Edition 62 - 2017, March / Images

Images in Pediatric Endocrinology: FRACTURES IN NEONATAL PERIOD – Ed. 62

Valeria De Dona, Paula Plomer, Gisela Viterbo

Servicio de Endocrinología. Hospital de Pediatría Juan. P Garrahan, Buenos Aires, Argentina

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Description: (A) Complete skeletal radiographs showing generalized severe low bone mineral density, multiple long-bone fractures, and deformities of both femurs (D). Severe metaphyseal involvement (C). Narrow chest, thin ribs and platyspondyly (B).

 

Case 1.

The patient was referred to our hospital at eleven days of life because of multiple bone fractures and respiratory distress, with a presumptive diagnosis of osteogenesis imperfecta.

The patient was a girl, first twin of a biamniotic and bichorionic pregnancy, born full-term, small for gestational age (weight: 1730 g; length: 41 cm, head circumference: 35 cm), by cesarean section. She was admitted soon after birth due to low weight, suspected sepsis and multiple bone fractures.

There was no parental consanguinity. Her father and a 9 year-old sister were both healthy. Her mother had had a total thyroidectomy.  The second twin was a boy born with adequate birth weight (weight: 2750g; length: 48 cm) and without remarkable findings. There was no family history of bone diseases or fractures.

Physical examination on admission revealed failure to thrive, weight 1730g (-3.4 SD), painful face, small biparietal diameter, gray scleras, narrow chest, unstable thorax , abdominal distention, lower limbs deformities, without spontaneous movements. The patient required mechanical ventilation and intravenous fluid therapy 80ml/kg/day.

Laboratory test showed hypercalcemia (11.4 mg/dl, reference values: 8.6-10.6), severe hypophosphatemia (< 0.4 mg/dl, RV: 5.8-7.5), hypokalemia (2.45 meq/l, RV: 3.5-5.5) and increased levels of Alkaline Phosphatase (ALP: 1934 UI/l, RV:<320), with normal levels of magnesium (1.91 mg/dl, RV1.6-2.4), creatinine (0.31 mg/dl, RV:<0.9), serum sodium (139 meq/l, RV: 135-145). The association of severe hypophosphatemia, mild hypercalcemia, severe generalized bone disease with increased fragility, metaphyseal involvement, elevated ALP, and maternal history of thyroidectomy suggested neonatal hyperparathyroidism. She was started on hyperhydration therapy and potassium and phosphorus intravenous were given. Further investigations to the patient and her mother were requested.

After initial therapy and under enteral feeding with preterm formula, hypotonia, serum calcium, and phosphorus levels showed great improvement (8.6 mg/dl and 3.6 mg/dl respectively). Elevated serum PTH levels (1349 pg/ml) and ALP (2072 UI/L) were confirmed. Severe vitamin D deficiency was detected (20).

Mother´s laboratory tests showed hypocalcemic hypoparathyroidism, and hypothyroidism (PTH 19 pg/ml, serum calcium 5.5 mg/dl, phosphorus 4.5 mg/dl, TSH 7.22 uUI/ml, fT41.38 ug/dl, T3 0.66 ng/ml). She had a total thyroidectomy due to Graves Basedow disease performed about one year before. Post- surgery she was under calcium and calcitriol treatment, but during pregnancy she received only 1000 mg/day elemental calcium and 150 mcg/day levothyroxine.

With a confirmed diagnosis of maternal hypoparathyroidism, the twin sibling was evaluated. On physical exam, at 15 days of life, the baby boy was doing well, his weight was 3650 g (-1.43 SD), lenght: 53.2 cm (-0.77 SD), without other remarkable antecedents. Radiographs showed mild osteopenia without other pathological findings. Biochemical studies revealed elevated PTH (283 pg/ml), normal serum calcium (9.2 mg/dl), mild hypophosphatemia (4.9 mg/dl), elevated ALP (542 UI/l), and normal thyroid hormone levels (TSH 0.74 uUI/ml, RV: 0.92-4.38; T4 10.4 ug/dl, RV: 6-16.4; fT4 1.32 ng/dl, RV: 1.01-2.08; T3 1.23ng/ml; RV: 0.93-2.3). During follow-up, he received preterm formula and biochemical parameters were normalized at 6th week of life.

During patient follow- up, at 25 days of life, neonatal hyperthyroidism diagnosis secondary to transplacental passage of maternal antibodies was made. Thyroid studies showed TSH 0.29 uUI/ml, T4 11.2ug/dl, fT4 1.2 ng/dl, T3 0.99 mg/ml, TBII 15% (RV: <10%). She was started on methimazole (MMI) 1.25 mg/d. After 3 weeks of treatment, as TSH levels raised up to 12uUI/ml and T4 and T3 decreased to 5.58 ug/dl and 1.13 ng/ml respectively, MMI was withdrawn. Two weeks later, because of persistent low fT4l, t4 and TSH, levothyroxine treatment (3.9mcg/kg/day) was started.

After 3 weeks of intensive care unit, under enteral nutrition with preterm formula and vitamin d treatment, the patient was extubated. Callus formation on the sites of fractures and recovery in the metaphyses were observed and no more fractures were noted. Intact PTH decreased to 27 pg/ml, serum calcium 10.3 mg/dl, ALP 408 UI/l and serum phosphorus raised up to 5.7 mg/dl and vitamin d 43 ng/ml, normalizing biochemical parameters at 3 months of life.

Comments

Neonatal hyperparathyroidism is a rare clinical entity with various etiologies; it can be primary or secondary. Primary hyperparathyroidism is extremely infrequent and is associated with the presence of biallelic CasR inactivating mutations. The secondary form is the result of maternal hypocalcemia during gestation which may be due to maternal hypoparathyroidism, pseudohypoparathyroidism, chronic renal failure and renal tubular acidosis.

Fetal bone mineralization, depends basically on an adequate active calcium transfer across the placenta. Maternal hypocalcemia causes reduced maternal-fetal calcium transfer and subsequently, persistent intra-uterine hypocalcemia thet stimulates fetal parathyroid glands. Parathyroid gland hyperplasia and elevated PTH levels can cause generalized skeletal demineralizarion, phosphorus renal loss and hypophosphatemia, generally associated with hypercalcemia, although serum calcium may be normal.

The duration and severity of fetal hyperparathyroidism are variable and essentially dependent on the severity of maternal hypocalcemia. Some patients with neonatal hyperparathyroidism can be asymptomatic without radiologic findings or can cause spontaneous abortions, stillbirth, generalized bone demineralization, bone deformities and multiple bone fractures. This condition can result in several complications including fatal respiratory distress.

A number of conditions including osteogenesis imperfecta,  hypophosphatasia and preterm metabolic bone disease, should be considered in the diagnosis of bone fragility and fractures in the newborn. Although radiological findings were similar in all these entities, laboratory assessment and the age at presentation are useful for differential diagnosis. Preterm bone disease usually appears at 6 weeks of life, hypophosphatasia shows extremely low levels of ALP while osteogenesis imperfecta does not present with abnormal biochemical parameters.

Although neonatal hyperparathyroidism is rare, in a hypotonic neonate with respiratory distress and pathological bone fractures, the diagnosis of congenital hyperparathyroidism should be considered. Family history, age at presentation and laboratory findings were useful in this case to determine appropriate diagnosis and therapeutic management.

Bibliographic references:

1) Ayfer Alikasifoglu, E; Nazli Gonc, et al. Neonatal Hyperparathyroidism Due to Maternal Hypoparathyroidism and Vitamin D Deficiency: A Cause of Multiple Bone Fractures.Clinical Pediatrics. April (2005) 267-269

2)  N. Demirel, M. Aydin, A. Hyperparathyroidism secondary to maternal hypoparathyroidism and vitamin D deficiency: an uncommon cause of neonatal respiratory distress.Annals of Tropical Paediatrics (2009) 29, 149–154

3) Thomas Aceto, J; Batt, R, et al. Intrauterine hyperparathyroidism: A complication of untreated maternal hypoparathyroidism. JCEM (1966) 487-492

4)Landing, B; Kamoshita, S. Congenital hyperparathyroidism secondary to maternal hypoparathyroidim.The Journal of Pediatrics, 77 (5) (1970) 842-847

5) Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Eighth Edition. Chapter 23.  Fetal Calcium metabolism


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