Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.

Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype-phenotype correlations. This cohort offers potential for further gene identification to address missing heritability.

Epileptic Encephalopathy in Adams-Oliver Syndrome Associated to a New DOCK6 Mutation: A Peculiar Behavioral Phenotype.

Adams-Oliver syndrome (AOS) is characterized by a combination of congenital scalp defects (aplasia cutis congenita) and terminal transverse limb malformations of variable severity. When neurological findings are present, patients are reported as AOS variants. We describe a child with compound heterozygosity of the DOCK6 gene, aplasia cutis, terminal transverse limb defects, cardiovascular impairment, intellectual disability, and brain malformations with intracranial calcifications. He suffers from a severe refractory epileptic encephalopathy characterized by polymorphic seizures with prolonged periods of electroencephalogram (EEG), continuous epileptiform activity related to clinical inactivity, and closure of eyes with an "ON-OFF" behavior.

Horizontal and vertical sections of scalp biopsy specimens from dermatomyositis patients with scalp involvement.

BACKGROUND: The histologic findings of scalp involvement in dermatomyositis are not well characterized on account of a lack of large series. OBJECTIVE: To systematize the histologic features of scalp involvement in dermatomyositis on horizontal and vertical sections. METHODS: A descriptive, prospective, cross-sectional study recruited 31 patients with pathologically and serologically confirmed dermatomyositis in Mexico City, Mexico, from June 2014 to June 2015. A total of 36 scalp biopsy specimens from 20 patients with scalp involvement in dermatomyositis were processed as 20 vertical and 16 horizontal sections. RESULTS: Dilated capillaries and diffuse mucin deposition were detected in all biopsy specimens, followed by interface dermatitis. Partial or segmental thickening of the basement membrane, hyperkeratosis, atrophic epidermis, and acrosyringeal hypergranulosis with hyperkeratosis were other very common findings. Preserved follicular architecture, with intact or slightly atrophic sebaceous glands, was present in most horizontal sections. There was decreased follicular density, with a terminal-to-vellus ratio of 4:1 and telogen count of 10.3%. Eosinophils were present in 15% and 25% of horizontal and vertical sections, respectively. LIMITATIONS: No special stains performed. CONCLUSION: Scalp involvement in dermatomyositis shows nonscarring pattern on horizontal sections that is consistent with chronic telogen effluvium. Telangiectasia and mucin are universal histologic features; eosinophils and acrosyringeal hypergranulosis with hyperkeratosis are new findings.

Incubatory environment of the scalp impacts pre-emergent hair to affect post-emergent hair cuticle integrity.

OBJECTIVES: To determine whether the oxidative stress transmitted to newly grown hair from an unhealthy scalp has physical consequences to the cuticular condition and function. METHODS: A uniquely designed 24-week clinical study included 8 weeks of pretreatment with a cosmetic shampoo and 16 weeks of treatment with either a potentiated zinc pyrithione (ZPT) antidandruff shampoo or a placebo cosmetic shampoo. This clinical design allowed the growth and acquisition of hair samples under conditions of varying but known scalp health as a result of treating a dandruff/seborrheic dermatitis (D/SD) population. Two complementary methods were used to characterize the integrity of the cuticular surface. Hair surface hydrophobicity was assessed by quantifying water wetting force using a Wilhelmy balance method. Surface structure and porosity were assessed using dynamic vapor sorption (DVS) to gravimetrically quantify water sorption. RESULTS: Chemical oxidative stress to pre-emergent hair has been shown to have negative consequences to hair surface structure. Compared to a placebo shampoo control, use of a potentiated ZPT shampoo improved scalp health and significantly improved the following attributes associated with healthy hair: hair surface hydrophobicity (surface energy) and cuticular moisture barrier effectiveness (dynamic vapor sorption). CONCLUSIONS: Pre-emergent hair can be negatively impacted by the oxidative stress that occurs with an unhealthy scalp, possibly due to metabolic activity of resident microbes. Manifestations of the oxidative stress include altered cuticle surface properties that are responsible for its protective function; these effects are similar in type to those observed by bleaching post-emergent hair. These alterations have the potential to make the hair, once emerged from the scalp, more susceptible to the cumulative physical and chemical insults responsible for hair feel and look, fiber integrity, and overall retention.

[Physiology of the scalp]. / Physiologie der Kopfhaut.

BACKGROUND: Human scalp reveals a remarkable difference to hairy skin of other body regions. The structure of the scalp offers effective protection against water loss and contributes to thermoregulation due to significant vascularization. The scalp is innervated by the trigeminus nerve. OBJECTIVES: The majority of the population complain about "sensitive" scalp. However, sensory, regional, ethnic or pathologic parameters contributing to "sensitive" scalp are largely unknown. MATERIALS AND METHODS: Quantitative sensory tests and superficial topical application test of irritant substances were performed. RESULTS: Extremely high thresholds to thermal and mechanical stimuli were recorded at the vertex compared to occipital or temporal scalp regions, or the hairy skin of other body regions such as trunk or distal extremities. Pronounced scalp hypersensitivity can be found in Asians as compared to Caucasians and under pathologic conditions, such as alopecia, dandruff, or migraine. CONCLUSIONS: Putative causes of "sensitive" scalp can be a facilitated transdermal penetration of irritant substances, altered neuronal innervation or receptor expression, or peripheral and central sensitization of sensory afferents.

Novel copy number variants and major limb reduction malformation: Report of three cases.

Limb reduction malformations are highly heterogeneous in their clinical presentation and so, predicting the underlying mutation on a clinical basis can be challenging. Molecular karyotyping is a powerful genomic tool that has quickly become the mainstay for the study of children with malformation syndromes. We describe three patients with major limb reduction anomalies in whom pathogenic copy number variants were identified on molecular karyotyping. These include a patient with hypoplastic phalanges and absent hallux bilaterally with de novo deletion of 11.9 Mb on 7p21.1-22.1 spanning 63 genes including RAC1, another patient with severe Holt-Oram syndrome and a large de novo deletion 2.2 Mb on 12q24.13-24.21 spanning 20 genes including TBX3 and TBX5, and a third patient with acheiropodia who had a nullizygous deletion of 102 kb on 7q36.3 spanning LMBR1. We discuss the potential of these novel genomic rearrangements to improve our understanding of limb development in humans.

Gender differences in scalp hair growth rates are maintained but reduced in pattern hair loss compared to controls.

BACKGROUND: Hair loss is related to follicular density, programmed regrowth and hair productivity. OBJECTIVE: The dissatisfaction with hair growth in patients experiencing hair loss might be due to slower linear hair growth rate (LHGR). METHODS: LHGR and hair diameter was evaluated in Caucasian controls and patients with patterned hair loss employing the validated non-invasive, contrast-enhanced-phototrichogram with exogen collection. RESULTS: We evaluated 59,765 anagen hairs (controls 24,609, patients 35,156) and found thinner hairs grew slower than thicker hairs. LHGR in normal women was generally higher than in normal men. LHGR correlates with hair diameter (P < 0.006) and global thinning is associated with slower growth rates. Compared with hair of equal thickness in controls, subjects affected with patterned hair loss showed reduced hair growth rates, an observation found in both male and female patients. Males with pattern hair loss showed further reduction in growth rates as clinical severity worsened. However, sample size limitations prevented statistical evaluation of LHGR in severely affected females. LIMITATIONS: Caucasian ethnicity. CONCLUSION: In pattern hair loss, LHGR significantly contributes to the apparent decrease in hair volume in affected areas. In early onset, LHRG might have a prognostic value in females but not in males.

Comparing cold-air analgesia, systemically administered analgesia and scalp nerve blocks for pain management during photodynamic therapy for actinic keratosis of the scalp presenting as field cancerization: a randomized controlled trial.

BACKGROUND: Photodynamic therapy (PDT) using methyl aminolaevulinate (MAL) is an effective treatment for extensive actinic keratosis (AK). However, pain is a major side-effect of this therapy. OBJECTIVES: To investigate whether scalp nerve blocks (group 1) provide adequate pain relief during MAL-PDT of the scalp and forehead in 32 men with baldness. METHODS: The patients received intravenous (IV) analgesia [piritramide 7.5 mg IV, plus oral metamizole (40 drops 30 min prior to PDT)] in combination with cold-air analgesia (group 2; IV analgesia) and cold-air analgesia alone (group 3). Maximum pain was evaluated by means of a visual analogue scale (VAS) during and up to 300 min after PDT. Pain during PDT was further analysed according to a pain perception scale. Furthermore, we measured haemodynamics and investigated stress hormone levels in blood samples at different time points. RESULTS: Maximum pain during PDT (primary end point) was significantly reduced in the treatment group receiving scalp nerve blocks (VAS 2.1 ± 1.3) compared with the treatment groups receiving IV analgesia (VAS 7.3 ± 1.1) and cold-air analgesia (VAS 8.4 ± 2.0; P < 0.05). No significant difference was found between groups 2 and 3 with regard to pain relief (P = 0.32). The increase in systolic blood pressure during the first 3 min of PDT was significantly lower for group 1 than for groups 2 and 3 (P < 0.001). No correlation between stress hormone levels and pain were found. CONCLUSIONS: Scalp nerve blocks provide an effective method for pain management during PDT for patients with extensive AK.

[Cutis verticis gyrata as an early rare presenting sign of acromegaly].

Cutis verticis gyrata (CVG) is a descriptive term for a dermal sign in which deep furrows and convoluted ridges are seen upon the scalp. They are formed due to thickening of the skin folds of the scalp and produce an appearance that resembles the gyri of the brain. The condition is classified primary when the etiology is unknown or neurologically based. CVG will be considered secondary when a definite cause, systemic or localized, is responsible for the sign. We describe a 34 year-old male who was presented with a one-month history of arthralgia in his interphalangeal joints. His physical examination revealed scalp changes compatible with CVG, which appeared 3 years earlier. Following a thorough investigation of the patient, acromegaly was diagnosed. Although CVG is a rare condition, it has been described in patients with acromegaly. The appearance of SVG as an early sign of acromegaly makes this case unique and important. In a patient developing CVG, acromegaly and other treatable disorders should always be excluded.

A comprehensive pathophysiology of dandruff and seborrheic dermatitis - towards a more precise definition of scalp health.

Despite an increasing knowledge of dandruff and seborrheic dermatitis (D/SD), the pathophysiological understanding is still incomplete but suggests a role of Malassezia yeasts in triggering inflammatory and hyper-proliferative epidermal responses. The objective of this report is to review published literature from in vivo studies of D/SD populations to provide a more complete description of overall scalp health. New biomolecular capabilities establish a depth of pathophysiological understanding not previously achievable with traditional means of investigation. Biomarkers representing inflammation, hyper-proliferation and barrier function are all perturbed by the D/SD condition and robustly respond to therapeutic resolution. These biomarkers can be sampled noninvasively, enabling their use in routine clinical evaluations as either surrogate endpoints or complementary ones to classical signs/symptoms to broaden the etiological learning.

Aberrant C nerve fibre function of the healthy scalp.

BACKGROUND: The scalp is commonly associated with itch and burning sensations. Previous studies have shown the scalp is highly innervated compared with other body areas. However, limited data are available on sensory testing associated with C nerve fibres of the healthy scalp. OBJECTIVE: To examine the function of C nerve fibre-mediated sensations such as warmth, heat pain, itch and neurogenic inflammation in two areas of the scalp (crown and occiput) in comparison to forearm skin. METHODS: Twenty-two healthy subjects (11 women, 11 men) underwent quantitative computerized thermosensory testing to assess warmth and heat pain thresholds. Itch was induced using histamine iontophoresis and application of cowhage spicules, and the intensity of each itch was assessed. Skin blood flow was measured at baseline and after each itch induction to assess degree of neurogenic inflammation. RESULTS: A majority (64%) of the crown warmth threshold measurements exceeded 50°C while all 22 forearm warmth thresholds measurements were significantly lower than 50°C. Both scalp sites had significantly higher warmth and heat pain thresholds compared with the forearm (P<0·001). Itch ratings of histamine and cowhage on both scalp sites were significantly lower than on the forearm (P≤0·001). Histamine and cowhage induced an increase in skin blood flow from baseline on the forearm compared with the scalp (P< 0·001). CONCLUSIONS: This study demonstrates a significant insensitivity of C nerve fibres of the scalp to warmth, heat pain, itch and neurogenic inflammation. These results suggest that the scalp has an aberrant response of C nerve fibres.

Tinea capitis en mujeres de edad avanzada: descripción de 4 casos / Tinea Capitis in Elderly Women: A Report of 4 Cases

La tinea capitis se ha considerado clásicamente como un proceso casi exclusivo de la infancia. Sin embargo, en las últimas décadas se han observado algunos cambios en su perfil epidemiológico, tanto en lo que concierne a las edades de presentación como a los agentes responsables. Se describen los casos de 4 mujeres mayores de 65 años diagnosticadas de tinea capitis. Una de ellas presentaba placas alopécicas con descamación, mientras que en las otras tres las lesiones eran inflamatorias y costrosas. Los cultivos fueron positivos para Trichophyton tonsurans (2 pacientes), Trichophyton rubrum y Trichophyton mentagrophytes. La relativa infrecuencia de la tinea capitis en la edad avanzada y, por otra parte, su frecuente atipicidad clínica condicionan un diagnóstico tardío, circunstancia que puede condicionar secuelas irreversibles e incrementa la posibilidad de contagios. El cultivo fúngico debería incorporarse en el estudio de las dermatosis del cuero cabelludo de curso atípico y persistente, especialmente en individuos de edad avanzada (AU)

Tinea capitis is a condition usually found only in children. However, its epidemiological profile has changed in recent decades, with regard to age at onset and the causative microorganisms. We report the cases of 4 women over 65 years of age diagnosed with tinea capitis. One presented plaques of alopecia with desquamation and the other 3 developed crusted inflammatory lesions. Cultures were positive for Trichophyton tonsurans (2 patients), Trichophyton rubrum, and Trichophyton mentagrophytes. The relative rarity of tinea capitis in the elderly and the frequently atypical presentation in this age group can delay diagnosis, leading to irreversible sequelae and increasing the risk of contagion. Fungal culture should be included in the study of persistent, atypical dermatoses of the scalp, particularly in the elderly (AU)

Hair through the female life cycle.

At a population level female scalp hair growth shows features of regression with chronological ageing, although there is wide interindividual variation in timing and degree. The subjective assessment of hair loss is classically determined by hair density but it is apparent that other factors contribute to the clinical picture. Changes can occur in hair cycling, hair density, hair diameter and pigmentation, and possibly in structural qualities of the hair fibre. These changes are most pronounced in female pattern hair loss. Although conventionally considered as the female counterpart of male androgenetic alopecia the evidence that female pattern hair loss is androgen dependent is less clear cut than in men and it probably has a multifactorial basis. The emerging evidence implicating environmental factors is of particular interest as, unlike genes, such factors may be amenable to intervention. The clinical signs in women complaining of hair loss may be variable. In evaluating the patient complaining of hair loss, while true pathology must always be considered, the clinician needs to be aware of how age affects hair growth. These changes form the focus of this article.

A novel cosmetic approach to treat thinning hair.

BACKGROUND: Many of today's treatments associated with 'thinning hair', such as female pattern hair loss and telogen effluvium, are focused on two of the key aspects of the condition. Over-the-counter or prescription medications are often focused on improving scalp hair density while high-quality cosmetic products work to prevent further hair damage and minimize mid-fibre breakage. Fibre diameter is another key contributor to thinning hair, but it is less often the focus of medical or cosmetic treatments. OBJECTIVES: To examine the ability of a novel leave-on technology combination [caffeine, niacinamide, panthenol, dimethicone and an acrylate polymer (CNPDA)] to affect the diameter and behaviour of individual terminal scalp hair fibres as a new approach to counteract decreasing fibre diameters. METHODS: Testing methodology included fibre diameter measures via laser scan micrometer, assessment of fibre mechanical and behavioural properties via tensile break stress and torsion pendulum testing, and mechanistic studies including cryoscanning electron microscopy and autoradiographic analysis. RESULTS: CNPDA significantly increased the diameter of individual, existing terminal scalp hair fibres by 2-5 µm, which yields an increase in the cross-sectional area of approximately 10%. Beyond the diameter increase, the CNPDA-thickened fibres demonstrated the altered mechanical properties characteristic of thicker fibres: increased suppleness/pliability (decreased shear modulus) and better ability to withstand force without breaking (increased break stress). CONCLUSIONS: Although cosmetic treatments will not reverse the condition, this new approach may help to mitigate the effects of thinning hair.

Erosive pustular dermatosis of the scalp: a successful treatment with photodynamic therapy.

Erosive pustular dermatosis of the scalp (EPDS) is a rare inflammatory disease of unknown aetiology that usually occurs in the elderly. It is characterized by sterile pustules, chronic crusted erosions, cicatricial alopecia, and skin atrophy. The histopathology is nonspecific, and its pathophysiology remains undetermined, with various types of local trauma possibly acting as the triggering factor. We describe a case of EPDS in a 75-year-old female in whom there was a marked response to photodynamic therapy with methyl 5-aminolaevulinic acid.