Hard questions about subcutaneous fat necrosis of the newborn and hypercalcemia

By Warren R. Heymann, MD, FAAD
May 8, 2024
Vol. 6, No. 19

Neonatal dermatoses are anxiety-provoking for both physicians and parents because of crucial questions — Are there associated systemic problems? What are long-term sequelae? How should the infant be followed? One of the most striking neonatal disorders is subcutaneous fat necrosis of the newborn (SCFN). I have seen a handful of cases in my career and needed to address each preceding question. This commentary is devoted to SCFN, focusing on the complication of hypercalcemia.

Although considered rare, I suspect that most DWI&I readers have encountered SCFN. The disorder is self-limited, predominantly affecting full-term and post-term neonates during the first 6 weeks of life. (1) More than half of cases of SCFN present in the first week; 92% develop lesions by day 28. Circum­scribed, mobile, erythematous-violaceous, subcutaneous nodules or plaques characterize SCFN. Lesions may be solitary or multiple, ranging from <1 cm to 8 cm in diameter. Although mostly firm, lesions can become fluctuant and rupture, with subsequent drainage of a necrotic, chalk-like fatty substance. (2) Nodules typically appear on the arms, shoulders, and back, although facial involvement may be observed. (3) Most lesions resolve spontaneously within months, although residual lipoatrophy [and scars] may be observed. (2)

The diagnosis of SCFN is usually based on clinical grounds, although the differential diagnosis of an abscess, cellulitis, sclerema neonatorum, or cold panniculitis warrants confirmatory testing. The diagnostic gold standard is histological evaluation by skin biopsy (more in a moment on how biopsies may be avoided). SCFN demonstrates lobular panniculitis consisting mainly of histiocytes (including multinucleated cells), admixed with lymphocytes, occasional eosinophils, needle-shaped clefts, and fat necrosis. In their review of 13 cases of SCFN, Ricardo-Gonzalez et al. observed that lesions could present with a neutrophil-rich variant, especially in early lesions. However, not all new lesions contain neutrophils. The neutrophil-rich variant of SCFN can be challenging to distinguish from an infection. The authors state, “in a neonate without systemic symptoms and with negative cultures, SCFN should be considered as an explanation for a neutrophilic panniculitis, in particular if there are hints of needle-shaped clefts.” (4)

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Other diagnostic options can include an ultrasound (demonstrating a hyperechoic appearance of involved adipose tissue, high blood flow, & calcifications) (5,6); MRI (this is not usually performed because of the need for sedation but shows a poorly defined area of thickening and stranding of the subcutaneous fat with intermediate to low signal on T1-W) (1); fine needle aspiration (revealing a “dirty” background with necrotic fat containing characteristic radially-oriented, refractile, needle-shaped clefts) (7); or obtaining exudate (with or without a 15 blade) and analyzing the slide with polarization — without any need for fixation or staining (demonstrating doubly refractile crystals). (8)

The most common risk factors associated with SCFN are hypothermia and birth hypoxia. Other less common risk factors include pre-eclampsia, maternal diabetes, cocaine abuse or use of calcium channel blockers during pregnancy, birth asphyxia, meconium, aspiration, hypoxemia, and hypoglycemia. (9) The pathophysiology of SCFN is incompletely understood, with the main hypotheses being local hypoxia, pressure on the skin, and a higher melting point in neonatal fat (containing higher saturated fatty acids), leading to crystallization at low temperatures. (10) Hypothermia is currently the standard of care in managing newborns with moderate to severe hypoxic-ischemic encephalopathy in infants. (2,11)

The most significant complications of SCFN are hypercalcemia (see below), thrombocytopenia (due to peripheral platelet sequestration), and dyslipidemias (due to mobilization of fatty acids from adipose tissue), and hypoglycemia. (2,10)

Granulomatous diseases such as sarcoidosis may be complicated by hypercalcemia. Presumably, hypercalcemia in SCFN is due to increased macrophage activity with enzymatic conversion to active 1,25 dihydroxyvitamin D3, thereby enhancing intestinal absorption of calcium. (2) Although it may be asymptomatic, hypercalcemia may manifest as vomiting, somnolence, muscle weakness, cardiac arrhythmias, and nephrocalcinosis. (12) Hypercalcemia is treated by hydration, diuretics, glucocorticoids, and bisphosphonates. (11,12)

Most references state that approximately half of SCFN is complicated by hypercalcemia. In their systematic review of 206 articles encompassing 320 cases of SCFN, Frank et al. observed that a serum calcium level was obtained in only 64.3% of the cases. From those, the majority showed hypercalcemia (70.5%), normocalcemia (25.1%), and hypocalcemia (4.3%). (12) Del Pozzo-Magaña and Ho proposed an algorithm on following patients with SCFN based on their retrospective review of 30 patients where hypercalcemia developed in 19 (63%), 3 of whom developed nephrocalcinosis. Recommendations include obtaining baseline platelets, triglycerides, glucose, ionized calcium, and renal function once the diagnosis of SCFN is established. If patients have hypercalcemia, calcium levels should be repeated twice weekly as dictated by clinical symptoms or until resolution. (Please see the manuscript for the variable permutations of the algorithm based on clinical and laboratory findings). (13)

Siegel et al. performed a retrospective review of 32 infants diagnosed with SCFN at the Lurie Children’s Hospital in Chicago. Of the 32 infants identified, 29 (91%) had calcium drawn, and all (100%) had hypercalcemia. Of the 29 infants with hypercalcemia, only one had an elevated total calcium value and not an elevated ionized calcium level. Six patients had complications of hypercalcemia. Of these 6 infants, half had a peak ionized calcium between 1.5 and 1.6 mmol/L (6.01–6.41 mg/dl), and half had a peak ionized calcium greater than 1.6 mmol/L (6.41 mg/dl). No infants with peak ionized calcium less than 1.5 mmol/L (6.41 mg/dl) developed complications of hypercalcemia. The authors concluded: “Hypercalcemia occurred in 100% of infants who had laboratory monitoring. We recommend obtaining an initial ionized calcium level when SCFN is suspected, and monitoring for the first 3 months of life if hypercalcemia has not been detected. In patients with asymptomatic hypercalcemia less than 1.5 mmol/L, there appears to be low likelihood of related complications. For symptomatic, markedly elevated (>1.6 mmol/L), or persistently elevated levels (>6 months) we suggest coordinated care with endocrinology or nephrology, consider hospitalization, and urinary system ultrasound.” (14)

It is difficult to compare one retrospective study to another — perhaps prior authors did not measure ionized calcium in all of their patients. I agree with Del Pozzo-Magaña and Ho, who opine, “there is a need for a well-controlled prospective study to determine the prevalence and incidence of complications in SFN [SCFN] and to establish guidelines for investigations, treatments, and follow-up in these patients.” (13) Regardless of the precise numbers, dermatologists must be ever-vigilant in monitoring for hypercalcemia patients with SCFN until the condition resolves.

Point to Remember: The most important complication of subcutaneous fat necrosis of the newborn is hypercalcemia. Recent studies suggest that it may be more common than previously reported. Screening and monitoring for hypercalcemia (measuring ionized calcium) is essential during the first few months of life.

Our expert’s viewpoint

Patrick J. McMahon, MD, FAAD
Dermatologist, Associate Professor of Medicine
Cooper Medical School of Rowan University

What’s the “skinny” on subcutaneous fat necrosis of the newborn?

The recent report from our esteemed pediatric dermatology colleagues at Lurie Children’s Hospital in Chicago (Siegel et al. Pediatric Dermatology, May-June 2023) showing a high rate (91%) of hypercalcemia in neonates with subcutaneous fat necrosis (SCFN) has certainly raised a few eyebrows. Personally, over the past 11 years in practice I can recall at least 12 cases of SCFN in neonates with only 2 who were found to have elevated ionized calcium levels — both of whom had larger lesions (several centimeters) on the back and shoulder. I recall being at the annual meeting of the Society for Pediatric Dermatology in July 2023 soon after this report made its splash and, while “chewing the fat” with others in the field, we began to wonder if there was some difference in the laboratory cut-off used or possibly a referral bias that could explain what seemed like a higher rate of hypercalcemia in SCFN than previously reported. Without a prospective trial we have a “fat chance” of getting to the bottom of these questions, but regardless there are some important take-aways to be gleaned from this report.

First, size may actually matter. In this cohort of 32 neonates with SCFN there was found to be a “weak positive correlation between lesion size and ionized and total calcium levels” which is in keeping with my clinical experience and would make sense physiologically. Although the exact mechanism underlying the cause of hypercalcemia in SCFN is not known, if there is an increased enzymatic conversion of vitamin D to its active form by macrophages in the lesions of SCFN it would make sense that the larger lesions would have higher enzymatic activity. Subsequently there would be a higher rate of calcium absorption and, thus, risk of hypercalcemia. This reminds me of the well-described mechanism of thyroid hormone deactivation in large infantile hemangiomas, usually in the liver, due to similar enzymatic activity prompting the need to check free T4 and reverse T3. In both of these clinical scenarios it would be helpful to have a recommended size of the SCFN lesion or infantile hemangioma that could reliably and safely predict the need to perform these blood tests. In this recent report, the size of the SCFN lesion ranged from 0.3 to 6 cm (with a mean of 2 cm) which seems very similar to my clinical experience. While it can be difficult to accurately assess the exact size of these lesions, if we deemed smaller lesions to not be associated with clinically significant elevation in calcium levels, it could minimize blood monitoring for a subset of patients.

Second, this paper also highlighted the importance of checking ionized calcium levels to screen for hypercalcemia in SCFN. They reported that 86% of the cases of hypercalcemia would have been missed if only a total serum calcium level was checked. It has been my clinical practice to check only an ionized calcium level in patients with SCFN, but per Dr. Heymann’s above review it seems prudent to begin checking platelets, renal function, glucose and triglycerides (TG) at least initially. If all is within normal limits, there is still one “big fat” question remaining: How long do I need to continue checking calcium levels?

The final lesson learned from this paper is that, while we have been taught for years that calcium levels should be checked intermittently for the first 6 months of life in patients with SCFN, we can likely stop checking after only 3 months in some cases. In this paper, they recommend checking ionized calcium levels weekly for month 1, then every other week until 3 months of age. If levels have been normal, they recommend discontinuing checking thereafter. In fact, only 1% of the patients with hypercalcemia in this study were initially found to have elevated levels after day 56 of life and none after 84 days. This is reassuring, especially given the high rate of hypercalcemia detected in this group.

Ultimately, while there may be a referral bias skewing the data in this study toward slightly more severe cases of SCFN than typically seen by a practicing dermatologist, I found this report helpful in driving home the following tidbits: 1) Larger lesions of SCFN likely need more aggressive monitoring for hypercalcemia; 2) always check ionized calcium levels in these cases (and consider initial screen for platelets, glucose, TG and renal function); and 3) if ionized calcium levels are normal at 90 days, there is likely not a need for continued monitoring. As the saying goes, “It ain’t over ‘til the fat lady sings… and the ionized calcium has normalized.”

1. Restrepo R, Inarejos Clemente EJ, Corral G, Mas TR, Fenlon EP 3rd, Jaramillo D. Subcutaneous fat necrosis of the newborn: a pictorial essay of an under-recognized entity. Pediatr Radiol. 2023 Feb;53(2):313-323. doi: 10.1007/s00247-022-05509-1. Epub 2022 Sep 24. PMID: 36151218.

2. Velasquez JH, Mendez MD. Newborn Subcutaneous Fat Necrosis. 2023 May 1. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 32491677.

3. Edafe O, Stenton S, Cohen MC, Beasley N, Carr S. Atypical facial presentation of subcutaneous fat necrosis of the newborn. Ann R Coll Surg Engl. 2021 Jul;103(7):e234-e237. doi: 10.1308/rcsann.2021.0035. PMID: 34192496; PMCID: PMC10334991.

4. Ricardo-Gonzalez RR, Lin JR, Mathes EF, McCalmont TH, Pincus LB. Neutrophil-rich subcutaneous fat necrosis of the newborn: A potential mimic of infection. J Am Acad Dermatol. 2016 Jul;75(1):177-185.e17. doi: 10.1016/j.jaad.2016.02.1151. Epub 2016 May 4. PMID: 27157147.

5. Dhanawade SS, Kinikar US. Subcutaneous Fat Necrosis of Newborn: An Atypical Presentation. Indian J Dermatol. 2022 Mar-Apr;67(2):194-196. doi: 10.4103/ijd.ijd_550_21. PMID: 36092212; PMCID: PMC9455116.

6. Tognetti L, Filippou G, Bertrando S, Picerno V, Buonocore G, Frediani B, Fimiani M, Rubegni P. Subcutaneous fat necrosis in a newborn after brief therapeutic hypothermia: ultrasonographic examination. Pediatr Dermatol. 2015 May-Jun;32(3):427-9. doi: 10.1111/pde.12454. Epub 2014 Dec 10. PMID: 25491115.

7. Schubert PT, Razak R, Jordaan HF. Fine-Needle Aspiration as a Method of Diagnosis of Subcutaneous Fat Necrosis of the Newborn. Pediatr Dermatol. 2016 May;33(3):e220-1. doi: 10.1111/pde.12851. Epub 2016 Apr 29. PMID: 27125326.

8. Harview CL, Chen A, Stone M, Fairley J. Rapid cytologic diagnosis of subcutaneous fat necrosis of the newborn. Pediatr Dermatol. 2023 Mar;40(2):387-388. doi: 10.1111/pde.15194. Epub 2022 Nov 21. PMID: 36411587.

9. Elmoghanni Y, Aldhafer A, Khalaf M, Cipe F, Komala G, Saleem T, Yavuz S. Subcutaneous Fat Necrosis of the Newborn After Whole-Body Cooling for Birth Asphyxia. Cureus. 2023 Feb 1;15(2):e34521. doi: 10.7759/cureus.34521. PMID: 36879717; PMCID: PMC9984657.

10. Andreasen L, Henrik-Nielsen R, Dyring-Andersen B. Subcutaneous Fat Necrosis of the Newborn. JAMA Dermatol. 2022 Jul 1;158(7):812. doi: 10.1001/jamadermatol.2022.1240. PMID: 35507354.

11. Martinelli S, Pitea M, Gatelli IF, Raouf T, Barera G, Vitelli O. Safety and Efficacy of Pamidronate in Neonatal Hypercalcemia Caused by Subcutaneous Fat Necrosis: A Case Report. Front Pediatr. 2022 Apr 28;10:845424. doi: 10.3389/fped.2022.845424. PMID: 35573963; PMCID: PMC9096199.

12. Frank L, Brandt S, Wabitsch M. Subcutaneous fat necrosis in newborns: a systematic literature review of case reports and model of pathophysiology. Mol Cell Pediatr. 2022 Nov 24;9(1):18. doi: 10.1186/s40348-022-00151-1. PMID: 36427118; PMCID: PMC9700527.

13. Del Pozzo-Magaña BR, Ho N. Subcutaneous Fat Necrosis of the Newborn: A 20-Year Retrospective Study. Pediatr Dermatol. 2016 Nov;33(6):e353-e355. doi: 10.1111/pde.12973. Epub 2016 Aug 30. PMID: 27574011.

14. Siegel LH, Fraile Alonso C, Tuazon CFR, Mancini AJ, Kruse LL, Miller JL, Wagner AM, Yun D, Kenner-Bell BM, Paller AS, Chamlin SL. Subcutaneous fat necrosis of the newborn: A retrospective study of 32 infants and care algorithm. Pediatr Dermatol. 2023 May-Jun;40(3):413-421. doi: 10.1111/pde.15219. Epub 2022 Dec 21. PMID: 36544364.

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