Vered Molho-Pessach

The H Syndrome Is Caused by Mutations in the Nucleoside Transporter hENT3

The H syndrome is a recently reported autosomal-recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature, hallux valgus, and fixed flexion contractures of the toe joints and the proximal interphalangeal joints. Homozygosity mapping in five consanguineous families resulted in the identification of mutations in the SLC29A3 gene, which encodes the equilibrative nucleoside transporter hENT3. Three mutations were found in 11 families of Arab and Bulgarian origin. The finding of several different mutations in a small geographic region implies that the H syndrome might be rather common. The identification of mutations in the SLC29A3 gene in patients with a mild clinical phenotype suggests that this is a largely underdiagnosed condition and strongly suggests that even oligosymptomatic individuals might have the disorder.

H syndrome: the first 79 patients.

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.

Emperipolesis: An Additional Common Histopathologic Finding in H Syndrome and Rosai–dorfman Disease

H syndrome is a recently described autosomal recessive disorder characterized by indurated, hyperpigmented, and hypertrichotic cutaneous plaques, mainly involving the lower abdomen and lower extremities. Associated systemic manifestations include hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height, and hyperglycemia. H syndrome is caused by mutations in the gene SLC29A3, which encodes hENT3, a member of the human equilibrative nucleoside transporter family. Histopathologically, cutaneous lesions of H syndrome consist of dermal and subcutaneous fibrosis with inflammatory infiltrate mostly composed of large histiocytes, some plasma cells, and scattered lymphoid aggregates. Recently, histopathologic and immunohistochemical studies have demonstrated that the immunophenotype of the histiocytes infiltrating the skin of a patient with H syndrome is similar to that of the lesions of Rosai-Dorfman disease. Furthermore, mutations in SLC29A3 gene have also been demonstrated in patients described as having an inherited form of Rosai-Dorfman disease, named Faisalabad histiocytosis or familial Rosai-Dorfman disease. We describe emperipolesis in the cutaneous lesions of a patient with H syndrome, further supporting the relationship between Rosai-Dorfman disease and H syndrome.

Mutation in KANK2, encoding a sequestering protein for steroid receptor coactivators, causes keratoderma and woolly hair

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 patients 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.

H syndrome: recently defined genodermatosis with distinct histologic features. A morphological, histochemical, immunohistochemical, and ultrastructural study of 10 cases.

This study analyzes the histopathological findings in H syndrome, a recently recognized autosomal recessive genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin in well-defined anatomical areas accompanied by various systemic manifestations. So far, descriptions of the histopathological skin changes in this disorder, as reported in a few small case series, were inconsistent, leading to diverse clinical interpretations. In an attempt to define standardized, diagnostic, morphological criteria that will distinguish this disorder from other fibrosing conditions, we studied skin biopsies from 10 patients with H syndrome. The characteristic morphology included widespread fibrosis (moderate in dermis and severe in subcutis); striking mononuclear infiltrates consisting mainly of monocyte-derived cells (small CD68+ histiocytes and CD34+ and FXIIIa+ dendrocytes) and plasma cells; and thickened, fragmented, and partially calcified elastic fibers, admixed with well-formed psammoma bodies, a previously unrecognized feature in nonneoplastic skin and subcutaneous conditions. In addition, the ultrastructure of CD68+ small histiocytes exhibited distended endoplasmic reticulum and scarcity of lysosomes, features typical for fibroblasts but unusual for histiocytes. These unusual findings in the histiocytes pose a question as to their possible role in the fibrotic cascade in this disorder. We conclude that the above findings are essential for the diagnosis of H syndrome and that incisional biopsies are mandatory for recognition of the full spectrum of histopathological findings.

A novel splice-site mutation in ECM-1 gene in a consanguineous family with lipoid proteinosis

Abstract:  Lipoid proteinosis (LP) (OMIM 247100) is a rare, autosomal recessive disorder. Recent studies have shown that LP is the result of reduced expression of the extracellular matrix protein gene (ECM‐1), in which loss‐of‐function mutations have been described. In the present report, we describe a large consanguineous family with LP. We identified a homozygous splice‐site mutation in intron 1 (IVS1 + 1G→C) in three clinically affected patients. This is the first splice‐site mutation reported in LP and is the most 5′ of all ECM‐1 mutations described thus far. It is predicted to result in the removal of the translation initiation site, thus ablating all three known ECM‐1 isoforms (ECM‐1a, ECM‐1b, and ECM‐1c). In addition, we found a novel splicing variant that is not associated with the disease (DQ010946) and results in the generation of a short, prematurely terminating transcript. This case further emphasizes the role of ECM‐1 in LP and highlights the unresolved genotype–phenotype correlation in this disease.

Diabetes mellitus may be the earliest and sole manifestation of the H syndrome

The H syndrome is a recently reported autosomal recessive disease with variable interand intra-familial clinical manifestations. The clinical, histopathological and molecular findings have been described in detail [1–3]. The major clinical findings include cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height, hallux valgus and hyperglycaemia ⁄ diabetes mellitus. Less common manifestations include facial telangiectasia, proptosis, ocular arcus senilis and dilated scleral vascularization, gynaecomastia, scrotal masses, varicose veins, malabsorption, lipoatrophy of the lateral buttocks and fixed flexion contractures of the toe joints and the proximal interphalangeal joints. The principle histological finding is inflammatory infiltrate consisting mainly of histiocytes, which is later replaced by deep dermal and subcutaneous fibrosis. Anaemia, mild to severe, and elevated erythrocyte sedimentation rate (usually more than 100 mm ⁄ h) are among the most common laboratory findings. The syndrome is caused by mutations in the human equilibrative nucleoside transporter 3 (hENT3) [1]. Despite the vast range of clinical phenotypes described above, some patients may have only one symptom at presentation, such as gynaecomastia or dilated scleral vascularization [1]. It is important to note that the disease has a progressive nature (e.g. patient may present with mild camptodactyly, later progressing to severe flexion contractures of the hands and feet) and symptoms accumulate with age. We reported previously that a Bulgarian patient [1], carrying the homozygous p.G427S mutation, showed a full range of H syndrome symptoms from the age of 10 years, including cutaneous hyperpigmentation and hypertrichosis, hepatomegaly, gynaecomastia, hypogonadism, facial telangiectases, proptosis, bilateral camptodactyly, malabsorption and diabetes mellitus, first appearing as ketoacidosis at age 14 years. His older brother was not available at the time of the initial examination and was reported to have only diabetes mellitus which presented at age 22 years, with ketoacidosis (glucose 24.8 mmol ⁄ l) and with negative anti-glutamic acid decarboxylase (GAD) antibody, without any other manifestations suggestive of the H syndrome. Recently, we found that the older brother also carries the same p.G427S homozygous mutation. Further examination of this patient at age 26 years revealed that he had developed some telangiectases at age 24 years. No other major or minor clinical findings were identified, except for mild non-specific short stature (1.60 m). No diabetic complications were observed. The patient’s weight was 56 kg, with a body mass index (BMI) of 21.9 kg ⁄ m. His prescribed medication consisted of 30 units of Actrapid and 18 units of Mixtard 30 ⁄ 70 (Novo Nordisk, Bagsværd, Denmark) daily. Glycated haemoglobin (HbA1c) was 7.2% and total cholesterol 3.2 mmol ⁄ l, high-density lipoprotein (HDL) 1.64 mmol ⁄ l and low-density lipoprotein (LDL) 2.8 mmol ⁄ l. Other laboratory findings were in the normal ranges [e.g. erythrocyte sedimentation rate (ESR) 13 mm ⁄ h, haemoglobin 14 g ⁄ dl]. In recent years it has become clear that not all diabetes cases presenting in childhood and adolescence are of Type 1 and c. 5% of cases are diagnosed as non-Type 1 diabetes [4]. Of these patients, about 10% have syndromic diabetes, which may be caused by a limited number of conditions. It is essential to recognize these syndromes early in order to identify treatable complications and potential treatment modalities, and for performing genetic testing of other family members [4]. Diabetes is a variable finding in the H syndrome, seen in approximately 20% of cases. Nevertheless, the patient presented herein shows the significance of including the H syndrome in the differential diagnoses of early onset diabetes mellitus. We conclude that diabetes mellitus may be the presenting and sole symptom of this disease.

Marie Unna hereditary hypotrichosis caused by a novel mutation in the human hairless transcript

Please cite this paper as: Marie Unna hereditary hypotrichosis caused by a novel mutation in the human hairless transcript. Experimental Dermatology 2010; 19: e320–e322.

Two Novel Homozygous Desmoplakin Mutations in Carvajal Syndrome.

Mutations 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).

Cytokine secretion and NK cell activity in human ADAM17 deficiency

Genetic deficiencies provide insights into gene function in humans. Here we describe a patient with a very rare genetic deficiency of ADAM17. We show that the patients PBMCs had impaired cytokine secretion in response to LPS stimulation, correlating with the clinical picture of severe bacteremia from which the patient suffered. ADAM17 was shown to cleave CD16, a major NK killer receptor. Functional analysis of patients NK cells demonstrated that his NK cells express normal levels of activating receptors and maintain high surface levels of CD16 following mAb stimulation. Activation of individual NK cell receptors showed that the patients NK cells are more potent when activated directly by CD16, albeit no difference was observed in Antibody Depedent Cytotoxicity (ADCC) assays. Our data suggest that ADAM17 inhibitors currently considered for clinical use to boost CD16 activity should be cautiously applied, as they might have severe side effects resulting from impaired cytokine secretion.