假性甲状旁腺功能减退症是一种罕见病，国内报道日渐增多。据悉，上海交通大学医学院附属新华医院新生儿科钱继红教授带领的临床团队对上海新华医院2008年至2018年的10年间住院收治的14例该病患儿资料进行了回顾性总结分析，对减少误诊和漏诊必将有所裨益。此外，国外已有专家共识。
在此，将相关资料汇总，择其要记之，望抛砖引玉。
1 假性甲状旁腺功能减退症的概要
因 G 蛋白介导的信号转导缺失而造成的对甲状旁腺素作用抵抗而导致的疾病。
根据特征性骨骼表型的存在与否、对甲状旁腺素的反应性、潜在的突变以及遗传模式可分为不同的类型。
临床表现为低钙血症、高磷血症和甲状旁腺素水平升高。
一些患者同时患有相关内分泌疾病。 甲状腺功能减退最常见，但性腺功能减退也可见到。
主要的治疗是通过补充钙剂、维生素 D 和噻嗪类利尿剂。 如有相关内分泌病可使用激素替代治疗。
潜在的信号转导缺陷是难以治愈的。
Results from resistance to the actions of parathyroid hormone (PTH) produced by a loss of G-protein-mediated signaling.
Different types are distinguished by the presence or absence of a characteristic skeletal phenotype, the responsiveness to PTH, the underlying mutations, and the inheritance pattern.
Manifests clinically with hypocalcemia, hyperphosphatemia, and elevated PTH levels.
Some patients have associated endocrinopathies. Hypothyroidism is the most common, but hypogonadism is also seen.
The mainstay of treatment is the normalization of calcium and phosphate levels using calcium supplementation, vitamin D, and thiazide diuretics. Associated endocrinopathies, if present, are treated with hormone replacement.
The underlying signaling defects are incurable.
2 定义
假性甲状旁腺功能减退症源于靶组织对甲状旁腺激素的生物学作用不敏感。它是由甲状旁腺激素信号转导通路中的基因突变引起的。 临床表现为低钙血症、甲状旁腺激素水平升高和高磷血症。 该病可有临床症状或无症状。 多样化表现与基因表达的组织特异性、剪接变异和携带者状态相关。 本病的某些类型与身材矮小、矮壮体型、肥胖，圆脸、牙齿发育不良、短掌骨、短跖骨和软组织钙化/骨化等特征性骨骼表型（称为 Albright 遗传性骨营养不良症）相关。
Definition
Pseudohypoparathyroidism (PHP) results from an insensitivity of target tissues to the biologic actions of parathyroid hormone (PTH). It is caused by genetic mutations in the PTH signaling pathway. The disease manifests clinically with hypocalcemia, high PTH levels, and hyperphosphatemia. The disease may be symptomatic or asymptomatic. The diverse presentations relate to tissue specificity of expression, splice variations, and carrier status. Some forms of the disease are associated with a characteristic skeletal phenotype of short stature, stocky habitus, obesity, round face, dental hypoplasia, brachymetacarpals, brachymetatarsals, and soft-tissue calcification/ossification referred to as Albright hereditary osteodystrophy.
为什么被称为假性甲状旁腺功能减退症？
甲状旁腺功能减退症是指甲状旁腺激素分泌过少和(或)效应不足而引起的一组临床综合征。其临床特征有低钙血症、高磷血症和由此引起的神经肌肉兴奋性增高及软组织异位钙化等，同时甲状旁腺激素水平低于正常或处于与血钙水平不相应的“正常”范围。
由于外周靶细胞对甲状旁腺激素抵抗所致的临床综合征称为假性甲状旁腺功能减退症，其具有与甲状旁腺功能减退症类似的生化表现，但甲状旁腺激素水平显著高于正常；部分并发典型的Albright遗传性骨营养不良。仅存在Albright遗传性骨营养不良特殊体征，但缺乏相应的生化及代谢异常者称为假-假性甲状旁腺功能减退症。
定义中提出“本病的某些类型与身材矮小、矮壮体型、肥胖，圆脸、牙齿发育不良、短掌骨、短跖骨和软组织钙化/骨化等特征性骨骼表型（称为 Albright 遗传性骨营养不良症）相关。”典型的标准化病人是什么样子的？
身材矮小、矮壮体型、肥胖，圆脸（a）、短掌骨（b，d）、短跖骨（c，e）、牙釉质发育不良（f） 、低钙抽搐（g）。
3 流行病学
假性甲状旁腺功能减退症极其罕见。目前只有一项研究收集了在全日本随机选取的儿科、内科、神经科和内分泌科的数据。1997 年，总共 203 名患者确诊患有假性甲状旁腺功能减退症，由此估计日本的患病率为 3.4/百万人。这些数字可能低估了实际情况，因为假性甲状旁腺功能减退症的表现形式多种多样。丹麦国家患者登记库2011年的一项审查发现了60 名患者，患病率为每10 万居民中1.1 例。专家认为，1a 型是最常见的假性甲状旁腺功能减退症 类型。 女性患者与男性患者的比例是 2:1。
Epidemiology
Pseudohypoparathyroidism (PHP) is extremely rare. One study collected data from randomly selected departments of pediatrics, internal medicine, neurology, and endocrinology throughout Japan. A total of 203 patients were diagnosed with PHP in 1997, providing an estimated prevalence of 0.34 cases of PHP per 100,000 inhabitants in Japan. These numbers are likely to be an underestimate given the wide range of presentations of PHP. One 2011 National Patient Registry review in Denmark identified 60 patients, a prevalence of 1.1 cases per 100,000 inhabitants. Based on expert opinion, type Ia is the most common form. The ratio of women to men is 2:1.
4 病因学
假性甲状旁腺功能减退症 (PHP) 由甲状旁腺素 (PTH)/PTH 相关肽受体 (PTHrP1) 的下游信号级联突变导致的。迄今为止，所有已发现的突变都会影响 GNAS （GNAS 负责编码鸟嘌呤核苷酸结合蛋白 [G 蛋白] Gsα 基因）。 但是，所有类型的假性甲状旁腺功能减退症的致病突变均未明确。Gsα 基因（定位在位于 20q13.3 染色体的 GNAS 基因位点）转录受基因组印迹——一种表观遗传（非 DNA 序列决定的）现象的影响，导致 Gsα 表达异常或不充分。基因印迹使得一个细胞只能表达一个等位基因，最常见的是母系起源基因，但父系遗传也有报道。这些源于亲代的代谢效应是由少数组织优先表达母源等位基因造成的。 GNAS 基因无效沉寂或甲基化也可能导致假性甲状旁腺功能减退症。Gsα 突变引起的亲代来源的代谢效应究竟涉及哪些组织尚未完全明确。少数受累组织有助于解释患者的独特临床表现。肥胖的病因可能是下丘脑室旁核中被印迹的 Gsα基因突变造成了能量消耗的减少。 假性甲状旁腺功能减退症的类型取决于 GNAS 突变、印迹组织和遗传模式。
Etiology
Pseudohypoparathyroidism (PHP) occurs as a result of mutations in the downstream signaling cascade of parathyroid hormone (PTH)/PTH-related peptide receptor (PTHrP1). All mutations identified to date affect GNAS, the gene coding for the guanine nucleotide-binding protein (G-protein) Gs-alpha. However, the causative mutation is not known for all forms of PHP. Gs-alpha gene (positioned on chromosome 20q13.3 at the GNAS locus) transcription is affected by genomic imprinting, an epigenetic (non-DNA -sequence determined) phenomenon, leading to aberrant or inadequate expression of Gs-alpha. Imprinting of a gene allows a cell to express only one allele, most commonly maternal origin, but paternal inheritance has also been described. These parent-of-origin metabolic effects are due to preferential expression from the maternal allele in a small number of tissues. Ineffective silencing or methylation of GNAS genes may also result in the findings of PHP. Tissues involved in the parent-of-origin metabolic effects of Gs-alpha mutation are not known completely. The small number of affected tissues helps to explain the unique presentation of these patients. The etiology for obesity has been suggested to be the result of reduced energy expenditure from an imprinted Gs-alpha mutation in the paraventricular nucleus of the hypothalamus. The type of PHP depends on the GNAS mutation, the imprinted tissue, and the inheritance pattern.
5 发病机制
甲状旁腺素 (parathyroid hormone, PTH) 主要涉及钙稳态的调节。在钙受体感知到离子钙减少时，甲状旁腺释放 PTH。PTH 从骨骼中释放钙，通过促进维生素 D 的合成和活化而增加肠道钙吸收，并促进肾脏重吸收钙并排磷。PTH 或 PTHrP（一种对生长发育非常重要的蛋白质）与其受体结合后，会发生一系列由 G 蛋白介导的级联事件。一旦配体结合其受体，G 蛋白被激活，刺激第二信使环磷酸腺苷 (cAMP) 的合成。由于 cAMP 信号系统分布广泛，cAMP 信号缺陷可能导致代谢、骨骼或更高级的精神功能异常。假性甲状旁腺功能减退症中最常见的缺陷是 PTH 抵抗（造成低钙血症）、促甲状腺激素抵抗（造成甲状腺功能减退）和特征性骨骼表型（Albright 遗传性骨营养不良症）。PTH 抵抗导致低钙血症。PTH 水平长期升高，因为低钙血症和高磷血症不断刺激 PTH 的产生，但升高的 PTH 却无法使血清钙水平恢复正常。
Parathyroid hormone (PTH) is primarily involved in calcium homeostasis. It is released from the parathyroid gland when a calcium receptor perceives decreased ionized calcium. PTH liberates calcium from bone, increases intestinal calcium absorption by promoting the synthesis and activation of vitamin D, and promotes calcium reabsorption and phosphate excretion in the kidneys. Binding of PTH or PTH-related peptide (PTHrP), a protein important for growth, to its receptor is followed by a cascade of events that are mediated by G proteins. Once the ligand binds to its receptor, the G-protein is activated and stimulates the synthesis of the second messenger, cyclic adenosine monophosphate (cAMP). Defects in cAMP signaling may result in metabolic, skeletal, or higher mental function abnormalities due to the broad distribution of this signaling system. The most common defects observed in PHP are PTH resistance (producing hypocalcemia), thyroid-stimulating hormone resistance (producing hypothyroidism), and the characteristic skeletal phenotype (Albright hereditary osteodystrophy). PTH resistance results in hypocalcemia. PTH levels become chronically elevated because the hypocalcemia and hyperphosphatemia continue to stimulate PTH production, which in turn is unable to restore calcium levels.
许多患者表现为慢性无症状性低钙血症，但也可出现神经和肌肉兴奋性升高、感觉异常、抽搐、焦虑和 ECG 异常（QT 延长）等症状。 如果症状性低钙血症患者的钙水平得不到纠正，可能会造成心律失常和死亡。
Many patients have chronic asymptomatic hypocalcemia, but symptoms of hypersensitivity of nerve and muscle, paresthesias, twitching, anxiety, and ECG abnormalities (QT prolongation) can occur. If calcium levels are not corrected in patients with symptomatic hypocalcemia, cardiac arrhythmia and death can occur.
PTH 抵抗也导致高磷血症，高磷血症则进一步刺激 PTH 分泌以降低血磷水平。 高磷血症导致骨骼外磷酸钙产生增加。 磷酸钙可在肾内沉积（导致肾结石）、脑内沉积（导致基底神经节钙化）、皮肤内沉积（导致皮下钙化和骨化）以及在眼内沉积（导致白内障）。
PTH resistance also leads to hyperphosphatemia, which stimulates PTH secretion in an effort to lower phosphate levels. Hyperphosphatemia leads to the increased formation of calcium phosphate in extraskeletal sites. Calcium phosphate can be deposited in the kidney (causing nephrolithiasis), the brain (causing calcification of the basal ganglia), the skin (causing subdermal calcification and ossification), and the eye (causing cataracts).
6 临床分型
1a 型由人类或其他哺乳动物的母系遗传的 Gsα基因发生功能丧失性杂合突变造成。G 蛋白偶联信号的减少可能造成 PTH、促甲状腺激素 、促性腺激素和生长激素释放激素的功能缺失。特征性骨骼表型包括身材矮小、矮壮体型、肥胖、圆脸、牙齿发育不良、短掌骨、短跖骨和软组织钙化/骨化。这种骨骼的特征性表型被称为 Albright 遗传性骨营养不良症。
Type Ia is caused by heterozygous loss-of-function mutations in Gs-alpha, inherited from the mother in humans and other mammals.This reduction of G-protein-coupled signaling may result in lack of function of PTH, thyroid-stimulating hormone (TSH), gonadotropins, and growth hormone-releasing hormone. A characteristic skeletal phenotype, including short stature, stocky habitus, obesity, round face, dental hypoplasia, brachymetacarpals, brachymetatarsals, and soft-tissue calcification/ossification also results. It is referred to as Albright hereditary osteodystrophy.
1b 型是由 GNAS 基因位点不严重的散发或常染色体显性突变造成，使 Gsα 表达降低，从而影响对 PTH 敏感的组织（主要是肾），有时也会影响对 TSH 敏感的组织（甲状腺）。 其他组织不会受影响，因此不会出现形态上的异常。
Type Ib is caused by less-severe sporadic or autosomal dominant mutations at GNAS locus, resulting in reduced expression of Gs-alpha affecting PTH-sensitive tissues (mostly the kidney) and sometimes TSH-sensitive tissues (the thyroid gland). Other tissues are spared, so there are no morphologic abnormalities.
1c 型的 Gsα 活性通常正常，也无 GNAS 突变。 但是，近期已在 1c 型中的 I 个亚组中检测到 GNAS 羧基末端突变。 1c 型的表型与 1a 型相似，出现全身性激素抵抗以及 Albright 遗传性骨营养不良症。1c 型的环磷酸腺苷 (cAMP) 反应迟钝，提示 cAMP 合成和分解循环存在缺陷。
Type Ic is typically associated with normal Gs-alpha activity and absence of GNAS mutations. However, mutations in the GNAS carboxy terminus have been recently detected in a subgroup of type Ic patients. The phenotype of type Ic is similar to that of type Ia, with generalized hormone resistance and Albright hereditary osteodystrophy. The cyclic adenosine monophosphate (cAMP) response is blunted in type Ic, suggesting that there is a defect in the cAMP synthesis and breakdown cycle.
2 型由尚未明确的功能丧失性突变造成，但 Gsα 的外显子并不发生突变。 2 型的表型不明显，形态上正常，PTH 抵抗为选择性。 2 型假性甲状旁腺功能减退症中，cAMP 对甲状旁腺激素有反应，表明缺陷位于 cAMP 下游。
Type II is caused by as-yet unidentified loss-of-function mutations without a mutation of the coding exons of Gs-alpha. The phenotype of type II is milder, with normal morphology and selective PTH resistance. The cAMP response to PTH is preserved in type II PHP, suggesting that the defect is located downstream of cAMP.
假假性甲状旁腺功能减退症由与 1a 和 1b 型 PHP 相同的突变造成，但突变遗传于父亲而非母亲。父源遗传不会造成激素抵抗，但是仍会出现特征性骨骼表型。原因是 Gsα 主要由肾脏中的母源等位基因表达。 如果母源等位基因发生无功能性突变，靶组织中 Gsα 介导的功能将会丧丢失，造成 PHP。 然而，如果父源等位基因携带了突变，Gsα 介导的功能在 PTH 靶组织仍将被保留。因为特征性骨骼表型的形成需要两个具有完整功能的等位基因存在，这些异常表型可见于某些类型的假性甲状旁腺功能减退症和假假性甲状旁腺功能减退症患者。
Pseudopseudohypoparathyroidism is caused by the same mutations as type Ia and Ib PHP, but the mutations are inherited from the father rather than from the mother. Paternal inheritance produces no hormone resistance, but the characteristic skeletal phenotype still occurs. The reason for this is that Gs-alpha is primarily expressed from the maternal allele in the kidney. If the maternal allele has a nonfunctioning mutation, Gs-alpha-mediated function will be lost in the target tissues, causing PHP. However, if the paternal allele carries the mutation, Gs-alpha-mediated function will be preserved in the target tissues. Because the tissues affected by the characteristic skeletal phenotype require both alleles to be fully functional, these abnormalities are seen in some types of PHP and in patients with pseudo-PHP.
F61.com简表如下
7 临床表现
PTH 抵抗造成低钙血症和高磷血症，具有独特的临床特征。 低钙血症不总是在出生时即表现出来，而是倾向于在 3 至 8 岁之间发病。 轻度低钙血症通常是无症状的。 有些患者可诉称肌肉痉挛。 严重的低钙血症是急症，对关键症状和体征保持警觉至关重要。 嘴唇、手指或脚趾感觉异常是常见的早期症状。 严重低钙血症会造成肌肉颤搐、痉挛或抽搐。 如果痉挛影响喉平滑肌，患者可发展为威胁生命的喘鸣。 患者可能诉称困倦或焦虑。 如果不治疗，患者可能发展成意识错乱、惊厥或致命的心律失常。 PHP 也可能是发作性运动障碍（不自主间歇性运动障碍）的一个病因。也可见到一些细微体征，如指甲变脆、头发干枯或耳廓钙化。
PTH resistance produces hypocalcemia and hyperphosphatemia, which produce distinct clinical features. Hypocalcemia does not always manifest at birth but tends to occur between 3 and 8 years of age. Mild hypocalcemia is often asymptomatic. Some patients may report muscle cramps. Severe hypocalcemia is a medical emergency, and it is important to be alert for the key symptoms and signs. Paresthesias affecting the lips, fingers, or toes are common early symptoms. Severe hypocalcemia can cause muscle twitches, spasm, or tetany. If spasms affect laryngeal smooth muscle, the patient may develop life-threatening stridor. The patient may report lethargy or anxiety. If left untreated, patients can develop confusion, convulsions, or a fatal cardiac arrhythmia. PHP may also be a cause of paroxysmal dyskinesias (involuntary intermittent movement disorders). Subtle signs such as brittle nails, dry hair, or calcification of the pinna of the ears may also be seen.
低钙血症可产生两种重要的临床体征。
Hypocalcemia produces two key clinical signs.
Chvostek 征是在患者稍微张开嘴巴的同时，用手指轻叩患者耳屏前面的面部神经引发。 同侧面部肌肉颤搐为阳性，是神经纤维兴奋性升高的体征。
Chvostek sign is elicited by tapping a finger on the facial nerve in front of the tragus of the ear with the mouth slightly opened. Twitching of the ipsilateral facial muscles is considered positive and is a sign of hypersensitivity of the nerve fibers.
Trousseau 征是将放置在肱动脉上的血压表袖带充气至高于收缩压 20 mmHg 并保持 5 分钟而诱发。 远端缺血引起手抽搐，掌指关节屈曲和指间关节伸展。 反应越快，血清钙含量越低。
Trousseau sign is elicited by inflating a blood pressure cuff placed over the brachial artery to 20 mmHg above systolic for 5 minutes. The distal ischemia produces tetany of the hand with flexion at the metacarpophalangeal joints and extension at the interphalangeal joints. The more rapid the response, the lower the serum calcium.
磷血症造成骨骼外组织中的磷酸钙沉积增加。磷酸钙结石在肾脏形成，可造成肾结石。磷酸钙在脑中沉积引起基底神经节钙化，是 PHP 在经典计算机体层成像 (CT) 片中的经典表现。磷酸钙在皮肤中沉积造成皮下钙化和骨化。磷酸钙在眼中沉积可造成白内障。所有患者均需要进行常规眼科检查，以发现是否形成白内障。
Hyperphosphatemia produces an increase in the deposition of calcium phosphate in extraskeletal tissues. Calcium phosphate stones can form in the kidney, producing nephrolithiasis. Calcium phosphate deposition in the brain produces basal ganglia calcification, a classic computed tomographic (CT) finding of PHP. Calcium phosphate deposition in the skin produces subdermal calcification and ossification. Calcium phosphate deposition in the eye can cause cataracts. Routine ophthalmologic exam is required in all patients to identify cataract formation.
8 鉴别诊断
9 治疗步骤
潜在的信号转导缺陷是难以治愈的。治疗甲状旁腺素 (parathyroid hormone, PTH) 抵抗的主要目的是将钙和磷的水平维持在正常范围内，同时避免高钙尿症。 有症状的低钙血症是一种急症，需要立即治疗。 无症状的低钙血症主要通过口服补充钙剂治疗。 相关内分泌疾病使用激素替代治疗。 治疗心智衰退的患者时需要对护理人员进行相应的指导，以确保正确的药物治疗。
Approach
The underlying signaling defects are incurable. The main aim of management of parathyroid hormone (PTH) resistance is to maintain levels of calcium and phosphorus within the normal range while avoiding hypercalciuria. Symptomatic hypocalcemia is a medical emergency and requires prompt treatment. Asymptomatic hypocalcemia can be managed primarily with oral calcium supplements. Associated endocrinopathies are treated with hormone replacement. Treating patients with diminished mental function requires instructing appropriate caregivers to ensure proper administration of medication.
10 有症状的低钙血症患者的管理
有症状的低钙血症是一种急症，应尽快静脉注射葡萄糖酸钙。 应通过注射的方式补钙，以降低钙水平的波动。 静脉补钙过程中需要心电监测可能出现的钙诱发的心脏传导缺陷。 如果静脉补钙的效果不够，可添加骨化三醇（一种维生素 D 代谢产物），以提高肠道的钙吸收；该方法对婴儿特别有益。 PHP患者的维生素 D 缺乏症并不常见，因此必须注意避免维生素 D 用药过量。 骨化三醇优于胆骨化醇或麦角钙化醇，这是因为它不需要 PTH 介导激活，而且由于半衰期短，且不是储存在脂肪组织中，它的毒性更容易逆转。一旦急性症状消失，患者应过渡到口服补钙。
Patients with symptomatic hypocalcemia
Symptomatic hypocalcemia is an acute medical emergency, and intravenous calcium gluconate should be given as soon as possible. Calcium should be given in an infusion to reduce fluctuations in levels. ECG monitoring is required during the administration of intravenous calcium to detect calcium-induced cardiac conduction defects. If the response to intravenous calcium is inadequate, calcitriol (a vitamin D metabolite) can be added to improve calcium absorption from the gut; this is particularly beneficial in infants. Patients with pseudohypoparathyroidism (PHP) do not usually have vitamin D deficiency, and care must be taken to avoid vitamin D overdosing. Calcitriol is preferred to cholecalciferol or ergocalciferol because PTH-mediated activation is not required, and calcitriol toxicity is easier to reverse as it has a short half-life and is not stored in adipose tissue. The patient should be transitioned to oral calcium supplements once the acute symptoms have resolved.
11 低钙血症的长期管理
长期管理涉及维持血清钙在正常下限从而减少骨骼外钙化，以及使血清磷水平恢复正常。 口服钙补充剂（例如，碳酸钙，醋酸钙）是维持正常血清钙的首选方法。 这些补充剂的优点是它们也可以作为磷酸盐结合剂，并减少肠道的磷酸盐吸收。 因此，它们可以维持钙水平而不增加骨骼外钙化的风险。 含钙食物中也含有较多的磷酸盐，因此通过此类食物提高钙的摄取量会增加骨骼外钙化的风险。 应避免使用磷酸铝结合剂。维生素 D 可增加肠道对钙的吸收；如果钙补充不能使血清钙恢复正常，可使用骨化三醇提高钙水平。 噻嗪类利尿剂可以减少钙的肾排泄，可加用该药物以进一步提高钙水平。
Long-term management of hypocalcemia
This involves the reduction of extraskeletal calcification by achieving serum calcium goal at the lower limit of laboratory normal range, and normalization of serum phosphorus. Oral calcium supplements (e.g., calcium carbonate and calcium acetate) are preferred for maintaining a normal serum calcium. The advantage of these supplements is that they also act as phosphate binders and reduce the absorption of phosphate from the gut. They therefore allow calcium levels to be maintained without increasing the risk of extraskeletal calcification. Dietary sources of calcium also contain high levels of phosphate, so increasing calcium intake from this source increases the risk of extraskeletal calcification. Aluminum phosphate binders should be avoided. Vitamin D enhances the absorption of calcium from the gut; calcitriol can be given to increase calcium levels if normalization of calcium levels is not achieved with calcium supplementation. Thiazide diuretics can reduce calcium loss through the kidney and can be added to further increase calcium levels.
12 相关内分泌疾病的治疗
相关内分泌疾病需要使用激素替代治疗。 最常见的是甲状腺功能减退，需要使用左甲状腺素长期治疗。 对于身材矮小的儿童，使用生长激素治疗可能有益。 成熟延迟的儿童可能需要外源性睾酮或雌激素。 1a 型 PHP 中生长激素缺乏的发病存在较大变化，使身材矮小的治疗时段受限。 目前正进行临床研究以确定病因和最佳治疗方案。 在该组中对人生长激素的作用进行了研究，研究人员证明青春期前儿童的可以达到正常的生长速度。 在这一较小规模的系列研究中，只有一名儿童最终达到了正常身高。 这些发现表明，缺乏足够的生长激素释放激素作用是身材矮小的主要因素。
Associated endocrinopathies
Associated endocrinopathies require treatment with hormone replacement. The most common is hypothyroidism, which requires long-term treatment with levothyroxine. In children with short stature, growth hormone therapy may be beneficial. Children with delayed maturation may require exogenous testosterone or estrogen. The onset of growth hormone deficiency in PHP type Ia is variable, making the time interval to treat short stature limited. Attempts to determine the etiology and best treatment regimen are ongoing. The effect of human growth hormone in this group has been studied and researchers demonstrated successful attainment of height velocity in prepubertal children. In this small series only one child attained normal final height. The findings suggested the lack of sufficient growth hormone-releasing hormone effect as a major component of short stature.
13 二级预防
如果假性甲状旁腺功能减退症患者想要受孕，应考虑进行胚胎植入前遗传学诊断，以减少和尽可能避免把 GNAS 突变传递给胎儿。通过胚胎植入前遗传学诊断，可以选择植入没有 GNAS 突变的胚胎。
Secondary prevention
If a patient with pseudo- hypoparathyroidism would like to conceive, preimplantation genetic diagnosis (PGD) should be considered to decrease and potentially eliminate the transmission of GNAS mutation to the fetus. PGD allows the selection of embryos without GNAS mutations for implantation.
14 监测
此外，需要监测假性甲状旁腺功能减退症 (PHP) 患者，以确保钙和磷水平回归正常。 必须定期监测钙、磷酸盐和 25-羟基维生素 D 水平，以避免治疗不足或过量。在急性疾病、快速生长期和妊娠期间，钙磷代谢不断变化，如果属于上述任一情况，必须增加监测频率。监测频率也取决于钙磷的达标速度和治疗失败率。Albright 遗传性骨营养不良症与 1a 型和 1c 型 PHP 相关，而 1a 型和 1c 型 PHP 是最有可能与甲状腺功能减退症相关的类型。如果患者患有 Albright 遗传性骨营养不良症和/或确诊的甲状腺功能减退症，需要每年评估一次促甲状腺激素水平。对怀疑因骨量减少而发生骨折的患者，应进行骨密度检测。性腺功能减退症患者也需要定期监测性激素水平。应进行常规眼科检查，以发现白内障。
Monitoring
Patients with pseudohypoparathyroidism (PHP) require monitoring to ensure normalization of calcium and phosphate levels. Calcium, phosphate, and 25-hydroxyvitamin D levels must be monitored regularly to avoid inadequate or excessive treatment. Calcium and phosphate metabolism changes during acute illness, growth spurts, and pregnancy, and the frequency of monitoring must be increased if any of these are present. The frequency of monitoring also depends on how quickly calcium and phosphorus goals are attained and the frequency of treatment failure. Albright hereditary osteodystrophy is associated with type Ia and Ic PHP, which are the forms most likely to be associated with hypothyroidism. If patients have Albright hereditary osteodystrophy and/or confirmed hypothyroidism, yearly evaluation of thyroid-stimulating hormone is required. In patients with fractures suspicious of osteopenia, bone-density scanning should be obtained. Patients with hypogonadism will also require regular monitoring of sex hormone levels. Regular ophthalmologic exams should be performed to detect cataract formation.
15 预后
由于假性甲状旁腺功能减退症很罕见，且发表的资料仅限于病例系列和病例报道，因此对于其长期结局所知甚少。PHP 的基础病因无法治愈。但在经过一段时间，某些患者的钙稳态适应甲状旁腺激素抵抗后，低钙血症会缓解。对 PTH 抵抗不能适应的患者需要终身补充钙。甲状腺功能减退患者需要长期左甲状腺素治疗。少数情况下，1a 型或 1c 型 PHP 可伴发其他内分泌疾病。促性腺激素抵抗可能会导致青春期延迟或不孕不育。生长激素释放激素抵抗可以造成生长激素缺乏。一定要对这些内分泌疾病的症状和体征保持警惕，并在必要时进行促性腺激素或生长激素释放激素的测定。
Prognosis
Little is known of the long-term outcomes of pseudohypoparathyroidism (PHP) because the condition is rare, and published data are confined to case series and case reports. The underlying cause of PHP is incurable. However, some patients have resolution of hypocalcemia with time as calcium homeostasis adapts to parathyroid hormone (PTH) resistance. Those who do not adapt to PTH resistance require lifelong calcium supplementation. Patients with associated hypothyroidism require long-term levothyroxine therapy. Rarely, other endocrinopathies can occur in type Ia or Ic PHP. Gonadotropin resistance can cause delayed puberty or infertility. Growth hormone-releasing hormone (GHRH) resistance can produce growth hormone deficiency. It is important to remain alert for symptoms and signs of these endocrinopathies, and to initiate testing of the gonadotropin or GHRH axes if required.
