Prevalence of Childhood Permanent Hearing Loss after Early Complex Cardiac Surgery.

OBJECTIVES: To estimate the prevalence of childhood permanent hearing loss (PHL) after early cardiac surgery. STUDY DESIGN: This prospective observational (1996-2015) study after complex cardiac surgery with cardiopulmonary bypass at ≤6 weeks of life reports audiology follow-up by registered pediatric-experienced audiologists at 6-8 months postsurgery, age 2 years, and as required throughout and thereafter to complete diagnoses. PHL at any frequency (500-4000 Hz) is defined as responses of >25-decibel hearing level in either ear. PHL was evaluated by type (conductive or sensorineural), pattern (flat or sloping), and severity (mild to profound). RESULTS: Survival rate was 83.4% (706 of 841 children) with a 97.9% follow-up rate (691 children); 41 children had PHL, 5.9% (95% CI 4.3%, 8.0%). By cardiac defect, prevalence was biventricular, 4.0% (95%CI 2.5%, 6.1%); single ventricle, 10.8% (95%CI 6.8%, 16.1%). Eighty-seven (12.6%) of 691 had syndromes/genetic abnormalities with known association with PHL; of these, 17 (41.5%) had PHL. Of 41 children, 4 had permanent conductive, moderate to severe loss (1 bilateral); 37 had moderate to profound sensorineural loss (29 bilateral with 20 sloping and 9 flat), 6 with cochlear implant done or recommended. CONCLUSIONS: Infants surviving complex cardiac surgery are at high risk for PHL. Over 40% with PHL have known syndromes/genetic abnormalities, but others do not have easily identifiable risk indicators. Early cardiac surgery should be considered a risk indicator for PHL.

Transmission of the rare HRAS mutation (c. 173C > T; p.T58I) further illustrates its attenuated phenotype.

Costello syndrome was delineated based on its distinctive phenotype including severe failure-to-thrive with macrocephaly, characteristic facial features, hypertrophic cardiomyopathy, papillomata, malignant tumors, and cognitive impairment. Heterozygous germline mutations in the proto-oncogene HRAS cause Costello syndrome, and its inheritance pattern would thus be autosomal dominant. With exception of two instances of parental mosaicism, one presumed gonadal and the other proven somatic mosaicism for the p.G12S change, all published cases resulted from de novo mutations, typically arising in the paternal germline. More than 90% of these mutations affect the glycine residues in position 12 or 13, and result in a gain-of-function of the altered protein. A rare heterozygous HRAS alteration (c.173C > T; p.T58I) associated with an attenuated phenotype was previously reported in one patient. We identified two additional individuals with this mutation, father and son. Further studies supported origin of the alteration in the grand-paternal germline. Transmission of the mutation underscores its attenuated phenotype compatible with reproduction. We reviewed the phenotype in the newly identified individuals (Patient 1, 2) and include updated information on the first previously reported individual with HRAS p.T58I (Patient 3). Macrocephaly was present in all three. Cardiac findings included hypertrophic cardiomyopathy with double-chambered right ventricle; or mitral valve prolapse in one patient each. While subtle neurologic abnormalities or developmental delay were present in all, only one showed significant cognitive and functional impairment. None developed papillomata or a malignant tumor. Genetic counseling for Costello syndrome needs to take into consideration the particular HRAS mutation.

Costello syndrome associated with novel germline HRAS mutations: an attenuated phenotype?

Costello syndrome is a rare congenital disorder typically characterized by severe failure-to-thrive, cardiac abnormalities including tachyarrhythmia and hypertrophic cardiomyopathy, distinctive facial features, a predisposition to papillomata and malignant tumors, neurologic abnormalities, developmental delay, and mental retardation. Its underlying cause is de novo germline mutations in the oncogene HRAS. Almost all Costello syndrome mutations affect one of the glycine residues in position 12 or 13 of the protein product. More than 80% of patients with Costello syndrome share the same underlying mutation, resulting in a G12S amino acid change. We report on two patients with novel HRAS mutations affecting amino acids 58 (T58I) and 146 (A146V), respectively. Despite facial features that appear less coarse than those typically seen in Costello patients, both patients show many of the physical and developmental problems characteristic for Costello syndrome. These novel HRAS mutations may be less common than the frequently reported G12S change, or patients with these changes may be undiagnosed due to their less coarse facial features. In addition to the findings previously known to occur in Costello syndrome, one of our patients had hypertrophic pyloric stenosis. This led us to review the medical histories on a cohort of proven HRAS mutation positive Costello syndrome patients, and we found a statistically significantly (P < 0.001) increased frequency of pyloric stenosis in Costello syndrome (5/58) compared to the general population frequency of 2-3/1,000. Thus we add hypertrophic pyloric stenosis to the abnormalities seen with increased frequency in Costello syndrome.

Intracranial calcification, retinopathy, and osteopenia: a new syndrome?

We describe two brothers with bilateral exudative retinopathy, intracranial calcifications, a sclerotic bony disorder, and normal intelligence. The younger brother also has osteopenia, mild splenomegaly, and pancytopenia. We review the literature with emphasis on the unique features of these patients.

Two-year neurodevelopmental outcomes of infants undergoing neonatal cardiac surgery for interrupted aortic arch: a descriptive analysis.

OBJECTIVE: This study determined neurodevelopmental outcomes of survivors of neonatal cardiac surgery for interrupted aortic arch through an interprovincial program and explored preoperative, intraoperative, and postoperative outcome predictors. METHODS: Children who underwent neonatal cardiac surgery for interrupted aortic arch at 6 weeks old or younger between 1996 and 2006 had a multidisciplinary neurodevelopmental assessment at 18 to 24 months old (mental and psychomotor developmental indices as mean +/- SD and delay [score <70]). Survivor outcomes were compared by univariate and multivariate analyses and compared between children with and without chromosomal abnormality. RESULTS: Outcomes were available for all 26 survivors (mortality, 3.7%). Mental and psychomotor developmental indices were 75.8 +/- 17.1 and 72.3 +/- 16.9, respectively, with significantly lower scores for children with chromosomal abnormalities, which accounted for 29% of the variance in developmental indices. For the remaining 17 children without chromosomal abnormalities, mental and psychomotor developmental indices were 82.7 +/- 14.5 and 79.1 +/- 14.3, respectively, with deep hypothermic circulatory arrest time and Apgar score at 5 minutes contributing 46% of the variance in mental developmental index. CONCLUSIONS: The neurodevelopmental indices of children who have undergone neonatal cardiac surgery for interrupted aortic arch are below normative values; those of children with chromosomal abnormalities are even lower. For children without a chromosomal abnormality, longer deep hypothermic circulatory arrest times and low Apgar scores predict lower mental developmental indices at 18 to 24 months of age.

Atypical facet of Möbius syndrome: association with facioscapulohumeral muscular dystrophy.

We describe a patient with facioscapulohumeral muscular dystrophy (FSHD) associated with Möbius syndrome and congenital ophthalmoplegia. This 7-year-old girl had profound limitation of extraocular movements since birth, congenital facial diplegia, neonatal hypotonia, and progressive limb-girdle weakness. FSHD genetic testing revealed a pathogenic haplotype with a D4Z4 repeat of 30 kb. The father carries the same allele, although is minimally affected. This unusual case expands the genotypic-phenotypic spectrum of FSHD.