概述
临床特征.
阿黑皮素原 (Proopiomelanocortin，POMC)缺乏症的特征是严重、早发性贪食的肥胖和先天性的肾上腺机能不全，后者仅次于肾上腺皮质激素（ACTH）缺乏症。在出生后的头几个月里，大多数患有POMC缺乏症的儿童经历了指数体重增加、高食、胆汁郁积和肾上腺机能不全。体重的增加会持续迅速，所以在1岁时，肥胖非常严重（也就是说，肥胖是非常严重的。体重远高于第98百分位，而身高不增加）。红头发和Fitzpatrick 1型皮肤（总是会灼伤皮肤，从不会晒黑）是很常见的，但并不是一成不变的。有时可伴发甲状腺机能减退（由甲状腺刺激激素TSH不足引起）、青少年性生长激素（GH）缺乏，以及因缺乏促黄体激素（LH）和促卵泡激素（FSH）而导致的青少年性低性腺性腺机能减退。
诊断/检测.
POMC缺乏症的诊断，检测到POMC基因双等位基因的致病性变异。
处置.
治疗疗程表现:治疗临床表现：新生儿肾上腺机能不全的治疗就是常规的氢化可的松替代治疗。尚无有效的治疗过度肥胖的药物；因此，生活方式是控制体重增加的必要手段。皮肤护理依赖于避免在中午的四小时内（即上午10点—下午2点）阳光照射，穿防晒服和涂抹高防晒系数的防晒霜。甲状腺功能减退通常用左旋甲状腺素治疗；然而，重要的是要注意的是，应该在肾上腺功能评价之后才能开始甲状腺激素替代疗法，并且如果存在肾上腺机能不全，也应该先行治疗。GH缺乏和性腺功能减退治疗，采用常规方法。
防原发症状:及时治疗ACTH、TSH、GH、LH和FSH缺乏症，可以预防这些激素缺乏的后果。
监测：一旦诊断，每年监测TSH、GH、LH和FSH的不足。根据纬度和阳光曝露历史，可能需要对皮肤进行恶性病变前的监测。尽管存在理论的恶性皮肤病变风险，但尚无与POMC缺乏相关的报道。
风险亲属的评估：如果已知家族中存在POMC致病性变异，产前检查可以明确高危妊娠的遗传状况，这样对这些有POMC缺陷的婴儿就可以在出生后尽快启动糖皮质激素治疗。如果已经在一个家庭中诊断了POMC缺乏症，但在这个家庭重要POMC的致病性变异不知道或者产前测试没有进行，需要评估所有高危新生儿（例如先证者,的同胞）的肾上腺机能不全的证据，并尽快启动糖皮质激素治疗。
遗传咨询.
POMC缺乏症以常染色体隐性遗传。理论上讲，受累者的每一个同胞有25%机会为受累者、50%机会为无症状的携带者，25%机会不受累并且不是携带者。如果在受影响的家庭成员中确定了POMC的致病变异，那么对高危亲属进行的携带者检测和妊娠期的产前检查是可能的。
诊断
目前还没有对POMC缺乏症的正式诊断标准。
如果先证者有以下临床和实验室发现，应该拟诊为POMC缺乏症：
- 严重的，在婴儿时期发病的贪食性肥胖
- 先天性肾上腺机能不全，由皮质激素（ACTH）缺乏所致
先证者 POMC缺乏症的诊断也可由以下临床和实验室发现获得支持：
- 非常白皙的皮肤（Fitzpatrick皮肤1型），永远不会晒黑，而且总是嗮伤[Roberts 2009]
- 红发
- 同胞或其他亲属中有阳性肥胖家族史，他们可能与先证者共享两个致病性变异
- 中心甲状腺机能减退（三碘甲状腺素、四碘甲状腺素和甲状腺激素，或TSH缺乏症）
- 在儿童后期或青少年时期的缺乏生长激素（GH）
- 性腺机能减退性性腺机能减退（促性腺素LH和FSH缺乏）
POMC缺乏症通过存在POMC致病性双等位基因获得确诊 (参见表 1).
表 1.
用于POMC缺乏症的分子遗传学读本检测
6.没有报道过POMC缺乏症有缺失或重复。(注:根据定义，缺失/重复分析确定重排，这些改变是用基因组DNA的序列分析是检测不出来的)。
临床特征
临床描述
在生命的最初几个月里，大多数患有阿黑皮素原（POMC）缺乏的儿童都经历了指数级体重增加、贪食症、胆汁郁积和肾上腺机能不全。体重增加的速度很快，所以在一周岁时，肥胖非常严重（例如体重远高于该年龄第98百分位，但身高不增加）。
红发和Fitzpatrick1型皮肤（总是晒伤，从不晒黑）是常见的，但并不总是存在。
Krude et al [1998] 报告了头两个患有POMC缺乏症的儿童，其中一个是3岁的女孩。两人都患有肾上腺机能不全、严重肥胖和红头发。
Krude et al [2003] 报道另外3个不相关的欧洲POMC缺乏症患儿，患先天性肾上腺机能不全，严重的早发性肥胖和红色的头发，其中两名患有轻微的中枢性甲状腺功能减退。
Farooqi et al [2006]描述了一个土耳其血统的孩子患有严重的肥胖和肾上腺机能减退，但没有红头发。
Clément et al [2008]描述了一个北非血统的人。除了肾上腺机能减退、肥胖和中枢性甲状腺功能减退外，患者在青春期开始时就出现了生长激素（GH）和促性腺激素缺乏。临床上，病人没有异常的色素沉着；然而，对头发色素的化学分析显示，与未受影响的亲属相比，该色素的产量增加了。
Mendiratta et al [2011] 报道一个18个月西班牙女孩先天性肾上腺机能不全（9个月时出现低血糖）和严重肥胖，由于纯合性的POMC致病性变异，导致过早的终止密码子。她没有典型的色素表型，没有描述对头发色素的详细分析。
Cirillo et al [2012]描述了一名3岁的北非洲血统的男孩，他们在出生后的头几天出现低血糖，在9个月大时被诊断出患有严重的肥胖，此时他已经患上了严重的肥胖，并在其后的三年逐渐恶化。尽管他的头发是深棕色的，但头发色素的分析显示，与其他家庭成员相比，头发黑色素的含量明显增加，而真黑素的含量轻度降低。
Aslan et al [2014]报道一患者，是POMC基因编码序列上游一种罕见的变异的纯合性突变，使基因不能转录。这个病人也有1型糖尿病和正常的胰岛素需求。
发病机制
在目标组织中减少或缺乏黑皮质素
蛋白信号导致了POMC缺乏的表型后果（包括肾上腺机能不全、色素沉着和严重肥胖）。例如：
- 在肾上腺皮质中，通过MC2R，缺陷的ACTH信号导致肾上腺机能减退（即没有肾上腺类固醇的发生）。
- 在皮肤黑色素细胞缺乏α-MSH诱导激活MC1R导致观察到某些受累个体的红头发和白皮肤。
- 在调节能量稳态的下丘脑核中，MC3和MC4R蛋白质的激活减少了，这导致了严重的早发性肥胖，类似于在MC4R蛋白本身缺乏的儿童身上观察到的严重的早发性肥胖。
基因型-表型相关性
大量的致病变异 (见 表 2) 导致如同在临床描述所描述的完全的表型。然而，一些所描述的个体在关键位置具有单一（即，杂合的）碱基对致病性变异，导致严重的，早发性肥胖而没有肾上腺机能不全或低色素[Challis et al 2002, Lee et al 2006, Dubern et al 2008].
命名
阿黑皮素 (Proopiomelanocortin，POMC)曾被称为阿皮素原（
proopiocortin，POC）。
相关的遗传 (等位基因) 疾病
在GeneReview中， 除本病之外没有其他类似表型，与POMC双等位基因的致病性变异相关。
杂合子表型.POMC-无效等位基因 杂合子(即 受累个体的生物学故事双亲和他的一些同胞即表兄弟）被认为患肥胖的风险增高，即使没有被描述的假设 [Farooqi et al 2006]。
鉴别诊断
激素原转换酶-1（Prohormone convertase-1，PC-）deficiency缺乏症 (OMIM 600955)模仿典型的POMC缺乏症的肥胖和肾上腺衰竭；然而，更胜一筹，PC-1缺乏症的特征还有多重内分泌病，有些病例小肠功能障碍导致严重的腹泻和吸收不良。
黑皮素-1受体(MC1R)缺乏症(OMIM 155555) 在一些群体中有常见变异(特别是欧洲人群)与红发相关。这种常见的变异很容易与另一种罕见的疾病共同遗传，从而导致早发性肥胖。
Beckwith-Wiedemann综合征 具有高出生体重和新生儿低血糖的表现。出生后的贪食症通常与BWS没有关联。
以下是儿童发病的所有原因：
T表2.
单基因肥胖综合征
| 单基因肥胖综合征 | 涉及的基因或染色体 1 | OMIM |
|---|---|---|
| 常染色体显性 | ||
| 脑源性神经营养因子 (Brain-derived neurotrophic factor，BDNF) 缺乏症 | BDNF | 113505 |
| 黑皮质素-4受体缺乏症（Melanocortin-4 receptor deficiency） | MC4R | 155541 |
| Rubinstein-Taybi 综合征 | CREBBP, EP300 | 180849; 613684 |
| TrkBy 缺乏症 | NTRK2 | 613886 |
| 尺骨一乳腺综合征（Ulnar-mammary syndrome） | TBX3 | 181450 |
| 常染色体隐性 | ||
| Alström综合征 | ALMS1 | 203800 |
| Bardet-Biedl综合征 | BBS1-16, ARL6, MKKS, MKS1, CEP290 | 209900 |
| Carpenter综合征 | RAB23 | 201000; 614976 |
| Cohen综合征 | VPS13B | 216550 |
| 瘦素缺乏（Leptin deficiency） | LEP | 614962 |
| 瘦素受体缺乏（Leptin receptor deficiency） | LEPR | 614963 |
| 巨体症，肥胖，大头症和眼畸形（Macrosomia, obesity, macrocephaly, and ocular abnormalities，MOMO）综合征 | Unknown; AR inheritance unconfirmed | 157980 |
| Majewski 骨性原始侏儒症II型（Majewski osteodysplastic primordial dwarfism type II） | PCNT | 210720 |
| 智力障碍，躯干肥胖，视网膜营养不良，小阴茎（Mental retardation, truncal obesity, retinal dystrophy, and micropenis，MORM）综合征 | INPP5E | 610156 |
| 激素原转化酶不足1/3型（Prohormone convertase 1/3 deficiency） | PCSK1 | 600955 |
| SIM1缺乏症（SIM1 deficiency） | SIM1 | 601665 |
| X-连锁 | ||
| Börjeson-Forssman-Lehman 综合征 | PHF6 | 301900 |
| Coffin–Lowry综合征 | RPS6KA3 | 303600 |
| 脆X综合征 | FMR1 | 300624 |
| 染色体缺陷 | ||
| 双倍体/三倍体嵌合 | Diploid/triploid 嵌合 | |
| 智力发育迟缓，肥胖，下颌前颌畸形，以及眼睛和皮肤异常（Mental retardation, obesity, mandibular prognathism, and eye and skin anomalies，MOMES）综合征 | del4q35.1, dup5p14.3 | 606772 |
| 微缺失 | ||
| 16p11.2 微缺失(SH2B 缺乏症) | SH2B | 613444 |
| 印记基因/区域 | ||
| Albright遗传性骨营养不良症（Albright hereditary osteodystrophy (假性甲状旁腺机能低下，pseudohypoparathyroidism） | GNAS | 103580 |
| Prader-Willi 综合征 | PWS region15q11-q13 (SNRPN, NDN, MAGEL2) | 176270 |
下面是糖皮质激素代谢的遗传疾病， 需要想到致肾上腺衰竭,因为他们可以继承与非综合征性肥胖glucocorticoid metabolism leading to adrenal failure need consideration, as they could be inherited in association with non-综合征性 obesity:
- Melanocortin-2 receptor deficiency (OMIM 202200)
- Melanocortin 2 receptor accessory protein (MRAP) deficiency (OMIM 607398)
- Steroidogenic acute regulatory protein (STAR) deficiency (OMIM 201710)
- Nicotinamide nucleotide transhydrogenase (NNT) deficiency (OMIM 614736)
- Autoimmune polyendocrine syndrome, type 1 (OMIM 240300)
- Natural killer cell and glucocorticoid deficiency with DNA repair defect (OMIM 609981)
- Combined pituitary hormone deficiency, type 1 and type 2
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with proopiomelanocortin (POMC) deficiency, the following evaluations are recommended:
- For adrenal insufficiency as a result of ACTH deficiency: 9 am plasma cortisol; plasma ACTH concentration; ACTH stimulation test
- For central hypothyroidism: TRH test, serum TSH, total T4
- For adolescent-onset growth hormone (GH) deficiency: insulin tolerance test and serum IGF-1 levels
- For adolescent-onset hypogonadism: FSH, LH, testosterone and/or estradiol
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
The main treatment for POMC deficiency is hormone replacement therapy with glucocorticoids with other hormones as required, as well as skin care in the sun.
Adrenal insufficiency. Adrenal insufficiency is treated in the usual manner with hydrocortisone replacement therapy. Care by a pediatric endocrinologist is recommended.
Severe obesity. Hyperphagic obesity is recognized in the neonatal period and persists into adolescence and adulthood. At present, there is no recognized effective medical therapy to prevent weight gain; therefore, lifestyle measures should be instigated.
Fair skin. The individual may need appropriate verbal and written sun care advice (avoidance of sun exposure in the middle 4 hours of the day [i.e., 10 am - 2 pm], cover-up clothing, high-factor sunscreen). Discussion about the potential lifelong risk for skin cancer is recommended.
Hypothyroidism. The mild central hypothyroidism reported in POMC deficiency is treated with levothyroxine. Importantly, thyroid hormone replacement should not be initiated until adrenal function has been evaluated and adrenal insufficiency (if present) has been treated. Care by a pediatric endocrinologist is recommended.
Growth hormone (GH) deficiency. Adolescent-onset GH deficiency (a rare manifestation of POMC deficiency) is treated with daily subcutaneous GH injections. Care by a pediatric endocrinologist is recommended.
Hypogonadotropic hypogonadism. Adolescent-onset hypogonadism (a rare manifestation of POMC deficiency) can be treated with sex hormone replacement. Care by an endocrinologist experienced in treating this disorder is recommended.
Prevention of Primary Manifestations
Prompt treatment of ACTH, TSH, GH, LH, and FSH deficiency prevents the consequences of these hormone deficiencies.
Surveillance
From the time of diagnosis, annual monitoring for deficiencies of TSH, GH, LH, and FSH is indicated.
Surveillance of skin for premalignant lesions may be necessary depending on latitude and history of sun exposure. Malignant skin lesions have not specifically been reported to be associated with POMC deficiency, though a theoretic risk is assumed to exist.
Evaluation of Relatives at Risk
If the pathogenic variants in the family are known, prenatal testing can clarify the genetic status of at-risk pregnancies so that glucocorticoid therapy can be initiated as soon as possible after birth in those newborns known to have POMC deficiency.
If POMC deficiency has been previously diagnosed in a family member, and if the pathogenic variants in the family are not known or if prenatal testing has not been performed, it is necessary to evaluate any at-risk newborn (e.g., sibs of a 先证者) for evidence of adrenal insufficiency and to initiate glucocorticoid therapy as soon as possible if adrenal insufficiency is found.
See Genetic Counseling for issues related to testing of at-risk relatives for 遗传咨询 purposes.
Therapies Under Investigation
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Genetic Counseling
Genetic counseling is the process ofproviding individuals and families with information on the nature, inheritance,and implications of genetic disorders to help them make informed medical andpersonal decisions. The following section deals with genetic risk assessment andthe use of family history and genetic testing to clarify genetic status forfamily members. This section is not meant to address all personal, cultural, orethical issues that individuals may face or to substitute for consultation witha genetics professional. —ED.
Mode of Inheritance
Proopiomelanocortin (POMC) deficiency is inherited in an 常染色体隐性遗传 manner.
Risk to Family Members
Parents of a 先证者
- Heterozygotes (carriers) are asymptomatic. Although they are not at risk of developing adrenal insufficiency, they have a predisposition to obesity [Farooqi et al 2006]. See Genetically Related Disorders.
Sibs of a 先证者
- Once an at-risk sib is known to be unaffected, the risk of his/her being a 携带者 is 2/3.
- Heterozygotes (carriers) are asymptomatic and are not at risk of developing adrenal insufficiency; however, a predisposition to obesity is conferred.
Offspring of a 先证者
- It is unknown whether fertility is reduced in individuals with POMC deficiency.
- The offspring of an individual with POMC deficiency are obligate heterozygotes (carriers) for a POMC 致病性变异.
Other family members
Carrier (Heterozygote) Detection
Carrier testing for at-risk relatives is possible if the POMC pathogenic variants in an 受累的 family member have been identified.
Related Genetic Counseling Issues
See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.
Family planning
- The optimal time for determination of genetic risk, clarification of 携带者 status, and discussion of the availability of prenatal testing is before pregnancy.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of 受累的 individuals.
Resources
GeneReviews staff has selected the following disease-specific and/orumbrella support organizations and/or registries for the benefit of individualswith this disorder and their families. GeneReviews is not responsible for theinformation provided by other organizations. For information on selectioncriteria, click here.
- National Adrenal Diseases Foundation (NADF)505 Northern BoulevardGreat Neck NY 11021Phone: 516-487-4992Email: nadfmail@aol.com
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. 鈥�ED.
Table A.
Proopiomelanocortin Deficiency: Genes and Databases
| Gene | Chromosome Locus | Protein | Locus-Specific Databases | HGMD | ClinVar |
|---|---|---|---|---|---|
| POMC | 2p23 | Pro-opiomelanocortin | POMC database | POMC | POMC |
Table B.
OMIM Entries for Proopiomelanocortin Deficiency (View All in OMIM)
Gene structure.POMC comprises three exons of 406, 102, and 838 bp and spans approximately 7.8 kb. The predominant transcript is 1426 bp nucleotides long and encodes for a 267-amino acid polypeptide.
Pathogenic variants.Krude et al [1998] reported the first cases of human POMC deficiency in two children:
- A girl age three years was 复合杂合 for two pathogenic nonsense variants in 外显子 3 (c.7013G>T, c.7133delC) which prevented the synthesis of ACTH and α-MSH.
Krude et al [2003] reported three additional unrelated European children with POMC deficiency who were either 复合杂合 (c.[6851A>T] + [6996del]; c.[3804C>A] + [7100insGG]) or 纯合性 (c.3804C>A) for POMC pathogenic variants.
Farooqi et al [2006] described a 纯合性 pathogenic frame shift variant (c.6906Cdel) in POMC in a child of Turkish background.
Clément et al [2008] described a novel 纯合性 variant (c.6922insC) that impaired the production of all POMC-derived peptides in an individual of North African ancestry.
Mendiratta et al [2011] reported a novel 纯合性 nonsense variant (c.231C>A) in a Hispanic girl age 18 months.
Cirillo et al [2012] described a novel 纯合性 nonsense variant (c.202C>T) in a boy age three years of North African ancestry.
Aslan et al [2014] described a novel 纯合性 variant in the 5' untranslated region (-11C>A) of POMC in an individual with POMC deficiency and coincidental type 1 diabetes mellitus. Functional studies of this variant showed that it strongly attenuated transcription of POMC.
See Table 3 (pdf) for a list of pathogenic variants discussed in this section.
Table 4.
POMC Genotypes Detected in Affected Individuals
| Variants Detected | References |
|---|---|
| c.7013G>T, c.7133delC compound 杂合子 (n=1) | Krude et al [1998] |
| c.3804C>A homozygote (n=2) | Krude et al [1998], Krude et al [2003] |
| c.6851A>T, 6996del compound 杂合子 (n=1) | Krude et al [2003] |
| c.3804C>A + 7100insGG compound 杂合子 (n=1) | Krude et al [2003] |
| c.6906Cdel homozygote (n=1) | Farooqi et al [2006] |
| c.6922InsC homozygote (n=1) | Clément et al [2008] |
| c.231C>A homozygote (n=1) | Mendiratta et al [2011] |
| c.202C>T homozygote (n=1) | Cirillo et al [2012] |
| -11C>A homozygote (n=1) | Aslan et al [2014] |
Normal 基因产物. The product of POMC is proopiomelanocortin, a complex polypeptide that is post-translationally processed by endoproteases in a tissue specific manner to produce a number of biologically active peptides. These include corticotropin (ACTH), β-endorphin, and α-, β- and γ-melanocyte stimulating hormone (MSH) which are implicated in a number of physiologic actions including energy homeostasis, adrenal steroidogenesis, and hair pigmentation. The biologic actions of melanocortin peptides are mediated by the melanocortin receptors (MC1R-MC5R), members of the G-protein coupled receptor family.
Abnormal 基因产物. The phenotypic consequences of POMC deficiency - including adrenal insufficiency, altered pigmentation, and severe obesity - result from an absence of melanocortin signaling in target tissues. For example, hypoadrenalism due to an absence of adrenal steroidogenesis results from impaired ACTH signaling through the MC2R in the adrenal cortex, whereas an absence of α-MSH induced activation of MC1R in skin melanocytes results in the red hair and pale skin observed in some 受累的 individuals. Severe early-onset obesity is caused by reduced activation of MC3- and MC4R in hypothalamic nuclei that regulate energy homeostasis. The importance of hypothalamic melanocortin signaling in the regulation of body weight is emphasised by the observation that human MC4R deficiency also results in severe obesity in children.
References
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Chapter Notes
Revision History
- 12 December 2013 (bp) Review posted live
- 13 August 2013 (bgc) Original submission