Stiff skin syndrome

INTRODUCTION — Stiff skin syndrome (SSS; MIM #184900) is a rare, noninflammatory, scleroderma-like disorder with onset usually in infancy or childhood. First described in 1971 [1], SSS is characterized by areas of stony-hard skin involving the trunk and extremities; joint contractures; decreased joint mobility, mainly involving the pelvic and shoulder girdles; and a slow, progressive course. A less severe, segmental variant has also been described [2]. Options for treatment are limited, and response is often unsatisfactory.

This topic will discuss the pathogenesis, clinical manifestations, diagnosis, and management of SSS. Pediatric systemic sclerosis and localized scleroderma (morphea) and other pediatric, scleroderma-like entities are discussed separately.

●(See "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis".)

●(See "Juvenile localized scleroderma".)

●(See "Scleredema".)

●(See "Sclerema neonatorum".)

●(See "Hutchinson-Gilford progeria syndrome".)

EPIDEMIOLOGY — SSS is exceedingly rare. Approximately 100 cases have been described in the literature [2,3]. All cases, except one, had a pediatric onset [4].

PATHOGENESIS — Heterozygous, missense variants in the fibrillin-1 (FBN1) gene have been shown to cause SSS [5]. The FBN1 protein is the major component of the 10 to 12 nm extracellular matrix microfibrils, which provide tissues with structural support and frame for elastin deposition. FBN1 contains many cysteine-rich domains homologous to the epidermal growth factor (EGF) and the latent transforming growth factor (TGF)-beta binding proteins. The latter is a family of profibrotic cytokines involved in the pathogenesis of several fibrotic diseases, including SSS and systemic sclerosis [5,6].

Variants affecting the TB4 domain of FBN1 cause impaired TGF-beta signaling, elevated TGF-beta concentration in the skin, impaired elastogenesis, excessive microfibrillar deposition, and ultimately unregulated skin fibrosis. This results in skin tightening, joint stiffness, immobilization, and progressive limitation of the range of motion of joints and thoracic walls [6-8].

FBN1 variants affecting different domains of FBN1 are associated with different phenotypes. As an example, variants affecting the TB5 domain of FBN1 cause the much more common Marfan syndrome. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders".)

The pathogenesis of segmental SSS is uncertain. It is probably a mosaic subtype of SSS, although somatic FBN1 variants have not been demonstrated in lesional skin. A case report has shown the possible implication of variants in interleukin (IL) 17 gene [9].

CLINICAL MANIFESTATIONS — Two clinical subtypes of SSS, widespread SSS and segmental SSS, have been described [2,10]. They are distinguished by the distribution of skin lesions, time of onset, and severity of musculoskeletal involvement.

Widespread stiff skin syndrome — Widespread SSS is the most common type. It presents insidiously during infancy or early childhood and can be quite subtle at first. "Congenital fascial dystrophy" is considered a subset of SSS with predominant fascial involvement and less severe skin tightening [11]:

●Cutaneous features – Progressive, bilateral skin induration overlying areas with abundant fascia, such as the buttocks and thighs [11], results in rock-hard skin that is firmly bound to the underlying tissues without a groove sign (picture 1A-B). Skin can be normal appearing or mildly hyperpigmented. Mild hypertrichosis is noted over the affected areas in approximately one-third of cases. Pelvic and shoulder girdle areas are primarily involved [10].

●Extracutaneous features – Ongoing skin induration leads to contractures of the large joints over months to years following disease onset, resulting in scoliosis, lordotic stance, and tiptoe gait [10]. Chronic exertional compartment syndrome requiring bilateral fasciotomy has been described in a father and son with bilateral lower limb pain and neurologic symptoms on exertion [12]. Severe cases can evolve to chest wall deformities, restrictive ventilatory defect, and growth retardation resulting in short stature. Neck mobility, chest wall deformities, and veinous access should be carefully evaluated preoperatively by an anesthesiologist to minimize complications [13]. (See "Chest wall diseases and restrictive physiology".)

Unlike systemic sclerosis or localized scleroderma, SSS is not accompanied by muscular, vascular, or internal organ involvement [14].

Segmental stiff skin syndrome — Segmental SSS is a less common or recognized form of SSS, with onset in childhood or early adolescence [2,15]. It presents with similar cutaneous and extracutaneous features as the widespread form but in a less severe fashion. Lesions are typically distributed unilaterally (picture 2) and result in joint contractures and mobility limitation in less than one-half of cases [2]. However, the involvement of large joints can cause significant morbidity [14].

PATHOLOGY — Both widespread SSS and segmental SSS show similar histopathologic features. The epidermis is normal. The dermis shows horizontally oriented, thickened collagen bundles; increased mucin; and lack of inflammatory infiltrate and adnexal entrapment (picture 3). Adipocyte entrapment by thickened collagen bundles in the reticular dermis and subcutaneous septa, resulting in a bland, hamartomatous appearance, is a hallmark of SSS (picture 4). Fibroblast density is usually normal but can be elevated in some patients [16]. In biopsies that include fascia, noninflammatory sclerosis and thickening of the fascia can be noted [2,10,17,18].

DIAGNOSIS — There are no defined diagnostic criteria for widespread SSS and segmental SSS. Patients are often initially diagnosed with systemic sclerosis, localized scleroderma, or other scleroderma-like disorders. (See 'Differential diagnosis' below.)

Patient history, physical examination, skin biopsy and careful clinicopathologic correlation, exclusion of disease mimickers, lack of response to anti-inflammatory therapies, and a high index of suspicion contribute to the diagnosis of SSS [2,10]. Genetic testing for variants of FBN1, if available, can confirm the diagnosis in patients with the widespread form:

●Patient history – Patients with SSS typically have a history of insidious onset of painless, progressive, bilateral skin induration, with onset in infancy or childhood and predominantly involving areas with abundant fascia, like the shoulders and pelvic girdles. Family history can be positive in patients with widespread SSS but is always negative in patients with the segmental form.

●Physical examination – A total body skin examination should be performed to assess the location and extent of indurated areas bound to underlying tissues; the presence of cutaneous inflammation or other findings associated with systemic or localized sclerosis (eg, Raynaud phenomenon, acral sclerosis, "groove sign" [area of depression at sites with underlying tendons and ligaments]); and the gentle extension of the large joints for flexion contracture. (See 'Differential diagnosis' below.)

●Biopsy – A deep, elliptical skin biopsy of a recently involved area, which includes the epidermis, dermis, subcutis, and, when possible, fascia, provides an adequate specimen for histopathologic examination. Routine stains, including mucin coloration and fibroblast markers, are recommended. (See "Skin biopsy techniques".)

●Laboratory tests – Complete blood cell count, sedimentation rate, C-reactive protein, urinalysis, creatinine, electrolytes, creatine kinase, thyroid-stimulating hormone, antinuclear antibodies, extractable nuclear antigen antibodies panel, and rheumatoid factor are performed to rule out inflammatory and immune-mediated diseases.

●Imaging studies – Imaging studies, including plain radiography, ultrasonography, and magnetic resonance imaging (MRI), can be used to assess joint contractures, skeletal deformities, and skin and fascia thickness and to rule out muscle and bone involvement that would suggest other diseases [19]. Ultrasound and MRI can also be used to monitor disease progression and response to treatment.

●Genetic testing – The identification of germline pathogenic variants in FBN1 by DNA sequencing can confirm the diagnosis of widespread SSS, when available [5]. Testing a biopsy of affected skin for somatic variants in FBN1 or other putative genes might be useful in segmental SSS.

DIFFERENTIAL DIAGNOSIS

●Systemic sclerosis/scleroderma – Systemic sclerosis is rare in children and presents with characteristic progressive, acral, and digital skin sclerosis; arthritis; internal organ involvement (lungs, kidneys); vascular changes (nailfold capillary changes, Raynaud phenomenon); and positive immunologic and inflammatory markers (scleroderma-specific antinuclear antibodies). (See "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis".)

●Eosinophilic fasciitis – Eosinophilic fasciitis is rare in children and typically affects middle-aged adults with a male predominance. It is characterized by acute onset of symmetric erythema, swelling, and woody skin induration of the extremities (forearm, calf) [19]. Skin changes include orange peel appearance and "groove signs" (picture 5). Blood eosinophils and inflammatory markers are elevated. (See "Eosinophilic fasciitis".)

●Localized scleroderma (morphea) – Linear scleroderma and deep morphea beginning in childhood can be difficult to differentiate clinically from segmental SSS (picture 6). Localized scleroderma typically shows absence of adnexa, whereas SSS can be associated with hypertrichosis. On histopathology, localized scleroderma shows inflammatory infiltrates in the dermis with adnexal entrapment, without adipocyte entrapment, and occasional fascial inflammation. Localized scleroderma will typically show a positive response to immunosuppressive therapy, whereas widespread SSS and segmental SSS do not [10,20,21]. (See "Juvenile localized scleroderma".)

●Scleredema – Scleredema is a rare condition that occurs more frequently in adults. In children, it typically follows a streptococcal infection of the upper respiratory tract. Scleredema presents acutely with induration of the skin of the face or neck, occasionally spreading downwards to the shoulders, arms, back, and chest (picture 7). Histology shows broad collagen bundles and dermal mucin deposits. Involvement of the fascia is absent. It can be differentiated from SSS by the abrupt onset, different body locations involved, and histopathology [10]. (See "Scleredema".)

●Rare pediatric entities – Several other rare conditions can be included in the differential diagnosis of SSS [10]:

•Hyaline fibromatosis syndrome – Hyaline fibromatosis syndrome (MIM #228600), which includes infantile systemic hyalinosis and juvenile hyaline fibromatosis, is an exceedingly rare, autosomal recessive disorder characterized by hyaline deposits in the papillary dermis and other tissues [22]. It presents in infancy with papules around the nose and mouth; gingival hypertrophy; thickened, firm skin; hyperpigmented patches over the joints; progressive joint contractures; and severe pain with movements. Hyaline fibromatosis syndrome is caused by biallelic pathogenic variants in ANTXR2, encoding the anthrax toxin receptor 2.

•Mucopolysaccharidoses – The mucopolysaccharidoses are a group of rare, inherited lysosomal diseases with a broad phenotypic spectrum caused by deficiency of enzymes involved in the breakdown of glycosaminoglycans. Mucopolysaccharidoses present in infancy or early childhood with focal skin thickening with a pebbled surface, coarse facial features, hepatosplenomegaly, bone disease, and with or without intellectual disability. The diagnosis is based on measurement of urinary mucopolysaccharides and enzyme activity in peripheral blood leucocytes and genetic testing. (See "Mucopolysaccharidoses: Clinical features and diagnosis".)

•Restrictive dermopathy – Restrictive dermopathy (MIM #275210) is a rare, lethal genodermatosis characterized by abnormally tight skin from birth (picture 8A-B). Joint contractures; ectropion; chest wall narrowing; hypoplastic clavicles; and a fixed, O-shaped mouth are additional findings. A skin biopsy shows flattened rete ridges, a thin dermis with horizontally oriented collagen, and incompletely developed skin appendages. In most cases, restrictive dermopathy is caused by autosomal recessive variants in ZMPSTE24, encoding a zinc metalloproteinase involved in the post-translational processing of lamin A precursor [23].

•Sclerema neonatorum – Sclerema neonatorum is a severe and often fatal panniculitis that develops in severely ill, premature neonates. The skin is thickened, adherent to underlying tissues, and can symmetrically involve the subcutaneous fat of the entire body. (See "Sclerema neonatorum".)

•Hutchinson-Gilford progeria syndrome – Skin changes in Hutchinson-Gilford progeria syndrome (MIM #176670), a very rare, autosomal dominant, premature aging disorder that manifests in childhood, include atrophy, sclerotic skin areas, reticulate hyperpigmentation, dimpling, and mottling, especially on the abdomen and thighs. Additional findings include a characteristic facial appearance, alopecia and prominent scalp veins, and joint contractures. (See "Hutchinson-Gilford progeria syndrome".)

•Subcutaneous fat necrosis of the newborn – Subcutaneous fat necrosis of the newborn is a self-limited panniculitis that most often affects full-term newborns and presents with erythematous nodules or indurated plaques on the cheeks, back, buttocks, or proximal extremities (picture 9). (See "Subcutaneous fat necrosis of the newborn".)

•Extra-abdominal desmoid tumor fibromatosis – Extra-abdominal desmoid tumor fibromatosis is a rare, locally aggressive soft tissue tumor resulting from a monoclonal proliferation of fibroblasts. Extra-abdominal desmoid tumor fibromatoses are, in most cases, located in the abdominal wall, buttocks, trunk, and extremities and are associated with pain, contractures, and functional impairment. (See "Desmoid tumors: Epidemiology, molecular pathogenesis, clinical presentation, diagnosis, and local therapy".)

REFERRAL — All pediatric patients with suspected or confirmed diagnosis of widespread SSS or segmental SSS should be referred to a clinician who is part of a multidisciplinary team (including pediatric rheumatology and dermatology) experienced in the diagnosis and management of this disorder. Ideally, this team should be an integral part of a tertiary pediatric facility with access to subspecialists and services (eg, orthopedic surgery, physical therapy, orthotics service, medical genetics).

MANAGEMENT — There are no curative treatments for SSS. The progressive and relentless nature of SSS and its minimal response to topical and systemic treatments are a challenge for patients, caregivers, and clinicians. Management primarily includes an exercise schedule to maintain functional ability and psychologic and social support.

Physical therapy — A carefully designed treatment program, including physiotherapy and massage, is beneficial for many children with SSS and should be started early. Physiotherapy maintains functional ability, muscle strength, and joint movement while preventing flexion contractures [24]. The use of corrective splints and gait analysis may also be helpful. Attention to positive joint alignment and muscle development is particularly important.

Pharmacologic therapy — Several pharmacologic agents, including systemic glucocorticoids, immunosuppressants, and drugs with antifibrotic or anti-transforming growth factor (TGF)-beta activity, have been tried in a few patients with SSS, in most cases with disappointing results [25-28]:

●Losartan – Losartan, an angiotensin II receptor antagonist, is known to have anti-TGF-beta activity in vitro [7,29]. It has been used in adult and pediatric patients with Marfan syndrome and has a favorable safety profile in patients with normal renal function [30,31]. In a single case report, oral losartan 0.7 mg/kg per day gradually increased up to 50 mg per day for two years induced mild improvement of skin tightening in a child with segmental SSS [25].

●Immunosuppressive agents – Mycophenolate mofetil is an immunosuppressive drug with antifibrotic properties [32]. In one report, mycophenolate mofetil 2 to 3 g per day for six months in combination with physical therapy induced mild improvement in skin induration and joint mobility in two young adult patients with segmental SSS [26].

Oral deflazacort, intravenous pulse methylprednisolone, methotrexate, and intravenous immunoglobulins have been tried with no or minimal improvement in a few patients with segmental SSS [10,25,27]. Some of these patients were initially diagnosed with localized scleroderma. Nonresponse to these therapies prompted diagnostic re-evaluation, leading to a final diagnosis of SSS.

●Biologic agents – In one case report, secukinumab, an anti-interleukin (IL) 17A antibody, given subcutaneously at the dose of 150 mg every four weeks for four months halted disease progression and increased the skin softness in an adolescent patient with segmental SSS [9]. The choice of an anti-IL-17 agent was based on the identification of a novel IL-17 mutation in the patient and their family. In another case report, one-year treatment with secukinumab 300 mg every four weeks halted disease progression and induced slight skin softening and complete pain resolution in a 17-year-old patient with segmental SSS [33].

There is no evidence that secukinumab or other biologic agents may be helpful in patients with SSS and FBN1 gene mutations.

Management of complications — Consultation with multiple specialists may be needed to manage complications of widespread SSS and segmental SSS:

●Orthopedic surgeon for scoliosis management

●Orthotist for gait abnormality management

●Respiratory therapist and pulmonologist for severe, restrictive pneumopathy

●Anesthesiologist for preoperative evaluation of airway, venous access, and restrictive pneumopathy

DISEASE COURSE AND PROGNOSIS — SSS is a nonfatal disorder that can cause major disability. It progresses gradually during the first years of life with contractures of the large joints, scoliosis, and gait anomalies. These complications are milder in the segmental form. There is no visceral involvement; however, chest wall deformities may cause a ventilatory, restrictive defect. (See "Chest wall diseases and restrictive physiology".)

FOLLOW-UP — Because of the gradual progression of the disease, periodic clinical follow-up should be performed, especially during the first years after the initial diagnosis. Evaluation of the extent of skin and joint involvement, mobility limitations, and physical therapy update are indicated.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Morphea (localized scleroderma)".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology and pathogenesis – Stiff skin syndrome (SSS) is an exceedingly rare, noninflammatory, scleroderma-like condition with onset during infancy or childhood. The widespread variant is caused by autosomal dominant, missense variants in the fibrillin-1 (FBN1) gene, encoding the FBN1 protein, a major component of the extracellular matrix microfibrils.

●Clinical manifestations – Widespread SSS presents in infancy or early childhood with progressive, bilateral skin induration primarily involving the pelvic and shoulder girdle areas. Later complications include contractures of the large joints with reduced mobility, scoliosis, chest wall deformities, and tiptoe gait. Segmental SSS begins later in childhood or early adolescence, is usually unilateral, and is less severe. Skin induration is unilaterally distributed and less severe than the widespread form, and less frequently results in joint contractures. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of SSS is made based on patient history, clinicopathologic correlation, exclusion of disease mimickers, lack of response to anti-inflammatory therapies, and a high index of suspicion (see 'Diagnosis' above). Genetic testing for variants of FBN1, if available, can confirm the diagnosis in patients with widespread SSS.

●Referral – All pediatric patients with suspected or confirmed SSS should be referred to a clinician who is part of a multidisciplinary team (including pediatric rheumatology and dermatology) experienced in the diagnosis and management of this disorder, with access to subspecialists and services (eg, orthopedic surgery, physical therapy, orthotics service, medical genetics).

●Management – There are no curative therapies for SSS. Physical therapy to maintain functional ability, muscle strength, and joint movement and to prevent flexion contractures is of primary importance. Systemic glucocorticoids and other immunosuppressants are generally ineffective and do not alter disease progression. Oral losartan, an angiotensin II receptor antagonist known to have anti-transforming growth factor (TGF)-beta activity, and secukinumab have been used in a limited number of patients, resulting in mild improvement of skin induration. (See 'Management' above.)