The aim of this systematic review was to identify published cases of diagnosed SCFN in newborns in the literature, to summarise the described clinical feature, to identify risk factors for the development of SCFN and to summarise hypotheses of pathophysiology. We screened n = 2.255 publications. N = 206 publications were finally included in our analysis. In these, n = 320 cases of newborns with SCFN were described. We have observed that (1) there were no gender differences in diagnosis of SCFN in newborns, (2) the typical skin lesions of SCFN appear usually 1 week after birth and were localized especially on the back, shoulders, cheeks and proximal limbs, (3) in most of the cases of newborns with SCFN, mothers reported GDM, hypertension or preeclampsia during pregnancy, (4) approximately 10 days after the presence of typical skin lesion of SCFN, altered serum calcium concentrations were described and 45.6% of the newborns with SFCN developed a hypercalcaemia (independent from PTH in 18% of the cases), (5) most of the skin lesions healed without complications within 3 months, (6) in those newborns with SCFN and with hypercalcaemia it has been observed that there was a longer duration of pregnancy, a higher birthweight, bigger skin lesions, more concomitant symptoms and a longer course of disease compared to newborns with SCFN and with normal serum calcium levels, (8) in 14.7% of the newborns with SCFN long-term consequences have been described.
Gender differences in diagnosis of SCFN
Our observation of equal distribution of sex in newborns diagnosed with SCFN is consistent with previous findings from literature [18, 19]. This observation indicated a sex-independent pathophysiological mechanism for the development of SCFN.
Relationship between maternal metabolic factors and SCFN in newborns
In the majority of the published cases of newborns with SCFN, the mother reported GDM, hypertension or preeclampsia during pregnancy. This is in line with literature, where it has been shown that the pregnancy metabolic complications such as GDM and hypertension or preeclampsia were significantly more frequent in mothers of children with SCFN compared to the total complications of pregnancy in the normal population (GDM 14.4 vs. 5.4%, hypertensive pregnancy diseases: 18.2 vs. ≤ 8%) [20, 21].
As a consequence of GDM, the fetus experiences an increased insulin secretion. This can lead to an increase in the amount of foetal adipose tissue and thus in an increase in the birth weight [22]. In the presented systematic review, n = 74 newborns (33.9%) with later diagnosed SCFN had birth weights > 4000 g or were explicitly described as macrosomia. This is in line with literature, where it has been described that the incidence of macrosomia in neonates with SCFN was higher than in the general population (33.9 vs. < 10%) [23, 24]. It is assumed that a birth weight > 4000 g is related to an increased mechanical pressure at birth and an associated hypoperfusion of the tissue [25].
It is supposed that a placental insufficiency, caused by hypertensive pregnancy complications, is the link between hypertension or preeclampsia during pregnancy and the development of SCFN in newborns. Placental insufficiency is associated with an increased risk of poorer foetal outcome, which includes a higher risk for the occurrence of birth complications [8, 26].
Relationship between birth complications and SCFN
42.2% of the described birth complications in newborns with SCFN (asphyxia, respiratory weakness, HIE, hypoxaemia, infection or sepsis, peripheral cyanosis, hypotension, anaemia, foetal distress, bradycardia) were related to peripheral tissue hypoxia. For 37.9% of the newborns with SCFN it has been described that a therapeutic intervention in the form of resuscitation and therapeutic hypothermia after birth was conducted. It is assumed that a peripheral oxygen depletion occurred in these infants because of the indication for the intervention or because of the intervention itself. It is hypothesised that an oxygen depletion leads to hypoxia and that a hypoxic cell damage promotes the necrosis in skin lesions [2]. Figure 3 summarizes the possible causes and influences leading to the hypoxic cell damage in the context of SCFN in the newborn.
Localisation of SCFN in newborns
In the case reports evaluated in the present review, the characteristic skin lesions of subcutaneous adipose tissue necrosis were most frequently on the back, buttocks, cheeks and proximal extremities. It is hypothesised that there is a relationship between the location of SCFN and the areas in which primary brown adipose tissue is localized in neonates. In the newborn, brown adipose tissue is localized interscapular (diamond-shaped), in the neck, infraclavicular and axillary, along the intercostal arteries, esophageal and tracheal, around large vessels, surrounding the kidneys and adrenal glands, and on the posterior abdominal wall [27,28,29]. Ichimiya et al. examined biopsy material from two children with SCFN from the affected skin sites. Immunohistochemical staining with antibodies against UCP-1, a protein specific for brown adipose tissue, demonstrated the presence of brown adipose tissue within the necrotic tissue [5]. But within the here presented systematic review, the affected skin areas of SCFN were only in 34.5% of all cases in areas for which the presence of brown adipose tissue has been described.
Age of onset and size of skin lesion typical for SCFN in newborns and duration until electrolyte disturbances were detected
For the majority of newborns with SCFN the presence of typical skin lesions has been described within the first week of birth. The presence of typical skin lesions for SCFN on a later time point has only been reported in newborns with SCFN and with diagnosed hypercalcaemia. The latest time point of presence of typical skin lesions for SCF has been reported at day 70 after birth. In 98% of the newborns with SCFN the associated electrolyte disturbance occurred within a period of 5 months. This observation is in line with a previous work, which described that electrolyte alterations in newborns with SCFN were obtained within the first 6 months [30]. In 70.5% of the newborns with SCFN and for which serum calcium levels have been reported, a hypercalcaemia has been described. In previous case reports and reviews of cases of newborns with SCFN, the frequency of hypercalcaemia has been reported in the range between 25 and 69% [18, 19]. The diagnosis of hypercalcaemia was described at a median of 10 days after the presence of typical skin lesion of SCFN. Since the presence of a hypercalcaemia is rare in neonates [31], this electrolyte disturbance seems to be related to SCFN in newborns. Interestingly, the time between the presence of typical skin lesions of SCFN and the diagnosis of an altered serum calcium level was shorter in the group of patients with SCFN and hypocalcaemia than in the group of patients with SCFN and hypercalcaemia. The evaluation of the size of the skin lesions showed no correlation with serum calcium levels newborns with SCFN. However, there is a tendency for larger lesions in the group of patients with hypercalcaemia compared to all other patients. Furthermore, we observed that the presence of a hypercalcaemia in newborns with SCFN is related to prolonged course of the disease, compared to newborns with SCFN and normal serum calcium levels. One hypothesis is, that this prolonged disease course is related to the tendency of larger skin lesions in newborns with SCFN and hypercalcaemia. It is assumed, that the size of skin lesion correlates with the extent of inflammation and the resulting immune response [10, 32, 33]. Since we observed in a subgroup of patients with reported levels of serum 1,25(OH)2D3 and parathyroid hormone (PTH) that the majority of these patients showed a suppressed PTH level, independent of serum 1,25(OH)2D3 levels, a PTH-independent but immune-stimulated hypercalcaemia is assumed.
Relationship between serum calcium level and calcifications in newborns with SCFN
In the presented systematic review, n = 70 newborns with SCFN showed calcifications, of which 84.3% were in the subgroup of newborns with SCFN and hypercalcaemia. 37.1% of the described calcifications were directly in the necrotic skin area and 47.4% were present in form of nephrocalcinosis/nephrolithiasis. Calcifications that occurred outside subcutaneous tissue were found exclusively in the group of newborns with SCFN and diagnosed hypercalcaemia. 58.7% of renal calcifications were still persistent at the last follow-up visits, without concomitant impairment of renal function. Retrospectively, patients with persistent nephrocalcinosis had the highest serum calcium levels. Calcifications in various tissues are a frequent complication of hypercalcaemia [34]. We assume that calcifications in subcutaneous tissues arise primarily from a local process that is probably triggered by the necrosis itself.
Relationship between the duration of the symptoms of SCFN and serum calcium levels
Within the presented systematic review, we observed that the duration of the symptoms of SCFN ranged between 14 and 365 days. We identified a dependency of duration of symptoms from measured serum calcium levels in newborns with SCFN. The duration of symptoms of SCFN was similarly in the group of newborns with SCFN with normal serum calcium levels and those with a hypocalcaemia, but was longer in newborns with SCFN and diagnosed hypercalcaemia. The longest described duration of symptoms in the amount of 365 days has been described in a patient with SCFN associated hypercalcaemia [35]. It is assumed that the presence of a hypercalcaemia in newborns with SCFN is a risk factor for a longer course of the disease. As we described before, newborns with SCFN and diagnoses hypercalcaemia tend to larger skin lesions. We hypothesise that a longer duration of symptoms in these patients could related to the larger size of skin lesion.
Therapy of SCFN-associated hypercalcaemia
Sixty percent of the newborns with SCFN with diagnosed hypercalcaemia were treated by i.v. fluid substitution, administration of loop diuretics and glucocorticoids. Other patients received a low-calcium/low-vitamin D diet. In 20% of the newborns with SCFN with diagnosed hypercalcaemia a bisphosphonate therapy was introduced. This form of therapy has primarily described for newborns with a severe form of hypercalcaemia [36,37,38]. To sum up, the treatment of a hypercalcaemia in neonates includes a low calcium/vitamin D diet, discontinuation of calcium/vitamin D, i.v. hydration and the use of loop diuretics (e.g. furosemide). In addition, glucocorticoids or bisphosphonates can be used [31].
Long-term consequences of SCFN
Long-term consequences have been identified in this systematic review in one of four newborns with SCFN. These long-term consequences include scars at the affected skin sites and persistent nephrocalcinosis. N = 13 infants died during the course of the disease, but in 60% of these the cause of death was not related to SCFN and in the remaining n = 5 infants, the cause of death remained unclear. However, it must always be taken into account when interpreting these observations that persistent calcifications are associated with the higher serum calcium concentrations in newborns within the course of the disease. As we have discussed in the section before, an early identification of altered serum calcium levels and the initiation of the treatment of increased serum calcium level may reduce the risk of persistence calcifications. The results of this work suggest that calcifications in subcutaneous tissues are mainly due to a local process that is probably triggered by necrosis itself. However, calcifications outside the subcutaneous tissue occurred only when there was a systemically effective elevation of serum calcium levels.
Discussion of possible pathomechanisms for the development of the SCFN in newborns
Mechanical compression as a cause of SCFN
In individual cases, skin lesions at sites that could be associated with a local traumatic event have been described in the literature [4]. In addition, shoulder dystocia during delivery was reported in several infants reported and their skin lesions subsequently appeared in the neck, shoulders, axilla, sites that may be consistent with the presence of shoulder dystocia [39,40,41]. However, because subcutaneous adipose tissue necrosis also occurs in infants without shoulder dystocia at the same sites, no causal relationship between a possible mechanical compression and the occurrence of the disease.
Therapeutic hypothermia as a cause of SCFN in newborns
In the literature, the implementation of therapeutic hypothermia in newborns is discussed as an important risk factor for the development of SCFN [14, 42]. During therapeutic hypothermia, the body temperature is lowered to a target temperature of 33.5 ± 0.5 °C (rectal) for a period of 72 h [33]. As a result of the physiological response to a cold stimulus, blood flow is redirected from the periphery to the vital organs [16, 17, 43]. It is assumed that the associated hypoxia in the skin leads to necrosis of adipocytes [14, 42]. The maintenance of this metabolism can only be ensured by an increase in perfusion. But it remains questionable whether the fall in temperature alone is sufficient to induce a great difference in oxygen demand and perfusion that is related to hypoxic cell damage in the adipocytes. We assumed rather that there is an interplay with other risk factors for the development of SCFN, such as the birth complications or macrosomia at birth.
Furthermore, an important role of the brown adipose tissue is discussed. Both, in animal models and in humans, it has been shown, that an exposure to a cold environment is related to an activation of thermogenesis in brown adipose tissue [27, 44, 45], to an increased glucose uptake into the brown adipocytes [46, 47], to an increased oxygen demand [12], and to an increase in perfusion [46, 48]. These findings suggest that the metabolism within the brown adipose tissue increases with a decrease in external temperature. In contrast, only in 34.5% of all patients SCFN appeared in locations, where brown adipose tissue has been detected before.
Furthermore, it is assumed that the use of therapeutic hypothermia is associated with a resolution of crystallisation of fat within adipocytes. A higher melting point of the subcutaneous adipose tissue of the neonate compared to adults due to the altered fatty acid composition is assumed to increase the risk of crystallisation. The adipose tissue of the newborn has a higher proportion of saturated fatty acids compared with the adipose tissue of adults [49, 50]. It is assumed that a lowering of the temperature, for example by therapeutic hypothermia in the subcutaneous adipose tissue is related to an easier crystallisation of the neonatal adipose tissue due to the higher melting point. The development of the melting temperature of fat was also studied by Channon and Harrison [3]. They showed an decrease of the melting temperature of fat with increasing age [3]. They also compared the adipose tissue of children with sclerema neonatorum, a disease which also belongs to the group of panniculitides, with adipose tissue of healthy children of the same age. Thereby, the children with sclerema neonatorum showed a higher melting temperature and a higher content of saturated fatty acids in the adipose tissue than healthy children of the same age [3]. Comparing the data of a neonate with SCFN with the data on fatty acid proportions in subcutaneous adipose tissue in adults [51], the diseased neonate shows a significantly higher proportion of saturated palmitic acid (48.4% versus 21.4% in adults) and a significantly lower proportion of unsaturated oleic acid (29.1% versus 38.2% in adults). The observations from this case report support the notion that there may be a relationship between the composition of neonatal subcutaneous adipose tissue and the development of the disease.
Discussion of pathomechanisms for the development of a hypercalcaemia in the presence of SCFN in newborns
Extrarenal vitamin D formation as a cause of hypercalcaemia
Within the presented systematic literature review, we observed that 89.3% of newborns with SCFN and with reported data on serum 1,25(OH)2D3 and on parathyroid hormone (PTH) had a suppressed PTH level, independent of the serum 1,25(OH)2D3 level. A PTH-independent hypercalcaemia is assumed. Within literature an extrarenal 1,25(OH)2D3 formation as a trigger for the elevation of serum calcium levels in newborns with SCFN is discussed [10, 32, 52]. The formation of the active 1,25(OH)2D3 (calcitriol) from its biologically inactive form 25OHD3 (=calcidiol) occurs by hydroxylation by the enzyme 25-hydroxyvitamin D3-1α-hydroxylase (1α-hydroxylase). The enzyme 1α-hydroxylase belongs to the group of CYP-450 enzymes [37] and is primarily expressed in the epithelial cells of the proximal renal tubule [6, 53, 54]. The physiological function and regulation of renal 1α-hydroxylase is characterised by the PTH-dependent stimulation and by a negative feedback mechanism through its own reaction product, 1,25(OH)2D3. This negative feedback mechanism is thereby mediated via nuclear vitamin D receptors (VDR) [55]. Since subcutaneous adipose tissue necrosis presents both, the histological picture of a granulomatous disease and a high risk of hypercalcaemia, a similar pathomechanism as in other granulomatous diseases (e.g. sarcoidosis or tuberculosis) is assumed [53]. Extrarenal expression of 1α-hydroxylase has been demonstrated in various patients with granulomatous diseases [7, 56, 57]. Farooque et al. [52] investigated the expression of 1α-hydroxylase in skin samples from two patients with histologically confirmed diagnosis of SCFN. He was able to demonstrate very strong expression of 1α-hydroxylase in the inflammatory infiltrate of subcutaneous adipose tissue necrosis in both cases. A crucial role seems to be played by the lack of feedback mechanisms in peripheral macrophages, triggered by the antagonistic effect of γ-interferon on 1,25(OH)2D3 effects at the level of mRNA (messenger RNA) synthesis in cells [26, 58]. The peripheral form of 1α-hydroxylase is mainly subject to immunoregulatory processes through IFN- γ and IL-2. Both IFN- γ and IL-2 contribute as cytokines to the development of granulomatous reactions by stimulating cell differentiation from macrophages to epithelioid and foreign body giant cells [59]. For many years, the literature has considered an exuberant reaction with an accumulation of T helper cells as a possible cause of sarcoidosis [60]. Ramstein et al. [61] recently described an increased transformation of Th17 cells to Th17.1 cells. They also demonstrated that Th17.1 cells are a major source of IFN-γ produced in sarcoidosis patients. It is assumed that also in patients with SCFN, the specific differentiation of certain T helper cells serves as a source of IFN-γ, leading to stimulation of peripheral 1α-hydroxylase.
The degradation of 1,25(OH)2D3 occurs by the enzyme 24α-hydroxylase to its inactive metabolite 24,25(OH)2D. This reaction step is stimulated by the increase in 1,25(OH)2D3, ensuring a constant 1,25(OH)2D3 level in plasma [56]. Bahadur et al. [32] observed elevated 1,25(OH)2D3 levels in their patient with SCFN concomitant with low levels of the inactive degradation product 24,25(OH)2D. They concluded an impaired degradation by the enzyme 24α-hydroxylase, which is encoded by the gene CYP2A41 [62]. The observations made in this patient support the findings of Vidal, Ramana and Dusso [63] who described the mechanism of decreased transcription of 24α-hydroxylase. It seems that there is a direct protein-protein interaction between the transcription factor STAT1 and the vitamin D receptor, preventing binding to the associated vitamin D response element (VDRE) and, as a consequence, no transcription of 24α-hydroxylase [63]. Assuming that the enzymatic regulatory mechanisms within the vitamin D balance is the same in SCFN as in other granulomatous diseases, it can be assumed that the increase in serum 1,25(OH)2D3 levels is the result of increased expression of the peripheral form of 1α-hydroxylase with concomitant decreased expression of peripheral 24α-hydroxylase.
Direct calcium release from the necrotic skin areas
Several authors suggest that in newborns with SCFN and associated hypercalcaemia, there is a direct release of calcium from the necrotic skin areas [9, 43, 63]. Due to the results of this review that there could not be found a correlation between the size of skin lesion and serum calcium level, this hypothesis does not seem to be the main cause of hypercalcaemia.
Methodological strengths of the work
A strength of this work lies in the systematic execution of the literature search following the guidelines of the PRISMA statement [64]. In the selection of literature databases, emphasis was placed on a close reference and the largest possible collection of publications on medical topics in order to obtain the largest possible number of hits. Thus, the search could be reproduced in n = 5 of the n = 6 databases searched. However, the use of the online search engine Google-Scholar cannot be compared to the other databases in terms of reproducibility, as search algorithms may change here over time, leading to different results. Because of the size of this database and the goal of identifying all case reports published to date, the online search engine was included despite its weakness. Regarding the search terms used, it should be noted that their selection before the actual search procedure may have resulted in reduced sensitivity. Thus, it cannot be ruled out that a limitation of the number of hits resulted from the search terms used and the application of a Boolean operator. Another strength of this study is the comparison of a large patient collective. In previous literature, only case series of up to n = 17 patients have been published. Thus, the amount of data generated here is clearly superior to previous publications in this regard and may thus provide new insights. Furthermore, no comparison of data depending on concomitant electrolyte disturbance has been published in the literature so far. The division into subgroups depending on the reported serum calcium level performed here aimed to identify possible risk factors favouring the occurrence of such an electrolyte disturbance. The systematic literature search was followed by the selection of studies to be included in this work. Two consecutive screening steps were performed. This was to ensure the most specificity of the included studies was achieved.