Keywords hypercalcemia - subcutaneous fat necrosis - zoledronic acid - neonate
Subcutaneous fat necrosis (SCFN) of neonates is a rare condition whose exact incidence
is unknown, affecting infants born at term or postterm in the very first weeks of
life. Major clinical features include firm, circumscribed, subcutaneous, flesh-colored-to-blue
nodules and plaques on the trunk, buttocks, thighs, arms, and cheeks. Prognosis is
good, with complete regression within a few weeks. The main acute complications are
dyslipidemia and thrombopenia, as well as hypercalcemia that may be severe and life-threatening.
The pathophysiology of SCFN remains unknown. The most common hypothesis is that systemic
or local conditions might induce subcutaneous hypoxemia and adipocyte necrosis. Predisposing
factors for this condition include maternal diseases (such as gestational diabetes,
preeclampsia, and exposure to cocaine or calcium blocker during pregnancy) and neonatal
conditions (such as hypothermia, infections, hypoxemia, cutaneous trauma, cord accidents,
meconium aspiration, anemia, and thrombocytosis).[1 ]
[2 ]
Case Presentation and Treatment
We describe a classic presentation of SCFN with hypercalcemia refractory to standard
treatment. Our patient was a full-term female infant, adequate for gestational age , born through emergency cesarean section due to fetal bradycardia. Her Apgar scores
at 1, 5, and 10 minutes were 5, 7, and 9 respectively. The baby at birth required
ventilatory support and was referred to the local NICU. She was hypotensive and anemic
(Ht 20%), requiring intravenous (IV) bolus administration of fluids and inotropes
(dopamine) as well as red blood cell transfusion.
When she was 3 weeks old, she was readmitted for failure to thrive and hyporexia.
On admission, the infant weighed 3,030 g (3rd percentile), and her length and her
head circumference were also at the 10th percentile. Her vital signs were normal;
her examination revealed hypotonia and lethargy. Laboratory tests are presented in
[Tables 1 ] and [2 ]
. Notably, the serum calcium level was 16.6 mg/dL (8.6–10.2 mg/dL). A renal ultrasound
disclosed dense medullary nephrocalcinosis ([Fig. 1 ]).
Fig. 1 Bilateral medullary nephrocalcinosis (renal ultrasound).
Table 1
Overview of the major laboratory exams results at admission and at discharge
Analyte
Results
Reference range (neonatal age)
Admission
Discharge
Calcium, mg/dL
16.6
10.1
8.6–10.2
Phosphate, mg/dL
5.0
4.3
4.5–6.7
Parathyroid hormone, pg/mL
3.11
10–65
Alkaline phosphatase, IU/L
151
100–400
25-Hydroxyvitamin D, ng/mL
50.4
36.8
20–100
Creatinine, mg/dL
0.6
0.4
0.2–0.4
Urea, mg/dL
14
9
5–25
Urine calcium:creatinine ratio
2.6
0.85
<0.86
Table 2
Daily trends of calcium serum and urine levels
Weeks of life
Serum calcium, 8.6–10.2 mg/dL
Urine calcium:creatinine ratio
< 0.86
3.5
16.6
3.6
15.4
4.1
13.7
4.2
1.03
4.3
2.61
4.4
11.0
5.2
1.13
5.4
12.4
2.1
5.5
13.4
5.6
14.4
6.0
15.1
1.49
6.1
11.6
6.2
9.5
0.85
During the second week of hospitalization, the infant developed indurated, erythematous
plaques on her left arm, back, and cheeks. Plaque's size varied from several millimeters
to 2 cm ([Figs. 2 ] and [3 ]).
Fig. 2 A 3-week-old infant with lesions of subcutaneous fat necrosis located on the left
arm, back, and cheeks.
Fig. 3 Subcutaneous fat necrosis on the left arm of the same infant.
A diagnosis of SCFN was made based on hypercalcemia and the finding of subcutaneous
nodules.
Hypercalcemia was managed with intravenous infusions of fluids and treatment with
furosemide, leading to transient normalization of calcium levels. Despite the therapy,
on the second week of hospitalization, total calcium was elevated (14.4 mg/dL). Treatment
with methylprednisolone (IV) (4 mg/kg/24 hour) was then started, but the calcium level
increased (15.1 mg/dL); therefore, we administered a single low dose of zoledronic
acid (0.025 mg/kg single dose) ([Fig. 4 ]). Subsequently, the patient's calcium level rapidly decreased from 15 to 9.5 mg/dL.
IV fluid therapy was stopped and methylprednisolone was tapered over the next week.
Fig. 4 Serum calcium levels and treatment.
The clinical patient's conditions normalized; the subcutaneous nodules progressively
decreased in size and then completely resolved at discharge. The renal findings suggestive
of nephrocalcinosis improved over time.
Despite that she was fed a standard infant formula, no other zoledronic acid administration
was needed. She was discharged on the seventh week of life with regular follow-up.
Discussion
SCFN is an inflammatory disorder of adipose tissue, usually occurring in full-term
healthy infants who have a history of intrauterine or perinatal distress. Ischemic
injury, hypoxia, or hypothermia can damage the subcutaneous adipose tissue, causing
fat to crystallize in necrotizing granulomas. SCFN is characterized by multiple indurated
plaques or nodules with or without erythema on the cheeks, buttocks, posterior trunk,
and extremities, which develop within the first weeks of life. SCFN usually is a self-limiting
process that progresses toward resolution in a period ranging from few weeks to 6
months, with lesions evolving into fibrotic scars with fat atrophy. This disease very
rarely leads to cutaneous sequelae; however, complications can be severe and require
pharmacological treatment.[3 ] The main clinical differential diagnosis is with sclerema neonatorum, which appears
in preterm, ill infants as a diffuse, white and yellowish, woody induration that rapidly
involves almost entirely the body surface except the palms, soles, and genitals, and
yields poor prognosis.[4 ] Erythema nodosum also has to be considered in the differential diagnosis; this is
a septal panniculitis, with little fat necrosis of the lobules and no crystals.[3 ]
Although SCFN of the newborn is often benign and self-limiting, the most important
complication is hypercalcemia (defined as total serum calcium > 10.8 mg/dL or ionized
calcium > 5.4 mg/dL), which can lead to neurologic or cardiac problems, nephrocalcinosis,
and nephrolithiasis.[5 ] Typically, hypercalcemic neonates are asymptomatic, but very high calcium levels
(>12,8 mg/dL) can cause lethargy, irritability, hypotonia, constipation, vomiting,
poor feeding, failure to thrive, and hypertension.[6 ] Hypercalcemia can significantly reduce urinary concentrating capacity, producing
polyuria; renal failure and dehydration may also occur. Hypercalcemia may be fatal
if unrecognized, with the development of seizures and ultimately cardiac arrest.[3 ]
[6 ]
In neonates, severe hypercalcemia occurs rarely and may be determined by iatrogenic
vitamin D intoxication or excessive calcium supplementation, granulomatous disease,
SCFN of the newborn, Williams' syndrome, and hyperparathyroidism.
Laboratory work-up for neonatal hypercalcemia should include phosphate, alkaline phosphatase,
25-hydroxyvitamin D, and parathyroid hormone measurement. If the diagnosis remains
unclear, blood samples for 1,25-dihydroxyvitamin D and DNA analysis (calcium-sensing
receptor and elastin genes) should be stored for later testing if necessary. Urine
calcium, phosphate, and creatinine levels can help determine whether the kidneys are
inappropriately retaining calcium, and a renal ultrasound should be performed if hypercalcemia
is persistent and severe.[6 ] Infants with SCFN typically have low parathormone levels with elevated 1,25-hydroxyvitamin
D levels, but 1,25-hydroxyvitamin D levels may occasionally be normal. Granulomatous
lesions, similar to sarcoidosis, can increase 1-hydroxylase activity, with increased
extrarenal production of 1,25-hydroxyvitamin D. Local inflammation may increase production
of bone-resorbing prostaglandin E, which, in turn, may lead to osteoclast activation.[7 ] Skin lesions typically resolve over a period of weeks to several months; however,
hypercalcemia can persist longer and requires continuous monitoring.
Management of neonatal hypercalcemia spans from conservative measures, such as IV
fluid therapy and restriction of vitamin D and calcium, to more aggressive interventions,
such as administration of furosemide, glucocorticoid, or bisphosphonate in severe
cases.[5 ]
Currently, the evidence in literature is scarce and does not allow to perform any
meta-analysis in this area. There is a lack of evidence coming from randomized controlled
studies, as recently pointed out in a comprehensive review that included only case
series and case reports.[8 ]
Several studies have reported so far the use of bisphosphonate products to manage
severe neonatal hypercalcemia. Use of pamidronate was reported by Samedi et al in
two infants with severe hypercalcemia associated with SCFN following therapeutic hypothermia
for hypoxic–ischemic encephalopathy.[9 ] Alos et al described four newborns presenting in the years 2001 to 2004 with severe
hypercalcemia complicating SCFN. These patients were given three to four doses (0.25–0.50
mg/kg/dose) of pamidronate following unsuccessful treatment with IV fluids, low calcium
diet, and furosemide. Urinary calcium/creatinine ratios and calcium levels decreased
within 48 to 96 hours. 1,25-dihydroxyvitamin D levels normalized with the resolution
of the skin lesions, and no persistent nephrocalcinosis was observed.[10 ] Pérez Martínez et al provided further evidence of etidronate as an alternative and
effective treatment for moderate-to-severe hypercalcemia.[11 ] Trullemans et al reported the case of a patient presenting with symptomatic hypercalcemia
complicated by nephrocalcinosis consecutive to SCFN after birth asphyxia at term.
Oral etidronate was then used for 3 weeks after failure of standard treatment, and
the evolution was favorable.[12 ] As for safety, it is worthy to mention that hypersensitivity reactions to etidronate
(rashes) have been occasionally described.[13 ]
Zoledronic acid is a third-generation bisphosphonate with a 100- to 200-fold higher
potency than pamidronate. Similar to other bisphosphonate products, zoledronic acid
inhibits osteoclast function and thus bone resorption. With its short infusion time
and the need for infrequent infusions, zoledronic acid has potential advantages over
pamidronate in the management of pediatric disease. It has been shown that reductions
of the starting dose of zoledronic acid may result in decreased incidence of postinfusion,
rebound hypocalcemia, thus improving safety. In addition, dosages tailored to the
body mass index or body surface area, instead of body weight, may further reduce the
incidence of rebound hypocalcemia.[14 ] In the literature, only scattered experiences have been reported so far on the use
of zoledronic acid in neonates. Di Bari et al treated an infant affected by SCFN and
whose serum calcium levels were extremely high (15 mg/dL) with prednisolone and low-dose
zoledronic acid. Serum calcium promptly normalized without rebound hypocalcemia, and
redosing of zoledronic acid was not necessary.[7 ]
Our report deserves attention for several reasons. First, we were able to manage very
high serum calcium levels that could have been fatal since the routine standard treatments
had not been effective. Second, we report on a novel use of a third-generation bisphosphonate
that proved to be rapidly effective with a schedule comprising only a single low dose,
with overall good tolerability. We acknowledge some limitations of this study, with
the main one being that ours is a case report study from a single center. Since SCFN-related
severe neonatal hypercalcemia is a rare condition, it seems difficult to get a numerically
significant sample to conduct a study providing higher levels of evidence.
Conclusion
Severe neonatal hypercalcemia following SCFN requires a prompt identification and
an effective treatment to prevent serious complications and death. Our case shows
how a single, low dose of zoledronic acid was effective in treating severe hypercalcemia
unresponsive to conventional treatments while minimizing the risk of rebound hypocalcemia.
Funding
None.
