Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment.

Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present, 17 genetic causes of OI and closely related disorders have been identified and it is expected that more will follow. Unlike most reviews that have been published in the last decade on the genetic causes and biochemical processes leading to OI, this review focuses on the clinical classification of OI and elaborates on the newly proposed OI classification from 2010, which returned to a descriptive and numerical grouping of five OI syndromic groups. The new OI nomenclature and the pre-and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Intravenous pamidronate treatment in children with moderate-to-severe osteogenesis imperfecta started under three years of age.

OBJECTIVE: Evaluate clinical outcome of early cyclic intravenous pamidronate treatment in children with moderate-to-severe osteogenesis imperfecta (OI), commenced before three years of age. METHODS: A retrospective review of 17 patients with moderate-to-severe OI. Development, anthropometry, fracture history, bone mineral density (BMD) and biochemistry were collected at baseline, 12 and 24 months. RESULTS: Four had OI type I, eleven had type III, one OI-FKBP10 type and one OI type V. Mean age at start of pamidronate was 14 ± 11 months. Pamidronate ranged from 6 to 12 mg/kg/year. No adverse reaction apart from fever and vomiting was noted. Long bone fracture decreased from a mean of 10.4/year to 1.2/year after 12 months and 1.4/year after 24 months (p = 0.02). Lumbar spine age- and height-matched BMD Z-scores increased (p < 0.005). Sixteen with vertebral compression fractures at baseline all showed improved vertebral shape (p < 0.001). Concavity index, likewise, improved (p < 0.005). Motor milestones compared to historical data show earlier attainment in rolling over, crawling, pulling to stand and walking independently but not sitting. CONCLUSION: Cyclic intravenous pamidronate, started under 3 years of age in children with moderate-to-severe OI, was well tolerated and associated with an increase in lumbar spine BMD, reduced fracture frequency, vertebral remodelling and attainment of motor milestones at an earlier age.

Homocysteine and erythrocyte sedimentation rate correlate with cerebrovascular disease in fabry disease.

BACKGROUND: Cerebrovascular disease (CVD) is a common clinical problem in Fabry disease; however, expression of this disease manifestation is not uniform and risk factors for its development are not well studied. A number of common CVD risk factors are known in the general population, and these may also play a role in the development of CVD in Fabry disease. AIM: To evaluate the potential associations between various risk factors and CVD in patients with Fabry disease. METHODS AND RESULTS: Thirty-two Fabry disease patients were studied, with 15 having evidence of CVD. T-tests were used to compare the positive and negative CVD groups and logistic regression was used to look for correlations with CVD history. CVD-positive patients were older (49.73 vs. 37.59 years, p<0.001) and had worse renal function (GFR 61.53 vs. 96.61 mL/min/1.73 m(2), p < 0.005), higher homocysteine (17.79 vs. 10.53 µmol/L, p < 0.05) and erythrocyte sedimentation rate (ESR) levels (23.8 vs. 7.64 mm/h, p < 0.001), and elevated Mainz Severity Score Index (MSSI) scores (23.8 vs. 11.8, p < 0.001). Correlations were found between age (odds ratio (OR) 1.11), DTPA glomerular filtration rate (OR 0.95), homocysteine concentration (OR 1.22), ESR (OR 1.16) and the MSSI (OR 1.19) scores with a positive CVD history (all p < 0.05). CONCLUSION: Elevated homocysteine and ESR are independent risk factors for CVD in Fabry disease. This finding adds to our ability to predict those patients with Fabry disease who are at a higher risk of developing CVD, and may be an aid in deciding which patients should have primary CVD prevention therapies.

Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry.

The Fabry Registry is a global observational research platform established to define outcome data on the natural and treated course of this rare disorder. Participating physicians submit structured longitudinal data to a centralized, confidential database. This report describes the baseline demographic and clinical characteristics of the first 1765 patients (54% males (16% aged < 20 years) and 46% females (13% < 20 years)) enrolled in the Fabry Registry. The median ages at symptom onset and diagnosis were 9 and 23 years (males) and 13 and 32 years (females), respectively, indicating diagnostic delays in both sexes. Frequent presenting symptoms in males included neurological pain (62%), skin signs (31%), gastroenterological symptoms (19%), renal signs (unspecified) (17%), and ophthalmological signs (11%). First symptoms in females included neurological pain (41%), gastroenterological symptoms (13%), ophthalmological (12%), and skin signs (12%). For those patients reporting renal progression, the median age at occurrence was 38 years for both sexes, but onset of cerebrovascular and cardiovascular events was later in females (median 43 and 47 years, respectively) than in males (38 and 41 years, respectively). This paper demonstrates that in spite of the considerable burden of disease in both sexes that begins to manifest in childhood or adolescence, the recognition of the underlying diagnosis is delayed by 14 years in males and 19 years in females. The Fabry Registry provides data that can increase awareness of common symptoms in all age groups, as well as insight into treated and untreated disease course, leading to improved recognition and earlier treatment, and possibly to improved outcomes for affected individuals.

Cyclic bisphosphonate therapy in osteogenesis imperfecta type V.

The clinical and radiographic features and management of a young person with recently delineated Osteogenesis Imperfecta Type V is described. A female aged 9 years presented with a history of multiple fractures since 3 years of age and bilateral dislocation of the elbows from infancy. She was commenced on a low dose frequent regimen of cyclic intravenous pamidronate, which resulted in progressive improvement in bone density, reduced fracture frequency and remission of symptoms of osteoporosis.

Desbuquois syndrome: clinical and radiological report of the first two Chinese cases from a consanguineous family.

Two siblings from China have been observed with severe short stature of prenatal onset and developmental delay. The radiographic features were characteristic of Desbuquois syndrome. The association of a genetic skeletal dysplasia and developmental delay is a relatively rare combination, although this syndrome is readily diagnosable from its distinctive radiographic features.

Opalescent dentine in two affected siblings.

This report describes the dental findings and management of siblings in a family in which three generations had been affected by osteogenesis imperfecta Type IV with opalescent dentine. Hereditary opalescent dentine, or opalescent teeth, is a pathologic dental condition characterised by a disturbance of dentine formation that occurs concurrently with osteogenesis imperfecta. Osteogenesis imperfecta is a genetically heterogenous group of systemic disorders of the connective tissue. The two siblings affected with opalescent dentine were treated under general anaesthesia, and included stainless steel crowns, extractions, and strip crowns on primary teeth. These reports highlight that appropriate treatment of the dentition of young patients with opalescent dentine should be carried out early in the primary dentition, and that this initial treatment can have long-term benefits in the mixed and permanent dentitions.

Lethal prenatal onset infantile cortical hyperostosis (Caffey disease).

We describe a sporadic case of lethal prenatal onset infantile cortical hyperostosis (Caffey disease), which resulted in early postnatal death at 30 weeks gestation. The mother presented with antepartum haemorrhage and preterm labour. She was found to have polyhydramnios. The infant showed extensive symmetrical diaphyseal subperiosteal cortical thickening throughout the skeleton with short extremities. Hepatomegaly and lung hypoplasia were present. Currently, in the absence of a specific marker, diagnostic ultrasound offers the only prospect of prenatal diagnosis. This diagnosis should be considered in infants with short angulated long bones, where the diaphyses are irregular and echodense, and where there is no sign of fractures.

Spondylometaphyseal dysplasia Sedaghatian type associated with lethal arrhythmia and normal intrauterine growth in three siblings.

Spondylometaphyseal dysplasia of the Sedaghatian type is a rare dysplasia, characterized by mild limb shortening, but lethal in the neonatal period. We describe three affected male siblings, the offspring of consanguineous parents. One was stillborn. Neonatal death was due to cardiac arrhythmia in two of the siblings. This report confirms the importance of cardiac pathology in this probably autosomal recessive disorder. This diagnosis should be excluded in any newborn with an arrhythmia as the clinical limb shortening may not be obvious.

Segregation of mutations in arylsulphatase E and correlation with the clinical presentation of chondrodysplasia punctata.

Sixteen males and two females with symmetrical (mild) type of chondrodysplasia punctata were tested for mutations in the X chromosome located arylsulphatase D and E genes. We identified one nonsense and two missense mutations in the arylsulphatase E gene in three males. No mutations were detected in the arylsulphatase D gene. Family studies showed segregation of the mutant genes establishing X linked inheritance for these families. Asymptomatic females and males were found in these studies. The clinical presentation varies not only between unrelated affected males, but also between affected males within the same family. We also conclude that clinical diagnosis of chondrodysplasia punctata in adults can be difficult. Finally, our results indicate that brachytelephalangy is not necessarily a feature of X linked symmetrical chondrodysplasia punctata.

A nonsense mutation in the carboxyl-terminal domain of type X collagen causes haploinsufficiency in schmid metaphyseal chondrodysplasia.

Type X collagen is a short-chain homotrimeric collagen expressed in the hypertrophic zone of calcifying cartilage. The clustering of mutations in the carboxyl-terminal NC1 domain in Schmid metaphyseal chondrodysplasia (SMCD) suggested a critical role for this type X collagen domain, but since no direct analysis of cartilage has been conducted in SMCD patients, the mechanisms of type X collagen dysfunction remain controversial. To resolve this problem, we obtained SMCD growth plate cartilage, determined the type X collagen mutation, and analyzed the expression of mutant and normal type X collagen mRNA and protein. The mutation was a single nucleotide substitution that changed the Tyr632 codon (TAC) to a stop codon (TAA). However, analysis of the expression of the normal and mutant allele transcripts in growth plate cartilage by reverse transcription PCR, restriction enzyme mapping, and a single nucleotide primer extension assay, demonstrated that only normal mRNA was present. The lack of mutant mRNA is most likely the result of nonsense-mediated mRNA decay, a common fate for transcripts carrying premature termination mutations. Furthermore, no mutant protein was detected by immunoblotting cartilage extracts. Our data indicates that a functionally null allele leading to type X collagen haploinsufficiency is the molecular basis of SMCD in this patient.

Abnormal compartmentalization of cartilage matrix components in mice lacking collagen X: implications for function.

There are conflicting views on whether collagen X is a purely structural molecule, or regulates bone mineralization during endochondral ossification. Mutations in the human collagen alpha1 (X) gene (COL10A1) in Schmid metaphyseal chondrodysplasia (SMCD) suggest a supportive role. But mouse collagen alpha1 (X) gene (Col10a1) null mutants were previously reported to show no obvious phenotypic change. We have generated collagen X deficient mice, which shows that deficiency does have phenotypic consequences which partly resemble SMCD, such as abnormal trabecular bone architecture. In particular, the mutant mice develop coxa vara, a phenotypic change common in human SMCD. Other consequences of the mutation are reduction in thickness of growth plate resting zone and articular cartilage, altered bone content, and atypical distribution of matrix components within growth plate cartilage. We propose that collagen X plays a role in the normal distribution of matrix vesicles and proteoglycans within the growth plate matrix. Collagen X deficiency impacts on the supporting properties of the growth plate and the mineralization process, resulting in abnormal trabecular bone. This hypothesis would accommodate the previously conflicting views of the function of collagen X and of the molecular pathogenesis of SMCD.

The phenotypic features of osteogenesis imperfecta resulting from a mutation of the carboxyl-terminal pro alpha 1 (I) propeptide that impairs the assembly of type I procollagen and formation of the extracellular matrix.

The features of a baby with lethal perinatal osteogenesis imperfecta (OI-II), resulting from the substitution of tryptophan 94 by cysteine in the carboxyl-terminal propeptide of pro alpha 1 (I) chains of type I procollagen, were studied. The limbs and torso were of normal length, shape, and proportion. Similarly, all bones were of relatively normal shape and the long bones showed normal metaphyseal modelling. These clinical and radiographic features were similar to those observed in another baby with OI-II resulting from a mutation of the carboxy-terminal propeptide of pro alpha 1 (I) chains but dissimilar from those reported in babies with OI-II resulting from helical mutations of type I collagen.

A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal.

Mutations in the gene SOX9 result in the syndrome of campomelic dysplasia (CD) which includes sex-reversal in 75% of 46,XY affected individuals. These mutations only affect a single allele of SOX9 suggesting a dominant mode of inheritance for this syndrome. Consequently, CD and autosomal sex reversal may result from haploinsufficiency of SOX9. The SOX9 gene maps to the long arm of human chromosome 17 and translocations in this region also result in CD. We report a family in which there were three affected patients, two of whom showed 46,XY sex-reversal. Interestingly, despite all three patients being heterozygous for a familial mutation in SOX9 (Insertion of a cytosine residue at nucleotide position 1096), their gonadal phenotypes varied widely. The proband was found to have 46,XY true hermaphroditism with ambiguous genitalia. The other two sibs were 46,XY and 46,XX, and both had bilateral ovaries with normal female genitalia. The somatic cells in both parents revealed wild-type SOX9 nucleotide sequences. However, mutational analysis of the SOX9 gene in the father's germ cells revealed they were mosaic for mutant and wild-type sequences. This family is particularly informative as it demonstrates that the same SOX9 mutation can produce very different 46,XY gonadal phenotypes. The range of gonadal morphologies observed may be explained by several possible mechanisms such as variable penetrance of the mutation, increased activity of the non-mutant SOX9 allele or stochastic environmental factors. These results also demonstrate that paternal germ cell mosaicism of a mutant SOX9 sequence can result in a CD phenotype amongst his offspring.

The Wolf-Hirschhorn syndrome in adulthood: evaluation of a 24-year-old man with a rec(4) chromosome.

We described a profoundly intellectually disabled 24-year-old man with Wolf-Hirschhorn syndrome, left hemiplegia, epilepsy, atrophy of the right cerebral hemisphere, and dilatation of the right ventricle. The patient had a small ventricular septal defect, was wheelchair bound, and totally dependent. He had no speech, but vocalised to show his feelings. In this patient, the del(4)(p15) was subtle and arose due to the inheritance of a recombinant chromosome (4) from a maternal pericentric inversion-46,XX,inv(4) (p15.32q35). Fluorescence in situ hybridisation with probe D4S96 confirmed the deletion. This is the second case of Wolf-Hirschhorn syndrome resulting from a large pericentric inversion of chromosome 4.

Multiexon deletions in the type I collagen COL1A2 gene in osteogenesis imperfecta type IB. Molecules containing the shortened alpha2(I) chains show differential incorporation into the bone and skin extracellular matrix.

Osteogenesis imperfecta (OI) type IB is a rare subset of the mildest form of OI, clinically characterized by moderate bone fragility, blue sclera, and dentinogenesis imperfecta. Cultured skin fibroblasts from two unrelated individuals (OI-197 and OI-165) with the typical features of OI type IB produced shortened alpha2(I) chains. Reverse transcription-polymerase chain reaction of the alpha2(I)-cDNA revealed deletions in the triple helical domain of 5 exons (exons 7-11) in OI-197, and 8 exons (exons 10-17) in OI-165. This exon skipping was caused by genomic deletions in one allele of COL1A2 with the breakpoints located in introns 6 and 11 in OI-197, and introns 9 and 17 in OI-165. The secretion and deposition of the mutant collagen into the matrix was measured in vitro in cultures of skin fibroblasts and bone osteoblasts, grown in the presence of ascorbic acid to induce collagen matrix formation and maturation, as well as in collagen extracts from skin and bone. The secretion of mutant collagen was impaired and long term cultures of fibroblasts showed that the mutant collagen was not incorporated into the mature collagenous matrix produced in vitro by skin fibroblasts from both patients. Likewise, the shortened alpha2(I) chain was not demonstrable in skin extracts. In contrast, bone extracts from OI-197 showed the presence of the mutant collagen. This incorporation of the abnormal collagen into the mature matrix was also demonstrated in long term cultures of the patient's osteoblasts. The deposition of the mutant collagen by bone osteoblasts but not by skin fibroblasts demonstrates a tissue specificity in the incorporation of mutant collagen into the matrix which may explain the primary involvement of bone and not skin in these patients.

Abnormalities of the spine in Goldenhar's syndrome.

The vertebral abnormalities present in 35 patients diagnosed with Goldenhar's syndrome are reported. There was no absolute correlation between the presence of any of the formative or segmentation vertebral defects and that of other concomitant malformations. This study supports the conclusion that patients with various groupings of Goldenhar-related anomalies should be considered as a single entity, to which the name Goldenhar association could be applied.

Overnight growth hormone secretion in achondroplasia: deconvolution analysis, correlation with sleep state, and changes after treatment of obstructive sleep apnea.

The normal profile for overnight GH secretion in achondroplasia has not been previously studied. Factors that have been shown to influence GH secretion include age, obesity, sleep state, and the presence of obstructive sleep apnea (OSA). We assessed GH levels in a group of subjects with achondroplasia, during overnight polysomnography. Nineteen subjects with achondroplasia were studied at 11.3 y of age (median 6.7, range 1.8-30.9). Levels of GH were measured using time-resolved immunofluorometric assay (DELFIA, Pharmacia Biotech Inc.) and analyzed by a deconvolution method. Five subjects were restudied after treatment for OSA. Secretion rates of GH were greater in slow wave (SWS) and rapid eye movement (REM) sleep than in stage one and two (SI-II = light non-REM) sleep (p < 0.01). Total overnight GH secretion decreased with increasing age (r2 = 0.22 p < 0.04). Neither the frequency of arousals, frequency of sleep state transitions nor the severity of OSA correlated with measures of GH secretion. Levels of IGF-I correlated independently with age, body weight (percent ideal), and GH secretion rate (r2 = 0.76, p < 0.001). In a group of five subjects treated for OSA, improved respiratory distress index and reduced sleep state transitions were not associated with significant changes in GH secretion rate by sleep stage; SWS [from 0.62 +/- 0.28 mIU/L/min to 1.02 +/- 0.25 mIU/L/min (NS)] and SI-II sleep [from 0.26 +/- 0.07 mIU/L/min to 0.60 +/- 0.16 mIU/L/min (NS)]. However, in those five subjects, a GH secretion peak during the first 2 h of SWS was initially absent, appearing only after treatment of OSA (1.09 +/- 0.38 mIU/L/min) compared with (2.40 +/- 0.59 mIU/L/min (p = 0.01). A profile of overnight GH secretion is presented for subjects with achondroplasia.

Treatment of obstructive sleep apnea in achondroplasia: evaluation of sleep, breathing, and somatosensory-evoked potentials.

The occurrence of obstructive sleep apnea (OSA) is achondroplasia has been linked to brain stem compression. Overnight sleep studies (11 subjects) and somatosensory-evoked potentials (SEP's, 10 subjects) were recorded before and after conventional treatment of OSA in achondroplasia. The two groups were derived from 30 subjects who underwent diagnostic sleep studies and SEPs, including 15 females and 15 males with a median age 6.6 years (range 1.0-47.6) at the time of the first study. In 30 initial studies there was no correlation between severity of OSA and abnormalities on SEP evaluation. Treatment of 17 subjects included adenotonsillectomy (n = 3), weight loss (n = 1), and nasal-mask continuous positive airway pressure (CPAP) (n = 13). Sleep studies in 11 subjects after a delay of 8.8 +/- 2.8 months showed a reduction in respiratory disturbance index (RDI) from 38.4 +/- 6.9 to 6.5 +/- 1.8 events hr(-1) (p < 0.001) and movements/arousals fell from 10.4 +/- 2.2 to 4.8 +/- 0.2 hr(-1) (p < 0.04). Obstructive events were reduced from 33.7 +/- 6.9 to 2.4 +/- 1.0 hr(-1) (p < 0.001). Improvement of respiratory indices was associated with an increased proportion of slow-wave sleep from 25.2 +/- 4.0% to 32.3 +/- 2.4% (p = 0.01), and decrease in stage 1-2 sleep from 59.3 +/- 5.8% to 46.6 +/- 1.9% (p = 0.03). There was no increase in the percentage of REM sleep (15.2 to 21.2%). Repeat SEP studies in 10 subjects, after clinically effective treatment of OSA, showed improvement of SEP score of at least 1 grade, in 5 of 7 (71%) with initially abnormal values. We conclude that treatment of relieve upper airway obstruction improves OSA in achondroplasia, accompanied by changes in sleep structure and, in some cases, improved studies of neurological function.