The cause of severe hypercalcaemia resistant to pamidronate treatment: subcutaneous fat necrosis with no visible skin lesion

Abstract

Subcutaneous fat necrosis (SCFN) is an uncommon cause of neonatal hypercalcaemia. It is usually seen in neonates after a complicated delivery within the first month of life. While uncommon, hypercalcaemia can be fatal. It is characterised by red-purple plaques in fatty points along with firm subcutaneous nodules. Rarely, SCFN may cause severe hypercalcaemia with no visible skin lesion. In this rare case, we report severe infancy hypercalcaemia without characteristic skin lesion on first physical examination, unresponsive to hydration, diuretic, prednisolone and standard dose of pamidronate treatment. As timely diagnosis and treatment are so important, this complication should be kept in mind even in such clinical presentations.

INTRODUCTION

Hypercalcaemia in infants is defined as total serum calcium levels above 11.30 mg/dl (2.8 mmol/l) [1]. The clinical manifestation may be failure to thrive with arrested weight gain. In moderate hypercalcaemia (total serum calcium level 12-13.5 mg/dl) polyuria, generalized weakness, constipation, and anorexia are commonly present. In severe hypercalcaemia (total serum calcium >13.5 mg/dl) nausea, vomiting, encephalopathic features, including coma and seizure and dehydration may occur [2].

Subcutaneous fat necrosis (SCFN) is a rare panniculitis in the neonatal period and usually present with skin lesions characterised by endured, erythematous plaques and nodules on the back, hips, cheeks and extremities. Factors that cause impaired placental circulation such as gestational diabetes, preeclampsia, calcium antagonists during pregnancy, smoking, cocaine use, perinatal complications such as birth trauma, meconium aspiration, hypoglycaemia, asphyxia, hypothermia and sepsis are major risk factors [3].

Pamidronate has been utilised as a medication for infants with resistant hypercalcaemia that do not benefit from hydration, systemic steroids and diuretics. There are just a few reports in the literature concerning the use of bisphosphonates in the treatment of SCFN-related hypercalcaemia [4]. We report an infant with SCFN who presented with severe symptomatic hypercalcaemia and nephrocalcinosis, and that was fortunately treated with two infusions of high dose pamidronate.

CASE REPORT

The first child of the family without consanguineous marriage was delivered by caesarean section, weighing 4.700 g. The neonate was followed-up at the neonatal intensive care unit with the diagnosis of hypoglycaemia and transient tachypnoea of the newborn. His mother was treated for gestational diabetes and hypothyroidism. The infant was brought to the hospital for poor sucking and restlessness on postnatal 32nd day. Based on physical examination, he had no weight gain after birth weight and he was heavily dehydrated, body temperature was 37.5°C, pulse rate was 182 beats/minute and respiration rate was 58 breaths/minute, blood pressure was 64/33 mmHg (3th percentile /49th percentile). In the laboratory tests, Calcium (Ca): 20.6 mg/dl, Phosphate (P): 4.7 mg/dl, magnesium (Mg): 1.4 mEq/l, parathyroid hormone (PTH): 1 pg/ml, alkaline phosphatase (ALP): 89 IU/l, 25-hydroxy vitamin D: 30 ng/ml, spot urine calcium/creatinine ratio: 1.8 and blood gas parameters were within the normal range (Table 1). For hypercalcaemia treatment, additional 200 ml/kg/day supplementation was added to breast milk followed by 2 mg/kg/day intravenous furosemide and 2 mg/kg/day intravenous methylprednisolone. When the infant’s control serum calcium level was detected as 17.4 mg/dl, pamidronate 1 mg/kg/dose was added intravenously to the treatment.

Table 1.

Age, laboratory values and treatment.

Age	1 day	3 day	32 day	33 day	34 day	35 day	36 day	37 day	40 day	59 day
Serum calcium (mg/dl)	9.7	8.8	20.6	17.4	16	16.8	12.3	10.9	9.5	10.6
Ionized calcium (mmol/l)		1.13	2.56
Phosphate (mg/dl)		6.6	4.7	3.7	3.2	3.8	2.5	2.9	3.7	6.2
ALP (IU/l)		123			103				126	302
PTH (pg/ml)			1	1	0				56	48.6
Creatinine (mg/dl)	1.16	0.9	0.97			0.67
25-hydroxy vitamin D (ng/ml)			30							29
Urine calcium/creatinine ratio			11/6		10.2/6				0.8/8
Prednisone (mg/kg/day)			2	2	2	2	1	1	-	-
Furosemide (mg/kg/day)			2	2	2	2	1	-	-	-
Pamidronate (mg/kg/dose)				1		1

In the first physical examination for the aetiology of hypercalcaemia, there was no skin finding of SCFN, and a 2.5 × 1 cm nodule under the left scapula was realized with careful palpation two days later (Figure 1). Ultrasonography showed an 8 mm calcific focus which is consistent with inflammation. Additionally increased echogenicity and thickness in left scapula subcutaneous adipose tissue were showed on ultrasonography (Figure 2). Renal ultrasonography demonstrated medullary nephrocalcinosis in both kidneys (Figure 3). Skin biopsy could not be performed, because the family did not give consent. The diagnosis of SCFN became clear with clinical examination and ultrasonographic findings. In spite of hydration, furosemide, methylprednisolone and high-dose pamidronate treatments, the infant was considered to have resistant hypercalcaemia by finding serum calcium level of 16.8 mg/dl on the fourth day of hospitalization, and pamidronate was re-administered intravenously as infusion at 1 mg/kg/dose and finally with Ca:10.9 mg/dl on the sixth day of treatment. He was discharged with the suggestion that he should not use 400 IU/day vitamin D which he was taking, to continue breastfeeding and to come to the outpatient clinic.

Figure 1.

Nodular lesion under the right scapula detected with careful palpation.

Figure 2.

Calcific focus with an approximately 8 mm diameter hypereoic shadow on the posterior ultrasound.

Figure 3.

Bilateral nephrocalcinosis on ultrasonography.

Discussion

Hypercalcaemia is defined as a serum calcium concentration higher than two standard deviations above the normal mean, which varies by age and gender and follows changes in the normal physiology at all developmental stages. Severe neonatal hypercalcaemia is an uncommon condition and can be caused by iatrogenic vitamin D intoxication or extreme calcium supplementation, hyperparathyroidism and SCFN [5]. Congenital hypothyroidism, hyperthyroidism, adrenal deficiency, congenital parathyroid hyperplasia due to maternal hypocalcaemia, and inactivating mutations at the calcium-sensing receptors are other causes of neonatal hypercalcaemia. A heterozygous mutation in the calcium-sensing receptor results in the advancement of moderate familial hypocalciuric hypercalcaemia, resulting in serious hypercalcaemia in infancy in the existence of homozygous mutation. Williams-Beuren syndrome, characterised by hyperparathyroidism and hypercalcaemia can be identified in infancy and results from microdeletion of 7q11.23 elastin gene. In extension to hypercalcaemia, these patients should also be examined for concomitant endocrine, cardiac and renal pathologies [6,7].

SCFN is a extraordinary form of panniculitis that develops in term neonates exposed to delivery trauma, asphyxia or therapeutic cooling in the first week of life. The etiopathogenesis of SCFN remains uncertain. We consider that the risk factors of obesity and pregnancy diabetes mellitus in our case bring about SCFN along with macrosomia and birth trauma. Although the majority of cases resolve spontaneously, it may be associated with metabolic complications including hypoglycaemia, hypercalcaemia and hypertriglyceridemia or with haematological complications, such as anaemia and thrombocytopenia [5,8]. Nonetheless, serum calcium levels are normal in most cases. Krafchik and Burden found calcium levels normal in seven of 11 patients [9]. Besides, in a case reported by Karochristou et al. [10], SCFN was related with hypocalcaemia [10]. In our present case, severe hypercalcaemia prevented weight gain and caused nephrocalcinosis, and there were no other metabolic complications. The highest serum calcium level in the literature was seen in our case of SCFN.

On physical examination, SCFN presents as red-purple painless nodules on palpation. In the initial physical examination of our patient, no important findings were found on the skin, but while the aetiology of hypercalcaemia was investigated during the follow-up, SCFN areas were detected with careful palpation. Similar to our patient, Bonnemains et al. [11] reported a case of SCFN with severe hypercalcaemia in which subcutaneous nodules could be detected after a detailed examination without typical skin findings. Accordingly, we consider that a careful skin examination in infancy with hypercalcaemia can shed light on the aetiology. While history and physical examination findings lead to the diagnosis, the diagnosis becomes clear with the presence of histiocyte, macrophage and giant cells around the typical fat necrosis in histopathology. Our patient was diagnosed with history, careful physical examination, laboratory examination and imaging.

Hypercalcaemia is a life-threatening complication, especially in patients with extensive skin participation. If the duration of exposure to hypercalcaemia is prolonged, metastatic calcifications, nephrocalcinosis and kidney failure, heart problems, band keratopathy, and basal ganglia calcifications may occur. In our patient, nephrocalcinosis was observed as a complication of hypercalcaemia. Severe hypercalcaemia in patients with SCFN might rarely need additional therapy such as bisphosphonates [4]. Pamidronate, like other bisphosphonates, is used successfully in treating hypercalcaemia related with SCFN, as it affects the bones to diminish osteoclastic resorption [4,6,7]. The first case was described by Khan et al. in 2001 [12]. Shumer et al. [8] administered pamidronate (1 mg/kg/dose) to a 21-day-old newborn with hypercalcaemia unresponsive to intravenous fluid, furosemide and prednisolone medication and they had a fast, enduring effect. Besides, Alos et al. [4] reported a treatment with 3-4 doses (0.25–0.50 mg/kg/dose) of pamidronate for SCFN for resistant hypercalcaemia. Contrary to the previous reports, our patient’s hypercalcaemia was resistant to the first dose of pamidronate at 1 mg/kg/dose, and we had to repeat the pamidronate infusion.

SCFN should be considered when investigating the aetiology of hypercalcaemia especially among those neonates with perinatal and postnatal risk factors even if there is no skin lesion. Nodular lesions of SCFN can be detected with careful palpation days after. Intravenous pamidronate proved to be an acceptable way of treating severe hypercalcaemia in patients with SCFN. It should be kept in mind that repeated doses may be required in cases where hypercalcaemia cannot be corrected with pamidronate infusion.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

FUNDING

None.

ETHICAL APPROVAL

For the publication of the medical details and photographs, informed consents were signed by the parents. The confidentiality of the patient’s data was ensured at every stage. The authors declare that ethics committee approval was not required for this case report.