提示性发现

具有以下实验室和X线特点的个体应该怀疑是否为永久性新生儿糖尿病（PNDM）：

实验室特点

• 小于6个月的婴儿的持续性高血糖（血浆葡萄糖水平>150-200 mg/dL）
• 典型的糖尿病症状（如，糖尿、酮尿、高酮血症）
• 相对于高血糖水平而言低水平的或检测不到的血浆胰岛素和C-肽
• 胰腺不发育或发育不全的婴儿表现出的粪便弹性蛋白酶水平低、高脂肪

注：检测糖化血红蛋白A1c水平对小于6个月的婴儿的糖尿病诊断是不适用的，因为相对血红蛋白A，胎儿血红蛋白的比例更高。

X线特点

• 通过超声、CT或MRI检查可识别胰腺发育不全
  注：新生儿的胰腺影像可能很难看到；胰腺功能不全的生化检测结果（如，低粪便弹性蛋白酶、高粪便脂肪）可能对于诊断这些婴儿有所帮助。

确诊

如果在婴儿出生6个月内诊断的糖尿病不能随时间缓解，则可确诊PNDM。推荐进行分子检测：确定是否为如 表1所列出的可以指导治疗的致病性变异（见管理）。

分子遗传学诊断包括一系列的单基因检测、应用多基因组套以及更全面的基因组检测。

一系列单基因检测

• 父母之一为糖尿病的患者：
  • 首先进行KCNJ11 基因的序列分析。
  • 如果没有找到KCNJ11的致病性变异，进行ABCC8和INS基因的序列分析。
• 父母双发均为糖尿病的患者：GCK和PDX1基因的序列分析
• 没有糖尿病家族史的患者：
  • 首先进行ABCC8和KCNJ11基因的序列分析（因为找到致病性变异可能改变治疗）。
  • 如果没有找到致病性变异，进行GCK和INS基因的序列分析。
• 如患者有胰腺的功能障碍或不发育，且不伴有胰腺外畸形：
  • 首先进行PDX1 基因的序列分析。
  • 如果没有找到致病性变异，考虑进行PTF1A基因的序列分析 [Houghton 等 2016]。
• 综合征型的PNDM患者：根据胰腺外的特征知道基因检测（见遗传相关疾病和鉴别诊断）。

注：   在序列分析结果为阴性时，应考虑对GCK、INS、PDX1和PTF1A基因（以及综合征型PNDM相关的基因）进行缺失/重复分析，因为这些基因的纯合型缺失与永久性新生儿糖尿病相关。

多基因组套包含了ABCC8、GCK、INS、KCNJ11、PDX1与其他相关基因（见鉴别诊断） 也可被考虑。注：（1）多基因组套包含的基因及检测的敏感性因实验室和检测时间而不同。（2）一些多基因组套中可能包含与GeneReview中讨论的情 况不相关的基因；因此，临床医生需要确定哪些多基因组套为找到致病基因提供了最好的机会，同时花费最为合适且间接发现少。（3）组套使用的方法包括序列分 析、缺失/重复分析和/或其他基于序列的检测。

更全面的基因组检测（如 可获得）包括全外显子组测序（WES）与全基因组测序（WGS）可供考虑，当系列单基因检测（和/或使用了包含ABCC8、GCK、INS、KCNJ11 和PDX1的多基因组套）不能够确认一个表现为PNDM特点的患者的诊断时。这种检测可能提供或提示之前没有考虑过的诊断（如，一个或多个不同基因的突变 导致类似的临床表现）。有关基因组检测结果的解读问题，点击此处。

临床描述

永久性新生儿糖尿病 (PNDM)以在出生后6个月内发生高血糖为特征，平均诊断年龄为7周（范围：出生至26周）[Gloyn 等 2004b]。

这种糖尿病伴有部分的或完全的胰岛素缺乏。

诊断时的临床表现可包括宫内 生长延迟（IUGR；反映了宫内的胰岛素缺乏）、高血糖、糖尿、渗透性多尿、严重脱水、生长发育停滞。

胰岛素治疗可纠正高血糖并可迅速促进生长。

基因-表型相关性

PNDM的病程因基因型不同而有高度的变异性。

ABCC8和KCNJ11.多数患有因ABCC8和KCNJ11基因的致病性变异导致的PNDM患者在3个月龄内即会被诊断，但有一小部分是在儿童期或成年早期被发现的。大多数患病的婴儿由于胎儿胰岛素产生较少导致出生体重较低。典型的表现是有症状的高血糖，以及在很多患者中发生的酮症酸中毒。

尽管多数因KCNJ11基因的致病性变异携带导致的患者都仅患有糖尿病，20%仍会伴有神经系统的特点，即DEND综合征（发育迟缓、癫痫和新生儿糖尿病）[Hattersley et al 2006]。一种较轻微的类型，称为中间型DEND综合征，表现为较轻的发育延迟并不伴有癫痫。对于携带KCNJ11基因致病性变异的患者，使用磺脲类药物可纠正高血糖[Pearson 等 2006]以及可能逆转部分神经系统的症状[Hattersley & Ashcroft 2005, Slingerland 等 2006]。通过使用这些药物进行早期治疗可能预防神经系统的症状[Greeley 等 2010] (见管理)。

GCK. 因双等位基因的GCK致病性变异携带所导致的PNDM具有IUGR的特点， 从出生后第一天开始即需要胰岛素治疗，并且父母双方都有高血糖。

INS. 因INS致病性变异杂合性携带或者INS基因双基因缺失导致的PNDM表现为糖尿病酮症酸中毒或显著的高血糖。多数新生儿胎龄较小[Støy 等 2007, Polak 等 2008]。诊断年龄的中位数为9周，但部分孩子在6个月后发病[Edghill 等 2008]。

PDX1. 因PDX1双等位基因致病性变异导致的胰腺发育不良可导致比ABCC8、GCK或KCNJ11相关的新生儿糖尿病更为严重的胰岛素缺乏，因而会具有较低的出生体重与诊断年龄。这些患者也具有胰腺外分泌功能不全。

基因型-表型相关性

ABCC8. 对于因ABCC8致病性变异导致的新生儿糖尿病，基因型-表型相关性并不很明显[Edghill et al 2010]。与显性的ABCC8致病性变异相关的新生儿糖尿病可能有一位亲代是携带同一ABCC8基因变异并患有2型糖尿病的，提示携带ABCC8致病性变异的患者其表型的严重性与发生糖尿病的年龄是各异的[Babenko et al 2006]。

INS. 基因型与表型的相关性开始出现于由 INS致病性变异导致的NDM中。INS致病性变异纯合或复合杂合携带者的糖尿病可能是永久性的或是暂时性的。变异c.-366_343del, c.3G>A, c.3G>T, c.184C>T, c.-370-?186+?del (一个646-bp的缺失) 以及 c.*59A>G 表现为PNDM，而变异c.-218A>C 和 c.-331C>A 或 c.-331C>G h在PNDM、TNDM、1b型糖尿病中都有报道[Støy 等 2010]。

KCNJ11. KCNJ11致病性变异相关的PNDM类型存在明确的基因型-表型相关性。

基因型-表型研究将KCNJ11的致病性变异与KATP通道对于ATP的敏感性降低程度相关联起来。

部分KCNJ11致病性变异与暂时性新生儿糖尿病（TNDM）相关；另一些与PNDM相关；两个变异，p.Val252Ala与p.Arg201His，与二者均有相关性[Colombo 等 2005, Girard 等 2006]。此外，功能性研究显示TNDM和PNDM相关的致病性变异的KATP通道电流量级存在部分重合[Girard 等 2006]。

KCNJ11致病性变异的位置看似可以预测疾病的严重性（单纯性的糖尿病、中间型的DEND综合征、DEND综合征），然而，也存在部分例外。定位于推定的ATP结合区域(Arg50, Ile192, Leu164, Arg201, Phe333)或定位于Kir6.2亚基的交界面 (Phe35, Cys42, and Gu332)或在Kir6.2与SUR1 (Gly53) 之间的致病性变异与单纯性的糖尿病相关。见分子遗传学，KCNJ11，正常基因产物中关于Kir6.2和ABCC8, Sur1的正常基因产物的讨论。

PNDM的严重程度与基因型相关表现为单纯性的糖尿病 、中间型的DEND综合征、DEND综合征[Proks 等 2004]。导致额外的神经系统特征的KCNJ11基因变异 (Gln52, Gly53, Val59, Cys166, and Ile296)定位于与ATP结合部位有一定距离的氨基酸残基的密码子 [Hattersley & Ashcroft 2005]。

• 在24名精氨酸残基Arg201发生致病性突变的个体中，除了3个人以外的其余人都是单纯性的PNDM。
• 变异p.Val59Met与中间型的DEND综合征相关。
• 以下与DEND综合征相关的致病性变异未见于症状较轻的患者：p.Gln52Arg, p.Val59Gly, p.Ile296Val, p.Cys166Phe [Gloyn 等 2006], p.Gly334Asp [Masia et al 2007b], p.Ile167Leu [Shimomura 等 2007], p.Gly53Asp, p.Cys166Tyr, 和 p.Ile296Leu [Flanagan 等 2006]。
• 磺脲类药物对于DEND综合征神经症状的改善作用看似是受到基因型影响的：携带变异p.Val59Met [Støy 等 2008, Mohamadi 等 2010]和p.Gly53Asp [Koster 等 2008]的儿童磺脲类治疗有效。

外显率

因KCNJ11与ABCC8致病性变异导致的PNDM被发现外显率降低[Flanagan 等 2007]。

系统命名法

一些患有“新生儿”糖尿病的患者可能直到3-6个月时才被诊断，因此曾有建议使用“婴儿糖尿病”或“先天性糖尿病”的名称取代“新生儿糖尿病”的说法[Massa 等 2005, Greeley 等 2011]。

患病率

永久性新生儿糖尿病估计的发病率为1:215,000到1:260,000活产儿[Stanik 等 2007, Slingerland 等 2009, Wiedemann 等 2010]。

首次诊断后的评估

对已诊断的因ABCC8 或 KCNJ11基因致病性变异导致的新生儿糖尿病的个体中应明确疾病的程度和需求，应当进行全面的神经系统评估。

对携带怀疑或者已确定的PDX1致病性变异的个体应明确疾病的程度，应当进行胰腺的影像学检查与胰腺外分泌功能的评估（粪便的弹性蛋白酶、血清中脂溶性维生素的浓度）。

应该在PNDM评估的早期与临床遗传学家和/或遗传咨询师进行探讨。

对症治疗

初始治疗. 水化和静脉输注胰岛素在诊断后应当立即开始，尤其是当婴儿伴有酮症酸中毒时。

长期医疗管理. 当婴儿情况已经稳定并可以耐受经口喂养时，应当确立一个适当的皮下胰岛素注射策略。几乎没有关于幼年婴儿最适用的胰岛素制剂的数据。

• 中效胰岛素制剂 (中效低精蛋白胰岛素 [NPH])在婴儿有作用时程更短的倾向，有可能是因为更小的剂量或更大的皮下血流量。
• 没有显著的作用高峰的长效胰岛素制剂 如Lantus® (甘精胰岛素)或Levemir® (地特胰岛素)对于小婴儿的作用可能更好。
• 对于胰岛素需求量非常小的个体，在谨慎使用的前提下稀释胰岛素(5 or 10 U/mL)可能更为恰当。
• 部分中心推荐为幼小的婴儿使用持续性的皮下胰岛素输注[Polak & Cave 2007]作为一个更安全、更符合生理特点且更准确的胰岛素给药方式。
• 小心：
  • 总体而言，速效的胰岛素制剂(lispro与aspart) 和短效的胰岛素制剂(regular)应避免使用(除非作为持续性静脉或皮下输注)，因为它们可能会导致严重低血糖事件。
  • 当使用稀释的胰岛素制剂时，应当非常小心以避免剂量的错误。

明确一个KCNJ11或ABCC8基因的致病性变异对于临床治疗是很重要的，因为多数携带这些致病性变异的个体是可以被口服磺脲类药物治疗的。携带KCNJ11或ABCC8基因的致病性变异的儿童可以被转为使用口服磺脲类药物治疗；通常需要较高剂量（格列本脲 0.4-1.0 mg/kg/天）。方法转换可在www.diabetesgenes.org获取。使用磺脲类治疗可以改善血糖控制[Hattersley & Ashcroft 2005, Pearson 等 2006, Thurber 等 2015, Babiker 等 2016]。

其他所有的PNDM都需要长时程的胰岛素治疗，尽管携带GCK致病性变异的患者被报道能够从口服磺脲类药物从轻微获益[Turkkahraman 等 2008, Hussain 2010]。

应保持高能量饮食以增加体重。

对于具有胰腺外分泌功能不全的患者需要使用胰腺酶替代治疗。

二级并发症的预防

强化治疗与频繁的血糖浓度监测对于避免例如糖尿病酮症酸中毒与低血糖的畸形并发症至关重要。

糖尿病相关的慢性并发症可通过将血糖保持在恰当范围而被显著减少。美国糖尿病学会推荐对于所有小儿年龄组使用以下血糖控制目标[美国糖尿病学会 2016a]：

• 小于6岁儿童的血糖控制目标：
  • 餐前 90-130 mg/dL
  • 睡前/夜间 90-150 mg/dL
• 糖化血红蛋白A1c水平 < 7.5%

监测

应一生进行血糖浓度监测(≥4x/天)以达到治疗目标。

患有PNDM的儿童，尤其是那些携带KCNJ11或ABCC8基因致病性变异的患者，应当进行定期的生长发育评估。

10岁后应当每年进行糖尿病相关的慢性并发症筛查，且应当包括以下项目：

• 尿微量白蛋白分析
• 眼科检查以筛查视网膜病变

需要避免的药剂/情况

总体来说，速效的胰岛素制剂(lispro与aspart) 和短效的胰岛素制剂(regular)应避免使用(除非作为持续性静脉或皮下输注)，因为它们可能会导致幼儿的严重低血糖事件。

评估亲属的患病风险

关于以遗传咨询为目的的对有风险亲属进行检测的问题参见遗传咨询。

孕期管理

患有PNDM的怀孕妇女的管理需要遵照妊娠期间其他类型糖尿病的治疗指南 [美国糖尿病学会 2016b]。孕期的血糖控制不仅对于预防母亲的并发症很重要，对于预防胎儿的过度生长（由于母体的葡萄糖穿过胎盘导致胎儿高胰岛素血症所致）与相关并发症也很重要。建议应当推荐至母婴医学专家处。此外，应在妊娠期间提供高分辨率超声和胎儿超声心动图以筛查胎儿的先天畸形。

直到最近，胰岛素成为孕期的支柱性的糖尿病疗法；然而，现有数据支持孕期使用优降糖治疗糖尿病的安全性和有效性[Moretti 等 2008]。因此，在妊娠前使用优降糖治疗的PNDM妇女中，若能够达到合适的血糖控制，延续这种治疗方法是合理的。

在研治疗方法

可通过检索ClinicalTrials.gov网站以获取多种疾病与情况下的临床试验信息。注：有可能没有这种疾病的临床实验。

遗传模式

永久性新生儿糖尿病(PNDM)的遗传模式因基因而各异：

• ABCC8和INS. 常染色体显性或常染色体隐性
• GCK和PDX1.常染色体隐性
• KCNJ11.常染色体显性

家庭成员的风险—常染色体显性遗传

先证者的父母 (见表2)

• 推荐对ABCC8、INS,或KCNJ11基因具有显见的新发致病性变异的先证者的父母进行评估包括分子遗传学检测和糖尿病临床检测(口服糖耐量试验)。
• 如果先证者的致病性变异不能够在父母之间任一方的白细胞DNA中检测到，则可能的解释包括先证者发生了一个新发的致病性变异或者父母一方存在生殖细胞嵌合。KCNJ11基因致病性变异的生殖细胞嵌合曾有报道[Gloyn 等 2004a, Edghill 等 2007]；生殖细胞嵌合的总发病率尚未知 。
• 通过父母评估可能会发现之前由于医护专家未能识别该综合征和/或表型轻微的原因而未被诊断的患者。因此，只有进行恰当的评估后才能够确认一个显见的隐性家族史。

先证者的同胞.先证者同胞的风险取决于先证者父母的遗传学状态。

• 如果先证者的父母之一患病，那么同胞的风险是50%。
• 当父母临床上未患病，则先证者的同胞患病的风险看似较低。
• 如果在先证者身上发现了ABCC8、INS或KCNJ11基因的致病性变异不能够在父母双方的白细胞DNA中检出，那么考虑到存在亲代生殖细胞嵌合的可能性，同胞的风险仅比一般人群略有升高（仍然<1%）。

先证者的后代. 以常染色体显性模式遗传的PNDM个体的每个孩子都有50%的机会遗传到ABCC8、INS或KCNJ11基因的致病性变异。

其他家庭成员. 其他家庭成员的风险取决于先证者父母的状态：如果父母之一是患者，那么他/她的家庭可能有此风险。

家庭成员的风险 — 常染色体隐性遗传

先证者的父母

• 常染色体隐性PNDM的儿童的父母一定是杂合子，并因而具有一个PNDM相关的致病性变异。
• 常染色体隐性PNDM的儿童的父母有可能患病也有可能不患病(见基因型-表型相关性)。
  • ABCC8. 在43%的患病个体中， ABCC8基因相关的PNDM以常染色体隐性的模式从不患病的携带致病性变异的杂合子父母处遗传而来[Patch 等 2007]。
  • INS相关的PNDM也曾被报道从不患病的父母处以常染色体隐性的模式遗传而来[Garin 等 2010]。与隐性遗传的NDM相关的INS基因致病性变异的杂合子可能发生成年发病的糖尿病[Raile 等 2011]。
  • GCK和PDX1.GCK与PDX1基因致病性变异的杂合子患有较轻类型的糖尿病（分别是GCK家族性单基因糖尿病和PDX1家族性单基因糖尿病）。

先证者的同胞

• 理论上，患者的每个同胞都有25%的机会成为患者、50%的机会成为杂合子以及25%的机会既不是患病者又不是携带者。
• GCK、INS或PDX1基因的致病性变异杂合子表现为较轻的糖尿病类型（如，GCK家族性单基因糖尿病，之前被称为MODY2，或PDX1家族性单基因糖尿病，之前被称为MODY4）。 ABCC8基因致病性变异的杂合子具有正常的葡萄糖耐量。

先证者的后代. 一个常染色体隐性遗传的新生儿糖尿病的后代一定是一个致病性变异的杂合子。

其他家庭成员. 每个先证者父母的同胞都有50%的机会是一个PNDM相关致病性变异的杂合子。

携带者（杂合子）的发现

要对有风险的亲属进行携带者检测需要首先确定家系中PNDM相关的致病性变异。

相关的遗传咨询问题

对于发生显见的新发致病性变异家庭的考虑. 当常染色体显性遗传病的先证者的父母双方都没有携带致病性变异或疾病的临床征象时，很有可能是先证者发生了新发致病性变异。然而，可能的非医学解释，包括其法律意义上的父母并非生物学父母（如，通过辅助生殖）或未公开的领养，也可能从中被发现。

家庭规划

• 确定遗传风险、明确携带者状态与讨论产前检测可行性的最佳时间是怀孕前。
• 为患病的、携带的或具有携带风险的青年人提供 遗传咨询（包括讨论后代可能的风险与生育选择）是适当的。

DNA储存  是将DNA（通常提取自血液白细胞）储存起来以作为未来之用。这是因为未来检测方法学以及我们对于基因、等位基因变异以及疾病的理解很可能会有所发展，储存的患病的个体的DNA应被重新考虑。

产前检测和植入前遗传学诊断

一旦在患病的家庭成员中确定了PNDM相关的致病性变异，即有可能进行PNDM高风险妊娠的产前检测和植入前诊断。

医疗专家和家庭成员对于产前检测的使用可能存在不同的观点，尤其是当检测被考虑用于终止妊娠而非早期诊断的目的时。尽管多数中心认为产前检测的决定是父母的选择，针对这些问题进行讨论仍是适当的。

引用文献

• American Diabetes Association. Children and adolescents. Diabetes Care. 2016a;39 Suppl 1:S86鈥揝93. [PubMed: 26696687]
• American Diabetes Association. Diabetes care in the hospital. Diabetes Care. 2016b;39 Suppl 1:S99鈥揝104. [PubMed: 26696689]
• Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006;355:456-66. [PubMed: 16885549]
• Babiker T, Vedovato N, Patel K, Thomas N, Finn R, Männikkö R, Chakera AJ, Flangan SE, Shepherd MH, Ellard S, Ashcroft FM, Hattersley AT. Successful transfer to sylfonylureas in KCNJ11 is determined by the mutation and duration of diabetes. Diabetologia. 2016;59:1162-6. [PMC free article: PMC4869695] [PubMed: 27033559]
• Bonnefond A, Lomberk G, Buttar N, Busiah K, Vaillant E, Lobbens S, Yengo L, Dechaume A, Mignot B, Simon A, Scharfmann R, Neve B, Tanyolaç S, Hodoglugil U, Pattou F, Cavé H, Iovanna J, Stein R, Polak M, Vaxillaire M, Froguel P, Urrutia R. Disruption of a novel Kruppel-like transcription factor p300-regulated pathway for insulin biosynthesis revealed by studies of the c.-331 INS mutation found in neonatal diabetes mellitus. J Biol Chem. 2011;286:28414-24. [PMC free article: PMC3151084] [PubMed: 21592955]
• Colombo C, Delvecchio M, Zecchino C, Faienza MF, Cavallo L, Barbetti F. Transient neonatal diabetes mellitus is associated with a recurrent (R201H) KCNJ11 (KIR6.2) mutation. Diabetologia. 2005;48:2439-41. [PubMed: 16205880]
• D’Amato E, Giacopelli F, Giannattasio A, D’Annunzio G, Bocciardi R, Musso M, Lorini R, Ravazzolo R. Genetic investigation in an Italian child with an unusual association of atrial septal defect, attributable to a familial GATA4 gene mutation, and neonatal diabetes due to pancreatic agenesis. Diabet Med. 2010;27:1195-200. [PubMed: 20854389]
• De Franco E, Shaw-Smith C, Flanagan SE, Shepherd MH, International NDM. Consortium, Hattersley AT, Ellard S. GATA6 mutations cause a broad phenotypic spectrum of diabetes from pancreatic agenesis to adult-onset diabetes without exocrine insufficiency. Diabetes. 2013;62:993-7. [PMC free article: PMC3581234] [PubMed: 23223019]
• Dimitri P, Warner JT, Minton JA, Patch AM, Ellard S, Hattersley AT, Barr S, Hawkes D, Wales JK, Gregory JW. Novel GLIS3 mutations demonstrate an extended multisystem phenotype. Eur J Endocrinol. 2011;164:437-43. [PubMed: 21139041]
• Durocher F, Faure R, Labrie Y, Pelletier L, Bouchard I, Laframboise R. A novel mutation in the EIF2AK3 gene with variable expressivity in two patients with Wolcott-Rallison syndrome. Clin Genet. 2006;70:34-8. [PubMed: 16813601]
• Edghill EL, Bingham C, Slingerland AS, Minton JA, Noordam C, Ellard S, Hattersley AT. Hepatocyte nuclear factor-1beta mutations cause neonatal diabetes and intrauterine growth retardation: support for a critical role of HNF-1beta in human pancreatic development. Diabet Med. 2006;23:1301-6. [PubMed: 17116179]
• Edghill EL, Flanagan SE, Ellard S. Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11. Rev Endocr Metab Disord. 2010;11:193-8. [PubMed: 20922570]
• Edghill EL, Flanagan SE, Patch AM, Boustred C, Parrish A, Shields B, Shepherd MH, Hussain K, Kapoor RR, Malecki M, MacDonald MJ, Støy J, Steiner DF, Philipson LH, Bell GI, Hattersley AT, Ellard S., Neonatal Diabetes International Collaborative Group. Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes. 2008;57:1034-42. [PubMed: 18162506]
• Edghill EL, Gloyn AL, Goriely A, Harries LW, Flanagan SE, Rankin J, Hattersley AT, Ellard S. Origin of de novo KCNJ11 mutations and risk of neonatal diabetes for subsequent siblings. J Clin Endocrinol Metab. 2007;92:1773-7. [PubMed: 17327377]
• Ellard S, Flanagan SE, Girard CA, Patch AM, Harries LW, Parrish A, Edghill EL, Mackay DJ, Proks P, Shimomura K, Haberland H, Carson DJ, Shield JP, Hattersley AT, Ashcroft FM. Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. Am J Hum Genet. 2007;81:375-82. [PMC free article: PMC1950816] [PubMed: 17668386]
• Flanagan SE, Clauin S, Bellanné-Chantelot C, de Lonlay P, Harries LW, Gloyn AL, Ellard S. Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mutat. 2009;30:170-80. [PubMed: 18767144]
• Flanagan SE, De Franco E, Lango Allen H, Zerah M, Abdul-Rasoul MM, Edge JA, Stewart H, Alamiri E, Hussain K, Wallis S, de Vries L, Rubio-Cabezas O, Houghton JAL, Edghill EL, Patch AM, Ellard S, Hattersley AT. Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man. Cell Metab. 2014;19:146-54. [PMC free article: PMC3887257] [PubMed: 24411943]
• Flanagan SE, Edghill EL, Gloyn AL, Ellard S, Hattersley AT. Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype. Diabetologia. 2006;49:1190-7. [PubMed: 16609879]
• Flanagan SE, Patch AM, Mackay DJ, Edghill EL, Gloyn AL, Robinson D, Shield JP, Temple K, Ellard S, Hattersley AT. Mutations in ATP-ésitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes. 2007;56:1930-7. [PubMed: 17446535]
• Florez JC, Burtt N, de Bakker PI, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson TJ, Schaffner SF, Daly MJ, Hirschhorn JN, Groop L, Altshuler D. Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes. 2004;53:1360-8. [PubMed: 15111507]
• Garin I, Edghill EL, Akerman I, Rubio-Cabezas O, Rica I, Locke JM, Maestro MA, Alshaikh A, Bundak R, del Castillo G, Deeb A, Deiss D, Fernandez JM, Godbole K, Hussain K, O'Connell M, Klupa T, Kolouskova S, Mohsin F, Perlman K, Sumnik Z, Rial JM, Ugarte E, Vasanthi T, Johnstone K, Flanagan SE, Martínez R, Castaño C, Patch AM, Fernández-Rebollo E, Raile K, Morgan N, Harries LW, Castaño L, Ellard S, Ferrer J, Perez de Nanclares G, Hattersley AT., Neonatal Diabetes International Group. Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis. Proc Natl Acad Sci U S A. 2010;107:3105-10. [PMC free article: PMC2840338] [PubMed: 20133622]
• Girard CA, Shimomura K, Proks P, Absalom N, Castano L, Perez de Nanclares G, Ashcroft FM. Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes. Pflugers Arch. 2006;453:323-32. [PubMed: 17021801]
• Gloyn AL, Cummings EA, Edghill EL, Harries LW, Scott R, Costa T, Temple IK, Hattersley AT, Ellard S. Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel. J Clin Endocrinol Metab. 2004a;89:3932-5. [PubMed: 15292329]
• Gloyn AL, Diatloff-Zito C, Edghill EL, Bellanne-Chantelot C, Nivot S, Coutant R, Ellard S, Hattersley AT, Robert JJ. KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features. Eur J Hum Genet. 2006;14:824-30. [PubMed: 16670688]
• Gloyn AL, Hashim Y, Ashcroft SJ, Ashfield R, Wiltshire S, Turner RC. Association studies of variants in promoter and coding regions of beta-cell ATP-sensitive K-channel genes SUR1 and Kir6.2 with Type 2 diabetes mellitus (UKPDS 53). Diabet Med. 2001;18:206-12. [PubMed: 11318841]
• Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004b;350:1838-49. [PubMed: 15115830]
• Gloyn AL, Reimann F, Girard C, Edghill EL, Proks P, Pearson ER, Temple IK, Mackay DJ, Shield JP, Freedenberg D, Noyes K, Ellard S, Ashcroft FM, Gribble FM, Hattersley AT. Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet. 2005;14:925-34. [PubMed: 15718250]
• Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S, McCarthy MI, Hattersley AT, Frayling TM. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes. 2003;52:568-72. [PubMed: 12540637]
• Greeley SA, Naylor RN, Philipson LH, Bell GI. Neonatal diabetes: an expanding list of genes allows for improved diagnosis and treatment. Curr Diab Rep. 2011;11:519-32. [PMC free article: PMC3226065] [PubMed: 21993633]
• Greeley SA, Tucker SE, Naylor RN, Bell GI, Philipson LH. Neonatal diabetes mellitus: a model for personalized medicine. Trends Endocrinol Metab. 2010;21:464-72. [PMC free article: PMC2914172] [PubMed: 20434356]
• Habener JF, Kemp DM, Thomas MK. Minireview: transcriptional regulation in pancreatic development. Endocrinology. 2005;146:1025-34. [PubMed: 15604203]
• Haldorsen IS, Vesterhus M, Raeder H, Jensen DK, Søvik O, Molven A, Njølstad PR. Lack of pancreatic body and tail in HNF1B mutation carriers. Diabet Med. 2008;25:782-7. [PubMed: 18644064]
• Hani EH, Boutin P, Durand E, Inoue H, Permutt MA, Velho G, Froguel P. Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians. Diabetologia. 1998;41:1511-5. [PubMed: 9867219]
• Hansen T, Ambye L, Grarup N, Hansen L, Echwald SM, Ferrer J, Pedersen O. Genetic variability of the SUR1 promoter in relation to beta-cell function and Type II diabetes mellitus. Diabetologia. 2001;44:1330-4. [PubMed: 11692183]
• Hart LM, van Haeften TW, Dekker JM, Bot M, Heine RJ, Maassen JA. Variations in insulin secretion in carriers of the E23K variant in the KIR6.2 subunit of the ATP-sensitive K(+) channel in the beta-cell. Diabetes. 2002;51:3135-8. [PubMed: 12351459]
• Hattersley A, Bruining J, Shield J, Njolstad P, Donaghue K. ISPAD Clinical Practice Consensus Guidelines 2006-2007. The diagnosis and management of monogenic diabetes in children. Pediatr Diabetes. 2006;7:352-60. [PubMed: 17212604]
• Hattersley AT, Ashcroft FM. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes. 2005;54:2503-13. [PubMed: 16123337]
• Houghton JA, Swift GH, Shaw-Smith C, Flanagan SE, de Franco E, Caswell R, Hussain K, Mohamed S, Abdulrasoul M, Hattersley AT, MacDonald RJ, Ellard S. Isolated pancreatic aplasia due to hypomorphic PTF1A mutation. Diabetes. 2016;65:2810-5. [PMC free article: PMC5001172] [PubMed: 27284104]
• Huopio H, Otonkoski T, Vauhkonen I, Reimann F, Ashcroft FM, Laakso M. A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1. Lancet. 2003;361:301-7. [PubMed: 12559865]
• Hussain K. Mutations in pancreatic ß-cell Glucokinase as a cause of hyperinsulinaemic hypoglycaemia and neonatal diabetes mellitus. Rev Endocr Metab Disord. 2010;11:179-83. [PubMed: 20878480]
• Izumi T, Yokota-Hashimoto H, Zhao S, Wang J, Halban PA, Takeuchi T. Dominant negative pathogenesis by mutant proinsulin in the Akita diabetic mouse. Diabetes. 2003;52:409-16. [PubMed: 12540615]
• Kawaguchi Y, Cooper B, Gannon M, Ray M, MacDonald RJ, Wright CV. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat Genet. 2002;32:128-34. [PubMed: 12185368]
• Kim YS, Kang HS, Takeda Y, Hom L, Song HY, Jensen J, Jetten AM. Glis 3 regulates neurogenin 3 expression in pancreatic ß-cells and interacts with its activator, Hnf6. Mol Cells. 2012;34:193-200. [PMC free article: PMC3465161] [PubMed: 22820919]
• Koster JC, Cadario F, Peruzzi C, Colombo C, Nichols CG, Barbetti F. The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy. J Clin Endocrinol Metab. 2008;93:1054-61. [PMC free article: PMC2266958] [PubMed: 18073297]
• Lango Allen H, Flanagan SE, Shaw-Smith C, De Franco E, Akerman I, Caswell R., International Pancreatic Agenesis Consortium. Ferrer J, Hattersley AT, Ellard S. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat Genet. 2011;44:20-2. [PMC free article: PMC4062962] [PubMed: 22158542]
• Masia R, De Leon DD, MacMullen C, McKnight H, Stanley CA, Nichols CG. A mutation in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM). Diabetes. 2007a;56:1357-62. [PubMed: 17317760]
• Masia R, Koster JC, Tumini S, Chiarelli F, Colombo C, Nichols CG, Barbetti F. An ATP-binding mutation (G334D) in KCNJ11 is associated with a sulfonylurea-insensitive form of developmental delay, epilepsy, and neonatal diabetes. Diabetes. 2007b;56:328-36. [PubMed: 17259376]
• Massa O, Iafusco D, D'Amato E, Gloyn AL, Hattersley AT, Pasquino B, Tonini G, Dammacco F, Zanette G, Meschi F, Porzio O, Bottazzo G, Crino A, Lorini R, Cerutti F, Vanelli M, Barbetti F. KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum Mutat. 2005;25:22-7. [PubMed: 15580558]
• Matschinsky FM. Regulation of pancreatic beta-cell glucokinase: from basics to therapeutics. Diabetes. 2002 Dec;51 Suppl 3:S394-404. [PubMed: 12475782]
• Metz C, Cave H, Bertrand AM, Deffert C, Gueguen-Giroux B, Czernichow P, Polak M. Neonatal diabetes mellitus: chromosomal analysis in transient and permanent cases. J Pediatr. 2002;141:483-9. [PubMed: 12378186]
• Mohamadi A, Clark LM, Lipkin PH, Mahone EM, Wodka EL, Plotnick LP. Medical and developmental impact of transition from subcutaneous insulin to oral glyburide in a 15-yr-old boy with neonatal diabetes mellitus and intermediate DEND syndrome: extending the age of KCNJ11 mutation testing in neonatal DM. Pediatr Diabetes. 2010;11:203-7. [PubMed: 19686306]
• Moretti ME, Rezvani M, Koren G. Safety of glyburide for gestational diabetes: a metab-analysis of pregnancy outcomes. Ann Pharmacother. 2008;42:483-90. [PubMed: 18349305]
• Nicolino M, Claiborn KC, Senée V, Boland A, Stoffers DA, Julier C. A novel hypomorphic PDX1 mutation responsible for permanent neonatal diabetes with subclinical exocrine deficiency. Diabetes. 2010;59:733-40. [PMC free article: PMC2828654] [PubMed: 20009086]
• Nielsen EM, Hansen L, Carstensen B, Echwald SM, Drivsholm T, Glumer C, Thorsteinsson B, Borch-Johnsen K, Hansen T, Pedersen O. The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes. Diabetes. 2003;52:573-7. [PubMed: 12540638]
• Njølstad PR, Sagen JV, Bjørkhaug L, Odili S, Shehadeh N, Bakry D, Sarici SU, Alpay F, Molnes J, Molven A, Søvik O, Matschinsky FM. Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes. 2003;52:2854-60. [PubMed: 14578306]
• Njølstad PR, Søvik O, Cuesta-Muñoz A, Bjørkhaug L, Massa O, Barbetti F, Undlien DE, Shiota C, Magnuson MA, Molven A, Matschinsky FM, Bell GI. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med. 2001;344:1588-92. [PubMed: 11372010]
• Patch AM, Flanagan SE, Boustred C, Hattersley AT, Ellard S. Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neonatal diabetes, permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period. Diabetes Obes Metab. 2007;9 Suppl 2:28-39. [PubMed: 17919176]
• Pearson ER, Flechtner I, Njolstad PR, Malecki MT, Flanagan SE, Larkin B, Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J, Robert JJ, Holst JJ, Clark PM, Ellard S, Sovik O, Polak M, Hattersley AT. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006;355:467-77. [PubMed: 16885550]
• Pinney SE, Oliver-Krasinski J, Ernst L, Hughes N, Patel P, Stoffers DA, Russo P, De León DD. Neonatal diabetes and congenital malabsorptive diarrhea attributable to a novel mutation in the human neurogenin-3 gene coding sequence. J Clin Endocrinol Metab. 2011;96:1960-5. [PMC free article: PMC3135203] [PubMed: 21490072]
• Polak M, Cave H. Neonatal diabetes mellitus: a disease linked to multiple mechanisms. Orphanet J Rare Dis. 2007;2:12. [PMC free article: PMC1847805] [PubMed: 17349054]
• Polak M, Dechaume A, Cavé H, Nimri R, Crosnier H, Sulmont V, de Kerdanet M, Scharfmann R, Lebenthal Y, Froguel P, Vaxillaire M., French Neonatal Diabetes Study Group. Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy: a report from the French ND (Neonatal Diabetes) Study Group. Diabetes. 2008;57:1115-9. [PubMed: 18171712]
• Porter JR, Shaw NJ, Barrett TG, Hattersley AT, Ellard S, Gloyn AL. Permanent neonatal diabetes in an Asian infant. J Pediatr. 2005;146:131-3. [PubMed: 15644838]
• Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM. Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. Proc Natl Acad Sci U S A. 2004;101:17539-44. [PMC free article: PMC536014] [PubMed: 15583126]
• Proks P, Arnold AL, Bruining J, Girard C, Flanagan SE, Larkin B, Colclough K, Hattersley AT, Ashcroft FM, Ellard S. A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Hum Mol Genet. 2006;15:1793-800. [PubMed: 16613899]
• Raile K, O'Connell M, Galler A, Werther G, Kühnen P, Krude H, Blankenstein O. Diabetes caused by insulin gene (INS) deletion: clinical characteristics of homozygous and heterozygous individuals. Eur J Endocrinol. 2011;165:255-60. [PubMed: 21566073]
• Rigoli L, Lombardo F, Di Bella C. Wolfram syndrome and WFS1 gene. Clin Genet. 2011;79:103-17. [PubMed: 20738327]
• Rohayem J, Ehlers C, Wiedemann B, Holl R, Oexie K, Kordonouri O, Salzano G, Meissner T, Burger W, Schober E, Huebner A, Lee-Kirsh MA., Wolfram Syndrome Diabetes Writing Group. Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype. Diabetes Care. 2011;34:1503-10. [PMC free article: PMC3120194] [PubMed: 21602428]
• Rubio-Cabezas O, Hattersley AT, Njølstad PR, Mlynarski W., Ellard S, White N, Chi DV, Craig ME. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes. 2014;15:47-64. [PubMed: 25182307]
• Rubio-Cabezas O, Minton JA, Kantor I, Williams D, Ellard S, Hattersley AT. Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities. Diabetes. 2010;59:2326-31. [PMC free article: PMC2927956] [PubMed: 20573748]
• Rubio-Cabezas O, Patch AM, Minton JA, Flanagan SE, Edghill EL, Hussain K, Balafrej A, Deeb A, Buchanan CR, Jefferson IG, Mutair A, Hattersley AT, Ellard S., Neonatal Diabetes International Collaborative Group. Wolcott-Rallison syndrome is the most common genetic cause of permanent neonatal diabetes in consanguineous families. J Clin Endocrinol Metab. 2009;94:4162-70. [PMC free article: PMC2775655] [PubMed: 19837917]
• Schwitzgebel VM, Mamin A, Brun T, Ritz-Laser B, Zaiko M, Maret A, Jornayvaz FR, Theintz GE, Michielin O, Melloul D, Philippe J. Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1. J Clin Endocrinol Metab. 2003;88:4398-406. [PubMed: 12970316]
• Sellick GS, Barker KT, Stolte-Dijkstra I, Fleischmann C, Coleman RJ, Garrett C, Gloyn AL, Edghill EL, Hattersley AT, Wellauer PK, Goodwin G, Houlston RS. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet. 2004;36:1301-5. [PubMed: 15543146]
• Senée V, Chelala C, Duchatelet S, Feng D, Blanc H, Cossec JC, Charon C, Nicolino M, Boileau P, Cavener DR, Bougnères P, Taha D, Julier C. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet. 2006;38:682-7. [PubMed: 16715098]
• Senée V, Vattem KM, Delépine M, Rainbow LA, Haton C, Lecoq A, Shaw NJ, Robert JJ, Rooman R, Diatloff-Zito C, Michaud JL, Bin-Abbas B, Taha D, Zabel B, Franceschini P, Topaloglu AK, Lathrop GM, Barrett TG, Nicolino M, Wek RC, Julier C. Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. Diabetes. 2004;53:1876-83. [PubMed: 15220213]
• Shalev SA, Tenebaum-Rakover Y, Horovitz Y, Paz VP, Ye H, Carmody D, Highland HM, Boerwinkle E, Hanis CL, Muzny DM, Gibbs RA, Bell GI, Philipson LH, Greeley SAW. Microcephaly, epilepsy, and neonatal diabetes due to compound heterozygous mutation in IER3IP1: insights into the natural history of a rare disorder. Pediatr Diabetes. 2014;15:252-6. [PMC free article: PMC3994177] [PubMed: 24138066]
• Shaw-Smith C, Flanagan SE, Patch AM, Grulich-Henn J, Habeb AM, Hussain K, Pomahacova R, Matyka K, Abdullah M, Hattersley AT, Ellard S. Recessive SLC19A2 mutations are a cause of neonatal diabetes mellitus in thiamine-responsive megaloblastic anaemia. Pediatric Diabetes. 2012;13:314-21. [PubMed: 22369132]
• Shaw-Smith C, De Franco E, Lango Allen H, Batlle M, Flanagan SE, Borowiec M, Taplin CE, van Alfen-van der Velden J, Cruz-Rojo J, Perez de Nanclares G, Miedzybrodzka Z, Deja G, Wlodarska I, Mlynarski W, Ferrer J, Hattersley AT, Ellard S. GATA4 mutations are a cause of neonatal diabetes in childhood-onset diabetes. Diabetes. 2014;63:2888-94. [PubMed: 24696446]
• Shimomura K, Horster F, de Wet H, Flanagan SE, Ellard S, Hattersley AT, Wolf NI, Ashcroft F, Ebinger F. A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain. Neurology. 2007;69:1342-9. [PubMed: 17652641]
• Slingerland AS, Nuboer R, Hadders-Algra M, Hattersley AT, Bruining GJ. Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene. Diabetologia. 2006;49:2559-63. [PubMed: 17047922]
• Slingerland AS, Shields BM, Flanagan SE, Bruining GJ, Noordam K, Gach A, Mlynarski W, Hattersley AT, Ellard S. Referral rates for diagnostic testing support an incidence of permanent neonatal diabetes in three European countries of at least 1 in 260,000 live births. Diabetologia. 2009;52:1683-5. [PMC free article: PMC2709852] [PubMed: 19499210]
• Smith SB, Qu HQ, Taleb N, Kishimoto NY, Scheel DW, Lu Y, Patch AM, Grabs R, Wang J, Lynn FC, Miyatsuka T, Mitchell J, Seerke R, Désir J, Eijnden SV, Abramowicz M, Kacet N, Weill J, Renard ME, Gentile M, Hansen I, Dewar K, Hattersley AT, Wang R, Wilson ME, Johnson JD, Polychronakos C, German MS. Rfx6 directs islet formation and insulin production in mice and humans. Nature. 2010;463:775-80. [PMC free article: PMC2896718] [PubMed: 20148032]
• Solomon BD, Pineda-Alvarez DE, Balog JZ, Hadley D, Gropman AL, Nandagopal R, Han JC, Hahn JS, Blain D, Brooks B, Muenke M. Compound heterozygosity for mutations in PAX6 in a patient with complex brain anomaly, neonatal diabetes mellitus, and microophthalmia. Am J Med Genet Part A. 2009;149A:2543-6. [PMC free article: PMC2783496] [PubMed: 19876904]
• Stanik J, Gasperikova D, Paskova M, Barak L, Javorkova J, Jancova E, Ciljakova M, Hlava P, Michalek J, Flanagan SE, Pearson E, Hattersley AT, Ellard S, Klimes I. Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers. J Clin Endocrinol Metab. 2007;92:1276-82. [PubMed: 17213273]
• Stoffers DA, Ferrer J, Clarke WL, Habener JF. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet. 1997a;17:138-9. [PubMed: 9326926]
• Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet. 1997b;15:106-10. [PubMed: 8988180]
• Støy J, Edghill EL, Flanagan SE, Ye H, Paz VP, Pluzhnikov A, Below JE, Hayes MG, Cox NJ, Lipkind GM, Lipton RB, Greeley SA, Patch AM, Ellard S, Steiner DF, Hattersley AT, Philipson LH, Bell GI. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci U S A. 2007;104:15040-4. [PMC free article: PMC1986609] [PubMed: 17855560]
• Støy J, Greeley SA, Paz VP, Ye H, Pastore AN, Skowron KB, Lipton RB, Cogen FR, Bell GI, Philipson LH., United States Neonatal Diabetes Working Group. Diagnosis and treatment of neonatal diabetes: a United States experience. Pediatr Diabetes. 2008;9:450-9. [PMC free article: PMC2574846] [PubMed: 18662362]
• Støy J, Steiner DF, Park S-Y, Ye H, Philipson LH, Bell GI. Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene. Rev Endocr Metab Disord. 2010;11:205-15. [PMC free article: PMC2974937] [PubMed: 20938745]
• Thurber BW, Carmody D, Tadie EC, Pastore AN, Dickens JT, Wroblewski KE, Naylor RN, Philipson LH, Greeley SAW. Age at time of sulfonylurea initiation influences treatment outcomes in KCNJ11-related neonatal diabetes. Diabetologia. 2015;58:1430-5. [PMC free article: PMC4641523] [PubMed: 25877689]
• Tjora E., Wathle G, Erchinger F, Engjom T, Molven A, Aksnes L, Haldorsen IS, Dimcevski G, Raeder H, Njølstad PR. Exocrine pancreatic function in hepatocyte nuclear factor 1beta-maturity-onset diabetes of the young (HNF1B-MODY) is only moderately reduced: compensatory hypersecretion from a hypoplastic pancreas. Diabet Med. 2013;30:946-55. [PubMed: 23600988]
• Turkkahraman D, Bircan I, Tribble ND, Akçurin S, Ellard S, Gloyn AL. Permanent neonatal diabetes mellitus caused by a novel homozygous (T168A) glucokinase (GCK) mutation: initial response to oral sulphonylurea therapy. J Pediatr. 2008;153:122-6. [PubMed: 18571549]
• Wang J, Cortina G, Wu SV, Tran R, Cho JH, Tsai MJ, Bailey TJ, Jamrich M, Ament ME, Treem WR, Hill ID, Vargas JH, Gershman G, Farmer DG, Reyen L, Martin MG. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N Engl J Med. 2006;355:270-80. [PubMed: 16855267]
• Wiedemann B, Schober E, Waldhoer T, Koehle J, Flanagan SE, Mackay DJ, Steichen E, Meraner D, Zimmerhackl LB, Hattersley AT, Ellard S, Hofer S. Incidence of neonatal diabetes in Austria-calculation based on the Austrian Diabetes Register. Pediatr Diabetes. 2010;11:18-23. [PubMed: 19496964]
• Yasuda T, Kajimoto Y, Fujitani Y, Watada H, Yamamoto S, Watarai T, Umayahara Y, Matsuhisa M, Gorogawa S, Kuwayama Y, Tano Y, Yamasaki Y, Hori M. PAX6 mutation as a genetic factor common to aniridia and glucose intolerance. Diabetes. 2002;51:224-30. [PubMed: 11756345]
• Yorifuji T, Kurokawa K, Mamada M, Imai T, Kawai M, Nishi Y, Shishido S, Hasegawa Y, Nakahata T. Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: Phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1beta gene due to germline mosaicism. J Clin Endocrinol Metab. 2004;89:2905-8. [PubMed: 15181075]
• Zeruth GT, Takeda Y, Jetten AM. The Krüppel-like protein Gli-similar 3 (Glis3) functions as a key regulator of insulin transcription. Mol Endocrinol. 2013;27:1692-705. [PMC free article: PMC3787130] [PubMed: 23927931]

推荐阅读

• Greeley SA, John PM, Winn AN, Ornelas J, Lipton RB, Philipson LH, Bell GI, Huang ES. The cost-effectiveness of personalized genetic medicine: the case of genetic testing in neonatal diabetes. Diabetes Care. 2011;2011;34:622-7. [PMC free article: PMC3041194] [PubMed: 21273495]
• Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab. 2008;4:200-13. [PubMed: 18301398]
• Rubio-Cabezas O, Ellard S. Diabetes mellitus in neonates and infants: genetic heterogeneity, clinical approach to diagnosis, and therapeutic options. Horm Res Paediatr. 2013;80:137-46. [PMC free article: PMC3884170] [PubMed: 24051999]
• Shield JP. Neonatal diabetes: new insights into aetiology and implications. Horm Res. 2000;53 Suppl 1:7-11. [PubMed: 10895036]

致谢

本文作者们获得了NIH的基金资助——R01DK098517、R01FD004095 (DDDL)；R37DK056268 (CAS)。

修改历史

• 29 July 2016 (sw) Comprehensive update posted live
• 23 January 2014 (me) Comprehensive update posted live
• 5 July 2011 (me) Comprehensive update posted live
• 4 March 2008 (cd) Revision: 序列分析 and 产前诊断 available for INS mutations
• 8 February 2008 (me) Review posted to live Web site
• 9 August 2007 (cas) Original submission