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The differential diagnosis for oral lentigines includes several syndromes with important associated systemic findings. McCune-Albright syndrome (MAS), a mosaic condition associated with café au lait pigmentation, is not typically considered a mucosal lentiginosis syndrome. The clinical phenotype of MAS is variable because of mosaicism, but oral pigmentation developing in mid-childhood to early adulthood should be recognized as a clinical feature of MAS.
We present 4 patients with MAS who developed oral mucosal pigmentation during childhood or early adulthood. All patients had other characteristic findings of MAS including hyperfunctioning endocrinopathies, polyostotic fibrous dysplasia, and café au lait pigmentation.
Oral pigmentation is an underrecognized finding in MAS and presents later in development compared with the other mucosal lentiginosis syndromes. The diagnosis of MAS is most commonly a clinical diagnosis because mutational analysis is challenging in mosaic conditions. Expanding the cutaneous phenotype to include oral pigmentation further characterizes the clinical findings in this mosaic condition, broadens the differential diagnosis of syndromes with oral pigmentation, and in some cases may aid in earlier diagnosis of MAS.
McCune-Albright syndrome (MAS) is a sporadic disorder characterized by polyostotic fibrous dysplasia (PFD), hyperfunctioning endocrinopathies, and café au lait skin pigmentation. It is caused by a somatic mutation of the guanine nucleotide-binding protein, α-stimulating (GNAS) (OMIM 139320) complex locus gene, leading to constitutive activation of the α subunit of the stimulatory G protein (Gsα).1 Skin pigmentation often covers a large geographic area with an irregular border, frequently described as a “coast of Maine” border, and is often the presenting sign of the syndrome. In a recent study of 140 patients with MAS, 66% demonstrated this classic pigmentary pattern.2 Early series of MAS manifestations described patients with oral pigmentation,3,4 a clinical finding that has not been subsequently well characterized in the literature.5 We describe 4 individuals with MAS with oral lentigines similar to those seen in Carney complex (CNC) and Peutz-Jeghers syndrome (PJS), thereby broadening the clinical phenotype of MAS and the differential diagnosis of mucosal lentiginosis syndromes.
An adolescent boy initially presented to an orthopedic surgeon at age 4 years with right leg pain and a limp. A bone scan and skeletal survey at that time revealed fibrous dysplasia of the cranium, ribs, bilateral arms, and right femur and tibia. The patient subsequently required 2 decompressive orbital surgical procedures. Endocrine evaluation revealed normal thyroid function but cystic lesions on thyroid ultrasound typical of those seen in MAS. He had growth hormone excess necessitating treatment with a somatostatin analogue. Ultrasound of the testes identified solid lesions commonly found in men and boys with MAS that likely represented Leydig cell hyperplasia. Cutaneous examination at age 11 years demonstrated a small café au lait patch on the right lateral chest (Figure 1A) and hyperpigmented macules on the lower lip (Figure 1B). The macules on the lip were first documented at age 11 years, and since that time the patient noted progressive darkening of the pigmentation in addition to new macules on the lip (Figure 1C) and bilateral anterior buccal mucosae.
A woman presented for evaluation of progressive oral mucosal pigmentation. She was otherwise healthy until age 18 years, when she experienced her first fracture while lifting a 2.3-kg weight. Several months later, the patient fractured the left femur while walking. Later that year she received a diagnosis of MAS following radiographic imaging that demonstrated polyostotic fibrous dysplasia involving bilateral humeri, the skull, the left maxilla, and several ribs. Her medical history was notable for menarche at age 9 years. Thyroid ultrasound demonstrated cystic changes of the thyroid without biochemical hyperthyroidism. Dermatologic examination revealed numerous large coast of Maine café au lait patches on the left temple, right abdomen, right back, right lower leg, and right posterior thigh, many of which she had been told were present at birth. She later developed multiple lentigines on the right first and second finger pads. The patient first noted hyperpigmented macules on the lips (Figure 2A) at age 18 years, which darkened over the past few years. She subsequently developed new hyperpigmented macules on the gingiva, tongue, and labial and buccal mucosa.
An adolescent boy fractured a left metatarsal at age 3 years, followed by a second fracture of the same foot later that year. Café au lait skin pigmentation was noted at that time, leading to the diagnosis of MAS. His skeletal survey at the time of evaluation at the National Institutes of Health revealed PFD involving the base and anterior portion of the skull, both humeri, left ulna, left thumb, both femurs, left tibia and fibula, and the left metatarsals. Ultrasound evaluation of the testes identified solid and cystic lesions typical of MAS. Ultrasound of the thyroid revealed several hypoechoic nodules, but the patient was biochemically euthyroid. Further investigation demonstrated growth hormone excess necessitating somatostatin analogue therapy. Dermatologic examination revealed a medium-sized café au lait patch on the left temple and the left sacrum and a smaller patch on the right lower abdomen. Several hyperpigmented macules were present on bilateral buccal mucosae and vermilion lips, which had developed at age 7 years (Figure 2B).
A woman had a history of vaginal bleeding and early breast maturation in childhood. She was seen at the National Institutes of Health at age 4 years and was prescribed testolactone to delay puberty. Polyostotic fibrous dysplasia of the cranium was also identified. During childhood, she developed PFD in the maxilla, mandible, and upper palate, around the optic foramen, and in the right ear canal. The patient later developed vision loss due to ananeurysmal bone cyst compressing the optic nerve. She underwent total thyroidectomy for hyperthyroidism. Dermatologic examination at age 22 years revealed 3 small café au lait patches on the posterior neck, left thigh, and sacral area. These had been present since birth. The patient also had a dark brown macule on the midline lower vermilion lip (Figure 2C) that developed at age 20 years and had progressively darkened.
McCune-Albright syndrome is caused by a somatic, postzygotic mutation in GNAS resulting in constitutive activity of the Gsα protein in affected cells only. Because MAS is a mosaic disorder, molecular testing requires affected tissue and is not routinely performed. Diagnosis is based on the presence of at least 2 of the 3 clinical findings of café au lait pigmentation, hyperfunctioning endocrinopathies, and PFD. Café au lait pigmentation in MAS is due to an increase in the production of a second messenger, cyclic adenosine monophosphate (cAMP), which is activated by the Gsα in the melanocytes bearing the mutation. This results in an increase in tyrosinase gene expression and melanin production.6 The pigmented lesions are isolated light to dark brown macules and patches that may be segmental and tend to respect the midline.3 The most common locations are the posterior neck, sacrum, and head.2 Although café au lait patches have previously been reported ipsilateral to the fibrous dysplasia, in a study of 140 patients with MAS, the location of skin pigmentation was not associated with the side of underlying bone involvement. In addition, the size of the café au lait pigmentation does not correlate with the extentof bone disease.2 These pigmented lesions may be present at birth or develop soon after, and they do not fade with age.
Oral mucosal pigmentation was documented in early reports of MAS,3,4 but MAS is not typically included in the differential diagnosis of syndromes with oral lentigines (Table). Acquired mucosal lentigines are a clinical feature of Laugier-Hunziker syndrome, but onset of mucosal pigmentation is typically in late adulthood and is not associated with internal disease. Early-onset mucosal lentigines are a classic finding in 2 genodermatoses associated with endocrine dysfunction, CNC and PJS. Carney complex is an autosomal-dominant disorder associated with an inactivating mutation of protein kinase, cAMP-dependent regulatory, type 1, α (PRKAR1α) gene on chromosome 17, as well as a second genetic locus on chromosome 2p16 that produces a milder phenotype.7 PRKAR1α encodes a regulatory subunit of protein kinase A (PKA), which, when mutated, leads to increased PKA activity. Among patients with CNC, 20% to 40% develop cutaneous, breast, and cardiac myxomas.7 There is a strong association between CNC and endocrine disease, including Cushing syndrome (30%), acromegaly (12%), elevated prolactin (64%), thyroid abnormalities (75%), testicular large-cell calcifying Sertoli cell tumors (41%), ovarian cystadenomas (14%), and pancreatic lesions (2.5%).7-9
Peutz-Jeghers syndrome is an autosomal-dominant disorder caused by an inactivating mutation in the tumor suppressor gene serine/threonine kinase 11 (STK11). Individuals with PJS develop gastrointestinal (GI) polyposis and malignancy of the GI tract, as well as other sites. The GI polyps are benign hamartomas most common in the jejunum, ileum, and the stomach but may lead to periodic abdominal pain from intussusception and obstruction.10 Interestingly, in addition to the shared finding of lentigines, both PJS and CNC are associated with large-cell calcifying Sertoli cell tumors, which may present with gynecomastia in boys as a result of aromatase activity of the tumors.11
In CNC, lentigines are present in 70% to 80% of affected individuals. The characteristic distribution includes the lips, conjunctiva, inner and outer canthi, and genital mucosa. Lentigines develop in childhood, darken during puberty, and often fade after the fourth decade of life. Blue nevi also occur in 40% of patients, but café au lait pigmentation is a less consistent finding.7,8 In PJS, lentigines may be present on the fingers, palms, and soles, as well as the oral, perianal, and genital mucosa.12 Oral lentigines in PJS are reported in up to 90% of individuals and, similar to CNC, begin in childhood and increase in number and size, as well as darkening.13 Early descriptions of PJS report that the lentigines fade after the third decade, except for those located on the oral mucosa.14 In contrast, the 4 patients with MAS in the present series developed perioral pigmentation between the ages of 7 and 20 years.
The shared clinical features in MAS, CNC, and PJS suggest common pathways leading to pigmentation, endocrine disease, and tumorigenesis. Zacharin et al5 reported 4 patients with MAS, 2 with perioral pigmentation, and all of whom had GI polyps that histopathologically resembled the hamartomatous polyps seen in PJS. Genetic analysis revealed GNAS mutationsin 3 of the 4 gastrointestinal samples. Collins et al2 also reported GI polyps in 7 of 140 patients with MAS, suggesting an increased incidence of GI hamartomas in MAS similar to that typically observed in PJS. Recently, Gaujoux et al15 described hepatobiliary or pancreatic lesions in 6 of 19 patients with MAS, including 3 with intraductal papillary mucinous neoplasms. The same group has reported a high prevalence of intraductal papillary mucinous neoplasms in patients with CNC.9,15 Salpea and Stratakis7 recently reviewed the shared molecular pathways between MAS and CNC. In MAS, constitutive activation of Gsα results in activated adenylyl cyclase, which produces cAMP, freeing the catalytic subunits of PKA. Carney complex leads to increased activity of PKA through loss of the regulatory subunit of PKA. A shared downstream effector pathway, therefore, is likely responsible for the overlapping clinical phenotype in certain tissues in both disorders.
We report a series of 4 patients with mucosal pigmentation in conjunction with the classic cutaneous, bone, and endocrine findings of MAS. In contrast to café au lait skin pigmentation, which is present at birth or during infancy, mucosal pigmentation in MAS develops later in life (ages 7-20 years in this series). Oral pigmentation may be under-reported because of its later onset but likely also manifests in a minority of patients with this mosaic condition. Nevertheless, MAS should be included in the differential diagnosis of syndromes associated with lentigines on the lips and oral mucosa, which includes PJS, CNC, and the acquired condition Laugier-Hunziker syndrome. In addition, this finding highlights the clinical overlap between mucosal lentiginosis syndromes and, in particular, a common risk of developing endocrine and gastrointestinal disease in MAS, CNC, and PJS. Last, because this is a mosaic condition with variable presentation that may be clinically delayed, recognition of oral pigmentation as a feature of MAS may facilitate early diagnosis, which has the potential to minimize MAS-associated morbidity, including fibrous dysplasia, precocious puberty, hyperthyroidism, Leydig and Sertoli cell hyperplasia, growth hormone excess, FGF23-mediated renal phosphate wasting, and Cushing syndrome.
Funding/Support: This study was supported in part by the Division of Intramural Research, National Institutes of Dental and Craniofacial Research, and the Center for Cancer Research, National Cancer Institute, National Institutes of Health.
Role of the Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Author Contributions: Drs Pichard and Cowen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: All authors.
Acquisition of data: All authors.
Analysis and interpretation of data: All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: All authors.
Obtained funding: Collins.
Administrative, technical, and material support: Collins.
Study supervision: Collins.
Conflict of Interest Disclosures: None reported.