© 2015 The Authors. doi: 10.2340/00015555-2145 Journal Compilation © 2015 Acta Dermato-Venereologica. ISSN 0001-5555 H syndrome (OMIM #602783) is an autosomal recessive genodermatosis, first described in 2008 (1). It has multisystemic involvement and is characterized by numerous clinical features, including cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, low height (short stature), hyperglycaemia (insulin-dependent diabetes mellitus), and hallux valgus/flexion contractures. Cutaneous hyperpigmentation, commonly accompanied by hypertrichosis and progressive sclerodermatous induration, typically affecting initially the medial thighs with sparing of the knees, is the hallmark of the disorder and is considered pathognomonic (1–3). Causative mutations have been identified in the SLC29A3 gene encoding the human equilibrative nucleoside transporter 3 (hENT3), which serves as a transporter of nucleosides in the late endosome/lysosomes, and across the inner mitochondrial membrane (4). Although numerous mutations have been reported since the initial description (3, 5–8), a solid genotype–phenotype correlation is lacking (3). Increased recognition of the disorder has led to the identification of approximately 100 patients with H syndrome worldwide (9). Novel clinical features have been associated with this condition, such as lymphadenopathy, pancreatic exocrine deficiency, and recurrent febrile episodes (3). Recently, complete agenesis of the inferior vena cava (IVC) was reported in a patient from Turkey who also had striking varicose veins (8). Oligosymptomatic patients with a very mild phenotype have also been described (2, 3, 7). Interestingly, patients with variable degrees of involvement have been described from the same family or geographical region with similar or even identical genetic mutations, reflecting the pleiotropic nature of this unique disorder (3, 6, 7). Histopathologically, H syndrome may simulate Rosai-Dorfman disease, displaying CD68+ S100+ CD1a– histiocytes with emperipolesis (3, 10, 11). Overall, H syndrome may be regarded as an inherited histiocytic disorder based on demonstration of increased CD68+ histiocytes in the skin and lymph nodes, suggesting a possible role of hENT3 in histiocyte turnover. This paper highlights the pleiotropic nature of H syndrome by reporting 2 unrelated Turkish patients from a single institution who share a common mutation in the SLC29A3 gene but demonstrate different phenotypes.

BackgroundMutations in various desmosomal proteins were shown to cause inherited forms of cardiomyopathy. Carvajal syndrome (Online Mendelian Inheritance in Man [OMIM] 605676) is characterized by the association of dilated cardiomyopathy, striate palmoplantar keratoderma, and woolly hair. It is caused by homozygous as well as heterozygous mutations in DSP, which encodes the desmosomal plaque protein desmoplakin. An overlapping cardiocutaneous phenotype was also described with homozygous mutations in genes encoding two other desmosomal proteins; plakoglobin (Naxos disease; OMIM 601214) and desmocollin-2 (OMIM 610476).MethodsWe performed clinical and molecular workups in two consanguineous Arab Palestinian families manifesting an autosomal recessive pattern of inheritance of the above mentioned clinical findings. Whole exome sequencing was employed in the search for the causing mutation.ResultsAffected family members suffered from biventricular involvement and arrhythmogenic right ventricular dysplasia based on echocardiography and magnetic resonance imaging. One patient who underwent implantation of an implantable cardioverter-defibrillator (ICD) is still alive at the age of 59years. Whole exome sequencing revealed two novel homozygous mutations in DSP, each affecting one family.ConclusionsThe association of woolly hair with palmoplantar keratoderma in a child should lead to a cardiac workup in the search for those at increased risk for sudden cardiac death. Early diagnosis and ICD implantation may be lifesaving. Whole exome sequencing should be utilized for rapid genetic analysis since the cardiocutaneous phenotype may result from mutations in one of several genes.

Background The combination of palmoplantar keratoderma and woolly hair is uncommon and reported as part of Naxos and Carvajal syndromes, both caused by mutations in desmosomal proteins and associated with cardiomyopathy. We describe two large consanguineous families with autosomal-recessive palmoplantar keratoderma and woolly hair, without cardiomyopathy and with no mutations in any known culprit gene. The aim of this study was to find the mutated gene in these families.Methods and results Using whole-exome sequencing, we identified a homozygous missense c.2009C>T mutation in KANK2 in the patients (p.Ala670Val). KANK2 encodes the steroid receptor coactivator (SRC)-interacting protein (SIP), an ankyrin repeat containing protein, which sequesters SRCs in the cytoplasm and controls transcription activation of steroid receptors, among others, also of the vitamin D receptor (VDR). The mutation in KANK2 is predicted to abolish the sequestering abilities of SIP. Indeed, vitamin D-induced transactivation was increased in patient's keratinocytes. Furthermore, SRC-2 and SRC-3, coactivators of VDR and important components of epidermal differentiation, are localised to the nucleus of epidermal basal cells in patients, in contrast to the cytoplasmic distribution in the heterozygous control.Conclusions These findings provide evidence that keratoderma and woolly hair can be caused by a non-desmosomal mechanism and further underline the importance of VDR for normal hair and skin phenotypes.

BACKGROUND:H syndrome is an autosomal recessive genodermatosis with multisystem involvement caused by mutations in SLC29A3.OBJECTIVE:We sought to investigate the clinical and molecular findings in 79 patients with this disorder.METHODS:A total of 79 patients were included, of which 13 are newly reported cases. Because of the phenotypic similarity and molecular overlap with H syndrome, we included 18 patients with allelic disorders. For 31 patients described by others, data were gathered from the medical literature.RESULTS:The most common clinical features (>45% of patients) were hyperpigmentation, phalangeal flexion contractures, hearing loss, and short stature. Insulin-dependent diabetes mellitus and lymphadenopathy mimicking Rosai-Dorfman disease were each found in approximately 20%. Additional systemic features were described in less than 15% of cases. Marked interfamilial and intrafamilial clinical variability exists. Twenty mutations have been identified in SLC29A3, with no genotype-phenotype correlation.LIMITATIONS:In the 31 patients described by others, data were collected from the medical literature.CONCLUSIONS:H syndrome is a multisystemic disease with clinical variability. Consequently, all SLC29A3-related diseases should be considered a single entity. Recognition of the pleomorphic nature of H syndrome is important for diagnosis of additional patients.

BACKGROUND:H syndrome is an autosomal recessive histiocytosis with multisystemic involvement caused by mutations in the SLC29A3 gene. The term H syndrome was coined to denote the major clinical findings which include hyperpigmentation, hypertrichosis, hearing loss, hepatosplenomegaly, hypogonadism, hyperglycemia/diabetes mellitus and hallux valgus/flexion contractures. Almost 100 individuals affected with this disorder have been reported, however, a thorough evaluation of the ophthalmologic features of H syndrome has not yet been performed.MATERIALS AND METHODS:Ophthalmic examination of a 50-year-old male with H syndrome. Mutation analysis of SLC29A3 was also performed in this patient.RESULTS:Ophthalmic findings included; shallow orbits with exorbitism, bilateral pterygium, limbal thickening, corneal arcus and cortical cataract. We also review ophthalmologic findings in previously reported H syndrome patients.CONCLUSIONS:The presence of dilated lateral scleral vessels, corneal arcus and shallow orbits should raise the suspicion of H syndrome, especially when seen in young age.

Deficiency of interleukin‐36 (IL‐36) receptor antagonist (DITRA; OMIM 614204) is a rare autoinflammatory disorder characterized by periodic fever associated with a generalized erythematous and pustular skin rash. A 6‐year‐old Arab‐Palestinian boy presented with a history of periodic fever and unremitting, erythematous, scaly skin rash accompanied by widespread pustules that had been present since the age of one month. The patient's skin lesions were compatible with generalized pustular psoriasis. Sequence analysis revealed a homozygous nonsense mutation, c.28C>T (p.Arg10X) in the IL36RN gene. The patient improved with oral methotrexate in combination with oral and topical corticosteroids. The molecular basis for DITRA has only recently been identified, and the mutation spectrum for this disorder in many populations is still obscure. This paper reports the presence of the c.28C>T mutation in an Arab‐Palestinian patient and thus represents the first description of this mutation in a non‐Japanese subject.

OBJECTIVE Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE syndrome) is an autoinflammatory syndrome recently described in children. We undertook this study to investigate the clinical phenotype, genetic cause, and immune dysregulation in 9 CANDLE syndrome patients. METHODS Genomic DNA from all patients was screened for mutations in PSMB8 (proteasome subunit β type 8). Cytokine levels were measured in sera from 3 patients. Skin biopsy samples were evaluated by immunohistochemistry, and blood microarray profile and STAT-1 phosphorylation were assessed in 4 patients and 3 patients, respectively. RESULTS One patient was homozygous for a novel nonsense mutation in PSMB8 (c.405C>A), suggesting a protein truncation; 4 patients were homozygous and 2 were heterozygous for a previously reported missense mutation (c.224C>T); and 1 patient showed no mutation. None of these sequence changes was observed in chromosomes from 750 healthy controls. Of the 4 patients with the same mutation, only 2 shared the same haplotype, indicating a mutational hot spot. PSMB8 mutation-positive and -negative patients expressed high levels of interferon-γ (IFNγ)-inducible protein 10. Levels of monocyte chemotactic protein 1, interleukin-6 (IL-6), and IL-1 receptor antagonist were moderately elevated. Microarray profiles and monocyte STAT-1 activation suggested a unique IFN signaling signature, unlike in other autoinflammatory disorders. CONCLUSION CANDLE syndrome is caused by mutations in PSMB8, a gene recently reported to cause "JMP" syndrome (joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced childhood-onset lipodystrophy) in adults. We extend the clinical and pathogenic description of this novel autoinflammatory syndrome, thereby expanding the clinical and genetic disease spectrum of PSMB8-associated disorders. IFN may be a key mediator of the inflammatory response and may present a therapeutic target.