Setmelanotide in Bardet‐Biedl Syndrome: A Case Report

ABSTRACT

Setmelanotide is a melanocortin‐4‐receptor agonist used for the treatment of hyperphagia in the genetic obesity syndrome Bardet‐Biedl. Presented is a case of diffuse hyperpigmentation in a patient treated with setmelanotide, which represents the most common side effect of this medication. Herein is a review of the literature for other potential side effects that warrant regular dermatologic screening, including alteration of existing melanocytic lesions. Exact screening guidelines have not been completely defined, though it is recommended that patients receive baseline and annual examinations while undergoing treatment with this agent.

1. Introduction

Bardet‐Biedl Syndrome (BBS) is a rare, autosomal recessive ciliopathy that consists of findings such as obesity, post‐axial polydactyly, learning difficulties, retinal dystrophy, renal issues, and hypogonadism [1]. The overall prevalence is estimated to be 1:160000 [2]. In BBS, immotile cilia do not function normally and lead to dysregulation of signal transduction pathways [1]. Alterations in these pathways result in complex and incompletely understood downstream effects that manifest clinically through disrupted receptor interactions, altered adipogenesis, abnormal intracellular trafficking leading to rod–cone dystrophy, and dysregulation of Wnt and hedgehog signaling, among others [1]. Patients living with BBS have a phenotype that evolves throughout the first decade of life, most being diagnosed in late childhood or early adulthood.

Obesity, which is reported in 72%–86% of the BBS population, can cause major comorbidities and is a primary clinical feature of this disease [1]. Many possible mechanisms have been proposed, though most revolve around inadequate trafficking of receptors responsible for satiety [2]. Specifically, the melanocortin‐4 receptor (MCR4) in the central hypothalamic melanocortin pathway, which normally promotes satiety, energy expenditure, and weight loss, is disturbed, leading to symptoms such as hyperphagia and reduced energy expenditure [3]. For patients who experience symptoms such as hyperphagia and obesity in association with BBS, the Food and Drug Administration (FDA) approved the use of a MCR4 agonist, setmelanotide, in 2020. Setmelanotide compensates for the upstream gene defects and can restore MC4R signaling, which is thought to be reduced in those with BBS due to a dysfunctional BBS protein that impairs the trafficking of leptin receptors in hypothalamic proopiomelanocortin neurons [4]. However, setmelanotide also activates the closely related melanocortin‐1 receptor (MCR1), which regulates the proliferation and differentiation of melanocytes, melanin synthesis, and DNA repair [5]. Skin hyperpigmentation, which has been reported to be reversible upon discontinuation of the drug, has been observed in treated patients, along with darkening of existing nevi. Additionally, although not indicated in the FDA labeling, there is a theoretical concern for the development of dysplastic nevi due to melanocytic proliferation. Given this, the FDA recommends full‐body skin examination prior to initiation to establish a baseline and periodically to monitor any darkening or new nevi [6]. Although specific monitoring frequency is not defined, dermatologists play a key role in establishing baseline cutaneous findings, performing longitudinal surveillance for new or changing lesions, and guiding further evaluation or management of treatment‐associated cutaneous changes.

2. Case Report

A 7‐year‐old female with a history of probable BBS, attention deficit hyperactivity disorder, asthma, and autism was referred by pediatric endocrinology for a full‐body skin examination after discussion of initiation of setmelanotide for her presumed diagnosis of BBS. At age 4 years, she was evaluated by endocrinology and nutrition for significant weight gain and tall stature, initially thought to be due to excessive caloric intake and familial stature. After evaluation by a second endocrinologist, who also attributed her presentation primarily to lifestyle factors, a genetics referral was requested at the family's insistence. She underwent genetic testing, which revealed three variants of undetermined significance (VUS), one in each of the genes BBS5, PLXNA1, and RAI1. At that time, no second change was identified in the paternal allele in BBS5 to support a diagnosis of Bardet‐Biedl syndrome, and the VUS in PLXNA1 (reported provisional gene association with developmental delay and autism) and RAI1 (pathogenic changes associated with Smith‐Magenis syndrome) were not felt to be consistent with her clinical picture.

Based on her clinical presentation and the presence of a heterozygous VUS, endocrinology considered a presumptive clinical diagnosis of BBS and initiated discussions with the family regarding treatment with setmelanotide for symptom control and metabolic management. Given the non‐diagnostic genetic results, further evaluations were pursued, including whole‐exome sequencing XL, which was negative, and a methylation assay, which was also negative. Management decisions were made collaboratively through ongoing discussions among her family, pediatricians, endocrinologists, and geneticists, with input from a third endocrinology specialist.

Given these findings and concern for obesity‐associated comorbidities, it was decided that she would trial setmelanotide. She was advised to establish care with dermatology for a baseline and annual skin exam if setmelanotide was initiated.

She was seen in pediatric dermatology after initiation of therapy 4 months prior. Per her mother, the patient had noted new onset significant diffuse hyperpigmentation. On physical exam, she demonstrated full‐body hyperpigmentation and scattered brown macules and papules consistent with known nevi. Additionally, there were hyperpigmented velvety plaques along the neck and axillae (Figure 1), as well as striae on the trunk (Figure 2) and hyperpigmentation along the arms (Figure 3).

FIGURE 1.

Hyperpigmented velvety patches along posterior neck consistent with acanthosis nigricans.

FIGURE 2.

Striae along lower back. Increasing hyperpigmentation within the striae and skin folds was noted after 4 months of setmelanotide treatment.

FIGURE 3.

Hyperpigmentation on the arms and hands after 4 months of setmelanotide treatment.

3. Discussion

The major skin findings in BBS are mostly believed to be those associated with obesity and metabolic disturbances such as acanthosis nigricans, acrochordons, and striae; however, there are data to suggest an increased prevalence of congenital melanocytic nevi in these patients, ostensibly due to a relationship between ciliary function and melanogenesis [7]. One prospective observational cohort study examined 31 individuals aged 2–69 years with BBS for cutaneous findings over a 12‐month period and found the most common associated dermatoses were: 80.6% keratosis pilaris, 54.8% nevi, 35.5% acanthosis nigricans, 32.2% striae, 29% pigmentation abnormalities (including traumatic hyperpigmentation, café au lait spots, confetti macular hypopigmentation, and solar lentigines), 22.5% acne vulgaris, 19.3% seborrheic dermatitis, 12.9% acrochordons, 12.9% eczema, and 9.6% hidradenitis suppurativa [8]. Another study with data from self‐reported surveys of 67 BBS patients showed that 23.9% had congenital melanocytic nevi, significantly more than the general population [7].

Setmelanotide is an MC4R agonist that can restore the dysregulated MC4R signaling in BBS [3]. MC4R is not believed to play a critical role in pigmentation, though setmelanotide also activates MCR1, which is responsible for regulation of the differentiation and proliferation of melanocytes, DNA repair, and synthesis of melanin [5]. Activation of MCR1 leads to tanning and can stimulate hair color change due to the increased ratio of eumelanin to pheomelanin. With activation of MCR1, there is a theoretical concern for development of melanoma due to stimulation and potential proliferation of melanocytes. However, in studies investigating patients with inactivating variants of MCR1, these patients had a higher risk of melanoma, due to the reduction of protective melanin. Therefore, external activation of MCR1 could also theoretically protect from development of melanoma due to the increase in melanin and protection from UV damage [9].

Given the effects of setmelanotide on pigmentation, the FDA recommends full‐body skin examination prior to and during treatment [6]. Dermatologists play a key role in establishing baseline cutaneous phenotype, monitoring for treatment‐associated changes, and ensuring early detection and management of atypical or malignant lesions that may arise in the setting of melanocortin pathway activation. Hyperpigmentation has been consistently seen in most patients undergoing setmelanotide treatment. In clinical trials, generalized or focal increases in skin pigmentation occurred in most patients treated with setmelanotide, including 67% of those aged ≥ 6 years and 83% of those aged 2 to < 6 years. This effect has been reported to be reversible upon discontinuation of the drug [6]. Other clinical trials reported, 78% of the 27 treated patients experienced skin hyperpigmentation [6]. In a phase 3 trial, followed by a 52‐week open label period, the most common treatment emergent events were skin hyperpigmentation in 61%, which was not transient but plateaued within the initial months of treatment [3]. Additionally, in a prospective cohort study of 26 patients analyzing the impact of setmelanotide on liver and kidney function in BBS patients, 100% of patients on setmelanotide developed skin hyperpigmentation [10].

In addition to the frequently encountered hyperpigmentation, there have been reports of dysplastic nevi and few melanomas among patients treated with setmelanotide. One study cites unpublished data from Rhythm Pharmaceuticals, the manufacturer of setmelanotide, describing one patient with BBS, fair skin, freckling, nevi, and a history of excessive sun exposure who developed pT1a melanoma after 3 years of continuous treatment [11]. Another BBS patient, Fitzpatrick II, with chronic UV‐related damage and living on an island near the equator, was diagnosed with pT1a melanoma after 6 months of setmelanotide treatment. This study highlighted that both individuals were at increased baseline risk for melanoma prior to setmelanotide initiation, but due to timely examination, the melanomas were detected early [11].

Development of new melanocytic nevi, as well as darkening or enlargement of existing nevi, occurred in 16% of patients aged ≥ 6 years and 33% of patients aged 2 to < 6 years [12]. One patient presented with what was classified as eruptive dysplastic nevi (> 20 new moles with two biopsied showing atypical features), hyperpigmentation, and increased pigmentation of existing nevi 14 weeks after initiation of setmelanotide [13]. In a phase 2 open‐label pilot study, 5 patients (2 with POMC mutations and 3 with LEPR mutations) were treated with setmelanotide and underwent dermatologic examinations. All patients developed skin hyperpigmentation, with increased pigmentation observed at early time points followed by stabilization during the long‐term course [14]. In one POMC patient with a history of dysplastic nevus syndrome, 8 nevi were excised due to enhanced pigmentation during treatment; 3 showed signs of dysplasia, but none demonstrated histologic evidence of malignancy [14].

4. Conclusion

The dermatologic features of BBS remain incompletely defined, with some evidence suggesting increased rates of nevi while other findings appear more closely related to obesity‐associated changes such as acanthosis nigricans, acrochordons, and striae. With the growing use of setmelanotide in this population, the potential for hyperpigmentation and dysplastic nevi further reinforces the importance of dermatologic monitoring. The long‐term effects of pharmacological activation of MCR1 remain unclear. Although it may actually be protective against the development of melanoma, baseline and ongoing skin examinations are essential in the care of patients with BBS receiving setmelanotide, both to establish their cutaneous phenotype, to monitor for pigmentary or melanocytic alterations, and to ensure early detection and management of atypical and malignant lesions.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.