Incontinentia pigmenti: XXY male with a family history

We report on the case of a male who from the start of life displayed vesicular lesions; on the trunk these were clustered and on the limbs they adopted a linear configuration. After biopsy of one such lesion, the histopathological study was compatible with a diagnosis of incontinentia pigmenti (IP). In the following months, hyperkeratotic lesions appeared which later became pigmented. The mother and other female members of the family also showed different degrees of alteration related to the same disease. The karyotype study showed the existence of 47,XXY (Klinefelter syndrome). The exceptional nature of this case is that although it is the third case reported in the literature of a male affected by incontinentia pigmenti with a previous family history, it is the only one combining this characteristic with the presence of a 47,XXY karyotype.     

Incontinentia pigmenti in adults

Incontinentia Pigmenti (IP; MIM 308300) is an X‐linked dominant genodermatosis caused by pathogenic variant in IKBKG. The phenotype in adults is poorly described compared to that in children. Questionnaire survey of 99 affected women showed an age at diagnosis from newborn to 41 years, with 53 diagnosed by 6 months of age and 30 as adults. Stage I, II, and III lesions persisted in 16%, 17%, and 71%, respectively, of those who had ever had them. IP is allelic to two forms of ectodermal dysplasia. Many survey respondents reported hypohidrosis and/or heat intolerance and most had Stage IV findings. This suggests that “Stage IV” may be congenitally dysplastic skin that becomes more noticeable with maturity. Fifty‐one had dentures or implants with 26 having more invasive jaw or dental surgery. Half had wiry or uncombable hair. Seventy‐three reported abnormal nails with 27 having long‐term problems. Cataracts and retinal detachment were the reported causes of vision loss. Four had microphthalmia. Respondents without genetic confirmation of IP volunteered information suggesting more involved phenotype or possibly misassigned diagnosis. Ascertainment bias likely accounts for the low prevalence of neurocognitive problems in the respondents.     

Abnormal Cutaneous Nerves in Incontinentia Pigmenti

Cutaneous nerves showed multiple ultrastructural abnormalities in a patient with incontinentia pigmenti. Fetal nerve bundles were seen both in the dermis and entering the epidermis. A cell with some Schwann cell features was identified above the basal layer amid keratinocytes. Dermal melanophages were in close apposition to Schwann cells. All of these features suggest that neural structures may be abnormal in incontinentia pigmenti and play a role in transfer of melanin from epidermis to dermis.     

Incontinentia pigmenti in a newborn male infant with DNA confirmation

We report on a woman with incontinentia pigmenti (IP), who had two successive term pregnancies. The first pregnancy ended in the birth of a male infant, who is alive and well at 2 years. A second liveborn male had early postnatal distress and died after 1 day of life, after a fulminating clinical course. Polymorphic microsatellite markers, closely linked to the IP gene on the X chromosome, showed that each son inherited a different X chromosome from his mother. Although in most instances IP appears to be prenatally lethal for the male, the phenotype is not completely known. We propose that the neonatal phenotype may be characterized by lethal disturbances in the hematopoietic and immunologic systems. Am. J. Med. Genet. 75:159–163, 1998. © 1998 Wiley-Liss, Inc.     

Incontinentia pigmenti in Arizona Indians including transmission from mother to son inconsistent with the half chromatid mutation model

Incontinentia pigmenti (IP) is an X-linked dominant disease, usually lethal to males. To explain occasional sporadic IP males, the half chromatid mutation model (Gartler & Francke 1975) has been invoked (Lenz 1975). We here report four cases of American Indians with IP. Two girls had sporadic IP. One affected boy's mother had IP. This is the first report of mother-to-son transmission of IP, indicating that a male with an inherited whole chromatid mutation for IP can escape lethality.     

一个色素失禁症家系的NEMO基因和假基因△NEMO缺失突变分析

目的 用长链聚合酶链反应进行检测家族性色素失禁症(incontinentia pigmenti,IP)患者的NEMO基因的缺失突变.方法 收集一色素失禁症家系的临床资料,选取NEMO基因特异引物In2/ff3R和假基因△NEMO的特异引物Rev-2/JF3R,采用长链聚合酶链反应对家系内成员NEMO基因和假基因△NEMO的缺失位点进行检测,同时对80名无血缘关系健康对照者的该位点进行同样检测.结果 所有患者皆有NEMO基因和假基因△NEMO基因共有序列NEMO△4-10缺失,而在家系内非患者以及80名正常对照者中均未发现NEMO基因和假基因△NEMO的共有序列NEMO4△-10缺失.结论 该家系为一个典型遗传早现现象的IP家系,NEMO基因和△NEMO的缺失突变导致其发病.长链PCR扩增技术可用于检测NEMO基因的缺失突变,对于遗传咨询具有一定的应用价值.     

Two cases of misinterpretation of molecular results in incontinentia pigmenti,and a PCR-based method to discriminate NEMO/IKKgamma dene deletion

Familial incontinentia pigmenti (IP) is a rare X-linked dominant disorder that affects ectodermal tissues. Over 90% of IP carrier females have a recurrent genomic deletion of exons 4-10 of the NEMO (IKBKG-IKKgamma) gene, which encodes a regulatory component of the IkB kinase complex, required to activate the NF-kB pathway. In IP, mutations in NEMOlead to the complete loss of NF-kB activation creating a susceptibility to cellular apoptosis in response to TNF-alpha. This condition is lethal for males during embryogenesis while females, who are mosaic as a result of X-inactivation, can survive. Recently, a second nonfunctional copy of the gene, DeltaNEMO, was identified, opposite in direction to NEMO in a 35.5-kb duplicated sequence tract. PCR-based detection of the NEMO deletion is diagnostic for IP disease. However, we present instances in which ex 4-10 DeltaNEMO pseudogene deletion occurs in unaffected parents of two females with clinically characteristic IP. These were missed by the currently standard PCR-based method, but can be easily discriminated by a new PCR-based test reported here that permits unambiguous molecular diagnosis and proper familial genetic counseling for IP.     

The gene for incontinentia pigmenti: failure of linkage studies using DNA probes to confirm cytogenetic localization

Probes for restriction fragment length polymorphisms mapping between Xp21 and Xq22.3 have been used in a linkage study of incontinentia pigmenti (IP). Six independent sporadic cases of disorders resembling IP with X-autosome translocations involving the same X chromosome breakpoint (Xp11) have been reported. These observations suggest that the IP gene may be located in the Xp11 chromosomal region. However, the linkage study with DNA probes has failed to confirm this localisation.     

A successful treatment of tadalafil in incontinentia pigmenti with pulmonary hypertension

We describe a female infant with incontinentia pigmenti complicated by severe pulmonary arterial hypertension that was markedly improved by tadalafil administration. The infant was referred to our institution because of neonatal seizures and generalized skin rash at the age of 1 day. She was diagnosed with incontinentia pigmenti on skin biopsy findings. In addition to incontinentia pigmenti, she had pulmonary arterial hypertension without structural heart disease. The pulmonary hypertension rapidly worsened at the age of 2 months and was confirmed by cardiac catheterization. The pulmonary artery pressure was equal to systemic pressure but it decreased in response to nitric oxide inhalation. We, therefore, initiated treatment with tadalafil of 1 mg/kg/day. The follow-up cardiac catheterization performed at 9 months revealed dramatic improvement in the pulmonary artery pressure. An IKBKG mutation with deletion of exons 4–10 was detected in the blood of both the patient and her mother. Our experience indicates that tadalafil may be beneficial in treating pulmonary arterial hypertension associated with incontinentia pigmenti.     

X-inactivation and marker studies in three families with incontinentia pigmenti: implications for counselling and gene localisation

Familial incontinentia pigmenti (IP) is an X-linked dominant disorder with an extremely variable clinical presentation. Ambiguous diagnosis can complicate genetic counselling and attempts to refine the gene location in Xq28. Marked skewing of X-inactivation patterns is a hallmark of IP and provides a means for investigating uncertain cases. We have conducted X-inactivation studies in three families where Xq28 marker studies were at odds with the original clinical assessment. The results indicate that no recombination between the disease locus and Xq28 loci has occurred and suggest that mosaicism is responsible for the discrepancy in one family.     

Partial sweat gland aplasia in incontinentia pigmenti Bloch-Sulzberger

Dermatoglyphic investigation of palm prints in patients with Incontinentia pigmenti revealed in five of eight cases a partial ridge dissociation with lack of sweat gland pores. This disease can, therefore, be accepted as a second X-linked anhidrotic ectodermal dysplasia, which, however, is only segregated in the female.     

Expression of eotaxin, an eosinophil-selective chemokine, parallels eosinophil accumulation in the vesiculobullous stage of incontinentia pigmenti

Incontinentia pigmenti (IP) is an X-linked dominant genodermatosis primarily affecting female children. The initial vesiculobullous stage of IP is characterized clinically by inflammatory papules, blisters, and pustules, and histopathologically by acanthosis, keratinocyte necrosis, epidermal spongiosis and massive epidermal eosinophil infiltration. The cause of this multisystem disease is attributed to the mutations of an X-linked regulatory gene, termed nuclear factor-kappaB essential modulator (NEMO). The exact mechanism of epidermal eosinophil accumulation has not yet been determined. We explored the possible role of an eosinophil-selective, nuclear factor-kappaB-activated chemokine, eotaxin, in the accumulation of eosinophils in the initial stage of the disease. Monoclonal antibody (6H9) specific for human eotaxin strongly labelled the suprabasal epidermis of IP skin, paralleling the upper epidermal accumulation of eosinophils, but did not label the epidermis of normal skin or lesional skin from patients with other inflammatory skin diseases not characterized by prominent eosinophil accumulation, namely dermatitis herpetiformis and selected cases of atopic dermatitis lacking significant numbers of eosinophils. In addition, endothelial cells in lesional skin of IP also exhibited strong expression of eotaxin, which correlated with perivascular and intravascular eosinophil infiltration. We also examined the in vitro effects on epidermally derived eotaxin of several cytokines that were nuclear factor-kappaB-activated and/or known to induce eotaxin expression. In normal human keratinocytes, proinflammatory cytokines either independently (IL-1alpha) or synergistically (tumour necrosis factor-alpha (TNF-alpha)/ interferon-gamma (IFN-gamma) and TNF-alpha/IL-4) up-regulated eotaxin expression. These studies suggest that release of cytokines during the initial inflammatory stage of IP induces epidermal expression of eotaxin, which may play a role in the epidermal accumulation of eosinophils.     

Male cases of incontinentia pigmenti: Case report and review

Male patients with Bloch-Sulzberger incontinentia pigmenti (IP type II) are rare and more severely affected than their female counterparts, with a significant occurrence of sex chromosome aneuploidy. This document introduces a new male IP type II patient and reviews 48 males reported with IP. Twenty-eight of the 49 patients meet current criteria for diagnosis of IP type II. The phenotype is variable and the incidence of documented developmental delay is 25%. Five patients had Klinefelter syndrome (47,XXY). Most patients were reported prior to 1961 when chromosome analysis was not available. Biopsy and laboratory reports considered to be “consistent with” the diagnosis of IP were seen in patients meeting criteria as well as those who would not currently be given the diagnosis. The histologic findings considered diagnostic are varied. This variability may be accounted for by differences in stage of disease, biopsy site, histologic technique, and reporting style. Conversely, this may indicate that the diagnostic weight given to the biopsy should be reconsidered. Eosinophilia was not a consistent finding. Overall, differences in reporting, ascertainment, and length of follow-up lead to difficulty in interpreting or predicting the natural history of males with IP type II. Based on the existing literature, they appear to have a higher rate of mental retardation than the general population, but there does not appear to be a correlation between severity of physical and mental involvement. The presence of sex chromosome aneuploidy documented in the more recent cases emphasizes the need for chromosome analysis in any male patient suspected of IP type II. Am. J. Med. Genet. 77:201–218, 1998. © 1998 Wiley-Liss, Inc.     

Gene for incontinentia pigmenti maps to band Xp11 with an (X;10) (p11;q22) translocation

Incontinentia pigmenti (IP) is a genetic disease that is usually lethal in males. We report finding an X;10 translocation in a girl with IP. Three other X/autosome translocations have been observed in females with IP: two involving chromosome 9 and one involving chromosome 17. The breakpoint in all four cases in the X chromosome was in band Xp11. The IP gene locus can therefore be confidently assigned to the X chromosome and, specifically, to band Xp11. The IP gene is most likely to subband Xp11.2. We propose that IP may prove to be a submicroscopic deletion.     

Application of diagnostic and treatment criteria for common variable immunodeficiency disorder

Common variable immunodeficiency disorder (CVID) is the most frequent symptomatic primary immune deficiency disorder in adults. It probably comprises a spectrum of polygenic disorders, with hypogammaglobulinemia being the overarching feature. While the majority of patients with CVID can be identified with relative ease, a significant proportion can present with minimal symptoms in spite of profound laboratory abnormalities. Here we discuss three patients who were presented to the Auckland Hospital immunoglobulin treatment committee to determine if they qualified for immunoglobulin replacement. Two were asymptomatic with profound laboratory abnormalities while the third patient was severely ill with extensive bronchiectasis. The third patient had less severe laboratory abnormalities compared with the two asymptomatic patients. We have applied four sets of published diagnostic and treatment criteria to these patients to compare their clinical utility. We have chosen these patients from the broad phenotypic spectrum of CVID, as this often illustrates differences in diagnostic and treatment criteria.     

Celiac disease: diagnostic criteria in progress

Until a few years ago, celiac disease (CD) was thought to be a rare food intolerance that was confined to childhood and characterized by severe malabsorption and flat intestinal mucosa. Currently, CD is regarded as an autoimmune disorder that is common in the general population (affecting 1 in 100 individuals), with possible onset at any age and with many possible presentations. The identification of CD is challenging because it can begin not only with diarrhea and weight loss but also with atypical gastrointestinal (constipation and recurrent abdominal pain) and extra-intestinal symptoms (anemia, raised transaminases, osteoporosis, recurrent miscarriages, aphthous stomatitis and associated autoimmune disorders), or it could be completely symptomless. Over the last 20 years, the diagnostic accuracy of serology for CD has progressively increased with the development of highly reliable tests, such as the detection of IgA tissue transglutaminase and antiendomysial and IgG antideamidated gliadin peptide antibodies. The routine use of antibody markers has allowed researchers to discover a very high number of 'borderline' cases, characterized by positive serology and mild intestinal lesions or normal small intestine architecture, which can be classified as potential CD. Therefore, it is evident that the 'old celiac disease' with flat mucosa is only a part of the spectrum of CD. It is possible that serology could identify CD in its early stages, before the appearance of severe intestinal damage. In cases with a positive serology but with mild or absent intestinal lesions, the detection of HLA-DQ2 and HLA-DQ8 can help reinforce or exclude the diagnosis of gluten sensitivity.     

Comparison of usefulness of clinical diagnostic criteria for hepatocellular carcinoma in a hepatitis B endemic area

Background/Aims

We compared the accuracy and usefulness of clinical diagnostic criteria for hepatocellular carcinoma in a hepatitis B virus (HBV)-endemic area.

Methods

We reviewed the medical records of 355 patients who had undergone liver resection or biopsy at our institution between January 2008 and December 2009. These patients were reevaluated using four noninvasive diagnostic criteria for hepatocellular carcinoma proposed by the European Association for the Study of the Liver (EASL), the American Association for the Study of Liver Diseases (AASLD), the Korean Liver Cancer Study Group and the National Cancer Center (KLCSG/NCC), and National Comprehensive Cancer Network (NCCN) guidelines.

Results

The overall sensitivity was highest using the KLCSG/NCC criteria (79.8%), followed by the AASLD (51.5%), EASL (38.4%), and NCCN (10.1%; P<0.001) criteria, whereas the specificity (84.5-98.3%) and positive predictive value (96.2-98.3%) were similar for all of the criteria. The KLCSG/NCC criteria had an acceptable false-positive rate and the highest sensitivity among all of the patients, including those positive for HBsAg, those without liver cancer, and those with a tumor of at least 2 cm.

Conclusions

The KLCSG/NCC and AASLD criteria exhibited the highest sensitivity, and all four guidelines had a high specificity among all of the patients. Based on the sensitivity and false-positive rate, the KLCSG/NCC criteria was the most useful in the majority of patients. Inclusion of HBV infection in the clinical diagnostic criteria for hepatocellular carcinoma would be reasonable and may lead to an improvement in the sensitivity, with acceptable false-positive rates, in HBV-endemic areas.