REVIEW URRENT C OPINION
What’s new with common genetic skin disorders? Jennifer L. Hand
Purpose of review Common genetic disorders such as neurofibromatosis type I (NF1), tuberous sclerosis, basal cell nevus syndrome (BCNS), incontinentia pigmenti, and X-linked ichthyosis have recognizable, cutaneous features. In children, cases often present without a prior diagnosis. This review highlights new information about diagnostic signs and care of affected patients. Recent findings Disruption of key regulatory pathways causes disorders such as BCNS, NF1, and tuberous sclerosis. The discovery of associated mutations in these pathways has led to molecular targeted therapies. For example, use of drugs such as vismodegib in BCNS and rapamycin in tuberous sclerosis complex is being studied. Also, patient review has refined the diagnostic criteria for tuberous sclerosis and incontinentia pigmenti and expanded the phenotype of X-linked ichthyosis. Preimplantation genetic diagnosis for disorders such as NF1 and incontinentia pigmenti is available. Summary Identification of nevus anemicus or juvenile xanthogranuloma in a young child may lead to an early diagnosis of NF1. Rapamycin offers noninvasive treatment for problematic skin lesions in pediatric patients with tuberous sclerosis. Providers can give early advice to affected families that reproductive technologies such as preimplantation genetic diagnosis are a consideration for future pregnancies. Keywords basal cell nevus syndrome, Gorlin, incontinentia pigmenti, neurofibromatosis type I, steroid sulfatase, tuberous sclerosis, X-linked ichthyosis
INTRODUCTION This review describes the most important recent findings pertaining to familiar, genetic disorders with recognizable, characteristic skin features that herald the diagnosis. Specifically, neurofibromatosis type I (NF1), tuberous sclerosis, basal cell nevus syndrome (BCNS), incontinentia pigmenti, and Xlinked ichthyosis (XLI) are discussed. New information relevant to the patient’s skin examination and early diagnosis is highlighted. Also, helpful information to prevent complications and provide treatment is emphasized.
NEUROFIBROMATOSIS I NF1 is one of the most common genetic disorders with an incidence of approximately 1 in 3000. Half of patients present with a de-novo (new) mutation and no family history. Therefore, a pediatric care provider is highly likely to encounter an undiagnosed patient. Although diagnostic criteria are established (Table 1) [1 ], patients under age 2 years are less likely to meet them [2 ]. Recently, the skin finding of nevus anemicus (Fig. 1) was reported to be &
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helpful to identify NF1 in these young patients. Nevus anemicus is a pale, macular birthmark caused by permanent vasoconstriction in the superficial dermis. Identified in 25% of patients with NF1, nevus anemicus is potentially useful for diagnosis in suspicious NF1. Juvenile xanthogranuloma (Fig. 2) is also noted with a higher than expected prevalence [3 ]. Ferrari et al. [2 ] proposed that each of these two skin lesions may aid in the early diagnosis of NF1. Plexiform neurofibroma is a diagnostic feature of NF1 (Table 1). These (Fig. 3) differ from common cutaneous neurofibromas (Fig. 4) because plexiform neurofibroma are typically congenital, larger than 3 cm, continuously slow growing, and may degenerate into malignant neurofibrosarcoma in 10% of &
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Department of Dermatology, Medical Genetics and Pediatric and Adolescent Medicine, Rochester, Minnesota, USA Correspondence to Jennifer L. Hand, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. Tel: +1 507 538 8249; e-mail: [email protected] Curr Opin Pediatr 2015, 27:460–465 DOI:10.1097/MOP.0000000000000245 Volume 27 Number 4 August 2015
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What’s new with common genetic skin disorders? Hand
KEY POINTS Nevus anemicus, in a patient under 2 years with suspected NF1, may be useful to make the diagnosis. Potential use of topical rapamycin for treatment in tuberous sclerosis has expanded to include cutaneous hypopigmented macules and subungual tumors in addition to facial angiofibromas. Presentation of a large ovarian fibroma in a pediatric patient may indicate BCNS is present. Retinopathy associated with incontinentia pigmenti appears similar to retinopathy of prematurity. Patients with a genetic diagnosis of XLI may have a milder skin phenotype than the dark brown, polygonal scales that were considered typical.
cases. In NF1, the number of cutaneous neurofibromas is well known to increase at puberty, whereas the impact of puberty on plexiform neurofibromas had been unknown. A common concern is that puberty will cause accelerated plexiform neurofibroma growth. A study by Dagalakis et al. [4 ] supports the idea that plexiform neurofibromas do not increase in growth over puberty, which is reassuring for patients. NF1 results from a mutation in neurofibromin that disrupts the rat sarcoma (RAS)-mitogen-activated protein kinases (MAPK) cascade. The dysregulated RAS-MAPK pathway alters synaptic plasticity, and therefore causes cognitive impairment in up to 80% of affected children. Specifically, difficulty with social functioning has emerged as a common feature of NF1. Children are more likely to be ‘shy’ or ‘awkward’ and more likely to be bullied than unaffected peers [5 ]. As a result, affected children are more likely &
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FIGURE 1. Nevus anemicus. The pale color of the skin is caused by permanent vasoconstriction of the underlying blood vessels.
to be diagnosed with autism spectrum disorders (ASDs), although compared with typical ASD, children with NF1 tend to have more social concerns and fewer restrictive and repetitive behaviors. Disorders other than NF1, such as Noonan syndrome, piebaldism, and cardiofaciocutaneous syndrome, are also caused by mutations in the RASMAPK pathway. These disorders share overlapping clinical features with NF1 (i.e., Noonan-like facies, cafe´-au-lait macules) and have been renamed ‘RASopathies’ as a group. Because of the change in nosology, many prominent academic centers in the United States have incorporated the word ‘RASopathy’ into the name of an appropriate clinic (e.g., Neurofibromatosis and RASopathy Center, Children’s Hospital of Wisconsin) and this may be a familiar term to patients who are internet savvy. Because of its high prevalence, NF1 is a common referral indication to clinics that use reproductive technology [6 ]. Preimplantation genetic diagnosis &
Table 1. Neurofibromatosis type I diagnostic criteria Two or more of the following are required for diagnosis: Six or more cafe´-au-lait macules (>0.5 cm prior to puberty or >1 cm after puberty) Axillary or inguinal freckling Two or more neurofibromas of any type or one plexiform neurofibroma Two or more iris hamartomas (Lisch nodules) A characteristic osseous lesion (sphenoid wing dysplasia, longbone dysplasia) An optic pathway glioma A first-degree relative with NF1 diagnosed by the above criteria Adapted from National Institutes of Health and Hirbe and Gutmann. Lancet; 2014. NF1, neurofibromatosis type I.
FIGURE 2. Juvenile xanthogranuloma on the lateral ankle of a 3-year-old girl.
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early about the availability of this reproductive option.
TUBEROUS SCLEROSIS COMPLEX Tuberous sclerosis is an autosomal dominant disorder that variably causes recognizable skin lesions, cognitive impairment, and hamartomas of the kidneys, heart, lungs, brain, and retina. In a recent update, diagnostic criteria describing the characteristic skin and tooth features of tuberous sclerosis were refined [7 ]. For example, a ‘forehead plaque’ was considered a major diagnostic criterion. This was revised to ‘fibrous cephalic plaque’ because of the recognition that typical plaques may present on the face and scalp away from the forehead. Also, ‘gingival fibromas’ have been refined to ‘intraoral fibromas’ because fibromas are not limited to the gingivae. Helpful numerical requirements were added for several cutaneous and oral lesions. For example, the number of angiofibromas must be at least three, dental enamel pits at least three, ungual fibromas at least two, and intraoral fibromas at least two. For the care of affected patients, recommendations for sun protection were added because hypomelanotic macules are prone to sunburn and sun exposure may encourage development of facial angiofibromas. Disfiguring facial angiofibromas reduce quality of life [8 ]. A scoring system called the Facial Angiofibroma Severity Index is a new tool that allows clinicians to quickly characterize facial disease involvement and response to treatment. Lesions are assessed according to size, color, and surface area of the face involved. As the Facial Angiofibroma Severity Index score is valid, reproducible, and simple to perform, it is considered useful in multicenter studies. This measurement tool is also of interest to providers as the use of targeted medical treatment becomes more common in the clinic. Tuberous sclerosis complex (TSC) is caused by mutations in TSC1 or TSC2, the genes that encode the hamartin-tuberin complex. When disrupted, the hamartin-tuberin complex causes over activation of mTORC1 (mammalian target of rapamycin inhibitors), which leads to hamartomatous overgrowth of affected tissues. The use of topical, specifically targeted mTOR inhibitor medications such as rapamycin is known to help flatten and shrink facial angiofibromas in TSC [9 ]. More recently, improvement of other TSC lesions has been reported, including their use in hypomelanotic macules [10 ] and subungual fibromas [11 ,12 ]. One noncutaneous cause of morbidity of tuberous sclerosis is seizures. Seizures associated with TSC, if present, typically begin between ages 3 and 5 months. With neonatal onset, however, large &&
FIGURE 3. Plexiform neurofibroma on the waistline of a boy with neurofibromatosis type I.
(PGD) tests embryos for a single-gene disorder prior to placement in the uterus with a plan to implant only unaffected embryos [6 ]. In 77 couples at risk of having an NF1-affected child who underwent 156 PGD cycles, 33 cycles (21%) resulted in a live birth. Clinicians are recommended to counsel patients &
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FIGURE 4. Typical cutaneous neurofibromas in a patient with neurofibromatosis type I. 462
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malformations of the cerebral cortex and a poor neuropsychological outcome are more likely. Therefore, surgical treatment of epilepsy may be helpful and should be considered early in this group of patients [13 ]. &&
syndromes in general, tumors are more likely to be multifocal. In BCNS syndrome, ovarian fibromas are more commonly bilateral than unilateral. Recently two separate BCNS-affected girls in the pediatric age group were reported who presented with unexpected ovarian fibromas at ages 6 [17 ] and 16 [18 ], respectively. &
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BASAL CELL NEVUS SYNDROME Basal cell nevus syndrome (BCNS), also known as Gorlin syndrome, is an autosomal dominant disorder associated with an increased risk of basal cell carcinoma (BCC), especially in those younger than 20 years (Griner et al. [14 ]). The traditional treatment of BCCs in Gorlin syndrome is surgical removal by Mohs technique. During ’Mohs,’ the surgeon checks each tissue margin for evidence of tumor and removes only the affected portion in another stepwise procedure until all margins are clear of tumor. Many studies support that Mohs surgery has a higher cure rate for BCC with possible disadvantages for patients being travel distance to a qualified center, an increased final defect size, and increased cost. An impressive case study appeared documenting a woman with BCNS who underwent more than 730 BCCs removals by a plastic surgeon by simple excision rather than Mohs over 40 years. Many excisions had positive margins that were not removed with a second procedure [14 ]. She was pictured with an excellent cosmetic outcome. Targeted medical therapies are under development. The Ptch1 (Patched 1) gene encodes a tumor suppressor protein, which is disrupted in BCNS. Normally, Patched 1 works together with transmembrane protein SMO (smoothened) to repress the development of BCCs. Vismodegib is a drug that specifically inhibits SMO. In a randomized, double-blind, placebo-controlled clinical trial of 41 BCNS patients, patients given the drug had statistically significant reduction in number and size of BCCs [15 ]. Fifty-four percent of patients discontinued treatment because of side-effects such as dysgeusia (loss of taste), muscle cramps, hair loss, and weight loss. Also, tumors recurred as resistance to the drug developed. Additional strategies for medical treatment such as a combinational approach with other drugs are being considered [15 ]. One such strategy is the application of a topical retinoid medication, tazarotene, as chemoprevention [16 ]. In a randomized, double-blind, vehicle controlled study of 34 BCNS patients, however, no benefit of chemoprevention was demonstrated with the use of tazarotene after 3 years of follow-up [16 ]. Ovarian fibromas are uncommon in the pediatric age group; however, they are common in Gorlin syndrome, occurring in 14–24% of affected women. As is typical of genetic tumor predisposition &&
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INCONTINENTIA PIGMENTI Incontinentia pigmenti is an X-linked dominant disorder, usually lethal in men, with an incidence of 0.2 in 100 000 births. Typically, incontinentia pigmenti presents with blisters at birth and is confused with infection, specifically herpes simplex (Fig. 5). For experienced clinicians, incontinentia pigmenti is recognizable by its characteristic appearance and pattern along developmental skin lines [19 ]. Diagnostic criteria were first established in 1993. More recently, Minic et al. [20 ] updated and refined the criteria pertaining to skin. Diagnostic descriptions were expanded to include details about skin lesions in four possible stages: vesicular, verrucous, hyperpigmented, and hypopigmented/atrophic appearing lesions that follow developmental skin lines. The timing and appearance of each stage may overlap, but typically all cases present within 1 week of birth [21 ] &
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FIGURE 5. Typical blister-like lesions that follow developmental skin lines of Blaschko in an infant with incontinentia pigmenti.
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In all cases of incontinentia pigmenti, an IKBKG gene mutation disrupts a protein important for cell survival that leads to an increased risk of cell apoptosis. Most patients (78%) have a similar deletion of exons 4 through 10 [19 ]. Repetitive DNA sequences surrounding these particular exons create an unusually high frequency of disease-associated recombination errors. Because of improved understanding of this structural architecture of the gene, the IKBKG locus is now considered a ‘genomic instability region’ linked to an inherited disease [19 ]. Because incontinentia pigmenti potentially affects ectodermal structures: hair, teeth, skin, and sweat glands, it is considered a member of the broader group of ectodermal dysplasias. In a large Swedish study, tooth findings were examined specifically. These authors noted not only oligodontia, but also that patients had abnormally shaped teeth, especially conical and tapered maxillary incisors and notching on the incisors and talon cusps. Almost half of the affected patients had lower salivary secretion than expected. The most frequently reported tooth changes were dental shape abnormalities, hypodontia, and delayed dentition, all of which were added to the updated diagnostic criteria. These authors recommended that assessment of salivary secretion should be part of every new incontinentia pigmenti patient assessment [22 ]. Eye involvement is increasingly recognized in incontinentia pigmenti. A review by Chen et al. [23 ] reports vision-threatening eye disease in 20% of affected individuals. An unexpectedly high number of patients have persistence of fetal vasculature on the retina, similar to retinopathy of prematurity. All infants, especially if abnormality is suspected, should have an eye examination, preferably under anesthesia and with fluorescein angiography in the first few weeks of life. The frequency of follow-up should be determined by the degree of retinopathy, with an increased interval if disease is stable by age 2 years [23 ]. Tumors under the nail are known to be a complication of incontinentia pigmenti, typically appearing after puberty. Incontinentia pigmenti-related subungual tumors are thought to be a benign process; however, Pena and Brewer [24 ] reported a case of a young woman with incontinentia pigmenti treated with amputation for a presumed squamous cell carcinoma presenting on the subungual thumb. She later presented with similar appearing verrucous papules on other fingers that were diagnosed pathologically as ‘subungual tumor if incontinentia pigmenti.’ These authors cautioned that possibly the squamous cell carcinoma was misdiagnosed and clinicians should be aware of subungual tumors as a benign, late complication of incontinentia pigmenti. Progress has been made in prenatal diagnosis, evidenced by a report of successful pregnancy by &
preimplantation genetic screening. Affected male pregnancies usually end in miscarriage. Kim et al. [25 ] reported a successful pregnancy to 29-year-old woman with phenotypically mild incontinentia pigmenti who had suffered three male miscarriages. Genetic testing for DNA on her blood revealed a pathogenic deletion in exon 9 of the IKBKG gene, which was useful to test embryos prior to implantation. &
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X-LINKED ICHTHYOSIS XLI is an X-linked recessive disorder that affects one out of every 1500 males. Clinically, XLI is characterized by dark brown, polygonal scaling of the skin, especially on extensor surfaces. Up to 90% of cases are caused by a chromosomal microdeletion that removes the entire STS gene. As use of screening that interrogates the entire genome (i.e., chromosomal microarray testing) increases, individuals are being diagnosed in the laboratory that may have not been recognized previously. A group of patients identified incidentally in the laboratory as having an STS deletion was found to have a milder skin phenotype of dryness or eczema, or both. This group lacked dark, polygonal scale, suggesting that a milder phenotype may be more common than previously realized, especially when the diagnosis is made incidentally [26 ]. This expanded phenotype may be important for others considering the implications of an incidental XLI diagnosis, as the literature describes at least five pregnancy terminations because of parental concern about the predicted skin phenotype based on prenatal laboratory testing. Females inherit the equivalent of one X chromosome from their mother and one from their father. Within each cell, one X is inactivated. In XLI, the mutated STS region is unusual because it escapes inactivation, so in any female cell, both copies of the STS gene are expressed. Therefore, a carrier female shows no features of the disorder. In 2014, a rare case of an affected female was reported because of a homozygous STS deletion, one on each X chromosome [27 ]. &
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CONCLUSION In summary, recent advances for common genodermatoses include refined diagnostic criteria based on patient review by experienced teams of clinicians (tuberous sclerosis, incontinentia pigmenti). A similar review of patient information has expanded the expected phenotype of a laboratory diagnosed disorder (XLI) to include milder forms. Advances also include the use of targeted medical therapies to replace traditional surgery (tuberous sclerosis, BCNS). Finally, new genetic technology such as Volume 27 Number 4 August 2015
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preimplantation genetic diagnosis (NF1, incontinentia pigmenti) is directly impacting patient care. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary ap& proach to care. Lancet Neurol 2014; 13:834–843. This review describes tumors and growths affecting various disparate organ systems, necessitating a multidisciplinary approach for patients with NF1. 2. Ferrari F, Masurel A, Olivier-Faivre L, Vabres P. Juvenile xanthogranuloma and && nevus anemicus in the diagnosis of neurofibromatosis type 1. JAMA Dermatol 2014; 150:42–46. This study proposes that the nevus anemicus may aid in the early diagnosis of NF1 in children younger than 2 years of age. 3. Jans SR, Schomerus E, Bygum A. Neurofibromatosis type 1 diagnosed in a & child based on multiple juvenile xanthogranulomas and juvenile myelomonocytic leukemia. Pediatr Dermatol 2015; 32:e29–e32. This well-written article reviews the association of NF1 and juvenile xanthogranuloma. 4. Dagalakis U, Lodish M, Dombi E, et al. Puberty and plexiform neurofibroma tumor & growth in patients with neurofibromatosis type I. J Pediatr 2014; 164:620–624. This study provides a detailed study of 41 patients by the National Institutes of Health, which shows no evidence that plexiform neurofibroma growth accelerates in puberty. 5. Plasschaert E, Descheemaeker MJ, Van Eylen L, et al. Prevalence of autism & spectrum disorder symptoms in children with neurofibromatosis type 1. Am J Med Genet B Neuropsychiatr Genet 2015; 168B:72–80. This is a study of 102 patients with NF1 assessed for evidence of ASDs. The discussion of the results clarifies the importance of social cognition deficits that are more prominent in NF1 in comparison with typical patients with ASDs. Repetitive behaviors are more common in ASDs than in NF1. 6. Merker VL, Murphy TP, Hughes JB, et al. Outcomes of preimplantation genetic & diagnosis in neurofibromatosis type 1. Fertil Steril 2015; 103:761–768; e761. This study describes the status of technology being used for preimplantation genetic diagnosis in NF1. 7. Teng JM, Cowen EW, Wataya-Kaneda M, et al. Dermatologic and dental && aspects of the 2012 International Tuberous Sclerosis Complex Consensus Statements. JAMA Dermatol 2014; 150:1095–1101. This is a consensus statement compiled by multiple experts following a review of extensive literature and patient photographs. Excellent photographs and dermatologic descriptions are provided. 8. Salido-Vallejo R, Ruano J, Garnacho-Saucedo G, et al. Facial angiofibroma & severity index (FASI): reliability assessment of a new tool developed to measure severity and responsiveness to therapy in tuberous sclerosis-associated facial angiofibroma. Clin Exp Dermatol 2014; 39:888–893. This article provides a description of the validation of an assessment tool (Facial Angiofibroma Severity Index), which can be used by clinician to assess progress in the treatment of facial angiofibromas and by researchers to assess possible treatments. 9. Park J, Yun SK, Cho YS, et al. Treatment of angiofibromas in tuberous & sclerosis complex: the effect of topical rapamycin and concomitant laser therapy. Dermatology 2014; 228:37–41. This article presents a series of cases, with photographs, of individuals treated by a combination of topical rapamycin and laser therapy. 10. Wataya-Kaneda M, Tanaka M, Yang L, et al. Clinical and histologic analysis of & the efficacy of topical rapamycin therapy against hypomelanotic macules in tuberous sclerosis complex. JAMA Dermatol 2015; doi: 10.1001/jamadermatol.2014.4298. [Epub ahead of print] This is a case series of individuals treated with topical rapamycin for hypomelanotic macules in tuberous sclerosis.
11. Muzic JG, Kindle SA, Tollefson MM. Successful treatment of subungual fibromas of tuberous sclerosis with topical rapamycin. JAMA Dermatol 2014; 150:1024–1025. This is a case study of a patient treated with topical rapamycin for subungual tumors in tuberous sclerosis. 12. Liebman JJ, Nigro LC, Matthews MS. Koenen tumors in tuberous sclerosis: a & review and clinical considerations for treatment. Ann Plast Surg 2014; 73:721–722. This is a case study of a patient treated with topical rapamycin for subungual tumors in tuberous sclerosis and review of treatment described in the literature. 13. Kotulska K, Jurkiewicz E, Domanska-Pakiela D, et al. Epilepsy in newborns && with tuberous sclerosis complex. Eur J Paediatr Neurol 2014; 18:714–721. This is a well-written article that details evidence for a poor prognosis in children with tuberous sclerosis who have an unusually early onset of seizures in the neonatal period. 14. Griner D, Sutphin D, Sargent LA. Surgical management of Gorlin syndrome: a && 4-decade experience using local excision technique. Ann Plast Surg 2015; 74:467–470; doi: 10.1097/SAP.0000000000000052. [Epub ahead of print] This article discusses an alternative approach for patients with BCNS considering surgical removal of skin cancer. Although only a single case study, the patient is followed for 40 years, adding to its value. Patients often ask about this option. 15. Athar M, Li C, Kim AL, et al. Sonic hedgehog signaling in basal cell nevus && syndrome. Cancer Res 2014; 74:4967–4975. This review provides a thorough discussion of the molecular mechanisms causing BCNS and related strategies for treatment. 16. Tang JY, Chiou AS, Mackay-Wiggan JM, et al. Tazarotene: randomized, & double-blind, vehicle-controlled, and open-label concurrent trials for basal cell carcinoma prevention and therapy in patients with basal cell nevus syndrome. Cancer Prev Res (Phila) 2014; 7:292–299. This is a well-designed study, which ultimately demonstrates a lack of benefit for the chemoprevention of BCC in patients with BCNS. 17. Jimbo T, Masumoto K, Urita Y, et al. Nevoid basal cell carcinoma syndrome & with a unilateral giant ovarian fibroma in a Japanese 6-year-old girl. Eur J Pediatr 2014; 173:667–670. This is a case study of a huge ovarian fibroma in a child with BCNS. 18. Singh AK, Lopez-Araujo A, Katabathina VS. Gorlin syndrome. J Pediatr 2014; & 164:1501–11501; e1501. This is a brief study with excellent radiologic images of jaw keratocyst and ovarian fibromas in a young patient with BCNS. 19. Conte MI, Pescatore A, Paciolla M, et al. Insight into IKBKG/NEMO locus: & report of new mutations and complex genomic rearrangements leading to incontinentia pigmenti disease. Hum Mutat 2014; 35:165–177. This is a review of the current knowledge about mutations that cause incontinentia pigmenti and the molecular mechanisms that predispose to them. 20. Minic S, Trpinac D, Obradovic M. Incontinentia pigmenti diagnostic criteria && update. Clin Genet 2014; 85:536–542. This article provides rationale and details behind updated diagnostic criteria for incontinentia pigmenti in a summary article. 21. Yang Y, Guo Y, Ping Y, et al. Neonatal incontinentia pigmenti: Six cases and a & literature review. Exp Ther Med 2014; 8:1797–1806. This is a case series of six patients diagnosed with neonatal incontinentia pigmenti in China. 22. Bergendal B. Orodental manifestations in ectodermal dysplasia-a review. Am & J Med Genet A 2014; 164A:2465–2471. This article provides a detailed review of the expected oral findings in several ectodermal dysplasias including incontinentia pigmenti. 23. Chen CJ, Han IC, Tian J, et al. Extended follow-up of treated and untreated && retinopathy in incontinentia pigmenti: analysis of peripheral vascular changes and incidence of retinal detachment. JAMA Ophthalmol 2015; 133:542– 548; doi: 10.1001/jamaophthalmol.2015.22. [Epub ahead of print] This article provides important information about vision loss as a potentially devastating complication of incontinentia pigmenti. Clinical signs that may predict complications in the eye and recommendations for ophthalmologic examination and follow-up are discussed in this article. 24. Pena ZG, Brewer JD. Multiple subungual squamous cell carcinomas in a & patient with incontinentia pigmenti. Dermatol Surg 2014; 40:1159–1161. This is a case study that outlines possible misdiagnosis of benign subungual tumors. 25. Kim MJ, Lyu SW, Seok HH, et al. A healthy delivery of twins by assisted & reproduction followed by preimplantation genetic screening in a woman with Xlinked dominant incontinentia pigmenti. Clin Exp Reprod Med 2014; 41:168–173. This a case study describing the successful use of PGD in incontinentia pigmenti. 26. Hand JL, Runke CK, Hodge JC. The phenotype spectrum of X-linked & ichthyosis identified by chromosomal microarray. J Am Acad Dermatol 2015; 26:617–627; doi: 10.1016/j.jaad.2014.12.020. [Epub ahead of print] This study describes a group of patients who were studied after having been diagnosed with steroid sulfatase deficiency (XLI) by molecular testing. The phenotype they expressed was, in general, less severe than expected based on previous descriptions in the literature. 27. Murtaza G, Siddiq S, Khan S, et al. Molecular study of X-linked ichthyosis: & report of a novel 2-bp insertion mutation in the STS and a very rare case of homozygous female patient. J Dermatol Sci 2014; 74:165–167. This is a rare case study of a woman with molecularly confirmed XLI. &
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What’s new with common genetic skin disorders? Jennifer L. Hand
Purpose of review Common genetic disorders such as neurofibromatosis type I (NF1), tuberous sclerosis, basal cell nevus syndrome (BCNS), incontinentia pigmenti, and X-linked ichthyosis have recognizable, cutaneous features. In children, cases often present without a prior diagnosis. This review highlights new information about diagnostic signs and care of affected patients. Recent findings Disruption of key regulatory pathways causes disorders such as BCNS, NF1, and tuberous sclerosis. The discovery of associated mutations in these pathways has led to molecular targeted therapies. For example, use of drugs such as vismodegib in BCNS and rapamycin in tuberous sclerosis complex is being studied. Also, patient review has refined the diagnostic criteria for tuberous sclerosis and incontinentia pigmenti and expanded the phenotype of X-linked ichthyosis. Preimplantation genetic diagnosis for disorders such as NF1 and incontinentia pigmenti is available. Summary Identification of nevus anemicus or juvenile xanthogranuloma in a young child may lead to an early diagnosis of NF1. Rapamycin offers noninvasive treatment for problematic skin lesions in pediatric patients with tuberous sclerosis. Providers can give early advice to affected families that reproductive technologies such as preimplantation genetic diagnosis are a consideration for future pregnancies. Keywords basal cell nevus syndrome, Gorlin, incontinentia pigmenti, neurofibromatosis type I, steroid sulfatase, tuberous sclerosis, X-linked ichthyosis
INTRODUCTION This review describes the most important recent findings pertaining to familiar, genetic disorders with recognizable, characteristic skin features that herald the diagnosis. Specifically, neurofibromatosis type I (NF1), tuberous sclerosis, basal cell nevus syndrome (BCNS), incontinentia pigmenti, and Xlinked ichthyosis (XLI) are discussed. New information relevant to the patient’s skin examination and early diagnosis is highlighted. Also, helpful information to prevent complications and provide treatment is emphasized.
NEUROFIBROMATOSIS I NF1 is one of the most common genetic disorders with an incidence of approximately 1 in 3000. Half of patients present with a de-novo (new) mutation and no family history. Therefore, a pediatric care provider is highly likely to encounter an undiagnosed patient. Although diagnostic criteria are established (Table 1) [1 ], patients under age 2 years are less likely to meet them [2 ]. Recently, the skin finding of nevus anemicus (Fig. 1) was reported to be &
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helpful to identify NF1 in these young patients. Nevus anemicus is a pale, macular birthmark caused by permanent vasoconstriction in the superficial dermis. Identified in 25% of patients with NF1, nevus anemicus is potentially useful for diagnosis in suspicious NF1. Juvenile xanthogranuloma (Fig. 2) is also noted with a higher than expected prevalence [3 ]. Ferrari et al. [2 ] proposed that each of these two skin lesions may aid in the early diagnosis of NF1. Plexiform neurofibroma is a diagnostic feature of NF1 (Table 1). These (Fig. 3) differ from common cutaneous neurofibromas (Fig. 4) because plexiform neurofibroma are typically congenital, larger than 3 cm, continuously slow growing, and may degenerate into malignant neurofibrosarcoma in 10% of &
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Department of Dermatology, Medical Genetics and Pediatric and Adolescent Medicine, Rochester, Minnesota, USA Correspondence to Jennifer L. Hand, MD, Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA. Tel: +1 507 538 8249; e-mail: [email protected] Curr Opin Pediatr 2015, 27:460–465 DOI:10.1097/MOP.0000000000000245 Volume 27 Number 4 August 2015
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What’s new with common genetic skin disorders? Hand
KEY POINTS Nevus anemicus, in a patient under 2 years with suspected NF1, may be useful to make the diagnosis. Potential use of topical rapamycin for treatment in tuberous sclerosis has expanded to include cutaneous hypopigmented macules and subungual tumors in addition to facial angiofibromas. Presentation of a large ovarian fibroma in a pediatric patient may indicate BCNS is present. Retinopathy associated with incontinentia pigmenti appears similar to retinopathy of prematurity. Patients with a genetic diagnosis of XLI may have a milder skin phenotype than the dark brown, polygonal scales that were considered typical.
cases. In NF1, the number of cutaneous neurofibromas is well known to increase at puberty, whereas the impact of puberty on plexiform neurofibromas had been unknown. A common concern is that puberty will cause accelerated plexiform neurofibroma growth. A study by Dagalakis et al. [4 ] supports the idea that plexiform neurofibromas do not increase in growth over puberty, which is reassuring for patients. NF1 results from a mutation in neurofibromin that disrupts the rat sarcoma (RAS)-mitogen-activated protein kinases (MAPK) cascade. The dysregulated RAS-MAPK pathway alters synaptic plasticity, and therefore causes cognitive impairment in up to 80% of affected children. Specifically, difficulty with social functioning has emerged as a common feature of NF1. Children are more likely to be ‘shy’ or ‘awkward’ and more likely to be bullied than unaffected peers [5 ]. As a result, affected children are more likely &
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FIGURE 1. Nevus anemicus. The pale color of the skin is caused by permanent vasoconstriction of the underlying blood vessels.
to be diagnosed with autism spectrum disorders (ASDs), although compared with typical ASD, children with NF1 tend to have more social concerns and fewer restrictive and repetitive behaviors. Disorders other than NF1, such as Noonan syndrome, piebaldism, and cardiofaciocutaneous syndrome, are also caused by mutations in the RASMAPK pathway. These disorders share overlapping clinical features with NF1 (i.e., Noonan-like facies, cafe´-au-lait macules) and have been renamed ‘RASopathies’ as a group. Because of the change in nosology, many prominent academic centers in the United States have incorporated the word ‘RASopathy’ into the name of an appropriate clinic (e.g., Neurofibromatosis and RASopathy Center, Children’s Hospital of Wisconsin) and this may be a familiar term to patients who are internet savvy. Because of its high prevalence, NF1 is a common referral indication to clinics that use reproductive technology [6 ]. Preimplantation genetic diagnosis &
Table 1. Neurofibromatosis type I diagnostic criteria Two or more of the following are required for diagnosis: Six or more cafe´-au-lait macules (>0.5 cm prior to puberty or >1 cm after puberty) Axillary or inguinal freckling Two or more neurofibromas of any type or one plexiform neurofibroma Two or more iris hamartomas (Lisch nodules) A characteristic osseous lesion (sphenoid wing dysplasia, longbone dysplasia) An optic pathway glioma A first-degree relative with NF1 diagnosed by the above criteria Adapted from National Institutes of Health and Hirbe and Gutmann. Lancet; 2014. NF1, neurofibromatosis type I.
FIGURE 2. Juvenile xanthogranuloma on the lateral ankle of a 3-year-old girl.
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early about the availability of this reproductive option.
TUBEROUS SCLEROSIS COMPLEX Tuberous sclerosis is an autosomal dominant disorder that variably causes recognizable skin lesions, cognitive impairment, and hamartomas of the kidneys, heart, lungs, brain, and retina. In a recent update, diagnostic criteria describing the characteristic skin and tooth features of tuberous sclerosis were refined [7 ]. For example, a ‘forehead plaque’ was considered a major diagnostic criterion. This was revised to ‘fibrous cephalic plaque’ because of the recognition that typical plaques may present on the face and scalp away from the forehead. Also, ‘gingival fibromas’ have been refined to ‘intraoral fibromas’ because fibromas are not limited to the gingivae. Helpful numerical requirements were added for several cutaneous and oral lesions. For example, the number of angiofibromas must be at least three, dental enamel pits at least three, ungual fibromas at least two, and intraoral fibromas at least two. For the care of affected patients, recommendations for sun protection were added because hypomelanotic macules are prone to sunburn and sun exposure may encourage development of facial angiofibromas. Disfiguring facial angiofibromas reduce quality of life [8 ]. A scoring system called the Facial Angiofibroma Severity Index is a new tool that allows clinicians to quickly characterize facial disease involvement and response to treatment. Lesions are assessed according to size, color, and surface area of the face involved. As the Facial Angiofibroma Severity Index score is valid, reproducible, and simple to perform, it is considered useful in multicenter studies. This measurement tool is also of interest to providers as the use of targeted medical treatment becomes more common in the clinic. Tuberous sclerosis complex (TSC) is caused by mutations in TSC1 or TSC2, the genes that encode the hamartin-tuberin complex. When disrupted, the hamartin-tuberin complex causes over activation of mTORC1 (mammalian target of rapamycin inhibitors), which leads to hamartomatous overgrowth of affected tissues. The use of topical, specifically targeted mTOR inhibitor medications such as rapamycin is known to help flatten and shrink facial angiofibromas in TSC [9 ]. More recently, improvement of other TSC lesions has been reported, including their use in hypomelanotic macules [10 ] and subungual fibromas [11 ,12 ]. One noncutaneous cause of morbidity of tuberous sclerosis is seizures. Seizures associated with TSC, if present, typically begin between ages 3 and 5 months. With neonatal onset, however, large &&
FIGURE 3. Plexiform neurofibroma on the waistline of a boy with neurofibromatosis type I.
(PGD) tests embryos for a single-gene disorder prior to placement in the uterus with a plan to implant only unaffected embryos [6 ]. In 77 couples at risk of having an NF1-affected child who underwent 156 PGD cycles, 33 cycles (21%) resulted in a live birth. Clinicians are recommended to counsel patients &
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FIGURE 4. Typical cutaneous neurofibromas in a patient with neurofibromatosis type I. 462
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What’s new with common genetic skin disorders? Hand
malformations of the cerebral cortex and a poor neuropsychological outcome are more likely. Therefore, surgical treatment of epilepsy may be helpful and should be considered early in this group of patients [13 ]. &&
syndromes in general, tumors are more likely to be multifocal. In BCNS syndrome, ovarian fibromas are more commonly bilateral than unilateral. Recently two separate BCNS-affected girls in the pediatric age group were reported who presented with unexpected ovarian fibromas at ages 6 [17 ] and 16 [18 ], respectively. &
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BASAL CELL NEVUS SYNDROME Basal cell nevus syndrome (BCNS), also known as Gorlin syndrome, is an autosomal dominant disorder associated with an increased risk of basal cell carcinoma (BCC), especially in those younger than 20 years (Griner et al. [14 ]). The traditional treatment of BCCs in Gorlin syndrome is surgical removal by Mohs technique. During ’Mohs,’ the surgeon checks each tissue margin for evidence of tumor and removes only the affected portion in another stepwise procedure until all margins are clear of tumor. Many studies support that Mohs surgery has a higher cure rate for BCC with possible disadvantages for patients being travel distance to a qualified center, an increased final defect size, and increased cost. An impressive case study appeared documenting a woman with BCNS who underwent more than 730 BCCs removals by a plastic surgeon by simple excision rather than Mohs over 40 years. Many excisions had positive margins that were not removed with a second procedure [14 ]. She was pictured with an excellent cosmetic outcome. Targeted medical therapies are under development. The Ptch1 (Patched 1) gene encodes a tumor suppressor protein, which is disrupted in BCNS. Normally, Patched 1 works together with transmembrane protein SMO (smoothened) to repress the development of BCCs. Vismodegib is a drug that specifically inhibits SMO. In a randomized, double-blind, placebo-controlled clinical trial of 41 BCNS patients, patients given the drug had statistically significant reduction in number and size of BCCs [15 ]. Fifty-four percent of patients discontinued treatment because of side-effects such as dysgeusia (loss of taste), muscle cramps, hair loss, and weight loss. Also, tumors recurred as resistance to the drug developed. Additional strategies for medical treatment such as a combinational approach with other drugs are being considered [15 ]. One such strategy is the application of a topical retinoid medication, tazarotene, as chemoprevention [16 ]. In a randomized, double-blind, vehicle controlled study of 34 BCNS patients, however, no benefit of chemoprevention was demonstrated with the use of tazarotene after 3 years of follow-up [16 ]. Ovarian fibromas are uncommon in the pediatric age group; however, they are common in Gorlin syndrome, occurring in 14–24% of affected women. As is typical of genetic tumor predisposition &&
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INCONTINENTIA PIGMENTI Incontinentia pigmenti is an X-linked dominant disorder, usually lethal in men, with an incidence of 0.2 in 100 000 births. Typically, incontinentia pigmenti presents with blisters at birth and is confused with infection, specifically herpes simplex (Fig. 5). For experienced clinicians, incontinentia pigmenti is recognizable by its characteristic appearance and pattern along developmental skin lines [19 ]. Diagnostic criteria were first established in 1993. More recently, Minic et al. [20 ] updated and refined the criteria pertaining to skin. Diagnostic descriptions were expanded to include details about skin lesions in four possible stages: vesicular, verrucous, hyperpigmented, and hypopigmented/atrophic appearing lesions that follow developmental skin lines. The timing and appearance of each stage may overlap, but typically all cases present within 1 week of birth [21 ] &
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FIGURE 5. Typical blister-like lesions that follow developmental skin lines of Blaschko in an infant with incontinentia pigmenti.
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In all cases of incontinentia pigmenti, an IKBKG gene mutation disrupts a protein important for cell survival that leads to an increased risk of cell apoptosis. Most patients (78%) have a similar deletion of exons 4 through 10 [19 ]. Repetitive DNA sequences surrounding these particular exons create an unusually high frequency of disease-associated recombination errors. Because of improved understanding of this structural architecture of the gene, the IKBKG locus is now considered a ‘genomic instability region’ linked to an inherited disease [19 ]. Because incontinentia pigmenti potentially affects ectodermal structures: hair, teeth, skin, and sweat glands, it is considered a member of the broader group of ectodermal dysplasias. In a large Swedish study, tooth findings were examined specifically. These authors noted not only oligodontia, but also that patients had abnormally shaped teeth, especially conical and tapered maxillary incisors and notching on the incisors and talon cusps. Almost half of the affected patients had lower salivary secretion than expected. The most frequently reported tooth changes were dental shape abnormalities, hypodontia, and delayed dentition, all of which were added to the updated diagnostic criteria. These authors recommended that assessment of salivary secretion should be part of every new incontinentia pigmenti patient assessment [22 ]. Eye involvement is increasingly recognized in incontinentia pigmenti. A review by Chen et al. [23 ] reports vision-threatening eye disease in 20% of affected individuals. An unexpectedly high number of patients have persistence of fetal vasculature on the retina, similar to retinopathy of prematurity. All infants, especially if abnormality is suspected, should have an eye examination, preferably under anesthesia and with fluorescein angiography in the first few weeks of life. The frequency of follow-up should be determined by the degree of retinopathy, with an increased interval if disease is stable by age 2 years [23 ]. Tumors under the nail are known to be a complication of incontinentia pigmenti, typically appearing after puberty. Incontinentia pigmenti-related subungual tumors are thought to be a benign process; however, Pena and Brewer [24 ] reported a case of a young woman with incontinentia pigmenti treated with amputation for a presumed squamous cell carcinoma presenting on the subungual thumb. She later presented with similar appearing verrucous papules on other fingers that were diagnosed pathologically as ‘subungual tumor if incontinentia pigmenti.’ These authors cautioned that possibly the squamous cell carcinoma was misdiagnosed and clinicians should be aware of subungual tumors as a benign, late complication of incontinentia pigmenti. Progress has been made in prenatal diagnosis, evidenced by a report of successful pregnancy by &
preimplantation genetic screening. Affected male pregnancies usually end in miscarriage. Kim et al. [25 ] reported a successful pregnancy to 29-year-old woman with phenotypically mild incontinentia pigmenti who had suffered three male miscarriages. Genetic testing for DNA on her blood revealed a pathogenic deletion in exon 9 of the IKBKG gene, which was useful to test embryos prior to implantation. &
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X-LINKED ICHTHYOSIS XLI is an X-linked recessive disorder that affects one out of every 1500 males. Clinically, XLI is characterized by dark brown, polygonal scaling of the skin, especially on extensor surfaces. Up to 90% of cases are caused by a chromosomal microdeletion that removes the entire STS gene. As use of screening that interrogates the entire genome (i.e., chromosomal microarray testing) increases, individuals are being diagnosed in the laboratory that may have not been recognized previously. A group of patients identified incidentally in the laboratory as having an STS deletion was found to have a milder skin phenotype of dryness or eczema, or both. This group lacked dark, polygonal scale, suggesting that a milder phenotype may be more common than previously realized, especially when the diagnosis is made incidentally [26 ]. This expanded phenotype may be important for others considering the implications of an incidental XLI diagnosis, as the literature describes at least five pregnancy terminations because of parental concern about the predicted skin phenotype based on prenatal laboratory testing. Females inherit the equivalent of one X chromosome from their mother and one from their father. Within each cell, one X is inactivated. In XLI, the mutated STS region is unusual because it escapes inactivation, so in any female cell, both copies of the STS gene are expressed. Therefore, a carrier female shows no features of the disorder. In 2014, a rare case of an affected female was reported because of a homozygous STS deletion, one on each X chromosome [27 ]. &
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CONCLUSION In summary, recent advances for common genodermatoses include refined diagnostic criteria based on patient review by experienced teams of clinicians (tuberous sclerosis, incontinentia pigmenti). A similar review of patient information has expanded the expected phenotype of a laboratory diagnosed disorder (XLI) to include milder forms. Advances also include the use of targeted medical therapies to replace traditional surgery (tuberous sclerosis, BCNS). Finally, new genetic technology such as Volume 27 Number 4 August 2015
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preimplantation genetic diagnosis (NF1, incontinentia pigmenti) is directly impacting patient care. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary ap& proach to care. Lancet Neurol 2014; 13:834–843. This review describes tumors and growths affecting various disparate organ systems, necessitating a multidisciplinary approach for patients with NF1. 2. Ferrari F, Masurel A, Olivier-Faivre L, Vabres P. Juvenile xanthogranuloma and && nevus anemicus in the diagnosis of neurofibromatosis type 1. JAMA Dermatol 2014; 150:42–46. This study proposes that the nevus anemicus may aid in the early diagnosis of NF1 in children younger than 2 years of age. 3. Jans SR, Schomerus E, Bygum A. Neurofibromatosis type 1 diagnosed in a & child based on multiple juvenile xanthogranulomas and juvenile myelomonocytic leukemia. Pediatr Dermatol 2015; 32:e29–e32. This well-written article reviews the association of NF1 and juvenile xanthogranuloma. 4. Dagalakis U, Lodish M, Dombi E, et al. Puberty and plexiform neurofibroma tumor & growth in patients with neurofibromatosis type I. J Pediatr 2014; 164:620–624. This study provides a detailed study of 41 patients by the National Institutes of Health, which shows no evidence that plexiform neurofibroma growth accelerates in puberty. 5. Plasschaert E, Descheemaeker MJ, Van Eylen L, et al. Prevalence of autism & spectrum disorder symptoms in children with neurofibromatosis type 1. Am J Med Genet B Neuropsychiatr Genet 2015; 168B:72–80. This is a study of 102 patients with NF1 assessed for evidence of ASDs. The discussion of the results clarifies the importance of social cognition deficits that are more prominent in NF1 in comparison with typical patients with ASDs. Repetitive behaviors are more common in ASDs than in NF1. 6. Merker VL, Murphy TP, Hughes JB, et al. Outcomes of preimplantation genetic & diagnosis in neurofibromatosis type 1. Fertil Steril 2015; 103:761–768; e761. This study describes the status of technology being used for preimplantation genetic diagnosis in NF1. 7. Teng JM, Cowen EW, Wataya-Kaneda M, et al. Dermatologic and dental && aspects of the 2012 International Tuberous Sclerosis Complex Consensus Statements. JAMA Dermatol 2014; 150:1095–1101. This is a consensus statement compiled by multiple experts following a review of extensive literature and patient photographs. Excellent photographs and dermatologic descriptions are provided. 8. Salido-Vallejo R, Ruano J, Garnacho-Saucedo G, et al. Facial angiofibroma & severity index (FASI): reliability assessment of a new tool developed to measure severity and responsiveness to therapy in tuberous sclerosis-associated facial angiofibroma. Clin Exp Dermatol 2014; 39:888–893. This article provides a description of the validation of an assessment tool (Facial Angiofibroma Severity Index), which can be used by clinician to assess progress in the treatment of facial angiofibromas and by researchers to assess possible treatments. 9. Park J, Yun SK, Cho YS, et al. Treatment of angiofibromas in tuberous & sclerosis complex: the effect of topical rapamycin and concomitant laser therapy. Dermatology 2014; 228:37–41. This article presents a series of cases, with photographs, of individuals treated by a combination of topical rapamycin and laser therapy. 10. Wataya-Kaneda M, Tanaka M, Yang L, et al. Clinical and histologic analysis of & the efficacy of topical rapamycin therapy against hypomelanotic macules in tuberous sclerosis complex. JAMA Dermatol 2015; doi: 10.1001/jamadermatol.2014.4298. [Epub ahead of print] This is a case series of individuals treated with topical rapamycin for hypomelanotic macules in tuberous sclerosis.
11. Muzic JG, Kindle SA, Tollefson MM. Successful treatment of subungual fibromas of tuberous sclerosis with topical rapamycin. JAMA Dermatol 2014; 150:1024–1025. This is a case study of a patient treated with topical rapamycin for subungual tumors in tuberous sclerosis. 12. Liebman JJ, Nigro LC, Matthews MS. Koenen tumors in tuberous sclerosis: a & review and clinical considerations for treatment. Ann Plast Surg 2014; 73:721–722. This is a case study of a patient treated with topical rapamycin for subungual tumors in tuberous sclerosis and review of treatment described in the literature. 13. Kotulska K, Jurkiewicz E, Domanska-Pakiela D, et al. Epilepsy in newborns && with tuberous sclerosis complex. Eur J Paediatr Neurol 2014; 18:714–721. This is a well-written article that details evidence for a poor prognosis in children with tuberous sclerosis who have an unusually early onset of seizures in the neonatal period. 14. Griner D, Sutphin D, Sargent LA. Surgical management of Gorlin syndrome: a && 4-decade experience using local excision technique. Ann Plast Surg 2015; 74:467–470; doi: 10.1097/SAP.0000000000000052. [Epub ahead of print] This article discusses an alternative approach for patients with BCNS considering surgical removal of skin cancer. Although only a single case study, the patient is followed for 40 years, adding to its value. Patients often ask about this option. 15. Athar M, Li C, Kim AL, et al. Sonic hedgehog signaling in basal cell nevus && syndrome. Cancer Res 2014; 74:4967–4975. This review provides a thorough discussion of the molecular mechanisms causing BCNS and related strategies for treatment. 16. Tang JY, Chiou AS, Mackay-Wiggan JM, et al. Tazarotene: randomized, & double-blind, vehicle-controlled, and open-label concurrent trials for basal cell carcinoma prevention and therapy in patients with basal cell nevus syndrome. Cancer Prev Res (Phila) 2014; 7:292–299. This is a well-designed study, which ultimately demonstrates a lack of benefit for the chemoprevention of BCC in patients with BCNS. 17. Jimbo T, Masumoto K, Urita Y, et al. Nevoid basal cell carcinoma syndrome & with a unilateral giant ovarian fibroma in a Japanese 6-year-old girl. Eur J Pediatr 2014; 173:667–670. This is a case study of a huge ovarian fibroma in a child with BCNS. 18. Singh AK, Lopez-Araujo A, Katabathina VS. Gorlin syndrome. J Pediatr 2014; & 164:1501–11501; e1501. This is a brief study with excellent radiologic images of jaw keratocyst and ovarian fibromas in a young patient with BCNS. 19. Conte MI, Pescatore A, Paciolla M, et al. Insight into IKBKG/NEMO locus: & report of new mutations and complex genomic rearrangements leading to incontinentia pigmenti disease. Hum Mutat 2014; 35:165–177. This is a review of the current knowledge about mutations that cause incontinentia pigmenti and the molecular mechanisms that predispose to them. 20. Minic S, Trpinac D, Obradovic M. Incontinentia pigmenti diagnostic criteria && update. Clin Genet 2014; 85:536–542. This article provides rationale and details behind updated diagnostic criteria for incontinentia pigmenti in a summary article. 21. Yang Y, Guo Y, Ping Y, et al. Neonatal incontinentia pigmenti: Six cases and a & literature review. Exp Ther Med 2014; 8:1797–1806. This is a case series of six patients diagnosed with neonatal incontinentia pigmenti in China. 22. Bergendal B. Orodental manifestations in ectodermal dysplasia-a review. Am & J Med Genet A 2014; 164A:2465–2471. This article provides a detailed review of the expected oral findings in several ectodermal dysplasias including incontinentia pigmenti. 23. Chen CJ, Han IC, Tian J, et al. Extended follow-up of treated and untreated && retinopathy in incontinentia pigmenti: analysis of peripheral vascular changes and incidence of retinal detachment. JAMA Ophthalmol 2015; 133:542– 548; doi: 10.1001/jamaophthalmol.2015.22. [Epub ahead of print] This article provides important information about vision loss as a potentially devastating complication of incontinentia pigmenti. Clinical signs that may predict complications in the eye and recommendations for ophthalmologic examination and follow-up are discussed in this article. 24. Pena ZG, Brewer JD. Multiple subungual squamous cell carcinomas in a & patient with incontinentia pigmenti. Dermatol Surg 2014; 40:1159–1161. This is a case study that outlines possible misdiagnosis of benign subungual tumors. 25. Kim MJ, Lyu SW, Seok HH, et al. A healthy delivery of twins by assisted & reproduction followed by preimplantation genetic screening in a woman with Xlinked dominant incontinentia pigmenti. Clin Exp Reprod Med 2014; 41:168–173. This a case study describing the successful use of PGD in incontinentia pigmenti. 26. Hand JL, Runke CK, Hodge JC. The phenotype spectrum of X-linked & ichthyosis identified by chromosomal microarray. J Am Acad Dermatol 2015; 26:617–627; doi: 10.1016/j.jaad.2014.12.020. [Epub ahead of print] This study describes a group of patients who were studied after having been diagnosed with steroid sulfatase deficiency (XLI) by molecular testing. The phenotype they expressed was, in general, less severe than expected based on previous descriptions in the literature. 27. Murtaza G, Siddiq S, Khan S, et al. Molecular study of X-linked ichthyosis: & report of a novel 2-bp insertion mutation in the STS and a very rare case of homozygous female patient. J Dermatol Sci 2014; 74:165–167. This is a rare case study of a woman with molecularly confirmed XLI. &
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