Xanthoma disseminatum: A progressive case with multisystem involvementAM Attia1, OA Bakry1, EE Mohamed2
1 Department of Dermatology, Andrology and Sexually Transmitted Diseases, Faculty of Medicine, Menoufiya University, Menoufiya, Egypt
2 Department of Ear, Nose, Throat, Faculty of Medicine, Menoufiya University, Menoufiya, Egypt
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.128817
Source of Support: None, Conflict of Interest: None
Xanthoma disseminatum (XD) is a rare, benign, non-Langerhans cell histiocytic disorder. The pathogenesis is not clear. It manifests with multiple, grouped, red-brown to yellow papules and nodules involving the skin, mucous membranes, and internal organs. We present a case of progressive XD in a 10-year-old male child. The patient presented with progressive, bilateral and symmetrical, reddish-brown, coalescent papules on the neck, around both eyes and all over his trunk and extremities. Skin lesions were accompanied by blurred vision and hoarseness of voice. Examination revealed xanthomatous infiltration of cornea, oral, pharyngeal, and laryngeal mucosae. The patient had diabetes insipidus that was diagnosed 2 years before the appearance of skin lesions. Medical treatment with corticosteroids (20 mg/day) and azathioprine (2 mg/kg/day) did not stop the disease progression.
Keywords: Disseminatum, non-Langerhans cell histiocytosis, progressive, xanthoma
Xanthoma disseminatum (XD) is a rare, benign proliferative disorder of unknown etiology. It is classified as a subset of cutaneous non-Langerhans cell histiocytosis (NLCH).  It occurs in children and adults and characterized by disseminated xanthomatous lesions. XD typically involves the skin, particularly the flexor folds, face, and trunk. It may also manifest in the central nervous system, ocular structures, and respiratory and gastrointestinal tracts. 
Most forms do not require early and intensive treatment. Lesions in critical anatomical locations may result in morbidity and mortality. Although many conservative treatments are unsatisfactory, active intervention may still be warranted for the noninvoluting or disfiguring type for cosmetic reasons or to prevent permanent functional impairments. 
A 10-year-old male child presented to us with numerous, reddish-brown lesions all over his body. Lesions appeared insidiously, 2 years before, around both eyes and progressed in few months. They were yellow to flesh red at first and changed to reddish-brown color with time. He was the first sibling of nonconsanguineous parents. Family history was noncontributary. His medical history included diabetes insipidus that was diagnosed at age of 6 years and controlled by oral vasopressin. He was also complaining of blurring of vision and dysphonia that started coincidentally with the skin eruption.
Clinical examination revealed firm, bilateral, and symmetrical coalescent papules on the neck, the front and back of the trunk, and all limbs [Figure 1]a and b. Similar lesions were found around both eyes [Figure 2]a. Oral mucosal examination showed yellowish papules on the soft palate [Figure 2]b. Liver and renal function tests, lipogram (serum triglycerides, total cholesterol, and high density lipoprotein cholesterol), and hemogram were normal. Thyroid function tests, immunoglobulins, erythrocyte sedimentation rate were all normal. Laryngoscopy was done and revealed small, yellow-colored nodules on laryngeal mucosa and on both vocal cords which showed limited mobility. Ocular examination revealed conjunctival and left corneal infiltration by yellow minute papules with normal visual field. Abdomino-pelvic ultrasonography, chest X-ray, upper and lower gastrointestinal endoscopy revealed no abnormality. Brain magnetic resonance imaging revealed thickening of posterior pituitary stalk.
Biopsy was taken from one representative skin lesion after taking mother's consent. Histopathological examination of hematoxylin and eosin-stained sections revealed dermal infiltration by histiocytes, many foam cells with occasional touton giant cells, and other chronic inflammatory cells [Figure 3]a. Immunohistochemical staining was negative for S100 and CD1a proteins but was positive for CD68 protein [Figure 3]b. On the basis of clinical and histopathological criteria, the diagnosis of XD was reached.
Laryngeal lesions were surgically removed. Oral prednisone (20 mg/day) and azathioprine (2 mg/kg/day) were prescribed for 3 months. Cutaneous lesions did not involute, new papules started to appear and laryngeal lesions recurred while on treatment.
XD is one of several heterogeneous conditions caused by a proliferation of non-X histiocytic cells.  It was first described in 1938 by Montgomery and Osterberg.  Since then, fewer than 100 cases have been reported. 
XD usually starts before the age of 25 years in about 60% of patients. It is more common in males. It may occur anywhere on the body including the scalp, face, trunk, and extremities. 
The prognosis is highly unpredictable for individual patients. Three clinical patterns have been suggested based on case reviews: (i) a rare, self-healing form with spontaneous resolution; (ii) a common persistent form in which lesions may never resolve; and (iii) a very rare, progressive form with organ dysfunction and central nervous system involvement.  We considered our patient to be affected with the progressive form.
The histogenesis is unclear, but it is thought to originate from the macrophage/monocyte series.  XD is considered a reactive disease rather than a neoplastic disease. It is characterized by foamy-appearing macrophages postulated to be caused by increased uptake, synthesis, or decreased efflux of lipids. The development of these foamy macrophages is thought to be triggered by a superantigen. Therefore, inflammatory reactions are thought to be important in the pathogenesis of this disease. 
The diagnosis of XD is based on clinical and pathological grounds. Biopsy findings of histiocytic proliferation suggest a histiocytic disorder. Immunophenotyping and ultrastructural studies are required to establish the diagnosis. CD68 positivity supports a histiocytic origin. Absence of S-100 binding rules out LCH.  Touton giant cells represent an exaggerated xanthomatoid reaction pattern. They are typical of xanthomatous histiocytoses and are absent in LCH. 
Mucous membrane involvement develops in 40%-60% of patients, most commonly affecting the oropharynx, larynx, or cornea and conjunctiva. 
The most common initial presentation of central nervous system involvement in XD is diabetes insipidus, which is often mild and transient.  It develops in 40% of patients due to infiltration of the hypothalamic-posterior pituitary axis by xanthomatoid cells. When present, it is controlled by vasopressin.  The condition may occur concurrently with the cutaneous manifestations or precede those as in our case.
Patients with XD are usually normolipemic, lipid deposition in the skin being secondary to histiocytic proliferation, and this has led some authors to classify XD as a normolipemic xanthomatosis. However, slightly elevated levels of serum cholesterol or triglycerides were seen in few patients.  The disease should be differentiated from other histiocytic normolipemic disorders [Table 1].
Xanthomatous lesions in critical anatomical locations may result in morbidity and mortality. Zak et al.,  reported an intracranial involvement of XD, which resulted in death of the patient. Bόyόkavci et al.,  described a case of XD with hepatic involvement, which resulted in sclerosing cholangitis. Mass effects from xanthomas can create serious problems. Ozηelik et al.,  reported upper airway obstruction with invasion of the respiratory mucosa; Kang and Kim  reported gastrointestinal complications accompanied by defecation difficulties with invasion of the perianal area. In our case, there was no evidence of these organs involvement with various investigations.
Numerous systemic modalities have been utilized in attempts to manage the disease, such as vasopressin, radiotherapy, corticosteroids, chemotherapy, and clofibrate, but none have proven particularly successful. ,,,
Reports of local management of XD are also characterized by diverse approaches with various results. Cryotherapy for single lesions has not been successful. Surgery appears to give the best results for readily accessible lesions. Other reports documented the use of CO2 laser, dermabrasion, electrocoagulation, and intralesional steroid injection with variable responses. 
The prognosis of XD is usually good in most cases. However, it can be worse if vital organs are involved.  We considered our case as a progressive form, due to the poor response to systemic corticosteroids and azathioprine treatment and the continuous, spreading clinical course.
Our patient was treated with oral corticosteroid and azathioprine after surgical excision of laryngeal lesions. Until recently, the disease was not well-controlled because new lesions are still emerging. We are planning to remove laryngeal papules surgically and use radiotherapy that may achieve control.
[Figure 1], [Figure 2], [Figure 3]