19 May 2023: Articles
Challenging differential diagnosisMohd Zulfikry Bin Ahmad1ABDEF, Nafiza Mat Nasir1ABDE*, Mazapuspavina Md Yasin1EF, Aimi Nadia Mohd Yusof 2EF, Ikmal Hisyam Bakrin 3E, Sern Chin Lim 4EF
Am J Case Rep 2023; 24:e940148
BACKGROUND: This case illustrates the challenges in diagnosing linear scleroderma (LS) in a child who presented to a primary care setting. Diagnosis of LS is easily missed due to the lack of prominent symptoms, subtle visible skin changes, and under-recognition of this condition.
CASE REPORT: A 7-year-old boy presented with a linear, painless, non-itchy rash at the center of his forehead, which has been present for 6 months. The rash extends vertically from the hairline to the bridge of the nose. The color gradually evolved from reddish to purplish-grey and shiny within 3 months. He had underlying eczema, allergic rhinitis, and allergic conjunctivitis since birth. His condition remained unrecognized despite consultations with various medical specialties, including family medicine specialist, ophthalmologist, otorhinolaryngologist, and a general pediatrician. Six months after the onset of his lesion, he was subsequently referred to a pediatric dermatologist and pediatric rheumatologist, who made the diagnosis of LS. Laboratory investigations for autoimmune disease showed that negative antinuclear antibodies (ANA) and inflammatory markers, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), were normal. Skin biopsy provided a tissue confirmation of the diagnosis. MRI of the lesion showed no extension into the underlying muscle or bone erosions. The patient was initially treated with intravenous (IV) methylprednisolone for 3 days, followed by oral methotrexate weekly and prednisolone. The lesion improved after 1 month of treatment, and after 15 months it was less pigmented and less noticeable.
CONCLUSIONS: LS is the commonest form of localized scleroderma in children. LS on the forehead can erode into the underlying tissues and is sometimes associated with extensive hemifacial atrophy. Treatment should be instituted early to prevent late irreversible fibrotic sequelae. This report aims to highlight the importance of early diagnosis and treatment of an uncommon but potentially disfiguring condition.
Keywords: Missed Diagnosis, Physicians, Primary Care, Scleroderma, Localized
Linear scleroderma (LS), also known as morphea, is the most common subtype of juvenile localized scleroderma in children. It is an idiopathic condition that affects the skin and subcutaneous tissues and is inflammatory and sclerosing . The incidence rate for linear scleroderma is 2.5 per million children per year, with girls being more affected than boys. The incidence is highest in children between the age of 5 and 10 [1,2].
Linear scleroderma can involve any part of the body, but the head and extremities are most frequently affected . The clinical features depend on the degree of tissue involvement. It appears as linear induration or depression and scarring at the frontoparietal area of the face and scalp and may involve underlying muscles and bone. Since it is a rare disorder, it is frequently missed in primary care settings, including general pediatrics settings. Apart from LS, the other subtypes of localized scleroderma are circumscribed, generalized, pansclerotic, and mixed . Craniofacial LS lesions can be either “en coup de sabre” (ECDS), which refers to paramedial linear lesions extending to the cheek, orbit, or scalp, or Parry Romberg syndrome (PRS), which presents with progressive unilateral hemifacial atrophy that can involve the dermis, subcutaneous tissue, muscle, and/or bones . Some evidence suggests that PRS represents the severe end of the spectrum of ECDS in LS .
This case illustrates the problem of diagnosing LS in a child who presented early with a linear rash over his forehead that progressed slowly. The challenges of diagnosis include its rarity, occurring at an early stage due to subtle skin lesions, and the complexity of differential diagnoses. Early diagnosis is important to prevent complications such as hair loss, disfigurement, and deep atrophy of underlying structures, including fascia and bone . Hence, this report aims to update knowledge and increase awareness to ensure early referral to the pediatric rheumatologist.
A 7-year-old boy with underlying eczema, allergic rhinitis, and allergic conjunctivitis presented to a primary care clinic with a skin lesion over his forehead with 6-month duration. Examination revealed a linear erythematous rash over his forehead, which extended downward from his frontal hairline to the nasal bridge.
It was a painless, non-itchy, erythematous rash and the color gradually evolved from reddish to purplish-grey and shiny within 3 months (Figure 1). His facial movement was symmetrical, and he was able to close his eyes fully and wrinkle his forehead bilaterally. There were no obvious dilated veins over the forehead and no similar skin lesion on other parts of the face, elsewhere, or other skin changes in the body. There were no signs of systemic sclerosis such as Raynaud phenomenon, nail-fold capillary changes, or sclerodactyly. He had no prior exposure to infections, toxins, chemicals, trauma, or positive family history for rheumatic or autoimmune diseases.
There were no other extracutaneous manifestations including fever, lymphadenopathy, fatigue, musculoskeletal involvements, oral, ocular, or neurologic manifestations. Laboratory investigations done to evaluate autoimmune disease showed negative antinuclear antibodies (ANA), and inflammatory markers, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), were normal. Serum immunoglobulin M (IgM), immunoglobulin G (IgG), immunoglobulin A (IgA), complement 3 (C3), and complement 4 (C4) were normal as well. He did not receive any treatment for the lesion prior to the final diagnosis.
He had multiple consultation visits with various medical specialties, including family medicine, ophthalmology, otorhinolaryngology, and general pediatric for his other comorbidities, including eczema, allergic rhinitis, and allergic conjunctivitis. Unfortunately, his condition remained unrecognized. As the lesion was progressively extending downward, he was subsequently referred to a pediatric dermatologist. Skin biopsy showed moderate perivascular and periadnexal inflammatory cells infiltrate (Figure 2) and thickened collagen bundles within reticular dermis (Figure 3), confirming the diagnosis. MRI brain was done to assess the severity of the disease and showed no extension into the underlying muscle or bone erosions.
He was then referred and managed by a pediatric rheumatologist. Initially, he was started on intravenous (IV) methylprednisolone for 3 days, followed by weekly oral methotrexate and prednisolone. Oral prednisolone was given for a total of 2 months, while he continued taking methotrexate on a weekly basis. There had been improvement of the lesion 1 month after treatment. After 15 months of treatment, the lesion has improved significantly and became less pigmented and less noticeable (Figure 4). There was no recurrence of the lesion and he is currently on 6-monthly follow-up with the pediatric rheumatologist.
This case illustrates the challenges in diagnosing uncommon cutaneous presentations in the primary care setting. LS is a rare and under-recognized disorder [2,5]. Underreporting of LS may occur due to referral bias and maybe mistaken for other cutaneous diseases. In the early stage, the lesion is usually subtle and can be misdiagnosed as skin infection, nevus, or salmon patch, and, in older children, ECDS can present as secondary alopecia . A retrospective study of 50 children with localized scleroderma found that none of them were diagnosed correctly by their general practitioners or pediatricians during their first presentation. The study also revealed that 44% of the children had not received a diagnosis during their first presentation, and the remaining 56% were misdiagnosed with other conditions, such as atopic eczema (20%), melanocytic nevus (8%), fungal infection (6%), bruise (4%), varicose vein (4%), bacterial infection (4%), and others .
LS commonly presents with skin lesions on the trunk and/or limbs, followed by lesions on the face and head. Among patients with face and head lesions, some experienced neurological symptoms such as seizures and headaches, while others had ocular-related complications such as uveitis and keratitis. These complications were equally common in both ECDS and PRS subtypes . Furthermore, pediatric patients are more likely than adults to exhibit extracutaneous manifestation such as orthopedic, ocular, and neurological symptoms .
The diagnosis of LS is mainly based on clinical findings, although a skin biopsy may be useful in diagnosing atypical cases and determining whether lesions are currently active or not . LS can be identified through various clinical clues such as skin lesions that appear in the form of stripes or bands and mainly affect one or more extremities, but can also occur on the face, neck or trunk. Additionally, skin hardening can be observed by pressing the affected skin and there is absence of typical systemic features found in systemic scleroderma . In the initial stages of linear scleroderma, the affected areas may exhibit signs of inflammation such as redness, swelling, a bruise-like or purplish appearance, smooth or waxy texture, hardness, pain, and/or itchiness. As the condition progresses and becomes inactive, the affected areas may develop yellow-white areas of hardening and thinning at various levels in the skin, including the epidermis, dermis, and subcutaneous tissue. Additionally, there may be changes in skin color and the appearance of telangiectasia .
Predominantly, the main findings of the histopathological examination of LS are dermal and subcutaneous sclerosis with thickened collagen bundles, a lymphoplasmacytic infiltrate, and endothelial cell swelling . Immune abnormalities have a role in the pathophysiology, resulting in endothelial damage and inflammation. The inflammation later progresses to dysregulation of fibroblasts and abnormal collagen production, inducing fibrosis . Although the exact cause of LS is unknown, it is likely caused by an inherent predisposition as well as external environmental factors such infection, medicines, trauma, radiation, autoimmunity, and microchimerism . Infections that may play a role in development of LS include
According to a study by Zulian and colleagues, 47.3% of patients with LS had ANA. However, the study did not find any significant correlation between the presence of these autoantibodies and LS, or other subtypes of localized scleroderma, or the progression of the disease . Typically, routine medical tests such as full blood count (FBC), blood chemistries, and urinalysis are expected to show normal results . Furthermore, the existence of systemic markers such as antinuclear factor (ANF), anti-centromere antibody (ACA), and Topoisomerase 1 antibody (Scl-70) does not necessarily indicate the presence of a systemic disease. However, autoantibodies like ACA, Ro/La, ribonucleoprotein (RNP), and Scl-70 can appear before the onset of systemic disease, so individuals with these changes should be monitored for several years .
It is important to diagnose LS early to prevent complications, which depend on the site of the lesion. Facial involvement can cause loss of scalp and eyebrow hair, depressed and atrophies skin, and asymmetric facial development. Perioral skin involvement can result in early loss of the deciduous teeth, delayed or abnormal eruption of the permanent teeth, and lack of bone growth. Orofacial complications may include malocclusion, overgrowth of the anterior lower third of the face, problems with chewing, dental anomalies, skeletal asymmetry, and bony or temporomandibular joint involvement. More severe complications that need to be prevented include growth retardation, muscle atrophy, flexion deformities, and poorly healing ulcerations .
Although standard treatment for localized scleroderma leads to remission for most patients, there are still some long-term challenges. Studies have consistently found a relapse rate of 25–48% when treatment is stopped. The risk of disease recurrence is higher in children than in adults, and relapses typically occur at 1–2.5 years after treatment ends. Certain factors increase the likelihood of relapse, such as the presence of ANA, delayed initiation of therapy, and the subtype of generalized scleroderma. Some patients experience extended periods of inactivity followed by activation, requiring long-term follow-up .
Therefore, it is crucial to diagnose LS early so that appropriate treatment can be initiated to prevent disfigurement and more severe extracutaneous manifestations. Early recognition is important because it allows intervention to limit the ultimate damage. Skin changes such as thickening or hardening of the skin might provide an early clue for recognizing LS.
LS is the most common subtype of localized scleroderma in children. It can be serious because it can involve muscles and bones, which can affect a child’s long-term health. However, diagnosing LS can be challenging due to its rarity and similarities in appearance to other skin lesions. Therefore, it is crucial to stay updated on the latest information and raise awareness about this disease. Through the discussion in this paper, we hope to provide a framework that ensures early referral to a pediatric rheumatologist for accurate diagnosis and prompt treatment. Early diagnosis is critical in preventing long-term complications and improving the prognosis for children with LS.
FiguresFigure 1.. Linear purplish-grey rash over forehead which extending downward from hairline to the nasal bridge. Figure 2.. Section from the punch skin biopsy shows rigid, squared silhouette at low power (A) (hematoxylin and eosin stain, original magnification ×50). Moderate perivascular (arrow) and periadnexal (star) inflammatory cells infiltrate are seen (B) (hematoxylin and eosin stain, original magnification ×100). Figure 3.. Thickened collagen bundles (star) within reticular dermis are shown, as well as early loss of periadnexal fat (arrowhead) (A) (hematoxylin and eosin stain, original magnification ×200). Mild septal panniculitis is observed, resulting in widening and thickening of the fat septa (arrow) (B) (hematoxylin and eosin stain, original magnification ×100). Figure 4.. Improvement of lesion 15 months after start of treatment.
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