Ilkka Kaitila

The diastrophic dysplasia gene encodes a novel sulfate transporter: Positional cloning by fine-structure linkage disequilibrium mapping

Diastrophic dysplasia (DTD) is a well-characterized autosomal recessive osteochondrodysplasia with clinical features including dwarfism, spinal deformation, and specific joint abnormalities. The disease occurs in most populations, but is particularly prevalent in Finland owing to an apparent founder effect. DTD maps to distal chromosome 5q and, based on linkage disequilibrium studies in the Finnish population, we had previously predicted that the DTD gene should lie about 64 kb away from the CSF1R locus. Here, we report the positional cloning of the DTD gene by fine-structure linkage disequilibrium mapping. The gene lies in the predicted location, approximately 70 kb proximal to CSF1R, and encodes a novel sulfate transporter. Impaired function of its product is likely to lead to undersulfation of proteoglycans in cartilage matrix and thereby to cause the clinical phenotype of the disease. These results demonstrate the power of linkage disequilibrium mapping in isolated populations for positional cloning.

Mutations in the RNA Component of RNase MRP Cause a Pleiotropic Human Disease, Cartilage-Hair Hypoplasia

The recessively inherited developmental disorder, cartilage-hair hypoplasia (CHH) is highly pleiotropic with manifestations including short stature, defective cellular immunity, and predisposition to several cancers. The endoribonuclease RNase MRP consists of an RNA molecule bound to several proteins. It has at least two functions, namely, cleavage of RNA in mitochondrial DNA synthesis and nucleolar cleaving of pre-rRNA. We describe numerous mutations in the untranslated RMRP gene that cosegregate with the CHH phenotype. Insertion mutations immediately upstream of the coding sequence silence transcription while mutations in the transcribed region do not. The association of protein subunits with RNA appears unaltered. We conclude that mutations in RMRP cause CHH by disrupting a function of RNase MRP RNA that affects multiple organ systems.

Splicing Mutations of 54-bp Exons in the COL11A1 Gene Cause Marshall Syndrome, but Other Mutations Cause Overlapping Marshall/Stickler Phenotypes

Stickler and Marshall syndromes are dominantly inherited chondrodysplasias characterized by midfacial hypoplasia, high myopia, and sensorineural-hearing deficit. Since the characteristics of these syndromes overlap, it has been argued whether they are distinct entities or different manifestations of a single syndrome. Several mutations causing Stickler syndrome have been found in the COL2A1 gene, and one mutation causing Stickler syndrome and one causing Marshall syndrome have been detected in the COL11A1 gene. We characterize here the genomic structure of the COL11A1 gene. Screening of patients with Stickler, Stickler-like, or Marshall syndrome pointed to 23 novel mutations. Genotypic-phenotypic comparison revealed an association between the Marshall syndrome phenotype and splicing mutations of 54-bp exons in the C-terminal region of the COL11A1 gene. Null-allele mutations in the COL2A1 gene led to a typical phenotype of Stickler syndrome. Some patients, however, presented with phenotypes of both Marshall and Stickler syndromes.

Mutations in Fibroblast Growth-Factor Receptor 3 in Sporadic Cases of Achondroplasia Occur Exclusively on the Paternally Derived Chromosome

More than 97% of achondroplasia cases are caused by one of two mutations (G1138A and G1138C) in the fibroblast growth factor receptor 3 (FGFR3) gene, which results in a specific amino acid substitution, G380R. Sporadic cases of achondroplasia have been associated with advanced paternal age, suggesting that these mutations occur preferentially during spermatogenesis. We have determined the parental origin of the achondroplasia mutation in 40 sporadic cases. Three distinct 1-bp polymorphisms were identified in the FGFR3 gene, within close proximity to the achondroplasia mutation site. Ninety-nine families, each with a sporadic case of achondroplasia in a child, were analyzed in this study. In this population, the achondroplasia mutation occurred on the paternal chromosome in all 40 cases in which parental origin was unambiguous. This observation is consistent with the clinical observation of advanced paternal age resulting in new cases of achondroplasia and suggests that factors influencing DNA replication or repair during spermatogenesis, but not during oogenesis, may predispose to the occurrence of the G1138 FGFR3 mutations.

Cartilage-hair hypoplasia — clinical manifestations in 108 Finnish patients

Cartilage-hair hypoplasia is an autosomal recessive metaphyseal chondrodysplasia with short-limbed short stature, hypoplastic hair, and defective immunity and erythrogenesis. We have analysed the clinical outcome of 108 Finnish patients. Birth length was below −2.0 SD in 70% of the patients; the adult heights ranged from −11.4 SD to −5.2 SD. The sitting height percentage was increased in all but 4 patients. Six patients had normal hair. Increased ligamentous laxity was present in 95%, limited extension of the elbows in 92%, increased lumbar lordosis in 85%, thoracal deformity in 68%, genu varum in 63% and scoliosis in 21% of the patients. Defective cellular immunity had been observed in 88% and increased susceptibility to infections in 56% of the patients. Six patients had died of primary infections. The incidence of malignancies was 6%. Childhood anaemia had occurred in 79% of the patients. It was usually mild, but severe in 14 patients. Hirschsprung disease had been observed in 8, anal stenosis in 1 and oesophageal atresia in 1 patient. The intrafamilial variation of the syndrome was considerable as studied in 16 sibships.

Mutation analysis of LMX1B gene in nail-patella syndrome patients

Nail-patella syndrome (NPS), a pleiotropic disorder exhibiting autosomal dominant inheritance, has been studied for >100 years. Recent evidence shows that NPS is the result of mutations in the LIM-homeodomain gene LMX1B. To determine whether specific LMX1B mutations are associated with different aspects of the NPS phenotype, we screened a cohort of 41 NPS families for LMX1B mutations. A total of 25 mutations were identified in 37 families. The nature of the mutations supports the hypothesis that NPS is the result of haploinsufficiency for LMX1B. There was no evidence of correlation between aspects of the NPS phenotype and specific mutations.

Quality of life in early adolescence: A sixteendimensional health-related measure (16D)

While data on the health-related quality of life (HRQOL) of adults are accumulating, very little is known about the HRQOL—and especially the perceived HRQOL—of children. In our study we introduced a 16-dimensional, generic self-assessment measure of HRQOL (16D) for early adolescents, and demonstrated its use with four populations of children aged 12–15: (1) 239 normal schoolchildren, (2) patients waiting for organ transplantation (n=5), (3) patients with genetic skeletal dysplasias (n=19), and (4) patients with epilepsy (n=32). The HRQOL profiles of the patients differed significantly according to the diagnosis, giving support to its construct validity. The reliability of the measure was high: its repeatability coefficient was 91%. The quality of life ratings of the healthy boys and their parents differed on the dimensions of distress, vitality, speech, mental function, and discomfort and symptoms (p<0.05). In addition, there were significant differences in the health-related valuations between the girls, boys and their parents. We conclude that the assessment of quality of life of adolescents should be based on data collected from the adolescents themselves. Further, the 16D is so far the only generic HRQOL measure designed specifically for this purpose. It is capable of differentiating the HRQOL of healthy adolescents as well as patients with various diagnoses. Our experience also indicates that it is easy to use, yet it seems comprehensive, reliable, and valid.

Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature.

Abstract Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive spondylo-epiphyseal dysplasia. The characteristic features of SIOD include 1) short stature with hyperpigmented macules and an unusual facies, 2) proteinuria with progressive renal failure, 3) lymphopenia with recurrent infections, and 4) cerebral ischaemia. Although 25 patients have been reported with this disorder, the clinical course and phenotype of SIOD are not well characterized. This report summarizes the clinical findings, course and treatment of reported patients and includes 14 additional patients with SIOD. We emphasize the high incidence of cerebral ischaemia and ocular abnormalities, define the high incidence of thyroid dysfunction and blood cytopenia, and confirm the absence of effective and durable medical therapies. Conclusion Schimke immuno-osseous dysplasia is a multi-system autosomal recessive disorder with variable expression that affects the skeletal, renal, immune, vascular, and haematopoietic systems. Medical therapy is limited especially for more severely affected individuals.

Abnormal copper metabolism and deficient lysyl oxidase activity in a heritable connective tissue disorder.

Biochemical abnormalities were studied in two brothers with bladder divericulas, inguinal hernias, slight skin laxity, and hyperelasticity and skeletal abnormalities including occipital exostoses. Lysyl oxidase activity was low in the medium of cultured skin fibroblasts, this abnormality being accompanied by reduced conversion of the newly synthesized collagen into the soluble form. Copper concentrations were markedly elevated in the cultured skin fibroblasts, but decreased in the serum and hair. Serum cerulophasmin levels were also low. The reduced lysyl oxidase activity is suggested to be responsible for ther clinical manifestations, but the deficiency in this copper-dependent enzyme may be secondary to the abnormalities in the metabolism of the cation. Nevertheless, a mutation directly affecting both lysyl oxidase and an intracellular copper transport protein cannot be excluded. The disease is tentatively classified as one subtype of the Ehlers-Danlos syndrome.

Quality of life in pre-adolescence: a 17-dimensional health-related measure (17D).

Although interest in the health-related quality of life (HRQOL) of children has increased in the last years, validated methods for assessing the HRQOL-and especially the perceived HRQOL—of children have been missing. We introduced a 17-dimensional, illustrated, generic measure of perceived HRQOL (17D) for pre-adolescents, and demonstrated its application to three populations of children aged 8–11 years: (1) 244 normal schoolchildren; (2) 22 patients surviving organ transplantation and (3) 10 patients with genetic skeletal dysplasias. The HRQOL scores and profiles of the patients differed significantly according to the diagnosis, giving support to its construct validity. The reliability of the measure was high: its repeatability coefficient was 95%. As a structured interview of 20–30 minutes, the measurement burden is reasonable. We conclude that the assessment of quality of life of pre-adolescents can and should be based on data collected from the children themselves. Our initial experience indicates that 17D is comprehensive, reliable, and valid.