), with an absence of permanent teeth.[9][14]

Effects on other organ systems

Additional congenital anomalies, effects on other organs, and less common features of JBS have included: imperforate anus(occlusion of the anus),[22] vesicoureteral reflux (reversal of the flow of urine, from the bladder back into the ureters, toward the kidneys);[14] duplex of the uterus and vagina in female infants,[7] neonatal cholestasis of the liver, with cirrhosis and portal hypertension (high blood pressure in the hepatic portal vein);[22] dilated cardiomyopathy,[23] dextrocardia (congenital displacement of the heart to the right side of the chest),[1] atrial and ventricular septal defect;[1] low birth-weight,[24] failure to thrive,[24] hypotonia (decreased muscle tone);[19] sacral hiatus (a structural deficiency of the sacral vertebrae),[24] congenital cataracts,[24] and cafe-au-lait spots.[2]

Genetics

Johanson-Blizzard syndrome has an autosomal recessive pattern of inheritance.

JBS is inherited in an autosomal recessive manner.[1] This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.

Pathophysiology

Johanson–Blizzard syndrome is caused by mutations in the UBR1 gene, which encodes one of several ubiquitin ligase enzymes of the N-end rule pathway.[1][6]

The protein ubiquitin is a universal, "ubiquitously" expressed protein common to eukaryotic organisms. Ubiquitin plays a role in the regulation of other proteins by tagging them for eventual degradation by proteasomes.[25] This process begins whenubiquitin ligase covalently attaches a ubiquitin molecule to the lysine side chain of the target protein substrate (the misfolded, damaged, malfunctioning or unneeded protein that needs to be degraded). This is repeated a number of times in succession forming a chain of ubiquitin molecules, which is a process referred to as polyubiquitination. The polyubiquitination of the target protein signals the proteasome to break it down, which it does via proteolysis.[25] The ubiquitin-proteasome system plays a crucial role in the non-lysosomal degradation of intracellular proteins, and ubiquitin can also participate in modifyingproteins to perform certain tasks.[25][26][27] Both degradation and modification of proteins within the cell are part of a broader regulatory scheme, necessary for cellular processes such as cell division, cell signalling, cell surface receptor function,apoptosis, DNA maintenance, inflammatory response and developmental quality control associated with the cell cycle andhomeostasis in general.[26][27]

Ubiquitin-mediated degradation of proteins occurs through the N-end rule pathway.[28][29] In eukaryotes, including humans, the N-end rule pathway is part of the ubiquitin system.[28] Composed of a highly selective single-residue code (a single amino acid nucleotide sequence), the N-end rule serves as a mechanism which can relate the stability of a protein to the identity of the amino acid at its N-terminus (the end of the polypeptide with an amino group, which in the ubiquitin system may be involved in the reactive destabilization of the protein).[28][29][30]

In JBS, mutations in the UBR1 gene alter, disrupt or prevent the synthesis of ubiquitin ligase.[1][6] In the pancreatic acinar cells,UBR1 is more highly expressed than anywhere else in the body.[1] Impairment of the ubiquitin-proteasome system directly related to insufficient activity of ubiquitin ligase has been established as the cause of both congenital and progressive inflammatory damage, fatty tissue replacement, connective tissue proliferation and errors in innervation of the acini and islets, correlating to failures of normal apoptotic destruction of damaged cells and constitutive malpresence of proteins.[1][3][6] This also applies to other areas affected by deleterious UBR1 expression, such as the craniofacial area, musculoskeletal and nervous systems, dentition and organs.[1][6][22]

Missense, nonsense and splice site mutations of the UBR1 gene in both parents have been found with JBS, confirming thehomozygous nature of the JBS phenotype. Variability of the phenotype, associated with residual ubiquitin ligase activity in some patients, has also been attributed to hypomorphic mutations occasionally found in either of the carrier parents.[1][3][6][22][23] The UBR1 gene is located on human chromosome 15.[6]

Treatment

While there is no cure for JBS, treatment and management of specific symptoms and features of the disorder are applied and can often be successful. Variability in the severity of JBS on a case-by-case basis determines the requirements and effectiveness of any treatment selected.

Pancreatic insufficiency and malabsorption can be managed with pancreatic enzyme replacement therapy, such aspancrelipase supplementation and other related methods.[1]

Craniofacial and skeletal deformities may require surgical correction, using techniques including bone grafts and osteotomyprocedures.[20] Sensorineural hearing loss can be managed with the use of hearing aids and educational services designated for the hearing impaired.[12][17]

Special education, specialized counseling methods and occupational therapy designed for those with mental retardation have proven to be effective, for both the patient and their families.[31] This, too, is carefully considered for JBS patients.

Eponym

Johanson–Blizzard syndrome was named after Ann J. Johanson and Robert M. Blizzard, the pediatricians who first described the disorder in a 1971 journal report.[15][32]