Proopiomelanocortin Deficiency – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
Synonym: POMC Deficiency
Ben G Challis, BSc, MPhil, PhD, MRCP(UK) and George WM Millington, BSc, MBBS, PhD, FRCP.
Author Information and AffiliationsInitial Posting: December 12, 2013.
Estimated reading time: 15 minutes
Summary
NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.
Clinical characteristics.
Proopiomelanocortin (POMC) deficiency is characterized by severe, early-onset hyperphagic obesity and congenital adrenal insufficiency, the latter secondary to corticotropin (ACTH) deficiency. In the first months of life most children with POMC deficiency experience exponential weight gain, hyperphagia, cholestasis, and adrenal insufficiency. Weight gain continues rapidly, so that by the end of the first year of life obesity is severe (i.e., weight well above the 98th centile for age, without increased height). Red hair and Fitzpatrick type 1 skin (which always burns and never tans) are common, but not invariably present. On occasion central hypothyroidism (resulting from thyroid stimulating hormone [TSH] deficiency), adolescent-onset growth hormone (GH) deficiency, and adolescent-onset hypogonadotropic hypogonadism resulting from deficiency of luteinizing hormone (LH) and follicule stimulating hormone (FSH) can be observed.
Diagnosis/testing.
The diagnosis of POMC deficiency is confirmed by the presence of biallelic POMC pathogenic variants.
Management.
Treatment of manifestations: Neonatal adrenal insufficiency is treated in the usual manner with hydrocortisone replacement therapy. No effective medical therapy for hyperphagic obesity is known; thus, lifestyle measures are necessary to control weight gain. Skin care relies on avoiding sun exposure in the middle four hours of the day (i.e., 10 am – 2 pm), cover-up clothing, and high-factor sunscreen. Hypothyroidism is treated in the usual manner with levothyroxine; however, it is important to note that thyroid hormone replacement therapy should not begin until adrenal function has been evaluated and adrenal insufficiency (if present) has been treated. GH deficiency and hypogonadotropic hypogonadism are treated in the usual manner.
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. 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 POMC 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 infants known to have POMC deficiency.
If POMC deficiency has been previously diagnosed in a family and if the POMC pathogenic variants in the family are not known or if prenatal testing has not been performed, it is necessary to evaluate any at-risk newborns (e.g., sibs of a proband) for evidence of adrenal insufficiency and to initiate glucocorticoid therapy as soon as possible.
Genetic counseling.
POMC deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the POMC pathogenic variants have been identified in an affected family member.
Diagnosis
There are no formal diagnostic criteria for proopiomelanocortin (POMC) deficiency.
The diagnosis of POMC deficiency is suspected in a proband with the following clinical and laboratory findings:
Severe, hyperphagic obesity of onset in infancy
Congenital adrenal insufficiency, resulting from corticotropin (ACTH) deficiency
The diagnosis of POMC deficiency in a proband may also be supported by the following clinical and laboratory findings:
Very fair skin (Fitzpatrick skin type 1) which will never tan and always burns [
Roberts 2009]
Red hair
Positive family history of obesity in sibs or other relatives who could share two pathogenic alleles with the
probandCentral hypothyroidism (triodothyronine, tetraiodothyronine and thyrotropin, or TSH deficiency)
Growth hormone (GH) deficiency in later childhood or adolescence
Hypogonadotropic hypogonadism (deficiency of the gonadotropins LH and FSH)
The diagnosis of POMC deficiency is confirmed by the presence of biallelic POMC pathogenic variants (see Table 1).
Table 1.
Molecular Genetic Testing Used in Proopiomelanocortin Deficiency
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| Gene 1 | Method | Variants Detected 2 | Pathogenic Variant Detection Frequency by Method 3 |
|---|
|
POMC
| Sequence analysis 4 | Sequence variants | Unknown |
| Deletion/duplication analysis 5 | Exon or whole-gene deletions or duplications | Unknown, none reported 6 |
Clinical Characteristics
Clinical Description
In the first months of life most children with proopiomelanocortin (POMC) deficiency experience exponential weight gain, hyperphagia, cholestasis, and adrenal insufficiency. Weight gain continues rapidly, so that by the end of the first year of life obesity is severe (i.e., weight well above 98th centile for age without increased height).
Red hair and Fitzpatrick type 1 skin (which always burns and never tans) are common but not invariably present.
Krude et al [1998] reported the first two children with POMC deficiency, one of whom was a girl age three years. Both had adrenal insufficiency, severe obesity, and red hair.
Krude et al [2003] reported three additional unrelated European children with POMC deficiency who had congenital adrenal insufficiency, severe early onset obesity, and red hair; two had mild central hypothyroidism.
Farooqi et al [2006] described a child of Turkish origin with severe obesity and hypoadrenalism but without red hair.
Clément et al [2008] described an individual of North African ancestry. In addition to hypoadrenalism, obesity, and central hypothyroidism, the patient developed growth hormone (GH) and gonadotropin deficiency at the onset of puberty. Clinically, the patient did not have abnormal pigmentation; however, chemical analysis of hair pigment revealed increased production of pheomelanin and eumelanin compared with unaffected relatives.
Mendiratta et al [2011] reported a Hispanic girl age 18 months with congenital adrenal insufficiency (presenting with hypoglycemia at age 9 months) and severe obesity due to homozygosity for a pathogenic POMC variant that results in a premature termination codon. She did not have the typical pigmentary phenotype; detailed analysis of hair pigment was not described.
Cirillo et al [2012] described a boy age three years of North African ancestry who experienced hypoglycemia in the first days of life and was diagnosed with ACTH deficiency at age nine months, by which time he had developed severe obesity which worsened during the second and third years of life. Although he had dark brown to black hair, hair pigment analysis revealed significantly increased levels of pheomelanin and minimally reduced eumelanin when compared with other family members.
Aslan et al [2014] reported an individual who was homozygous for a rare variant upstream of the POMC coding sequence that abolished gene transcription. This patient also had type 1 diabetes mellitus with normal insulin requirements.
Pathogenesis
The phenotypic consequences of POMC deficiency (including adrenal insufficiency, altered pigmentation, and severe obesity) result from reduced or absent melanocortin signaling in target tissues. For example:
Impaired ACTH signaling through the MC2R in the adrenal cortex results in hypoadrenalism (i.e., absence of adrenal steroidogenesis).
Absence of α-MSH induced activation of MC1R in skin melanocytes results in the red hair and pale skin observed in some affected individuals.
Reduced activation of MC3- and MC4R proteins in the hypothalamic nuclei that regulate energy homeostasis causes severe early-onset obesity, in a manner similar to the severe early-onset obesity observed in children with deficiency of the MC4R protein itself.
Nomenclature
Proopiomelanocortin (POMC) was previously called proopiocortin (POC).
Prevalence
POMC is an extremely rare disease. Fewer than 50 affected individuals have been reported in the world literature.
There is no known increased prevalence in any particular ethnic group or geographic location.
Differential Diagnosis
Prohormone convertase-1 (PC-1) deficiency (OMIM 600955) mimics the obesity and adrenal failure of classic POMC deficiency; however, in addition, PC-1 deficiency is characterized by multiple other endocrinopathies and, in some instances, small-intestine dysfunction resulting in severe diarrhea and malabsorption.
Melanocortin-1 receptor (MC1R)
deficiency (OMIM 155555) has a common genetic variant in the population (particularly in European populations) that is associated with red hair. This common variant could easily be co-inherited with another rarer disorder leading to early-onset obesity.
Beckwith-Wiedemann syndrome presents with high birth weight and neonatal hypoglycemia. Postnatal hyperphagia is not typically associated with BWS.
The following are all causes of childhood-onset obesity:
Table 2.
Monogenic Obesity Syndromes
View in own window
| Monogenic Obesity Syndrome | Gene(s) or Chromosome(s) Involved 1 | OMIM |
|---|
|
Autosomal dominant
|
| Brain-derived neurotrophic factor (BDNF) deficiency |
BDNF
|
113505
|
| Melanocortin-4 receptor deficiency |
MC4R
|
155541
|
|
Rubinstein-Taybi syndrome
|
CREBBP, EP300
| 180849; 613684 |
| TrkB deficiency |
NTRK2
|
613886
|
| Ulnar-mammary syndrome |
TBX3
|
181450
|
|
Autosomal recessive
|
|
Alström syndrome
|
ALMS1
|
203800
|
|
Bardet-Biedl syndrome
|
BBS1-16, ARL6, MKKS, MKS1, CEP290
|
209900
|
| Carpenter syndrome |
RAB23
| 201000; 614976 |
|
Cohen syndrome
|
VPS13B
|
216550
|
| Leptin deficiency |
LEP
|
614962
|
| Leptin receptor deficiency |
LEPR
|
614963
|
| Macrosomia, obesity, macrocephaly, and ocular abnormalities (MOMO) syndrome | Unknown; AR inheritance unconfirmed |
157980
|
| Majewski osteodysplastic primordial dwarfism type II |
PCNT
|
210720
|
| Mental retardation, truncal obesity, retinal dystrophy, and micropenis (MORM) syndrome |
INPP5E
|
610156
|
| Prohormone convertase 1/3 deficiency |
PCSK1
|
600955
|
| SIM1 deficiency |
SIM1
|
601665
|
|
X-linked
|
| Börjeson-Forssman-Lehman syndrome |
PHF6
|
301900
|
|
Coffin-Lowry syndrome
| RPS6KA3 |
303600
|
|
Fragile X syndrome
|
FMR1
|
300624
|
|
Chromosome defect
|
| Diploid/triploid mosaicism | Diploid/triploid mosaicism | |
| Mental retardation, obesity, mandibular prognathism, and eye and skin anomalies (MOMES) syndrome | del4q35.1, dup5p14.3 |
606772
|
|
Microdeletion
|
| 16p11.2 microdeletion (SH2B deficiency) |
SH2B
|
613444
|
|
Imprinted gene/region
|
| Albright hereditary osteodystrophy (pseudohypoparathyroidism) |
GNAS
|
103580
|
|
Prader-Willi syndrome
| PWS region15q11-q13 (SNRPN, NDN, MAGEL2) |
176270
|
- 1.
Chromosome locus included when gene is unknown
The following inherited disorders of glucocorticoid metabolism leading to adrenal failure need consideration, as they could be inherited in association with nonsyndromic 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 proband) 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 genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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 of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
Proopiomelanocortin (POMC) deficiency is inherited in an autosomal recessive manner.
Risk to Family Members
Parents of a proband
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
pathogenic variant).
Sibs of a proband
Offspring of a proband
Other family members
Each sib of the
proband’s parents is at a 50% risk of being a
carrier.
Carrier (Heterozygote) Detection
Carrier testing for at-risk relatives is possible if the POMC pathogenic variants in an affected family member have been identified.
Prenatal Testing and Preimplantation Genetic Testing
Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for POMC deficiency are possible.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
Proopiomelanocortin Deficiency: Genes and Databases
View in own window
Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
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:
The second unrelated child was
homozygous for a
pathogenic variant (
c.3804C>A) within the 5'-untranslated region which introduced an additional, out-of-frame start site and prevented translation of normal POMC-derived peptides.
Krude et al [2003] reported three additional unrelated European children with POMC deficiency who were either compound heterozygous (c.[6851A>T] + [6996del]; c.[3804C>A] + [7100insGG]) or homozygous (c.3804C>A) for POMC pathogenic variants.
Farooqi et al [2006] described a homozygous pathogenic frame shift variant (c.6906Cdel) in POMC in a child of Turkish background.
Clément et al [2008] described a novel homozygous 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 homozygous nonsense variant (c.231C>A) in a Hispanic girl age 18 months.
Cirillo et al [2012] described a novel homozygous nonsense variant (c.202C>T) in a boy age three years of North African ancestry.
Aslan et al [2014] described a novel homozygous 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.
Normal gene product. 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 gene product. 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 affected 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
Literature Cited
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Chapter Notes
Revision History
16 April 2020 (ma) Chapter retired: extremely rare
12 December 2013 (bp) Review posted live
13 August 2013 (bgc) Original submission
