Axenfeld-Rieger syndrome: more than meets the eye.

BACKGROUND: Axenfeld-Rieger syndrome (ARS) is characterised by typical anterior segment anomalies, with or without systemic features. The discovery of causative genes identified ARS subtypes with distinct phenotypes, but our understanding is incomplete, complicated by the rarity of the condition. METHODS: Genetic and phenotypic characterisation of the largest reported ARS cohort through comprehensive genetic and clinical data analyses. RESULTS: 128 individuals with causative variants in PITX2 or FOXC1, including 81 new cases, were investigated. Ocular anomalies showed significant overlap but with broader variability and earlier onset of glaucoma for FOXC1-related ARS. Systemic anomalies were seen in all individuals with PITX2-related ARS and the majority of those with FOXC1-related ARS. PITX2-related ARS demonstrated typical umbilical anomalies and dental microdontia/hypodontia/oligodontia, along with a novel high rate of Meckel diverticulum. FOXC1-related ARS exhibited characteristic hearing loss and congenital heart defects as well as previously unrecognised phenotypes of dental enamel hypoplasia and/or crowding, a range of skeletal and joint anomalies, hypotonia/early delay and feeding disorders with structural oesophageal anomalies in some. Brain imaging revealed highly penetrant white matter hyperintensities, colpocephaly/ventriculomegaly and frequent arachnoid cysts. The expanded phenotype of FOXC1-related ARS identified here was found to fully overlap features of De Hauwere syndrome. The results were used to generate gene-specific management plans for the two types of ARS. CONCLUSION: Since clinical features of ARS vary significantly based on the affected gene, it is critical that families are provided with a gene-specific diagnosis, PITX2-related ARS or FOXC1-related ARS. De Hauwere syndrome is proposed to be a FOXC1opathy.

A report of GJB2 (N14K) Connexin 26 mutation in two patients--a new subtype of KID syndrome?

Keratitis-ichthyosis-deafness syndrome is a rare congenital ectodermal disorder, characterized by presence of skin lesions, neurosensory hearing loss, and vascularizing keratitis. Several autosomal dominant mutations in the Connexin 26 gene (GJB2) have been discovered as a cause of this syndrome. We report two patients who presented with a combination of clinical features of keratitis-ichthyosis-deafness syndrome (e.g., congenital bilateral neurosensory hearing loss and erythrokeratoderma), however, lacking other characteristics typical of this condition. In addition, they both demonstrated striking mucocutaneous findings (e.g., chronic lip fissuring, gingival hyperemia), resulting in diagnostic difficulties. In both patients, a GJB2 mutation (N14K) was identified, which shares the same gene with classic Keratitis-ichthyosis-deafness syndrome but has never been described in patients with this condition. We propose that the findings observed in our patients are a distinct subtype of Keratitis-ichthyosis-deafness syndrome, thus expanding the spectrum of connexin-associated keratodermias.

A novel GJA 1 mutation in oculo-dento-digital dysplasia with curly hair and hyperkeratosis.

Oculo-dento-digital dysplasia (ODDD) is a rare autosomal dominant congenital disorder mainly affecting the development of the face, eyes, skeletal system, heart and dentition. ODDD has been mapped to chromosome 6q22-q24 and germline mutations have been identified in the connexin 43 gene, GJA1. Abnormalities of the skin, hair, and nails have been recognized in ODDD but are often easily overlooked. We report an ODDD patient with curly hair, early trichorrhexis nodosa and discrete keratoderma. Molecular genetic studies revealed a novel GJA1 mutation affecting the amino terminus of the gap junction protein alpha-1 (Cx43). In the light of the cutaneous findings in our patient and based on recent ectodermal dysplasia classification systems, we propose to include ODDD in the group of ectodermal dysplasias.

Self-healing collodion membrane and mild nonbullous congenital ichthyosiform erythroderma due to 2 novel mutations in the ALOX12B gene.

BACKGROUND: Collodion phenotype is a term applied to the condition affecting a newborn involving a parchmentlike membrane covering the whole body surface (collodion membrane). This presentation is common to several different forms of autosomal recessive congenital ichthyoses, including nonbullous congenital ichthyosiform erythroderma (NCIE), lamellar ichthyosis (LI), and harlequin ichthyosis (HI). Recent years have seen considerable advances in our understanding of the molecular basis of autosomal recessive forms of congenital ichthyosis. Several genetic loci have been identified for LI and NCIE. OBSERVATIONS: We describe the clinical and molecular features of 2 cases of self-healing newborns of collodion phenotype developing mild NCIE. A dramatic improvement of the skin was observed in the first few weeks after birth in both cases. The molecular analysis of the ALOX12B gene demonstrated that both patients were compound heterozygous for previously unreported mutations. CONCLUSIONS: Both patients were compound heterozygous for novel ALOX12B mutations, underscoring the concept that mutations in at least 2 different genes, ALOX12B and TGM1, may result in this unusual clinical phenotype.

KRT14 haploinsufficiency results in increased susceptibility of keratinocytes to TNF-alpha-induced apoptosis and causes Naegeli-Franceschetti-Jadassohn syndrome.

Naegeli-Franceschetti-Jadassohn syndrome (NFJS) is a rare autosomal dominant disorder characterized by loss of dermatoglyphics, reticulate hyperpigmentation of the skin, palmoplantar keratoderma, abnormal sweating, and other developmental anomalies of the teeth, hair, and skin. We recently demonstrated that NFJS is caused by heterozygous nonsense or frameshift mutations in the E1/V1-encoding region of KRT14, but the mechanisms for their deleterious effects in NFJS remain elusive. In this study, we further expand the spectrum of NFJS-causing mutations and demonstrate that these mutations result in haploinsufficiency for keratin 14 (K14). As increased apoptotic activity was observed in the epidermal basal cell layer in NFJS patients and as previous data suggested that type I keratins may confer resistance to tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis in epithelial tissues, we assessed the effect of down-regulation of KRT14 expression on apoptotic activity in keratinocytes. Using a HaCaT cell-based assay, we found that decreased KRT14 expression is associated with increased susceptibility to TNF-alpha-induced apoptosis. This phenomenon was not observed when cells were cultured in the presence of doxycycline, a known negative regulator of TNF-alpha-dependant pro-apoptotic signaling. Collectively, our results indicate that NFJS results from haploinsufficiency for K14 and suggest that increased susceptibility of keratinocytes to pro-apoptotic signals may be involved in the pathogenesis of this ectodermal dysplasia syndrome.

A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis.

Familial tumoral calcinosis (FTC) is a rare autosomal recessive disorder characterized by the progressive deposition of calcified masses in cutaneous and subcutaneous tissues, which results in painful ulcerative lesions and severe skin and bone infections. Two major types of FTC have been recognized: hyperphosphatemic FTC (HFTC) and normophosphatemic FTC (NFTC). HFTC was recently shown to result from mutations in two different genes: GALNT3, which codes for a glycosyltransferase, and FGF23, which codes for a potent phosphaturic protein. To determine the molecular cause of NFTC, we performed homozygosity mapping in five affected families of Jewish Yemenite origin and mapped NFTC to 7q21-7q21.3. Mutation analysis revealed a homozygous mutation in the SAMD9 gene (K1495E), which was found to segregate with the disease in all families and to interfere with the protein expression. Our data suggest that SAMD9 is involved in the regulation of extraosseous calcification, a process of considerable importance in a wide range of diseases as common as atherosclerosis and autoimmune disorders.

Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14.

Naegeli-Franceschetti-Jadassohn syndrome (NFJS) and dermatopathia pigmentosa reticularis (DPR) are two closely related autosomal dominant ectodermal dysplasia syndromes that clinically share complete absence of dermatoglyphics (fingerprint lines), a reticulate pattern of skin hyperpigmentation, thickening of the palms and soles (palmoplantar keratoderma), abnormal sweating, and other subtle developmental anomalies of the teeth, hair, and skin. To decipher the molecular basis of these disorders, we studied one family with DPR and four families with NFJS. We initially reassessed linkage of NFJS/DPR to a previously established locus on 17q11.2-q21. Combined multipoint analysis generated a maximal LOD score of 8.3 at marker D17S800 at a recombination fraction of 0. The disease interval was found to harbor 230 genes, including a large cluster of keratin genes. Heterozygous nonsense or frameshift mutations in KRT14 were found to segregate with the disease trait in all five families. In contrast with KRT14 mutations affecting the central alpha -helical rod domain of keratin 14, which are known to cause epidermolysis bullosa simplex, NFJS/DPR-associated mutations were found in a region of the gene encoding the nonhelical head (E1/V1) domain and are predicted to result in very early termination of translation. These data suggest that KRT14 plays an important role during ontogenesis of dermatoglyphics and sweat glands. Among other functions, the N-terminal part of keratin molecules has been shown to confer protection against proapoptotic signals. Ultrastructural examination of patient skin biopsy specimens provided evidence for increased apoptotic activity in the basal cell layer where KRT14 is expressed, suggesting that apoptosis is an important mechanism in the pathogenesis of NFJS/DPR.