The microphthalmia with linear skin defects syndrome (MLS) is an X-linked dominant disorder characterized by unilateral or bilateral microphthalmia and linear skin defects--which are limited to the face and neck, consisting of areas of aplastic skin that heal ... The microphthalmia with linear skin defects syndrome (MLS) is an X-linked dominant disorder characterized by unilateral or bilateral microphthalmia and linear skin defects--which are limited to the face and neck, consisting of areas of aplastic skin that heal with age to form hyperpigmented areas--in affected females and in utero lethality for males (Wimplinger et al., 2006). A similar form of congenital linear skin defects, also limited to the face and neck and associated with microcephaly, facial dysmorphism, and other congenital anomalies (300887) is caused by mutation in the COX7B gene (300885) on chromosome Xq21.
In 2 females with de novo X;Y translocations, Al Gazali et al. (1990) described manifestations including irregular linear areas of erythematous skin hypoplasia involving the head and neck, along with eye findings that included microphthalmia, corneal opacities, and ... In 2 females with de novo X;Y translocations, Al Gazali et al. (1990) described manifestations including irregular linear areas of erythematous skin hypoplasia involving the head and neck, along with eye findings that included microphthalmia, corneal opacities, and orbital cysts. The features were considered distinct from those of either focal dermal hypoplasia (FDH; 305600) or incontinentia pigmenti (308300). Cytogenetic analysis showed that the breakpoint in the X chromosome was at Xp22.3 in both females. Al Gazali et al. (1990) suggested that deletion or disruption of DNA sequences in the region of Xp22.3 was responsible for this syndrome. It had been suggested that focal dermal hypoplasia maps to the same region, Xp22.31. Temple et al. (1990) reported a third case with a terminal deletion of Xpter-p22.2. Allanson and Richter (1991) reported a newborn female with identical skin findings of the head and neck, bilateral microphthalmia, and corneal opacities; the terminal deletion of the X chromosome with breakpoint at Xp22.2 was also present. Diaphragmatic hernia, causing severe respiratory distress, led to death after unsuccessful surgical repair. Necropsy showed absence of the septum pellucidum with an ectopic area of gray and white matter. The mother was found to have an identical terminal deletion of the X chromosome with the breakpoint at Xp22.2. She was of normal intelligence but her height was less than the third centile. She had depigmented patches of skin visible either with the naked eye or with ultraviolet light, and 3 of 4 wisdom teeth were unerupted. This disorder is presumably lethal in the hemizygous male (Ballabio, 1993). Happle et al. (1993) reported an affected female with this disorder, which they called MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome, who died at age 9 months from cardiomyopathy resulting in ventricular fibrillation. Happle et al. (1993) maintained that MIDAS syndrome is distinct from FDH and noted that deletion at Xp22.3 has never been demonstrated in typical cases of FDH, but only in cases with the MIDAS complex. They argued that, in contrast to FDH, the aplastic skin lesions of the MIDAS syndrome are limited to the upper half of the body, often involving the face and neck exclusively, and they do not show herniation of fatty tissue. Moreover, several other manifestations of FDH, such as perioral papillomatous lesions, clefting of the hands or feet, syndactyly, and coloboma are absent in MIDAS syndrome. They contended that these marked clinical differences supported the notion that the gene for FDH could not be assigned to Xp22.3 or to a neighboring locus. Wapenaar et al. (1993) used cell lines from patients with deletions and translocations involving the Xp22 region to map the loci for ocular albinism type I (OA1; 300500) and MLS. A 2.6-Mb YAC contig, spanning the critical regions of these 2 disorders, was assembled. Restriction analysis of the contigs established the sizes of the critical regions to be 200 kb for OA1 and 800-925 kb for MLS. Ten potential CpG islands, representing candidate sites for genes, were mapped within the 2.6-Mb region. MLS was found to lie proximal to OA1. Wapenaar et al. (1993) pointed out that other features in these patients--retinal lacunae, agenesis of the corpus callosum, costovertebral abnormalities, mental retardation, and seizures--overlap with features of the Aicardi syndrome (304050) and Goltz syndrome (focal dermal hypoplasia), suggesting that different defects in the same gene may be responsible for these 3 disorders. Lindsay et al. (1994) described the clinical, cytogenetic, and molecular characteristics of 3 patients with MLS. In 2 of them, females, a terminal Xpter-p22.2 deletion was present. One of these 2 patients had an aborted fetus with anencephaly and the same chromosome anomaly. The third patient was an XX male with an Xp/Yp exchange spanning the SRY gene (480000), resulting in distal Xp monosomy. Extensive clinical variability observed in these patients and the results of molecular analysis suggested that X-inactivation plays an important role in determining the phenotype of the MLS syndrome. They proposed that MLS, Aicardi syndrome, and Goltz syndrome are due to involvement of the same gene or genes, and the different patterns of X-inactivation are responsible for the phenotypic differences observed in the 3 disorders. However, they could not rule out that each component of the MLS phenotype is caused by deletion of a different gene, i.e., that MLS represents a contiguous gene syndrome. Mucke et al. (1995) described MIDAS syndrome in a mother and her daughter who showed strikingly similar features. The daughter was pictured at age 2 years with bilateral microphthalmia and sclerocornea. Bilateral anterior chamber eye anomaly had caused glaucoma, resulting in a spontaneous perforation on the right side. At the age of 11, the patient was found to have hypertrophy of the clitoris with a normal vagina and rudimentary uterus as well as a dysgenetic testis on the right and an ovotestis on the left. The mother, who was blind, had linear skin defects in the mandibular area similar to those in the daughter. Corneal opacities were not found in the mother. Mucke et al. (1995) stated that this was the first report of a familial occurrence of definite full-blown MIDAS syndrome. Furthermore, they insisted that MIDAS syndrome is distinct from Goltz syndrome and Aicardi syndrome. They stated that at least 4 of 16 cases of MIDAS syndrome have displayed anomalies of external or internal genitalia. With the exception of 1 XX male, the MIDAS syndrome had so far occurred exclusively in females. An X/Y translocation had been documented in 5 cases, including the 2 patients reported by Mucke et al. (1995). Patients with MIDAS syndrome are often short of stature. Zvulunov et al. (1998) reviewed 21 reported patients with aplasia cutis congenita and microphthalmia. Tabulation of the significant features showed that in addition to the characteristic reticulolinear facial skin defects, which were present in all cases, and microphthalmia, which was present in 18 (86%) of the 21 patients, short stature was another prevalent feature, present in 10 (83%) of the 12 patients for whom stature had been described. Stratton et al. (1998) reported a second 46,XX male with MIDAS syndrome. In addition to microphthalmia and linear skin streaks, he had a secundum ASD, hypospadias with chordee, anal fistula, and agenesis of the corpus callosum with colpocephaly (dilation of the posterior portions of the lateral ventricles). Biopsy of a linear streak showed smooth muscle hamartomata rather than the presumed dermal aplasia. Detailed ophthalmologic examination did not show retinal lacunae typical of Aicardi syndrome. DNA studies with distal Xp-specific probes indicated a deletion of 1 X chromosome, and fluorescence in situ hybridization studies with X- and Y-specific probes demonstrated the presence of a derivative X chromosome from an X;Y translocation. Ogata et al. (1998) described a female infant with microphthalmia with linear skin defects syndrome and monosomy for the Xp22 region. The clinical features included right microphthalmia and sclerocornea, left corneal opacity, linear red rash and scar-like skin lesions on the nose and cheeks, and absence of the corpus callosum. Microsatellite analysis disclosed monosomy for Xp22 involving the critical region for the MLS gene. X-inactivation analysis for the methylation status of the PGK1 gene (311800) indicated the presence of inactive normal X chromosomes. They concluded from this and other findings that functional absence of the MLS gene caused by inactivation of the normal X chromosome plays a pivotal role in the development of MLS in patients with Xp22 monosomy. Kayserili et al. (2001) described a case of MLS. Cytogenetic and molecular analysis identified the region within which the MLS gene may reside as being a 260-kb interval between the 5-prime end of the MID1 gene (300552) and the 3-prime end of the ARHGAP6 gene (300118). Using FISH probes and molecular investigations to study the mother and daughter with MLS reported by Mucke et al. (1995), Kotzot et al. (2002) determined the exact physical location of the centromere of the X chromosome and the presence of SRY on one X chromosome. In addition, they demonstrated lack of signals for STS (300747) and Kallmann (300836) probes on this X chromosome. Therefore, the breakpoint was mapped proximally to the STS and Kallmann loci. Kotzot et al. (2002) stated that apart from their familial cases, 8 sporadic patients with MLS and a 46,XX,t(X;Y) karyotype had been reported. In all patients the breakpoints were mapped to Xp22.3. Anguiano et al. (2003) described twin brothers with microphthalmia, facial dermal hypoplasia, sclerocornea, and supraventricular tachycardia. They were found to have an XX chromosome modality with a subtle Xp/Yp translocation proven by the presence of the SRY gene. The pregnancy was complicated by fetal supraventricular tachycardia, which was treated with digoxin prenatally. Postnatally, both twins required treatment with adenosine, digoxin, and propanolol to remain in normal sinus rhythm. Both twins had a selective X inactivation of the derivative X chromosome carrying the Xp/Yp translocation.
Morleo et al. (2005) reported the clinical, cytogenetic, and molecular characterization of 11 patients, 7 of whom had not been described previously. Chromosomal abnormalities of the short arm of the X chromosome were present in 7 of the ... Morleo et al. (2005) reported the clinical, cytogenetic, and molecular characterization of 11 patients, 7 of whom had not been described previously. Chromosomal abnormalities of the short arm of the X chromosome were present in 7 of the patients, 1 of whom displayed an interstitial Xp22.3 deletion. Four patients with clinical features of MLS had apparently normal karyotypes, verified by FISH analysis using genomic clones spanning the MLS minimal critical region, and with genomewide analysis using a 1-Mb resolution BAC microarray. Direct sequencing of coding regions and splice junctions for 3 candidate genes in the critical region, MID1, HCCS, and ARHGAP6, did not reveal any pathogenic changes. Wimplinger et al. (2006) investigated the family with MLS in which the youngest daughter, who had a classic phenotype and normal karyotype, had previously been studied by Morleo et al. (2005) and no pathogenic mutations had been found in the MID1, HCCS, or ARHGAP6 genes. The eldest daughter of the family had a milder phenotype. The mother, who had no obvious signs of MLS but had a history of skin lesions in infancy that disappeared over time, had 3 miscarriages early in the first trimester and also gave birth to a daughter with bilateral clinical anophthalmia who died at 6 hours. DNA analysis revealed the presence of a heterozygous 8.6-kb deletion encompassing part of the HCCS gene (300056.0001) in the mother and the 2 affected daughters; the deletion was not found in 3 sons or an unaffected daughter. Wimplinger et al. (2006) performed sequence analysis of the HCCS gene in 2 unrelated girls with MLS and normal karyotypes and identified heterozygosity for a de novo nonsense mutation (300056.0002) and a de novo missense mutation (300056.0003), respectively. Noting that cytochrome c is the final product of HCCS activity, Wimplinger et al. (2006) suggested that disturbance of both oxidative phosphorylation and the balance between apoptosis and necrosis, as well as X-inactivation patterns, may contribute to the variable phenotype observed in patients with MLS.