CASE PRESENTATION

1. CASE PRESENTATION By: Patricia Baile September 16, 2009

2. Patient is a NB baby boy with weak cry

3. Birth History • Patient born PT at 34 weeks • NSVD • Birth Weight: 2050g • APGAR 7,8

4. Maternal History • 28 year old G1P0 • Regular PNCU • Negative serologic studies • No known medical condition • No HTN, no DM • Denies smoking, alcohol, drug use • No medication use

5. Family History • No known medical condition

6. Pertinent PE Findings • GS: hypertonic and irritable, with weak cry • HEENT: +hypertelorism, jaw held tightly closed even during crying, no cleft lip or palate • C/L: SCE, no retraction, CTA • CV: RRR, + gr 3/6 holosystolic murmur, LPSB 4th ICS, full and equal pulses on all extremities, good perfusion

7. Pertinent PE Findings • Abdomen: benign • Extremities: hypertonic extremities

9. Labs • CBC: WNL • CMP: WNL except Ca • Ca: 6.0 mg/dL • P: 9.2 mg/dL (4.5-9.0) • Mg: 1.5 mEq/L (1.3-2.0) • PTH: 44 pg/mL (N 40-100)

10. Ancillary Tests • 2D Echo reveals a small VSD • Hypoplastic thymus • FISH study for deletions on chromosme 22q11.2 was negative

11. Problem List • Hypocalcemia • Hypoparathyroidism • VSD • Hypoplastic thymus

12. Clinical Course • Patient stayed in NICU for 5 weeks because of difficulty feeding and persistent hypocalcemia • Currently receiving supplementary Ca and Vitamin D

13. HYPOCALCEMIA

14. Definition of Hypocalcemia • Total serum Ca less than: • 7.0 mg/dL in Preterm infants • 8.0 mg/dL in Term newborns • 8.8 mg/dL in children

15. Pathogenesis • Ca is the most abundant mineral in the body • 99% in bone, 1% in ECF • 50% of serum Ca is ionized and considered active • 40% bound to protein (albumin) • 10% in chelated form

16. Hormonal Regulation

17. Clinical Manifestations • Neuromuscular excitability • Tetany • Seizures • Stridor or cyanosis from laryngospasm • Hypotension • Impaired cardiac contractility

18. PTH Vitamin D metabolites (calcidiol and calcitriol) Total Ca Ionized Ca Phosphorus Liver function Renal function Magnesium Work up

19. Hypocalcemia in Neonatal Period • Early Onset: refers to the first few days after birth • Usually seen in preterm babies, neonates stressed from asphyxia or sepsis, or by being infants of a diabetic mother • Late onset: occurs after the fifth postnatal day • Often related to immaturity of parathyroid glands, dietary phosphate loading, or hypomagnesemia

20. Childhood Hypocalcemia • Vitamin D-related • Vitamin D-deficient rickets • Vitamin D-dependent rickets type 1 and type II • PTH-related • Hypoparathyroidism • pseudohypoparathyroidism

21. Childhood Hypocalcemia • Calcium/Phosphorus-related • Malabsorption • Hyperphosphatemia • Organ-related • Hepatic rickets • Acute pancreatitis • Renal osteodystrophy

22. Chronic causes of Hypocalcemia • Disorders involving PTH • Hypoparathyroidism • Pseudohypoparathyroidism • Disorders related to vitamin D • Lack of exposure ot UVB radiation • Inadequate intake • Fat malabsorption • Lack of liver activity to promote 25-hydroxylation • Genetic deficiency of renal 1-alpha-hydroxylase

23. Management • IV bolus infusion of 20mg/kg elemental Ca over 10-20 mins with careful cardiac monitoring • Continuous infusion • Neonates: 500mg/kg 10% Ca gluconate over 24h • Children: 200mg/kg/24h

24. DI GEORGE SYNDROME

25. DiGeorge Syndrome • Congenital immunodeficiency characterized by abnormal facies; congenital heart defects; hypoparathyroidism with hypocalcemia; cognitive, behavioral, and psychiatric problems; and increased susceptibility to infections

26. Pathological hallmarks include conotruncal abnormalities and absence or hypoplasia of thymus and parathyroid glands • Constellation of defects is not a syndrome resulting from a single cause, but rather the failure of an embryological field to develop normally  DiGeorge Anomaly

27. Pathophysiology • Characterized by malformations attributed to abnormal development of pharyngeal arches and pouches • Common thread among organs involved in DiGeorge anomaly is that their development depends on migration of neural crest cells to the region of pharyngeal pouches

28. 22q11.2 deletion • Mechanism of deletion has been linked to low copy number repeats (LCRs) • An aberrant unequal, interchromosomal meiotic exchange is the dominant mechanism

29. 22q11.2 deletion • 30-50 genes present within the commonly deleted region of chromosome 22q11.2 • TBX1 is the gene mainly responsible for the phenotypic features • Important in cardiac development • Expressed in pharyngeal mesenchyme and endodermal pouch • Also expressed in the region that gives rise to the mesenchyme of the brain

30. History • Genetic • Reported to be inherited in AD, AR and X-linked fashions • Approx 17% of patients with phenotypic features of DiGeorge anomaly have no detectable genomic deletion

31. History / Manifestations • Exposure history to alcohol and other toxins like isotretinoin • Endocrine • Hypoparathyroidism leading to hypocalcemia (observed in 60% of patients)

32. History / Manifestations • Cardiac • TOF: 17% • VSD: 14% • Interrupted aortic arch: 14% • Pulmonary atresia: 10% • Truncus arteriosus: 9%

33. History / Manifestations • Immunologic • Thymic hypoplasia or aplasia leading to defective T-cell function • Partial DiGeorge: below-normal proliferative response to mitogens • Complete DiGeorge: no T-cell response to mitogens

34. History / Manifestations • Other Manifestations • Growth retardation • Behavioral and psychiatric problems • Neurologic abnormalities • GU malformation • Eczema

35. History / Manifestations • Infectious • Increased susceptibility to infections caused by organisms typically associated with T-cell dysfunction • Systemic fungal infections • Pneumocystis jiroveci • Disseminated viral infections

36. Physical Manifestations • Facies: • Hypertelorism • Micrognathia • Short philtrum with fish-mouth appearance • Telecanthus with short palpebral fissures

40. Physical Manifestations • Otolaryngic • Low-set ears, often with defective pinna • Cleft palate • Submucous cleft • Velopharyngeal insufficiency

42. Differential Diagnoses • Include all 22q11 deletion syndromes and exposure to teratogens during pregnancy

43. Differential Diagnoses • Velocardiofacial syndromes (VCFS or Shprintzen syndrome) • Conotruncal anomaly face syndrome • Cayler syndrome • Opitz-GBBB syndrome • CHARGE syndrome

44. Laboratory Studies • Fluorescent in situ hybridization (FISH) to detect deletion of chromosome 22q11.2 • PCR • Who to screen: • Neonatal hypocalcemia • Interrupted aortic arch • Velopharyngeal insufficiency • Pulmonary atresia

45. Laboratory Studies • Assessment of Immune System • In vitro studies of T cell function • Flow cytometry to estimate number of T cells in peripheral blood and the proliferative responses to mitogens and antigens • Lymphocyte phenotyping and stimulation tests • Assessment of parathyroid function

46. Imaging Studies • Lateral-view CXR • MRI • 2D Echocardiography

47. Treatment • Endocrine • Hypoparathyroidism and hypocalcemia are managed with Ca supplements and vitamin D administration • Cardiac • Surgical intervention as necessary

48. Treatment • Immunodeficiency • Prophylactic regimens for T and B cell deficiency • Transplantation of HLA-identical bone marrow • Thymus transplantation

49. Questions???

50. Thank you 