Integrated analysis of COL2A1 variant data and classification of type II collagenopathies.

The COL2A1 gene encodes the alpha-1 chain of type II procollagen. Type II collagen, comprised of three identical alpha-1 chains, is the major component of cartilage. COL2A1 gene variants are the etiologies of genetic diseases, termed type II collagenopathies, with a wide spectrum of clinical presentations. To date, at least 460 distinct COL2A1 mutations, identified in 663 independent probands, and 21 definite disorders have been reported. Nevertheless, a well-defined genotype-phenotype correlation has not been established, and few hot spots of mutation have been reported. In this study, we analyzed data of COL2A1 variants and clinical information of patients obtained from the Leiden Open Variation Database 3.0, as well as the currently available relevant literature. We determined the characteristics of the COL2A1 variants and distributions of the clinical manifestations in patients, and identified four likely genotype-phenotype correlations. Moreover, we classified 21 COL2A1-related disorders into five categories, which may assist clinicians in understanding the essence of these complex phenotypes and prompt genetic screening in clinical practice.

Sanjad-Sakati Syndrome: Oral Health Care.

OBJECTIVES: The aim of this report is to describe the orofacial manifestations and dental management of a girl with Sanjad-Sakati syndrome. CLINICAL PRESENTATION AND INTERVENTION: The facial features included microcephaly, thin lips, beaked nose, low set ears, and a retrognathic mandible. An oral examination revealed oligodontia/hypodontia, small dental arches, a high arched palate, and a deep overbite and increased overjet. Oral rehabilitation involved full coverage prosthetic crowns on the upper central incisors, stainless steel crowns on the lower molars, and removable partial prostheses to replace missing teeth. CONCLUSION: Recognition of orofacial features might help in the diagnosis of Sanjad-Sakati syndrome. Dental management of affected patients might be complicated by intellectual, neurological, and endocrine abnormalities.

Skull Base and Cervical Spine Involvement in Jansen Syndrome: Case Report.

INTRODUCTION: Metaphyseal chondrodysplasia, Jansen type (JMD), is a rare form of endochondral ossification resulting in short limbs and dwarfism. CASE REPORT: A child presented with JMD and was found to have involvement of the cervical spine. Conservative treatment was given to the patient who at the long-term follow-up continues to have no neurological findings or cervical spine instability. CONCLUSIONS: To our knowledge, this case represents the first report of involvement of the superior cervical spine in a patient with JMD. Clinicians should be aware of this potential albeit rare finding.

IMAGe and Related Undergrowth Syndromes: The Complex Spectrum of Gain-of-Function CDKN1C Mutations.

CDKN1C is a cyclin-dependent kinase Inhibitor and negative regulator of cellular proliferation. Recently, gain-of-function mutations in the PCNA domain of CDKN1C have been reported as the genetic basis of various growth-retarded syndromes including IMAGe syndrome, Russell Silver syndrome as well as a novel undergrowth syndrome that additionally exhibited early adulthood onset diabetes. This review summarizes the key clinical features and the molecular advances that have contributed to our understanding of this complex phenotypic spectrum.

A Review and Proposed Approach to the Neutrophilic Dermatoses of Childhood.

Neutrophilic dermatoses (NDs) are inflammatory skin conditions that are not associated with infection. The classification and clinical approach to these conditions in children is poorly described. This review classifies these conditions into five nosological subtypes: Sweet's syndrome, pyoderma gangrenosum, aseptic pustules, neutrophilic urticarial dermatoses, and Marshall's syndrome. In addition, we review the various secondary diseases that need to be excluded in the clinical management of the NDs of childhood, with a focus on the autoinflammatory conditions that the reader may not be familiar with. We propose a practical clinical approach to these disorders.

Dominant mutations in the type II collagen gene, COL2A1, produce spondyloepimetaphyseal dysplasia, Strudwick type.

The chondrodysplasias are a heterogeneous group of disorders characterized by abnormal growth or development of cartilage. Current classification is based on mode of inheritance as well as clinical, histologic, and/or radiographic features. A clinical spectrum of chondrodysplasia phenotypes, ranging from mild to perinatal lethal, is due to defects in the gene for type II collagen, COL2A1. This spectrum includes Stickler syndrome, Kniest dysplasia, spondyloepiphyseal dysplasia congenita (SEDC), achondrogenesis type II, and hypochondrogenesis. Individuals affected with these disorders exhibit abnormalities of the growth plate, nucleus pulposus, and vitreous humor, which are tissues that contain type II collagen. The Strudwick type of spondyloepimetaphyseal dysplasia (SEMD) is characterized by disproportionate short stature, pectus carinatum, and scoliosis, as well as dappled metaphyses (which are not seen in SEDC). The phenotype was first described by Murdoch and Walker in 1969, and a series of 14 patients was later reported by Anderson et al. The observation of two affected sibs born to unaffected parents led to the classification of SEMD Strudwick as an autosomal recessive disorder. We now describe the biochemical characterization of defects in alpha 1(II) collagen in three unrelated individuals with SEMD Strudwick, each of which is due to heterozygosity for a unique mutation in COL2A1. Our data support the hypothesis that some cases, if not all cases, of this distinctive chondrodysplasia result from dominant mutations in COL2A1, thus expanding the clinical spectrum of phenotypes associated with this gene.

Kniest and Stickler dysplasia phenotypes caused by collagen type II gene (COL2A1) defect.

Kniest and Stickler dysplasia are two chondrodysplasias characterized by specific phenotypes. No basic defect has been found in patients with Kniest dysplasia, whereas Stickler dysplasia is one of four chondrodysplasias for which mutations of type II procollagen gene (COL2A1) have been identified. We studied a 2-year-old girl presenting with manifestations of Kniest dysplasia and her mother showing a Stickler phenotype. Analysing COL2A1 in both patients, we detected the same 28 basepair deletion spanning the 3'-exon/intron boundary of exon 12 in mother and daughter. We were able to prove a somatic mosaic status for this mutation in the mother which accounts for her milder Stickler-like phenotype.

Inactivating PTH/PTHrP signaling disorders (iPPSDs): evaluation of the new classification in a multicenter large series of 544 molecularly characterized patients.

OBJECTIVE: Pseudohypoparathyroidism and related disorders belong to a group of heterogeneous rare diseases that share an impaired signaling downstream of Gsα-protein-coupled receptors. Affected patients may present with various combination of symptoms including resistance to PTH and/or to other hormones, ectopic ossifications, brachydactyly type E, early onset obesity, short stature and cognitive difficulties. Several years ago we proposed a novel nomenclature under the term of inactivating PTH/PTHrP signaling disorders (iPPSD). It is now of utmost importance to validate these criteria and/or improve the basis of this new classification. DESIGN: Retrospective study of a large international series of 459 probands and 85 relatives molecularly characterized. METHODS: Information on major and minor criteria associated with iPPSD and genetic results were retrieved from patient files. We compared the presence of each criteria according to the iPPSD subtype, age and gender of the patients. RESULTS: More than 98% of the probands met the proposed criteria for iPPSD classification. Noteworthy, most patients (85%) presented a combination of symptoms rather than a single sign suggestive of iPPSD and the overlap among the different genetic forms of iPPSD was confirmed. The clinical and molecular characterization of relatives identified familial history as an additional important criterion predictive of the disease. CONCLUSIONS: The phenotypic analysis of this large cohort confirmed the utility of the major and minor criteria and their combination to diagnose iPPSD. This report shows the importance of having simple and easily recognizable signs to diagnose with confidence these rare disorders and supports a better management of patients.

The Erlenmeyer flask bone deformity in the skeletal dysplasias.

Erlenmeyer flask bone deformity (EFD) is a long-standing term used to describe a specific abnormality of the distal femora. The deformity consists of lack of modeling of the di-metaphysis with abnormal cortical thinning and lack of the concave di-metaphyseal curve resulting in an Erlenmeyer flask-like appearance. Utilizing a literature review and cohort study of 12 disorders we found 20 distinct disorders were associated with EFD. We interrogated the International Skeletal Dysplasia Registry (ISDR) radiographic database (1988-2007) to determine which skeletal dysplasias or syndromes were highly associated with EFD, whether it was a uniform finding in these disorders, and if forms of EFD could be differentiated. EFD was classified into three groups. The first catogory was the typical EFD shaped bone (EFD-T) resultant from absent normal di-metaphyseal modeling with relatively normal appearing radiographic trabecular bone. EFD-T was identified in: frontometaphyseal dysplasia, craniometaphyseal dysplasia, craniodiaphyseal dysplasia, diaphyseal dysplasia-Engelmann type, metaphyseal dysplasia-Pyle type, Melnick-Needles osteodysplasty, and otopalatodigital syndrome type I. The second group was the atypical type (EFD-A) due to absence of normal di-metaphyseal modeling with abnormal radiographic appearance of trabecular bone and was seen in dysosteosclerosis and osteopetrosis. The third group was EFD-marrow expansion type (EFD-ME) in which bone marrow hyperplasia or infiltration leads to abnormal modeling (e.g., Gaucher disease). Further, radiographic review determined that it was not always a consistent finding and that there was variability in both appearance and location within the skeleton. This analysis and classification aided in differentiating disorders with the finding of EFD.

Articular Cartilage Lesion Characteristic Reporting Is Highly Variable in Clinical Outcomes Studies of the Knee.

OBJECTIVE: The purpose of this study was to investigate the degree of standardized evaluation and reporting of cartilage lesion characteristics in high-impact clinical studies for symptomatic lesions of the knee. We hypothesized that there are significant inconsistencies in reporting these metrics across orthopedic literature. DESIGN: A total of 113 clinical studies on articular cartilage restoration of the knee were identified from 6 high-impact orthopedic journals between 2011 and 2016. Full-text review was used to evaluate sources for details on study methodology and reporting on the following variables: primary procedure, location, size, grade, and morphology of cartilage lesions. RESULTS: All studies reported on the type of primary cartilage procedure and precise lesion location(s). Approximately 99.1% reported lesion morphology (chondral, osteochondral, mixed). For lesion size, 32.7% of articles did not report how size was measured and 11.5% did not report units. The lesion sizing method was variable, as 27.4% used preoperative magnetic resonance imaging to measure/report lesion size, 31.0% used arthroscopy, and 8.8% used both. The majority of studies (83.2%) used area to report size, and 5.3% used diameter. Formal grading was not reported in 17.7% of studies. Only 54.8% of studies reported depth when sizing osteochondral defects. CONCLUSIONS: Recent literature on cartilage restoration provides adequate information on surgical technique, lesion location, and morphology. However, there is wide variation and incomplete reporting on lesion size, depth, and grading. Future clinical studies should include these important data in a consistent manner to facilitate comparison among surgical techniques.

Inactivating PTH/PTHrP Signaling Disorders.

Pseudohypoparathyroidism (PHP), pseudo-PHP, acrodysostosis, and progressive osseous heteroplasia are heterogeneous disorders characterized by physical findings, differently associated in each subtype, including short bones, short stature, a stocky build, ectopic ossifications (features associated with Albright's hereditary osteodystrophy), as well as laboratory abnormalities consistent with hormone resistance, such as hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) and thyroid-stimulating hormone levels. All these disorders are caused by impairments in the cAMP-mediated signal transduction pathway and, in particular, in the PTH/PTHrP signaling pathway: the main subtypes of PHP and related disorders are caused by de novo or autosomal dominantly inherited inactivating genetic mutations, and/or epigenetic, sporadic, or genetic-based alterations within or upstream of GNAS, PRKAR1A, PDE4D, and PDE3A. Here we will review the impressive progress that has been made over the past 30 years on the pathophysiology of these diseases and will describe the recently proposed novel nomenclature and classification. The new term "inactivating PTH/PTHrP signaling disorder," iPPSD: (1) defines the common mechanism responsible for all diseases, (2) does not require a confirmed genetic defect, (3) avoids ambiguous terms like "pseudo," and (4) eliminates the clinical or molecular overlap between diseases.

Expanding the phenotype of SPONASTRIME dysplasia to include short dental roots, hypogammaglobulinemia, and cataracts.

SPONASTRIME dysplasia (SD) is an autosomal recessive skeletal dysplasia of the spondyloepimetaphyseal dysplasia (SEMD) type. The name was derived from "spondylar and nasal alterations with striated metaphyses" [Fanconi et al. 1983; Helv Paediat Acta 38: 267-280]. We follow two previously reported patients with SD [Patients 3, 4 in Langer et al. 1996; Am J Med Genet 63: 20-27]. Since the original publication, additional findings were identified in these patients.

A multiplex family with possible metaphyseal Spahr-type dysplasia and exclusion of RMRP and COL10A1 as candidate genes.

We report a consanguineous Lebanese family where six individuals had disproportionate short stature, short limbs, and bilateral genu varum that were apparent after 2 years of age. Major radiographic features in infancy included flared, cupped, and ragged metaphyses of all long bones, delayed maturation of the scaphoid, trapezoid, and trapezium bones, wide and slightly irregular ribs, short femoral necks, flat femoral heads, and irregularity of the iliac crest. Radiographs of an affected adult showed diminished metaphyseal changes and slightly short femoral necks, when compared to the younger patients. We suggest that this family is affected with the Spahr type of metaphyseal chondrodysplasia. Sequencing of RMRP, and a haplotype analysis using highly informative markers around the COL10A1 excluded both genes from being pathogenic in this family. We are aware of only two previous reports of families with clinical features similar to the Spahr type of metaphyseal chondrodysplasia.

The Shwachman-Bodian-Diamond syndrome gene mutations cause a neonatal form of spondylometaphysial dysplasia (SMD) resembling SMD Sedaghatian type.

The Shwachman-Bodian-Diamond syndrome (SBDS) gene is a causative gene for Shwachman-Diamond syndrome, an autosomal recessive disorder with exocrine pancreatic insufficiency, bone marrow dysfunction and skeletal dysplasia. We report here on two patients with skeletal manifestations at the severest end of the phenotypic spectrum of SBDS mutations. An 11-year-old Japanese girl presented with neonatal respiratory failure necessitating lifelong ventilation support, severe short stature and severe developmental delay. She developed neutropenia in infancy, and decreased serum amylase was noted in childhood. A British boy was a stillbirth with pulmonary hypoplasia and hepatic fibrosis found on autopsy. Both cases had neonatal skeletal manifestations that included platyspondyly, lacy iliac crests and severe metaphysial dysplasia, and thus did not fall in the range of the known Shwachman-Diamond syndrome skeletal phenotype but resembled spondylometaphysial dysplasia (SMD) Sedaghatian type. The girl harboured a recurrent mutation (183TA-->CT) and a novel missense mutation (79T-->C), whereas the boy carried two recurrent mutations (183TA-->CT and 258+2T-->C). We also examined SBDS in one typical case with SMD Sedaghantian type and eight additional cases with neonatal SMD, but failed to discover SBDS mutations. Our experience expands the phenotypic spectrum of SBDS mutations, which, at its severest end, results in severe neonatal SMD.

The skeletal dysplasias: clinical-molecular correlations.

The skeletal dysplasias or osteochondrodysplasias are a clinically and genetically heterogeneous group of disorders of bone and/or cartilage. They are characterized by abnormalities in pattering, linear growth, differentiation, and maintenance of the human skeleton. While they have been considered to be generalized disorders of endochondral and/or membranous ossification, the extent of their clinical and molecular heterogeneity is still being elucidated. In the 2006 revision of the International Nosology and Classification of Genetic Skeletal Disorders, 372 different conditions were listed in 37 groups defined by such molecular, biochemical, and/or radiographic criteria. The evaluation of patients with chondrodysplasias mandates a multidisciplinary approach involving clinical geneticists, radiologists, molecular biologists, and biochemical geneticists for diagnosis, and a host of surgical specialists for management of their many complications. Our International Skeletal Dysplasia Registry is a worldwide referral center for the skeletal dysplasias, and we have received cases from over 3000 physicians from 50 different countries and have been involved in the identification of the molecular defect in over 40 disorders involving over 25 different genes. Instructions on accessing the Registry, using the diagnostic services provided and contributing cases for collaborative research can be found at http://www.csmc.edu/skeletaldysplasia.

From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network.

OBJECTIVE: Disorders caused by impairments in the parathyroid hormone (PTH) signalling pathway are historically classified under the term pseudohypoparathyroidism (PHP), which encompasses rare, related and highly heterogeneous diseases with demonstrated (epi)genetic causes. The actual classification is based on the presence or absence of specific clinical and biochemical signs together with an in vivo response to exogenous PTH and the results of an in vitro assay to measure Gsa protein activity. However, this classification disregards other related diseases such as acrodysostosis (ACRDYS) or progressive osseous heteroplasia (POH), as well as recent findings of clinical and genetic/epigenetic background of the different subtypes. Therefore, the EuroPHP network decided to develop a new classification that encompasses all disorders with impairments in PTH and/or PTHrP cAMP-mediated pathway. DESIGN AND METHODS: Extensive review of the literature was performed. Several meetings were organised to discuss about a new, more effective and accurate way to describe disorders caused by abnormalities of the PTH/PTHrP signalling pathway. RESULTS AND CONCLUSIONS: After determining the major and minor criteria to be considered for the diagnosis of these disorders, we proposed to group them under the term 'inactivating PTH/PTHrP signalling disorder' (iPPSD). This terminology: (i) defines the common mechanism responsible for all diseases; (ii) does not require a confirmed genetic defect; (iii) avoids ambiguous terms like 'pseudo' and (iv) eliminates the clinical or molecular overlap between diseases. We believe that the use of this nomenclature and classification will facilitate the development of rationale and comprehensive international guidelines for the diagnosis and treatment of iPPSDs.

International nosology and classification of constitutional disorders of bone (2001).

The last International Classification of Constitutional Disorders of Bone was published in 1998. Since then rapid advances have been made in identifying the molecular changes responsible for defined conditions and new disorders are constantly being delineated. For these reasons a further update on the classification is appropriate. It has been expended to not only the osteochondrodysplasias (33 groups) but also genetically determined dysostoses (3 groups).

A rare form of spondylometaphyseal dysplasia-type A4.

We present 2 cases of a previously apparently unreported spondylo-metaphyseal dysplasia comprising dwarfism, severe metaphyseal changes, ovoid vertebrae and mild platyspondyly with anterior tonguing of the vertebral bodies. The inheritance may be autosomal recessive.

Spondylo-metaphyseal dysplasia Algerian type: confirmation of a new syndrome.

We report on a further case of a recently described type of spondylo-metaphyseal dysplasia in a 12(10/12)-year-old Polish boy. The original paper described the disorder in five relatives in an Algerian family.

Melnick-Needles syndrome in males: a lethal multiple congenital anomalies syndrome.

A male fetus with decreased calvarial mineralization and suspected omphalocele was identified prenatally in a woman with oligohydramnios and Melnick-Needles syndrome (MNS). At autopsy, exophthalmos, prune belly sequence with urethal atresia and megacystis, tetralogy of Fallot, atrioventricular canal defect, and complete malrotation of the gut were identified. Mandibular hypoplasia and delicate, bowed, irregular, long bones and ribs with widening and deep cupping of the metaphyses were found radiographically. In addition, we review 3 previously reported cases of males with similar, lethal malformations, all born to mothers with MNS. It is our conclusion that these anomalies characterize the male MNS phenotype. A review of all reported viable individuals with MNS identified 2 distinct entities: a mild form found only in females, compatible with normal life expectancy in most cases and inherited in an X-linked dominant male lethal or sex limited autosomal dominant pattern, and a different, more severe disorder, termed precocious osteodysplasty, found in both males and females and inherited as an autosomal recessive trait.