A number sign (#) is used with this entry because of evidence that linear skin defects with multiple congenital anomalies-3 (LSDMCA3) is caused by heterozygous mutation in the NDUFB11 gene (300403) on chromosome Xp11.

Linear skin defects with multiple congenital anomalies-3 (LSDMCA3) is an X-linked dominant disorder characterized by linear skin defects mostly on the face and neck, ocular anomalies without microphthalmia or sclerocornea, and early-onset cardiomyopathy. Severe brain anomalies and seizures have been reported (Van Rahden et al., 2015).

For a discussion of genetic heterogeneity of linear skin defects with multiple congenital anomalies, see LSDMCA1 (309801).

A hemizygous missense mutation in the NDUFB11 gene (300403.0003) has been found in 1 male patient with mitochondrial complex I deficiency (see 252010). That patient died in infancy (Kohda et al., 2016).

Van Rahden et al. (2015) reported 2 unrelated girls with linear skin defects of the face and neck at birth, cardiomyopathy, and various other congenital anomalies. In 1 patient, the skin defects disappeared within the first few months of life; she also exhibited axial hypotonia and failure to thrive. Ocular examination showed lacrimal duct atresia. At 6 months of age, she was hospitalized after cardiac arrest and underwent repeated treatment of ventricular fibrillation and tachycardia, but died within a few weeks. Autopsy revealed histiocytoid cardiomyopathy and thyroid abnormalities, including sites of oncocytic metaplasia and C-cell hyperplasia. The other patient had corpus callosum agenesis and dilated lateral ventricles diagnosed on prenatal ultrasound. At 2 months of age, she had seizures and also developed dilated cardiomyopathy, for which she underwent cardiac transplantation at age 6 months. Eye examination at age 15 months showed myopia, nystagmus, and strabismus. Severe psychomotor delay became evident over time; she started walking at age 3 years and could speak simple sentences and had sphincter control by age 7 years. Severe muscular hypotonia and delayed dentition were also present. Neither patient exhibited microphthalmia or sclerocornea, and blood lactate levels were normal in both. In the second family, ultrasound in the next pregnancy showed thickened myocardium, pericardial effusion, corpus callosum dysgenesis, small cerebellum, connection between a lateral ventricle and the cavum septum pellucidum, and intrauterine growth retardation; the pregnancy was terminated.

The heterozygous mutation in the NDUFB11 gene that was identified in patient 1 with LSDMCA3 by van Rahden et al. (2015) occurred de novo. The heterozygous mutation in patient 2 of van Rahden et al. (2015) was inherited from the unaffected mother.

In 2 unrelated girls with linear skin defects, cardiomyopathy, and various other congenital anomalies, van Rahden et al. (2015) identified heterozygosity for truncating mutations in the NDUFB11 gene (R88X, 300403.0001 and c.402delG, 300403.0002). In 1 family, the proband's unaffected mother was also heterozygous for the c.402delG mutation, as was an aborted affected female fetus. Both the mother and the proband had complete skewing of X-chromosome inactivation (XCI, 100:0) in peripheral blood cells, whereas the ratio in the fetus was 99:1. The affected girl in the other family showed a highly skewed pattern in leukocyte-derived DNA (10:90), whereas her healthy mother, who did not carry the R88X mutation, had a less skewed XCI ratio of 20:80. By shRNA-mediated NDUFB11 knockdown in HeLa cells, van Rahden et al. (2015) demonstrated that NDUFB11 is essential for assembly and activity of complex I in the mitochondrial respiratory chain, as well as for cell growth and survival.