| #609734 | ||||||||||
| PROOPIOMELANOCORTIN DEFICIENCY | ||||||||||
| Alternative titles; symbols | ||||||||||
| OBESITY, EARLY-ONSET, ADRENAL INSUFFICIENCY, AND RED HAIR | ||||||||||
| Phenotype Gene Relationships | ||||||||||
| ||||||||||
| TEXT | ||||||||||
| A number sign (#) is used with this entry because proopiomelanocortin deficiency is caused by mutation in the proopiomelanocortin gene (POMC; 176830). | ||||||||||
| Clinical Features | ||||||||||
| Krude et al. (1998) observed an unrelated 3-year-old girl and 5-year-old boy who had obesity, red hair pigmentation, and ACTH deficiency. The girl had normal weight at birth and developed cholestasis at 3 weeks of age. Because of a history of adrenal hypoplasia in her earlier-born brother, ACTH deficiency was diagnosed at 23 days and hydrocortisone substitution led to resolution of cholestasis. Pituitary-derived POMC peptides could not be demonstrated in her serum even after stimulation, although normal values of all other anterior pituitary-derived hormones excluded developmental defects of the pituitary and hypothalamus. The parents reported an increased appetite beginning at 4 months of age, leading to severe obesity that interfered with her ability to walk until she was 2 years old; mental development was normal. The boy had transient neonatal hypoglycemia; his birth weight was normal, and obesity was first noted at the age of 5 months. After a febrile seizure, blood glucose measurement showed hypoglycemia and hyponatremia leading to an endocrinologic investigation which showed complete ACTH deficiency. With hydrocortisone substitution, the boy's subsequent development was uneventful apart from abnormal eating behavior causing progressive obesity. His intellectual and emotional assessments yielded normal results. Both patients had normal pituitary morphology on MRI. Krude et al. (2003) reported 3 additional unrelated children with early-onset obesity, red or red-brown hair and pale skin, and isolated ACTH deficiency manifesting in infancy with hypoglycemic seizures. The children were treated with daily low-dose hydrocortisone; despite the low dosage, all 3 developed extreme obesity within the first year of life. No other family members had red hair; in 2 of the patients, hair color changed to brown in the second and third years of life. All parents reported that their children had been hyperphagic from the first weeks of life and that their behavior was always determined by their search for food. Mental development was normal in all, and mild delay in motor skills was believed to be explained by their extreme obesity. | ||||||||||
| Molecular Genetics | ||||||||||
| In an unrelated 3-year-old girl and 5-year-old boy with obesity, red hair pigmentation, and adrenal insufficiency, Krude et al. (1998) identified compound heterozygosity (176830.0001 and 176830.0002) and homozygosity (176830.0003), respectively, for mutations in the POMC gene. In 3 children with early-onset obesity, red hair, and secondary hypocortisolism, Krude et al. (2003) identified homozygosity or compound heterozygosity for mutations in the POMC gene (see {176830.003}-176830.0007). The authors noted that all of the heterozygous parents had BMIs in the high normal to overweight range. | ||||||||||
| Animal Model | ||||||||||
| Yaswen et al. (1999) generated POMC-null mice, which developed obesity and had defective adrenal development and altered pigmentation. When treated with a stable alpha-melanocyte-stimulating hormone agonist, mutant mice lost more than 40% of their excess weight after 2 weeks. Yaswen et al. (1999) concluded that POMC-null mice provide a model for studying human POMC deficiency. | ||||||||||
| REFERENCES | ||||||||||
| ||||||||||
| ||||||||||