Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening?

OBJECTIVES: To give an overview of the genetic and structural abnormalities occurring in fetuses with nuchal translucency (NT) measurement exceeding the 95th percentile at first-trimester screening and to investigate which of these abnormalities would be missed if cell-free fetal DNA (cfDNA) were used as a first-tier screening test for chromosomal abnormalities. METHODS: This is a national study including 1901 pregnancies with NT≥95th percentile referred to seven university hospitals in the Netherlands between 1 January 2010 and 1 January 2016. All cases with unknown pregnancy outcome were excluded. Results of detailed ultrasound examinations, karyotyping, genotyping, pregnancy and neonatal outcomes, investigation by a clinical geneticist and post-mortem investigations were collected. RESULTS: In total, 821 (43%) pregnancies had at least one abnormality. The rate of abnormalities was 21% for fetuses with NT between 95th and 99th percentile and 62% for fetuses with NT≥99th percentile. Prevalence of single-gene disorders, submicroscopic, chromosomal and structural abnormalities was 2%, 2%, 30% and 9%, respectively. CONCLUSION: Although cfDNA is superior to the combined test, especially for the detection of trisomy 21, 34% of the congenital abnormalities occurring in fetuses with increased NT may remain undetected in the first trimester of pregnancy, unless cfDNA is used in combination with fetal sonographic assessment, including NT measurement.

Heterozygous deletion of AKT1 rescues cardiac contractility, but not hypertrophy, in a mouse model of Noonan Syndrome with Multiple Lentigines.

Noonan Syndrome with Multiple Lentigines (NSML) is associated with congenital heart disease in form of pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Genetically, NSML is primarily caused by mutations in the non-receptor protein tyrosine phosphatase SHP2. Importantly, certain SHP2 mutations such as Q510E can cause a particularly severe form of HCM with heart failure in infancy. Due to lack of insight into the underlying pathomechanisms, an effective custom-tailored therapy to prevent heart failure in these patients has not yet been found. SHP2 regulates numerous signaling cascades governing cell growth, differentiation, and survival. Experimental models have shown that NSML mutations in SHP2 cause dysregulation of downstream signaling, in particular involving the protein kinase AKT. AKT, and especially the isoform AKT1, has been shown to be a major regulator of cardiac hypertrophy. We therefore hypothesized that hyperactivation of AKT1 is required for the development of Q510E-SHP2-induced HCM. We previously generated a transgenic mouse model of NSML-associated HCM induced by Q510E-SHP2 expression in cardiomyocytes starting before birth. Mice display neonatal-onset HCM with initially preserved contractile function followed by functional decline around 2months of age. As a proof-of-principle study, our current goal was to establish to which extent a genetic reduction in AKT1 rescues the Q510E-SHP2-induced cardiac phenotype in vivo. AKT1 deletion mice were crossed with Q510E-SHP2 transgenic mice and the resulting compound mutant offspring analyzed. Homozygous deletion of AKT1 greatly reduced viability in our NSML mouse model, whereas heterozygous deletion of AKT1 in combination with Q510E-SHP2 expression was well tolerated. Despite normalization of pro-hypertrophic signaling downstream of AKT, heterozygous deletion of AKT1 did not ameliorate cardiac hypertrophy induced by Q510E-SHP2. However, the functional decline caused by Q510E-SHP2 expression was effectively prevented by reducing AKT1 protein. This demonstrates that AKT1 plays an important role in the underlying pathomechanism. Furthermore, the functional rescue was associated with an increase in the capillary-to-cardiomyocyte ratio and normalization of capillary density per tissue area in the compound mutant offspring. We therefore speculate that limited oxygen supply to the hypertrophied cardiomyocytes may contribute to the functional decline observed in our mouse model of NSML-associated HCM.

Anesthesia and LEOPARD syndrome: a review of forty-nine anesthetic exposures.

OBJECTIVES: LEOPARD syndrome is a rare congenital disease that can manifest with cardiac anomalies, multiple lentigines, ocular hypertelorism, growth retardation, and deafness. The purpose of this case series was to review the most prominent comorbidities associated with LEOPARD syndrome, and describe perioperative outcomes in a series of patients undergoing anesthesia. DESIGN: Retrospective case series review SETTING: Tertiary care institution PARTICIPANTS: Patients diagnosed with LEOPARD syndrome who underwent surgical procedures requiring anesthesia at this institution. INTERVENTION: The medical and anesthesia records of patients with LEOPARD syndrome were reviewed. Demographic information, clinical features of LEOPARD syndrome, comorbidities, intraoperative and postoperative events and complications were recorded. A systematic literature review also was conducted. MEASUREMENTS AND MAIN RESULTS: Nine patients with LEOPARD syndrome underwent 49 procedures under general anesthesia (n = 40) or monitored anesthesia care (n = 9). The majority of operations were related to correction of cardiac anomalies (n = 20). The most common cardiac malformations were ventricular septal hypertrophy and pulmonary (or subpulmonary) stenosis, and major perioperative complications were related to severe arrhythmias and/or cardiac decompensation. CONCLUSIONS: Dominant pathology associated with perioperative complications in patients with LEOPARD syndrome is related to cardiac disease. A large proportion of patients with this condition have ventricular septal hypertrophy, which tends to progress with age; therefore, these patients undergoing anesthesia should have recent cardiologist evaluation.

An unusual cause for recurrent syncope in a female adult with LEOPARD syndrome.

The LEOPARD syndrome is a rare autosomal dominant, multisystem disease involving the skin, skeletal and cardiovascular systems. Echocardiography including stress testing was used in a patient with LEOPARD syndrome and recurrent syncope to reveal the hemodynamic relevance of a giant aneurysm of the interventricular membraneous septum ballooning into the right ventricular outflow tract. This case impressively underlines the vital necessity of dynamic testing particularly in patients with symptoms during exercise even if these symptoms might be addressed to other findings.

A standard echocardiographic and tissue Doppler study of morphological and functional findings in children with hypertrophic cardiomyopathy compared to those with left ventricular hypertrophy in the setting of Noonan and LEOPARD syndromes.

BACKGROUND: Several clinical and echocardiographic studies describe morphological and functional findings in patients with hypertrophic cardiomyopathy. Less is known regarding morphological and functional characteristics of the left ventricular hypertrophy found in the setting of the Noonan and LEOPARD syndromes. OBJECTIVE: To compare non-invasively the morphological and functional findings potentially affecting symptoms and clinical outcome in children with hypertrophic cardiomyopathy as opposed to Noonan and LEOPARD syndromes. PATIENTS AND METHODS: We studied by echo-Doppler 62 children with left ventricular hypertrophy, dividing them into two subgroups matched for age and body surface area. The first group, of 45 patients with a mean age of 7.5 +/- 5.2 years and body surface area of 0.9 +/- 0.44 mq, had idiopathic hypertrophic cardiomyopathy. The second group, of 17 patients, all had left ventricular hypertrophy in the setting of Noonan or LEOPARD syndromes. Their mean age was 6.6 +/- 5 years, and body surface area was 0.8 +/- 0.36 mq. In all patients, we assessed the left ventricular maximal mural thickness, expressed as a Z-score, along with any obstructions in the left and right ventricular outflow tracts. In addition, to define left ventricular diastolic function, we used mitral flow and pulsed Tissue Doppler to record the Ea, Aa, Ea/Aa, E/Ea indexes in the apical 4-chamber view at the lateral corner of the mitral annulus. We also measured the diameters of the coronary arteries in the diastolic frame. RESULTS: Compared to those with hypertrophic cardiomyopathy, those with syndromic left ventricular hypertrophy showed a significantly increased Z-score for mural thickness, and a higher prevalence of obstruction in the left ventricular outflow tract. In addition, the patients with Noonan or LEOPARD syndromes showed a significantly decrease of Ea and increase of Aa, with a decreased Ea/Aa ratio, all suggestive of left ventricular abnormal relaxation. Moreover, the E/Ea ratio was significantly increased in these patients. The presence of right ventricular hypertrophy, mainly associated with dynamic obstruction in the outflow tract, was detected in only 5 of the 17 patients with Noonan or LEOPARD syndromes, as was dilation of the coronary arteries. CONCLUSIONS: Compared to children with hypertrophic cardiomyopathy, those with left ventricular hypertrophy in the setting of Noonan or LEOPARD syndromes show more ventricular hypertrophy and diastolic dysfunction, due to both abnormal relaxation and reduced compliance. They also exhibit an increased prevalence of obstruction of the left ventricular outflow tract, along with dynamic obstruction of the right ventricular outflow tract and dilated coronary arteries. These morphological and functional findings could explain the different symptoms and clinical events, and potentially define the more appropriate therapeutic options in children with left ventricular hypertrophy of different aetiology.

In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy.

Noonan Syndrome with Multiple Lentigines (NSML, formerly LEOPARD syndrome) is an autosomal dominant "RASopathy" disorder manifesting in congenital heart disease. Most cases of NSML are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11), encoding the SH2 domain-containing PTP-2 (SHP2) protein. We previously generated knock-in mice harboring the PTPN11 mutation Y279C, one of the most common NSML alleles; these now-termed SHP2Y279C/+ mice recapitulate the human disorder and develop hypertrophic cardiomyopathy (HCM) by 12 weeks of age. Functionally, heart and/or cardiomyocyte lysates from SHP2Y279C/+ mice exhibit increased basal and agonist-induced AKT and mTOR activities. Here, we sought to determine whether we could reverse the hypertrophy in SHP2Y279C/+ mice using ARQ 092, an oral and selective allosteric AKT inhibitor currently in clinical trials for patients with PI3K/AKT-driven tumors or Proteus syndrome. We obtained echocardiographs of SHP2Y279C/+ and wildtype (SHP2+/+) littermates, either in the presence or absence of ARQ 092 at 12, 14, and 16 weeks of age. While SHP2Y279C/+ mice developed significant left ventricular hypertrophy by 12 weeks, as indicated by decreased chamber dimension and increased posterior wall thickness, treatment of SHP2Y279C/+ mice with ARQ 092 normalized the hypertrophy in as early as 2 weeks following treatment, with hearts comparable in size to those in wildtype (SHP2+/+) mice. In addition, we observed an increase in fractional shortening (FS%) in SHP2Y279C/+ mice, an effect of increased compensatory hypertrophy, which was not apparent in SHP2Y279C/+ mice treated with ARQ 092, suggesting functional improvement of HCM upon treatment with the AKT inhibitor. Finally, we found that ARQ 092 specifically inhibited AKT activity, as well as its downstream effectors, PRAS and S6RP in NSML mice. Taken together, these data suggest ARQ 092 may be a promising novel therapy for treatment of hypertrophy in NSML patients.