Analysis of short stature homeobox-containing gene ( SHOX) and auxological phenotype in dyschondrosteosis and isolated Madelung deformity.

Dyschondrosteosis (DCO; also called Léri-Weill syndrome) is a skeletal dysplasia characterised by disproportionate short stature because of mesomelic shortening of the limbs. Madelung deformity is a feature of DCO that is distinctive, variable in expressivity and frequently observed. Mutations of the SHOX (short stature homeobox-containing) gene have been previously described as causative in DCO. Isolated Madelung deformity (IMD) without the clinical characteristics of DCO has also been described in sporadic and a few familial cases but the genetic defect underlying IMD is unknown. In this study, we have examined 28 probands with DCO and seven probands with IMD for mutations in the SHOX gene by using polymorphic CA-repeat analysis, fluorescence in situ hybridisation (FISH), Southern blotting, direct sequencing and fibre-FISH analyses. This was combined with auxological examination of the probands and their family members. Evaluation of the auxological data showed a wide intra- and interfamilial phenotype variability in DCO. Out of 28 DCO probands, 22 (79%) were shown to have mutations in the SHOX gene. Sixteen unrelated DCO families had SHOX gene deletions. Four novel DCO-associated mutations were found in different families. In two additional DCO families, the previously described nonsense mutation (Arg195Stop) was detected. We conclude that mutations in the SHOX gene are the major factor in the pathogenesis of DCO. In a female proband with severe IMD and her unaffected sister, we detected an intrachromosomal duplication of the SHOX gene.

Asn540Lys mutation in fibroblast growth factor receptor 3 and phenotype in hypochondroplasia.

UNLABELLED: Hypochondroplasia is characterized by a disproportionate short stature with rhizomelic shortening of the limbs. Amino acid substitutions Asn540Lys, Asn540Thr and Ile538Val in the fibroblast growth factor receptor 3 (FGFR3) are considered to cause hypochondroplasia. In this study we examined the FGFR3 gene for the previously described hypochondroplasia mutations and the phenotype of 23 probands with clinically and radiologically diagnosed hypochondroplasia. For the phenotype comparison, the patients were divided into two groups: Group 1: hypochondroplasia with Asn540Lys substitution; Group 2: hypochondroplasia with no mutations identified so far. A three-generation family negative for the known hypochondroplasia mutations was examined with polymorphic markers flanking the FGFR1, FGFR2 and FGFR3 genes. Nine (39%) of 23 probands were found to be heterozygous for the Asn540Lys substitution. The individuals positive for the Asn540Lys substitution were significantly more disproportionate than the individuals without this mutation. In this respect, a genotype-phenotype correlation was found in our patients. However, some individuals belonging to the group without mutations identified so far showed similarly abnormal proportions. Genotyping/haplotyping in the three-generation family with hypochondroplasia showed that FGFR1, FGFR2 and FGFR3 genes were not linked to the hypochondroplasia phenotype in this family, thus further confirming the genetic heterogeneity of hypochondroplasia. CONCLUSION: Individuals with hypochondroplasia heterozygous for the Asn540Lys substitution are significantly more disproportionate than individuals without this mutation. Our study further confirms the clinical and genetic heterogeneity of hypochondroplasia.

Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia.

Dyschondrosteosis (DCO) and hypochondroplasia (HCH) are common skeletal dysplasias characterized by disproportionate short stature. The diagnosis of these conditions might be difficult to establish especially in early childhood. Point mutations and deletions of the short stature homeobox containing gene (SHOX) are detected in DCO and idiopathic short stature with some rhizomelic body disproportion, whereas mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are found in 40-70% of HCH cases. In this study, we performed mutational analysis of the coding region of the SHOX gene in five DCO and 18 HCH patients, all of whom tested negative for the known HCH-associated FGFR3 mutations. The polymorphic CA-repeat analysis, direct sequencing and Southern blotting were used for detection of deletions and point mutations. The auxological and radiological phenotype of these patients was carefully determined. Three novel mutations in DCO patients were found: (1) a deletion of one base (de1272G) (according to GenBank accession nos. Y11536, Y11535), resulting in a premature stop codon at position 75 of the amino acid sequence; (2) the transversion C485G resulting in the substitution Leu132Val; and (3) the transversion G549T causing an Arg153Leu substitution. These substitutions segregate with the DCO phenotype and affect evolutionarily conserved homeodomain residues, based on a comparison of homeobox containing proteins in 13 species. Moreover, these changes were not found in 80 unrelated, unaffected individuals. This strongly suggests that these mutations are pathogenic. The phenotype of our patients with DCO and HCH varied from mild to severe shortness and body disproportion. These results further support clinical and genetic heterogeneity of dyschondrosteosis and hypochondroplasia.

A novel missense mutation Ile538Val in the fibroblast growth factor receptor 3 in hypochondroplasia. Mutations in brief no. 122. Online.

Hypochondroplasia and achondroplasia are skeletal dysplasias, characterized by autosomal dominant inheritance and disproportionate short stature, which occurs mainly due to growth failure of the extremities. Both dysplasias have been mapped to fibroblast growth factor receptor 3 (FGFR3) gene. For hypochondroplasia, two point mutations, both responsible for the Asn540Lys substitution in the region coding the tyrosine kinase domain have been reported. Here we report an A to G transition at position 1651, predicting an Ile538Val substitution in the FGFR3, in hypochondroplasia. The substitution is found in a swedish family with three affected members. The criteria for hypochondroplasia were disproportionate short stature and radiological evidence of shortened long bones and decrease or absence of normal increase in interpedicular distances of the lumbar column. The mutation was detected by direct sequencing and restriction enzyme Tai I digestion. The base change was not found in the FGFR3 genes of unaffected members of the family nor in seventy-five unrelated unaffected individuals, suggesting that it was not a polymorphism. The Ile538Val substitution is a conservative amino acid change (a hydrophobic amino acid incorporated for another hydrophobic amino acid). Nevertheless, it is located in the stretch of nine amino acids, which is highly conserved among all the human fibroblast growth factor receptors. Considering the location of this substitution and the segregation with the phenotype in this family, we propose that it is a causative mutation of hypochondroplasia. It is difficult to establish whether the Ile538Val substitution is rare in hypochondroplasia patients or whether the individuals, who have a moderate degree of short stature, rarely seek medical help for the short stature and consequently are rarely diagnosed as affected by hypochondroplasia.

Luxation of the elbow complicated by proximal radio-ulnar translocation.

Luxation of the elbow complicated by proximal radio-ulnar translocation is a rare entity. The clue to diagnosis is the reversed position of the bones of the proximal forearm. In the a.p. projection the radial head articulates with the trochlea and the ulna with the capitellum. This unexpected anatomic relationship is easily overlooked. Delayed reduction may result in permanent impairment of elbow motility. Our experience with three recent cases is presented.

Hip instability in myelomeningocele. 158 patients followed for 15 years.

In 158 patients with myelomeningocele, the prevalence of hip dislocation at birth and subluxation or dislocation of unoperated on hips at 2 and 15 years of age were assessed. In neonates examined during the first 10 weeks of life, 10 percent of the hips were dislocated. In children with a thoracic or L1-2 neurologic level, the cumulative incidence of dislocated hips increased from 8 to 26 percent and subluxations from 33 to 45 percent. In children with L3 and L4 levels, one fourth of the hips had dislocations and nearly half subluxations. At L5 and the sacral motor level, dislocations did not occur, but one fifth of the hips had subluxations. Children with L3 or L4 neurologic levels had bilateral hip dislocation at an earlier age than those with higher levels of paralysis. There appears to be no risk of developing hip dislocation at neurologic levels below L4, and spasticity promotes hip dislocation above L3.

Development of hypertension and uraemia after pyelonephritis in childhood: 27 year follow up.

OBJECTIVE: Determination of the long term incidence of uraemia, hypertension, and toxaemia in pregnancy associated with non-obstructive focal renal scarring after pyelonephritis in childhood 25-35 years earlier. DESIGN: 27 Year follow up of patients with non-obstructive focal scarring identified from a retrospective review of intravenous urograms performed in childhood between 1951 and 1967. SETTING: Paediatric primary referral centre and urological clinic in tertiary referral centre. PATIENTS: 30 Patients (mean age 33 (range 22-41] with non-obstructive focal renal scarring first detected between 1951 and 1967 and a history of febrile urinary tract infection. MAIN OUTCOME MEASURE: Hypertension and complications of renal damage. RESULTS: Three patients had developed end stage renal disease, seven had developed hypertension, two of 16 women had a history of toxaemia during pregnancy, and seven patients had undergone renal surgery during follow up. Of the 20 patients who had neither had renal surgery nor had end stage renal disease, all had a significantly lower glomerular filtration rate and renal plasma flow and higher diastolic blood pressure, mean arterial blood pressure, plasma renin activity, and serum beta 2 microglobulin concentration than 13 healthy age matched controls. Diastolic blood pressure and plasma renin activity were positively correlated (r = 0.50, p less than 0.05) and so were fractional sodium excretion and both systolic and diastolic blood pressures (r = 0.54, p less than 0.01, r = 0.51, p less than 0.01 respectively). The progress of renal damage was unrelated to the incidence of recurrent infections. CONCLUSIONS: Children with focal renal scarring due to pyelonephritis are at high risk of serious long term consequences. It is essential that they are given adequate attention and care during adolescence and pregnancy.

The percentage of migration as indicator of femoral head position.

In childhood subluxation of one or both hips may develop rather insidiously. For lack of generally accepted objective methods of assessment, ambiguous interpretations of findings in serial examinations are common. Many subluxations are overlooked during the early stages. In order to overcome such disadvantages, determination of the percentage of migration seems to be a reasonably easy and reliable technique facilitating evaluation of impending dislocation. This investigation was carried out in order to establish norms applicable to patients in the pediatric age interval. The 98th percentile of migration increases with age from 16 per cent in patients less than 4 years of age to 24 per cent in patients greater than or equal to 12 years. Higher figures represent subluxation. If the migration exceeds 80 per cent a manifest luxation is present. A difference in migration between the two hips larger than 12 per cent indicates abnormality calling for clinical and radiologic follow-up.

Wilms' tumor complicated by veno-occlusive disease of the liver (VOD): current concepts and a case report.

A 2-year-old boy, undergoing treatment for Wilms' tumor, developed in some respects unusual manifestations of veno-occlusive disease of the liver. Reporting the case, we also review the current clinical and radiological concepts of this neglected complication of cancer therapy. Misinterpretation of symptoms and signs is probably rather common and may prove fatal. Recognition of the disorder calls for immediate discontinuation of chemotherapy and irradiation. Supportive intensive care is frequently necessary. Following recovery, cautiously tailored tumor therapy may be reinstated.

Ultrastructure of hyaline cartilage. 2. Recent developments in preparatory procedures of electron microscopy and immunocytochemistry for the classification of bone dysplasias.

Recent developments in preparatory procedures for electron microscopy and immunocytochemistry are presented as a background for the morphological diagnosis of bone dysplasia. With the new low temperature embedding techniques and the availability of monoclonal antibodies raised against the main matrix macromolecules, biopsies have proved to be an important complement to clinical and radiological workup and they may sometimes provide the final clue to the diagnosis.

Suprarenal haematoma versus neuroblastoma complicated by haemorrhage. A diagnostic dilemma in the newborn.

Concomitant neonatal suprarenal haemorrhage and neuroblastoma is rare. The clinical and radiologic manifestations recorded in 11 patients with this entity are compared with the findings in 32 cases with simple adrenal haemorrhage. Because of the many similarities in presentation the combined lesion must always be considered when a neonate is found to have a retroperitoneal, extra-renal mass. Our present approach to the investigation includes conventional chest and abdominal radiography aimed to demonstrate possible paravertebral widening. Serial ultrasonographies are easy to carry out and indispensable. The low specificity of urography makes us refrain from this modality as a routine. Scintigraphy, in infants and children considered useful in demonstrating extent and spread of neuroblastoma, has hardly been employed in neonates. The true value of the modality in this particular age group remains to be settled. CT scanning does not seem to provide essential information additional to that of sonography and may therefore be excluded from the protocol. Determination of urinary excretion of catecholamine metabolites is of crucial significance and a compulsory part of the investigation.

[Erroneous diagnosis of nephroblastoma (Wilm's tumor) based on SIOP data]. / Oshibochnyi diagnoz nefroblastomy (opukholi Vil'msa) po materialam SIOP.

Available films of 21 cases of erroneously diagnosed Wilms' tumor in the European Wilms' material have been studied. The diagnosis has been reassessed and the reasons for agreement in 6 cases and disagreement in the remaining 15 are discussed. General diagnostic recommendations are given to help secure optimal diagnostic information.

Veno-occlusive disease and peliosis of the liver complicating the course of Wilms' tumour.

Veno-occlusive disease (VOD) of the liver was diagnosed in 8 patients with Wilms' tumour and peliosis hepatis (PH) in one. Fever of obscure origin, vague abdominal pain, hepatomegaly or hepatosplenomegaly, severe anaemia or sudden, unexplained drop in haemoglobin, thrombocytopenia, increasing serum transaminase levels, jaundice and ascites recorded within the first weeks or months of tumour diagnosis should arise suspicion of non-metastatic vascular hepatopathy. General or focal decreased accumulation of isotope at liver scintigraphy belong to the early radiologic findings. Sonography and CT may show a generalized irregular echogenicity or attenuation but no unequivocal metastases. One patient with PH had multiple low attenuating foci in both liver lobes and angiographically abnormal pooling of contrast medium in the liver. It is important to recognize these conditions as alternatives to suspected liver metastases, which as a rule develop much later yet on occasions may have very similar radiologic appearances. Therefore the relation in time between tumour diagnosis, initial operation and development of obscure hepatic manifestations is of critical significance for the recognition of VOD or PH. In these patients chemotherapy and irradiation must be discontinued without delay. If the disorders are adequately treated the prognosis may be considered fair.

Thoracic neuroblastoma of the neonate.

Five cases of neonatal thoracic neuroblastoma were either clinically asymptomatic or presented as uncharacteristic respiratory distress. Chest radiography demonstrated a spectrum of abnormalities varying from a lobulated, apical thoracic mass with or without evidence of expansion, to a spindle-shaped paraspinal soft tissue widening, or a homogeneously dense hemithorax. In the newborn a neoplasm in the posterior mediastinum most likely represents a neuroblastoma, either primary or metastatic. In a high percentage of cases the primary tumour as well as possible skeletal metastases have an increased uptake of radiopharmaceuticals. Therefore a bone scan should be the next step for evaluation of the neoplasm. Supplementary sonographic screening of the retroperitoneum and lesser pelvis is easily performed and may contribute significant information. Urography is hardly mandatory any longer. Metrizamide CT myelography, highly recommended in infants and children, may be omitted in the neonate with no neurologic deficit. Urinary excretion of catecholamine metabolites is usually elevated and must always be determined.

Correlation of detrusor vesicae activity to radiologic findings in childhood myelodysplasia.

In selected cases of childhood myelodysplasia associated with incontinence oral anticholinergics, e.g. atropine, may significantly improve the results of continence training programs. At present, the differentiation of patients who may benefit from this kind of pharmacotherapy from those who do not respond calls for laborious recordings of the intravesical pressure. Urography and micturition cystourethrography routinely used for the morphologic evaluation of the urinary tract were compared with the pressure tracings. No useful correlation between findings was obtained, thus excluding the possibility to replace the pressure studies by the much simpler radiologic examinations.

Epidermolysis bullosa dystrophica with urinary tract involvement.

A case of epidermolysis bullosa dystrophica ( EBD ), neonatally corrected atresia of the pylorus and early infantile development of urinary tract manifestations is reported. Owing to misinterpretation of radiological findings, instrumental treatment of the urethra was employed. It resulted in complete and permanent obliteration of the lumen. While the skin disorder has remained slight to moderate in severity, recurrent keratitis has resulted in impaired vision.

Prenatal diagnosis of chondroectodermal dysplasia with fetoscopy.

Chondroectodermal dysplasia (Ellis-van Creveld syndrome) has previously been diagnosed prenatally only once, using fetoscopy. We report on two consecutive pregnancies in a woman at risk of having a child with the syndrome during which fetoscopic visualization was performed. Ellis-van Creveld syndrome was diagnosed prenatally in one instance, while it could be excluded in the other one. Non-invasive prenatal diagnosis of the syndrome is discussed.

Renoprival growth following treatment of unilateral Wilms' tumour.

The renal growth pattern following uninephrectomy for Wilms' tumour was analysed in 18 boys and 18 girls by means of a comparison between renal parenchymal and body surface area. No straightforward correlation was noted between age at nephrectomy, chemo- and radiation therapy applied, and subsequent renoprival dimensions. Five years on average after operation, a mean renal size corresponding to approximately 125 per cent of the normal for one of two healthy kidneys was recorded. However, wide variations in size were observed, but only 10 patients had a compensatory growth of the remaining kidney equivalent to that seen in patients nephrectomized for unilateral, non-malignant renal disease.