Microphthalmia with linear skin defects (MLS) syndrome: Clinical, cytogenetic, and molecular characterization of 11 cases

Abstract

The microphthalmia with linear skin defects (MLS) syndrome (MIM 309801) is a severe and rare developmental disorder, which is inherited as an X-linked dominant trait with male lethality. In the vast majority of patients, this syndrome is associated with terminal deletion of the Xp22.3 region. Thirty-five cases have been described to date in the literature since the first description of the syndrome in the early 1990s. We now report on the clinical, cytogenetic, and molecular characterization of 11 patients, 7 of whom have not been described previously. Seven of these patients have chromosomal abnormalities of the short arm of the X-chromosome, which were characterized and defined by fluorescence in situ hybridization (FISH) analysis. Intriguingly, one of the patients displays an interstitial Xp22.3 deletion, which to the best of our knowledge is the first reported for this condition. Finally we report on the identification and molecular characterization of four cases with clinical features of MLS but apparently normal karyotypes, verified by FISH analysis using genomic clones spanning the MLS minimal critical region, and with genome-wide analysis using a 1 Mb resolution BAC microarray. These patients made it possible to undertake mutation screening of candidate genes and may prove critical for the identification of the gene responsible for this challenging and intriguing genetic disease.

Microphthalmia with Linear Skin Defects: A Case Report and Review

“…Other associated characteristics of MLS syndrome (described in detail in Table 2) include short stature, developmental delay, congenital heart defects, diaphragmatic hernia, agenesis of the corpus callosum, anencephaly, hydrocephalus, and seizures. As in our patient, preauricular pits and abnormal or failed hearing tests have also been reported (10,12,16,24). In addition, many of the published cases of MLS syndrome describe genitourinary malformations including ambiguous genitalia, penile hypospadias, and bicornuate uterus (2,12,15,17,19,23).…”

Microphthalmia with Linear Skin Defects: A Case Report and Review

“…Other associated characteristics of MLS syndrome (described in detail in Table 2) include short stature, developmental delay, congenital heart defects, diaphragmatic hernia, agenesis of the corpus callosum, anencephaly, hydrocephalus, and seizures. As in our patient, preauricular pits and abnormal or failed hearing tests have also been reported (10,12,16,24). In addition, many of the published cases of MLS syndrome describe genitourinary malformations including ambiguous genitalia, penile hypospadias, and bicornuate uterus (2,12,15,17,19,23).…”

Microphthalmia with linear skin defects (MLS) syndrome evaluated by prenatal karyotyping, FISH and array comparative genomic hybridization

“…Linear skin defects and eye abnormalities typically seen with MLS syndrome were present, as well as central nervous system involvement, including agenesis of the corpus callosum and ventriculomegaly. In addition, our patient had a severe structural cardiac defect, a rarer feature of MLS syndrome (Morleo et al, 2005). Prenatal karyotype analysis showed an X;Y translocation that was confirmed and further characterized by array CGH and FISH.…”

Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome

“…A few individuals had developmental delay, short stature and facial dysmorphism (Table 1). Rarely, hearing loss and anal atresia with ectopic anus and fistula, as seen in patient 5 have also been observed in other cases [13,35,40,41]. Patient 2 and one reported girl [4] carried the HCCS nonsense mutation c.589C > T (p.R197*).…”

Microphthalmia with Linear Skin Defects: A Case Report and Review

“…Other associated characteristics of MLS syndrome (described in detail in Table 2) include short stature, developmental delay, congenital heart defects, diaphragmatic hernia, agenesis of the corpus callosum, anencephaly, hydrocephalus, and seizures. As in our patient, preauricular pits and abnormal or failed hearing tests have also been reported (10,12,16,24). In addition, many of the published cases of MLS syndrome describe genitourinary malformations including ambiguous genitalia, penile hypospadias, and bicornuate uterus (2,12,15,17,19,23).…”

Microphthalmia with linear skin defects (MLS) syndrome evaluated by prenatal karyotyping, FISH and array comparative genomic hybridization

“…Linear skin defects and eye abnormalities typically seen with MLS syndrome were present, as well as central nervous system involvement, including agenesis of the corpus callosum and ventriculomegaly. In addition, our patient had a severe structural cardiac defect, a rarer feature of MLS syndrome (Morleo et al, 2005). Prenatal karyotype analysis showed an X;Y translocation that was confirmed and further characterized by array CGH and FISH.…”

Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome

“…A few individuals had developmental delay, short stature and facial dysmorphism (Table 1). Rarely, hearing loss and anal atresia with ectopic anus and fistula, as seen in patient 5 have also been observed in other cases [13,35,40,41]. Patient 2 and one reported girl [4] carried the HCCS nonsense mutation c.589C > T (p.R197*).…”

Microphthalmia with Linear Skin Defects: A Case Report and Review

“…Other associated characteristics of MLS syndrome (described in detail in Table 2) include short stature, developmental delay, congenital heart defects, diaphragmatic hernia, agenesis of the corpus callosum, anencephaly, hydrocephalus, and seizures. As in our patient, preauricular pits and abnormal or failed hearing tests have also been reported (10,12,16,24). In addition, many of the published cases of MLS syndrome describe genitourinary malformations including ambiguous genitalia, penile hypospadias, and bicornuate uterus (2,12,15,17,19,23).…”

Microphthalmia with linear skin defects (MLS) syndrome evaluated by prenatal karyotyping, FISH and array comparative genomic hybridization

“…Linear skin defects and eye abnormalities typically seen with MLS syndrome were present, as well as central nervous system involvement, including agenesis of the corpus callosum and ventriculomegaly. In addition, our patient had a severe structural cardiac defect, a rarer feature of MLS syndrome (Morleo et al, 2005). Prenatal karyotype analysis showed an X;Y translocation that was confirmed and further characterized by array CGH and FISH.…”

Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome

“…A few individuals had developmental delay, short stature and facial dysmorphism (Table 1). Rarely, hearing loss and anal atresia with ectopic anus and fistula, as seen in patient 5 have also been observed in other cases [13,35,40,41]. Patient 2 and one reported girl [4] carried the HCCS nonsense mutation c.589C > T (p.R197*).…”