Faculty Bibliography

BACKGROUND: The spectrum of clinical findings associated with PTEN tumor suppressor gene germline mutations, referred to as PTEN hamartoma-tumor syndrome (PHTS), includes Cowden and Bannayan-Riley-Ruvalcaba syndromes. Although the skin is the ectodermal structure most often affected by these autosomal dominant genodermatoses, abnormalities of neural tissues are frequently observed. OBSERVATIONS: We describe a 5-year-old boy with macrocephaly, prominent corneal nerves, and progressive development of multiple painful, dome-shaped, translucent pink to skin-colored papules on the vermilion portion of the upper lip, fingers, palms, and shins. Histologic evaluation demonstrated dermal proliferation of well-demarcated nerve bundles associated with abundant mucin and surrounded by a distinct perineural sheath, findings diagnostic of a nonencapsulated neuroma. Genetic analysis revealed a novel heterozygous germline nonsense mutation in PTEN, predicted to result in a truncated PTEN protein. To our knowledge, this represents the first report of multiple neuromas as the sole mucocutaneous manifestation of PHTS. CONCLUSIONS: This article highlights neuromas as a cutaneous sign of PHTS, drawing attention to manifestations of PHTS in neural tissues of the skin, eye, gastrointestinal tract, and brain. Along with multiple endocrine neoplasia type 2B, PHTS should be considered in the differential diagnosis of multiple mucocutaneous neuromas, particularly those involving extrafacial sites

Localized autosomal recessive hypotrichosis (LAH) is a recently defined disorder characterized by fragile, short, sparse hairs on the scalp, trunk, and extremities. Mutations in desmoglein 4 (DSG4), a novel member of the desmosomal cadherin family that is expressed in the hair follicle as well as the suprabasal epidermis, have been found to underlie LAH. Thus far, the allelic series includes a recurrent intragenic deletion identified in affected Pakastani kindreds and a missense mutation detected in an Iraqi family. We report three siblings of Iraqi and Iranian origin with LAH that presented with congenital scalp erosions and monilethrix-like hairs, features that have not been previously described in this disorder. Follicular hyperkeratotic papules and marked pruritus were also prominent clinical findings. Novel compound heterozygous DSG4 mutations, including a splice-site mutation and a missense mutation that disrupts a conserved calcium-binding site in the extracellular (EC)2-EC3 interface, were found to underlie the disease in this family. These observations broaden the phenotypic and genotypic spectrum of LAH, further illustrating the consequences of DSG4 dysfunction on epidermal and hair shaft integrity

A 7-year-old girl presented with asymptomatic bruise-like hairy nodules on her right lower leg since 8 months of age. Histopathology demonstrated an increased number of blood vessels and eccrine glands, thicker collagen bundles, and a terminal hair follicle in catagen phase. The patient was diagnosed with multiple eccrine pilar angiomatous nevi, an unusual variant of eccrine angiomatous hamartomas. The natural course of eccrine angiomatous hamartomas is typically slow growth and benign behavior. Simple excision is usually curative and is reserved for painful or cosmetically disfiguring lesions. Our patient's nevus is large and multifocal, making excision more challenging

An 11-year-old boy had a history of easy bruising and poorly healing wounds since infancy and severe, early-onset periodontitis. He also exhibited mild hypermobility of the small joints of the hands, long limbs with striking arachnodactyly, and a triangular face with delicate features. Analysis of type I and type III collagens revealed no abnormalities. These findings were consistent with a diagnosis of Ehlers-Danlos syndrome type VIII (EDS-VIII), an autosomal dominant connective tissue disorder that was recently mapped to chromosome 12q13. We draw attention to the clinical features that typify EDS-VIII, including extensive pretibial bruising, a marfanoid body habitus, and characteristic facies, as well as childhood onset of progressive periodontal disease

BACKGROUND: Atopic dermatitis (AD) is increasingly common, with a point prevalence of more than 30% in some countries, and is characterized by visible skin lesions and intense itching. OBJECTIVE: The International Study of Life with Atopic Eczema (ISOLATE) is the first large-scale study to assess the effect of AD on the lives of patients and society, how patients and caregivers manage the condition, and how well patients and caregivers currently believe that AD is controlled. METHODS: Two thousand two patients (>13 years) and caregivers of children (2-13 years) with moderate-to-severe AD randomly selected from 8 countries underwent standardized telephone interviews using questions developed in collaboration with national eczema patient groups and physicians. RESULTS: During each year, patients spend, on average, 1 of 3 days in flare. The majority of patients receive prescription topical corticosteroids to treat flares; however, 49% of respondents are concerned about using these agents. On average, patients and caregivers delay initiating treatment for 7 days after onset of a flare. Only 24% of patients and caregivers feel confident they can manage AD flares adequately. Seventy-five percent of caregivers and patients feel that being able to effectively control AD would be the single most important improvement to their or their child's quality of life. The avoidable secondary economic cost of AD is estimated at 2 billion Euro per year across the European Union. CONCLUSION: ISOLATE highlights the need to improve patients' control of AD to reduce the significant effect this condition has on the patient and society. CLINICAL IMPLICATIONS: ISOLATE shows that patients with AD are untreated for half the time they are in flare, and thus there is an urgent need for physicians to ensure that the patients are educated and confident in using medication as prescribed to gain disease control

A 4-year-old girl presented with a 3-year history of demarcated, salmon-pink, hyperkeratotic plaques, which were symmetrically distributed on the elbows, knees, ankles, and dorsal aspects of the hands and feet. A diffuse, orange-pink palmoplantar keratoderma was also evident. Clinical and histologic findings were consistent with a diagnosis of pityriasis rubra pilaris (PRP), type IV (circumscribed juvenile). Type IV PRP develops in prepubertal children, is typically localized to the distal aspects of the extremities, and has an unpredictable course. Although ultraviolet (UV) radiation can potentially exacerbate PRP, our patient has improved with broad-band UVB phototherapy

A 13-year-old boy presented with a lifelong history of tightly-adherent, brown, polygonal scales that covered the extensor surfaces of the extremities, lateral aspects of the trunk, and neck. The clinical presentation and the history of a similar skin condition in the patient's male maternal relatives helped establish the diagnosis of X-linked recessive ichthyosis (XLI). Systemic manifestations of the steroid sulfatase (STS) deficiency underlying XLI include cryptorchidism, asymptomatic corneal opacities, and maternal failure to progress during labor. Most cases of XLI are caused by deletions of the STS gene, and contiguous gene syndromes may occur when the deletions extend to neighboring genes on the distal short arm of the X chromosome

A 3-year-old girl presented with a 6-month history of multiple, light-pink, flat-topped papules over the dorsal aspects of the metacarpophalangeal and interphalangeal joints of the hands and feet. Nailfold telangiectases, ragged cuticles, and a heliotrope color of the upper eyelids were also evident, but there was no clinical evidence of muscle weakness and levels of muscle enzymes were normal. A biopsy specimen from one of the papules showed a vacuolar interface dermatitis consistent with a diagnosis of dermatomyositis. This report draws attention to juvenile amyopathic dermatomyositis, which is an uncommon subtype of dermatomyositis with an excellent prognosis

Summary Tyrosinase, the rate-limiting enzyme of melanin synthesis, is a di-copper metalloprotein that catalyzes the conversion of l-tyrosine to l-DOPAquinone. Phenylthiourea (PTU) is a well-known inhibitor of tyrosinase and melanin synthesis and is known to interact with sweet potato catechol oxidase, an enzyme possessing copper binding domain homology to tyrosinase. While PTU is frequently used to induce hypopigmentation in biological systems, little is known about its effects on tyrosinase and other melanogenic proteins. We have found that PTU induces degradation of tyrosinase but not of other melanogenic proteins including the tyrosinase-related metalloproteins tyrosinase-related protein (Tyrp)1 and Tyrp2. Using pulse-chase analysis coupled with glycosidase digestion, we observed that tyrosinase degradation occurs following complete maturation of the protein and that degradation was reversed by cysteine protease inhibitor E64 but not proteasome inhibitor N-acetyl-l-leucinyl-l-leucinyl-l-norleucinal. We conclude that PTU specifically induces tyrosinse degradation following Golgi maturation. Our data suggest that in addition to well-known ER-directed quality control, tyrosinase is also subject to post-Golgi quality control

With the advent of new biological agents, interest in the treatment of psoriasis has been renewed. Vitamin A and its derivatives (retinoids) have been used successfully in the treatment of psoriasis for over 30 years. In this paper, data on the efficacy and safety of oral retinoids for the treatment of various forms of psoriasis is reviewed. Studies have shown that retinoids are particularly effective in the treatment of pustular and palmoplantar psoriasis. When used in conjunction with ultraviolet therapy, retinoids appear to have a synergistic effect and can be used safely as long-term maintenance therapy. The most common side effects of oral retinoids are usually modest, treatable or reversible, and predominantly affect the liver, musculoskeletal and neurological systems. Potential teratogenicity remains the primary concern with use in women. Oral retinoids appear to be well tolerated in paediatric and HIV-infected patients