Treatment of dyskeratosis congenita with Granulocyte Colony-Stimulating Factor and Erythropoietin

Aplastic anaemia is both frequent and difficult to manage in patients with dyskeratosis congenita (DC). We recently treated a 23-year-old male for a year with granulocyte colony-stimulating factor (G-CSF) and erythropoietin (Ep), with an excellent neutrophil response, and a transient effect on haemoglobin levels. G-CSF alone or combined with other cytokines may provide at least a partial effect in pancytopenic patients with DC.     

Lethal Congenital Muscular Dystrophy with Arthrogryposis Multiplex Congenita: Three New Cases and Review of the Literature

Congenital muscular dystrophy (CMD) comprises a heterogeneous group of muscle disorders. We report on two stillborn sibs with early lethal CMD and a prematurely born boy who died within minutes after birth. The pregnancies were complicated by polyhydramnios. All presented with arthrogryposis multiplex congenita, severe muscle wasting, lung hypoplasia, and hydrops. The muscle biopsies showed fibrosis, variation in fiber size, and extensive fat replacement compatible with muscular dystrophy. Fatal CMD seems to be distinct from CMD with survival after birth and is probably autosomal recessively inherited.     

Aplasia cutis congenita of the scalp with large underlying skull defect: a case report

Localised agenesis of the scalp is the most frequent patern in aplasia cutis congenita (ACC), a congenital absence of the skin and occasionally of deeper layers. Several clinical groups are characterised by the location and pattern of skin defects, associated malformations and the mode of inheritance. Death occurs in 20% of cases, secondary to the associated anomalies, to infections or to haemorrhage from ulceration of the sagittal sinus when there is also a defect of the underlying skull. In this latter case, we close the defect by two rotational scalp flaps (Orticochea technique) at birth. A three-dimensional CT study is useful for showing the extent of the skull defect and the deformity of the craniofacial complex and the changes in the bone after treatment.     

Dyskeratosis congenita: Unusual onset with isolated neutropenia at an early age

A 3.5 year old male patient with dyskeratosis congenita (DC) presented at the age of 13 months with isolated neutropenia preceding characteristic skin findings. The average absolute neutrophil count of 500/mm³ persisted without the presence of anemia or thrombocytopenia during the follow up. Neutropenia responded to granulocyte-colony stimulating factor (G-CSF) at a dose of 10 μg/kg per day. Immunologic findings were normal as was the chromosomal stability and sister chromatid exchange.     

Central nervous system involvement in arthrogryposis multiplex congenita: Overview of causes,diagnosis, and care

Arthrogryposis or AMC, arthrogryposis multiplex congenita, is defined as multiple congenital joint contractures in more than two joints and in different body areas. The common cause of all AMC is lack of movement in utero, which in turn can have different causes, one of which is CNS involvement. Intellectual disability/CNS involvement is found in approximately 25% of all AMC. AMC with CNS involvement includes a large number of genetic syndromes. So far, more than 400 genes have been identified as linked to AMC, with and without CNS involvement. A number of neonatally lethal syndromes and syndromes resulting in severe disability due to CNS malfunction belong to this group of syndromes. There are several X‐linked disorders with AMC, which are primarily related to intellectual disability. A number of neuromuscular disorders may include AMC and CNS/brain involvement. Careful clinical evaluation by a geneticist and a pediatrician/pediatric neurologist is the first step in making a specific diagnosis. Further investigations may include MRI of the brain and spinal cord, electroencephalogram, blood chemistry for muscle enzymes, other organ investigations (ophtalmology, cardiology, gastrointestinal, and genitourinary systems). Nerve conduction studies, electromyogram, and muscle pathology may be of help when there is associated peripheral nervous system involvement. But most importantly, genetic investigations with targeted or rather whole exome or genome sequencing should be performed. A correct diagnosis is important in planning adequate treatment, in genetic counselling and also for future understanding of pathogenic mechanisms and possible new treatments. A multidiciplinary team is needed both in investigation and treatment.     

The molecular basis for inherited bullous diseases

In the past 5 years enormous progress have been made in our understanding of the molecular basis for a number of inherited skin diseases characterized by easy blistering of the skin and the mucous membranes after minor physical trauma. This increased fragility of the skin or its appendages is due to molecular defects in genes coding for different intra- and extracellular structural proteins which are responsible for mechanical strength at their sites of expression. These diseases encompass the group of epidermolysis bullosa and disorders of cornification such as bullous forms of ichthyosis, palmoplantar keratoderma, and pachyonychia congenita. On the basis of clinical, morphological, and ultrastructural observations the epidermolysis bullosa group has been divided into three major categories. In epidermolysis bullosa simplex blister formation appears within the basal cell layer of the epidermis, and many mutations have been found in the genes of keratin 5 and 14 which are both expressed in basal keratinocytes. Epidermolytic hyperkeratosis leads to an epidermal separation in the suprabasal cell layers. In these patients numerous point mutations have now been described in the suprabasally expressed genes of keratin 1 and 10. In ichthyosis bullosa of Siemens blisters occur in the more upper suprabasal epidermis coincidental with the expression of keratin 2e, and mutations have been detected in the corresponding gene. In epidermolytic palmoplantar hyperkeratosis the suprabasal epidermal splitting is restricted to palms and soles of the patient. In keratin 9, which reveals such an exclusive expression pattern, molecular defects have indeed been recognized. Most recently in two different clinical subtypes of pachyonychia congenita, which is characterized by defective nails and focal palmoplantar hyperkeratosis, point mutations have been found in the genes coding for keratins 6, 16, and 17. In junctional epidermolysis bullosa the separation takes place within the dermal-epidermal basement membrane at the level of the lamina lucida, and mutations have been found in three genes coding for different laminin chains, in the ₄ gene of ₆₄ integrin, and in the gene of collagen XVII. In dystrophic epidermolysis bullosa the tissue separation occurs beneath the basement membrane within the papillary dermis at the level of the anchoring fibrils, and several mutations have been identified in the collagen VII gene. The rapid unraveling of molecular defects in these disabling or even lethal inherited skin diseases makes possible a more precise and earlier prenatal diagnosis, creates new options for suitable therapeutic regimens, and even offers the hope of curing these diseases by means of somatic cell gene therapy.Abbreviations BM Basement membrane - BPAg Bullous pemphigoid antigen - DEB Dystrophic epidermolysis bullosa - EB Epidermolysis bullosa - EBS Epidermolysis bullosa simplex - EHK Epidermolytic hyperkeratosis - EPPK Epidermolytic palmoplantar keratoderma - IBS Ichthyosis bullosa of Siemens - JEB Junctional epidermolysis bullosa - KIF Keratin intermediate filaments - NC Noncollagenous domain - NEPPK Nonepidermolytic palmoplantar keratoderma - PC Pachyonychia congenita     

Ultrastructural aspects of chondrodystrophia calcificans congenita (syndrome of Conradi-Hünermann)

Summary An ultrastructural study of chondrodystrophia calcificans congenita is reported. Foci of initial calcification of cartilage are characterized by coexistence of three different types of crystals, probably due to abnormal proteoglycan composition of cartilage matrix. The calcification process in chondrodystrophia calcificans congenita is apparently not related to matrix vesicles as it is in normal cartilage.     

Novel chloride channel gene mutations in two unrelated Japanese families with Becker's autosomal recessive generalized myotonia

We investigated the skeletal muscle voltage-gated chloride channel gene (CLCN1) in two unrelated Japanese patients with Becker's myotonia congenita. The non-myotonic parents of each patient were consanguineous. The proband of each family shares generalized myotonia, transient weakness after rest, and leg muscle hypertrophy. However, the disease severity related to the degree of myotonia differed, even in view of the response to long train nerve stimulation tests. CLCN1 gene analysis revealed a novel Ala659Val missense mutation identified to be homozygous in the more severe patient, while a novel Gln445Stop nonsense mutation was present in the other patient. Both mutations were absent in 90 Japanese normal controls. This is the first report of Japanese cases of Becker's myotonia congenita with CLCN1 gene mutations.