提示性发现

• 青少年期没有或有部分青春期表现；生化检测显示低水平的血清睾酮或雌二醇
• Tanner分期确定体格检查有不完全性成熟的结果 (见 Table 1):
  • IGD男性通常有Tanner I-II期生殖器（青春期前睾丸体积＜4毫升）；然而，一些男性有部分青春期的成熟表现 [Pitteloud et al 2001].
  • IGD女性通常有Tanner I期乳腺发育和闭经；然而，有些会有自发性乳腺发育和偶尔的月经 [Shaw et al 2011].
  • IGD男性和女性通常有Tanner II-III期的阴毛，因为阴毛发育部分受控于肾上腺雄激素。
  在很少的男性患者中，IGD可能发生在成年之后（即成年起病的IGD）。然而，在这些患者中，青春期没有中断，性成熟是完全的，第二性征可能得到充分发展。成年起病的IGD诊断要依靠促性腺激素分泌不足的性腺功能减退（HH）并排除其他可继发导致HH的原因。

• IGD的实验室检查结果 (见 Figure 1 和 Figure 2 的程序)
  • 男性总睾酮 (T) <100 ng/dL，女性雌二醇 (E2) <50 pg/mL
  • 在低循环浓度的性类固醇激素的存在下，有异常低或正常血清LH（黄体生成素）和FSH（促卵泡刺激素）。其他垂体前叶激素水平通常是正常的。
• IGD的影像学检查结果
  • IGD患者的下丘脑和垂体MRI检查通常表现正常。
  • 卡尔曼综合征患者通常显示不发育或发育不全的嗅球/沟/束。
• 嗅觉检查结果. 嗅觉功能通过病史和正规的诊断性嗅觉测试来评估，如宾夕法尼亚大学的嗅觉识别测试（UPSIT）、“一刮即嗅”测试，识别40微囊化气味的能力评估，这些检测易于操作可在多数临床检测中应用 [Doty 2007]。嗅觉缺失，嗅觉减退，或使用UPSIT手册正常识别确定的无嗅觉异常，结合测试年龄和性别，获得个人评分。
  IGD患者或者是自述完全的嗅觉丧失，或者是经UPSIT测试发现嗅觉减退/嗅觉缺失而被诊断为KS的个体，而那些嗅觉功能正常的则被诊断为normosmic IGD（nIGD） [Lewkowitz-Shpuntoff et al 2012].

Figure 1.

诊断男性孤立性促性腺激素缺乏症（IGD）的检测程序

Figure 2.

诊断女性孤立性促性腺激素缺乏症（IGD）的检测程序

建立诊断

IGD先证者的诊断是根据上面描述的临床和生化研究建立的； Table 2a 和Table 2b列出了用基因诊断可识别致病变异的基因。

Table 2a为最常见的遗传原因（即> 2% IGD是由包含在该表中的任一基因的致病变异所致）和Table 2b为不常见的遗传原因（即表中任一基因的致病变异仅在几个家庭中被报道）。

分子检测方法包括用一个多基因组合进行的 系列单基因检测和更为广泛的基因检测。

系列单基因检测被认为是基于遗传方式和临床所见，尤其是非生殖表型特征表明一个特定基因的致病变异是最有可能的。如果没有发现 致病变异，首先对感兴趣的基因进行序列分析，其次是基因靶向缺失/重复分析。

下图可以帮助优选系列单基因检测的顺序  (见Figure 3 和 Figure 4):

Figure 3.

通过嗅觉和遗传方式选择的促性腺素释放素缺乏症(IGD)相关基因

Figure 4.

基于表型的IGD患者检测的基因优选建议指南 [改编自 Au et al 2011]

• 嗅觉
  • CHD7, FGF8, FGF17, FGFR1, HS6ST1, NSMF (NELF), PROK2, PROKR2 和WDR11基因的致病变异可致卡尔曼综合征 (KS) 和无嗅觉异常的 IGD (nIGD).
  • ANOS1 (KAL1), CCDC141, FEZF1, IL17RD, SEMA3A, SEMA3E和OX10基因的致病变异导致KS.
  • GNRH1, GNRHR, KISS1, KISS1R (GPR54), TAC3和TACR3基因的致病变异导致nIGD.
• 遗传方式
  • X-连锁.ANOS1 (KAL1)的序列分析是最有效的分子遗传学检测。
  • 常染色体显性遗传. 在有明确常染色体显性遗传的家系中，考虑检测CHD7, FGFR1, FGF8 和 SOX10基因。
  • 常染色体隐性遗传. 在常染色体隐性遗传的nIGD家系中，考虑检测 GNRH1, GNRHR, KISS1, KISS1R, TAC3和TACR3基因；常染色体隐性遗传的KS家系中，考虑检测FEZF1, PROK2 和 PROKR2基因。
  •  
• 相关的表型特征. 一些相关的临床表型特征的存在也可能有助于优化IGD基因检测 [ Costa-Barbosa et al 2013]. 见 Figure 4.

一个多基因组合，可以考虑包括表 2a和 表 2b所列的基因和其他感兴趣基因（见鉴别诊断）。当 先证者没有明显受累的家庭成员和/或没有相关的表型特征时，多基因面板应该作为第一步检测方法。 注：（1）组合中包含的基因和每个基因检测的诊断敏感性因实验室和时间的推移而有所不同。 （2）某些多基因组合可能包含与genereview讨论状态不相关的基 因；因此，临床医生需要确定哪一种多基因组合能为确定遗传原因提供最佳机会，以最合理的成本同时限制继发结果。（3）在组合中使用的方法可包括 序列分析，缺失/重复分析 和/或其他非测序为基础的检测。

更多关于多基因组合的信息请点击此处。

更为综合的基因检测（当可用时）包括 外显子组测序和基因组测序可以考虑。这种测试可以提供或提示一个以前没有考虑的诊断（例如，不同基因突变的或导致相似临床表现的基因）。更多关于综合的基因组测序请点击 这里。

临床描述

孤立性促性腺激素释放激素缺陷症（IGD）的临床表现取决于生殖轴缺陷首先发生的阶段–婴儿期，青春期还是成年期（很少）。大多数IGD个体在青春期确诊；然而，提示性临床特征可能会表现于婴儿期。

病理生理学

促性腺激素释放激素脉冲式分泌进入垂体门脉循环标志着两性神经内分泌初始步骤在下丘脑-垂体-性腺（HPG）轴中的调控。因此，这个专门的GnRH 神经网络在这种生物层次中起着决定性作用，控制GnRH的分泌，调节性腺类固醇激素的反馈，并最终决定青春期发育的启动或抑制及整个生命周期的生育能力 [ Hoffman & Crowley 1982, Crowley et al 1985]。

在正常情况下，GnRH神经网络经历了一系列从胎儿到成年的动态变化。GnRH分泌的启动是在胎儿生命早期发起并持续直到婴儿期头几个月（表现为“小青春期”），然后在几年的儿童“静息”期内受到显著抑制 [Waldhauser et al 1981]。在青春期，未知的生物触发重新激动GnRH的分泌，导致完全性成熟。因此，生殖轴的控制是在动态变化中，启动和关闭取决于对生殖生命周期的各个点上未知生物信号的应答。

在IGD个体中，促性腺激素的脉冲模式的分析证明了异常发育模式相当广泛，从GnRH诱导的LH脉冲完全缺失到与青春早期别无二致的睡眠产生的GnRH释放 [Spratt et al 1987, Nachtigall et al 1997, Raivio et al 2007]. 这种广泛的神经内分泌活动说明了在IGD患者中观察到的多变的生殖表型。

基因型-表型相关性

基因特异的表型已被标记； 见 Table 3 和 Figure 4.

没有生殖或非生殖表型是具体到一个单一的致病变异或任何IGD相关基因致病变异的特定类型。

外显率

潜在的遗传病因通常决定着生殖和非生殖表型的外显度。

KS表型（包括IGD和嗅觉缺失症）通常是在一个有 ANOS1（KAL1）致病变异的男性中是完全外显的。然而，其他非生殖表型即使在有相同 ANOS1（KAL1）基因缺陷的情况下也可能有不同的外显率。ANOS1 (KAL1)基因存在一个小 缺失的一组同卵双胎男性已被证实存在不一致的神经内分泌和非生殖表型：一对有室间隔 缺损和对一系列LH-RH刺激试验有更大的LH和FSH反应，而其他的有外斜视并对LH-RH刺激试验有低反应。[ Matsuo et al 2000]。

当双等位基因状态的致病变异发生时（即隐性变异）(FEZF1, GNRH1, GNRHR, IL17RD, KISS1, KISS1R, TAC3, TACR3)，IGD外显率也相当高。然而，对于那些在几乎所有已知的IGD相关基因的 杂合致病变异，其生殖表型的外显率不完全，如同有正常性腺功能的人是已记载基因的致病变异杂合子。KS同卵双胞胎的不一致中也被证明，提示额外的改变可能在表型表现中发挥作用 [Hipkin et al 1990]。

ANOS1 (KAL1)致病变异男性的嗅觉缺失的 外显率通常是完全的，然而，IGD个体和一些基因(CHD7, FGFR1, FGF8, FGF17, HS6ST1, NSMF, PROK2, PROKR2)的杂合致病变异个体的异常嗅觉功能的外显率是不完全的，可见嗅觉正常、嗅觉减退或嗅觉缺失 [Pitteloud et al 2006a, Cole et al 2008, Falardeau et al 2008, Miraoui et al 2013, Balasubramanian et al 2014]。

术语

生化术语“促性腺激素分泌不足的性腺功能减退症”随着生殖生理的认识的增加演变而来。

“性腺功能低下”一词是指性发育障碍，基于个人的临床病史（如闭经、潮热、勃起功能障碍）以及体格检查（例如，小睾丸，阴道苍白）的研究结果。

随着对下丘脑-垂体-性腺（HPG）轴（见Pathophysiology）的了解越来越多和尿促性腺激素测量的介绍，“ 高促性腺激素的”性腺功能低下用来识别那些具有原发性腺缺陷，而“ 低促性腺激素的”性腺机能减退用来鉴别那些中枢性（即垂体或下丘脑）缺陷。

当中枢性性腺功能减退的解剖学因素被确定，“特发性”或“孤立性”促性腺激素分泌不足的性腺功能低下（IHH）被用来表示那些继发导致HH原因被排除的个体。

随后检测外源性GnRH治疗的效果表明，绝大多数的“特发性”HH个体有GnRH功能缺陷，由GnRH生物合成、分泌和/或作用（即“孤立性 GnRH缺陷症”[ IGD ]）的缺陷导致。除了下丘脑GnRH缺陷，IGD个体通常垂体功能试验正常，且他们的性腺机能减退通常会对生外源性GnRH的生理治疗有反应 [Hoffman & Crowley 1982]。

在这一点上，“孤立性GnRH缺陷症”（IGD）更恰当地反映当前临床本质的理解而非之前的IHH的生化描述，因此是一个比IHH更好的词。

患病率

最近在芬兰的一项流行病学研究表明，KS男性和女性中的发病率最小值分别为1:30,000和1:125,000 [Laitinen et al 2011]。

在作者的250例IGD的队列研究中，男性占主导地位，男女比例近4:1[Seminara et al 1998]。

孤立性促性腺激素释放激素缺陷症（IGD）患者中近三分之二是KS。

特定发育阶段的IGD鉴别诊断

婴儿期. 虽然IGD男性出生时可有隐睾和/或小阴茎，但这些特点并非是IGD特异的。许多疾病可以引起这些生殖缺陷，从 孤立的研究结果到Prader-Willi 综合征或垂体发育异常（见 PROP1-相关联合垂体激素缺乏症）。隐睾是尤为准确的、男性生殖器最常见的出生缺陷。

青春期. 也许最难的区别是IGD和原发性的青春期延迟（CDP）。时间是鉴别这两个状况的关键因素。在CDP中，自发的和其他正常的青春期最终发生，而在IGD中 任何时间都不会发生自发的性成熟。有证据表明，CDP和IGD不是离散的临床存在，而是一个表型谱的一部分。在IGD家庭，青春期延迟发生在其他的“正 常”家庭成员的频率要高于一般人群的发生率，这表明CDP可以代表一个IGD 表型温和的临床变异 [ Waldstreicher et al 1996, Pitteloud et al 2006a]。

虽然在任何年龄短CDP和IGD的差异不能被可靠地区分，但习惯上认为18岁是IGD的可确诊年龄；然而，最近一些人IGD“逆转”的描述发生在20多岁以后，提示这些人可能是的CDP严重形式 [Raivio et al 2007]。相比之下，与IGD相关的其他临床特征（例如嗅觉丧失，联带运动）( Table 3)可能会导致IGD在18岁之前被确诊。

目前，临床上尚无测试能可靠区分CDP与IGD。数据分析表明，在GnRH或hCG（人绒毛膜促性腺激素）刺激后，CDP个体的LH和性激素的平均 血清浓度与IGD个体有显著差异。然而，在GnRH或hCG刺激后检测血清LH和性激素浓度的的临床效果受限于个体血清LH和性激素浓度的显著变化，导致 CDP与IGD群体间有相当大的重叠 [Degros et al 2003]。

Figure 1 和 Figure 2分别提供了用于建立男性和女性孤立性GnRH缺陷症的检测流程。

初步诊断后评估

建议使用以下对诊断为IGD的个体建立疾病程度与需求的评估：

• 基于个体的年龄和性别的性腺功能低下症临床表现的评估，是否未作为诊断建立的一部分来执行（见 Diagnosis 和 Table 1）
• 低促性腺素性功能减退症实验室检查*的评估，是否未作为诊断建立的一部分来执行对性腺功能实验室检查评估是否已经进行的诊断工作的一部分
  * 血清LH（黄体生成素）和FSH（卵泡刺激素）浓度，男性总睾酮（T） <100 ng/dL和女性雌二醇（E 2） <50 pg/mL
• 可能的非生殖特征表现的评估包括：肾超声检查（检测单侧肾缺如），听力测试（检测感音神经性耳聋），骨骼测量（检测肢体/脊柱骨性畸形），牙科检查（检测牙发育不全），视力检查（检测虹膜和脉络膜视网膜缺损）和发育评估（是否有发育延迟的证据）
• 除了评估性腺功能减退/促性腺激素释放激素缺乏的程度，在骨骼健康的潜在恶化可能由低循环性激素导致这个问题需要解决。根据青春期的时间，GnRH缺乏的持续时间，和其他骨质疏松症的危险因素（如糖皮质激素过量，吸烟），患病个体应该考虑接受骨矿物质密度检测（见 继发并发症的预防）
• 咨询临床遗传学家和/或遗传顾问

对症治疗

一个IGD管理的欧洲专家共识已于最近出版 [Boehm et al 2015] (全文)。
通常，一个明确的IGD诊断大约在18岁左右确立。然而，偶尔会有一个临床高度怀疑的IGD可能在青春期出现，表现为嗅觉丧失和青春期延迟或在婴儿期出现小阴茎、隐睾。

二级并发症的预防

鼓励摄取最佳剂量的钙和维生素D，根据骨矿化程度考虑双膦酸盐用于骨量减少的特异性治疗（见 初步诊断后评估）。

监督

有IGD提示性检查发现的两种性别儿童(如, 小阴茎， 嗅觉缺失) 应该从11岁开始定期监测以下情况：

• 通过Tanner分期对性成熟的评价(Table 1)
• 男性血清LH、FSH、总睾酮（T）的测定，女性雌二醇（E2）的测定
• 骨龄测定

IGD确诊个体, 血清类固醇水平 (用以指导最佳激素替代治疗) 和骨矿物质密度应该定期检测。

亲属风险评估

评估受累个体无明显临床症状的老年人和年轻人高危亲属，以期尽早明确那些受益于监管的人，促使其尽快开始治疗。

评估包括:

• 如果家庭中存在已知的致病变异，则进行分子遗传检测。然而，一个带有已知致病性变异的青春期孩子可以正常方式度过青春期，或者青春期延迟，或者完全没有延迟。因此，随着时间的推移，对这些人进行重新评估是非常重要的，只有IGD伴有青春期发育缺陷时才应开始激素治疗。
• 如果家庭中存在未知的致病变异，需要对处于青春期的高危亲属进行临床检查，以评估青春期发育的临床起始表现，如果有延迟，需要启动适当的青春期诱导治疗。

以遗传咨询为目的的高危亲属检测问题详见 Genetic Counseling 。

在研究中的治疗

搜索ClinicalTrials.gov获取各种疾病的临床研究信息取。注意：有些疾病可能没有临床试验

遗传方式

孤立性促性腺激素释放激素(GnRH) 缺陷 (IGD) 可以 X-连锁, 常染色体显性, 或常染色体隐性方式遗传(见 Figure 3).

几乎所有的IGD相关基因也与不确定的或寡基因遗传相关（特别是一个IGD相关 致病变异的杂合状态时）[Sykiotis et al 2010b, Hanchate et al 2012, Miraoui et al 2013])。

家庭成员的风险 – X-连锁遗传

男性先证者的父母

• 男性患者的父亲将不会有此疾病，也不会是ANOS1 (KAL1) 致病变异的半合子; 因此，他不需要进一步的评估和检测.
• 一个家庭有一个以上的受累个体，则男性患者的母亲是一个肯定杂合子（ 携带者）。注意：如果一位女性有一个以上受累的儿子，而没有其他受累的亲属，如果她的白细胞DNA检测未发现 致病变异，她极有可能是生殖腺嵌合（目前尚无ANOS1基因母源生殖腺嵌合的报告）
• 如果家系成员中仅有一名男性受累（即一个 单发病例），其母亲可能是杂合子（携带者）或这受累男性可能有ANOS1致病变异的新生突变 ，这种情况下，其母就不是携带者。约70%的男性患者表现为单发病例。

男性先证者的同胞。同胞的罹患风险取决于母亲的遗传状态:

• 如果先证者 的母亲有一个 ANOS1致病变异，每次怀孕致病基因的传递几率是50%。遗传此致病性变异的男性同胞将 患病；遗传此致病性变异的女性同胞为该致病变异的杂合子，将显示一些临床特点。
• 如果先证者是一个单发病例（即在一个家庭中独立发生），如果母亲的白细胞DNA检测不到 致病变异，因为母源生殖腺嵌合的理论可能性，同胞的风险略高于一般人群（仍然＜1%）

男性先证者的后代

• 经过治疗的男性IGD患者可以生育.
• 男性患者可将ANOS1 致病变异 :
  • 传递给所有的女儿, 她们将是杂合子且有一些临床特点。
  • 不会传递给儿子.

其他家系成员.先证者 的舅父可能有 受累风险，其姨母有成为ANOS1致病变异携带者的风险。姨母的后代, 根据他们的性别, 可有成为携带者或受累的风险。

杂合子 (携带者) 检测. 如果先证者已确定有ANOS1致病变异，其高危女性亲属的分子遗传学检测是明确他们遗传状况最翔实的方法。

注: (1) 女性 ANOS1致病变异的杂合子  偶尔会有诊断为IGD的临床表现[Shaw et al 2011]. (2) 女性杂合子鉴定需要 (a) 家系中预先明确的 ANOS1致病变异，或 (b) 如果受累 男性不可检测，首先通过序列分析进行 分子遗传学检测，如果没有确定致病性变异, 再行靶向基因的 缺失/重复分析。

家系成员风险 – 常染色体显性遗传

先证者的父母

• 一些常染色体显性IGD个体有受累的父母。
• 常染色体显性IGD先证者可因一个 新生 致病变异而发病。由新生致病变异所致疾病的比例未知。
• 有新生 致病变异的 先证者父母的评估建议包括：
  • 父母双方详细的青春期发育史；和
  • 对于先证者中确认的致病变异，要对其双方父母进行该位点的分子遗传学检测。
• 如果在父母的白细胞DNA中均未检测到先证者所带的 致病变异，可能的解释包括：先证者存在一个新生致病变异或父母一方有 生殖腺嵌合 (IGD相关致病变异的生殖腺嵌合在一个家庭中有报道 [Sato & Ogata 2006]).
• 对父母的评估可以确定其中之一有先证者具有的 致病变异，但是会因轻微表型，降低的外显率，或疾病晚发而忽略之前的诊断。因此，只有执行恰当的评估，才能证实一个明显阴性的家族史。

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状态:

• 如果先证者的父母之一受累和/或有致病变异，其同胞遗传该致病变异的几率是50%，由于 可变的表现度和降低的外显率，他们实际风险是更低的。
• 如果先证者的致病变异未在其父母白细胞DNA检测到，其同胞的风险会稍高于一般人群，因为存在父母 生殖腺嵌合的可能[Sato & Ogata 2006]。

先证者的后代.常染色体显性遗传IGD患者的后代有50%的几率遗传 致病变异；然而，由于可变的表现度和降低的 外显率，实际风险可能会低于50%。

其他家庭成员. 其他家庭成员的风险取决于先证者父母的遗传状态：如果父母之一 受累或者有一个已知致病变异，他或她的家庭成员可能存在风险。

其他家庭成员的风险 – 常染色体隐性遗传

先证者的父母

• 常染色体隐性IGD患儿的父母都是肯定杂合子（即某个 致病变异的携带者）。
• 杂合子通常不会发病。
• 偶尔, 杂合子会有IGD的临床表现[Cole et al 2008, Gianetti et al 2010, Sykiotis et al 2010b, Chan et al 2011, Miraoui et al 2013]；这可能是由于未知的环境、表观或寡基因因素。

先证者的同胞

• 在概念上，常染色体隐性IGD患者的每个同胞都有25%的几率 发病，有50%的几率成为无症状携带者，有25%的几率完全正常或非携带者。
• 偶尔, 杂合子会有IGD的临床表现 [ Cole et al 2008, Gianetti et al 2010, Sykiotis et al 2010b, Chan et al 2011, Miraoui et al 2013]；这可能是由于未知的环境、表观或寡基因因素。

先证者的后代.患者的后代是IGD相关的 致病变异的肯定杂合子（携带者）。

其他家庭成员.先证者父母的每个同胞有50%的风险成为IGD相关的 致病变异的携带者。

杂合子(携带者) 检测.杂合子的确定需要预先明确家系中的IGD相关的致病变异。

家庭成员风险 — 不确定或寡基因遗传

不明原因或寡基因遗传的IGD单发的先证者（一个家庭中的单独发病的个体）家庭成员的确切风险是不确定的，可能高达50%。

相关的遗传咨询问题

见风险亲属评估的管理，评估风险亲属的信息，以便及早诊断和治疗。

生育计划

• 怀孕前是确定遗传风险，明确携带者的状态，讨论产前检查有效性的最佳时机。
• 向 患病的、携带者或者有携带者风险的年轻人提供 遗传咨询（包括后代的潜在风险和生殖选择的讨论）是合适的。

DNA存储是对将来可能用到的DNA（通常从白细胞提取）进行存储。因为将来我们可能对检测方式和对基因、等位基因变异和疾病的理解有所改进，应考虑存储患者的DNA。

产前检测和植入前遗传学诊断

患病家庭成员IGD相关的致病变异一旦被确定，高危孕妇的IGD产前检测和 植入前遗传学诊断就成为可能。

分子遗传发病机理

在过去的三十年里，临床研究策略与现代遗传学研究方法的结合已揭示了超过25个致病/促成非综合征型IGD的基因，具有不同的遗传方式。大致有两种 遗传途径与IGD有关：(i) 神经发育基因支配的GnRH神经元的起源，通常导致卡尔曼综合征型IGD（KS）。(ii) 一组神经内分泌基因控制GnRH的分泌或作用导致的嗅觉正常的 孤立性促性腺激素释放激素缺乏型IGD（nIGD）。一小部分的基因可引起 KS和nIGD型IGD，这表明这些基因可以控制GnRH迁移和GnRH分泌/作用(见 Table 2a and Table 2b)。

除了孟德尔遗传方式，IGD复杂遗传结构（发生在10% - 15%的病例）现已有记录，其中两个或两个以上IGD相关基因的致病性变异在一个单一个体存在。这些致病性变异通常是 杂合子，本身不足以导致IGD，但是在另外一个 基因存在额外致病性变异的情况下，可导致IGD [Sykiotis et al 2010]。几乎所有已知IGD相关基因与 寡基因遗传有关。这些寡基因致病变异可能具有协同作用的方式，可能导致IGD的一些 可变表现度和外显不全。

发布的准则/共识声明

1. Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R, Young J. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. Available online. 2015. Accessed 2-27-17. [PubMed: 26194704]

引用文献

1. Au MG, Crowley WF Jr, Buck CL. Genetic counseling for isolated GnRH deficiency. Mol Cell Endocrinol. 2011;346:102–9. [PMC free article: PMC3185214] [PubMed: 21664415]
2. Balasubramanian R, Choi JH, Francescatto L, Willer J, Horton ER, Asimacopoulos EP, Stankovic KM, Plummer L, Buck CL, Quinton R, Nebesio TD, Mericq V, Merino PM, Meyer BF, Monies D, Gusella JF, Al Tassan N, Katsanis N, Crowley WF Jr. Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency. Proc Natl Acad Sci U S A. 2014;111:17953–8. [PMC free article: PMC4273325] [PubMed: 25472840]
3. Balasubramanian R, Chew S, MacKinnon SE, Kang PB, Andrews C, Chan WM, Engle EC. Expanding the phenotypic spectrum and variability of endocrine abnormalities associated with TUBB3 E410K syndrome. J Clin Endocrinol Metab. 2015;100:E473–7. [PMC free article: PMC4333039] [PubMed: 25559402]
4. Bédécarrats GY, Kaiser UB. Mutations in the human gonadotropin-releasing hormone receptor: insights into receptor biology and function. Semin Reprod Med. 2007;25:368–78. [PubMed: 17710733]
5. Bianco SD, Kaiser UB. The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol. 2009;5:569–76. [PMC free article: PMC2864719] [PubMed: 19707180]
6. Bick D, Curry CJ, McGill JR, Schorderet DF, Bux RC, Moore CM. Male infant with ichthyosis, Kallmann syndrome, chondrodysplasia punctata, and an Xp chromosome deletion. Am J Med Genet. 1989;33:100–7. [PubMed: 2750777]
7. Bin-Abbas B, Conte FA, Grumbach MM, Kaplan SL. Congenital hypogonadotropic hypogonadism and micropenis: effect of testosterone treatment on adult penile size why sex reversal is not indicated. J Pediatr. 1999; 134:579–83. [PubMed: 10228293]
8. Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R, Young J. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2015;11:547–64. [PubMed: 26194704]
9. Bouligand J, Ghervan C, Tello JA, Brailly-Tabard S, Salenave S, Chanson P, Lombès M, Millar RP, Guiochon-Mantel A, Young J. Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation. N Engl J Med. 2009;360:2742–8. [PubMed: 19535795]
10. Burris AS, Rodbard HW, Winters SJ, Sherins RJ. Gonadotropin therapy in men with isolated hypogonadotropic hypogonadism: the response to human chorionic gonadotropin is predicted by initial testicular size. J Clin Endocrinol Metab. 1988;66:1144–51. [PubMed: 3372679]
11. Cariboni A, Davidson K, Rakic S, Maggi R, Parnavelas JG, Ruhrberg C. Defective gonadotropin-releasing hormone neuron migration in mice lacking SEMA3A signalling through NRP1 and NRP2: implications for the aetiology of hypogonadotropic hypogonadism. Hum Mol Genet. 2011;20:336–44. [PubMed: 21059704]
12. Cariboni A, Pimpinelli F, Colamarino S, Zaninetti R, Piccolella M, Rumio C, Piva F, Rugarli EI, Maggi R. The product of X-linked Kallmann's syndrome gene (KAL1) affects the migratory activity of gonadotropin-releasing hormone (GnRH)-producing neurons. Hum Mol Genet. 2004;13:2781–91. [PubMed: 15471890]
13. Cariboni A, André V, Chauvet S, Cassatella D, Davidson K, Caramello A, Fantin A, Bouloux P, Mann F, Ruhrberg C. Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome. J Clin Invest. 2015; 125:2413–28. [PMC free article: PMC4497752] [PubMed: 25985275]
14. Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi Syndrome. Genet Med. 2012;14:10–26. [PubMed: 22237428]
15. Cerrato F, Shagoury J, Kralickova M, Dwyer A, Falardeau J, Ozata M, Van Vliet G, Bouloux P, Hall JE, Hayes FJ, Pitteloud N, Martin KA, Welt C, Seminara SB. Coding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadism. Eur J Endocrinol. 2006 Nov;155 Suppl 1:S3–S10. [PubMed: 17074994]
16. Chan YM, Broder-Fingert S, Paraschos S, Lapatto R, Au M, Hughes V, Bianco SD, Min L, Plummer L, Cerrato F, De Guillebon A, Wu IH, Wahab F, Dwyer A, Kirsch S, Quinton R, Cheetham T, Ozata M, Ten S, Chanoine JP, Pitteloud N, Martin KA, Schiffmann R, Van der Kamp HJ, Nader S, Hall JE, Kaiser UB, Seminara SB. GnRH-deficient phenotypes in humans and mice with heterozygous variants in KISS1/Kiss1. J Clin Endocrinol Metab. 2011;96:E1771–81. [PMC free article: PMC3205899] [PubMed: 21880801]
17. Chan YM, de Guillebon A, Lang-Muritano M, Plummer L, Cerrato F, Tsiaras S, Gaspert A, Lavoie HB, Wu CH, Crowley WF Jr, Amory JK, Pitteloud N, Seminara SB. GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2009; 106:11703–8. [PMC free article: PMC2710623] [PubMed: 19567835]
18. Chew S, Balasubramanian R, Chan WM, Kang PB, Andrews C, Webb BD, MacKinnon SE, Oystreck DT, Rankin J, Crawford TO, Geraghty M, Pomeroy SL, Crowley WF Jr, Jabs EW, Hunter DG, Grant PE, Engle EC. A novel syndrome caused by the E410K amino acid substitution in the neuronal β-tubulin isotype 3. Brain. 2013;136:522–35. [PMC free article: PMC3572929] [PubMed: 23378218]
19. Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougnères P, Lebouc Y, Froguel P, Guy-Grand B. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392:398–401. [PubMed: 9537324]
20. Cole LW, Sidis Y, Zhang C, Quinton R, Plummer L, Pignatelli D, Hughes VA, Dwyer AA, Ravio T, Hayes FJ, Seminara SB, Huot C, Alos N, Speiser P, Takeshita A, Van Vliet G, Pearce S, Crowley WF Jr, Zhou QY, Pitteloud N. Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotropin-releasing hormone deficiency: molecular genetics and clinical spectrum. J Clin Endocrinol Metab. 2008;93:3551–9. [PMC free article: PMC2567850] [PubMed: 18559922]
21. Costa-Barbosa FA, Balasubramanian R, Keefe KW, Shaw ND, Al-Tassan N, Plummer L, Dwyer A, Buck CL, Choi J-H, Seminara SB, Quinton R, Monies D, Meyer B, Hall JE, Pitteloud N, Crowley WF. Prioritizing Genetic Testing in Patients With Kallmann Syndrome Using Clinical Phenotypes. J Clin Endocrinol Metab. 2013;98:E943–53. [PMC free article: PMC3644607] [PubMed: 23533228]
22. Crowley WF Jr, Filicori M, Spratt DI, Santoro NF. The physiology of gonadotropin-releasing hormone (GnRH) secretion in men and women. Recent Prog Horm Res. 1985;41:473–531. [PubMed: 3931190]
23. de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A. 2003; 100:10972–6. [PMC free article: PMC196911] [PubMed: 12944565]
24. de Roux N, Young J, Misrahi M, Genet R, Chanson P, Schaison G, Milgrom E. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med. 1997;337:1597–602. [PubMed: 9371856]
25. Degros V, Cortet-Rudelli C, Soudan B, Dewailly D. The human chorionic gonadotropin test is more powerful than the gonadotropin-releasing hormone agonist test to discriminate male isolated hypogonadotropic hypogonadism from constitutional delayed puberty. Eur J Endocrinol. 2003;149:23–9. [PubMed: 12824862]
26. Dodé C, Levilliers J, Dupont JM, De Paepe A, Le Du N, Soussi-Yanicostas N, Coimbra RS, Delmaghani S, Compain-Nouaille S, Baverel F, Pecheux C, Le Tessier D, Cruaud C, Delpech M, Speleman F, Vermeulen S, Amalfitano A, Bachelot Y, Bouchard P, Cabrol S, Carel JC, Delemarre-van de Waal H, Goulet-Salmon B, Kottler ML, Richard O, Sanchez-Franco F, Saura R, Young J, Petit C, Hardelin JP. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet. 2003; 33:463–5. [PubMed: 12627230]
27. Doty RL. Office procedures for quantitative assessment of olfactory function. Am J Rhinol. 2007;21:460–73. [PubMed: 17882917]
28. Dwyer AA, Sykiotis GP, Hayes FJ, Boepple PA, Lee H, Loughlin KR, Dym M, Sluss PM, Crowley WF Jr, Pitteloud N. Trial of recombinant follicle-stimulating hormone pretreatment for GnRH-induced fertility in patients with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2013;98:E1790–5. [PMC free article: PMC3816270] [PubMed: 24037890]
29. Falardeau J, Chung WC, Beenken A, Raivio T, Plummer L, Sidis Y, Jacobson-Dickman EE, Eliseenkova AV, Ma J, Dwyer A, Quinton R, Na S, Hall JE, Huot C, Alois N, Pearce SH, Cole LW, Hughes V, Mohammadi M, Tsai P, Pitteloud N. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice. J Clin Invest. 2008;118:2822–31. [PMC free article: PMC2441855] [PubMed: 18596921]
30. Gianetti E, Hall JE, Au MG, Kaiser UB, Quinton R, Stewart JA, Metzger DL, Pitteloud N, Mericq V, Merino PM, Levitsky LL, Izatt L, Lang-Muritano M, Fujimoto VY, Dluhy RG, Chase ML, Crowley WF Jr, Plummer L, Seminara SB. When genetic load does not correlate with phenotypic spectrum: lessons from the GnRH receptor (GNRHR). J Clin Endocrinol Metab. 2012;97:E1798–807. [PMC free article: PMC3431570] [PubMed: 22745237]
31. Gianetti E, Tusset C, Noel SD, Au MG, Dwyer AA, Hughes VA, Abreu AP, Carroll J, Trarbach E, Silveira LF, Costa EM, de Mendonça BB, de Castro M, Lofrano A, Hall JE, Bolu E, Ozata M, Quinton R, Amory JK, Stewart SE, Arlt W, Cole TR, Crowley WF, Kaiser UB, Latronico AC, Seminara SB. TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J Clin Endocrinol Metab. 2010;95:2857–67. [PMC free article: PMC2902066] [PubMed: 20332248]
32. Grumbach MM. A window of opportunity: the diagnosis of gonadotropin deficiency in the male infant. J Clin Endocrinol Metab. 2005;90:3122–7. [PubMed: 15728198]
33. Guran T, Tolhurst G, Bereket A, Rocha N, Porter K, Turan S, Gribble FM, Kotan LD, Akcay T, Atay Z, Canan H, Serin A, O'Rahilly S, Reimann F, Semple RK, Topaloglu AK. Hypogonadotropic hypogonadism due to a novel missense mutation in the first extracellular loop of the neurokinin B receptor. J Clin Endocrinol Metab. 2009;94:3633–9. [PMC free article: PMC4306717] [PubMed: 19755480]
34. Hanchate NK, Giacobini P, Lhuillier P, Parkash J, Espy C, Fouveaut C, Leroy C, Baron S, Campagne C, Vanacker C, Collier F, Cruaud C, Meyer V, García-Piñero A, Dewailly D, Cortet-Rudelli C, Gersak K, Metz C, Chabrier G, Pugeat M, Young J, Hardelin JP, Prevot V, Dodé C. SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. PLoS Genet. 2012;8:e1002896. [PMC free article: PMC3426548] [PubMed: 22927827]
35. Hipkin LJ, Casson IF, Davis JC. Identical twins discordant for Kallmann's syndrome. J Med Genet. 1990;27:198–9. [PMC free article: PMC1017005] [PubMed: 2325096]
36. Hoffman AR, Crowley WF Jr. Induction of puberty in men by long-term pulsatile administration of low-dose gonadotropin-releasing hormone. N Engl J Med. 1982;307:1237–41. [PubMed: 6813732]
37. Hou JW. Detection of gene deletions in children with chondrodysplasia punctata, ichthyosis, Kallmann syndrome, and ocular albinism by FISH studies. Chang Gung Med J. 2005;28:643–50. [PubMed: 16323556]
38. Hutchins BI, Kotan LD, Taylor-Burds C, Ozkan Y, Cheng PJ, Gurbuz F, Tiong JD, Mengen E, Yuksel B, Topaloglu AK, Wray S. CCDC141 Mutation Identified in Anosmic Hypogonadotropic Hypogonadism (Kallmann Syndrome) Alters GnRH Neuronal Migration. Endocrinology. 2016;157:1956–66. [PMC free article: PMC4870868] [PubMed: 27014940]
39. Jackson RS, Creemers JW, Farooqi IS, Raffin-Sanson ML, Varro A, Dockray GJ, Holst JJ, Brubaker PL, Corvol P, Polonsky KS, Ostrega D, Becker KL, Bertagna X, Hutton JC, White A, Dattani MT, Hussain K, Middleton SJ, Nicole TM, Milla PJ, Lindley KJ, O'Rahilly S. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest. 2003;112:1550–60. [PMC free article: PMC259128] [PubMed: 14617756]
40. Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC, O'Rahilly S. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet. 1997;16:303–6. [PubMed: 9207799]
41. Jongmans MC, van Ravenswaaij-Arts CM, Pitteloud N, Ogata T, Sato N, Claahsen-van der Grinten HL, van der Donk K, Seminara S, Bergman JE, Brunner HG, Crowley WF Jr, Hoefsloot LH. CHD7 mutations in patients initially diagnosed with Kallmann syndrome--the clinical overlap with CHARGE syndrome. Clin Genet. 2009;75:65–71. [PMC free article: PMC2854009] [PubMed: 19021638]
42. Kim HG, Ahn JW, Kurth I, Ullmann R, Kim HT, Kulharya A, Ha KS, Itokawa Y, Meliciani I, Wenzel W, Lee D, Rosenberger G, et al. WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet. 2010;87:465–79. [PMC free article: PMC2948809] [PubMed: 20887964]
43. Kim HG, Kurth I, Lan F, Meliciani I, Wenzel W, Eom SH, Kang GB, Rosenberger G, Tekin M, Ozata M, Bick DP, Sherins RJ, Walker SL, Shi Y, Gusella JF, Layman LC. Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet. 2008;83:511–9. [PMC free article: PMC2561938] [PubMed: 18834967]
44. Kotan LD, Hutchins BI, Ozkan Y, Demirel F, Stoner H, Cheng PJ, Esen I, Gurbuz F, Bicakci YK, Mengen E, Yuksel B, Wray S, Topaloglu AK. Mutations in FEZF1 cause Kallmann syndrome. Am J Hum Genet. 2014;95:326–31. [PMC free article: PMC4157145] [PubMed: 25192046]
45. Kotan LD, Cooper C, Darcan Ş, Carr IM, Özen S, Yan Y, Hamedani MK, Gürbüz F, Mengen E, Turan İ, Ulubay A, Akkuş G, Yüksel B, Topaloğlu AK, Leygue E. Idiopathic Hypogonadotropic Hypogonadism Caused by Inactivating Mutations in SRA1. J Clin Res Pediatr Endocrinol. 2016;8:125–34. [PMC free article: PMC5096466] [PubMed: 27086651]
46. Laitinen EM, Vaaralahti K, Tommiska J, Eklund E, Tervaniemi M, Valanne L, Raivio T. Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland. Orphanet J Rare Dis. 2011; 6:41. [PMC free article: PMC3143089] [PubMed: 21682876]
47. Lalani SR, Belmont JW. CHARGE syndrome. In: Lang F, ed. Encyclopedia of Molecular Mechanisms of Disease. Springer Publishing House. 2009.
48. Lee PL, Johnson DE, Cousens LS, Fried VA, Williams LT. Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor. Science. 1989;245:57–60. [PubMed: 2544996]
49. Lewkowitz-Shpuntoff HM, Hughes VA, Plummer L, Au MG, Doty RL, Seminara SB, Chan YM, Pitteloud N, Crowley WF Jr, Balasubramanian R. Olfactory phenotypic spectrum in idiopathic hypogonadotropic hypogonadism: pathophysiological and genetic implications. J Clin Endocrinol Metab. 2012;97:E136–44. [PMC free article: PMC3251934] [PubMed: 22072740]
50. Liu PY, Baker HW, Jayadev V, Zacharin M, Conway AJ, Handelsman DJ. Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin-deficient infertile men: predictors of fertility outcome. J Clin Endocrinol Metab. 2009;94:801–8. [PubMed: 19066302]
51. Mainieri AS, Elnecave RH. Usefulness of the free alpha-subunit to diagnose hypogonadotropic hypogonadism. Clin Endocrinol (Oxf) 2003;59:307–13. [PubMed: 12919153]
52. Margolin DH, Kousi M, Chan YM, Lim ET, Schmahmann JD, Hadjivassiliou M, Hall JE, Adam I, Dwyer A, Plummer L, Aldrin SV, O'Rourke J, Kirby A, Lage K, Milunsky A, Milunsky JM, Chan J, Hedley-Whyte ET, Daly MJ, Katsanis N, Seminara SB. Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. N Engl J Med. 2013;368:1992–2003. [PMC free article: PMC3738065] [PubMed: 23656588]
53. Martin C, Balasubramanian R, Dwyer AA, Au MG, Sidis Y, Kaiser UB, Seminara SB, Pitteloud N, Zhou QY, Crowley WF Jr. The Role of the prokineticin 2 pathway in human reproduction: evidence from the study of human and murine gene mutations. Endocr Rev. 2011;32:225–46. [PMC free article: PMC3365793] [PubMed: 21037178]
54. Martin K, Santoro N, Hall J, Filicori M, Wierman M, Crowley WF Jr (1990) Clinical review 15: Management of ovulatory disorders with pulsatile gonadotropin-releasing hormone. J Clin Endocrinol Metab. 71:1081A-G. [PubMed: 2229271]
55. Massin N, Pecheux C, Eloit C, Bensimon JL, Galey J, Kuttenn F, Hardelin JP, Dode C, Touraine P. X chromosome-linked Kallmann syndrome: clinical heterogeneity in three siblings carrying an intragenic deletion of the KAL-1 gene. J Clin Endocrinol Metab. 2003; 88:2003–8. [PubMed: 12727945]
56. Matsumoto S, Yamazaki C, Masumoto KH, Nagano M, Naito M, Soga T, Hiyama H, Matsumoto M, Takasaki J, Kamohara M, Matsuo A, Ishii H, Kobori M, Katoh M, Matsushime H, Furuichi K, Shigeyoshi Y. Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. Proc Natl Acad Sci U S A. 2006;103:4140–5. [PMC free article: PMC1449660] [PubMed: 16537498]
57. Matsuo T, Okamoto S, Izumi Y, Hosokawa A, Takegawa T, Fukui H, Tun Z, Honda K, Matoba R, Tasumi K, Amino N. A novel mutation of the KAL1 gene in monozygotic twins with Kallmann syndrome. Eur J Endocrinol. 2000;143:783–7. [PubMed: 11124862]
58. Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung W, Feng B, Beenken A, Clarke J, Pers TH, Dworzynski P, Keefe K, Niedziela M, Raivio T, Crowley WF Jr, Seminara SB, Quinton R, Hughes VA, Kumanov P, Young J, Yialamas MA, Hall JE, Van Vliet G, Chanoine JP, Rubenstein J, Mohammadi M, Tsai PS, Sidis Y, Lage K, Pitteloud N. Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013;92:725–43. [PMC free article: PMC3644636] [PubMed: 23643382]
59. Monnier C, Dode C, Fabre L, Teixeira L, Labesse G, Pin JP, Hardelin JP, Rondard P. PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity. Hum Mol Genet. 2009; 18:75–81. [PMC free article: PMC3298864] [PubMed: 18826963]
60. Nachtigall LB, Boepple PA, Pralong FP, Crowley WF Jr. Adult-onset idiopathic hypogonadotropic hypogonadism--a treatable form of male infertility. N Engl J Med. 1997;336:410–5. [PubMed: 9010147]
61. Oliveira LM, Seminara SB, Beranova M, Hayes FJ, Valkenburgh SB, Schipani E, Costa EM, Latronico AC, Crowley WF Jr, Vallejo M. The importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristics. J Clin Endocrinol Metab. 2001;86:1532–8. [PubMed: 11297579]
62. Pedersen-White JR, Chorich LP, Bick DP, Sherins RJ, Layman LC. The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Mol Hum Reprod. 2008;14:367–70. [PMC free article: PMC2434956] [PubMed: 18463157]
63. Pingault V, Bodereau V, Baral V, Marcos S, Watanabe Y, Chaoui A, Fouveaut C, Leroy C, Vérier-Mine O, Francannet C, Dupin-Deguine D, Archambeaud F, Kurtz FJ, Young J, Bertherat J, Marlin S, Goossens M, Hardelin JP, Dodé C, Bondurand N. Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness. Am J Hum Genet. 2013;92:707–24. [PMC free article: PMC3644631] [PubMed: 23643381]
64. Pinto G, Abadie V, Mesnage R, Blustajn J, Cabrol S, Amiel J, Hertz-Pannier L, Bertrand AM, Lyonnet S, Rappaport R, Netchine I. CHARGE syndrome includes hypogonadotropic hypogonadism and abnormal olfactory bulb development. J Clin Endocrinol Metab. 2005; 90:5621–6. [PubMed: 16030162]
65. Pitteloud N, Acierno JS Jr, Meysing A, Eliseenkova AV, Ma J, Ibrahimi OA, Metzger DL, Hayes FJ, Dwyer AA, Hughes VA, Yialamas M, Hall JE, Grant E, Mohammadi M, Crowley WF Jr. Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2006a;103:6281–6. [PMC free article: PMC1458869] [PubMed: 16606836]
66. Pitteloud N, Boepple PA, DeCruz S, Valkenburgh SB, Crowley WF Jr, Hayes FJ. The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metab. 2001;86:2470–5. [PubMed: 11397842]
67. Pitteloud N, Hayes FJ, Boepple PA, DeCruz S, Seminara SB, MacLaughlin DT, Crowley WF Jr. The role of prior pubertal development, biochemical markers of testicular maturation, and genetics in elucidating the phenotypic heterogeneity of idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2002a;87:152–60. [PubMed: 11788640]
68. Pitteloud N, Hayes FJ, Dwyer A, Boepple PA, Lee H, Crowley WF Jr. Predictors of outcome of long-term GnRH therapy in men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2002b; 87:4128–36. [PubMed: 12213860]
69. Pitteloud N, Meysing A, Quinton R, Acierno JS Jr, Dwyer AA, Plummer L, Fliers E, Boepple P, Hayes F, Seminara S, Hughes VA, Ma J, Bouloux P, Mohammadi M, Crowley WF Jr. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol. 2006b;254-255:60–9. [PubMed: 16764984]
70. Quinton R, Duke VM, Robertson A, Kirk JM, Matfin G, de Zoysa PA, Azcona C, MacColl GS, Jacobs HS, Conway GS, Besser M, Stanhope RG, Bouloux PM. Idiopathic gonadotropin deficiency: genetic questions addressed through phenotypic characterization. Clin Endocrinol (Oxf) 2001;55:163–74. [PubMed: 11531922]
71. Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA, Cole LW, Pearce SH, Lee H, Boepple P, Crowley WF Jr, Pitteloud N. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med. 2007;357:863–73. [PubMed: 17761590]
72. Richards MR, Plummer L, Chan YM, Lippincott MF, Quinton R, Kumanov P, Seminara SB. Phenotypic spectrum of POLR3B mutations: isolated hypogonadotropic hypogonadism without neurological or dental anomalies. J Med Genet. 2017;54:19–25. [PMC free article: PMC5189673] [PubMed: 27512013]
73. Rugarli EI, Lutz B, Kuratani SC, Wawersik S, Borsani G, Ballabio A, Eichele G. Expression pattern of the Kallmann syndrome gene in the olfactory system suggests a role in neuronal targeting. Nat Genet. 1993; 4:19–26. [PubMed: 8513320]
74. Salian-Mehta S, Xu M, Knox AJ, Plummer L, Slavov D, Taylor M, Bevers S, Hodges RS, Crowley WF Jr, Wierman ME. Functional consequences of AXL sequence variants in hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2014;99:1452–60. [PMC free article: PMC3973777] [PubMed: 24476074]
75. Santoro N, Filicori M, Crowley WF Jr. Hypogonadotropic disorders in men and women: diagnosis and therapy with pulsatile gonadotropin-releasing hormone. Endocr Rev. 1986;7:11–23. [PubMed: 3082615]
76. Sato N, Ogata T. Kallmann syndrome. Nihon Rinsho. 2006 Suppl 2:220–4. [PubMed: 16817388]
77. Segal TY, Mehta A, Anazodo A, Hindmarsh PC, Dattani MT. Role of gonadotropin-releasing hormone and human chorionic gonadotropin stimulation tests in differentiating patients with hypogonadotropic hypogonadism from those with constitutional delay of growth and puberty. J Clin Endocrinol Metab. 2009;94:780–5. [PubMed: 19017752]
78. Seminara SB, Hayes FJ, Crowley WF Jr. Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann's syndrome): pathophysiological and genetic considerations. Endocr Rev. 1998;19:521–39. [PubMed: 9793755]
79. Seminara SB, Acierno JS Jr, Abdulwahid NA, Crowley WF Jr, Margolin DH. Hypogonadotropic hypogonadism and cerebellar ataxia: detailed phenotypic characterization of a large, extended kindred. J Clin Endocrinol Metab. 2002;87:1607–12. [PubMed: 11932290]
80. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O'Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349:1614–27. [PubMed: 14573733]
81. Semple RK, Achermann JC, Ellery J, Farooqi IS, Karet FE, Stanhope RG, O'rahilly S, Aparicio SA. Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2005;90:1849–55. [PubMed: 15598687]
82. Shaw ND, Seminara SB, Welt CK, Au MG, Plummer L, Hughes VA, Dwyer AA, Martin KA, Quinton R, Meriq V, Merino PM, Gusella JF, Crowley WF Jr, Pitteloud N, Hall JE. Expanding the phenotype and genotype of female GnRH deficiency. J. Clin. Endocrinol. Metab. 2011;96:E566–76. [PMC free article: PMC3047229] [PubMed: 21209029]
83. Sidhoum VF, Chan YM, Lippincott MF, Balasubramanian R, Quinton R, Plummer L, Dwyer A, Pitteloud N, Hayes FJ, Hall JE, Martin KA, Boepple PA, Seminara SB. Reversal and relapse of hypogonadotropic hypogonadism: resilience and fragility of the reproductive neuroendocrine system. J Clin Endocrinol Metab. 2014;99:861–70. [PMC free article: PMC3942233] [PubMed: 24423288]
84. Spratt DI, Carr DB, Merriam GR, Scully RE, Rao PN, Crowley WF Jr. The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations. J Clin Endocrinol Metab. 1987;64:283–91. [PubMed: 3098771]
85. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998;18:213–5. [PubMed: 9500540]
86. Suzuki E, Izumi Y, Chiba Y, Horikawa R, Matsubara Y, Tanaka M, Ogata T, Fukami M, Naiki Y. Loss-of-function SOX10 mutation in a patient with Kallmann syndrome, hearing loss, and iris hypopigmentation. Horm Res Paediatr. 2015;84:212–6. [PubMed: 26228106]
87. Sykiotis GP, Hoang XH, Avbelj M, Hayes FJ, Thambundit A, Dwyer A, Au M, Plummer L, Crowley WF Jr, Pitteloud N. Congenital idiopathic hypogonadotropic hypogonadism: evidence of defects in the hypothalamus, pituitary, and testes. J Clin Endocrinol Metab. 2010a;95:3019–27. [PMC free article: PMC2902061] [PubMed: 20382682]
88. Sykiotis GP, Plummer L, Hughes VA, Au M, Durrani S, Nayak-Young S, Dwyer AA, Quinton R, Hall JE, Gusella JF, Seminara SB, Crowley WF Jr, Pitteloud N. Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proc Natl Acad Sci U S A. 2010b; 107:15140–4. [PMC free article: PMC2930591] [PubMed: 20696889]
89. Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Ozbek MN, Imamoglu S, Akalin NS, Yuksel B, O'Rahilly S, Semple RK. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet. 2009;41:354–8. [PMC free article: PMC4312696] [PubMed: 19079066]
90. Topaloglu AK, Tello JA, Kotan LD, Ozbek MN, Yilmaz MB, Erdogan S, Gurbuz F, Temiz F, Millar R, Yuksel B. Inactivating KISS1 mutation and hypogonadotropic hypogonadism. NEJM. 2012;366:629–35. [PubMed: 22335740]
91. Tornberg J, Sykiotis GP, Keefe K, Plummer L, Hoang X, Hall JE, Quinton R, Hughes V, Seminara SB, Van Uum S, Crowley WF, Habuchi H, Kimataf K, Piteloud N, Bülow HE. Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2011;108:11524–9. [PMC free article: PMC3136273] [PubMed: 21700882]
92. Trarbach EB, Abreu AP, Silveira LF, Garmes HM, Baptista MT, Teles MG, Costa EM, Mohammadi M, Pitteloud N, de Mendonca BB, Latronico AC. Nonsense mutations in FGF8 gene causing different degrees of human gonadotropin-releasing deficiency. J Clin Endocrinol Metab. 2010a;95:3491–6. [PMC free article: PMC3213864] [PubMed: 20463092]
93. Trarbach EB, Teles MG, Costa EM, Abreu AP, Garmes HM, Guerra G Jr, Baptista MT, de Castro M, Mendonca BB, Latronico AC. Screening of autosomal gene deletions in patients with hypogonadotropic hypogonadism using multiplex ligation-dependent probe amplification: detection of a hemizygosis for the fibroblast growth factor receptor 1. Clin Endocrinol (Oxf) 2010b;72:371–6. [PubMed: 19489874]
94. Van Dop C, Burstein S, Conte FA, Grumbach MM. Isolated gonadotropin deficiency in boys: clinical characteristics and growth. J Pediatr. 1987;111:684–92. [PubMed: 2889818]
95. Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, van der Vliet WA, Huys EH, de Jong PJ, Hamel BC, Schoenmakers EF, Brunner HG, Veltman JA, van Kessel AG. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet. 2004;36:955–7. [PubMed: 15300250]
96. Waldhauser F, Weissenbacher G, Frisch H, Pollak A. Pulsatile secretion of gonadotropins in early infancy. Eur J Pediatr. 1981;137:71–4. [PubMed: 6791927]
97. Waldstreicher J, Seminara SB, Jameson JL, Geyer A, Nachtigall LB, Boepple PA, Holmes LB, Crowley WF Jr. The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human. J Clin Endocrinol Metab. 1996;81:4388–95. [PubMed: 8954047]
98. Whitcomb RW, Crowley WF Jr. Clinical review 4: Diagnosis and treatment of isolated gonadotropin-releasing hormone deficiency in men. J Clin Endocrinol Metab. 1990;70:3–7. [PubMed: 2403572]
99. Xu N, Kim HG, Bhagavath B, Cho SG, Lee JH, Ha K, Meliciani I, Wenzel W, Podolsky RH, Chorich LP, Stackhouse KA, Grove AM, Odom LN, Ozata M, Bick DP, Sherins RJ, Kim SH, Cameron RS, Layman LC. Nasal embryonic LHRH factor (NELF) mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome. Fertil Steril. 2011;95:1613–20.e1. [PMC free article: PMC3888818] [PubMed: 21300340]
100. Young J. Approach to the male patient with congenital hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2012;97:707–18. [PubMed: 22392951]

推荐阅读

1. Ballabio A, Rugarli EI. Kallmann syndrome. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill. Chap 225. Available online.
2. Crowley WF, Balasubramanian R, eds. Special Issue: Genetics of GnRH Deficiency. Available online. 2011.
3. Semple RK, Kemal Topaloglu A. The recent genetics of hypogonadotropic hypogonadism - novel insights and new questions. Clin Endocrinol (Oxf) 2010;72:427–35. [PubMed: 19719764]

作者历史

Margaret Au, MBE, MS, CGC; Massachusetts General Hospital (2010-2013)
Ravikumar Balasubramanian, MD, PhD (2013-present)
Cassandra Buck, MS, CGC; Massachusetts General Hospital (2013-2017)
Marissa Caudill; University of Connecticut Health Center (2007-2010)
William F Crowley Jr, MD (2007-present)
J Carl Pallais, MD, MPH; Massachusetts General Hospital (2007-2013)
Nelly Pitteloud, MD; Massachusetts General Hospital (2007-2013)
Stephanie Seminara, MD; Massachusetts General Hospital (2007-2013)

修订历史

• 2 March 2017 (ha) Comprehensive update posted live
• 18 July 2013 (me) Comprehensive update posted live
• 18 August 2011 (cd) Revision: 序列分析 and 产前诊断 available clinically for mutations in FGF8 causing Kallmann syndrome 6
• 4 January 2011 (cd) Revision: changes in nomenclature, Tanner staging, and test availability; references added
• 8 April 2010 (me) Comprehensive update posted live
• 23 May 2007 (me) Review posted to live Web site
• 1 June 2006 (jcp) Original submission