Pyoderma Gangrenosum in a Patient With Dubowitz Syndrome: a New Comorbidity?

Dubowitz syndrome is a rare genetic and developmental disorder with an autosomal recessive inheritance that was described for the first time in 1965.¹ This genetic disorder entails a plethora of clinical manifestations, including growth restriction, microcephaly, intellectual disability, eczema, facial dysmorphism, and increased risk of developing such malignancies as leukemia and lymphoma. As of now, a little more than 200 cases have been reported in the literature.²

PG is a neutrophilic dermatosis that presents with inflammatory and ulcerative lesions on the skin. More than 50% of patients have a comorbid disease,³ and several autoinflammatory disorders are associated with PG.⁴ The authors of the current article report an unusual case of PG in a patient affected by Dubowitz syndrome.

A 50-year-old female was admitted to the authors’ department with a 4-month history of multiple necrotic and painful ulcers on the back. The patient had Dubowitz syndrome diagnosed at birth. While interviewing the patient, the authors learned she had Hodgkin lymphoma that had been in remission for 4 years since undergoing treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine. Other relevant comorbid diseases were osteoporosis, thalassemia minor, and osteonecrosis. Written informed consent was obtained from the patient for the publication of the case report and any accompanying pictures.

The patient reported a 2-year-history of febrile episodes (up to 39°C [102.2°F]), fatigue, and generalized weakness. Blood work was negative for antinuclear antibodies, extractable nuclear antigen, anti–double-stranded DNA, and rheumatoid factor; a complete blood count showed mild leukopenia and microcytic anemia. Serum protein electrophoresis showed slightly elevated alpha-1 globulin. The patient had been treated 3 months prior in a different hospital with a course of oral betamethasone antibiotics (trimethoprim-sulfamethoxazole and cefotaxime) after swab culture from the lesions grew Serratia marcescens and Staphylococcus aureus. The patient’s fever resolved with treatment, but the ulcerating lesions remained unchanged.

On examination, the lesions presented as punched-out, painful ulcers with necrotic tissue adherent to the wound bed with moderate exudate disseminated over the dorsal and lumbar region (Figure 1A). Pictures taken by the patient before admission showed the characteristic violaceous overhanging edge (“lilac ring”) indicating a possible clinical diagnosis of PG.

An incisional biopsy was performed on an ulcerative lesion at the level of the back to rule out other possible diagnoses. Histopathologic evaluation showed intracorneal pustules, dermal fibrosis, mixed polymorphonuclear neutrophils, and lymphocytic infiltrates with plasma cells and scant eosinophils. Periodic acid Schiff staining for fungi and mucins stain gave negative response without features indicating vasculitis. The pathology report was not consistent with other diseases, so a diagnosis of PG was made. Furthermore, biopsy-induced pathergy was appreciated at the site of the procedure with a slight worsening of the lesion, which became more inflamed and enlarged.

After wound cleaning, chemical debridement was performed. Moist wound dressings, including hydrogel with alginate and hydrocolloid patches, were then applied. The necrotic portion of the wound was incised with a scalpel to favor the activity of the hydrogel and promote the resolution of the necrotic tissue.⁵ A mild improvement was noticed 3 weeks later (Figure 1B).

Oral methylprednisolone 4 mg daily was initiated 3 weeks after debridement and administered for 21 days. At the 28-day follow-up evaluation after the initiation of the systemic methylprednisolone therapy, the patient’s condition had improved significantly. The necrotic tissue sloughed off, healthy granulation tissue was observed at the level of the wound bed, and the lesions were less painful. Only a few ulcers retained a fibrinous layer while most ulcers had healthy granulation tissue covering them (Figure 1C and D).

Dubowitz syndrome is an extremely rare genetic disorder, and its etiology is still not clearly elucidated due to its numerous phenotypic variants. Two causal genes have been suggested in this genetic disease’s pathogenesis (NSUN2 and LIG4),⁶ but a definitive cause is still uncertain due to its broad clinical heterogeneity.

The authors of the current case study report a possible association between PG and Dubowitz syndrome that had not been previously identified in the literature. Genetic susceptibility can be a relevant factor for the development of PG, and familial cases have been reported.⁷ PG is already associated with such autoinflammatory syndromes as PAPA (pyogenic arthritis, pyoderma gangrenosum, acne) syndrome, PAPASH (pyogenic arthritis, pyoderma gangrenosum, acne, suppurative hidradenitis) syndrome, and PASH (pyoderma gangrenosum, acne, suppurative hidradenitis). PAPA syndrome is correlated with mutations of the PSTPIP1/CD2BP1 gene on chromosome 15 that encodes for CD2-binding protein.⁸ This protein binds pyrin, triggering the inflammasome activation.

Dubowitz syndrome has been associated with several medical conditions, cognitive deficits, and language disorders.⁹ Facial characteristics, such as micrognathia, narrower face with sloping forehead, low-set ears, ptosis, and shallow supraorbital ridge are common features. Furthermore, growth retardation characterized by hypotonia, delayed bone maturation, and skeletal malformations have been reported. Numerous case reports have described various comorbid diseases present in patients with Dubowitz syndrome. Acute leukemia, lymphoma, achalasia, congenital heart defects, and neurological disorders are extensively reported.¹⁰ Although this patient developed lymphoma some years before the ulcerative skin manifestations, PG can also be associated with solid organ malignancies. Skin abnormalities, such as keloids, ichthyosis, and eczema, have been noted,⁹ but ulcerative lesions have never been seen in a patient with Dubowitz syndrome. More typically, skin lesions reported in patients with PG have been mainly ichthyosiform eruptions, such as lamellar scales on the lower extremities and erythematous, itchy, and inflamed lesions described as “eczematous” on the upper extremities.⁹ No small, red papule or pustule that developed into a large, painful ulcer has ever been reported. A direct genetic link between PG and this syndrome has not been established. Since different skin conditions have been linked to Dubowitz syndrome, the authors
believe a causative gene linked to abnormalities of the integumentary system might be found in the foreseeable future.

This case report has potential limitations. The current case is limited by the number of patients studied. Although this case report is limited to a single patient, the authors do believe that a possible association between Dubowitz and a neutrophilic dermatosis may exist. General recommendations for the treatment of this peculiar case cannot be done but only suggested.

To conclude, the authors report a possible association between Dubowitz syndrome and a neutrophilic dermatosis, which may represent a novel characterization for this genetic syndrome that has not been previously linked to autoinflammatory diseases. Furthermore, a feasible treatment based on topical and systemic therapy may improve the clinical outcome and patient quality of life.