Pilomatricomas in a patient with Rubinstein–Taybi syndrome: diagnostic and therapeutic clues

Abstract

Pilomatricoma is a rare benign neoplasm originating from hair cortex cells and typically manifests in children as a slow-growing bluish-red, superficial and firm mass. Multiple pilomatricomas can be associated with genetic mutations and syndromic disorders, most commonly with Rubinstein–Taybi syndrome, Gardner syndrome, myotonic dystrophy, Turner syndrome, and Sotos syndrome. Ultrasound examination allows this tumor to be characterized, to assess the involvement of deeper structures and to plan treatment. Pilomatricoma shows some distinctive ultrasonographic features that aid in its diagnosis and it may be seen on ultrasound as an ovoid complex mass. Complications and malignant transformation of pilomatricomas have been described as a possible tumor evolution, and surgical resection is recommended. We present a rare case of a 17-year-old female patient with intellectual disability and microcephaly, and with the evidence of multiple pilomatricomas in the head-neck region on ultrasound examination. The syndromic features of the patient and genetic tests led to a diagnosis of Rubinstein–Taybi syndrome. We also focused on the association between pilomatricomas and genetic mutations in patients with Rubinstein–Taybi syndrome.

Plain language summary

How to recognize a rare syndrome.

A 17-year-old female patient was referred to our Pediatric Clinic Department for skin lesions on her face and neck. These lesions appeared as painful ovoid masses with a hard consistency on clinical examination. Ultrasonography was useful to identify these alterations, revealing complex masses with inhomogeneous echogenicity, punctate calcifications and vascularity. The family agreed to the surgical removal of lesions, and pathological examination was consistent with pilomatricomas, a rare benign tumor of the skin. Pilomatricomas can sometimes be associated with specific genetic syndromes, as in the case we report.

Introduction

Pilomatricoma, also known as pilomatrixoma or calcifying epithelioma of Malherbe, is a rare benign skin tumor derived from the hair cortex matrix cells and its common location is deep dermal or subcutaneous tissues. ¹ Pilomatricoma mainly affects children, with a female predominance, and it exhibits two peaks of incidence, occurring in the first two decades and in the sixth decade of life. ¹ Approximately, 50% of cases involve the head and neck regions, followed by extremities and trunk. ² Less common locations include the temporal, cheek, periorbital and preauricular areas. Clinically, pilomatricoma manifests as a painless, mobile and firm mass, covered by normal skin ³ ; nevertheless, it can occur as a painful mass, and the overlying skin can have a bluish-red appearance due to the presence of small vessels around the lesion. ⁴ Suppurative superinfection, presenting as skin inflammation or ulceration, is the most common complication and it requires prompt treatment. ⁴ Pilomatricomas typically exhibit slow growth and when multiple can be sporadic, familial or associated with clinical syndromes. ⁴ Although rare, malignant transformation of pilomatricomas has been described as a possible evolution, and surgical resection is the treatment of choice.^1,5 Differential diagnosis includes multiple pathological conditions such as epidermal inclusion cysts, hemangioma, giant cell tumors, melanocytic lesions and other skin tumors. ¹ General imaging and ultrasound examination are important diagnostic tools to reach a final diagnosis, to study the morphological characteristics of the lesions, and to rule out other conditions. In the literature, familial forms of pilomatricomas are associated with multiple lesions and several syndromes; in particular, a strong connection has been established with three different genetic disorders: Steinert myotonic dystrophy; Gardner syndrome (GS); Rubinstein–Taybi syndrome (RSTS). ⁵ Only few cases describe the association between pilomatricomas and RSTS, and none of these have found a direct correlation between these two entities.

The purpose of this case report is to illustrate the most common ultrasound findings of pilomatricomas in children with Rubinstein–Taybi syndrome in order to address the correct management of this pathological condition. The case we report conforms to the Consensus-based Clinical Case Reporting Guidelines (CARE). ⁶

Case report

A 17-year-old female patient, who was a long-standing patient at our hospital due to intellectual disability and microcephaly, was admitted to our Pediatric Clinic Department for painful skin lesions on her face. She was the second-born child of non-consanguineous parents, and no history of genetic diseases was reported in her family. She was born at term (39 weeks), via caesarean section and the pregnancy was uneventful. Her birth weight was 2.2 kg (25th–50th percentile), head circumference 29.6 cm (<3rd percentile), and length 49 cm (<3rd percentile). She was admitted to Pediatric Department 4 months after birth being small for gestational age. At 5 months, she weighed 5.2 kg (3rd–10th percentile) and measured 59 cm in length (<3rd percentile). Her head circumference was 37 cm (<3rd percentile), thus confirming microcephaly. Furthermore, she exhibited high hair implantation, epicanthus, small ears, a saddle-shaped and pointed nose with small, anteverted nostrils, micrognathia and ogival palate. Neurological examination revealed discrete interaction with the environment, responsiveness to stimuli, and the ability to hold her head, but not to maintain a stable sitting position. Mild hypertonicity was noted in the lower limb muscles, which were otherwise of normal size. Osteotendinous reflexes were present and responsive, and her sensitivity was intact. Brain MRI exhibited slight dilatation of subarachnoid spaces in the posterior cranial fossa, extensively communicating with the IV ventricle, which was within normal volume limits. Additionally, mild hypoplasia of the inferior portion of the cerebellar vermis was detected, consistent with a mild-grade cerebellar vermis hypoplasia of the posterior cranial fossa malformation type. These findings suggested a possible syndromic habitus. However, the first array-CGH test showed normal results. The patient practiced psychomotor and speech therapy 2–3 times per week. She was diagnosed with hypothyroidism and started levothyroxine replacement therapy. In 2020, her last brain MRI revealed hyperintense spots in T2 and FLAIR in the periventricular and subcortical areas bilaterally, consistent with nonspecific gliotic alterations. The fourth ventricle remained slightly hypoplastic. Neuroimaging scans conducted during the follow-up period remained unchanged. At 17, her weight was 39 kg (<3rd percentile), height was 134 cm (<<3rd percentile) and head circumference was 47 cm (<<3rd percentile). She also presented with convergent strabismus of the right eye, asymmetric thoracic cage, with the right shoulder lower than the left, winged scapulae, dorsal kyphosis, and left mandibular deviation. Slightly xerotic skin with subcutaneous nodules in the left frontal region, in the anterior region of the neck and in the right cheek were also observed. These nodules were painful on palpation and the overlying skin showed signs of inflammation (Figure 1). Consequently, the patient underwent a B-mode ultrasound examination, with colour, power and duplex Doppler assessment vascularity using a linear transducer. Ultrasonography revealed solid oval-shaped structures (approximately 14 mm × 5 mm and 15 mm × 5 mm in diameter), within the subcutaneous soft tissues characterized by inhomogeneous echogenicity, peripheral and intralesional vascular signals on Eco-Color-Doppler evaluation, and thickening of the subcutaneous adipose tissue at this level, suggesting inflammation changes (Figures 2 and 3). Calcifications without posterior acoustic shadowing were also observed within the lesions (Figure 2). These findings warranted further evaluation and correlation with clinical, laboratory and genetic data. A multidisciplinary consensus recommended surgical removal of subcutaneous nodules for histopathological examination, which revealed pilomatricomas. Whole Exome Sequencing (WES) performed on the trio revealed a de novo deletion in the EP300 gene (NM_001429.3:c.2700_2701del). ⁷ This frameshift variant (p.Leu901SerfsTer7) is classified as pathogenic and associated with Rubinstein–Taybi syndrome 2 (OMIM #613684). ⁸

Figure 1.

Clinical pictures of pilomatricomas. Multiple subcutaneous nodules with slightly xerotic skin and signs of inflammation were identified in the left frontal region (a), in the anterior region of the neck (b), and in the right arm (c) on clinical examination. The nodules were painful on palpation.

Figure 2.

(a) Ultrasound examination in a 17-year-old female patient with a symptomatic pilomatricoma located in the frontal region of face. Ultrasound detects an ovoid capsulated well-defined mass characterized by iso-hypoechogenicity and punctate calcifications without posterior acoustic shadowing (white dotted circles). Note the inflammatory changes around the lesion, with hyperechogenicity and thickening of the subcutaneous tissues (double yellow arrow). (b) Tumour shows vascularity on Eco-Color-Doppler examination.

Figure 3.

Subcutaneous nodule in the anterior region of the neck. Eco-Color-Doppler examination identifies the presence of prominent blood vessels within a well-defined suprafascial (curved yellow line) lesion of subcutaneous tissue. On pathological examination, the lesion revealed to be a pilomatricoma.

Discussion

Pilomatricomas are benign neoplasms originating from hair matrix cells, which were first described by Malherbe and Chenantais in 1880. ⁹ They most frequently occur in pediatric age, presenting as solitary skin lesions in the first and second decades of life; multiple pilomatricomas occur in 2.4% to 5% of patients. ¹⁰ The pathogenesis is uncertain and multifactorial, with a probable genetic component associated with external injury such as trauma, insect bites or surgical procedures. ¹¹

In the scientific literature, different authors have reported an association between pilomatricoma and various genetic conditions including Rubinstein–Taybi syndrome, GS, MYH associated polyposis, myotonic dystrophy, Sotos syndrome, Turner syndrome, gliomatosis cerebri, trisomy and tetrasomy 9p (Table 1).

Table 1.

Genetic mutations associated with pilomatricomas and related syndromes.

Gene location	Gene/locus	OMIM phenotype	Inheritance	Associated syndrome
16p13.3	CREBBP	180849	AD	Rubinstein–Taybi syndrome Type 1
22q13.2	EP300	613684	AD	Rubinstein–Taybi syndrome Type 2
19q13.32	DMPK	160900	AD	Myotonic Dystrophy 1 (DM1); Steinert Disease
3p22.1	CTNNB1	132600	Somatic mutation	Epithelioma Calcificans of Malherbe
1p34.1	MUTYH	608456	AR	Familial Adenomatous Polyposis 2 (FAP 2)
1p34.1	MUTYH	613659	Somatic mutation	Gastric Cancer
5q35.3	NSD1	117550	AD	Sotos syndrome
4q24	TET2	619126	AR	Immunodeficiency 75 with Lymphoproliferation (IMD75)
7p22.3	MAD1L1	620189	AR	Mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predisposition (MVA7)

These associations suggest dysregulation of cell-signaling pathways. ⁹ In their literature review, Jones et al. investigated potential genetic aetiologies, highlighting the potential role of Wnt signaling pathway mutations and altered proto-oncogenes expression in basophilic and shadow cells in tumor pathogenesis. ⁹ In pilomatricoma and its malignant form, known as pilomatrix carcinoma, a mutated gene named CTNNB1 encodes β-catenin, a downstream component in the Wnt signaling pathway. ¹² This factor influences various cellular mechanisms, including cell differentiation within the hair follicle, cellular adhesion, and cellular proliferation. ⁹ Additional immunohistochemical studies showed an increased expression of the proto-oncogene bcl-2 within the basophilic cells of pilomatricoma. ⁹ Several studies have identified mutations frequently associated with pilomatricomas development. Although the association between pilomatricoma and alterations in the Wnt signaling pathway is well established, genetic testing in our patient revealed an inactivating variant of the EP300 gene (NM_00149.3:c.2700_2701del) associated with Rubinstein–Taybi syndrome (RSTS, OMIM #613684). RSTS is a developmental disorder caused by mutations in the CREBBP or EP300 genes, which are crucial for chromatin remodeling and transcriptional co-activation. CREBBP mutations account for approximately 60% of RSTS cases, while EP300 mutations are responsible for 8%–10% of cases. These genes impact a wide range of cellular processes due to their interaction with over 400 different proteins. Mutations in CREBBP and EP300 have also been identified in various tumors, including diffuse large B-cell lymphoma, follicular lymphoma, and acute myeloid leukemia. ¹³

RSTS is characterized by developmental delay, postnatal growth retardation, intellectual disability, microcephaly, skeletal anomalies of thumbs and toes, short stature, and facial anomalies.^9,14 An association between this syndrome and the development of keloids is frequently reported in the literature, as described by Yagi et al. in their study.^{15 –17} Approximately, 30% of patients with RSTS may develop additional tumours, including meningiomas and less frequently, hemangiomas. ¹⁸ According to a recent review by Cammarata-Scalisi, the correlation between RSTS syndrome and pilomatricomas was first documented in 1994 and only ten cases have been described to date, six of which presenting with multiple lesions. ¹⁰ Interestingly, mutations in EP300 have been rarely associated with pilomatricoma. ⁷ Although EP300 mutations are well-established in RSTS, the connection between EP300 germline mutations and tumourigenesis, particularly in pilomatricomas, remains underexplored. Pilomatricomas have primarily been associated with mutations in other tumor suppressor genes, such as APC, where somatic loss of heterozygosity (LOH) has been documented. ¹⁹ However, to our knowledge, there have been no studies directly investigating the role of LOH or a second-hit mutation in EP300 specifically within pilomatricomas. This gap in our knowledge highlights the need for further research into the potential involvement of EP300 mutations and LOH in the pathogenesis of pilomatricomas in RSTS.

The diagnosis of pilomatricomas in patients with Rubinstein–Taybi syndrome is based on a combination of clinical and genetic features; ultrasonography does not allow a differential diagnosis between RSTS and other syndromes based only on imaging features of the tumour. However, the integration of clinical and imaging features, including characteristic facies of the patients and the number of skin lesions may guide diagnosis. ²⁰ Histologically, pilomatricoma appears as a clearly defined tumor composed of irregular clusters of epithelial cells within a relatively dense cellular stroma. At the tumor periphery, epithelial cells with basophilic cytoplasm are arranged in an “arc-like” pattern. ²¹ A key histopathologic feature of pilomatricomas is the transition of basaloid cells into shadow cells (also known as ‘ghost cells’), which are centrally located and associated with nodular proliferation. ²¹ Shadow cells lack nuclei, contain keratin and appear eosinophilic. Transitional cells, located between basaloid and shadow cells, are apoptotic cells transforming into shadow cells. ²¹ The stroma consists of collagen and includes dilated blood vessels. Chronic inflammation, accompanied by a foreign body reaction, may occur in the stroma surrounding the shadow cells causing calcium deposition around cells and stroma. ²¹ Calcium deposition occurs in approximately 69%–85% of cases. ²¹ Calcifications are a common finding in long-standing lesions, reflecting chronic inflammation. ²² The study of Li et al. identified various histological stages of tumor by showing different types of calcifications. Scattered dot calcifications were predominantly observed in early and mature stages, while arc-shaped calcifications were mainly seen in the regressive stages. Clumps of calcification may appear at any histological stage. ¹ Clinically, pilomatricoma appears as a painless mobile firm mass, with a lobulated or irregular surface and covered by normal or altered (ulcerated, telangiectatic and erythematous) skin.^3,4 Pilomatricomas usually manifest as slow-growing lesions, primarily located in the head and neck region. Occasionally, this tumor demonstrates rapid growth, mimicking a malignant lesion, requiring prompt surgical excision. ⁴ Malignant transformation of pilomatricoma is rare and primarily reported in adult patients. However, the differential diagnosis between benign and malignant lesions can be challenging in cases with unusual clinical presentations or complicated lesions. Ultrasonography is the first-line imaging modality for cutaneous masses in children, since it does not use ionizing radiation. US characterizes pilomatricomas, assessing the involvement of deeper structures and establishing the preoperative assessment of the tumor through the identification of the region involved, shape, rim and dimension. ¹ According to the classification of Solivetti et al., pilomatricomas can exhibit different ultrasound patterns, ranging from a fully calcified lesion (type 1), to a predominantly hypoechoic solid lesion with a tiny internal calcification (type 2), to a macrolobulated lesion with internal cystic areas, which may or not contain coarse calcifications (type 3), to a pseudocystic lesion with thick walls and thin septa (type 4), to a solid and irregular large lesion with pseudo-tumoural appearance (type 5). ²³ Ultrasound examination usually identifies a well-defined mass, surrounded by a hypoechoic connective tissue capsule. ²¹ The lesion may appear hyperechoic or isoechoic with or without posterior acoustic shadowing due to the presence of tiny or coarse calcifications. ²¹ Cystic degeneration was first reported in the literature in 2007 by Lim et al. describing two cases of pilomatricoma with anechoic appearance and pseudo-cystic internal changes. ²¹ Eco-Color-Doppler examination is useful to demonstrate the presence of blood vessels within or around the lesion; most pilomatricomas show mild to moderate Eco-Color-Doppler signals. ²⁴ In addition, dermoscopy can also be a valuable diagnostic tool, as it can reveal several characteristic patterns. ²⁵ Dermoscopic features of pilomatricoma, first described by Zaballos et al. in 2008 and further detailed in subsequent studies, include the presence of polymorphous vessels, streaked yellowish-white structures, blue-grey unstructured areas, and uniform reddish regions. ²⁶ The pathognomonic pattern is the “tricolour type,” which appears as a homogeneous blue-yellow-reddish area.^25,27

The treatment of pilomatricomas is still debated. Although pilomatricomas often exhibit characteristic clinical and imaging features, unusual or complicated presentations can pose diagnostic challenges, particularly in distinguishing them from malignant lesions. No formally defined diagnostic criteria have been established for the diagnosis of this tumor. Moreover, differentiating pilomatricoma from its malignant counterpart, pilomatrix carcinoma, is often difficult and requires histopathology examination. Therefore, the definitive diagnosis is anatomopathological and complete excision is the treatment of choice, as spontaneous regression of pilomatrixomas has never been observed. ⁹

In the case we report, the patient exhibited a psychomotor developmental delay, short stature, facial dysmorphisms, and a medical history of microcephaly documented by previous instrumental examinations. She also presented multiple symptomatic subcutaneous nodules in the frontal region of the face and in the anterior region of the neck, associated with signs of inflammation, and covered by xerotic skin. Clinical presentation was misleading, however, ultrasound examination proved helpful in diagnosis, revealing three well-defined, ovoid masses in the subcutaneous tissue of the face and neck. These masses exhibited inhomogeneous echogenicity, calcifications without posterior acoustic shadowing, vascularity within the lesion and peritumoural hyperechogenicity, reflecting inflammation changes. Our patient underwent complete excision of the lesions for both diagnostic and therapeutic purposes, with subsequent resolution of her symptoms. Following histological confirmation of multiple pilomatricomas, the patient, who also presented with psychomotor developmental abnormalities and dysmorphic features, underwent WES, confirming the diagnosis of RSTS. In our clinical case, ultrasound was pivotal not only in the early identification of the pilomatricoma but also in facilitating the prompt surgical excision of the symptomatic lesion. This timely intervention allowed for histological confirmation, further corroborating the clinical suspicion of a syndromic condition. The final diagnosis was definitely established by WES, underscoring the value of integrating imaging, clinical evaluation, and genetic testing in managing this complex and rare case.

Conclusion

Pilomatricoma is a rare benign tumor associated with various genetic syndromes. It may rarely exhibit malignant transformation requiring prompt treatment. The diagnosis of pilomatricoma can be a real challenge for clinicians and radiologists. Ultrasound plays a primary role in the early identification of the tumor, avoiding unnecessary additional imaging examinations. Three main imaging features of pilomatricoma are peritumoural hyperechogenicity, calcification with or without acoustic shadowing, and vascularity within the lesion. Ultrasound examination provides useful information facilitating a rapid and correct diagnosis of pilomatricoma, which must be confirmed histologically. Pediatricians should suspect the diagnosis of Rubinstein–Taybi syndrome in children presenting multiple skin lesions, growth retardation, psychomotor and cognitive delay, and specific body dysmorphisms. Radiologists should become familiar with the ultrasound characteristics of pilomatricomas and tumor complications in children.

Supplemental Material

sj-pdf-1-trd-10.1177_26330040251330316 – Supplemental material for Pilomatricomas in a patient with Rubinstein–Taybi syndrome: diagnostic and therapeutic clues

Supplemental material, sj-pdf-1-trd-10.1177_26330040251330316 for Pilomatricomas in a patient with Rubinstein–Taybi syndrome: diagnostic and therapeutic clues by Laura Battaglia, Corrado Ini’, Manuela Lo Bianco, Roberta Leonardi, Eleonora Ini’, Pietro Valerio Foti, Stefano Palmucci, Marco Fichera, Martino Ruggieri and Antonio Basile in Therapeutic Advances in Rare Disease