Moise L. Levy

Genomic rearrangement in NEMO impairs NF-κB activation and is a cause of incontinentia pigmenti: The International Incontinentia Pigmenti (IP) Consortium

Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males. In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring1. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation2. The reasons for cell death in females and in utero lethality in males are unknown. The locus for IP has been linked genetically to the factor VIII gene in Xq28 (ref. 3). The gene for NEMO (NF-κB essential modulator)/IKKγ (IκB kinase-γ) has been mapped to a position 200 kilobases proximal to the factor VIII locus4. NEMO is required for the activation of the transcription factor NF-κB and is therefore central to many immune, inflammatory and apoptotic pathways5,6,7,8,9. Here we show that most cases of IP are due to mutations of this locus and that a new genomic rearrangement accounts for 80% of new mutations. As a consequence, NF-κB activation is defective in IP cells.Familial incontinentia pigmenti (IP; MIM 308310) is a genodermatosis that segregates as an X-linked dominant disorder and is usually lethal prenatally in males. In affected females it causes highly variable abnormalities of the skin, hair, nails, teeth, eyes and central nervous system. The prominent skin signs occur in four classic cutaneous stages: perinatal inflammatory vesicles, verrucous patches, a distinctive pattern of hyperpigmentation and dermal scarring. Cells expressing the mutated X chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation. The reasons for cell death in females and in utero lethality in males are unknown. The locus for IP has been linked genetically to the factor VIII gene in Xq28 (ref. 3). The gene for NEMO (NF-κB essential modulator)/IKKγ (IκB kinase-γ) has been mapped to a position 200 kilobases proximal to the factor VIII locus. NEMO is required for the activation of the transcription factor NF-κB and is therefore central to many immune, inflammatory and apoptotic pathways. Here we show that most cases of IP are due to mutations of this locus and that a new genomic rearrangement accounts for 80% of new mutations. As a consequence, NF-κB activation is defective in IP cells.

Desmoglein 4 in Hair Follicle Differentiation and Epidermal Adhesion: Evidence from Inherited Hypotrichosis and Acquired Pemphigus Vulgaris

Cell adhesion and communication are interdependent aspects of cell behavior that are critical for morphogenesis and tissue architecture. In the skin, epidermal adhesion is mediated in part by specialized cell-cell junctions known as desmosomes, which are characterized by the presence of desmosomal cadherins, known as desmogleins and desmocollins. We identified a cadherin family member, desmoglein 4, which is expressed in the suprabasal epidermis and hair follicle. The essential role of desmoglein 4 in skin was established by identifying mutations in families with inherited hypotrichosis, as well as in the lanceolate hair mouse. We also show that DSG4 is an autoantigen in pemphigus vulgaris. Characterization of the phenotype of naturally occurring mutant mice revealed disruption of desmosomal adhesion and perturbations in keratinocyte behavior. We provide evidence that desmoglein 4 is a key mediator of keratinocyte cell adhesion in the hair follicle, where it coordinates the transition from proliferation to differentiation.

A Controlled Trial of Acyclovir for Chickenpox in Normal Children

BACKGROUND Chickenpox, the primary infection caused by the varicella-zoster virus, affects more than 3 million children a year in the United States. Although usually self-limited, chickenpox can cause prolonged discomfort and is associated with infrequent but serious complications. METHODS To evaluate the effectiveness of acyclovir for the treatment of chickenpox, we conducted a multicenter, double-blind, placebo-controlled study involving 815 healthy children 2 to 12 years old who contracted chickenpox. Treatment with acyclovir was begun within the first 24 hours of rash and was administered by the oral route in a dose of 20 mg per kilogram of body weight four times daily for five days. RESULTS The children treated with acyclovir had fewer varicella lesions than those given placebo (mean number, 294 vs 347; P less than 0.001), and a smaller proportion of them had more than 500 lesions (21 percent, as compared with 38 percent with placebo; P less than 0.001). In over 95 percent of the recipients of acyclovir no new lesions formed after day 3, whereas new lesions were forming in 20 percent of the placebo recipients on day 6 or later. The recipients of acyclovir also had accelerated progression to the crusted and healed stages, less itching, and fewer residual lesions after 28 days. In the children treated with acyclovir the duration of fever and constitutional symptoms was limited to three to four days, whereas in 20 percent of the children given placebo illness lasted more than four days. There was no significant difference between groups in the distribution of 11 disease complications (10 bacterial skin infections and 1 case of transient cerebellar ataxia). Acyclovir was well tolerated, and there was no significant difference between groups in the titers of antibodies against varicella-zoster virus. CONCLUSIONS Acyclovir is a safe treatment that reduces the duration and severity of chickenpox in normal children when therapy is initiated during the first 24 hours of rash. Whether treatment with acyclovir can reduce the rare, serious complications of chickenpox remains uncertain.

Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive genodermatosis characterized by a poikilodermatous rash starting in infancy, small stature, skeletal abnormalities, juvenile cataracts, and predisposition to specific cancers. We have identified a contemporary cohort of 41 patients to better define the clinical profile, diagnostic criteria, and management of patients with RTS. Patients with the diagnosis of RTS were ascertained by referrals from dermatology, ophthalmology, genetics, and oncology or from direct contact with the patients family. Medical information was obtained from interviews with physicians, patients, and their parents and a review of medical records. The age range at ascertainment was 9 months to 42 years (28 males and 13 females; M:F, 2:1). All subjects displayed a characteristic rash. Thirteen subjects had osteosarcoma (OS) (32%), eight had radial defects (20%), seven had gastrointestinal findings (17%), two had cataracts (6%), and one had skin cancer (2%). Twenty-two of 28 patients without OS were less than 15 years old and thus remain at significant risk for this tumor. This case-series study reveals a clinical profile of RTS that includes a higher prevalence of OS and fewer cataracts, compared with historical reports. These differences may reflect either allelic or genetic heterogeneity. This study documents the frequency of clinical anomalies in a contemporary cohort of RTS patients and revises guidelines for diagnosis and management of RTS.

Multiple Endocrine Neoplasia Type 2a Associated with Cutaneous Lichen Amyloidosis

PURPOSE To describe and characterize the association of hereditary cutaneous lichen amyloidosis with multiple endocrine neoplasia type 2a (MEN 2a). DESIGN Survey of a family for two diseases. SETTING Evaluation of patients at a clinical research center. PATIENTS Nineteen family members with MEN 2a. MEASUREMENTS AND MAIN RESULTS In this family cutaneous lichen amyloidosis presented as multiple infiltrated papules overlying a well-demarcated plaque in the scapular area of the back (right or left). Immunohistochemical studies showed amyloid that stained for keratin but not calcitonin. Three family members had the characteristic skin lesion and also carried the gene for MEN 2a; two additional members carried the gene for MEN 2a, but did not manifest the observable skin changes associated with lichen amyloidosis. CONCLUSIONS From the findings in this kindred and in another recently reported but unrelated family with an identical type of pruritic skin rash and MEN 2a, several conclusions can be drawn. First, the syndrome of cutaneous amyloidosis and MEN 2a is a clearly defined autosomal dominant hereditary syndrome. Second, the dermal amyloid appears to be caused by deposition of keratin-like peptides rather than by calcitonin-like peptides. Third, known families with hereditary lichen amyloidosis should be screened to determine the true frequency of this syndrome.

Atypical Forms of Incontinentia Pigmenti in Male Individuals Result from Mutations of a Cytosine Tract in Exon 10 of NEMO (IKK-γ)

Familial incontinentia pigmenti (IP [MIM 308310]), or Bloch-Sulzberger syndrome, is an X-linked dominant and male-lethal disorder. We recently demonstrated that mutations in NEMO (IKK-gamma), which encodes a critical component of the NF-kappaB signaling pathway, were responsible for IP. Virtually all mutations eliminate the production of NEMO, causing the typical skewing of X inactivation in female individuals and lethality in male individuals, possibly through enhanced sensitivity to apoptosis. Most mutations also give rise to classic signs of IP, but, in this report, we describe two mutations in families with atypical phenotypes. Remarkably, each family included a male individual with unusual signs, including postnatal survival and either immune dysfunction or hematopoietic disturbance. We found two duplication mutations in these families, at a cytosine tract in exon 10 of NEMO, both of which remove the zinc (Zn) finger at the C-terminus of the protein. Two deletion mutations were also identified in the same tract in additional families. However, only the duplication mutations allowed male individuals to survive, and affected female individuals with duplication mutations demonstrated random or slight skewing of X inactivation. Similarly, NF-kappaB activation was diminished in the presence of duplication mutations and was completely absent in cells with deletion mutations. These results strongly indicate that male individuals can also suffer from IP caused by NEMO mutations, and we therefore urge a reevaluation of the diagnostic criteria.

Evidence-Based Recommendations for the Diagnosis and Treatment of Pediatric Acne

INTRODUCTION: Acne vulgaris is one of the most common skin conditions in children and adolescents. The presentation, differential diagnosis, and association of acne with systemic pathology differs by age of presentation. Current acknowledged guidelines for the diagnosis and management of pediatric acne are lacking, and there are variations in management across the spectrum of primary and specialty care. The American Acne and Rosacea Society convened a panel of pediatric dermatologists, pediatricians, and dermatologists with expertise in acne to develop recommendations for the management of pediatric acne and evidence-based treatment algorithms. METHODS: Ten major topic areas in the diagnosis and treatment of pediatric acne were identified. A thorough literature search was performed and articles identified, reviewed, and assessed for evidence grading. Each topic area was assigned to 2 expert reviewers who developed and presented summaries and recommendations for critique and editing. Furthermore, the Strength of Recommendation Taxonomy, including ratings for the strength of recommendation for a body of evidence, was used throughout for the consensus recommendations for the evaluation and management of pediatric acne. Practical evidence-based treatment algorithms also were developed. RESULTS: Recommendations were put forth regarding the classification, diagnosis, evaluation, and management of pediatric acne, based on age and pubertal status. Treatment considerations include the use of over-the-counter products, topical benzoyl peroxide, topical retinoids, topical antibiotics, oral antibiotics, hormonal therapy, and isotretinoin. Simplified treatment algorithms and recommendations are presented in detail for adolescent, preadolescent, infantile, and neonatal acne. Other considerations, including psychosocial effects of acne, adherence to treatment regimens, and the role of diet and acne, also are discussed. CONCLUSIONS: These expert recommendations by the American Acne and Rosacea Society as reviewed and endorsed by the American Academy of Pediatrics constitute the first detailed, evidence-based clinical guidelines for the management of pediatric acne including issues of special concern when treating pediatric patients.

Subcutaneous Fat Necrosis of the Newborn and Hypercalcemia: Case Report and Review of the Literature

Abstract: Subcutaneous fat necrosis of the newborn (SCFN) alone is an uncommon condition, its association with hypercalcemia has been reported in 19 neonates since 1926. The two occur in full‐term to postterm newborns with perinatal complications associated wtth delivery. Erythematous to violaceous, firm, subcutaneous nodules appear approximately 1 to 4 weeks after delivery, preceding the development of signs and symptoms of hypercalcemia. Although SCFN and hypercalcemia are rare complications in neonates with perinatal problems, death due to the sequelae of hypercalcemia occurred in 3 of the 19 patients. A neonate who develops skin lesions consistent with SCFN should be followed for possible onset of hypercalcemia and treated in a timely fashion.

PHACE: a neurocutaneous syndrome with important ophthalmologic implications: Case report and literature review

OBJECTIVES To introduce PHACE syndrome (Posterior fossa malformations, Hemangiomas, Arterial anomalies, Coarctation of the aorta and other cardiac defects, and Eye abnormalities) to the ophthalmologic literature; to report the first case of PHACE syndrome associated with congenital glaucoma; and to review the ocular and systemic findings that may occur in this entity. DESIGN Case report and literature review. METHODS The authors report a child with PHACE syndrome and congenital glaucoma and review the ophthalmologic and systemic manifestations of this syndrome. RESULTS A 9-month-old girl with PHACE syndrome was treated. She had a large right facial hemangioma, central nervous system (CNS) abnormalities, and cardiac anomalies. Glaucoma was detected in her left eye, and she underwent glaucoma surgery. She did well following two glaucoma procedures, and the facial hemangioma is responding to medical treatment. CONCLUSIONS Ophthalmologists who examine children with large facial hemangiomas should consider PHACE syndrome in the differential diagnosis and should obtain appropriate CNS imaging studies and cardiac evaluation when the diagnosis is suspected. Congenital glaucoma should be added to the list of PHACE-associated ocular anomalies.

Intron-Size Constraint as a Mutational Mechanism in Rothmund-Thomson Syndrome

Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder caused by deleterious mutations in the RECQL4 gene on chromosome 8. The RECQL4 gene structure is unusual because it contains many small introns <100 bp. We describe a proband with RTS who has a novel 11-bp intronic deletion, and we show that this mutation results in a 66-bp intron too small for proper splicing. Constraint on intron size may represent a general mutational mechanism, since human-genome analysis reveals that approximately 15% of genes have introns <100 bp and are therefore susceptible to size constraint. Thus, monitoring of intron size may allow detection of mutations missed by exon-by-exon approaches.