A number sign (#) is used with this entry because of evidence that linear skin defects with multiple congenital anomalies-2 (LSDMCA2) is caused by mutation in the COX7B gene (300885) on chromosome Xq21.

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

Zvulunov et al. (1998) described a female infant, born of unrelated Jewish parents, who at birth had extensive areas of denuded skin over the neck and face with reepithelialization already apparent in some of the lesions. In addition, well-defined depressed linear scars were present along the midline of the nose and chin, and over the extensor surfaces of the fourth fingers on both hands. Histologic examination of perilesional skin did not show intraepidermal or subepidermal cleavage, and there was regeneration of the dermis and a mild perivascular lymphocytic infiltrate in the upper dermis. Electron microscopy of perilesional skin revealed 'peculiar' cytoplasmic bodies within keratinocytes that measured about 80 to 100 nm in diameter and had an electron-dense membrane; the bodies resembled viral particles but none contained chromatin and there was no cytopathic effect in the nuclei. Histologic examination of uninvolved skin was unremarkable. At 2 years of age, facial dysmorphism was noted that included hypertelorism, high forehead, and long philtrum. She also had short stature, small head circumference, and weight below the 3rd centile for age; psychomotor development was normal. The mother had 3 subsequent pregnancies, 2 of which terminated in spontaneous abortion during the first trimester and 1 of which resulted in the birth of a healthy girl. Zvulunov et al. (1998) noted that the clinical presentation strikingly resembled that reported in the syndrome of linear facial skin defects with microphthalmia (LSDMCA1; 309801), which was associated with deletion on chromosome Xp22; however, FISH analysis using Xp22.3-specific probes showed normal labeling of the X chromosomes in this patient.

Indrieri et al. (2012) studied 2 female patients with linear skin defects and facial dysmorphism, 1 of whom was the patient originally reported by Zvulunov et al. (1998), as well as an affected mother and daughter. The previously unreported girl was born at term of nonconsanguineous parents and presented with poor growth, microcephaly, multiple linear skin defects on the face and neck, an asymmetric face with limited eyelid closure, small chin, and right clubfoot. Cranial ultrasound revealed a thin corpus callosum but no ocular abnormalities, and echocardiogram showed ventricular hypertrophy, pulmonary hypertension, and a small atrial septal defect. A right diaphragmatic hernia was surgically corrected, and she had left renal agenesis and ureteral duplication of the right kidney. Follow-up examination showed short stature; linear skin defects had healed over time, although they were still evident on the cheeks and chin; and she had mild psychomotor delay and learning difficulties. The affected mother and daughter had linear skin defects apparent at birth; the daughter was the product of the mother's fourth pregnancy, the 3 earlier pregnancies having ended in spontaneous abortion in the first trimester. Additional features in the daughter included microcephaly, linear and patchy erythroderma on the cheeks and neck, facial dysmorphism including telecanthus, arched eyebrows, long upslanting palpebral fissures, short nose, mild retrognathia, and posteriorly rotated ears. She had tetralogy of Fallot, an asymmetric thorax with widely spaced nipples, bilateral clinodactyly of the fifth fingers, and bilateral sandal gap. She developed intellectual disabilities and was diagnosed with attention-deficit/hyperactivity disorder at 4 years of age; brain MRI showed delayed myelination. She had poor vision, and ophthalmologic examination revealed pale optic discs and altered visual evoked potentials. Array CGH excluded deletion of the Xp22 region; she had a 387-kb microduplication of unknown clinical significance on chromosome 12p13.33 that was also present in her healthy father.

In 4 female patients, including the patient originally reported by Zvulunov et al. (1998), with linear skin defects reminiscent of those associated with mutation or deletions at chromosome Xp22 (see LSDMCA1, 309801) but in whom FISH studies or array CGH excluded deletion or translocation of the Xp22 region, Indrieri et al. (2012) analyzed the candidate mitochondrial respiratory chain-associated gene COX7B (300885) on Xq21 and identified heterozygosity for a 1-bp deletion, a splice site mutation, and a nonsense mutation, respectively (300885.0001-300885.0003). Although none of these patients had microphthalmia, downregulation of the COX7B ortholog in medaka fish resulted in microcephaly and microphthalmia that recapitulated the LSDMCA1 phenotype. Indrieri et al. (2012) suggested that lack of microphthalmia in their patients might be explained by a selective pattern of X inactivation.