Abstract
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Nadia Hasan, DO,1 Mari M. Batta, DO,2 & Tamara B. Fedec, DO3
1 PGY 3 Family Medicine Co-chief Resident, Lankenau Family Medicine Residency - City Line Family Medicine
2 Milstein Batta Dermatology, LLC - Teaching Faculty, Lankenau Family Medicine Residency
3 Associate Program Director, Lankenau Family Medicine Residency City Line Family Medicine
Hasan, Batta, Fedec Inherited Patterned Lentiginosis: A Diagnosis of Exclusion 41
QUESTIONS:
After a thorough imaging and lab work up that was negative for abnormality, what is the diagnosis?
Carney Complex
Inherited Patterned Lentiginosis
LEOPARD syndrome
Peutz Jeghers syndrome
Squamous cell carcinoma
What differentiates the lentigines of Inherited Patterned Lentiginosis from Peutz Jeghers syndrome (PJS)?
Lentigines can be present on buccal mucosa in PJS, whereas the buccal mucosa is spared in Inherited Patterned Lentiginosis.
Lentigines of PJS histologically resemble ephelides (freckles)
The lentigines seen in Inherited Patterned Lentiginosis are autosomal dominant.
The lentigines seen in PJS get darker in adulthood
There are no differences; the two conditions cannot be
differentiated based on physical appearance alone.
The most serious and potentially fatal manifestation of Carney Complex syndrome is:
Ovarian carcinoma
Metastic melanoma
Thyroid storm
Cardiac myxoma
Thrombotic thrombocytopenia purpura (TTP)
Differences between lentigines and ephelides include all of the following EXCEPT:
Ephelides do not generally indicate systemic disease
Lentigines will darken with sun exposure, whereas ephelides are not affected by UV light
Ephelides histologically show increased melanin and a normal amount of melanocyte, whereas lentigines present histologically with increased melanocytes
Lentigines are seen predominately in people of African descent, whereas ephelides are most common in northern and western European descent
Lentigines appear on non-sun exposed skin, ephelides are
typically are confined to sun-exposed skin
FIGURE 1:
Facial lentigines
FIGURE 2:
Lentigines on forearms
42 Osteopathic Family Physician | Volume 8, No. 4 | July/August, 2016
ANSWERS
After a thorough imaging and lab work up that was negative for abnormality, what is the diagnosis?
The correct Answer is:
What differentiates the lentigines of Inherited Patterned Lentiginosis from Peutz Jeghers syndrome (PJS)?
The correct Answer is:
A) Lentigines can be present on buccal mucosa in PJS, whereas the buccal mucosa is spared in Inherited Patterned Lentiginosis.
The most serious and potentially fatal manifestation of Carney Complex syndrome is:
The correct Answer is:
D) Cardiac myxoma
Differences between lentigines and ephelides include all of the following EXCEPT:
The correct Answer is:
B) Lentigines will darken with sun exposure, whereas ephelides are not affected by UV light
DISCUSSION
The distribution and characteristics of the macules on the face and arms appeared consistent with lentigines. However, because the patient also presented with nevus spilus, blue nevus, and a café-au- lait macule, as well as gastrointestinal (GI) complaints, a family his- tory of GI malignancy, and endocrine abnormality of hypothyroid- ism, further studies were obtained to rule out familial lentiginosis syndromes such as Carney complex and Peutz Jeghers syndrome.
Through a diagnosis of exclusion, the patient was determined to have Inherited Patterned Lentiginosis. Inherited patterned len- tiginosis is an uncommonly described benign cutaneous condi- tion originally described by John F O’Neill and William D James in 1989 in the Archives of Dermatology.1 Although rarely studied or noted in research articles, this condition appears to be inherited in an autosomal dominant fashion and is most commonly seen in lighter-pigmented African Americans, particularly those with mixed American Indian heritage.2 Cutaneous findings include lentigines, which are small hyperpigmented macules that present in early childhood1 and often increase in amount as a child ages and enters puberty.2 These lentigines are commonly found on the
central face, lips, as well as hands, elbows, and buttocks. There is sparing of the mucous membranes. In contrast to other lentigino- sis syndromes, there are no associated systemic diseases and it is therefore a benign condition.3
While lentigines often clinically resemble ephelides (freckles), len- tigines typically do not darken with sun exposure and can appear on non-sun-exposed skin. Histologically, a lentigo will show basal cell layer hyperpigmentation with increased number and hyperpla- sia of melanocytes.4 In contrast, ephelides generally present with increased melanin within basal keratinocytes and a normal number of melanocytes.
The differential diagnosis for facial lentigines are familial lentigi- nes syndromes, including Peutz-Jeghers syndrome (PJS), Carney Complex (CNC), LEOPARD syndrome, and Cronkhite-Canada syndrome, as well as more rare disorders, such as Laugier-Hun- ziker syndrome. Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder that usually presents in early teenage years. It is a mutation of the STK11 gene on chromosome 19p13.3.5 Cells overgrow characteristically in the GI tract and manifest as multiple hamartomatous polyps. Rarely, polyps have been reported in ure- ters, nasal and respiratory tracts, and the gallbladder.6
The hamartomatous polyps of PJS have a high risk of turning into malignant carcinoma, and patients have a greater likelihood of de- veloping other cancers including breast, cervical, GI, pancreatic, and endometrial carcinoma. One meta-analysis has cited a 93% cu- mulative risk of developing cancer.6 It is therefore imperative that this condition be diagnosed early with colonoscopy and endoscopy so cancer screening can be implemented immediately.5,6
Cutaneous manifestations of PJS that are similar to inherited pat- terned lentiginosis include multiple 1-5 cm blue-gray to brown macules found around the eyes, nostrils, mouth, and occasionally on hands, feet and anal region.6 The lentigines are seen in 95% of patients affected with PJS, and tend to be most visible in childhood, fading by adulthood.7 A key difference between PJS and inherited patterned lentiginosis is the presence of lentigines on buccal mu- cosa in PJS.
Diagnostic criteria for PJS require at least one of the following: 1) 2 or more polyps histologically confirmed to be PJS, 2) any number of polyps plus a family history of PJS, 3) mucocutaneous pigmentation plus a family history, 4) Peutz Jegher polyps and mucocutaneous pigmentation.8
Carney Complex (CNC) is an autosomal dominant disorder as- sociated with a mutation of the PRKAR1A gene on chromosome 17q22-24.7 Cardiac myxomas are the most serious manifestation of CNC with a 16% sudden cardiac death rate.9 Endocrine tumors and therefore endocrine hypo-and hyper-activity are also a com- mon finding. Primary pigmented nodular adrenocortical disease, growth hormone-secreting pituitary adenomas, thyroid carcino- mas, testicular tumors and ovarian cysts have all been associated with CNC.9
Cutaneous manifestations of CNC include lentigines located on the conjunctiva and vermilion border of lips that are most noticeable in adolescence and fade with age. Blue nevi of less than 5 mm have been reported on the face, trunk and limbs. Café-au-lait macules, nevus spilus, and cutaneous myxomas are also present, with the myxomas seen on the face, ears and trunk in 30-55% of patients.4
Hasan, Batta, Fedec Inherited Patterned Lentiginosis: A Diagnosis of Exclusion 43
Diagnosis usually begins with findings suggestive of CNC based on the cutaneous manifestations and family history. Testing for endocrine abnormalities initially include thyroid panels, blood glucose, and urinary cortisol. If abnormal, plasma adrenocortico- tropic hormone (ACTH), growth hormone (GH), insulin-like growth factor and dexamethasone suppression testing can be performed. Patients should be evaluated with echocardiogram to rule out a cardiac myxoma. Other imaging may be performed based on lab values and clinical suspicion, including adrenal CT scans, thyroid US, testicular US, ovarian US, and pituitary MRI.7
LEOPARD syndrome is a rare autosomal dominant disorder caused by a mutation of the PTPN11 gene on chromosome 12q24.1.10 Its name is an acronym for the various manifestations of this syn- drome: Lentigines, Electrocardiogram abnormalities, Ocular hy- pertolerism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, and sensorineural Deafness. The lentigines of LEOP- ARD syndrome are found primarily on the upper trunk and face, but not oral mucosa – a feature that distinguishes it from PJS but is similar to inherited patterned lentiginosis. Unlike PJS and CNC, the lentigines start in infancy and then increase in number with age. Often, lentigines are the first clinical clue to diagnosis,10 and it is made if lentigines plus two of the other features are present. If lentigines are absent (only 10% of cases), diagnosis is established if a first degree relative is affected and three of the aforementioned features are present.7
Cronkhite–Canada syndrome (CCS) is a rare, non-familial syn- drome that presents around the 6th decade. It is characterized by hamartomatous polyps throughout the GI tract that are phenotyp- ically similar to those seen in PJS. These polyps are associated with other mucosal changes and protein losing enteropathy that lead to severe malabsorption.11 A patient will present with sudden onset severe malnutrition, as well as alopecia, onycholysis and lentigines of the palms and dorsal hands. Lentigines have not been reported on the face or buccal mucosa.12
Laugier-Hunziker syndrome (LHS) is a benign acquired syndrome where 2-5 mm blue-black and brown macules appear as either soli- tary or multiple lesions commonly on the tongue and gingiva. They are seen after puberty and histologically look more like ephelides than lentigines, with increased melanin and normal melanocytes. Additionally, buccal mucosa and nails can be involved 60% of the time.13
CONCLUSION
A 55 year old African American female presented with lentigines and other cutaneous and systemic abnormalities that raised sus- picion for systemic disease. A full work up was obtained and all results were benign, ruling out familial lentiginosis syndromes. The lentigines on her face were not bothersome, and the patient opted to conservatively manage with monthly self-skin checks, daily sunscreen application and strict photo protection, and rou- tine follow up with her dermatologist. If the patient had opted for skin treatment, her PCP could refer her to dermatology for intense pulsed light source (IPL) therapy, which has been shown to com- pletely clear facial lentigines caused by PJS.14 There are multiple other types of lasers that have also been shown to lighten or com- pletely remove lentigines.15 There are skin-lightening agents that can be prescribed that have been shown to lighten lentigines, but a
prescriber should be experienced in such agents and use with cau- tion, especially if they are to be applied to face. Agents used alone, in combination therapy or as an adjuvant to cryotherapy include fluocinolone acetonide 0.01%, hydroquinone 4% and tretinoin 0.05%.16
Inherited patterned lentiginosis, a diagnosis of exclusion, is highly prevalent in the African American community, but has gained mini- mal attention in medical research and literature due to its benign nature. It poses no harm to patients, does not progress, and usually does not get formally diagnosed.1,3 However, if a patient presents with the cutaneous presentation of inherited lentigines along with any of the signs and symptoms of an underlying systemic disease, it is imperative to be aggressive in ruling out other conditions, as lentigines may be the first indication of a more serious issue.
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