Cutaneous findings

Affected infants typically present with one or several indurated, variably circumscribed, violaceous or red plaques or subcutaneous nodules from one to several centimeters in diameter on the buttocks, thighs, trunk, face, and/or arms (Figs 27.1–27.4). In some cases, the nodules may be subtle, not associated with overlying color change, and only appreciated by careful palpation of the underlying fat. Rarely, large plaques may cover extensive areas of the trunk or extremities. However, lesions are usually freely movable over subjacent muscles and fascia. Although SCFN may be tender, affected infants are afebrile and usually asymptomatic.

Most SCFN regresses spontaneously without scarring over several weeks to months. Rarely nodules persist for over 6 months.⁹ Occasionally, fluctuance and abscess-like changes occur, resulting in spontaneous drainage and scar formation. Variable amounts of calcification develop, which can be appreciated radiographically.¹⁰

Etiology and pathogenesis

Some investigators have proposed that SCFN results from hypoxic injury to fat caused by local trauma, particularly in the child with perinatal complications.^11,12 This is supported by the observation that fat necrosis occurs commonly over bony prominences. Others have suggested that the susceptibility to SCFN results from an increased proportion of the saturated fats palmitic and stearic acid, relative to the monounsaturated fat oleic acid in neonatal subcutaneous tissue.^9,11,13 Saturated fatty acids have a higher melting point than unsaturated fats, which may predispose newborn fat to crystallization at higher ambient temperatures than fat in older children and adults. Consequently, even in the setting of mild hypothermia, crystallization of fat may occur, with subsequent fat necrosis. Finally, an underlying defect in neonatal fat composition or metabolism, possibly related to immaturity, in the setting of perinatal stress, may lead to fat necrosis.

Diagnosis

Although SCFN is usually diagnosed clinically, when the presentation is atypical or the infant is ill, the diagnosis can be confirmed by skin biopsy showing the characteristic histopathologic findings of patchy areas of necrosis and crystallization of fat. The involved fat lobules contain pathognomonic needle-shaped clefts surrounded by a mixed inflammatory infiltrate composed of lymphocytes, histiocytes, fibroblasts, and foreign body giant cells.⁵ Fine-needle aspiration biopsy is a safe and reliable alternative.¹⁴

Although laboratory tests are usually normal, hypercalcemia occurs occasionally from 1 to 4 months after the appearance of skin lesions.^9,11–13 The risk of hypercalcemia increases with the severity of the perinatal insult and extent of fat necrosis.¹⁵ Rarely hypercalcemia is severe, and has been implicated in the deaths of three infants. Nephrocalcinosis, vomiting, failure to thrive, poor weight gain, irritability, and seizures can complicate high calcium levels or chronic moderate elevations.^2,7 Although the exact cause of hypercalcemia is unknown, several explanations, including elevated parathyroid hormone levels, prostaglandin E₂ release, calcium release from necrotic fat, and elevated levels of vitamin D, have been proposed. Calcitriol produced by macrophages in the inflammatory infiltrate of SCFN with increased calcium absorption in the gastrointestinal tract is the favored explanation.^4,5,11–13

Soft tissue calcification may occur in the absence of hypercalcemia and can be detected radiographically. Tests of parathyroid function, vitamin D metabolites, and urinary prostaglandins may be useful in the evaluation of infants with hypercalcemia. Hypocalcemia with pseudohypoparathyroidism requiring therapy,¹⁶ as well as transient hypoglycemia, hypertriglyceridemia, and thrombocytopenia,¹⁷ have also been reported in several children.

Differential diagnosis

The subcutaneous nodules that follow the abrupt withdrawal of systemic steroids can be difficult to distinguish from those of SCFN. However, they usually occur on the cheeks, arms, and trunk 1–2 weeks after discontinuation of steroids. SCFN can be distinguished from sclerema neonatorum, lipogranulomatosis, infectious panniculitis, and nodular panniculitis by the general well-being of the infant with SCFN and characteristic clinical and histopathologic features. Infants with sclerema neonatorum present with diffuse skin stiffness and severe multisystem disease. Deep soft tissue infections in neonates are usually associated with fever and other signs of sepsis. Subcutaneous hemangiomas, soft tissue tumors such as rhabdomyosarcomas, fibromatosis of infancy, and histiocytosis can be excluded by imaging studies, disease course, and histologic findings. When hypercalcemia and/or soft tissue calcification is present, primary hyperparathyroidism, osteoma cutis, and calcification associated with Albright osteodystrophy should be excluded.

Management

In most infants with SCFN, treatment is limited to parental reassurance and supportive measures.^4,11–13 Hypercalcemia, if present, may have clinical signs such as poor growth or irritability, or may be entirely asymptomatic. Although onset is most commonly noted at 4–6 weeks of age and usually resolves by 4 months, some cases have reported to persist for 6 months. As a consequence, at-risk infants should be monitored for the first 6 months of life and should not receive vitamin D supplementation for rickets prophylaxis during this period.^3,15 Treatment of hypercalcemia may require intravenous saline, calcium-wasting diuretics, and rarely, intravenous corticosteroids. Etidronate therapy has also been reported to be successful in controlling severe hypercalcemia in SCFN.¹³ Ulcerated lesions, which rarely occur in otherwise healthy infants, usually respond to topical antibiotics and bio-occlusive dressings.

Cutaneous findings

Diffuse hardening of the skin usually appears suddenly on the 3rd or 4th day of life, starting over the lower extremities, especially the calves, spreading to the thighs, buttocks, and cheeks, and eventually the trunk.^5,20–24 Sclerema eventually involves most of the skin, particularly in premature infants, with the exception of the palms, soles, and genitals. The skin feels cold, smooth, hard, and bound down. The joints are immobile, and the face appears mask-like.

Extracutaneous findings

Affected infants are usually poorly nourished, dehydrated, hypotensive, hypothermic, and septic. Necrotizing enterocolitis, pneumonia, intracranial hemorrhage, hypoglycemia, and electrolyte disturbances are also often associated with sclerema.^5,21–26

In most cases, sclerema is limited to the subcutaneous fat. However, in two infants, autopsy revealed identical changes in the visceral fat.²⁷

Etiology and pathogenesis

The development of sclerema is probably a result of dysfunction of the neonatal enzymatic system involved in the conversion of saturated palmitic and stearic acids to unsaturated oleic acid. Immaturity of the neonatal lipoenzymes is further compromised by hypothermia, infection, shock, dehydration, and surgical and environmental stresses. The relative abundance of saturated fatty acids and depletion of unsaturated fatty acid allows for fat solidification to occur more readily, with the subsequent development of sclerema.^5,20,21

Diagnosis

On gross pathologic examination, the subcutaneous tissue of affected infants is markedly thickened, firm, and lard-like, with fibrous bands seen to extend from the fat into the lower dermis. Microscopically, early lesions demonstrate distinctive lipid crystals within fat cells, forming rosettes of fine, needle-like clefts.^5,21 Although there is usually no inflammatory reaction to fat necrosis, occasionally some giant cells are present. Older lesions often show thickened septa, and rarely calcification.

Other laboratory findings in neonates with sclerema are nonspecific and usually reflect the underlying systemic medical problems. Thrombocytopenia, neutropenia, active bleeding, and worsening acidosis carry a poor prognosis.^5,25,26

Differential diagnosis

In healthy infants who develop widespread slowly progressive scleroderma-like plaques on the trunk and proximal extremities, the diagnosis of stiff skin syndrome should be considered (see below). However, this is a primary disorder of fascia and, unlike sclerema, is not associated with systemic symptoms. The lack of inflammation and extensive involvement of the subcutis help to distinguish sclerema from SCFN and cold panniculitis, in which the lesions are localized and associated with exuberant granulomatous inflammation. Diffuse edema resulting from hemolytic anemia, renal, and/or cardiac dysfunction manifests as pitting edema, unlike sclerema. Congenital lymphedema or Milroy disease is nonpitting and often widespread. However, in lymphedema, the infant is otherwise healthy, and a skin biopsy reveals normal fat and dilated lymphatics. Erysipelas or lymphangitis is red, tender, and more localized than sclerema. Diffuse sclerodermatous changes associated with systemic sclerosis, which is extremely rare in the newborn, can also mimic sclerema. However, histology demonstrates characteristic hypertrophy and sclerosis of collagen, which eventually replaces the fat in scleroderma.

Treatment

Attention to the maintenance of a neutral thermal environment, electrolyte and water balance, adequate hydration and ventilation, and aggressive treatment of shock and infection in the modern nursery intensive care unit, undoubtedly account for the extremely low incidence of sclerema today. Although most infants with sclerema succumb to sepsis and shock, reversal of the underlying systemic disease can result in recovery.

The role of systemic steroids in the management of infants with sclerema is controversial. Several investigators have reported a favorable outcome when exchange transfusion was combined with conventional therapy.^21,26

Cutaneous findings

Stiff skin syndrome presents in infancy or early childhood with scleroderma-like plaques initially affecting the trunk and proximal extremities, particularly the buttocks and thighs. In the first stages, the condition may seem subtle and somewhat localized. Progression of the rock-hard indurated bound-down skin over large areas of the body, including the extremities, results in contractures, scoliosis, a narrow thorax, and a characteristic tiptoe gait. A variable increase in hair may be noted over areas of cutaneous involvement.^{28,29,31–35}

Extracutaneous findings

Orthopedic abnormalities result from the cutaneous and fascial plaques that produce contractures, especially over large joints. Although restrictive pulmonary changes and growth retardation have occasionally been reported, immunologic, visceral, bony, muscular, and vascular involvement is characteristically absent.^29,32–34

Etiology and pathogenesis

Although the cause is unclear, investigators have proposed a primary fibroblastic defect resulting in increased mucopolysaccharide deposition in the dermis, a primary fascial dystrophy resulting from increased collagen, and an inflammatory process.^29,32–34 Some patients with stiff skin syndrome have been noted to have increased myofibroblastic activity in fascia, with overproduction of type VI collagen. Similar findings have been observed in extra-abdominal desmoid tumors, juvenile hyaline fibromatosis, scleroderma, and the tight skin mouse model which is transmitted in an autosomal dominant pattern and is located on chromosome 2.³⁶ Cutaneous fibrosis in the Tsk mouse appears to be caused by a mutation in Fibrillin-1. A mutation in Fibrillin-1 has also been demonstrated in 4 families with autosomal dominant stiff skin syndrome.³¹

Diagnosis

In infants and young children with progressive bound-down plaques beginning on the trunk, limited joint mobility, and no evidence of systemic disease, stiff skin syndrome should be considered. Varying histologic changes from patient to patient and in the same patient over time, may reflect different triggers which result in similar clinical findings.^32–34,36 In some cases, thickening of the collagen in the fascia was noted, whereas in others the fascia was normal and increased mucopolysaccharide deposition was found in the dermis. Noninflammatory sclerosis in the deep reticular dermis extending into the subcutaneous fat has also been noted. A recent report suggests that, although noninflammatory fibrosis of the fat and fascia is typical but not specific for incisional biopsies of stiff skin syndrome, the presence of a lattice-like array of thickened, horizontally oriented collagen bundles may be a clue to diagnosis.³⁷

Differential diagnosis

Firm, woody induration of the skin with joint contractures may occur in geleophysic dysplasia, progeria, neonatal mucolipidosis II, and Farber lipomatosis. These disorders can be distinguished from stiff skin syndrome by their characteristic clinical, histologic, biochemical, and genetic findings. The clinical features of scleroderma overlap with some cases of stiff skin syndrome. Although thickening of the fascia does not usually occur in scleroderma, in some cases of linear scleroderma, deep soft tissues and bone can be involved. However, the lesions are usually self-limited. Eosinophilic fasciitis, which presents with acral scleroderma-like changes, can also be distinguished by characteristic clinical features, course, and histology. Sclerema neonatorum and subcutaneous fat necrosis of the newborn demonstrate a distinctive panniculitis and clinical course, and infantile systemic hyalinosis can be distinguished by the presence of hyaline deposits in the skin, multiorgan failure, and death in early childhood. In milder cases, the condition may mimic a connective tissue nevus, smooth muscle hamartoma, or myofibroma.

Treatment

Although the disorder is usually slowly progressive, in some patients lesions have been noted to stabilize or improve. Treatment is generally limited to supportive and rehabilita­tive care.

Cutaneous findings

Symmetric, tender, indurated nodules and plaques 1–3 cm in diameter typically appear on the cheeks of infants 1–2 days after cold exposure.^{38,39,42–44} The overlying skin appears red to violaceous (Fig. 27.5), and the infant is otherwise well. In a study by Rotman³⁹ the application of an icecube to the volar aspect of the forearm of an 8-month-old girl resulted in mild transient erythema for 15 min. A red plaque developed 12–18 h later and resolved after 13 days. Lesions usually soften, flatten, and heal over 2–3 weeks, leaving post-inflammatory pigmentary changes, particularly in darkly pigmented individuals.

As in subcutaneous fat necrosis of the newborn and sclerema neonatorum, exposure to low ambient temperatures is thought to result in crystallization of the subcutaneous tissue in infants, which is relatively high in saturated fats compared to that of older children and adults. Applying ice to the skin for 50 seconds results in nodules in all newborns, but only in 40% of 6-month-old and only occasionally in 9-month-old infants.⁴³ In 1966, Duncan and colleagues⁴⁵ described a child in whom nodules followed the application of ice for several minutes at 6 months of age, and 8 min at 18 months of age. When the child was 22 months old, ice applied for 15 min did not trigger panniculitis. The resistance to cold injury correlates with the relative increase in unsaturated fats in the subcutaneous tissue of older infants and children.

Diagnosis

The development of subcutaneous nodules in any neonate or young infant exposed to ice or subfreezing temperatures in the preceding 1–3 days should suggest the diagnosis of cold panniculitis. Histologic changes evolve over several days.⁴⁵ The earliest changes 24 h after cold injury include an infiltrate of macrophages and lymphocytes at the dermoepidermal junction extending into the dermis and fat. At 48 h, the inflammation is more intense and fat necrosis is present. Lipid from ruptured fat cells forms large cystic structures surrounded by histiocytes, neutrophils, and lymphocytes. These changes become more pronounced over the next few days, and subside completely in 2 weeks.

Other laboratory studies, including blood counts, cold agglutinins, cryoglobulins, and general chemistry studies, are usually normal.

Differential diagnosis

The history of cold exposure in an otherwise healthy infant will help to distinguish cold panniculitis from other causes of subcutaneous nodules. Clinical lesions of SCFN can overlap with those of cold panniculitis. Although a skin biopsy is not usually necessary to distinguish these two disorders, the distribution of nodules and histological changes is usually distinctive. Cellulitis should also be considered in any child with tender red facial nodules. However, the lack of progression of lesions or fever in a healthy-appearing infant is against the diagnosis of infection.

Post-steroid panniculitis can be clinically indistinguishable from cold panniculitis.⁴⁶ Subcutaneous nodules or plaques appear on the cheeks of infants within 2 weeks of rapidly discontinuing high-dose systemic steroids after a prolonged course. A biopsy reveals granulomatous inflammation in the fat lobules and needle-shaped clefts within histiocytes identical to those of SCFN. However, in a child with a typical history, a biopsy is unnecessary, and nodules resolve over a period of months without treatment.

Treatment and course

Although skin lesions are self-limiting and no treatment is recommended, early recognition of cold panniculitis is important to prevent unnecessary parental anxiety or laboratory studies. Nodules heal in 1–3 weeks without scarring.

Cutaneous findings

Firm, subcutaneous nodules may follow blunt trauma to the skin, especially in areas prone to trauma where the fat is in close proximity to the underlying bone.⁴⁷ This occurs most commonly on the cheeks in children between 6 and 12 years old. However, nodules can also develop in infants and over other bony prominences after accidental or deliberate injury.

Diagnosis

Traumatic fat injury should be considered in any child with subcutaneous nodules over injury-prone areas. Skin biopsies will demonstrate fat necrosis with granulomatous inflammation. Late histologic changes may include fibrosis, small fat cysts, and dystrophic calcification.⁴⁸ However, a biopsy is usually not necessary.

Treatment and course

Nodules slowly resolve over 6–12 months without treatment. In some patients localized lipoatrophy can lead to a depression with normal overlying epidermis and dermis.

Cutaneous findings

Firm, asymptomatic, itchy, or tender, subcutaneous nodules commonly appear 1–2 days after vaccinations in the buttocks or thighs in infants, and in the deltoid area in older children and adults.^49,50 Although lesions occasionally result from direct trauma to the subcutaneous tissue when the needle is accidentally placed in the fat, some patients develop aluminum granulomas when an aluminum-adsorbed vaccine is used.

Diagnosis

The diagnosis is apparent when one or several nodules develop in a vaccination injection site. Skin biopsies demonstrate characteristic findings, including lymphoid follicles with germinal centers and a dense surrounding infiltrate of lymphocytes, histiocytes, plasma cells, and eosinophils. Staining for aluminum is also positive, confirming the diagnosis.⁴⁹

Differential diagnosis

Other foreign material injected into the skin can produce panniculitis, with nodule formation and fat necrosis. This can occur with certain medications and intravenous fluid extravasation.⁵¹ Munchhausen syndrome by proxy should be considered when recurrent panniculitis with associated cellulitis and/or ulceration occurs in an otherwise healthy infant without a clear diagnosis.

Treatment and course

Injection-site granulomas usually resolve without scarring within 2 weeks, although they can last much longer. Occasionally, liponecrosis leads to ulceration and/or lipoatrophy, with persistent dimpling of the skin.

Cutaneous findings

Septic emboli produce tender, red, subcutaneous nodules that are usually confined to one area, such as a portion of an extremity, but widespread dissemination can occur (Fig. 27.6).

Infected children are febrile, irritable, and appear ill. There may be other signs of systemic infection or sepsis. Although infectious panniculitis is more common in immunocompromised individuals,⁵⁵ it has rarely been reported in immunocompetent children.⁵²

Etiology and pathogenesis

Infectious panniculitis has been associated with Gram-positive (Staphylococcus aureus, S. epidermidis, Streptococcus sp.) and Gram-negative (Pseudomonas sp., Klebsiella sp., Fusobacterium, Fusarium) bacteria, fungi (Candida sp., Nocardia sp.), and atypical mycobacteria.

Diagnosis

Skin biopsies from subcutaneous nodules reveal a mixed septal–lobular panniculitis with infiltration by neutrophils.^52,53,55 Special stains demonstrate organisms scattered throughout fat lobules. Blood cultures and cultures of other body fluids may also be positive.

Differential diagnosis

Other conditions to be considered in the setting of possible panniculitis associated with fever include erythema nodosum, Henoch–Schönlein purpura (HSP), and cellulitis. The most difficult of these to exclude is erythema nodosum, an immunologically mediated phenomenon commonly associated with streptococcal and other infections. In erythema nodosum, the panniculitis occurs primarily in the fat septa, and the infecting organisms are not found in the skin nodules. HSP is not usually associated with fever, and skin biopsy shows leukocytoclastic vasculitis.

Treatment and course

Treatment should be directed against the specific organism. Skin biopsy for pathology and cultures, blood cultures, and other appropriate cultures will hopefully identify a specific organism and direct antibiotic and/or antifungal therapy.