Subcutaneous fat necrosis in an infant with hypoxic ischaemic encephalopathy stage 3: an uncommon association

Abstract

Subcutaneous fat necrosis (SCFN) is inflammation and necrosis of adipose tissue associated with hypoxia and hypothermia. It leads to various metabolic abnormalities, of which the most dreaded is hypercalcaemia. We report a case of a 7-week-old boy with history of birth asphyxia (hypoxic ischaemic encephalopathy stage 3) who presented to us with features suggestive of hypercalcaemia with bilateral nephrocalcinosis. On examination, there were multiple subcutaneous nodules on both arms. Evaluation revealed suppressed parathyroid activity along with low levels of 25(OH)vitamin D₃ and elevated 1,25-dihydroxyvitamin D₃. Skin biopsy confirmed the diagnosis of SCFN. He was managed with intravenous fluids, single dose of intravenous furosemide and oral prednisolone. Hypercalcaemia responded within 14 days of admission, prednisolone was tapered and stopped in a month. SCFN, in our case, can be attributed to the underlying perinatal asphyxia along with use of therapeutic hypothermia. Through this case, we wish to sensitise practicing neonatologists for the need of screening and early identification of these abnormalities, which if missed can be fatal.

Background

Subcutaneous fat necrosis (SCFN) is a self-limiting disorder characterised by panniculitis of subcutaneous adipocytes. It has been associated with various metabolic manifestations, the most serious of which is life-threatening hypercalcaemia. It is frequently seen among post-term neonates with history of birth asphyxia or a complicated neonatal course. Associated hypercalcaemia is secondary to extrarenal production of calcitriol (1,25(OH)2D) from subcutaneous adipose tissue, which leads to increased calcium absorption and, subsequently, secondary parathyroid suppression. SCFN secondary to asphyxia and therapeutic hypothermia results in hypercalcaemia which can manifest as severe dehydration, fatal arrhythmias and even death. Presentation of hypercalcaemia can be before the appearance of skin lesions, which makes it imperative to have knowledge about this disorder, not only for early diagnosis and management but also to prevent associated mortality.

Case presentation

A 7-week-old infant was presented to the emergency department with lethargy and three to four episodes of vomiting for the past 2 days and increased passage of urine for the past 1 week. There was no history of loose stools or constipation. The parents denied any history of fever or refusal to feed. He was born to a 38-year-old second gravida mother at term gestation with birth weight of 4 kg (75th centile as per the WHO growth chart) through emergency lower segment caesarean section (passage of meconium in utero). The parents were non-consanguineous. He did not cry at birth and required intubation, chest compressions and epinephrine in the delivery room. The baby was shifted to the Neonatal intensive care unit (NICU) for post-resuscitation care. Apgar scores were 1, 3 and 5 at 1, 5 and 10 min, respectively. First blood gas showed severe metabolic acidosis with lactate 18 mmol/L. Therapeutic hypothermia was started but was prematurely terminated at 48 hours as the child developed severe persistent pulmonary hypertension of the neonate. Inhaled nitric oxide treatment was subsequently started at a dose of 20 ppm. With subsequent improvement in partial pressures of oxygen in arterial blood gas, the dose was gradually reduced as per protocol and tapered over a total duration of 72 hours. He remained on cardiorespiratory support and was successfully weaned to room air on the 10th day of life. Neurological examination was suggestive of hypoxic ischaemic encephalopathy (HIE) stage 3 according to modified Sarnat and Sarnat staging system.¹ The baby had intractable seizures secondary to HIE which were controlled on four antiepileptic drugs. His neurological examination at discharge was abnormal in the form of generalised hypotonia, brisk deep tendon reflexes and absent Moro reflex. He was accepting feeds with bottle though with difficulty. Brain imaging was suggestive of severe hypoxic ischaemic insult, involving almost the entire cerebral cortex. Electroencephalogram revealed burst suppression pattern with no epileptiform discharges. He was regularly followed up at the high-risk clinics and was receiving early stimulation therapy for severe perinatal asphyxia and delayed milestones. The mother denied history of any multivitamin or calcium supplementation. He was receiving 400 IU of vitamin D daily.

During the present episode of illness, the child was severely dehydrated with sunken eyes and poor peripheral pulses at the time of admission. He presented with failure to thrive with observed length of 54 cm (10th–25th centile), weight of 4500 g (25th centile) and head circumference of 35 cm (<3rd centile) as opposed to expected weight, length and head circumference for his age of 58 cm, 5600 g and 39 cm, respectively. There were multiple subcutaneous nodules on both arms which were noticed few days back by the mother. Systemic examination revealed abnormal neurological examination with delayed milestones. His respiratory and cardiovascular system were normal. Abdomen was soft on palpation and bowel sounds were audible.

Investigations

Sepsis screen was normal. Blood and urine culture were sterile. His laboratory parameters have been summarised in table 1 and figure 1. ECG depicted short QT_c interval. Echocardiography was normal. Renal ultrasound was suggestive of bilateral nephrocalcinosis. X-ray of the abdomen was grossly normal. Fluorescent in situ hybridisation (FISH) for 22q11.2 deletion was normal. In view of persistent hypercalcaemia with history of perinatal asphyxia and therapeutic hypothermia, SCFN was suspected and skin biopsy was done. It showed radially arranged needle-shaped crystals and lobular infiltrate of histiocytes and giant cells wedged between fat cells supplementing the clinical diagnosis of SCFN (figure 2).

Table 1.

Overview of the major laboratory examination results at admission and at discharge

Analyte	Results		Reference range (neonatal age)
	Admission	Discharge
Calcium (total), mg/dL	20	9.62	8.5–11
Ionised calcium, mmol/L	1.92	1.1	1–1.25
Phosphate, mg/dL	4.6	4.3	4.5–6.7
Parathyroid hormone, pg/mL	1.90		10–65
Alkaline phosphatase, IU/L	165		100–400
25-Hydroxyvitamin D, ng/mL	14.8		20–100
1,25-Hydroxyvitamin D, pg/mL	105		25–49
Urine calcium:creatinine ratio	2.1	0.76	<0.86
Creatinine, mg/dL	0.43	0.42	0.2–0.4
Urea, mg/dL	120	15	5–25
Vitamin A levels, μmol/L	0.32		0.7–1.5
Serum triglyceride, mg/dL	512		40–175
Platelet count/L	230×109	280×109	150×109 to 450×109

Figure 1.

The X-axis depicts day of admission and the Y-axis depicts total serum calcium (mg/dL).

Figure 2.

Photomicrograph depicting subcutaneous fat lobules with evidence of fat necrosis. There is variable size mature adipocytes with some containing cytoplasm strands, granules and clefts containing needle like crystals (arrow heads) with foci of giant cell reactions (arrows) lymphocytes and histiocytic infiltration (H&E 200x).

Differential diagnosis

Neonatal hyperparathyroidism and related disorders could be ruled out due to decreased parathyroid levels and absence of significant family history. Iatrogenic hypercalcaemia, which is one of the most common causes of infantile hypercalcaemia, was excluded based on absence of history of any exogenous supplementation. Another closely related differential was severe form of idiopathic hypercalcaemia known as William’s syndrome, which is characterised by ‘elfin facies’ present in two-thirds of the affected infants. Biochemical markers associated with it are hypercalcaemia, hypervitaminosis D and supressed parathyroid functions, which were also present in our patient. Normal echocardiography of heart and normal FISH ruled out William’s syndrome in our case. Normal sepsis workup ruled out sclerema neonatorum, which is characterised by wax hardening of the skin with hypercalcaemia.

Treatment

The baby received saline boluses in emergency room at admission in view of significant dehydration following which saline infusion was started in view of hypercalcaemia. Since hypercalcaemia persisted even after correction of dehydration, furosemide was started after 48 hours of admission rehydration. Meanwhile, sonogram of kidneys revealed nephrocalcinosis. So furosemide was stopped after single dose and prednisolone was started in dose of 2 mg/kg/day.

Outcome and follow-up

Serum calcium levels improved following prednisolone administration and became normal on day 10 of admission (figure 1). The baby was discharged after 14 days on oral prednisolone, which was tapered and stopped over a month. Low calcium and phosphate formula was planned but formulation was not available in India. The child is being followed up for more than a year with paediatric nephrologist, endocrinologist and development specialist along with neonatal high-risk clinic. He is thriving well and had no further episodes of hypercalcaemia. He is having normal renal functions with normal blood pressure. Medullary nephrocalcinosis has resolved on serial ultrasonography. He continues to be spastic and is undergoing physiotherapy and occupational therapy for the same.

Discussion

SCFN is a benign disorder seen commonly in post-term newborns with eventful perinatal period characterised by inflammation and subsequent necrosis of subcutaneous adipose tissue. It has been commonly seen in babies with significant birth asphyxia or those who received therapeutic hypothermia.² It leads to the formation of hard reddish-blue nodules seen on the shoulders, arms, back, buttocks and face. Majority of the neonates present within the first 6 weeks of life but it has also been reported up to 6 months of life.³ Index patient was also depressed at birth and required resuscitation, followed by treatment with therapeutic hypothermia and subsequently developed HIE stage 3. There was appearance of skin lesions by the sixth week of life, subsequently the patient presented to us at seventh week with features of hypercalcaemia.

Pathogenesis of the disease has been linked to multiple neonatal and maternal risk factors which ultimately led to impaired tissue perfusion and hypoxic tissue damage.⁴ The hypodermis of neonates have increased amount of saturated fatty acids, which has very high melting point. If exposed to hypothermia, it undergoes crystallisation followed by inflammation and necrosis.⁵ Metabolic abnormalities associated with it are hypertriglyceridaemia, thrombocytopenia, hypoglycaemia and hypercalcaemia, which is the most serious of all. Thrombocytopenia in these patients is due to entrapment of platelets within metastatic calcifications of blood vessels and is rarely symptomatic. Hypertriglyceridaemia is thought to be secondary to mobilisation of fatty acids from adipose tissues. Hypoglycaemia, although rare, has been reported in the literature mostly secondary to associated hypoxia. The index patient had profound hypercalcaemia at presentation along with raised serum triglycerides. However, thrombocytopenia and hypoglycaemia was not observed throughout the hospital stay.

Hypercalcaemia has been observed in 25% of the patients affected with SCFN and is responsible for significant mortality and morbidity.⁴ Pathogenesis of hypercalcaemia has been linked with excess production of calcitriol in the necrotic tissue which enhances intestinal calcium absorption. It has also been postulated that hypercalcaemia is secondary to increased release of calcium from the necrotic fatty tissue along with increased activity of prostaglandin E₂, as observed in these patients. In 90% of babies, hypercalcaemia is detected within 56 days of onset of skin lesions.⁵ In infants presenting with hypercalcaemia post SCFN, 76% had resolution of hypercalcaemia within 28 days of detection.⁵ Most of the affected infants can be asymptomatic as reported by Shumer et al, while the rest present as vomiting, lethargy, polyuria, polydipsia and constipation, and if left untreated, can lead to serious cardiac arrhythmias.⁶ Long-standing profound hypercalcaemia impairs concentrating ability of kidneys manifesting as polyuria. It has also been associated with renal calcification and renal failure.⁷ Index patient presented with symptomatic hypercalcaemia as dehydration secondary to vomiting and polyuria along with ECG changes.

Treatment of symptomatic hypercalcaemia is largely conservative, through adequate hydration and furosemide, which leads to loss of calcium in urine. Further restriction of calcium in diet has been advised. If serum calcium levels do not normalise by these measures, glucocorticoids like prednisolone are indicated.⁸ Nephrocalcinosis is a known complication of severe hypercalcaemia. Few case series report incidence of nephrocalcinosis as high as 83%.⁷ Since long use of furosemide is also associated with nephrocalcinosis in premature babies, we need to be cautious in using furosemide in babies who have hypercalcaemia and nephrocalcinosis. In such cases, correction of hydration and low calcium diet should be followed by use of corticosteroids. Bisphosphonates like etidronate, pamidronate and zolindronate are other treatment modalities in resistant cases of hypercalcaemia secondary to SCFN.^{9 10} In our patient, we used hydration followed by intravenous furosemide. Since sonogram of kidney depicted nephrocalcinosis, furosemide was stopped and prednisolone was started. Hypercalcaemia started to respond after 48 hours of initiation of glucocorticoids, subsequently complete resolution was achieved. Thus, SCFN should be thought of in any neonate with significant hypercalcaemia, and a history of significant perinatal events.

SCFN is an uncommon, benign disorder. However, hypercalcaemia secondary to it can contribute to significant morbidity. Therefore, babies with SCFN should be screened for hypercalcaemia. In 90% of infants, hypercalcaemia presented within 56 days of onset of skin lesions. It is recommended to screen for hypercalcaemia at diagnosis of SCFN and again at 30, 45 and 60 days following resolution of skin lesions.⁵ Skin biopsy is not readily available and is invasive. Typical findings on ultrasound with a history and biochemistry in keeping with SCFN may suffice for diagnosis and histology is not always required.

Patient’s perspective.

I am satisfied with the treatment doctors provide at hospital. My child is under regular follow up and is receiving therapy for developmental problems.

Learning points.

• Subcutaneous fat necrosis (SCFN) can happen in neonates with hypoxic ischaemic encephalopathy either as a result of primary illness or secondary to therapeutic hypothermia.

• Although SCFN is a benign disorder, associated hypercalcaemia can contribute to significant morbidity.

• Intravenous fluids, furosemide and prednisolone are commonly used treatment modalities.

• Babies with hypoxic ischaemic encephalopathy and therapeutic hypothermia should be screened by serum calcium levels in follow-up so that complications could be averted.

Ethics statements

Patient consent for publication

Parental/guardian consent obtained.