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Subcutaneous fat necrosis of the newborn

Subcutaneous fat necrosis of the newborn
Literature review current through: Aug 2023.
This topic last updated: Aug 18, 2023.

INTRODUCTION — Subcutaneous fat necrosis of the newborn (SCFN) is an uncommon panniculitis of neonates. Classically, red, red-brown, or violaceous subcutaneous nodules and indurated plaques develop on the back, buttocks, proximal extremities, or cheeks within the first few weeks of life (picture 1A-B) [1]. Although SCFN is a self-limited condition, recognition of this entity is important, as affected infants require monitoring for associated hypercalcemia or other complications. SCFN generally has a good outcome, with spontaneous resolution of skin lesions over weeks to months. However, death from hypercalcemia has been reported in a few infants with SCFN [2].

The epidemiology, pathogenesis, clinical manifestations, diagnosis, and management of SCFN are discussed here. Sclerema neonatorum, a rare, severe panniculitis that develops in critically ill neonates, is discussed separately. (See "Sclerema neonatorum".)

EPIDEMIOLOGY — Subcutaneous fat necrosis of the newborn (SCFN) is an uncommon condition, and its precise incidence is unknown. A retrospective study at a tertiary referral center identified 30 infants diagnosed with SCFN over a 20-year period and reported a nearly equal male-to-female ratio (1.14:1) [3].

Risk factors — SCFN most often develops in full-term (>37 weeks gestational age) neonates who have experienced hypoxia or other perinatal stress. Therapeutic hypothermia with cooling of the body or head for neonatal asphyxia is an additional risk factor [4]. In many cases of SCFN, the pregnancy was complicated by factors such as maternal diabetes, hypertension, hypothyroidism, preeclampsia, or placental abruption [3]. Although classically a disease of full-term infants, some cases of SCFN in premature neonates have been described [5].

PATHOGENESIS — The pathogenesis of subcutaneous fat necrosis of the newborn (SCFN) remains elusive. One hypothesis proposes that SCFN results from the combination of local tissue hypoxia and mechanical pressure. Another suggests that the enrichment of stearic acids and saturated palmitic acids in neonatal adipose tissue predisposes it to crystallization at low temperatures [2]. As the majority of reported SCFN cases have developed in the setting of hypoxia or hypothermia, these hypotheses are attractive. However, the exact pathogenetic mechanisms of SCFN remain unclear.

Approximately 50 percent of newborns with SCFN develop hypercalcemia. The pathogenesis of SCFN-associated hypercalcemia is also not well understood. Granulomatous inflammatory cells in SCFN express high levels of 1-alpha-hydroxylase, the enzyme that converts 25-hydroxyvitamin D3 to its active form of 1,25-dihydroxyvitamin D3 [6]. 1,25-dihydroxyvitamin D3 promotes calcium mobilization from bone and increases intestinal absorption of calcium. Therefore, it is plausible that increased 1,25-dihydroxyvitamin D3 production in affected tissue of SCFN results in secondary hypercalcemia [7,8]. Possible links between SCFN-related hypercalcemia and increased prostaglandin E or parathyroid hormone levels have been postulated. However, prostaglandin E and parathyroid hormone levels are often normal in infants affected by SCFN with hypercalcemia [9,10]. Additionally, it has been suggested that decreased renal calcium clearance may contribute to SCFN-associated hypercalcemia [11].

CLINICAL MANIFESTATIONS — Subcutaneous fat necrosis of the newborn (SCFN) typically develops in full-term neonates within the first six weeks of life as erythematous to violaceous nodules or indurated plaques on the cheeks, back, buttocks, or proximal extremities (picture 1A-C). The chest and abdomen tend to be spared. A case of SCFN presenting with localized scalp alopecia overlying an erythematous nodule has been described [12].

Lesions are frequently tender. One study found that notable pain developed in 25 percent of patients (4 out of 16) in their case series, with two infants requiring morphine for adequate analgesia [13].

COMPLICATIONS

Hypercalcemia — Hypercalcemia, a potentially life-threatening complication of subcutaneous fat necrosis of the newborn (SCFN), occurs in over 50 percent of affected neonates [11,14]. In a systematic review of published cases of SCFN, hypercalcemia was detected in 32 of 56 patients (57 percent) in the first 28 days of life and in 17 (30 percent) in the following 28 days [11]. In a series of 32 infants with SCFN, 25 (86 percent) had hypercalcemia in the first 28 days of life [1].

Hypercalcemia may be asymptomatic or may present with irritability, hypotonia, weakness, anorexia, vomiting, constipation, failure to thrive, or encephalopathy. Hypercalcemia may decrease renal concentrating ability, leading to polyuria, dehydration, and calcifications. Nephrocalcinosis is a commonly observed complication of hypercalcemia and may persist, but in most cases, it does not cause significant renal dysfunction [15-17]. (See "Nephrocalcinosis in neonates".)

Metastatic calcification in other tissues, such as pericardium and brain, have also been described in the context of SCFN-associated hypercalcemia [18].

As late presentation of SCFN-associated hypercalcemia has been reported, some experts have recommended screening serum calcium for six months after skin lesions appeared [19]. However, this approach may be overly conservative.

In a systematic review of 127 published cases of SCFN, only 4 percent developed hypercalcemia >10 weeks after diagnosis of skin lesions, and hypercalcemia resolved within four weeks after detection in the majority of patients (76 percent) [11]. Based on these observations, the following monitoring is recommended:

Screening for hypercalcemia (with measurement of serum calcium and ionized calcium) at time of diagnosis of SCFN and again at 30, 45, and 60 days after skin lesions resolve.

Screening for hypercalcemia for any infant with SCFN who demonstrates signs or symptoms of hypercalcemia within six months of skin lesion resolution.

Among infants with SCFN found to have mild hypercalcemia (<12 mg/dL [<3 mmol/L]) symptoms, weekly screening for hypercalcemia and monitoring for symptoms should be performed until resolution of hypercalcemia.

For affected infants with moderate hypercalcemia (total serum calcium 12 to 14 mg/dL [3 to 3.5 mmol/L] or ionized calcium >8 mg/dL [>2 mmol/L]), increased monitoring with twice-weekly calcium screening and monitoring for symptoms is indicated. If infants with calcium levels between 12 to 14 mg/dL exhibit symptoms, consideration should be given to inpatient admission for management.

Hospitalization for hypercalcemic crisis is recommended for affected infants with severe hypercalcemia (total serum calcium ≥14 mg/dL [≥3.5 mmol/L] or ionized calcium ≥10 mg/dL [≥2.5 mmol/L]).

If hypercalcemia is detected on screening laboratory analysis, renal ultrasound should be performed. If nephrocalcinosis is found, pediatric nephrology should be consulted.

Other — Thrombocytopenia, elevated triglycerides, anemia, and hypoglycemia occur in some infants with SCFN [3,20]. Infrequently, infants with SCFN exhibit thrombocytosis [21]. In most cases, these laboratory abnormalities occur early in the disease course and are mild and transient.

CLINICAL COURSE — Typically, subcutaneous fat necrosis of the newborn (SCFN) skin nodules and plaques spontaneously regress within weeks to a few months without cutaneous sequelae. There is a single report of an SCFN case with extensive lesions that failed to regress by the age of nine months and required surgical excision [22]. In some cases, firm, calcified nodules develop. Diseased fat may also liquify into fluctuant bullae, which drain chalk-like or yellow discharge [23]. A case report describes an infant with SCFN and thrombocytopenia who rapidly developed a large hematoma at the evolving SCFN lesion site and required surgical debridement and full-thickness skin grafting [24]. Uncommonly, scarring or cutaneous atrophy persist at sites of resolved SCFN lesions [13].

DIAGNOSIS — Subcutaneous fat necrosis of the newborn (SCFN) is diagnosed clinically in most cases. However, if the diagnosis is in question, skin biopsy is the gold standard to provide histopathologic confirmation (see 'Pathology' below). Alternatively, fine needle aspiration is a minimally invasive procedure that can rapidly establish the diagnosis by cytologic examination [25,26]. Typical diagnostic findings on fine needle aspiration include refractile, needle-shaped crystals oriented in radial arrays within fat cells, with variable amounts of fat necrosis, accompanied by macrophages, multinucleated giant cells, neutrophils, and lymphocytes. Early lesions demonstrate less fat necrosis and less inflammatory infiltrate as compared with more established lesions [26].

Magnetic resonance imaging (MRI) and ultrasound are not recommended to diagnose SCFN. However, imaging findings have been described in several infants ultimately diagnosed with SCFN by skin biopsy [27-30]. MRI shows linear abnormality of signal intensity limited to the fat (low signal intensity on T1-weighted images or high signal on fat-suppressed, T2-weighted images) without a discrete mass [27-29]. Ultrasound appears to be less specific, with lobulated hyperechoic masses being described [27,28]. Acoustic shadows may be appreciated on ultrasound if calcification is present within the lesions [30].

Pathology — Histopathologic findings of subcutaneous fat necrosis include the following [31,32]:

Lobular panniculitis with a dense infiltrate of histiocytes, eosinophils, and multinucleated giant cells

Radial arrays of crystal cleft spaces within adipocytes similar to the crystal cleft spaces observed in sclerema neonatorum

Focal calcification within lesions

DIFFERENTIAL DIAGNOSIS — Conditions that mimic subcutaneous fat necrosis of the newborn (SCFN) include:

Cold panniculitis – Cold panniculitis typically manifests as firm, well-demarcated, erythematous plaques at sites where the skin has been in direct contact with cold objects (picture 2). Generally, cold panniculitis appears within hours to days after the cold exposure and spontaneously resolves within two weeks. Facial ice application for management of supraventricular tachycardia and the use of cooling blankets during cardiac surgery have been implicated in pediatric cases of cold panniculitis [33]. Histopathologically, the absence of needle-shaped clefts within lesional fat in cold panniculitis distinguishes it from SCFN. Additionally, cystic spaces thought to correlate with ruptured fat calls may be seen in cold panniculitis [31,32]. (See "Panniculitis: Recognition and diagnosis".)

Sclerema neonatorum – Sclerema neonatorum is a rare panniculitis that affects critically ill preterm and low-birthweight newborns and is associated with a high mortality rate [34]. Skin tightens symmetrically and becomes fixed to underlying tissues. Hardened skin may appear waxy, purple, or mottled. Generally, the eruption spreads quickly to involve all skin with underlying fat but spares genitalia, palms, and soles, which lack subcutaneous adipose tissue. Joint contractures, impairment of chest wall movement with respiration, and feeding difficulty may develop. Histopathology shows needle-shaped clefts within adipocytes, like those seen in SCFN, but the lack of an inflammatory cell infiltrate in sclerema neonatorum differentiates it from SCFN [31,32]. (See "Sclerema neonatorum".)

Scleredema Scleredema is a rare condition that develops in newborns exposed to cold environments or severe infection during the first week of life. In scleredema, affected skin is thickened, wax-like, and edematous. In contrast to SCFN and sclerema neonatorum, scleredema demonstrates pitting upon pressure and tends to affect the legs preferentially [34]. Histopathology demonstrates edema of the dermis and subcutaneous fat and a lymphohistiocytic lobular panniculitis. Infantile scleredema must be distinguished from adult scleredema; thickening of collagen and increased mucin are noted only in adult scleredema (scleredema adultorum of Buschke). (See "Scleredema".)

MANAGEMENT

Skin lesions — The nodules and plaques of subcutaneous fat necrosis of the newborn (SCFN) typically resolve spontaneously without scarring over several weeks [35]. Infrequently, skin lesions ulcerate or evolve into liquid-filled bullae that require local wound care.

Analgesia, escalating from acetaminophen to morphine, may be required for infants with painful lesions [13]. (See "Prevention and treatment of neonatal pain".)

Hypercalcemia — The treatment of hypercalcemia in infants with SCFN requires expert input from a pediatric endocrinologist. In some cases, the addition of a neonatologist, pediatric hospitalist, or pediatric nephrologist to the care team is also needed [1].

A renal ultrasound should be performed to examine for nephrocalcinosis after any level of hypercalcemia is confirmed. Signs of nephrocalcinosis may suggest that extensive excretion of calcium in the urine is helping to maintain serum calcium levels at the upper range of normal, and if exhaustion of renal calcium excretion occurs, calcium levels may quickly rise [36]. Findings of calcium deposition in the kidneys should prompt consultation with a pediatric nephrologist (see "Nephrocalcinosis in neonates"):

Mild hypercalcemia – Mild hypercalcemia (calcium <12 mg/dL [<3 mmol/L]) is typically asymptomatic and can be managed on an outpatient basis with immediate discontinuation of any vitamin D supplementation. Switching to a low-calcium infant formula or mixing breast milk with low-calcium infant formula may be necessary if laboratory calcium values do not improve.

Moderate symptomatic hypercalcemia and severe hypercalcemia – Infants with moderate hypercalcemia (12 to 14 mg/dL [3 to 3.5 mmol/L]) with symptoms or severe hypercalcemia (≥14 mg/dL [≥3.5 mmol/L]) are best managed in the inpatient setting. Historically, first-line treatment has involved restriction of supplemental calcium and vitamin D, hyperhydration with intravenous fluids, and calcium-wasting loop diuretics (eg, furosemide) with or without systemic corticosteroids [15]. However, bisphosphonates regulate calcium levels more quickly and are associated with fewer potential side effects than systemic corticosteroids in SCFN [37-40]. Zoledronic acid, a third-generation bisphosphonate that is more potent and has a faster onset and longer duration of action than pamidronate, has demonstrated benefit for treating hypercalcemia in SCFN [41,42].

Calcitonin may be a helpful adjunctive therapy to bisphosphonates for managing severely elevated calcium levels in infants with SCFN [42,43].

SUMMARY AND RECOMMENDATIONS

Definition and risk factors – Subcutaneous fat necrosis of the newborn (SCFN) is a self-limited panniculitis that most often affects full-term newborns who undergo birth asphyxia, other perinatal stress, or therapeutic hypothermia. Additional risk factors include maternal diabetes, hypothyroidism, hypertension, preeclampsia, and placental abruption. (See 'Introduction' above and 'Risk factors' above.)

Clinical presentation – SCFN develops in the first weeks of life with indurated, red-to-purple nodules and plaques on the back (picture 1A-B), buttocks, or cheeks. (See 'Clinical manifestations' above.)

Complications – Hypercalcemia, a potentially life-threatening complication of SCFN, occurs in approximately 50 percent of affected neonates. It may be asymptomatic or may present with irritability, hypotonia, anorexia, constipation, or vomiting. Blood calcium levels must be checked at the time of diagnosis of SCFN and again at 30, 45, and 60 days after skin lesions resolve in infants with SCFN. (See 'Hypercalcemia' above.)

Diagnosis – SCFN is usually diagnosed from the clinical history and examination findings. However, if the clinical diagnosis is in question, skin biopsy provides histopathologic confirmation. (See 'Diagnosis' above.)

Management:

Skin lesions – No specific treatment other than general skin care is needed for skin lesions. SCFN nodules and plaques generally involute without scarring within several weeks. (See 'Skin lesions' above.)

Hypercalcemia The treatment of hypercalcemia in infants with SCFN requires expert input from a pediatric endocrinologist. A renal ultrasound should be performed to examine for nephrocalcinosis after any level of hypercalcemia is confirmed:

-Mild hypercalcemia – Mild hypercalcemia (calcium <12 mg/dL [<3 mmol/L]) is typically asymptomatic and can be managed on an outpatient basis with immediate discontinuation of any vitamin D supplementation. Switching to a low-calcium infant formula or mixing breast milk with low-calcium infant formula may be necessary if laboratory calcium values do not improve.

-Moderate symptomatic hypercalcemia and severe hypercalcemia – Infants with moderate hypercalcemia (12 to 14 mg/dL [3 to 3.5 mmol/L]) with symptoms or severe hypercalcemia (≥14 mg/dL [≥3.5 mmol/L]) are best managed in the inpatient setting. Historically, treatment included restriction of supplemental calcium and vitamin D, intravenous fluids, loop diuretics, and systemic corticosteroids. However, bisphosphonates, which regulate calcium levels more quickly and are associated with fewer potential adverse effects than loop diuretics and systemic corticosteroids, may be considered a first-line therapy for severe hypercalcemia associated with SCFN. (See 'Hypercalcemia' above.)

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References

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