王若光教授专题之［出生缺陷］（29）前脑无裂序列征

病例来源：

2017-3-29

遗传诊断大师群（一）、遗传诊断大牛群（一）

孙维娜 济南红会医院：

各位老师，这是刚刚引产分娩的死胎，如图：

超声报告：

王若光 若光医学中心

这个病例是：前脑无裂序列征（Holoprosencephaly Sequence），（无嗅脑-猴头畸形-独眼：脊索前中胚层原发异常）。非常典型。

相关资料参考如下：

1

概述

前脑不能正常分裂形成两侧大脑半球，导致侧脑室和第三脑室融合，颜面和脑组织结构及功能缺陷。发病率约为胚胎中1:250，出生婴儿1:5000～10000。性别比：男:女=1:3（无分叶型）；男:女=1:1（分叶型）。病因见本文后面所述。非染色体异常所致的全前脑多为散发性，其再发生风险率约6%。

2

发育

在胚胎发育的第3周，脊索前中胚层向脊索前方移行是形态学上发生前脸或前脑的必要步骤。脊索前中胚层异常可导致不同程度的脸中线发育异常，尤其是中线鼻发育（切牙骨）和前脑的形态发育不全。

3

表型

前脑无裂畸形者大脑皮质发育差而常出现小头，但有脑积水时头可增大。由于大脑半球分不开，可形成一系列不同程度的面部中线结构畸形。

（一）独眼是早期脸中线发育严重异常的表现。眼融合，嗅觉基板融合成为管状象鼻样结构，位于眼的上方，筛骨等其他中线结构缺如。独眼畸形中，前脑分裂失败形成形态学上不完全的前脑。

（二）在畸形较轻的病例中，可表现为眼距过近和不同程度的中脸或前脑发育不全，通常含有唇、腭裂。

（三）中线器官发育不全，如器官距离过近、人中或鼻中隔缺如、单一中心门齿、先天性鼻梨形孔狭窄、上唇系带缺如等，提示存在严重脑发育不良或功能异常。

（四）根据大脑半球的分开程度，前脑无裂畸形有以下3种类型：

1）无叶全前脑：最严重，大脑半球完全融合未分开，大脑镰及半球裂隙缺失，仅单个原始脑室，丘脑融合成一个。

2）半叶全前脑：为一种中间类型，介于无叶全前脑和叶状全前脑之间。颞叶及枕叶有更多的大脑组织，大脑半球及侧脑室仅在后侧分开，前方仍相连，仍为单一侧脑室，丘脑常融合或不完全融合。

3）叶状全前脑：大脑半球及脑室均完全分开，大脑半球的前后裂隙发育尚好，丘脑亦分为左右各一，但仍有一定程度的结构融合，如透明隔消失。

4

超声诊断

无叶全前脑可根据单一侧脑室、丘脑融合、脑中线结构消失及长鼻、眼距过近或独眼等做出诊断。有报道经阴道超声在14孕周前可做出诊断。

半叶全前脑如能仔细检查，仔细辨认脑内结构和面部畸形，可于产前做出诊断。

叶状全前脑由于脑内结构异常及面部结构异常不明显，胎儿期很难被检出。

无叶全前脑

1）脑内结构紊乱：正常结构如侧脑室、丘脑，不能很好分辨，不能显示两个侧脑室、两侧丘脑，仅可见一个较大的原始脑室，中央见单一丘脑回声结构，呈融合状。脑中线结构消失，如脑中线回声消失，透明隔腔及第三脑室消失。胼胝体消失，脑组织变薄。

2）面部结构严重异常：可出现长鼻畸形或象鼻畸形，单眼眶或眼眶缺失，单眼球，中央唇裂。

3）早孕期表现：早孕期不能显示大脑镰，胎头呈“气球样”。

半叶全前脑

1）前部为单一脑室腔且明显增大，后部可分开为两个脑室，丘脑融合，枕后叶部分形成。

2）颅后窝内囊性肿物，多为增大的第四脑室或颅后窝池。

3）可合并Dandy-Walker畸形。

4）眼眶及眼距可正常，扁平鼻。也可合并有严重面部畸形，如猴头畸形、单鼻孔畸形等。

叶状全前脑

1）胎儿期超声诊断困难，不易识别。

2）透明隔腔消失时应想到本病可能，可伴有胼胝体发育不全，冠状切面上侧脑室前角可在中线处相互连通。

3）面部结构一般正常。

5

病因

多数病例均为散发，原因不明。

现认为前脑无裂畸形是遗传与环境多因素综合作用的结果。

严重的染色体结构异常包括del 2p21、dup 3pter、del 7q36、del 13q、de1 18p和del 21q22.3均需考虑可能为本病的病因。

此外，一些导致本病相关的突变基因已得到证实，如一些常染色体显性遗传畸形中，最多见的是7q36位点的Shh基因突变的结果。其他基因如位于13q32的ZIC2、2q21的SIX3和18pl1.3的tgif等基因突变与散发及家族病例有关。其他一些与脑发育相关的重要信号传导通路基因如PATCHED1(ptch)和GLI2，与Shh信号及与转化生长因子(TGF-β)通路有关的TDGF1和FAST1突变，也与本病有关。

应检查患儿的父母是否存在单一门齿、上唇系带缺如和鼻软骨缺如。

此外，患糖尿病的母亲或患Meckel-Gruber综合征的女患者可能生育前脑无裂的胎儿。

前脑无裂畸形可见于如下综合征：

13三体综合征、18三体综合征、l8p缺失综合征、1lq缺失综合征、13q缺失综合征、22q 11.2缺失综合征、缺指（趾）-外胚层发育不良-唇楞裂综合征、胎儿乙内酰脲综合征、同卵双生及结构畸形、Pallister-Hall综合征、Smith-Lemli-Opitz综合征、三倍体综合征。

（点击上图可以放大查看）

6

预后

无叶全前脑和半叶全前脑常为致死性的，出生后不久即夭折。而叶状全前脑可存活，但常伴有脑发育迟缓，智力低下。

由于此类畸形患者的中枢神经系统功能预后很差，建议对确诊为严重前脑发育异常的存活者慎用超出常规的支持治疗。

检索文献：

Cyclopia，Holoprosencephaly，Holoprosencephaly Sequence

Cyclopia

This article is about the congenital disorder. For other uses, see Cyclopia (disambiguation).

Cyclopia (also cyclocephaly or synophthalmia) is a rare form of holoprosencephaly and is a congenital disorder (birth defect) characterized by the failure of the embryonic prosencephalon to properly divide the orbits of the eye into two cavities. Its incidence is 1 in 16,000 in born animals and 1 in 200 in miscarried fetuses.[1][2]

Presentation

Typically, the nose is either missing or replaced with a non-functioning nose in the form of a proboscis. Such a proboscis generally appears above the central eye, or on the back, and is characteristic of a form of cyclopia called rhinencephaly orrhinocephaly.[3] Most such embryos are either naturally aborted or are stillborn upon delivery.

Although cyclopia is rare, several cyclopic human babies are preserved in medical museums (e.g. The Vrolik Museum, Amsterdam).[4]

Some extreme cases of cyclopia have been documented in farm animals (horses, sheep, pigs, and sometimes chickens). In such cases, the nose and mouth fail to form, or the nose grows from the roof of the mouth obstructing airflow, resulting in suffocation shortly after birth.[5]

Causes

Genetic defects or toxins can misdirect the embryonic forebrain-dividing process.[6] One highly teratogenic alkaloid toxin that can cause cyclopia is cyclopamine or 2-deoxyjervine, found in the plant Veratrum californicum (also known as corn lily or false hellebore). Grazing animals are most likely to ingest this plant and induce cyclopia in offspring. The mistake of humans ingesting Veratrum californicum while pregnant is often due to hellebore, an unrelated plant with the same name, being recommended as a "natural" treatment for vomiting, cramps, and poor circulation, three conditions which may be present in the early stages of pregnancy. [7] Cyclopia occurs when certain proteins are inappropriately expressed,[8] causing the brain to stay whole, rather than developing two distinct hemispheres. This leads to the fetus having one optic lobe and one olfactory lobe, resulting in the eye and nose malformations of cyclopia.[9]

The sonic hedgehog (SHH) gene regulator is involved in the separation of the single eye field into two bilateral fields. Although not proven, it is thought that SHH emitted from the prechordal plate suppresses Pax6, which causes the eye field to divide into two. If the SHH gene is mutated, the result is cyclopia, a single eye in the center of the face (Gilbert, 2000).

Notable cases

§  A British description from 1665 of a colt apparently suffering from cyclopia reads:

First, That it had no sign of any Nose in the usual place, nor had it any, in any other place of the Head, unless the double Bagg CC that grew out of the midst of the forehead, were some rudiment of it. Next, That the two Eyes were united into one Double Eye which was placed just in the middle of the Brow.[10]

§  On 1 March 1793 a 46-year-old woman in Boalts Torp, Glimåkra, Sweden gave birth to a child with cyclopia that died after 2 hours. The child was 35 cm long, its face without nose and nostrils, the lidless eye with no eyebrow sat raised on the middle of the forehead like a large blueberry. The wrists were somewhat crooked as well as the right foot which was completely crooked and bent inwards. It was not clear whether it was a boy or a girl but it was believed to be the former.[11]

A Swedish description from 1793 of a newborn with cyclopia

§  On December 28, 2005, a kitten with cyclopia, "Cy", was born in Redmond, Oregon,United States and died about one day after birth.[12]

§  In 2006, a baby girl in India with cyclopia was born. Her only eye was in the center of her forehead. She did not have a nose and her brain was fused into a single hemisphere.[13]The child died one day after her birth.[14]

§  In 2011 a cyclops shark fetus was discovered in the body of a caught shark in Mexico, with no discernible nose and one giant eye. The unborn fetus was turned over for medical studies.[15]

§  On October 10, 2012, a small kitten was born. Its eye was in the center of the forehead and there was no developed nose to be found. The small cat died shortly after it was born. It was nicknamed Cleyed the Cyclops.[16]