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 microdeletion in 19q13.2 associated with mental retardation, skeletal malformations, and Diamond-Blackfan anaemia suggests a novel contiguous gene syndrome.

Diamond-Blackfan anaemia (DBA) is a constitutional red blood cell hypoplasia which may be associated with a variety of developmental abnormalities. A gene for DBA was recently mapped to chromosome 19q13.2 and subsequently cloned. Analysis of 19q marker alleles in DNA of sporadic DBA cases showed de novo microdeletions in three patients also presenting with mental retardation. We have studied one of these patients and characterised the deletion by fluorescence in situ hybridisation (FISH) to extended DNA fibres. The deletion was shown to be continuous over a 3.2 Mb region and the fibre-FISH analysis showed both chromosomal breakpoints. In combination, the clinical and molecular findings suggest a contiguous gene syndrome with a gene locus for mental retardation and, probably, skeletal malformations included in the deletion.

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.

Long-term prognosis of post-infectious renal scarring in relation to radiological findings in childhood--a 27-year follow-up.

In a previous report the long-term prognosis of 30 patients with renal scarring after pyelonephritis in childhood was described. In this study, we have related the extent of renal scarring present in childhood to the conditions in early adulthood. A radiological progression of scarring from childhood to adulthood was seen in one-third of the kidneys. The 7 patients with bilateral scarring in childhood had a smaller renal area, lower glomerular filtration rate and higher plasma vasopressin at follow-up than 13 healthy controls. The 20 patients who had unilateral scarring in childhood had a smaller renal area, lower glomerular filtration rate, higher diastolic blood pressure and higher plasma renin at follow-up than controls; 4 had hypertension. The most important finding was that children with unilateral disease are at risk of serious long-term complications. Filtration fraction at follow-up was higher in patients with extensive renal scarring in childhood compared with those with a normal renal area or small scars in childhood (r = -0.43, P less than 0.05). This may indicate glomerular hyperfiltration by remnant glomeruli. This paper emphasizes t the potential seriousness of childhood urinary tract infections especially when early infantile infections are overlooked. A follow-up of more than 4 decades may be necessary before the ultimate prognosis can be established, especially in patients with unilateral renal disease. It is advised that most patients with post-infectious renal scars are followed as high-risk patients, and that treatment continuity is established between paediatricians, nephrologists and, when required, obstetricians.

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.

Altered vasopressin release and osmotic regulation during exercise in patients with pyelonephritic renal scarring.

Children and adults with pyelonephritic renal scarring are at high risk of developing hypertension. The objectives of the present investigation were to study if it is possible to detect early disturbances in blood pressure (BP) control and secretion of hormones involved in the regulation of BP and renal function, in patients with renal scarring. We studied renal function at rest, BP regulating hormones and BP at rest and during graded bicycle exercise until exhaustion. The 22 patients with renal scarring had significantly lower glomerular filtration rate and renal blood flow than the 13 healthy age-matched controls. At rest, the patients had higher diastolic (p less than 0.01) and mean arterial BP (p less than 0.02), higher plasma renin (p = 0.06) and higher serum osmolality (p less than 0.001) but there were no significant differences in systolic BP, angiotensin II, aldosterone or vasopressin (AVP). The patients with renal scarring had higher AVP than the controls during light and moderate exercise and 15 min after maximal exercise. BP and renal hormones increased significantly but similarly during exercise in both patients and controls. There were no significant differences in BP control or release of pressure-regulating hormones at maximal exercise. Maximal exercise did not evoke pathological BP response in normotensive young adults with pyelonephritic renal scarring. The increase in serum osmolality and hypersecretion of AVP during light and moderate exercise may be important in the pathogenesis of hypertension in this group of patients.

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.

Scoliosis in myelomeningocele.

Prevalence, type, and magnitude of scoliosis were studied in 163 patients with myelomeningocele. A scoliosis was diagnosed in 143 of them, congenital in 15 percent of the cases and developmental in the remaining patients. The severity of scoliosis increased with age and was more severe the higher the level of the neurologic deficit. The direction of the curves was correlated with pelvic obliquity, but not with hip dislocation. Although some patients with low level anomalies may develop severe scoliosis, patients with levels above L3 run a considerably higher risk in this respect. The radiographic baseline examination of the spine carried out in the newborn seems to permit a reasonable prognosis in regard to future scoliosis. Gross syringohydromyelia caused or contributed to scoliosis in 5 percent of the cases. However, less extensive syringohydromyelia and Chiari malformations due to abnormal neuromuscular control also promote the development of scoliosis in these patients.

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.

Conventional spinal radiography as a supplement to the neurologic assessment in myelomeningocele.

In patients born with a myelomeningocele early assessment of the severity of the anomaly is mandatory for planning of therapy. Conventional spinal radiography, although a routine examination, in many hospitals has been regarded as less rewarding. However, in this retrospective investigation of 92 patients, a reasonable conformity was found between conventional radiograms and neurologic deficit at follow-up. There was no significant difference between the results of radiologic examinations carried out during the first 1 to 10 weeks after birth and the later neurologic findings. Hence, the simple radiologic assessment has proved a valuable baseline examination in these patients. In cases with discrepancy between the conventional radiologic and the neurologic findings, and in cases with a course diverging from the anticipated, more sophisticated methods of imaging are recommended.