Multiple pilomatricomas by the numbers

By Warren R. Heymann, MD
February 24, 2021
Vol. 3, No. 8

I have always been beguiled by pilomatricomas (PM). From the time I first heard the term “calcifying epithelioma of Mahlerbe” or pondering “is it pilomaticoma or pilomatrixoma?” this benign lesion has been a source of wonder. There is a sense of satisfaction making the diagnosis clinically by observing a firm subcutaneous nodule (characteristically on the head and neck of a child), often with a hint of red-blue, and displaying a “teeter-totter” sign. Frayed nerves of parents can usually be calmed. Regardless, compulsive dermatologists will question whether the lesion is associated with any of the multiple syndromes that have been reported with PM. Are there any guidelines to help?

PM usually occur in pediatric patients, and it is the second most common benign skin tumor, after epidermal cysts, occurring within the first two decades of life. There appears to be a bimodal pattern of occurrence, with the first peak being at 5–15 years and the second peak occurring at 50–65 years. PM are more frequently in females and most commonly occur in the head and neck area, followed by the trunk and extremities. Rare anetodermatous, bullous, and giant variants have been reported. (1) Usually asymptomatic, inflammation or secondary infection may cause pain and ulceration. Despite being considered benign, malignant transformation has been described. (2)

Histologically, PM demonstrate lobules of basaloid cells and eosinophilic “shadow” cells. (3) This may be accompanied by calcification and granulomatous inflammation. As stated by Kentley et al: “Pilomatrixomas are a benign appendageal tumour of the hair matrix that present as a firm nodule on the head and neck. The majority of pilomatrixomas are the result of a somatic mutation in the CTNNB1 gene, coding for β‐catenin, an intracellular signalling protein that plays a key role in maintaining epithelial architecture via the Wnt pathway. The resulting mutant β‐catenin is resistant to ubiquitination and phosphorylation, leading to increased levels in the nucleus and cytoplasm of basaloid cells. Increased Wnt signalling leads to decreased apoptosis and abnormal matrix cell proliferation and formation of a pilomatrixoma.” (4)

While the typical PM is a solitary lesion, patients may have multiple lesions in up to 3.5% of cases. (5) Richet et al performed a detailed retrospective literature review of 1458 children with PM and reported that associated disease was found in 32 children (2.2%), most of whom had several pilomatricomas (n = 23); 9 had a single lesion. Although the risk of an associated disease seems to be higher in patients with multiple PM, an associated disorder cannot be ruled out with a solitary PM. Based on this literature review, the authors recommend reassuring the family and then conducting a detailed interview regarding past medical and family history and a thorough clinical examination for signs of Turner syndrome, constitutional mismatch repair deficiency, Kabuki syndrome, Steiner’s myotonic dystrophy, or Gardner syndrome. (3) Other rare associations include trisomy 9, spina bifida, gliomatosis cerebri, and sarcoidosis. (6) Rizzoli et al detail familial papular epidermal nevus with “skyline” basal cell layer (PENS) and multiple pilomatricomas, in a 12-year-old girl (with a history of seizures) and her mother. As PENS and PENS syndrome (PENSS) are recently described entities, further research is warranted to determine if the association with PM is fortuitous or genuine. (7)

As a rule of thumb, unless there is a family history of a particular syndrome, you can be reasonably reassuring if a patient has a solitary lesion. Just as most clinicians, myself included, do not become riled up over a singular neurofibroma (NF-1), trichilemmoma (Cowden syndrome), fibrofolliculoma (Birt-Hogg- Dubé), or others, we need not be overly concerned about a solitary PM with an unremarkable family history in an otherwise healthy child.

When should we worry? Ciriacks et al offer us guidance. They identified 66 syndromic cases from 52 publications, with the majority (54) of cases representing myotonic dystrophy, familial adenomatous polyposis-related syndromes (including Gardner syndrome), Turner syndrome, or Rubinstein-Taybi syndrome. Twenty-five of the 54 cases (46.3%) had six or more pilomatricomas. Of sporadic cases, 128 out of 134 (95.5%) had five or less pilomatricomas. Syndromes may have been missed in sporadic cases. The presence of six or more pilomatricomas was highly suggestive of an underlying syndrome (>95% specificity). Such patients should undergo additional screening. Importantly, PM may develop prior to phenotypic expression of a syndrome. This was most consistent in the familial adenomatous polyposis-related syndromes where 100% (6/6) of patients developed multiple PM before their syndrome was diagnosed. Patients with less than six pilomatricomas and family history of myotonic dystrophy, first-degree relative with colon cancer or FAP-related syndrome, or family history of pilomatricomas should also undergo further screening by genetics. In summary, the authors suggest considering additional screening for those patients with:

• Six or more PM

• Even one PM in the setting of a family history of myotonic dystrophy, first‐degree relative with colon cancer or FAP‐related syndrome, or family history of PM

• Even one pilomatricoma in the setting of clinical features suggestive of Turner or Rubinstein‐Taybi syndromes (8)

Point to Remember: Pilomatricomas are usually solitary lesions. When multiple (notably > 6) a careful assessment is warranted to determine if there is an associated syndrome, which may not yet have become apparent. This could even be lifesaving for patients whose PM are associated with familial adenomatous polyposis-related syndromes.

Our expert's viewpoint

Howard B. Pride, MD

What could be worse? A perfectly harmless pediatric lesion, easily diagnosed and just is easily ignored, lulls us into complacency only to deliver the gut punch of a serious underlying genetic disease. The joy of one of my favorite diagnoses has been sucked out of my soul. Fear not. First off, this article relied on reported cases and the true denominator of pilomatricomas unassociated with a genetic syndrome is enormously under-represented. Secondly, the article provides valuable clues to ruling out an association without the need for extensive testing and handwringing. Using less than six pilomatricomas as the initial screen and family history as the next, most cases can be easily dismissed as an isolated finding.

Am I even going to remember what the associations are by the time I see my next pilomatricoma? That is what computers are for. I created a smart phrase in our electronic health record that I named “pilomatricomaassociations.” I did not include Kabuki and Sotos syndrome since there has only been one report of each which was likely coincidental. The text of the smart phrase is:

Myotonic Dystrophy: Pilomatricomas may precede diagnosis, autosomal dominant, progressive weakness, and wasting of distal muscles and diaphragm

Familial Adenomatosis Polyposis syndrome (including Gardner Syndrome): Pilomatricomas may precede diagnosis, autosomal dominant, premalignant adenomatous polyps (usually colon), congenital hypertrophy of retinal pigment epithelium (CHRPE), osteomas

Turner: Generally pilomatricomas come after diagnosis, sporadic inheritance, short stature, premature ovarian failure, webbed neck, lymphedema, café au lait macules, low-set and malrotated ears, widely space nipples, coarctation of aorta

Rubinstein-Taybi: Generally pilomatricomas come after diagnosis, sporadic inheritance, short stature, mental retardation, brachyonychia (racquet nails), dental anomalies

1. Han G. Kim AR Song HJ, Hwan C, Jeon J. Updated view on epidemiology and clinical aspects of pilomatricoma in adults. Int J Dermatol 2017; 56: 1032-1036.

2. Mesa-Álvarez L, Batalla A, Iglesias-Puzas Á, Álvarez C, Flórez Á. Multiple pilomatricomas: A retrospective study and literature review. Am J Dermatopathol 2019; 41: 293-295.

3. Richet C, Maza A, Dreyfus I, Bourrat E, Mazereeuw J. Childhood pilomatricomas: Associated anomalies. Pediatr Dermatol 2018; 35: 548-551.

4. Kentley J, Nasir S, Lloyd K, Markiewicz D, Harwood CA. Multiple pilomatrixomas as a presentation of myotonic dystrophy. Clin Exp Dermatol 2019; 44; e149-150.

5. Hikiami R, Kakudo N, Morimoto N, Hihara M, Kusumoto K. Multiple giant pilomatricomas of the shoulder and upper limbs. Eplasty. 2018 Sep 28;18:ic20.

6. Stevenson P, Rodins K, Susman R. The association between multiple pilomatricomas and APC gene mutations. Australas J Dermatol 2018; 59: e273-e519.

7. Rizzoli L, Balestri R, Rech G, Zorzi MG, et al. Familial papular epidermal nevus with “skyline” basal cell layer and multiple pilomatricomas: A new association? Pediatr Dermatol 2018; 35: e147-150

8. Ciriacks K, Knabel D, Waite MB. Syndromes associated with multiple pilomatricomas: When should clinicians be concerned? Pediatr Dermatol 2020: 37: 9-17.

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