Dermal Aplasia Research Articles

Microphthalmia, Dermal Aplasia, and Sclerocornea Syndrome: A Case Report and Review of Literature

Abstract Microphthalmia, dermal aplasia, and sclerocornea (MIDAS) syndrome is a rare syndrome manifesting at birth with a wide variety of abnormalities which include microphthalmia and/or anophthalmia, sclerocornea, linear skin defects with dermal aplasia limited to the face and neck, ocular abnormalities, central nervous system involvement, cardiac anomalies, hearing impairment, and genitourinary malformations. This report describes MIDAS syndrome in a 6-day-old female neonate who presented with multiple erosions with crusted plaques over the face and neck since birth and bilateral microphthalmia with microcornea with corneal opacity.

Epidermolysis Bullosa Heriditaria

A brief survey of the disease epidermolysis bullosa heriditaria is given. In the Faroe Islands, epidermolysis bullosa has been found to occur in two families. Among a total of 73 affected individuals, 56 are still alive. The disease was found to be systematically transmitted by a dominant, autosomal gene. According to a review of the clinical findings in the indívidual cases, the dísease was of dystrophic type, the symptoms including deformities of nails, scarring after bullae, miliae and, in some cases, bullae involving the mucous membranes. In one of the families, six members had congenital dermal aplasia of the feet.

Geometric Facial Erosions on a Newborn

When a newborn exhibits dermal aplasia on the face and neck, especially if there are ocular anomalies, further investigation is needed to determine if they have MiDAS (microphthalmia, dermal aplasia, and sclerocornea) or other syndromes with associated skin findings. It is essential to diagnose MiDAS syndrome early in life to allow for thorough workup to determine if there are any associated abnormalities in the child that require treatment. While the skin lesions of MiDAS syndrome heal spontaneously, other associated abnormalities require early intervention and can be life threatening.

Mutations in NDUFB11, Encoding a Complex I Component of the Mitochondrial Respiratory Chain, Cause Microphthalmia with Linear Skin Defects Syndrome

Microphthalmia with linear skin defects (MLS) syndrome is an X-linked male-lethal disorder also known as MIDAS (microphthalmia, dermal aplasia, and sclerocornea). Additional clinical features include neurological and cardiac abnormalities. MLS syndrome is genetically heterogeneous given that heterozygous mutations in HCCS or COX7B have been identified in MLS-affected females. Both genes encode proteins involved in the structure and function of complexes III and IV, which form the terminal segment of the mitochondrial respiratory chain (MRC). However, not all individuals with MLS syndrome carry a mutation in either HCCS or COX7B. The majority of MLS-affected females have severe skewing of X chromosome inactivation, suggesting that mutations in HCCS, COX7B, and other as-yet-unidentified X-linked gene(s) cause selective loss of cells in which the mutated X chromosome is active. By applying whole-exome sequencing and filtering for X-chromosomal variants, we identified a de novo nonsense mutation in NDUFB11 (Xp11.23) in one female individual and a heterozygous 1-bp deletion in a second individual, her asymptomatic mother, and an affected aborted fetus of the subject's mother. NDUFB11 encodes one of 30 poorly characterized supernumerary subunits of NADH:ubiquinone oxidoreductase, known as complex I (cI), the first and largest enzyme of the MRC. By shRNA-mediated NDUFB11 knockdown in HeLa cells, we demonstrate that NDUFB11 is essential for cI assembly and activity as well as cell growth and survival. These results demonstrate that X-linked genetic defects leading to the complete inactivation of complex I, III, or IV underlie MLS syndrome. Our data reveal an unexpected role of cI dysfunction in a developmental phenotype, further underscoring the existence of a group of mitochondrial diseases associated with neurocutaneous manifestations.

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.

BackgroundSegmental Xp22.2 monosomy or a heterozygous HCCS mutation is associated with the microphthalmia with linear skin defects (MLS) or MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome, an X-linked disorder with male lethality. HCCS encodes the holocytochrome c-type synthase involved in mitochondrial oxidative phosphorylation (OXPHOS) and programmed cell death.MethodsWe characterized the X-chromosomal abnormality encompassing HCCS or an intragenic mutation in this gene in six new female patients with an MLS phenotype by cytogenetic analysis, fluorescence in situ hybridization, sequencing, and quantitative real-time PCR. The X chromosome inactivation (XCI) pattern was determined and clinical data of the patients were reviewed.ResultsTwo terminal Xp deletions of ≥11.2 Mb, two submicroscopic copy number losses, one of ~850 kb and one of ≥3 Mb, all covering HCCS, 1 nonsense, and one mosaic 2-bp deletion in HCCS are reported. All females had a completely (>98:2) or slightly skewed (82:18) XCI pattern. The most consistent clinical features were microphthalmia/anophthalmia and sclerocornea/corneal opacity in all patients and congenital linear skin defects in 4/6. Additional manifestations included various ocular anomalies, cardiac defects, brain imaging abnormalities, microcephaly, postnatal growth retardation, and facial dysmorphism. However, no obvious clinical sign was observed in three female carriers who were relatives of one patient.ConclusionOur findings showed a wide phenotypic spectrum ranging from asymptomatic females with an HCCS mutation to patients with a neonatal lethal MLS form. Somatic mosaicism and the different ability of embryonic cells to cope with an OXPHOS defect and/or enhanced cell death upon HCCS deficiency likely underlie the great variability in phenotypes.

Dermatoscopic aspects of the Microphthalmia with Linear Skin Defects (MLS) Syndrome

The association of microphthalmia and linear skin defects was named microphthalmia with linear skin defects syndrome (MLS) or MIDAS syndrome (microphthalmia, dermal aplasia, and sclerocornea), an X-chromosomal disorder manifesting mainly in females. We examined a female newborn with facial linear skin defects following the Blaschko lines. Computer tomography and ophthalmological examination confirmed bilateral microphthalmia. An interstitial microdeletion at Xp22.2, encompassing the entire HCCS gene, was identified. Dermatoscopic examination showed erythematous linear areas with telangectasias and absence of sebaceous glands, which appear as brilliant white dots. Vellus hairs were also absent in the red areas. Dermatoscopy could help to establish the diagnosis of MLS/MIDAS syndrome by confirming the aplastic nature of the lesions.

Microphthalmia with Linear Skin Defects Syndrome

Microphthalmia with linear skin defects (MLS) or microcornea, dermal aplasia and sclerocornea (MIDAS) syndrome is a rare X-linked-dominant disorder. We present a patient with agenesis of corpus callosum, ocular abnormalities, and multiple skin defects. The cytogenetic studies of the MLS critical region (Xp22.2) were normal, but a skewed X-chromosome inactivation pattern (85:15) was observed.

MIDAS (microphthalmia, dermal aplasia, sclerocornea) syndrome with central nervous system abnormalities

MIDAS (microphthalmia, dermal aplasia, sclerocornea) syndrome with central nervous system abnormalities

X‐chromosome inactivation: role in skin disease expression

AbstractThe occurrence of X inactivation in mammals has the consequence that all women are functional mosaics. In X‐linked skin disorders, Lyonization usually gives rise to a mosaic pattern, as manifest by the appearance of the lines of Blaschko. This arrangement of lesions is observed in male‐lethal X‐linked traits, such as incontinentia pigmenti, focal dermal hypoplasia, Conradi–Hünermann–Happle syndrome, oral–facial–digital syndrome type 1 and MIDAS (microphthalmia, dermal aplasia and sclerocornea) syndrome, as well as in various X‐linked non‐lethal phenotypes, such as hypohidrotic ectodermal dysplasia of Christ–Siemens–Touraine, IFAP (ichthyosis follicularis–alopecia–photophobia) syndrome and X‐linked dyskeratosis congenita. Analogous X‐inactivation patterns have been documented in human bones, teeth, eyes and, possibly, the brain. Patterns that are distinct from the lines of Blaschko are also seen, such as the lateralization observed in CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, and the chequerboard pattern seen in women heterozygous for X‐linked congenital hypertrichosis. Exceptional cases of either severe or absent involvement in a woman heterozygous for an X‐linked trait can be explained by skewing of X inactivation. Some X‐linked skin disorders are caused by genes that escape inactivation, which is why heterozygous female ‘carriers’ of these disorders do not show mosaicism. A well‐known example is X‐linked recessive ichthyosis due to steroid sulphatase deficiency, the locus for which is situated at the tip of the short arm of the X chromosome and does not undergo Lyonization. On the other hand, in the case of Fabry disease, the gene encoding α‐galactosidase A is subject to inactivation. Remarkably, however, the skin lesions of women do not show a mosaic pattern. Conclusion: In the various X‐linked skin disorders, affected women show quite dissimilar degrees of involvement and forms of manifestation because X inactivation may give rise to different patterns of functional mosaicism. Paradoxically, no such pattern is observed in women with Fabry disease. Like many X‐linked diseases, Fabry disease should neither be called recessive nor dominant, because these dichotomous terms are obscured by the mechanism of X inactivation.

X-chromosome inactivation: role in skin disease expression

The occurrence of X inactivation in mammals has the consequence that all women are functional mosaics. In X-linked skin disorders, Lyonization usually gives rise to a mosaic pattern, as manifest by the appearance of the lines of Blaschko. This arrangement of lesions is observed in male-lethal X-linked traits, such as incontinentia pigmenti, focal dermal hypoplasia, Conradi-Hünermann-Happle syndrome, oral-facial-digital syndrome type 1 and MIDAS (microphthalmia, dermal aplasia and sclerocornea) syndrome, as well as in various X-linked non-lethal phenotypes, such as hypohidrotic ectodermal dysplasia of Christ-Siemens-Touraine, IFAP (ichthyosis follicularis-alopecia-photophobia) syndrome and X-linked dyskeratosis congenita. Analogous X-inactivation patterns have been documented in human bones, teeth, eyes and, possibly, the brain. Patterns that are distinct from the lines of Blaschko are also seen, such as the lateralization observed in CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, and the chequerboard pattern seen in women heterozygous for X-linked congenital hypertrichosis. Exceptional cases of either severe or absent involvement in a woman heterozygous for an X-linked trait can be explained by skewing of X inactivation. Some X-linked skin disorders are caused by genes that escape inactivation, which is why heterozygous female 'carriers' of these disorders do not show mosaicism. A well-known example is X-linked recessive ichthyosis due to steroid sulphatase deficiency, the locus for which is situated at the tip of the short arm of the X chromosome and does not undergo Lyonization. On the other hand, in the case of Fabry disease, the gene encoding alpha-galactosidase A is subject to inactivation. Remarkably, however, the skin lesions of women do not show a mosaic pattern. In the various X-linked skin disorders, affected women show quite dissimilar degrees of involvement and forms of manifestation because X inactivation may give rise to different patterns of functional mosaicism. Paradoxically, no such pattern is observed in women with Fabry disease. Like many X-linked diseases, Fabry disease should neither be called recessive nor dominant, because these dichotomous terms are obscured by the mechanism of X inactivation.

Prenatal diagnosis of MIDAS/MLS syndrome associated with a deletion at Xp22.1

Deletions of Xp22 have been associated with a phenotype involving micropthalmia, linear skin defects of the upper half of the body, and corneal opacities. This phenotype has been described under a variety of names including MIDAS syndrome (Microphthalmia, Dermal Aplasia, and Sclerocornea), MLS (Microphthalmia with Linear Skin defects) and Gazali-Temple syndrome. The condition has been reported exclusively in females, with the exception of at least two XX phenotypic males. The severity in females is variable. Mild cases may be characterized by short stature and minimal residual facial scarring. More severe cases can include the skin lesions and eye anomalies, as well as more severe anatomic defects such as agenesis or hypoplasia of the corpus callosum, congenital heart defects, genital anomalies, and rarely, diaphragmatic hernia. We describe the first prenatal diagnosis of this condition in the absence of a family history. An amniocentesis performed at 18 weeks gestational age due to sonographic detection of a diaphragmatic hernia revealed a karyotype of 46,X,del(X)(p22.1). Parental karyotypes were normal. Communication with the cytogenetics laboratory suggested that the phenotype of the fetus would most likely be similar to Turner syndrome, with an unrelated diaphragmatic hernia. Additional sonographic findings at 25 weeks included mild ventriculomegaly, polyhydramnios, and poor visualization of the cavum septum pellucidum, suggesting agenesis of the corpus callosum. Based on the cytogenetic and sonographic findings, a diagnosis of MIDAS/MLS syndrome was suspected. Autopsy performed following elective termination revealed a left diaphragmatic hernia, bilateral linear skin defects of the face and neck, and probable agenesis of the corpus callosum. Pathological evaluation of the eyes was not performed, although on gross evaluation the eyes were noted to be small. These post mortem findings are consistent with MIDAS/MLS syndrome. Prenatal detection of Xp22 deletions should prompt a detailed evaluation for features of MIDAS/MLS syndrome.

Ocular manifestations of genetic and developmental diseases.

Significant advances were reported this year in our understanding of the association of lens opacities with neurofibromatosis type 2 and the genetics of the aniridia-Wilms' tumor association. The first successful surgical reattachment of detached retinas in patients with incontinentia pigmenti are reported. An important retrospective review of young adults with congenital rubella syndrome implies that the timing of infection during gestation is not related to the incidence of individual ocular conditions. The ophthalmic features of the MELAS syndrome, a mitochondrially inherited encephalomyopathy, are described. Cytogenetic techniques are utilized for the first time to investigate the association between conjunctival and uveal melanomas with the dysplastic nevus syndrome. Familial Duane's syndrome and urogenital abnormalities were associated with a bisatellited marker derived from chromosome 22. Finally, another case of the newly described association of microphthalmia, dermal aplasia, and sclerocornea (MIDAS syndrome) is reported.

MIDAS syndrome (microphthalmia, dermal aplasia, and sclerocornea): An X‐linked phenotype distinct from Goltz syndrome

Bilateral microphthalmia with blepharophimosis, linear lesions of dermal aplasia involving the face, and microcephaly were present in a newborn girl who died at age 9 months from cardiomyopathy resulting in ventricular fibrillation. Autopsy showed an atrial septum defect, persistent gross trabeculation of the left ventricle, and an arteria lusoria. This case represents a further example of a new entity for which we propose the term MIDAS syndrome. The acronym stands for microphthalmia, dermal aplasia, and sclerocornea. Our patient is the second with this syndrome to have a major congenital heart defect. Cytogenetic studies reported in previous cases indicate that the underlying gene defect can be assigned to Xp22.3. This new X-linked male-lethal trait should be distinguished from focal dermal hypoplasia that will be found to map elsewhere on the X-chromosome.