Proopiomelanocortin Deficiency – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY

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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 THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.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 pathogenic variants.

MANAGEMENT

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. Prompt treatment of ACTH, TSH, GH, LH, and FSH deficiency prevents the consequences of these hormone deficiencies. 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. 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 infants known to have POMC deficiency. If POMC deficiency has been previously diagnosed in a family 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 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 pathogenic variants have been identified in an affected family member.