Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1.

Although it is well recognized that a peripheral vasculopathy may occur in patients with neurofibromatosis 1 (NF1), it is unclear whether cardiovascular abnormalities are more common. We reviewed the frequency of cardiovascular abnormalities, in particular, cardiovascular malformations (CVMs), among 2322 patients with definite NF1 in the National Neurofibromatosis Foundation International Database from 1991-98. Cardiovascular malformations were reported in 54/2322 (2.3%) of the NF1 patients, only 4 of whom had Watson syndrome or NF1-Noonan syndrome. There was a predominance of Class II "flow" defects [Clark, 1995: Moss and Adams' Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult. p 60-70] (43/54, 80%) among the NF1 patients with CVMs. Pulmonic stenosis, that was present in 25 NF1 patients, and aortic coarctation, that occurred in 5, constitute much larger proportions of all CVMs than expected. Of interest was the paucity of Class I conotruncal defects (2 patients with tetralogy of Fallot), and the absence of atrioventricular canal, anomalous pulmonary venous return, complex single ventricle and laterality defects. Besides the 54 patients with CVMs, there were 27 patients with other cardiac abnormalities (16 with murmur, 5 with mitral valve prolapse, 1 with intracardiac tumor, and 5 with electrocardiogram abnormalities). No patient in this study had hypertrophic cardiomyopathy. There were 16 patients who had a peripheral vascular abnormality without an intracardiac CVM, plus an additional 4 patients among those with a CVM who also had a peripheral vascular abnormality.

Bone marrow transplantation for infantile ceramidase deficiency (Farber disease).

Infantile ceramidase deficiency (Farber disease) is an uncommon, progressive lysosomal storage disease characterized by multiple ceramide-containing nodules (lipogranulomata) in the subcutaneous tissue and upper aerodigestive tract, painful periarticular swelling, psychomotor retardation, and varying degrees of ocular, pulmonary or hepatic involvement. Management of Farber disease has been limited to symptomatic supportive care, and few affected infants survive beyond 5 years of age. We performed an allogeneic bone marrow transplant (BMT) from an HLA-identical heterozygous sister in a 9.5-month-old female with minimally symptomatic Farber disease who received a pre-transplant regimen of busulfan and cyclophosphamide. Ceramidase activity in peripheral blood leukocytes increased from 6% before transplant to 44% (donor heterozygote level) by 6 weeks after BMT. By 2 months after transplant, the patient's subcutaneous lipogranulomata, pain on joint motion, and hoarseness had resolved. Despite modest gains in cognitive and language development, hypotonia and delayed motor skills persisted. Gradual loss of circulating donor cells with autologous hematopoietic recovery occurred; VNTR analyses showed 50% donor DNA in peripheral blood cells at 8.5 months after BMT and only 1% at 21 months after transplant. Interestingly, leukocyte ceramidase activity consistently remained in the heterozygous range despite attrition of donor cells in peripheral blood. This novel observation indicates ongoing hydrolase production by non-circulating donor cells, possibly in the mononuclear phagocytic system, and uptake by recipient leukocytes. Although lipogranulomata and hoarseness did not recur, the patient's neurological and neurocognitive status progressively declined. She died 28 months after BMT (age 37.5 months) with pulmonary insufficiency caused by recurrent aspiration pneumonias. Allogeneic BMT improves the peripheral manifestations of infantile ceramidase deficiency, but may not prevent the progressive neurological deterioration, even when carried out in minimally symptomatic patients.

Chiari malformation, cervical spine anomalies, and neurologic deficits in velocardiofacial syndrome.

The purpose of this investigation was to evaluate the prevalence of Chiari malformation, cervical spine anomalies, and neurologic deficits in patients with velocardio-facial syndrome. This study was a prospective evaluation of 41 consecutive patients with velocardiofacial syndrome, documented by fluorescence in situ hybridization, between March of 1994 and September of 1998. The 23 girls and 18 boys ranged in age from 0.5 to 15.2 years, with a mean age of 6.7 years. Nineteen patients were assessed with magnetic resonance imaging, 39 underwent lateral cephalometric radiography, and all patients were examined for neurologic deficits. Eight of 19 patients (42 percent) had anomalies of the craniovertebral junction, including Chiari type I malformations (n = 4), occipitalization of the atlas (n = 3), and narrowing of the foramen magnum (n = 1). One patient with Chiari malformation required suboccipital craniectomy with laminectomy and decompression. Fourteen of 41 patients (34 percent) had demonstrated neurologic deficits; 10 patients (24 percent) had velar paresis (6 unilateral and 4 bilateral). Chiari malformations, cervical spine anomalies, and neurologic deficits are common in velocardiofacial syndrome. Because these findings may influence the outcome of surgical intervention, routine assessment of patients with velocardiofacial syndrome should include careful orofacial examination, lateral cephalometric radiography, and magnetic resonance imaging of the craniovertebral junction.