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Subcutaneous fat necrosis of the newborn associated with hypercalcemia after therapeutic hypothermia.

CLINICAL FEATURES

Subcutaneous fat necrosis of the newborn (SCFN) is a rare, benign, and self-limiting panniculitis of neonates that presents in the first few weeks of life. It mainly affects term and post-term neonates. Neonatal risk factors include hypoxia, meconium aspiration, sepsis, hypothermia, obstetric trauma, anemia, and thrombocytopenia; maternal risk factors include gestational diabetes, preeclampsia, smoking, and family history of thrombosis. (1,2) Cold exposure is a known risk factor for SCFN. As therapeutic hypothermia has been becoming a routine protocol for hypoxic ischemic encephalopathy (HIE) in neonatal intensive care units, SCFN as a complication of whole-body cooling has been increasingly reported in the past several years." Studies reporting its incidence are limited. In a study by Strohm et al., 12 (1%) of 1,239 newborns with therapeutic whole-body hypothermia developed SCFN. (8) Shankaran et al. reported 1 (1%) of 102 newborns with therapeutic whole-body hypothermia developed SCFN. (9)

SCFN usually presents as circumscribed, erythematous, indurated nodules and plaques on fat-bearing areas such as face, chest, back, buttocks, arms, and thighs; fluctuant skin lesion was rarely reported. (6) The skin lesions are often painless and not warm to palpation. Pain was seen in 25% of patients in one case series. (1) The skin lesions usually appear 2-10 days after the completion of cooling therapy. (3,4,6,7,10,11) The skin lesions usually resolve spontaneously in weeks to months, but hematoma formation requiring skin debridement and grafting was rarely reported. (8) Complications of SCFN include dyslipidemia, hypoglycemia, thrombocytopenia, and hypercalcemia. (1,5) The most serious complication, hypercalcemia, may occur several days to six months after the onset of skin lesions. (1,6,12) Hypercalcemia as a complication of SCFN has been seen in 20%-69% of patients in previous case series. (1,2,12) Strohm et al. reported hypercalcemia was seen in 8 (67%) of 12 SCFN patients after therapeutic hypothermia. (8) Clinically, hypercalcemia manifests from asymptomatic to irritability, weight loss, hypotonia, lethargy, poor feeding, dehydration, and growth retardation. (3,11,13) In severe cases, metastatic calcification occurs in kidney, myocardium, major vessel, liver, and brain. (1,8,12)

PATHOLOGIC FINDINGS

The diagnosis of SCFN is based on clinicopathologic correlation and histopathologic examination of skin punch biopsy. SCFN characteristically shows a lobular panniculitis with a dense infiltrate of lymphocytes, histiocytes, multinucleated giants cells and occasional eosinophils, and radially arranged needle-shaped clefts in adipocytes and histiocytes. (14) The needle-shaped clefts represent triglyceride crystals that are extracted during specimen processing; the crystals are derived from stearic and palmitic acids, normal components of neonatal subcutaneous adipose tissue. In late stage of the disease, septal fibrosis and calcification can be seen in the fat lobules.

Fine-needle aspiration and touch imprint cytology of drainage material have been used as alternative tools for diagnosis in few case reports. (15) Aspiration and drainage can provide quick and less invasive evaluation, but the sensitivity is limited compared to skin biopsy. Cytology findings consist of fat droplets containing radially arranged refractile needle-shaped crystals in a background of inflammatory cells, including lymphocytes, histiocytes, and multinucleated giant cells, with or without calcifications. The background appearance may range from scanty inflammation with no significant necrosis of adipocytes to numerous inflammatory cells with dirty necrotic background, depending on the stage of the disease. (15)

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of SCFN can be broad, and clinicopathologic correlation is essential to make the correct and timely diagnosis so that appropriate measures can be taken to prevent the potential serious complication hypercalcemia. (14)

When fluctuant nodules or skin rashes are present, especially in critically ill or immunocompromised patients, infectious etiology such as bacterial cellulitis, toxic shock syndrome, abscess, and erysipelas should be ruled out first. Skin and subcutaneous infection generally manifests in warmth, swelling, and pain of the lesion, whereas SCFN remains normothermic to palpation. Histopathologically, infection of skin and subcutaneous tissue can show mostly neutrophilic lobular panniculitis or suppurative granulomas, which may require special stains (Gram, periodic acid-Schiff, acid-fast stain) to identify pathogenic microorganisms. Cultures of skin lesions may be necessary if special stains fail to detect pathogens and clinical suspicion for infection remains high. Needle-shaped clefts are generally absent in adipocytes. Skin lesions due to infection usually resolve with systemic antibiotic therapy.

Cold panniculitis is inflammation of subcutaneous adipose tissue caused by direct exposure to cold. The clinical appearance of cold panniculitis may overlap with early stage SCFN. It usually has no maternal factors and tends to occur within 72 hours of cold exposure. Clinically, it usually presents as red-blue indurated plaques or nodules. Histopathologically, cold panniculitis is a lobular panniculitis with nonspecific inflammatory infiltrate of lymphocytes and histiocytes, most prominent at the dermosubcutaneous junction in the fat lobules and without needle-shaped clefts and adipocyte necrosis. Cold panniculitis generally resolves spontaneously after further cold exposure is avoided.

Sclerema neonatorum is a very rare panniculitis affecting primarily ill preterm neonates in the first week of life. Unlike SCFN, which has aforementioned risk factors, sclerema neonatorum usually has no maternal factors with an uneventful delivery and is often associated with congenital anomalies, serious respiratory illness, and sepsis. Sclerema neonatorum manifests as diffuse hardening of the skin--sparing soles, palms, and genitalia--which firmly attaches to the underneath muscle and bone, leading to impaired feeding and breathing; whereas SCFN presents as circumscribed hardening of the skin, which moves freely over the underneath muscle and bone. Histopathologically, sclerema neonatorum is characterized by thickening of the connective tissue septa of the subcutaneous fat; absent to sparse inflammatory infiltrate of lymphocytes, histiocytes and multinucleate giant cells; radially arranged needle-shaped clefts in adipocytes; and absence of adipocyte necrosis and calcification. Unlike SCFN, which is localized and self-limiting with an excellent prognosis, sclerema neonatorum rapidly generalizes and has a poor prognosis with a mortality rate of 75%. The presence of needle-shaped clefts is rather a nonspecific feature for SCFN and sclerema neonatorum, and hence, clinical presentation and degree of inflammation are more important for diagnosis.

Scleredema is a rare and self-limiting skin condition affecting primarily preterm neonates in the first week of life. The risk factors of scleredema include cold injury, dehydration, diarrhea, vomiting, and infection. Clinically, scleredema manifests as generalized firm pitting edema more commonly seen in lower extremities. Histopathologically, scleredema is characterized by a lobular panniculitis with inflammation and marked edema of skin and subcutaneous tissue without needle-shaped clefts and adipocyte necrosis. The prognosis of scleredema is good, and skin lesions heal spontaneously with supportive care.

Poststeroid panniculitis is a rare panniculitis occurring in neonates who had an abrupt taper or sudden withdrawal of high-dose systemic corticosteroids therapy. Clinically, poststeroid panniculitis presents as erythematous nodules on the cheek and chin within days to weeks after the withdrawal of corticosteroids. Histopathologically, poststeroid panniculitis can mimic SCFN by displaying a mixed inflammation of less intensity, as well as needle-shaped clefts in adipocytes and histiocytes.

PATHOGENESIS

The pathogenesis of SCFN and hypercalcemia is unclear. It has been suggested that perinatal events, such as birth asphyxia or hypothermia, can shunt blood from peripheral skin and subcutaneous tissue to central vital organs and result in subcutaneous stresses, e.g. hypoperfusion and hypoxemia, which in turn lead to injury and crystallization of adipocytes, inflammation, and granulomatous reaction. Normal adipose tissue contains triglycerides in a variable proportion of saturated and unsaturated fatty acids. The neonatal adipose tissue has a higher ratio of saturated to unsaturated fatty acids than the adult counterpart, which determines a higher melting point and a lower solidification point of the adipose tissue. These unique features predispose neonatal adipose tissue to an increased risk for crystallization on exposure to stress factors such as hypothermia.

The most popular hypothesis of hypercalcemia in SCFN is the extrarenal production of 1, 25-[(OH).sub.2][D.sub.3], leading to increased intestinal absorption of calcium. SCFN can exhibit a strong expression of 1a-hydroxylase in inflammatory infiltrate, suggesting that 1, 25-[(OH).sub.2][D.sub.3] may be produced by macrophages in subcutaneous granulomas. (1) However, Burden et al. showed that elevated serum 1,25-[(OH).sub.2][D.sub.3] was observed in only one out of four patients. (2) Therefore, other possible mechanisms such as activation of osteoclasts and enhanced bone calcium turnover resulting from elevated prostaglandin E2 may also play a role in the pathogenesis of hypercalcemia.

TREATMENT AND PROGNOSIS

SCFN is usually treated symptomatically. Painful lesions can be managed with acetaminophen or opiate analgesia such as morphine; refractory cases can add short-term prednisolone that has a synergistic effect with morphine. (10,13) Tran et al. (2003) showed that aspiration of skin lesions may be used to relieve pain and skin breakdown. Hypercalcemia can be managed by conservative and symptomatic treatment such as low calcium and vitamin D formula, intravenous hydration, and loop diuretics. Severe cases can be treated with corticosteroids, bisphosphonate, and calcitonin. Serum calcium levels should be monitored weekly or biweekly for up to six months or until the resolution of fat necrosis. Filippi et al. (2012) proposed that using a cooling blanket in an automatic "gradient variable mode," where the circulating water was maintained at minimal change in temperature along with a special nursing protocol to change position of neonates every three hours by alternating pronation/supination during cooling, may reduce the risk of developing SCFN. (16) Therefore, it is prudent to change the skin contact site of cooling device more frequently and avoid direct pressure of cooling device against skin to minimize subcutaneous stress.

SCFN is generally self-limiting with an excellent prognosis. Skin lesions usually resolve spontaneously in weeks to months without long-term sequelae, and most cases require only conservative and symptomatic treatment. Previous case series demonstrated good prognosis even when associated with hypercalcemia; (1,2,8) however, SCFN complicated by hypercalcemia can be fatal if left untreated. (12)

CONCLUSIONS

SCFN is a rare, benign and self-limiting panniculitis of neonates. It can present as fluctuant lesions or with concurrent infection, which may result in delayed diagnosis. The differential diagnosis of SCFN can be broad, and clinicopathologic correlation is essential to make the correct and timely diagnosis. With the increasing use of therapeutic whole-body hypothermia, SCFN may become more prevalent. Physicians should be aware of this uncommon disease because of its potential serious complication. The patient should be monitored closely for skin involvement because skin lesions can appear several days after the completion of cooling therapy. The patient should be followed weekly or biweekly for serum calcium levels until skin lesions resolve, because hypercalcemia may occur weeks to six months after the onset of skin lesions. The parents should be educated with the signs and symptoms of SFCN and hypercalcemia.

REFERENCES

(1.) Mahe E, Girszyn N, Hadj-Rabia S, Bodemer C, Hamel-Teiilac D, De Prost Y. Subcutaneous fat necrosis of the newborn: a systematic evaluation of risk factors, clinical manifestations, complications and outcome of 16 children. The British journal of dermatology. Apr 2007;156(4):709-715.

(2.) Burden AD, Krafchik BR. Subcutaneous fat necrosis of tire newborn: a review of 11 cases. Pediatric dermatology. Sep-Oct 1999;16(5):384-387.

(3.) Akcay A, Akar M, Oncel MY, et al. Hypercalcemia due to subcutaneous fat necrosis in a newborn after total body cooling. Pediatric dermatology. Jan-Feb .

(4.) Hogeling M, Meddles K Berk DR, et al. Extensive subcutaneous fat necrosis of the newborn associated with therapeutic hypothermia. Pediatric dermatology. Jan-Feb 2012;29(1):59-63.

(5.) Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns witir hypoxic ischaemic encephalopatiry. Cochrane Database Syst Rev. 7013-1-CD003311

(6.) Oza V, Treat j, Cook N, Tetzlaff MT, Yan A. Subcutaneous fat necrosis as a complication of whole-body cooling for birtir asphyxia. Archives of dermatology. Aug 2010;146(8):882-885.

(7.) Sivanandan S, Rabi Y, Kamaluddeen M, Akierman A, Lodha A. Subcutaneous fat necrosis as a complication of therapeutic hypothermia in a term neonate. Indian journal of pediatrics. May 2012;79(5):664-666.

(8.) Stiohm B, Hobson A, Brocklehurst P, Edwards AD, Azzopardi D. Subcutaneous fat necrosis after moderate therapeutic hypothermia in neonates. Pediatrics. Aug 2011;128(2):e450-452.

(9.) Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. The New England Journal of Medicine. Oct 13 2005;353(15):1574-1584.

(10.) Woods AG, Cederholm CK. Subcutaneous fat necrosis and whole-body cooling therapy for neonatal encephalopathy. Advances in neonatal care official journal of the National Association of Neonatal Nurses. Dec 2012;12(6):345-348.

(11.) Zifman E, Mouler M, Eliakim A, Nemet D, Pomeranz A. Subcutaneous fat necrosis and hypercalcemia following therapeutic hypothermia--a patient report and review of the literature. Journal of pediatric endocrinology & metabolism'. JPEM. Nov 2010;23(11):1185-1188.

(12.) Norwood-Galloway A, Lebwohl M, Phelps RG, Raucher H. Subcutaneous fat necrosis of the newborn with hypercalcemia. Journal of the American Academy of Dermatology. Feb 1987;16(2 Pt 2):435-439.

(13.) Wiadrowski TP, Marshman G. Subcutaneous fat necrosis of the newborn following hypothermia and complicated by pain and hypercalcaemia. The Australasian journal of dermatology. Aug 2001;42(3):207-210.

(14.) Requena L, Sanchez Yus E. Panniculitis. Part II. Mostly lobular panniculitis. Journal of the American Academy of Dermatology. Sep 2001;45(3):325-361; quiz 362-324.

(15.) Schubert PT, Razack R, Vermaak A, Jordaan HF. Fine-needle aspiration cytology of subcutaneous fat necrosis of the newborn: the cytology spectrum with review of the literature. Diagnostic cytopathology. Mar 2012;40(3):245-247.

(16.) Filippi L, Catarzi S, Padrini L, et al. Strategies for reducing the incidence of skin complications in newborns treated with whole-body hypothermia. The journal of maternal-fetal & neonatal medicine official journal of the European Association of Perinatal Medicine, the Federation of Asia and Perinatal Societies, the International Society of Perinatal Obstet. Oct 2012;25(10):2115-2121.

Zhuang Feng, MD, PhD; Baofeng Guo, MD; Zhenzhen Zhang, MD, MPH

Dr. Feng is with the Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans. Dr. Guo is with the Department of Emergency Medicine, China-Japan Union Hospital of Jilin University, Changchun, China. Dr. Zhang is with the Department of Epidemiology and Biostatistics, Michigan State University East Lansing, Michigan.
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Author:Feng, Zhuang; Guo, Baofeng; Zhang, Zhenzhen
Publication:The Journal of the Louisiana State Medical Society
Date:May 1, 2014
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