Persistent Neonatal Hypocalcemia Dilemma

HISTORY Female baby, 37/40 ( Elective LSCS ) Birth weight 3.56 kg (>90thCentileas per Fenton s chart) Mother: 30 years, Primipara, No H/O Consanguinity, Euglycemic Uneventful Antenatal Period. APGAR 91 105 Needed no active Resuscitation at birth.

CLINICAL EXAMINATION No obvious dysmorphic features. Activity and Reflexes were normal. Blood sugar monitoring: Normal. All systemic examinations: normal. Breast Feeding Initiated and established.

INVESTIGATIONS: Day 3 of life: blood for Group/ Rh, Serum Bilirubin, Serum Calcium, Serum Albumin ,7 condition IEM Panel sent(as per protocol). Serum Calcium 4.4 mg/dl. Serum Albumin 3.99 mg/dl. Ionized Calcium 0.8 mmol/l (normal> 1.2) Corrected serum Calcium <4.5 mg/dl. IV 10% Calcium Gluconate( 8ml/kg/day) was started.

DILEMMA Asymptomatic Early Onset Neonatal Hypocalcemia in a Large for Date Term baby (with normal blood sugar & without any phenotypical abnormalities): ? Cause

EARLY NEONATAL HYPOCALCEMIA: CAUSES Prematurity. Maternal Preeclampsia. Infant of diabetic mother. Perinatal asphyxia. Maternal intake of anticonvulsants (phenytoin & Phenobarbitone). Maternal hyperparathyroidism. Iatrogenic ( Alkalosis, diuretic therapy, phototherapy, lipid infusion etc).

FURTHER INVESTIGATIONS: Paramete rs Day 4 Day 7 Day 14 Interpretation: Persistent hypocalcemia beyond 7 days despite calcium supplementation. Normal Magnesium Increased Phosphate Increased PTH, Low normal Vit D Normal urine Ca: Cr Se Ca (mg/dl) 4.64 5.42 6.72 Se Alb (mg/dl) 3.96 3.89 3.92 Se Mg (mg/dl) 2.62 2.64 Se PO4 (mg/dl) 8.64 8.26 7.96 Se Vit D (ng/ml) 15.92 21.62 26.42 Se PTH (pg/ml) 171.40 168.62 156.72 Urine Ca: Cr 0.106 0.102

CASE PROFILE: Term, Asymptomatic, Large for date, female newborn. Significant early onset hypocalcemia in routine blood tests done on day 3. Absence of any risk factors associated with early onset neonatal hypocalcemia. Persistence of hypocalcemia beyond 2 weeks despite supplementation of calcium and vitamin D analogue Maternal serum calcium ,phosphorous and PTH level were normal.

PERSISTANT/PROLONGED HYPOCALCEMIA

SIGNIFICANT INVESTIGATIONS Biochemical Absence of Features of AHO Persistently low corrected serum calcium. High Serum phosphate. High serum PTH Normal serum Magnesium Normal TSH Normal urinary Calcium Creatinine ratio

Pseudohypoparathyroidism (PHP) First described by Fuller Albright in 1942. Incidence 0.79 per 100 patients. Hypocalcemia, Hyperphosphatemiaand elevated PTH levels in blood due to end organ unresponsiveness to PTH. Albright s Osteodystrophy: PHP associated with rounded facies, brachydactyly, short stature, subcutaneous ossifications, cognitive impairment

PHP: Subtypes Variables PHP Ia PHP Ib PHP Ic PHP II PseudoPHP AHO Features Present Absent Present Absent Present Multiple hormone resistance Present Transient Present Absent Absent PTH induced cAMP excretion No increase No Increase No Increase No Increase Normal PTH induced Phosphate excretion No Increase No Increase No increase Decreased Normal ErythrocyteG s alpha activity Decreased Normal Normal Normal Decreased Genetics Significant Significant Significant Significant Significant

Diagnostic Pointers in this case Persistence of biochemical abnormalities associated with Pseudohypoparathyroidism. In the absence of characteristic features of Albrights Hereditary Osteodystrophy. Tests to detect urinary cAMP and phosphate excretion to exogenous PTH and RBC Gs alpha activity: Not done due to logistic limitations. Provisional Diagnosis: PHP Type Ib. Genetic tests requested at follow up and discharded with oral calcium and calcitriol supplements.

Follow up: Till 6 months Weight above 50thCentile. Chronological age appropriate development. No phenotypical features suggestive of Albrights Hereditary Osteodystrophy. Child was asymptomatic on calcitriol 0.25microgram/day and calcium supplements. Serum calcium 7.8mg/dl ,Serum phosphate 6.9mg/dl, PTH 90 pg/ml. Normal serum TSH and Calcitonin levels.

GENETIC ANALYSIS Segmental Uniparental Disomyof the Long arm of chromosome 20 involving the GNAS Locus (20q 13.2-13.3).

SUMMARY A rare case of PHP Type 1b presenting with early onset asymptomatic hypocalcemia in a term large for date newborn. No evidence of associated AHO. Genetic analysis revealed presence of segmental uniparental disomyof long arm of chromosome 20 containing the GNAS Locus.

PHP 1b with Uniparental Disomy Segmental uniparental disomy involving the GNAS locus in chromosome 20 was first reported in 2001. 7 more similar cases of sporadic PHP 1b were reported with UPD. All were symptomatic At birth 2 were large for date Pseudohypoparathyroi dism Type 1b due to Paternal Uniparental Disomyof Chromosome 20q A. Dixit et al patUPD20 should be considered in the evaluation of patients with sporadic PHP1b. (J Clin Endocrinol Metab 98: E103 E108, 2013)

TAKE HOME MESSAGE Neonatal pseudohypoparathyroidism may present as early onset hypocalcemia even in an asymptomatic newborn. patUPD20 should be considered in the evaluation of patients with sporadic PHP1b.

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