Sclerema neonatorum

INTRODUCTION — Sclerema neonatorum is an uncommon, severe panniculitis that manifests as diffuse skin hardening in critically ill, premature and low birth weight infants [1]. Skin and subcutaneous fat become bound down and adherent to underlying muscle and bone, such that critical functions of breathing, feeding, and movement can be impeded. Affected newborns typically suffer from comorbid conditions, including sepsis, dehydration, intracranial hemorrhage, severe respiratory or gastrointestinal disease, and congenital malformations. Mortality rates among cases of sclerema neonatorum are high; however, with modern neonatal intensive care resources, sclerema neonatorum is uncommon. Regardless, rare cases of sclerema neonatorum continue to be reported [2], and it is important that clinicians can diagnose and treat this entity.

This topic reviews the pathogenesis, clinical manifestations, diagnosis, and management of sclerema neonatorum. Subcutaneous fat necrosis of the newborn is discussed separately. (See "Subcutaneous fat necrosis of the newborn".)

EPIDEMIOLOGY — The incidence of sclerema neonatorum is not known. The largest case series describing sclerema neonatorum were published between 1940 and 1970 [3]. Aggregation of case reports suggests that males may be affected slightly more often than females (male-to-female ratio, 1.6:1) [1]. Maternal parity does not appear to be a risk factor [4].

It is hypothesized that improved perinatal intensive care has substantially reduced the number of infants affected by sclerema neonatorum, rendering sclerema neonatorum an uncommon diagnosis in the setting of modern neonatal intensive care [5]. Limited data suggest that the incidence of sclerema neonatorum may be higher in areas with less access to high acuity neonatal care. A study evaluating premature newborns at a tertiary pediatric hospital in Bangladesh from 1998 to 2003 reported a 10 percent incidence of sclerema neonatorum [6].

PATHOGENESIS — The pathogenesis of sclerema neonatorum remains unknown. Subcutaneous adipose tissue in neonates is enriched in saturated fats compared with the subcutaneous fat composition of older individuals. This biochemical property of subcutaneous fat makes it more likely to harden in a cold environment. It has been suggested that decreased body temperature encountered in clinical shock triggers subcutaneous adipose hardening in sclerema neonatorum [7]. However, fat hardening should not occur until skin temperature is below the freezing point, which argues against this explanation. Alternative theories propose that sclerema neonatorum is a consequence of abnormal fat metabolism, results from dysfunction of the connective tissue surrounding the adipocytes, or is a downstream effect triggered by systemic toxicity [8-10].

CLINICAL MANIFESTATIONS — Sclerema neonatorum characteristically affects newborn infants and typically develops within the first week of life, although a few cases have been reported to occur beyond the neonatal period. Affected newborns typically suffer from comorbid conditions, including sepsis, dehydration, intracranial hemorrhage, severe respiratory or gastrointestinal disease, and congenital malformations.

The skin is waxy appearing, tight, and adherent to underlying tissues. In some infants, the skin appears purple or mottled. The skin cannot be lifted, pinched, or depressed. Sclerema neonatorum classically develops symmetrically on the trunk, thighs, or buttocks, and then the skin hardening quickly spreads to involve the subcutaneous fat of the entire body (except for the fat-free areas of the genitalia, palms, and soles). Hardening of the facial skin may manifest as a mask-like, fixed facies.

Skin tightening limits chest wall expansion and respiration, and it may also restrict feeding and other movements. Joint contractures are frequently noted. Compartment syndrome of an extremity in sclerema neonatorum has been described [11]. (See "Acute compartment syndrome of the extremities".)

DIAGNOSIS

Clinical — The diagnosis of sclerema neonatorum is made clinically, based upon the observation of diffuse skin hardening in a gravely ill newborn. The affected skin is fixed to underlying tissue and cannot be folded, pinched, or pitted. If the diagnosis is in question, skin biopsy may offer histopathologic support to the diagnosis. (See 'Pathology' below.)

Pathology — Histopathologic findings of sclerema neonatorum include [5,12]:

●Necrosis of subcutaneous fat without significant inflammatory infiltrate and with no prominent granulomatous changes

●Formation of needle-shaped clefts in adipocytes, sometimes in a radial arrangement

●Fibrous thickening of tissue surrounding fat lobules

DIFFERENTIAL DIAGNOSIS

Subcutaneous fat necrosis of the newborn — Subcutaneous fat necrosis of the newborn typically presents around one to four weeks of life as circumscribed, red-brown, firm plaques in healthy-term or post-term neonates (picture 1). As opposed to sclerema neonatorum, lesions tend to remain localized and develop later in life; although firm, the affected skin freely moves over the underlying tissue (table 1). Risk factors for subcutaneous fat necrosis of the newborn include hypoxia, perinatal distress, and therapeutic hypothermia [13,14]. On histopathology, subcutaneous fat necrosis of the newborn demonstrates fat necrosis and a robust, inflammatory infiltrate including histiocytes, eosinophils, and multinucleated giant cells. Crystal cleft spaces similar to those in sclerema neonatorum may be observed within adipocytes, and calcification may be present [5,12]. The clinical findings and the extensive, inflammatory infiltrate on histopathology encountered in subcutaneous fat necrosis of the newborn help to distinguish it from sclerema neonatorum. (See "Subcutaneous fat necrosis of the newborn".)

Cold panniculitis — Cold panniculitis is characterized by erythematous, firm, well-demarcated plaques that develop at sites where the skin has been subjected to cold temperatures (picture 2) [13]. It appears within hours to a few days after cold exposure and resolves spontaneously. Cases of cold panniculitis in infants have been reported after application of ice to the face to treat supraventricular tachycardia and after use of cooling blankets during cardiac surgery [15]. Whereas the clinical findings may be very similar, the histopathology of cold panniculitis lacks the characteristic needle-shaped clefts observed in subcutaneous fat necrosis of the newborn or sclerema neonatorum, and cystic spaces are often apparent where fat cells have presumably ruptured [12].

Scleredema — Scleredema has been rarely described among infants exposed to cold temperatures or those with severe diarrhea or infection during the first week of life [16,17]. Affected skin in neonatal scleredema is visibly thickened and wax like. The legs are involved more frequently than other body sites. In contrast to sclerema neonatorum, the skin is edematous and exhibits easy pitting [1]. Histopathology shows edema of the dermis and subcutaneous fat and lymphohistiocytic inflammation of the fat lobules.

Scleredema in adults (scleredema adultorum of Buschke) differs from that described in infants. Scleredema adultorum is associated with increased mucin disposition and thickened collagen. (See "Scleredema".)

Restrictive dermopathy — Restrictive dermopathy is a lethal genetic disease characterized by abnormally tight skin from birth. Affected newborns are usually premature and have diffusely hard skin that may shear or tear at areas of skin folding, such as the neck, inguinal folds, and lower abdomen (picture 3A-B). Additional clinical findings include joint contractures, ectropion, chest wall narrowing, hypoplastic clavicles, and a fixed O-shaped mouth. This condition is associated with polyhydramnios and pulmonary hypoplasia and is generally fatal in the newborn period. Histopathology shows flattened rete ridges, a thin dermis with horizontally oriented collagen, and incompletely developed skin appendages [18]. Recessive mutations in ZMPSTE24, which encodes a zinc metalloproteinase that processes the important nuclear envelope protein lamin A (encoded by LMNA), are responsible for most cases; however, dominant LMNA mutations have been found in restrictive dermopathy as well [19,20].

Hutchinson-Gilford progeria syndrome — Sclerodermatous skin tightening has been uncommonly reported in infants with Hutchinson-Gilford progeria, with the youngest reported affected child being approximately two weeks of age [21]. Findings of prominent skin veins, alopecia, frontal bossing, bird-like nose, and micrognathia support the diagnosis. Skin biopsy typically demonstrates thickened dermal collagen but is nonspecific. Most cases are due to an autosomal dominant LMNA mutation [22]. (See "Hutchinson-Gilford progeria syndrome".)

MANAGEMENT — Diagnosis and treatment of concurrent illnesses is paramount for infants affected by sclerema neonatorum. Infections, metabolic disturbance, cardiac disease, and other congenital malformations must be treated promptly. Body temperature, fluid status, and electrolyte levels should be monitored and actively maintained within normal ranges.

In the 1960s and 1970s, the use of systemic corticosteroids for sclerema neonatorum did not appear to improve survival, although in some cases, systemic corticosteroids may have limited the expansion of existing lesions [4,23-25]. A 2017 case report describes successful treatment of a 1550 g preterm infant with progressive sclerema neonatorum in the context of hypoglycemia and sepsis with parenteral hydrocortisone, antibiotics, and supportive intensive care management [26]. However, additional study is needed to determine the efficacy of systemic corticosteroids for treatment of sclerema neonatorum in the context of modern neonatal intensive care practices.

Exchange transfusion has been utilized in the treatment of sclerema neonatorum [27-29]. One randomized clinical study that included 40 newborns with sepsis and sclerema neonatorum reported 50 percent mortality in infants treated with exchange transfusion versus 95 percent in untreated infants [27]. In a single case report, intravenous immunoglobulin infusion in a full-term infant with biopsy-proven sclerema neonatorum induced a transitory, mild clinical improvement of the skin, although the child died of respiratory failure secondary to chest wall skin tightening at six weeks of age [30].

PROGNOSIS — Sclerema neonatorum is associated with a high mortality rate. Case series estimate that 13 to 39 percent of affected neonates survive [1]. Among survivors, there are generally no long-term skin complications [31].

SUMMARY AND RECOMMENDATIONS

●Definition – Sclerema neonatorum is an uncommon, severe, diffuse panniculitis that develops in critically ill neonates. Premature and low birth weight infants are the most susceptible. (See 'Introduction' above and 'Epidemiology' above.)

●Clinical presentation – Affected skin in sclerema neonatorum is waxy, tight, and adherent to underlying tissues. Skin hardening develops symmetrically on the trunk, thighs, and buttocks but quickly spreads to involve the entire body symmetrically, sparing the areas that lack subcutaneous fat (eg, palms, soles, and genitalia). Affected infants typically suffer from comorbid disease, including sepsis, congenital malformations, and severe respiratory or gastrointestinal illness. (See 'Clinical manifestations' above.)

●Diagnosis – Sclerema neonatorum is typically diagnosed clinically. If the diagnosis is uncertain, a skin biopsy may be helpful for confirmation. On histopathology, sclerema neonatorum shows needle-shaped clefts in adipocytes and fibrotic change around fat lobules without significant inflammation or granulomatous infiltrate. (See 'Diagnosis' above and 'Pathology' above.)

●Management – As sclerema neonatorum develops within the context of serious illness (most often in premature and low birth weight neonates), prompt diagnosis and treatment of associated disease is critical. Limited available data suggest that exchange transfusion may help reduce mortality in affected infants. (See 'Management' above.)

●Prognosis – Sclerema neonatorum is associated with a high mortality rate. Based on case series, it is estimated that 13 to 39 percent of affected neonates survive. (See 'Prognosis' above.)