[A 32-year old male patient with pathological humeral fracture, splenomegaly and thrombocytopenia]. / 32-jähriger Patient mit pathologischer Humerusfraktur, Splenomegalie und Thrombozytopenie.

We describe the case of a 32-year old male patient who presented with a pathological fracture of his right humerus, splenomegaly and thrombocytopenia, the typical symptoms of Gaucher's disease, a lysosomal storage disease. Diagnosis was confirmed by bone marrow biopsy (detection of lipid engorged macrophages - Gaucher cells), by a markedly diminished activity of acid, beta-Glucosidase and by showing two different mutations (764T/A, 1187G/A) in the gene encoding acid beta-Glucosidase. The first mutation causes an amino-acid substitution (phenylalanine to tyrosine). The second mutation causes a premature termination at amino-acid position 396. Enzyme replacement therapy was started with 60 Units/kg body weight, because of severe bone symptoms. Following the decrease in spleen size and increase in platelet count the dose was gradually tapered to 20 U/kg. After two years of enzyme replacement therapy platelet count and spleen volume have normalized and the bone lesions have almost disappeared.

T-cell-depleted peripheral blood stem cell transplantation for alpha-mannosidosis.

Alpha-mannosidosis (alpha-mannosidosis) is a lysosomal storage disease characterized by accumulation of oligosaccharides in various tissues leading to symptoms such as coarse facial features, dysostosis multiplex, hearing disabilities, mental developmental delay and skeletal involvement (dysostosis multiplex). Without treatment, the severe infantile onset form of this autosomal recessive disease leads to progressive neurodegeneration and sometimes to early death. Stem cell transplantation has been shown to be an effective treatment. In the five patients published so far, correction of skeletal abnormalities and improvement of neuropsychological capabilities have been observed. We report the first patient who received a T-cell-depleted peripheral blood stem cell transplantation (PBSCT) for alpha-mannosidosis. The diagnosis of alpha-mannosidosis was made at the age of 14 months. At the age of 24 months, he underwent PBSCT with T-cell depletion by CD34-positive selection from his HLA phenotypically identical mother. Conditioning was carried out with busulfan (20 mg/kg), cyclophosphamide (200 mg/kg), OKT3 and methylprednisolone. The patient is alive and well 27 months after PBSCT and has made significant developmental progress. The pattern of urinary oligosaccharides has returned to almost normal. CD34-positive-selected PBSCT is a feasible option to reduce risk for GVHD for these patients.

Detection of neonatal argininosuccinate lyase deficiency by serum tandem mass spectrometry.

Argininosuccinate lyase (ASL) deficiency (McKusick 207900) is an inborn error of the urea cycle. The leading symptom is progressive hyperammonaemia, which is a life-threatening condition, particularly in patients with a neonatal onset. Early diagnosis and treatment of the hyperammonaemia are necessary to improve survival and the long-term outcome of ASL-deficient patients. Currently, the diagnosis of ASL deficiency is based on the measurement of urea cycle intermediates and amino acids by automated quantitative ion exchange chromatography in plasma and urine. Here, we report a newborn presenting with coma and severe hyperammonaemia. ASL deficiency was suspected on the basis of an adapted tandem mass spectrometric (MS-MS) procedure which allows determination of argininosuccinate in addition to the amino acids in serum samples. MS-MS measurements revealed a characteristic increase of argininosuccinate, a moderate increase of citrulline, and lowered levels of arginine and ornithine in the serum of the patient. The diagnosis was confirmed by the detection of a novel homozygous frameshift mutation in exon 14 of the argininosuccinate lyase gene. We propose MS-MS as a diagnostic tool suitable for the rapid detection of specific alterations in the amino acid spectra caused by ASL deficiency.

A combination of a common splice site mutation and a frameshift mutation in the COL7A1 gene: absence of functional collagen VII in keratinocytes and skin.

We describe a patient with severe generalized dystrophic epidermolysis bullosa (EBD) and a novel combination of compound heterozygous mutations in the COL7A1 gene. The maternal mutation was an A-to-G transition (425-A --> G) at position -2 of the donor splice site within exon 3 that causes aberrant splicing of two abnormal transcripts. One includes intron 3, and one excludes both exon 3 and intron 3. Both splice variants contained a premature termination of the translation. The paternal mutation is a 25-bp deletion in exon 20 (2638de125) that leads to a frameshift and a premature termination codon 133 bp downstream from the site of deletion. This combination of mutations allowed expression of collagen VII mRNA. Immunofluorescence staining of the patient's skin and cultured keratinocytes with domain-specific collagen VII antibodies, however, demonstrated markedly reduced levels of alpha1(VII) polypeptides, and no stable collagen VII protein could be extracted from the patient's cells. Electron microscopy showed severely hypoplastic fibrils below the lamina densa, without evidence of normal anchoring fibrils. The clinically unaffected parents were heterozygous for the mutations, suggesting that both COL7A1 gene defects were recessively inherited disease-causing mutations that are "silent" in heterozygous carriers but in combination can severely interfere with the dermal-epidermal adhesion and lead to severe EBD.

Clinical and ultrastructural findings in three patients with geleophysic dysplasia.

Geleophysics dysplasia, a rare disorder with autosomal-recessive inheritance, is characterized by short stature with a "happy-looking" facial appearance. Nonskeletal findings, particularly in an advanced stage, include hepatosplenomegaly and valvular cardiopathy. Based on the clinical picture and the detection of lysosome-like inclusions in hepatocytes, the underlying cause of the condition is considered to be a storage defect in the metabolism of glycoproteins. The clinical course, with progressive worsening of the condition favors this hypothesis. We report on 3 further cases, in which light and electron microscopic studies of iliac crest biopsies and cultured skin fibroblasts provided additional evidence that geleophysic dysplasia represents a lysosomal storage disease. The additional discovery of storage vacuoles in chondrocytes and skin fibroblasts strongly suggests that the condition is a generalized storage defect. To date, it has not yet been possible to identify the presumed biochemical defect in the metabolic pathways of glycoproteins.

Type II collagenopathies: are there additional family members?

The type II collagenopathies represent a group of chondrodysplasias sharing clinical and radiological manifestations which are expressed as a continuous spectrum of phenotypes, ranging from perinatally lethal to very mild conditions. Their common molecular bases are mutations in the type II collagen gene (COL2A1). We describe one case of lethal platyspondylic dysplasia, Torrance type, and a variant of lethal Kniest dysplasia, neither of which has been reported as a type II collagenopathy. Biochemical studies of cartilage collagens and morphological analysis of cartilage sections suggest that abnormalities of type II collagen structure and biosynthesis are the main pathogenetic factors in both cases. Thus, the phenotypic spectrum of type II collagenopathies might be greater than hitherto suspected.

The spectrum of free neuraminic acid storage disease in childhood: clinical, morphological and biochemical observations in three non-Finnish patients.

N-acetylneuraminic acid (sialic acid) storage disease is a rare autosomal recessive lysosomal disorder. Clinically two major forms exist, an infantile type with severe progression leading to early death, and a milder form (Salla disease) with a protracted course. Intermediate forms may also exist. Diagnosis rests on the determination of an excessive excretion of sialic acid in urine and concomitant storage in fibroblasts, the severe forms exhibiting the highest excretion and storage. We present clinical, morphological, and biochemical data on three non-Finnish patients with sialic acid storage disease. Patient 1 was a preterm infant with neonatal ascites, coarse face, hepatosplenomegaly, pale skin, and wispy hair. Vacuolated lymphocytes were abundant in a peripheral blood smear and he excreted large amounts of free sialic acid. High levels of free sialic acid were also found in cultured skin fibroblasts. He died at age 6 months from progressive respiratory insufficiency. Patient 2 was an 11-month-old Egyptian girl with coarse face, frequent upper respiratory tract infections, hepatosplenomegaly, and severe psycho-motor retardation. Sialic acid excretion was elevated, likewise the storage in fibroblasts. Histological investigations documented vacuolar storage in a skin biopsy and in iliac crest tissue. Patient 3 was a 16-year-old girl with slightly coarse face, severe generalized muscular hypotonia, ataxia, and kyphoscoliosis originally diagnosed as having post-partum asphyxia. She suffered progressive motor function loss and had dysarthria. Urinary sialic acid was elevated and a skin biopsy demonstrated vacuolization. The clinical variability of sialic acid storage disease is exemplified by these three cases. Simple urinary screening for free sialic acid facilitates the diagnosis. The degree of urinary excretion may indeed correlate with clinical presentation and progression.

[Possible errors in ultrasound hip imaging in patients with osteogenesis imperfecta]. / Fehlermöglichkeiten der sonographischen Hüftbeurteilung bei Patienten mit Osteogenesis imperfecta.

In ultrasonographic diagnosis of the hip severe bony deformities due to osteogenesis imperfecta are potential pitfalls. In this condition, even x-ray of the pelvis is unreliable, whereas MRT is a helpful diagnostic method.

[Pelvic vein thrombosis in protein C deficiency after infectious mononucleosis]. / Beckenvenenthrombose bei Protein-C-Mangel nach infektiöser Mononukleose.

Subsequent to an infectious mononucleosis a 15 year old girl developed a thrombosis of the iliaca vein. Laboratory evaluation revealed a heterozygous form of protein C deficiency. An infusion with r-tPA (= recombinant tissue plasminogen activator) at a rate of 0.02 mg/kg BW/h over 96 hours failed to reopen the vessel. After intermittent heparin therapy longterm treatment with coumarin began. Three months later the iliaca vein was partially recanalised.

[Osteogenesis imperfecta in childhood and adolescence]. / Osteogenesis imperfecta in Kindheit und Adoleszenz.

BACKGROUND: 209 patients with osteogenesis imperfecta type I, III and IV were studied to provide data on the natural course of the disease until the end of the second decade. RESULTS: Weight and length at birth were normal in most cases of type I and IV, markedly reduced in type III. Fractures and deformities at birth were most frequent in type III. High fracture rates occurred in type III and IV up to 8-10 years of age. Skeletal deformities developed primarily in the lower extremities and the spine, again most frequently in type III. Radiological features were--besides osteopenia--Wormian bones of the skull, pseudoarthroses, deformity of the pelvis, popcorn epiphyses (most frequent in type III) and hyperplastic callus (most frequent in type IV). Longitudinal growth of patients with type I was in the lower normal range, while patients with type III and IV developed marked growth deficiency. Motor performance was not severely impaired in most cases of type I; however, all type III patients and 71% of type IV patients were confined to a wheelchair in later life. CONCLUSION: As defined, type I patients had a mild clinical course until early adulthood. Type III and IV represented a spectrum of severely affected patients. Although type IV patients were less affected at birth, their postnatal course in some respects resembled that of type III.

Familial insulin resistant diabetes associated with acanthosis nigricans, polycystic ovaries, hypogonadism, pigmentary retinopathy, labyrinthine deafness, and mental retardation.

Two sibs, whose parents are first cousins, had diabetes mellitus with hyperinsulinism, insensitive insulin receptors, and acanthosis nigricans. Both patients had pigmentary retinopathy, secondary cataracts, labyrinthine deafness, mental retardation, and cerebral atrophy. They were disproportionately short with relatively broad hands and feet and slightly coarse face. The young woman had secondary amenorrhea and polycystic ovaries and the boy gynecomastia and hypergonadotrophic hypogonadism. This appears to be the second family with a new autosomal recessive disorder differing from Alström syndrome by the presence of mental retardation and absence of renal insufficiency. Impaired insulin receptor binding and polycystic ovaries are described as part of this syndrome.

[Early infantile malignant osteopetrosis. Experiences with drug therapy]. / Frühinfantile maligne Osteopetrose. Erfahrungen mit der medikamentösen Therapie.

The autosomal recessive form of osteopetrosis becomes manifest in early infancy and often is lethal during the first decade of life. In an infant diagnosed at the age of eight weeks, a therapy with Calcitriol (Rocaltrol) was initiated with the intention to stimulate the osteoclast activity and to improve the bone marrow insufficiency. During therapy, a massive diarrhoea has been observed as potential and previously undescribed side effect of Calcitriol. Therefore the therapy had to be discontinued. A simultaneous trial with Ca-depleted diet did not show any effect. In the absence of a suitable donor, a bone-marrow transplantation could not be performed. The patient died at the age of five month.

[Aluminum poisoning caused by the phosphate binder in a non-dialysed child with chronic renal insufficiency]. / Aluminiumintoxikation durch Phosphatbinder bei einem nicht dialysierten Kind mit chronischer Niereninsuffizienz.

In patients with chronic renal failure, aluminium, which is included in the dialysate or released from phosphate binders, cannot be eliminated adequately. It forms a deposit in the tissues and leads to intoxication. After a 6-month therapy with aluminium-containing phosphate binders in a non-dialysed baby with chronic renal insufficiency, an osteomalacia arose with distinct subepiphyseal and metaphyseal changes attributable to disorders of mineralization. The consequence of this was a "bone-within-bone" appearance and pathological fractures. After a change of therapy, the bone alterations receded within a few months. Simultaneously, the distinctly elevated serum level of aluminium fell. Therefore, aluminium should be avoided in non-dialysed children with chronic renal insufficiency.

Lymphadenopathy in connection with human herpes virus type 6 (HHV-6) infection.

Two siblings and their mother developed afebrile generalized lymphadenopathy. The lymph nodes were movable and painless. During the course of the illness, the mother and one child developed an uncharacteristic rash. Increased titers of human herpes virus type 6 (HHV-6) antibodies were found in all three family members and in an unrelated patient with lymphadenitis colli. The enlarged lymph nodes decreased in size within several weeks. We speculate these symptoms to be caused by an infection with this lymphotropic virus.

Brachyolmia: a skeletal dysplasia with an altered mucopolysaccharide excretion.

A 15-year-old girl is described with brachyolmia. She presented with short-trunked dwarfism, hypolordosis of the lower spine and radiological features of the disease. She was initially considered to have a mucopolysaccharidosis (type III Sanfilippo) on account of a pathological urinary glycosaminoglycan excretion pattern. The amount of urinary glycosaminoglycans was normal, but we found an increased amount of an undersulphated chondroitin sulphate molecule. Our finding of an undersulphated glycosaminoglycan points to a disturbance in chondroitin sulphate synthesis, and it is rare that a defect in glycosaminoglycan synthesis leads to a skeletal dysplasia. To our knowledge, this is the second case of brachyolmia with a possible defect in chondroitin sulphate-sulphotransferase.

[Exanthema subitum, encephalopathy and hepatitis caused by human herpesvirus type 6 (HHV-6) in a 10-month-old infant]. / Exanthema subitum, Enzephalopathie und Hepatitis durch humanes Herpesvirus Typ 6 (HHV-6) bei einem 10 Monate alten Säugling.

We describe the unusual clinical course in a case of exanthema subitum with affection of the liver and central nervous system in a 10-months-old girl. HHV-6 infection was confirmed serologically (positive HHV-6 IgM from 10th to 29th day, increasing IgG-titres). At the beginning of the illness convulsions with preference to the right side were noticed, which were consistent with an encephalitis (on top to a suspected pre/perinatal lesion) and resulting in spastic triplegia. Nuclear magnetic resonance imaging and cranial computertomographic results showed severe, predominantly left-sided cerebral lesions. In addition there was clinical and biochemical evidence of an associated hepatitis. Human herpesvirus-6 has been identified as the cause of exanthema subitum. In addition, the virus is known to cause other clinical entities (lymphadenopathy, febril seizures, hepatitis, postinfectious chronic fatigue a.o.) and has been identified in brain tissues. Our observations show that the course of exanthema subitum can be complicated by affection of the liver and central nervous system. At present it is impossible to estimate the clinical outcome in our patient.

[Cu deficiency as a cause of spontaneous fracture in a premature infant]. / Cu-Mangel als Ursache einer Spontanfraktur bei einem Frühgeborenen.

We report on a male preterm infant of 25th week of gestation, who developed a spontaneous fracture of the right femur at an age of four months. Besides an "impressed" fracture radiologically a generalized osteopenia of the skeleton and cupped metaphysis alterations were observed. An alimentary copper deficiency could be diagnosed. Additionally clinical signs were repeated apneic episodes, anaemia, neutropenia and a low serum level of both coeruloplasmin and copper. We substituted the patient orally with CuCl2 (1.2 mumol/kg/KG/d) over a period of four months resulting in a complete healing of the fracture and an improvement of the other clinical symptoms and laboratory alterations.

[A case of prepuberty periodontitis--a classification based on laboratory results]. / Ein Fall von präpubertärer Parodontitis.

The rare entity of periodontitis in a 4 1/2-year old child and subsequent changes over a 4-year follow-up period will be presented. Various examinations (among other immunological tests, biochemical differentiation of dermal fibroblasts, and ultrastructural skin biopsies) were made to identify whether this was a case of genuine prepuberty periodontitis or of periodontitis secondary to a general disease. On the basis of the results the case was diagnosed as Ehlers-Danlos Disease Type VIII, although at the same time signs of impaired granulocyte function were observed.

[Clinical picture and course of children with CHARGE association]. / Klinisches Bild und Verlauf von Kindern mit CHARGE-Association.

Four children are described who presented malformations according to CHARGE-Association. The primary abnormalities were choanal atresia and/or Coloboma. All four cases exhibited esophageal malformations: atresia and/or fistulas. At autopsy, three children showed arhinencephaly which is rarely observed in patients with CHARGE-Association. Patients with the main features of CHARGE-Association have a very poor prognosis depending on the severity of the malformations.