Bettina F. Cuneo

Evolution of latent hypoparathyroidism in familial 22q11 deletion syndrome

Latent hypoparathyroidism (LHP), the inability to increase midmolecular parathyroid hormone levels appropriately during a hypocalcemic challenge, was reported previously in an asymptomatic woman with tetralogy of Fallot. This womens fourth child died with DiGeorge anomaly. Seven years later, we restudied the index patient with LHP and evaluated three generations of her family for parathyroid dysfunction, cardiac abnormalities, and del 22(q11). Deletions were found in six relatives, three with conotruncal cardiac defects and three with a structurally normal heart. We found significant transgenerational noncardiac phenotypic variability, including learning difficulties, dysmorphic facial appearance, and psychiatric illness. A spectrum of parathyroid gland dysfunction associated with the del 22(q11) was seen, ranging from hypocalcemic hypoparathyroidism to normocalcemia with abnormally low basal intact parathyroid hormone (iPTH) levels. In addition, LHP found in the index patient 7 years ago had evolved to frank hypocalcemic hypoparathyroidism. In this family, which is the largest family with 22q11 deletions studied to date, parathyroid gland dysfunction evolved over time. We suggest that the calcium parathyroid hormone axis of unrelated patients with del 22(q11) be followed closely for the development of hypocalcemic hypoparathyroidism.

Latent Hypoparathyroidism in Children With Conotruncal Cardiac Defects

BACKGROUNDnDiGeorge anomaly is characterized by hypoplasia or atresia of the thymus and parathyroid glands resulting in T cell-mediated deficiency, hypocalcemic hypoparathyroidism, and conotruncal cardiac defects. It usually is associated with deletions of chromosomal region 22q11. We hypothesized that the stimulated (secretory reserve) but not the constitutive secretion of parathyroid hormone would be reduced in normocalcemic children with conotruncal cardiac defects but no overt immune deficiency and would be related to the presence of a deletion in the DiGeorge chromosomal region of 22q11.nnnMETHODS AND RESULTSnBlood-ionized calcium and serum-intact parathyroid hormone were measured at baseline and seven more times during hypocalcemia induced during cardiopulmonary bypass in 22 patients and 10 control subjects with an atrial septal defect. Chromosomal deletions were detected by fluorescent in situ hybridization and DNA dosage analysis. There were no differences in basal calcium and parathyroid hormone levels between patients and control subjects. All had increased parathyroid hormone in response to hypocalcemia; despite lower calcium levels, parathyroid hormone levels were lower in patients. The parathyroid hormone secretory reserve in 14 of 22 patients was reduced compared with control subjects; 4 of the 14 had deletions.nnnCONCLUSIONSnA significant number of children with conotruncal cardiac defects have normocalcemia and a normal constitutive level of parathyroid hormone but deficient parathyroid hormone secretory reserve; about 30% also have 22q11 deletions. Such children may be at risk for the later development of hypocalcemic hypoparathyroidism.

Autosomal dominant transmission of familial laterality defects

Heterotaxy results from failure to establish normal left-right asymmetry during embryonic development. Most familial cases are thought to be autosomal recessive. We have identified a family in which 4 individuals from 3 generations manifest laterality defects. Twenty-five family members have been examined. Two have complete reversal of normal laterality (situs inversus) while 2 others have asplenia, midline liver, and complex cardiac malformations (situs ambiguus). Two additional obligate gene carriers are anatomically normal (situs solitus). Male-to-male transmission confirms autosomal inheritance. Identification of this family establishes an autosomal dominant form of laterality defect, suggesting that a portion of sporadic cases may be new-mutation dominant or unrecognized familial cases. The finding of all forms of laterality (solitus, ambiguus, and inversus) among obligate disease gene carriers within a single family may be relevant to genetic evaluation and counseling in apparently isolated patients with laterality disturbance.

Conduction System Disease in Fetuses Evaluated for Irregular Cardiac Rhythm

Objectives: To determine the prevalence of 1st and 2nd degree AV block in fetuses with an irregular cardiac rhythm, and to summarize outcome of these pregnancies. Background: The diagnosis of irregular cardiac rhythm or ‘skipped beats’ includes isolated ectopy that resolves spontaneously. Recently, Doppler measurements of the ‘mechanical’ PR interval have been shown to identify AV conduction disease prenatally. Prenatal therapy of these conduction abnormalities may limit the progression to more advanced disease either in utero or after birth. Methods: A retrospective review was performed of fetuses evaluated between 1996 and 2004 with the findings of irregular cardiac rhythm. 1st or 2nd degree AV block was diagnosed on Doppler and M-mode recordings, and confirmed using either fetal magnetocardiography (fMCG) or postnatal 12-lead ECG. Dexamethasone was administered to 4 mothers with abnormal fetal AV conduction in the setting of anti-Ro/anti-La antibodies. Results: Of 702 fetuses initially referred for arrhythmia, 306 had an irregular rhythm. Eight (2.6%) had intermittent 1st or 2nd degree AV block confirmed by fMCG and/or postnatal 12-lead ECG. AV block was presumed idiopathic in 2, associated with congenital long QT syndrome in 2 or with clinically unsuspected maternal anti-Ro or anti-La antibodies in 4. During the intrauterine period there was no progression to complete AV block and all were born alive at 34–40 weeks of gestation. Conclusion: A small but clinically significant population of fetuses with irregular rhythm will have 1st or 2nd degree AV block. Transplacental therapy may limit the intrauterine progression to more advanced disease.

An expanded phenotype of maternal SSA/SSB antibody-associated fetal cardiac disease

Objectives.u2003Conventional manifestations of fetal Sjögrens antibodies (SSA/SSB) associated cardiac disease include atrioventricular block (AVB), transient sinus bradycardia, endocardial fibroelastosis (EFE) and dilated cardiomyopathy. We describe other manifestations of cardiac disease. Methods.u2003We describe three fetuses with unique myocardial and conduction system disease. Results.u2003One had isolated EFE with subsequent mitral and tricuspid valve chordal avulsion, the second had sinoatrial and infrahissian conduction system disease, and in both, neonatal progression to life threatening disease occurred. The third had sinus node dysfunction and atrial flutter. Conclusion.u2003These findings expand the clinical phenotype of maternal SSA/SSB antibody associated fetal cardiac disease.

Magnetocardiography in the evaluation of fetuses at risk for sudden cardiac death before birth

BACKGROUNDnWe hypothesized that fetuses at risk for sudden death may have abnormal conduction or depolarization, ischemia, or abnormal heart rate variability (HRV) detectable by magnetocardiography.nnnMETHODSnUsing a 37-channel biomagnetometer, we evaluated 3 groups of fetuses at risk for sudden death: group 1, critical aortic stenosis (AS); group 2, arrhythmias; and group 3, heart failure and in utero demise. Five to 10 recordings of 10-minute duration were recorded, and signal was averaged to determine rhythm, conduction intervals, HRV, and T-wave morphology.nnnRESULTSnIn group 1, 2 of 3 had atrial and ventricular strain patterns. In (n = 53) group 2, 15% had prolonged QTc and 17% had T-wave alternans (TWA). Of 23 group 2 fetuses with atrioventricular block, 74% had ventricular ectopy, 21% had junctional ectopic tachycardia, and 29% had ventricular tachycardia. Group 3 (n = 2) had abnormal HRV and TWA.nnnCONCLUSIONnRepolarization abnormalities, unexpected arrhythmias, and abnormal HRV suggest an arrhythmogenic mechanism for sudden cardiac death before birth.

Development and validation of a fetal cardiovascular disease severity scale

Prenatal heart disease spans the spectrum of severity from very mild to severe life-threatening conditions. An accepted scale for grading fetal cardiovascular disease severity would aid in anomaly standardization, counseling, and future research. The Fetal Cardiovascular Disease Severity Scale with seven severity grades ranging from mild (grade 1) to severe (grade 7) disease was developed. Severity grade relates to the cardiovascular condition diagnosed by fetal echocardiography, with factors including postnatal intervention, number of interventions anticipated, likelihood of two-ventricle repair versus single-ventricle palliation, and overall prognosis. A survey describing 25 cardiac anomalies was offered to fetal cardiologists at six institutions for validation of scale reliability among practitioners. The study participants graded defects using this scale. A smaller group graded anomalies again more than 2xa0weeks after the initial survey. The intraclass correlation coefficient (ICC) was used to assess agreement of the respondents. The survey participants were 14 experienced fetal cardiologists: 9 from the Children’s Hospital of Philadelphia (CHOP) and 5 from five additional institutions in the United States. The initial survey ICC was high [0.93; 95 % confidence interval (CI) 0.88–0.96]. The subanalysis showed a higher ICC for the participants outside CHOP (0.95; 95 % CI 0.91–0.98 vs. 0.92; 95 % CI 0.86–0.96, respectively). The ICCs were high for all the fetal cardiologists participating in the repeat evaluation, ranging from 0.92 to 0.99 (95 % CI 0.65–1.00). The Fetal Cardiovascular Disease Severity Scale demonstrated good inter- and intrarater reliability among experienced fetal cardiologists and is a valid tool for standardization of prenatal cardiac diagnostic assessment across institutions. The scale has applications for parental counseling and research in fetal cardiovascular disease.

Novel approach to the newborn with hypoplastic left heart syndrome and intact atrial septum

A prenatally diagnosed fetus with hypoplastic left heart syndrome and intact atrial septum was delivered in the cardiac catheterization suite. Using radio frequency energy, a transseptal perforation of the thickened and intact atrial septum was immediately performed following transcatheter cannulation of the right atrium via the umbilical vein. Serial cutting balloon septostomies followed by static balloon septostomies resulted in effective left atrial decompression, atrial mixing, and optimal pulmonary and systemic perfusion. The child is now thriving after both stage I Norwood and bidirectional Glenn procedures.

Flow patterns in the ductus arteriosus during open fetal myelomeningocele repair

The objective of this study is to perform a longitudinal evaluation of blood flow patterns in the ductus arteriosus (DA) during the perioperative period in fetal myelomeningocele (MMC) surgical patients.

Myocardial tissue Doppler velocities in fetuses with hypoplastic left heart syndrome.

Background: Tissue Doppler Imaging (TDI) is a sensitive index of myocardial function. Its role in the fetus has not been extensively evaluated. Objective: To compare myocardial tissue Doppler velocities in fetuses with hypoplastic left heart syndrome (HLHS) to those of normal fetuses (matched for gestational age.) Methods: Cross-sectional retrospective study conducted at 2 large perinatal centers (2003-2007). Fetuses with HLHS (n = 13) were compared with normal fetuses (n = 207) in 5 gestational age groups. TDI data included peak systolic (s’), peak early (e’), and late diastolic velocities (a’). Linear regression was used to compare TDI parameters in fetuses with HLHS to normal fetuses matched for gestational age. Results: Fetuses with HLHS had significantly reduced lateral tricuspid annular e’ as compared to normal fetuses. Both normal fetuses and those with HLHS had linear increase in TDI velocities with advancing gestational age. Conclusions: TDI velocities are abnormal in fetuses with HLHS. TDI can be useful in serial follow-up of cardiac function in fetuses with HLHS.