A dermatological perspective: eosinophilic eruption of hematoproliferative disease as a clinical and histological dilemma.

The emergence of de novo or recurrent cutaneous eruptions in individuals with hematological diseases presents a challenge when determining whether they indicate secondary dissemination or an unrelated diagnosis. Eosinophilic eruption of hematoproliferative disease is a rare nonspecific manifestation accompanying lymphoproliferative disorders, including chronic lymphocytic leukemia (CLL). We present the case of a 70-year-old man with CLL in remission (previously treated with two 6-month cycles of fludarabine-cyclophosphamide plus rituximab, 2 and 5 years earlier) with an acute, disseminated polymorphic skin eruption. Skin biopsies from two sites (bulla and infiltrated nodule) were taken for histopathological examination. The pathologist reported giant spongiform vesicle formation with eosinophils with dermal and hypodermal inflammatory infiltrate composed of lymphocytes (predominantly T cells, fewer B cells) and eosinophils. Secondary neoplasm dissemination and sarcoidosis were excluded by means of immunohistochemistry. A diagnosis of eosinophilic eruption of hematoproliferative disease in the CLL patient post-chemotherapy and without active disease was established. Two weeks after skin remission, the patient worsened with enlarged lymph nodes and a leukocyte count of 291 × 10^9/l. CLL relapse was confirmed. Leukocytapheresis was performed and ibrutinib 140 mg three times daily was prescribed. Our case underscores the importance of recognizing this relatively common but underreported eosinophilic eruption associated with hematoproliferative diseases.

The unknown silent drug reaction in acne patients: rare case of isotretinoin-induced haematuria.

BACKGROUND: Acne vulgaris is one of the most frequent visits to primary care physicians and dermatologists alike. Isotretinoin is the backbone of acne treatment. In most countries, depending on the health care system, isotretinoin is prescribed by dermatologists but primary care physicians are a part of the follow-up and interpreting analysis. Adverse effects of isotretinoin on the kidney and urinary system are mostly limited to sparse case reports. Specifically, gross and microscopic haematuria is not mentioned to be associated with isotretinoin. Lack of data regarding these adverse effects can lead to doubt regarding further patient management not only with dermatologists but also primary care physicians. OBJECTIVE: We report a 16-year-old male patient with isotretinoin-induced haematuria with multiple episodes and subsequent challenge and de-challenge. No personal or familial history of nephrological disease was present. Ultrasound imaging and nephrology workup was within normal limits. Other aetiologies were excluded. Nephrology consult stated there was no contraindication for isotretinoin use and was reinstated at 0.6 m/kg/day. More frequent observation was indicated until completion of isotretinoin. CONCLUSION: Our case raises awareness to other dermatologists and primary care physicians that haematuria can be secondary to isotretinoin but not a contraindication for further use if asymptomatic and microscopic. More extensive evaluation and monitoring should be done if the patient is symptomatic with other abnormalities and symptoms. Urinalysis should be a part of routine follow-up monitoring in patients on isotretinoin. Furthermore, delineating and differentiating when to refer to a nephrologist is essential for physicians, patients, and the health care system overall.

Red blood cells in the urine (called haematuria), whether seen by the eye or seen only on urinalysis can be caused by many diseases and/or drugs. The most effective treatment of acne is isotretinoin and its side effects are for the most part known. Renal and/or urinary side effects are extremely rare. We report a 16-year-old male patient with isotretinoin-induced haematuria with multiple episodes and subsequent challenge and de-challenge. When isotretinoin was discontinued, no red blood cells were seen in the urine. When isotretinoin was reinstituted, red blood cells were seen once again in the urine. It is important for physicians to know of this rare side effect as it prevents unnecessary referrals to nephrologists, while on the other hand raises awareness of the connection and helps in understanding when isotretinoin should be potentially discontinued and patients referred.

The Impact of the IKBKG Gene on the Appearance of the Corpus Callosum Abnormalities in Incontinentia Pigmenti.

Incontinentia pigmenti (IP) is a rare skin disease combined with anomalies of the teeth, eyes, and central nervous system (CNS). Mutations of the IKBKG gene are responsible for IP. Among the most frequent CNS abnormalities found in IP using magnetic resonance imaging (MRI) are corpus callosum (CC) abnormalities. The aim of the study was to determine the presence of CC abnormalities, their relationship with the IKBKG mutations, and the possible presence of mutations of other genes. A group of seven IP patients was examined. Analyses of the IKBKG gene and the X-chromosome inactivation pattern were performed, as well as MRI and whole exome sequencing (WES) with the focus on the genes relevant for neurodegeneration. WES analysis showed IKBKG mutation in all examined patients. A patient who had a mutation of a gene other than IKBKG was excluded from further study. Four of the seven patients had clinically diagnosed CNS anomalies; two out of four had MRI-diagnosed CC anomalies. The simultaneous presence of IKBKG mutation and CC abnormalities and the absence of other mutations indicate that IKBKG may be the cause of CC abnormalities and should be included in the list of genes responsible for CC abnormalities.

Effectiveness and safety of topical calcipotriol in the treatment of flat seborrheic keratosis on the face.

Seborrheic keratosis is the most common slow-growing, benign epithelial tumour, usually appearing on sun-exposed areas. Treatment modalities for seborrheic keratosis may be uncomfortable and/or time-consuming. We present a case series of 12 patients with solitary seborrheic keratosis localized on the face treated with 0.005% calcipotriol ointment. The treatment lasted 3-8 months and resulted in complete regression of the lesions. Remission (follow-up period) lasted from 6 to 10 years. We conclude that topical calcipotriol may be a useful treatment option for seborrheic keratosis.

Dermoscopy in the Diagnostics of Incontinentia Pigmenti Skin Lesions.

Introduction: Incontinentia pigmenti (IP) is a rare X-linked geno-dermatosis characterized by numerous findings. Skin biopsy and histopathological analysis are considered as minor criteria for the diagnosis of IP. We assume that dermoscopy can assist the earlier diagnosis of IP. Objectives: To gain experience in earlier diagnosis of IP by observing dermoscopic findings of cutaneous changes. Methods: We revised confirmed cases of IP and examined them using dermoscopy, comparing histopathological and dermoscopic results. Results: Stage I presented solitary and grouped vesicles in linear arrangement on erythematous skin. Early stage II presented star-shaped verrucous lesions on erythematous or pigmented skin. In well-developed lesions, dotted vessels surround keratotic part, some with thrombosed capillaries, resembling a viral wart. Stage III presented linear brown dots on the pigmented areas. Dermoscopic image was uniform in all the examined pigmented Blaschko linear changes. Stage IV presented numerous dotted vessels on the hypopigmented skin. Terminal hair was scarce or absent in all four stages. The surrounding normal skin had perifollicular depigmentations in stages III and IV. Conclusions: Dermoscopy of all four stages is very specific compared to the dermoscopy of inflammatory dermatoses and pigmentations. Stage III has very close clinical, histological and dermoscopic mimickers and needs to be carefully examined with obligatory genetic testing. Dermoscopy of the stage IV closely corresponds to histopathological findings and may be crucial as a quick tool in revealing potential IP gene carriers. Dermoscopy should be used in addition to clinical examination since the two methods are complementary.

Challenges in Rare Diseases Diagnostics: Incontinentia Pigmenti with Heterozygous GBA Mutation.

Rare diseases represent a diagnostic challenge due to their number, variety of clinical phenomena, and possibility of a simultaneous presence of two or more diseases. An illustration of this challenge is an occurrence of a late diagnosis of a proband initially diagnosed with West syndrome, later revealed to be caused by Incontinentia pigmenti (IP). Furthermore, 20 years later, it was discovered that the proband was also a carrier of a heterozygous GBA gene mutation. The methods used in diagnostics were as follows: IKBKG gene analysis, the X-chromosome inactivation assay, analyses of the genes relevant for neurodegeneration, WES analysis, analysis of biochemical parameters typical for Gaucher disease (GD), and autoantibodies including IFN-α2a and IFN-ω. To avoid overlooking IP and other possible rare disease diagnoses, carefully searching for dermatological signs in these conditions is recommended. It is important that the diagnostic criteria are based on quality and extensive data from multiple studies of each rare disease. Establishing precise diagnostic criteria for as many rare diseases as possible and establishing a publicly accessible database of rare diseases with a search possibility according to phenotypic abnormalities and genetic mutations would greatly facilitate and speed up the establishment of an accurate diagnosis.

A Novel Frameshift Mutation of the IKBKG Gene Causing Typical Incontinentia Pigmenti.

INTRODUCTION: Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis. Mutations of the IKBKG gene are responsible for IP. A deletion of exons 4-10 can be found in 80% of patients with IP. There are 69 different mutations of the IKBKG gene that have been reported. CASE OUTLINE: A proband, female patient from a family without previously diagnosed IP is reported. She had skin and dental changes typical of IP. The diagnosis was made according to updated IP criteria. Pathohistological and ultrastructural analysis of skin biopsy confirmed the diagnosis. However, the common deletion of exons 4-10 in the IKBKG gene could not be detected. Sequencing revealed the indel (deletion/insertion) mutation c.641_647delGCATGGAinsAT (p.Arg214HisfsX38) in exon 5 of the IKBKG gene. Because this mutation could not be detected in the unaffected mother of the proband, it seems to be a de novo mutation. CONCLUSION: The registered novel frameshift/KBKG mutation c.641_647delGCATGGAinsAT (p.Arg214HisfsX38) can be considered to be the cause of IP in this case.

First IKBKG gene mutation study in Serbian incontinentia pigmenti patients.

INTRODUCTION: Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis. Mutations of the IKBKG gene are the only known cause of IP. The presence or other than skin changes is important in the diagnosis of atypical IP cases when skin changes are discrete. OBJECTIVE: The study was designed to analyze clinical manifestation, family histories and the frequency of IKBKG gene mutation in IP patients in Serbia for the first time and to compare them with other reported findings. METHODS: Two Serbian unrelated families with eight female subjects were investigated. Blood samples were used for IKBKG exon 4-10 deletion testing using modified PCR protocol. For probands pathohistological and ultrastructural analyses of skin biopsies were done. RESULTS: Positive clinical diagnosis according to IP criteria was present in seven cases. In six of them, including probands, positive molecular gene testing for IKBKG exon 4-10 deletion was present. CONCLUSION: This is the first report of genetically confirmed IP in two Serbian families. The IP patients presented a common IKBKG exon 4-10 deletion. The frequency and type of IKBKG mutation found in investigated IP patients in Serbia were similar to results of other studies. Various clinical features of investigated patients have allowed us to demonstrate that molecular genetic testing which specifically detects the common IKBKG mutations, the only known cause of IP, is useful in diagnosing IP especially in mild or atypical cases. The molecular genetic testing of the IKBKG mutations may be helpful for rapid confirmation of IP diagnosis, prenatal diagnosis and carrier detection.

Blaschko line analogies in the central nervous system: a hypothesis.

In X-chromosome-linked skin disorders the pattern of involvement follows Blaschko lines. Patterns of changes analogous to cutaneous Blaschko lines in different X-linked diseases existed in other organs. There is no commonly accepted analogy to Blaschko lines in the central nervous system (CNS). The objective of this study was to consider a hypothesis of the existence of Blaschko lines in the CNS in the example of incontinentia pigmenti (IP). Articles were analyzed in which brain imaging methods were used in IP patients with CNS anomalies. In IP patients with neurological signs brain lesions usually were localized and extended radially. Affected areas did not correspond to territories vascularized by any determined artery. Radially distributed brain lesions morphologically match the radial unit model of cortical development. It can be proposed that in IP in CNS Blaschko line analogies, similar to those in the skin, represent the trace of development of the clone of neurons arising from the cell marked with IKBKG mutation. The hypothesis of the existence of Blaschko line analogies in CNS is supported by radially distributed CNS image findings in IP, the radial unit model of CNS development, and the common embryonic origin of skin, CNS, and eyes.

Systematic review of central nervous system anomalies in incontinentia pigmenti.

The objective of this study was to present a systematic review of the central nervous system (CNS) types of anomalies and to consider the possibility to include CNS anomalies in Incontinentia pigmenti (IP) criteria. The analyzed literature data from 1,393 IP cases were from the period 1993-2012. CNS anomalies were diagnosed for 30.44% of the investigated IP patients. The total number of CNS types of anomalies per patient was 1.62. In the present study there was no significantly higher number of anomalies per patient in females than males. The most frequent CNS types of anomalies were seizures, motor impairment, mental retardation, and microcephaly. The most frequently registered CNS lesions found using brain imaging methods were brain infarcts or necrosis, brain atrophies, and corpus callosum lesions. IKBKG exon 4-10 deletion was present in 86.00% of genetically confirmed IP patients. The frequency of CNS anomalies, similar to the frequency of retinal anomalies in IP patients, concurrent with their severity, supports their recognition in the list of IP minor criteria.

Dental and oral anomalies in incontinentia pigmenti: a systematic review.

OBJECTIVES: Incontinentia pigmenti (IP) is an X-linked genodermatosis caused by a mutation of the IKBKG gene. The objective of this study was to present a systematic review of the dental and oral types of anomalies, to determine the total number and sex distribution of the anomalies, and to analyze possible therapies. MATERIALS AND METHODS: We analyzed the literature data from 1,286 IP cases from the period 1993-2010. RESULTS: Dental and/or oral anomalies were diagnosed for 54.38% of the investigated IP patients. Most of the anomaly types were dental, and the most frequent of these were dental shape anomalies, hypodontia, and delayed dentition. The most frequent oral anomaly types were cleft palate and high arched palate. IKBKG exon 4-10 deletion was present in 86.36% of genetically confirmed IP patients. CONCLUSIONS: According to the frequency, dental and/or oral anomalies represent the most frequent and important IP minor criteria. The most frequent mutation was IKBKG exon 4-10 deletion. The majority of dental anomalies and some of the oral anomalies could be corrected. CLINICAL RELEVANCE: Because of the presence of cleft palate and high arched palate in IP patients, these two anomalies may be considered as diagnostic IP minor criteria as well.

Ocular anomalies in incontinentia pigmenti: literature review and meta-analysis.

INTRODUCTION: Incontinentia pigmenti (IP) is an X-linked genodermatosis in which skin changes are combined with dental, eye and central nervous system anomalies. OBJECTIVE: The goal of the study was to analyze ocular findings, IP minor criteria in available literature concerning IP cases published until now. METHODS: We have done meta-analysis of 1931 IP patients found in 302 references published until 2010. Comparison of data published for the 1906-1976 and 1976-2010 periods was made. The collected data were mainly frequencies of ocular anomalies. Chi-square test was used to compare observed frequencies with their expectations. RESULTS: Of total number of IP patients, 1227 were ophthalmologically investigated. In 449 such patients 972 eye anomalies were registered, 2.16 anomalies per patient. Proportion of ophthalmologically investigated IP patients in the period 1906-1975 (70%) was higher than corresponding proportion (60%) for the period 1976-2010. For 1906-2010 period 36.5% IP patients with eye anomalies were diagnosed. The number of amaurotic eyes per patient did not significantly differ for the two periods (p = 0.50; > 0.05). The total number of eye anomalies per patient significantly differed for the same periods (p = 0.00005; < 0.05). Retinal anomalies were most frequent in both periods. CONCLUSION: This study suggests that IP is far more frequent than anyone could estimate. We believe that this study, covering 1906-2010 period, gives more reliable information about ophthalmological findings in IP; considering them as severe anomalies. Early detection and treatment of ophthalmological, neurological etc. findings may prevent severe consequences that IP may cause.

Ophthalmological findings in series of incontinentia pigmenti patients from Serbia.

INTRODUCTION: Incontinentia pigmenti (IP) is a rare complex X-linked genodermatosis in which skin changes are combined with anomalies of other organs. Mutations of the NEMO gene localized on chromosome Xq28 are responsible for IP. Clinical manifestations of IP according to evolution and prognosis can be considered as skin changes and dental, eye and central nervous system changes. OBJECTIVE: The aim of our study was to investigate type and frequency of ocular features in Serbian population. METHODS: We investigated the total of 9 families with 22 subjects, 20 females and 2 males, at the Institute of Dermatovenerology, Clinical Centre of Serbia, in the period from 1989 to 2009. Our subjects were diagnosed clinically by a dermatologist and the diagnosis confirmed by cutaneous histopathology and ultrastructural analysis. The pedigrees, karyotype analyses, routine laboratory findings, additional specialized clinical examinations were done for all subjects. RESULTS: Among 22 IP patients from our study, different ophthalmological anomalies were observed in 16% of subjects. In female subjects, all of them with clinical characteristics of IP, we observed the following anomalies: retinal detachment, microphthalmia, cataract, strabismus and nystagmus. CONCLUSION: Compared to available literature data, our percentage of IP patients with anomalies was lower. It may be due to differences in examined populations or due to the fact that the patients in our study were firstly admitted to the Institute of Dermatology. Ophthalmological findings may be often considered as very severe anomalies in IP. It is very important to detect IP as early as possible, medically help and monitor these patients.

Two male patients with incontinentia pigmenti.

BACKGROUND: Incontinentia pigmenti (IP) is a rare, complex, X-linked genodermatosis in which skin changes are combined with defects of other organs. It appears almost exclusively in females and is usually lethal in men. It is estimated that according to the available reported cases, there have been approximately 900-1,200 affected individuals, out of which 60 males. The aim of the study was to report two additional individual male cases with IP. CASE REPORTS: We discovered two male patients with IP according to standard IP diagnostic criteria. The diagnosis was made by a dermatologist and confirmed by cutaneous histopathology and ultrastructural analysis. The pedigrees, karyotype analyses and routine laboratory findings were made. Two male probands were the only ones with IP in their families, with no history of miscarriages. Both probands had normal karyotype. In one proband, acrocentric chromosomes of the group D had tendency of forming associations. Histopathological and ultrastructural skin analyses revealed findings typical for IP. CONCLUSION: The detection of each male case is very valuable because of their rarity. Application of the standard diagnostic criteria is necessary for comparison and epidemiological analysis. Monitoring such probands allows a better determination of how genetic transmission occurs, and is important because of the different degrees of severity of IP.

Clinical features of incontinentia pigmenti with emphasis on oral and dental abnormalities.

One of interesting aspects in dermatology is the fact that skin may reflect the presence of anomalies in other organs and tissues. One such example is incontinentia pigmenti (IP), a rare, complex, X-linked genodermatosis. Clinical manifestations of IP according to evolution and prognosis can be considered as skin, as well as dental, eye, and central nervous system, changes. We have investigated a total of nine families with 25 subjects, 23 females and 2 males. In 12 female and 2 male subjects, all of them with clinical characteristics of IP, we observed the following abnormalities: teeth-shape anomalies (coni- or peg-like teeth), the presence of numerous cariotic teeth, early dental loss, delayed eruption, partial anodontia, and gothic palate. To our knowledge, this is the first time that the presence of gothic palate in patients with IP has been documented. As we found out, in two female subjects and one male subject, in which nonrandomed X inactivation did not occur, gothic palate could be supposed as characteristic of IP.