Obesity, Early-Onset, With Adrenal Insufficiency And Red Hair

A number sign (#) is used with this entry because of evidence that early-onset obesity, adrenal insufficiency, and red hair (OBAIRH) is caused by homozygous or compound heterozygous mutation in the POMC gene (176830) on chromosome 2p23.

Description

OBAIRH is an autosomal recessive endocrine disorder characterized by early-onset obesity due to severe hyperphagia, pigmentary abnormalities, mainly pale skin and red hair, and secondary hypocortisolism. In the neonatal period, affected individuals are prone to hypoglycemia, hyperbilirubinemia, and cholestasis that may result in death if not treated. The disorder results from mutation in the POMC gene, which encodes a preproprotein that is processed into a range of bioactive peptides, including alpha-melanocyte-stimulating hormone (MSH) and ACTH (summary by Kuhnen et al., 2016 and Clement et al., 2008).

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. Her earlier-born brother died at age 7 months from hepatic failure following severe cholestasis associated with adrenal insufficiency and adrenal hypoplasia. In the proband, 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. A second unrelated 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. In a follow-up of the patient reported by Krude et al. (1998), Kuhnen et al. (2016) noted that the woman, who was 21 years of age, had not gone through puberty.

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.

Clement et al. (2008) reported an 18-year-old woman, born of consanguineous parents of North African descent, with OBAIRH. She presented in infancy with obesity and hypothalamic endocrine abnormalities, including ACTH deficiency. At 4 weeks of age, she had persistent hypoglycemia associated with undetectable levels of plasma cortisol, ACTH, and lipotropin hormone. Brain imaging showed a normal pituitary gland and agenesis of the corpus callosum. She did not develop signs of puberty, and laboratory studies showed gonadotropin deficiency. Additional features included growth hormone deficiency and TSH deficiency that developed during the teenage years, both requiring hormone replacement treatment. Her brother died at age 3 months from hepatomegaly, hepatic insufficiency, hypoglycemia, and acidosis. Clement et al. (2008) noted that the proband did not have clinically apparent skin or hair pigmentation abnormalities, although hair melanin analysis showed an increase in eumelanin and pheomelanin, which may reflect a defect in MC1R (155555).

Clinical Management

Kuhnen et al. (2016) reported successful treatment of 2 unrelated obese adult patients with genetically confirmed POMC deficiency using setmelanotide, a melanocortin-4 receptor (MC4R; 155541) agonist. The patients had sustainable reduction in hyperphagia and hunger, as well as substantial weight loss and overall improvement in the quality of life. One of the patients had previously been reported by Krude et al. (1998) and the other by Clement et al. (2008). Before treatment, both patients had very high levels of leptin, suggesting leptin resistance.

Inheritance

The transmission pattern of OBAIRH in the families reported by Krude et al. (1998) was consistent with autosomal recessive inheritance.

Molecular Genetics

In an unrelated 3-year-old girl and 5-year-old boy with OBAIRH, Krude et al. (1998) identified compound heterozygosity (176830.0001; 176830.0002) and homozygosity (176830.0003), respectively, for mutations in the POMC gene.

In 3 children with OBAIRH, Krude et al. (2003) identified homozygosity or compound heterozygosity for mutations in the POMC gene (see 176830.0003-176830.0007). The authors noted that all of the heterozygous parents had BMIs in the high normal to overweight range.

In an 18-year-old woman, born of consanguineous parents of North African descent, with OBAIRH, Clement et al. (2008) identified a homozygous truncating mutation in the POMC gene (176830.0008). The mutation, which was found by direct sequencing based on the clinical presentation of the patient, segregated with the disorder in the family and was not found in 363 aged-matched controls in France. Functional studies of the variant were not performed, but the patient had undetectable levels of plasma cortisol, ACTH, and lipotropin hormone.

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.