Germline thymidylate synthase deficiency impacts nucleotide metabolism and causes dyskeratosis congenita.

Dyskeratosis congenita (DC) is an inherited bone-marrow-failure disorder characterized by a triad of mucocutaneous features that include abnormal skin pigmentation, nail dystrophy, and oral leucoplakia. Despite the identification of several genetic variants that cause DC, a significant proportion of probands remain without a molecular diagnosis. In a cohort of eight independent DC-affected families, we have identified a remarkable series of heterozygous germline variants in the gene encoding thymidylate synthase (TYMS). Although the inheritance appeared to be autosomal recessive, one parent in each family had a wild-type TYMS coding sequence. Targeted genomic sequencing identified a specific haplotype and rare variants in the naturally occurring TYMS antisense regulator ENOSF1 (enolase super family 1) inherited from the other parent. Lymphoblastoid cells from affected probands have severe TYMS deficiency, altered cellular deoxyribonucleotide triphosphate pools, and hypersensitivity to the TYMS-specific inhibitor 5-fluorouracil. These defects in the nucleotide metabolism pathway resulted in genotoxic stress, defective transcription, and abnormal telomere maintenance. Gene-rescue studies in cells from affected probands revealed that post-transcriptional epistatic silencing of TYMS is occurring via elevated ENOSF1. These cell and molecular abnormalities generated by the combination of germline digenic variants at the TYMS-ENOSF1 locus represent a unique pathogenetic pathway for DC causation in these affected individuals, whereas the parents who are carriers of either of these variants in a singular fashion remain unaffected.

Vitamin D status in children with congenital melanocytic nevi.

Congenital melanocytic nevi (CMN) are rare, pigmented birthmarks that can predispose patients to melanoma of the central nervous system and skin. Data from non-CMN melanoma cohorts suggest that vitamin D levels may be connected to outcome, prompting this study of 25-hydroxyvitamin D levels in plasma samples from 40 children with CMN. While 27% were insufficient and 13% deficient, this was representative of European populations, and UK supplementation guidelines are already in place. Our data support routine vitamin D supplementation for all CMN patients during winter months, without routine serum measurement.

Congenital melanocytic naevus syndrome and Dandy-Walker malformation - a mistaken association: case report and literature review.

Congenital melanocytic naevus (CMN) syndrome, previously termed neurocutaneous melanosis, is a rare disease caused by postzygotic mosaic mutations occurring during embryogenesis in precursors of melanocytes. The severity of neurological manifestations in CMN patients is related to central nervous system abnormalities found at magnetic resonance imaging. The association between CMN and Dandy-Walker malformation (DWM) has been described in the literature, but recent advances in imaging and genetics lead to diagnostic criteria revision. In this paper, we aim to re-evaluate the proposed association by reviewing the available literature and present a patient with CMN and a large posterior fossa cyst.

Impact of public exhibition on the perception of birthmarks.

BACKGROUND: The importance of photographs in social media, the steep rise in popularity of tattoos, and the prominence of individuals with visibly different skin in fashion are likely to be changing the landscape of self- and public perception of birthmarks. Study objectives were to assess the impact of a photoshoot and public exhibition on the self-perception of individuals with extensive birthmarks, and to explore the viewing public's reactions. METHODS: Thirty individuals with congenital melanocytic nevi (CMN) were recruited internationally. Each had a professional photoshoot portrait with their skin exposed, resulting in a public exhibition in London entitled "How do you C Me Now?" Participants/parents completed pre- and post-questionnaires relating to self-perception and the impact of their birthmarks on behavior. Over 8000 members of the public viewed the exhibition, 464 completing an on-site questionnaire on its effects. RESULTS: All participants/parents rated the experience as positive, valuable and helpful. Scores on self-appreciation and self-confidence were significantly higher after the photo shoot. Members of the general public overwhelmingly reported the exhibition increased their positive feelings towards people with birthmarks. The majority of public respondents also reported that the exhibition made them feel better about their own skin and about their looks in general. CONCLUSION: This unique exhibition and the associated research has provided a striking new perspective on potential psychological interventions for individuals with birthmarks.

Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis.

RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in DKC1, NOP10, or NHP2 cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition. Here, we report a phenotype comprising nephrotic syndrome, cataracts, sensorineural deafness, enterocolitis, and early lethality in two pedigrees: males with DKC1 p.Glu206Lys and two children with homozygous NOP10 p.Thr16Met. Females with heterozygous DKC1 p.Glu206Lys developed cataracts and sensorineural deafness, but nephrotic syndrome in only one case of skewed X-inactivation. We found telomere attrition in both pedigrees, but no mucocutaneous abnormalities suggestive of DC. Both mutations fall at the dyskerin-NOP10 binding interface in a region distinct from those implicated in DC, impair the dyskerin-NOP10 interaction, and disrupt the catalytic pseudouridylation site. Accordingly, we found reduced pseudouridine levels in the ribosomal RNA (rRNA) of the patients. Zebrafish dkc1 mutants recapitulate the human phenotype and show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. We therefore propose that this human disorder is the consequence of defective snoRNP pseudouridylation and ribosomal dysfunction.

Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities.

PURPOSE: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. METHODS: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies. RESULTS: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI. CONCLUSION: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex.

Inherited duplications of PPP2R3B predispose to nevi and melanoma via a C21orf91-driven proliferative phenotype.

PURPOSE: Much of the heredity of melanoma remains unexplained. We sought predisposing germline copy-number variants using a rare disease approach. METHODS: Whole-genome copy-number findings in patients with melanoma predisposition syndrome congenital melanocytic nevus were extrapolated to a sporadic melanoma cohort. Functional effects of duplications in PPP2R3B were investigated using immunohistochemistry, transcriptomics, and stable inducible cellular models, themselves characterized using RNAseq, quantitative real-time polymerase chain reaction (qRT-PCR), reverse phase protein arrays, immunoblotting, RNA interference, immunocytochemistry, proliferation, and migration assays. RESULTS: We identify here a previously unreported genetic susceptibility to melanoma and melanocytic nevi, familial duplications of gene PPP2R3B. This encodes PR70, a regulatory unit of critical phosphatase PP2A. Duplications increase expression of PR70 in human nevus, and increased expression in melanoma tissue correlates with survival via a nonimmunological mechanism. PPP2R3B overexpression induces pigment cell switching toward proliferation and away from migration. Importantly, this is independent of the known microphthalmia-associated transcription factor (MITF)-controlled switch, instead driven by C21orf91. Finally, C21orf91 is demonstrated to be downstream of MITF as well as PR70. CONCLUSION: This work confirms the power of a rare disease approach, identifying a previously unreported copy-number change predisposing to melanocytic neoplasia, and discovers C21orf91 as a potentially targetable hub in the control of phenotype switching.

Misaligned foveal morphology and sector retinal dysfunction in AKT1-mosaic Proteus syndrome.

PURPOSE: Proteus syndrome arises as a result of a post-zygotic mosaic activating mutation in the AKT1 oncogene, causing a disproportionate overgrowth of affected tissues. A small number of ocular complications have been reported. We present the unique findings in a patient who had molecular confirmation of AKT1 mosaicism alongside fulfilling the clinical criteria for Proteus syndrome. METHODS: Pattern electroretinography, visual evoked potentials and multifocal electroretinography testing were performed alongside detailed retinal imaging and clinical examination to detail the ophthalmic characteristics. RESULTS: Electrophysiological findings characterised unilateral macular dysfunction alongside sector retinal dysfunction of the right eye. This was demonstrated through optical coherence tomography and ultra-wide-field imaging to be associated with a misaligned foveal morphology and sector retinal dysfunction extending into the temporal retina. CONCLUSION: We propose this patient has asymmetric foveal development and concomitant sector retinal dysfunction as the result of the mosaic AKT1 mutation, either through disruption in the retinal PI3K-AKT1 signalling pathway or through mechanical distortion of ocular growth, resulting in disproportionate inner retinal development. The findings expand the ocular phenotype of Proteus syndrome and encourage early assessment to identify any incipient ocular abnormalities.

Epidermal choristoma: a case series and review of the literature.

Epidermal choristoma is a rare, congenital lesion in which islands of ectopic skin are found within the oral cavity. They present as pigmented macules or papules on the tongue. Histologic appearances are characteristic and benign. We present three cases review the current literature and recommend observation of the lesion rather than complete excision should be considered as a reasonable management option.

Keratinocytic epidermal nevi associated with localized fibro-osseous lesions without hypophosphatemia.

Keratinocytic epidermal nevi (KEN) are characterized clinically by permanent hyperkeratosis in the distribution of Blaschko's lines and histologically by hyperplasia of epidermal keratinocytes. KEN with underlying RAS mutations have been associated with hypophosphatemic rickets and dysplastic bone lesions described as congenital cutaneous skeletal hypophosphatemia syndrome. Here, we describe two patients with keratinocytic epidermal nevi, in one associated with a papular nevus spilus, who presented with distinct localized congenital fibro-osseous lesions in the lower leg, diagnosed on both radiology and histology as osteofibrous dysplasia, in the absence of hypophosphatemia or rickets, or significantly raised FGF23 levels but with distinct mosaic HRAS mutations. This expands the spectrum of cutaneous/skeletal mosaic RASopathies and alerts clinicians to the importance of evaluating for bony disease even in the absence of bone profile abnormalities.

The biker-glove pattern of congenital melanocytic nevi.

Congenital melanocytic nevi (CMN) are common birthmarks with 20% occurring on the limbs. We describe 4 patients with acral CMN with a "biker-glove" distribution with sparing of the distal digits, as has previously been described in acral infantile hemangiomas (IH). The existence of the biker-glove pattern suggests that CMN arise from early mutations in melanocyte precursors and supports the recently described Kinsler-Larue hypothesis of mesenchymal distribution of melanocyte migration occurring in a circular field from a central point. Developmental errors in mesenchymal precursors with similar migration patterns may explain this shared pattern among CMN and IH.

Striking contiguous depigmentation across the lower limbs in piebaldism and its implications for understanding melanocytic migration and development.

Piebaldism is a rare autosomal dominant disorder of pigmentation that is characterized by variable patches of depigmentation on the face, chest, abdomen, and extremities. We describe two cases of piebaldism, in whom the remarkable asymmetric distribution of the depigmented patches in a connected, contiguous pattern across the legs provides embryologic insights. This finding is not explained by the traditional theory that melanocytic migration only originates in the neural crest and progresses unilaterally down each leg. We propose that our cases, and other similar cases, can be explained by a recent theory of mesodermal melanocyte migration.

Aggressive melanoma in an infant with congenital melanocytic nevus syndrome and multiple, NRAS and BRAF mutation-negative nodules.

We report the case of a newborn boy with multinodular NRAS and BRAF mutation-negative congenital melanocytic nevi and cerebral lesions compatible with congenital intraparenchymal melanosis. Histopathology from skin lesions showed atypical nodular melanocytic proliferation with marked melanocytic atypia and a large number of mitoses and apoptosis, indicating aggressive proliferation. The child developed several new subcutaneous tumors and multiple internal lesions, which were confirmed to be metastases, and died at 5 months of age. This case may represent an infantile melanoma developing from a giant congenital melanocytic nevus or a congenital melanoma.

MEK inhibition appears to improve symptom control in primary NRAS-driven CNS melanoma in children.

BACKGROUND: Primary melanoma of the CNS in children is extremely rare, and usually linked to congenital melanocytic naevus syndrome, caused by mosaicism for oncogenic NRAS mutations. Outcome is fatal in all cases. Data from murine and in vitro studies suggest that MEK inhibition is a possible therapeutic option. METHODS: Four children with NRAS-mutated CNS melanoma were treated with Trametinib on a compassionate basis. RESULTS: All four had an improvement in symptoms and objectively in signs. These varied from mild improvement for 1 month, to a sustained symptom-free period of 9 months in one case. In all cases there was eventual disease progression through treatment, followed by rapid death after discontinuation. There were no clinically-significant side effects. CONCLUSIONS: Trametinib is the first therapy to show any objective or measurable effect in NRAS-mutated primary CNS melanoma, with few side effects in this small series. The role of this therapy should be explored further in this rare paediatric tumour.

The adverse effect profile of oral azathioprine in pediatric atopic dermatitis, and recommendations for monitoring.

BACKGROUND: Azathioprine is efficacious in the treatment of severe childhood atopic dermatitis; however, robust data on adverse effects in this population are lacking. OBJECTIVE: We sought to assess adverse effects of azathioprine treatment in a pediatric atopic dermatitis cohort, and make recommendations for monitoring based on these data. METHODS: Blood test results for all 82 children prescribed oral azathioprine for atopic dermatitis in our department between 2010 and 2012 were collated prospectively, and clinical notes were reviewed retrospectively. RESULTS: Mean age at commencing azathioprine was 8.3 years (SEM 0.4). Mean maximum doses were 2.4 mg/kg (SEM 0.1) and 1.5 mg/kg (SEM 0.1) for normal and reduced serum thiopurine-S-methyltransferase levels, respectively. Adverse effects on blood indices occurred in 34 of 82 patients (41%), with pronounced effects in 18 of 82 (22%) after a median time of 0.4 years. Two patients stopped therapy as a result of abnormal blood indices. Clinical adverse effects occurred in 16 of 82 (20%), two resulting in cessation of therapy. Incidence of adverse effects was unaffected by age, sex, thiopurine-S-methyltransferase level, and drug dose on multivariate regression. LIMITATIONS: Comparison with other studies is limited by varying definitions of adverse effects. CONCLUSION: Oral azathioprine was associated with few pronounced adverse effects for the duration of use and dosage in this cohort. Recommendations for monitoring are made.