A Novel Osteochondrodysplasia With Empty Sella Associates With a TBX2 Variant.

Skeletal dysplasias comprise a heterogenous group of developmental disorders of skeletal and cartilaginous tissues. Several different forms have been described and the full spectrum of their clinical manifestations and underlying genetic causes are still incompletely understood. We report a three-generation Finnish family with an unusual, autosomal dominant form of osteochondrodysplasia and an empty sella. Affected individuals (age range 24-44 years) exhibit unusual codfish-shaped vertebrae, severe early-onset and debilitating osteoarthritis and an empty sella without endocrine abnormalities. Clinical characteristics also include mild dysmorphic features, reduced sitting height ratio, and obesity. Whole-exome sequencing excluded known skeletal dysplasias and identified a novel heterozygous missense mutation c.899C>T (p.Thr300Met) in TBX2, confirmed by Sanger sequencing. TBX2 is important for development of the skeleton and the brain and three prior reports have described variations in TBX2 in patients portraying a complex phenotype with vertebral anomalies, craniofacial dysmorphism and endocrine dysfunctions. Our mutation lies near a previously reported disease-causing variant and is predicted pathogenic with deleterious effects on protein function. Our findings expand the current spectrum of skeletal dysplasias, support the association of TBX2 mutations with skeletal dysplasia and suggest a role for TBX2 in development of the spinal and craniofacial structures and the pituitary gland.

Safety of laronidase delivered into the spinal canal for treatment of cervical stenosis in mucopolysaccharidosis I.

Enzyme replacement therapy with laronidase (recombinant human alpha-l-iduronidase) is successfully used to treat patients with mucopolysaccharidosis type I (MPS I). However, the intravenously-administered enzyme is not expected to treat or prevent neurological deterioration. As MPS I patients suffer from spinal cord compression due in part to thickened spinal meninges, we undertook a phase I clinical trial of lumbar intrathecal laronidase in MPS I subjects age 8 years and older with symptomatic (primarily cervical) spinal cord compression. The study faced significant challenges, including a heterogeneous patient population, difficulty recruiting subjects despite an international collaborative effort, and an inability to include a placebo-controlled design due to ethical concerns. Nine serious adverse events occurred in the subjects. All subjects reported improvement in symptomatology and showed improved neurological examinations, but objective outcome measures did not demonstrate change. Despite limitations, we demonstrated the safety of this approach to treating neurological disease due to MPS I.

Common somatic alterations identified in maffucci syndrome by molecular karyotyping.

Maffucci syndrome (MS) is a rare congenital disorder characterized by multiple central cartilaginous tumors (enchondromas) in association with cutaneous spindle cell hemangiomas. These patients have a high incidence of malignant transformation. No familial case is known and the etiopathogenic cause remains unknown. In enchondromatosis (Ollier disease, OD), which is comprised of enchondromas only, 4 mutations in the PTHR1 gene have been identified in 4 patients; 3 were somatic and 1 was germline. No PTHR1 mutations have been detected in MS, whereas somatic IDH1 and, more rarely, IDH2 mutations have been observed in 77% of patients with MS and 81% of patients with OD. These genetic alterations are shared with other tumors, including glioma, leukemia and carcinoma. To search for underlying somatic genomic causes, we screened MS tissues using Affymetrix SNP-chips. We looked for CNVs, LOH and uniparental isodisomy (UPID) by performing pairwise analyses between allelic intensities in tumoral DNA versus the corresponding blood-extracted DNA. While common chromosomal anomalies were absent in constitutional DNA, several shared CNVs were identified in MS-associated tumors. The most frequently encountered somatic alterations were localized in 2p22.3, 2q24.3 and 14q11.2, implicating these chromosomal rearrangements in the formation of enchondromas and spindle cell hemangiomas in MS. In one chondrosarcoma specimen, large amplifications and/or deletions were observed in chromosomes 3, 6, 9, 10, 12, 13, and 19. Some of these genetic changes have been reported in other chondrosarcomas suggesting an etiopathogenic role. No LOH/UPID was observed in any Maffucci tissue. Our findings identify frequent somatic chromosomal rearrangements on 2p22.3, 2q24.3 and 14q11.2, which may unmask mutations leading to the lesions pathognomonic of MS.

Immune response to intrathecal enzyme replacement therapy in mucopolysaccharidosis I patients.

BACKGROUND: Intrathecal (IT) enzyme replacement therapy with recombinant human α-L-iduronidase (rhIDU) has been studied to treat glycosaminoglycan storage in the central nervous system of mucopolysaccharidosis (MPS) I dogs and is currently being studied in MPS I patients. METHODS: We studied the immune response to IT rhIDU in MPS I subjects with spinal cord compression who had been previously treated with intravenous rhIDU. We measured the concentrations of specific antibodies and cytokines in serum and cerebrospinal fluid (CSF) collected before monthly IT rhIDU infusions and compared the serologic findings with clinical adverse event (AE) reports to establish temporal correlations with clinical symptoms. RESULTS: Five MPS I subjects participating in IT rhIDU trials were studied. One subject with symptomatic spinal cord compression had evidence of an inflammatory response with CSF leukocytosis, elevated interleukin-5, and elevated immunoglobulin G. This subject also complained of lower back pain and buttock paresthesias temporally correlated with serologic abnormalities. Clinical symptoms were managed with oral medication, and serologic abnormalities were resolved, although this subject withdrew from the trial to have spinal decompressive surgery. CONCLUSION: IT rhIDU was generally well tolerated in the subjects studied, although one subject had moderate to severe clinical symptoms and serologic abnormalities consistent with an immune response.

Health-related quality of life and socioeconomic situation among diastrophic dysplasia patients in Finland.

OBJECTIVE: The purpose of the present study was to gain a comprehensive view of the quality of life and socio-economic conditions in a more representative sample of patients with diastrophic dysplasia than previously presented. METHODS: The study sample comprised 115 patients with diastrophic dysplasia, aged over 18 years. The patients were contacted, and 68 patients (59%) agreed to participate in the study. They answered a structured questionnaire, which included the items of RAND-36 and Finn-Health Assessment Questionnaire (Finn-HAQ) questionnaires. The Finn-HAQ items were linked to the categories of the International Classification of Functioning, Disability and Health (ICF). Population controls for matching the participating patients for age and sex were identified in the Finnish population registry. Demographic and social factors (educational status, employment status and household income) were collected in separated questions. RESULTS: RAND-36 showed significantly lower physical functioning in the group of diastrophic dysplasia patients than in the control group. Also, the differences in scores for energy and social functioning were significant. In the mental component scales, no significant difference was found between the groups. When compared with the controls, we found significantly lower levels in all 3 ICF components of functioning in the group of patients when Finn-MDHAQ items linked to ICF were used. Almost 75% of patients with diastrophic dysplasia belonged to the group of people with minor/low income. Some or clear worsening of economic situation due to diastrophic dysplasia was reported by 25 (58%) female and 17 (68%) male patients. CONCLUSION: In their daily living, patients with diastrophic dysplasia have marked physical difficulties, which affect their quality of life, participation in society and their financial situation. It seems that the mental situation is not greatly affected, but a more detailed study is needed to evaluate and illuminate the psychological consequences of this severe skeletal dysplasia. Overall, the pieces of information in the present study are of high importance when designing and reorganizing rehabilitation and in supportive therapy and treatment of patients with diastrophic dysplasia.

[Marfan syndrome]. / Marfanin oireyhtymä.

This review on Marfan syndrome is focused on the clinical heterogeneity and variability, the new diagnostic criteria as delineated by an expert group in 2010, the current knowledge on the molecular and pathogenetic etiology, and the options of the medical and surgical treament. Defined clinical findings, family history and mutations in the FBN1 gene only differentiate Marfan syndrome from the other aortic syndromes. The involvement of the cellular TGF-beta-signaling in pathogenesis allows new approach for medical treatment with ATR-blockers for which, however, evidence based indications are still lacking. Finally, a suggestion is made how to arrange the diagnostic workup, appropriate treatment and follow-up of the Marfan patients in the Finnish health care.

Prevalence and natural course of craniocervical junction anomalies during growth in patients with osteogenesis imperfecta.

Pathology in the craniocervical junction is a serious complication of osteogenesis imperfecta (OI). Our aim was to analyze the prevalence and natural course of craniocervical junction anomalies in patients with OI during growth. In a one-center retrospective study, we analyzed lateral skull radiographs and midsagittal magnetic resonance images of 76 patients with either type I, III, or IV OI. The material included longitudinal series of 31 patients. In total, 150 patient images taken at ages 0 to 39 years were analyzed and compared with age-matched control data. Craniocervical anomalies were observed in 37% of patients and in all OI types studied. Of the three types of anomalies, basilar invagination was seen in 13%, basilar impression in 15%, and platybasia in 29% of the patients. From those with an abnormal finding, 44% displayed more than one type of anomaly. At a group level, we found no evidence of progression of craniocervical junction pathology with age. We provide longitudinal and cross-sectional data on craniocervical junction dimensions in growing patients with OI and, based on those, suggest a radiological management strategy for diagnosis of cranial base pathology. A higher risk of having any of the pathological conditions was associated with a lower height Z-score. Careful follow-up of cranial base anomalies particularly in subjects with OI and severe growth failure is warranted.

Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation.

Homozygous inactivating mutations in DMP1 (dentin matrix protein 1), the gene encoding a noncollagenous bone matrix protein expressed in osteoblasts and osteocytes, cause autosomal recessive hypophosphatemia (ARHP). Herein we describe a family with ARHP owing to a novel homozygous DMP1 mutation and provide a detailed description of the associated skeletal dysplasia and carrier phenotype. The two adult patients with ARHP, a 78-year-old man and his 66-year-old sister, have suffered from bone pain and lower extremity varus deformities since early childhood. With increasing age, both patients developed severe joint pain, contractures, and complete immobilization of the spine. Radiographs showed short and deformed long bones, significant cranial hyperostosis, enthesopathies, and calcifications of the paraspinal ligaments. Biochemistries were consistent with hypophosphatemia owing to renal phosphate wasting; markers of bone turnover and serum fibroblast growth factor 23 (FGF-23) levels were increased significantly. Nucleotide sequence analysis of DMP1 revealed a novel homozygous mutation at the splice acceptor junction of exon 6 (IVS5-1G > A). Two heterozygous carriers of the mutation also showed mild hypophosphatemia, and bone biopsy in one of these individuals showed focal areas of osteomalacia. In bone, DMP1 expression was absent in the homozygote but normal in the heterozygote, whereas FGF-23 expression was increased in both subjects but higher in the ARHP patient. The clinical and laboratory observations in this family confirm that DMP1 has an important role in normal skeletal development and mineral homeostasis. The skeletal phenotype in ARHP may be significantly more severe than in other forms of hypophosphatemic rickets.

Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients.

Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (P<0.01). Overall, 20 of 23 sporadic patients with a COL2A1 mutation had either a cleft palate or retinal detachment with vitreous anomalies. The presence of vitreous anomalies, retinal tears or detachments, cleft palate and a positive family history were shown to be good indicators for a COL2A1 defect. In conclusion, we confirm that Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as >90% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome.

Three-generation familial visceral myopathy with alpha-actin-positive inclusion bodies in intestinal smooth muscle.

We report the clinical and histopathologic findings of a family with 7 affected members in 3 generations suffering from autosomal dominant visceral myopathy. All patients presented with chronic intestinal pseudo-obstruction affecting especially the entire small bowel. Histologic abnormalities involved intestinal smooth muscle, with degeneration and fibrosis of the muscularis propria. In addition, the inner circular layer of the muscularis propria contained alpha-smooth muscle actin-positive and, in more advanced disease, also periodic acid-Schiff-positive inclusion bodies. The inclusions were invisible in routine hematoxylin-eosin-stained sections, but were visible in immunohistochemical stainings for alpha-smooth muscle actin. No abnormality was evident in muscularis mucosae or in blood vessels, and the findings remained unidentified in mucosal biopsy specimens. To our knowledge, this is the first reported alpha-actin-positive inclusion body finding in familial visceral myopathy.

Extended follow-up of the Finnish cartilage-hair hypoplasia cohort confirms high incidence of non-Hodgkin lymphoma and basal cell carcinoma.

Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia with short stature, sparse hair and defective cell-mediated immunity. It is caused by mutations in the RMRP (ribonuclease mitochondrial RNA processing) gene, encoding the RNA component of the ribonuclease complex RNase MRP. The aim of this study was to further elucidate the risk and spectrum of cancer in CHH. A cohort of 123 Finnish patients with CHH (51 males) was followed for malignancy through the Finnish Cancer Registry. The number of identified cancers was compared with expected numbers of cancer using population-based data to obtain standardized incidence ratios (SIR). Hospital records were reviewed for clinical data related to the malignancies. During the follow-up (2,365 person-years; mean 19.2 years), 14 cases of cancer were diagnosed in the CHH cohort (expected number 2.0; SIR 7.0, CI 3.8-12). Non-Hodgkin lymphoma was the most frequent cancer type (n = 9; SIR 90.2, CI 39.0-180) followed by squamous cell carcinoma (3), leukemia (1) and Hodgkin lymphoma (1). One tumor was not histologically classified. Nine of the 14 cancers were diagnosed in patients less than 45 years of age. In addition, ten patients had basal cell carcinoma of the skin (expected number 0.3; SIR 33.2, CI 16-61). Patients with CHH have significantly increased risk for developing non-Hodgkin lymphoma or basal cell carcinoma at early age; the overall prognosis is poor. The underlying pathogenetic mechanisms remain to be elucidated in future studies. Careful follow-up, extending beyond pediatric age, is warranted for early diagnosis of malignancies.

Metabolic control and growth during exclusive growth hormone treatment in X-linked hypophosphatemic rickets.

BACKGROUND: GH may improve phosphate balance and height in X-linked hypophosphatemic rickets (XLH). This study evaluated the impact of exclusive rhGH therapy on phosphate homeostasis and growth. METHODS: Ten children (median age 12.2 years) with XLH were included in a 12-month trial with GH. Conventional treatment was discontinued 1 month prior GH (0.033 mg/kg/day); 1alpha-hydroxyvitamin D was added at 6 months and oral phosphate at 12 months, when GH was discontinued. Patients were followed 1-3 monthly until 18 months for clinical, biochemical and radiographic parameters. RESULTS: Serum phosphate Z-score increased significantly from baseline at 6 months (p = 0.005) and 9 months (p = 0.009) but returned to baseline by 12 months. Serum 1,25-dihydroxyvitamin D also increased significantly. Parathyroid function normalized. The median height Z-score was -2.2 (-2.7 to +0.4) at GH onset and -1.7 (-2.3 to +0.3) at 12 months. One patient showed a significant increase in radiographic rickets activity and 3 patients aggravation of lower limb deformity; the others showed no changes or improvement in these parameters. CONCLUSIONS: GH treatment improved serum phosphate and 1,25-dihydroxyvitamin D, normalized parathyroid function and improved longitudinal growth in XLH. It may however aggravate pre-existing skeletal deformities.

Type and level of RMRP functional impairment predicts phenotype in the cartilage hair hypoplasia-anauxetic dysplasia spectrum.

Mutations in the RMRP gene lead to a wide spectrum of autosomal recessive skeletal dysplasias, ranging from the milder phenotypes metaphyseal dysplasia without hypotrichosis and cartilage hair hypoplasia (CHH) to the severe anauxetic dysplasia (AD). This clinical spectrum includes different degrees of short stature, hair hypoplasia, defective erythrogenesis, and immunodeficiency. The RMRP gene encodes the untranslated RNA component of the mitochondrial RNA-processing ribonuclease, RNase MRP. We recently demonstrated that mutations may affect both messenger RNA (mRNA) and ribosomal RNA (rRNA) cleavage and thus cell-cycle regulation and protein synthesis. To investigate the genotype-phenotype correlation, we analyzed the position and the functional effect of 13 mutations in patients with variable features of the CHH-AD spectrum. Those at the end of the spectrum include a novel patient with anauxetic dysplasia who was compound heterozygous for the null mutation g.254_263delCTCAGCGCGG and the mutation g.195C-->T, which was previously described in patients with milder phenotypes. Mapping of nucleotide conservation to the two-dimensional structure of the RMRP gene revealed that disease-causing mutations either affect evolutionarily conserved nucleotides or are likely to alter secondary structure through mispairing in stem regions. In vitro testing of RNase MRP multiprotein-specific mRNA and rRNA cleavage of different mutations revealed a strong correlation between the decrease in rRNA cleavage in ribosomal assembly and the degree of bone dysplasia, whereas reduced mRNA cleavage, and thus cell-cycle impairment, predicts the presence of hair hypoplasia, immunodeficiency, and hematological abnormalities and thus increased cancer risk.

Skull base abnormalities in osteogenesis imperfecta: a cephalometric evaluation of 54 patients and 108 control volunteers.

OBJECT: Osteogenesis imperfecta (OI), which usually results from mutations in type I collagen genes, causes bone fragility and deformities. The head is often abnormally shaped, and changes in skull base anatomy in the form of basilar impression and basilar invagination have been reported. The authors analyzed the skull base anatomy on standardized lateral cephalograms from 54 patients with OI (Types I, III, and IV) and 108 control volunteers. They were surprised to find that the previously used diagnostic measures for basilar abnormality in patients with OI were exceeded in 6.5 to 7.4% of the controls, and hence needed to be reevaluated. METHODS: The authors calculated the distance from the odontoid process to four reference lines, including a novel one, in the controls. The normal mean distances were exceeded by more than two standard deviations (SDs) in 28.3 to 35.2%, and by more than three SDs in 13.2 to 16.6% of the patients with OI. The latter figures reliably reflect the prevalence of basilar impression. As a sign of basilar invagination the odontoid process protruded into the foramen magnum or reached the foramen magnum level in 22.2% of the patients with OI, whereas none of the controls showed this feature. Platybasia (an anterior cranial base angle > 146 degrees) was present in 11.1% of the patients but in none of the controls. CONCLUSIONS: Platybasia, basilar impression, and basilar invagination were often coexpressed, but each was also present as an isolated abnormality. These three abnormalities and wormian bones were predominantly found in OI Types III and IV as well as in patients exhibiting dentinal abnormality.

Growth hormone treatment in 35 prepubertal children with achondroplasia: a five-year dose-response trial.

BACKGROUND: Achondroplasia is a skeletal dysplasia with extreme, disproportionate, short stature. AIM: In a 5-y growth hormone (GH) treatment study including 1 y without treatment, we investigated growth and body proportion response in 35 children with achondroplasia. METHODS: Patients were randomized to either 0.1 IU/kg (n = 18) or 0.2 IU/kg (n = 17) per day. GH treatment was interrupted for 12 mo after 2 y of treatment in prepubertal patients to study catch-down growth. Mean height SDS (HSDS) at start was -5.6 and -5.2 for the low- and high-dose groups, respectively, and mean age 7.3 and 6.6 y. RESULTS: Mean growth velocity (baseline 4.5/4.6 cm/y for the groups) increased significantly by 1.9/3.6 cm/y during the first year and by 0.5/1.5 cm/y during the second year. During the third year, a decrease of growth velocity was observed at 1.9/1.3 cm/y below baseline values. HSDS increased significantly by 0.6/0.8 during the first year of treatment and in total by 1.3/1.6 during the 5 y of study. Sitting height SDS improved significantly from -2.1/-1.7 to -0.8/0.2 during the study. Body proportion (sitting height/total height) or arm span did not show any significant change. CONCLUSION: GH treatment of children with achondroplasia improves height during 4 y of therapy without adverse effect on trunk-leg disproportion. The short-term effect is comparable to that reported in Turner and Noonan syndrome and in idiopathic short stature.

Association of migraine-like headaches with Schimke immuno-osseous dysplasia.

Schimke immuno-osseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia, nephropathy, and T-cell deficiency. SIOD is caused by mutations in the putative chromatin remodeling protein SMARCAL1. We report an 8-year-old boy with SIOD and recurrent, severe, refractory migraine-like headaches. Through a retrospective questionnaire-based study, we found that refractory and severely disabling migraine-like headaches occur in nearly half of SIOD patients. We have also found that the vasodilator minoxidil provided symptomatic relief for one patient. We hypothesize that these headaches may arise from an intrinsic vascular, neuroimmune, or neurovascular defect resulting from loss of SMARCAL1 function.

Craniofacial features in osteogenesis imperfecta: a cephalometric study.

Osteogenesis imperfecta (OI) is a heterogeneous group of connective tissue diseases that mainly manifest as bone fragility and skeletal deformity. In most families it segregates as a dominant trait and results from mutations in type I collagen genes. In this study we analyzed the size and form of the bony structures in heads of 59 consecutive patients with OI types I, III, or IV (Sillence classification), using lateral radiographs. Paired controls were matched for gender and age. The purpose was to obtain baseline information of craniofacial development in OI patients that have not received bisphosphonate treatment. In OI type I we found smaller than normal linear measurements, indicating a general growth deficiency, but no remarkable craniofacial deformity. In OI types III and IV, the growth impairment was pronounced, and the craniofacial form was altered as a result of differential growth deficiency and bending of the skeletal head structures. We found strong support both for an abnormally ventral position of the sella region due to bending of the cranial base, and for a closing mandibular growth rotation. Vertical underdevelopment of the dentoalveolar structures and the condylar process were identified as the main reasons for the relative mandibular prognathism in OI. Despite of the widespread intervention with bisphosphonates, the facial growth impairment will probably remain characteristic for many OI patients, and their orthodontic treatment should be further developed.

Lack of correlation between the type of COL1A1 or COL1A2 mutation and hearing loss in osteogenesis imperfecta patients.

Osteogenesis imperfecta (OI) is caused by mutations in COL1A1 and COL1A2 that code for the alpha1 and alpha2 chains of type I collagen. Phenotypes correlate with the mutation types in that COL1A1 null mutations lead to OI type I, and structural mutations in alpha1(I) or alpha2(I) lead to more severe OI types (II-IV). However, correlative analysis between mutation types and OI associated hearing loss has not been previously performed. A total of 54 Finnish OI patients with previously diagnosed hearing loss or age 35 or more years were analyzed here for mutations in COL1A1 or COL1A2. Altogether 49 mutations were identified, of which 41 were novel. The 49 mutations represented the molecular genetic background of 41.1% of the Finnish OI population. A total of 38 mutations were in COL1A1 and 11 were in COL1A2. Of these, 16 were glycine substitutions and 16 were splicing mutations in alpha1(I) or alpha2(I). In addition, 17 null allele mutations were detected in COL1A1. A total of 32 patients (65.3%) with a mutation had hearing loss. That is slightly more than in our previous population study on Finnish adults with OI (57.9%). The association between the mutation types and OI type was statistically evident. Patients with COL1A1 mutations more frequently had blue scleras than those with COL1A2 mutations. In addition, patients with COL1A2 mutations tended to be shorter than those with COL1A1 mutations. However, no correlation was found between the mutated gene or mutation type and hearing pattern. These results suggest that the basis of hearing loss in OI is complex, and it is a result of multifactorial, still unknown genetic effects.