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糖尿病相关新生儿畸形

<font size="5">Diabetic fetopathy associated with bilateral adrenal hyperplasia and
ambiguous genitalia: a case report</font size>
Patou Tantbirojn*1, Mana Taweevisit2, Suchila Sritippayawan1 and
Boonchai Uerpairojkit1
Address: 1Department of Obstetrics and Gynecology Faculty of Medicine, Chulalongkorn University, Rama IV road, Bangkok 10330, Thailand and
2Department of Pathology, Faculty of Medicine, Chulalongkorn University, Rama IV road, Bangkok 10330, Thailand
Email: Patou Tantbirojn* - two_devil@hotmail.com; Mana Taweevisit - dr.mana4@gmail.com;
Suchila Sritippayawan - suchilaob@hotmail.com; Boonchai Uerpairojkit - boonchaiu@hotmail.com
* Corresponding author   
Journal of Medical Case Reports 2008, 2:251 doi:10.1186/1752-1947-2-251

[[i] 本帖最后由 宇宙的琴弦 于 2008-8-23 11:25 编辑 [/i]]

可惜没看到中文..........

楼主把你翻译的也贴上吧...

Case presentation
A 19-year-old Thai primipara presented at our outpatient
department for routine antenatal care at 18 weeks gesta-
tion. She had no history of any underlying disease and
denied family history of genetic abnormality or congeni-
tal adrenal hyperplasia. Her mother had a history of dia-
betes mellitus (DM), unknown type. Her 14-year-old
brother also had a history of DM type 1 and was treated
with insulin injections. However, the woman had never
been tested for diabetes. 50 g glucose challenge test was
performed at the first antenatal visit due to her family his-
tory of diabetes, showing 234 mg/dl, thus a 100 g oral glu-
cose tolerance test was done. The result were 118, 227,
234 and 173 mg/dl at fasting, 1 hour, 2 hours and 3 hours
post 100 g glucose ingestion, respectively. Gestational DM
type 2 was diagnosed and the woman was treated with
insulin injections. She had poor compliance with the
treatment and had rather poor diabetic control. HbA1C
level was high and the patient refused to be admitted as an
inpatient to control her diabetes. Targeted ultrasono-
graphic examination was postponed several times due to
poor compliance and was finally carried out at 28 weeks
gestation, revealing a single viable fetus in unstable lie
with polyhydramnios and multiple fetal anomalies, con-
sisting of holoprosencephaly, hypotelorism, median cleft
lip and polydactyly of the right hand. Prenatal chromo-
somal testing was offered, but the woman refused and
counseling of the fetal prognosis was subsequently pro-
vided to the couple. Low transverse cesarean section was
performed at 30 weeks of gestation due to fetal transverse
lie when she had preterm labor. The newborn with ambig-
uous genitalia was delivered with Apgar scores at 1 and 5
minutes of 4 and 3 respectively and was handed to the
waiting neonatologist in the operative room. The new-
born finally expired due to respiratory failure eighteen
minutes after birth. The subsequent fetal chromosomal
study revealed 46,XX.

An autopsy was performed four hours after death, show-
ing an ambiguous sex infant weighing 1,720 grams and
measuring 38 cm in length. The head, chest and abdomi-
nal circumference were 40, 20 and 20 cm respectively.
Multiple facial anomalies were seen, consisting of a prom-
inent forehead, hypotelorism, an absent nose, absent
bilateral ears, and a median cleft lip and palate. Preaxial
polydactyly of the right hand (figure 1A) and ambiguous
external genitalia, with clitoral hypertrophy and hyperpig-
mentation (figure 1B), were observed. On examination of
the internal organs, the uterus and both ovaries were in
the normal anatomical position. There were two small
accessory spleens identified at the splenic hilum. Mark-
edly enlarged adrenal glands were seen (figure 1C) and
serial sectioning revealed a homogenous tan-brown cut
surface. The other internal organs were unremarkable.
Examination of the brain revealed a single dilated ven-
tricular cavity with no falx, corpus callosum or interhemi-
spheric fissure (figure 2) and hydrocephalus with
cerebrospinal fluid of 200 ml. Examination of the pla-
centa and umbilical cord revealed only a single umbilical
artery with no other significant abnormality.

病例
患者儿母亲19岁，初次生育，妊娠18周时入院接受常规产前护理，没有基础病史，否认家族遗传病史以及先天性肾上腺增生症，其母患有糖尿病（类型不详），其14岁兄弟患1型糖尿病并接受胰岛素治疗，但她本人从未接受糖尿病筛查。该孕妇第1次入院产前护理时接受了50g葡萄糖耐量试验，血糖峰值高达234mg/dl，于是再次进行了100g OGTT试验，空腹、餐后1h、2h和3h血糖分别为118、227、234和173mg/dl。在确诊为T2DM、妊娠糖尿病后，患者开始接受胰岛素注射治疗。该孕妇治疗顺应性极差，血糖控制很不理想，虽然HbA1c较高但拒绝接受住院治疗糖尿病。由于患者血糖控制不佳，定向超声检查数次延搁，最终患者妊娠28周，超声检查发现一存活胎儿，但羊水过多且严重畸形，包括前脑无裂、眼距过窄、唇正中裂和右手多指。孕妇拒绝了产前染色体检查，并对新生儿诊断进行了咨询。妊娠30周，胎儿横位且孕妇出现早产迹像，低位横切口剖宫产出一双性婴儿。出生第1和第5分钟Apgar评分分别为4分和3分，手术中立即转交新生儿专家。出生后第18分钟，新生儿因呼吸衰竭死亡，染色体检查为46，XX。
患儿死亡后4小时进行了病理检查：患者双性，体重1,720g，身长38cm。头、胸和腹围分别为40、20和20cm。面部多处异常，包括前额突出、眼距过低、鼻缺如、双耳缺如以及唇、腭正中裂。此外可见右手轴前多指畸形、双性别外生殖器以及阴蒂增生、色素沉着。内脏检查发现，子宫与卵巢解剖位置正常，脾门内可见两个副脾，肾上腺异常增生，切面呈均质棕红色。其他内脏未见明显异常。脑检查发现脑室扩张，镰、胼胝体和半球间裂缺如，脑水肿，脑脊液200ml。胎盘及脐带检查发现单行脐动脉，其余未见明显异常。

Discussion
Malformations in infants of diabetic mothers are well
known. Infants born to insulin-dependent diabetic moth-
ers have a 2- to 3-fold increased risk of congenital malfor-
mations and spontaneous abortion. The prevalence of
major congenital malformations in the offspring of
affected women is approximately 4–8%. The exact ter-
atogenic mechanism of this malformation is unknown.
On the basis of a recent animal study by Loeken,
increased glucose delivery to embryos results in activation
of pathways that are stimulated by high glucose, such as
the hexosamine biosynthetic pathway, or hypoxia; there-
fore, oxidative stress in embryos is increased. Because oxi-
dative stress may impair embryo gene expression and
consequent apoptosis, or disturb organogenesis, fetal
malformation eventually occurs.
The most frequently noted malformations are anomalies
of the cardiovascular, genitourinary and central nervous
system. In addition, infants with caudal dysplasia, femo-
ral hypoplasia and unusual facial features are born more
frequently to diabetic mothers .
Multiple anomalies were identified in this case. Alobar
holoprosencephaly with midline facial defects (hypo-
telorism, arhinia, median cleft lip and palate) and bilat-
eral auricular atresia are compatible with diabetic
fetopathy. Interestingly, preaxial polydactyly or hallucal
polydactyly is also observed in this case. This condition
was reported by some authors as a distinctive anomaly in
diabetic embryopathy and might be a useful clinical
marker for the diagnosis of diabetic embryopathy .
We also identified other unusual associated anomalies in
this case, such as accessory spleens and a single umbilical
artery. However, the most striking associated anomaly
was bilateral adrenal hyperplasia with virilization of
female external genitalia.
Congenital adrenal hyperplasia is the most common
genetic cause of ambiguous genitalia in female newborns.
Other causes of fetal female virilization during pregnancy
include maternal progesterone, androgen or androgenic
drug administration, and androgen production by mater-
nal adrenal or ovarian tumors. As these factors were not
identified in this case, and given the additional finding of
markedly enlarged adrenal glands, adrenal hyperplasia
was most likely to be the cause of the ambiguous genita-
lia.
In general, congenital adrenal hyperplasia is an autosomal
recessive disease, caused by one of five different enzymatic
defects in cortisol biosynthesis from cholesterol. Clinical
manifestations are related to the degree of cortisol defi-
ciency or aldosterone deficiency or a deficiency of both.
Deficiency of 21-hydroxylase enzyme accounts for more
than 90% of cases . Androgen levels are increased and
manifested in the female as clitoral hypertrophy, labial
fusion, and sometimes scrotalization of the labia majora.
Unfortunately, the investigation of specific precursor
metabolites was not performed in this case, so the definite
type of adrenal hyperplasia was unknown. Further genetic
studies to identify specific gene mutations such as CYP21
(6q21.3) or CYP11B1 (8q24) loci may have a role, but it
is not generally available. It is well documented that con-
genital hyperplasia may be the cause of hyperglycemia or
diabetes , but hyperglycemia cannot explain the
pathogenesis of adrenal hyperplasia in this case. It is con-
troversial whether adrenal hyperplasia can be a novel fea-
ture of diabetic fetopathy or just a coincidental finding.
Further observation and investigation are needed in such
cases.
Conclusion
We describe a case of diabetic fetopathy with classic facial
malformation and preaxial hallucal polydactyly which
has been proposed as a marker of diabetic embryopathy.
Adrenal hyperplasia with ambiguous genitalia was also
identified as an uncommon associated anomaly at
autopsy.

[[i] 本帖最后由 宇宙的琴弦 于 2008-8-23 12:13 编辑 [/i]]

讨论
众所周知，糖尿病母亲易产出畸形婴儿，胰岛素依赖可使糖尿病孕妇产出婴儿先天畸形或自然流产的危险提高2~3倍。糖尿病女性的后代先天畸形发病率约为4~8%，这种情况的致畸机制至今不详。Loeken进行的一项动物试验研究认为，向胚胎辅送过高的葡萄糖会导致相应的信号通路被激活，例如己糖胺合成途径，或者因缺氧导致胚胎内氧化应激反应升高。氧化应激可以损伤胚胎的基因表达，引起细胞凋亡或干扰器官发育，最终导致新生儿畸形。
最常见的畸形包括心血管、泌尿生殖器和中枢神经系统异常。此外，糖尿病母亲生育的婴儿好发尾部畸形、股骨发育不良以及少见的面部畸形。
本例患儿呈现多种畸形，面正中线缺陷（眼距过低、无鼻、唇与腭正中裂）合并无脑叶畸形与双耳廓闭锁符合糖尿病新生儿病变。值得一提的是，本病例还出现了轴前多指畸形，或称拇指畸形，这种情况可见于一些作者报道的罕见糖尿病胚胎发育畸形病例，也可以作为糖尿病胚胎发育畸形的诊断依据。本病例还包括罕见的相关畸形，如副脾和单脐动脉，但最突出的是双侧肾上腺增生和女性外生殖器男性化。
先天性肾上腺增生是最常见的导致女婴双性畸形的遗传学病因，其他导致女婴男性化的病因包括孕妇妊娠期间使用孕酮、雄激素或雄激素类药物，以及可以产生雄激素的肾上腺或卵巢肿瘤。由于本病例未找到其他因素，而病理检查中发现了增大的肾上腺，因此肾上腺增生最有可能是本例患儿双性畸形的原因。
一般说来，先天性肾上腺增生是常染色体隐性遗传病，由5种催化胆固醇合成糖皮质激素中的1种酶缺陷引起，其临床表现与糖皮质激素缺乏、酮固醇缺乏或二者同时缺乏有关，90%的病例为21-羟化酶缺乏。雄激素升高可以造成阴蒂增生、阴唇融合，有时甚至是大阴唇阴茎化。不幸地是，本例患儿诊断过程中并未发现特异性前驱标志物，因此肾上腺增生的确切类型不能确定。进一步的遗传学检查发现了一些基因变异位点，例如CYP21(6q21.3)或CYP11B1(8q24)，这些基因可能起重要作用但不普遍。有确凿的证据表明高血糖或糖尿病可以引起先天性增生，但无法解释本例患儿肾上腺增生的病理机制。肾上腺增生是糖尿病新生儿病变的一大特征还是偶见合并症还存在争议，未来还需在此类疾病中还要继续观察并研究。