Homozygous CHST11 mutation in chondrodysplasia, brachydactyly, overriding digits, clino-symphalangism and synpolydactyly.

BACKGROUND: Carbohydrate sulfotransferase 11 (CHST11) is a membrane protein of Golgi that catalyses the transfer of sulfate to position 4 of the N-acetylgalactosamine residues of chondroitin. Chondroitin sulfate is the predominant proteoglycan in cartilage, and its sulfation is important in the developing growth plate of cartilage. A homozygous deletion encompassing part of the gene and the embedded miRNA MIR3922 had been detected in a woman with hand/foot malformation and malignant lymphoproliferative disease. Chst11-deficient mouse has severe chondrodysplasia, congenital arthritis and neonatal lethality. We searched for the causative variant for the unusual combination of limb malformations with variable expressivity accompanied by skeletal defects in a consanguineous Pakistani kindred. METHODS: We performed detailed clinical investigations in family members. Homozygosity mapping using SNP genotype data was performed to map the disease locus and exome sequencing to identify the underlying molecular defect. RESULTS: The limb malformations include brachydactyly, overriding digits and clino-symphalangism in hands and feet and syndactyly and hexadactyly in feet. Skeletal defects include scoliosis, dislocated patellae and fibulae and pectus excavatum. The disease locus is mapped to a 1.6 Mb region at 12q23, harbouring a homozygous in-frame deletion of 15 nucleotides in CHST11. Novel variant c.467_481del (p.L156_N160del) is deduced to lead to the deletion of five evolutionarily highly conserved amino acids and predicted as damaging to protein by in silico analysis. Our findings confirm the crucial role of CHST11 in skeletal morphogenesis and show that CHST11 defects have variable manifestations that include a variety of limb malformations and skeletal defects.

Living with inborn errors of cholesterol biosynthesis: lessons from adult patients.

In the last decades, nine inherited errors of the distal part of cholesterol biosynthesis have been recognized. Affected patients present complex malformation syndromes involving different organs and systems with variable degrees of severity. We report on the phenotype evolution of three patients with enzymatic defects at three distinct steps of such pathway: Smith-Lemli-Opitz syndrome, X-linked dominant chondrodysplasia punctata type 2 and congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome. The patients' natural history, from childhood to adulthood, is thoroughly described in order to contribute for a better knowledge of these diseases. Our ultimate goals are to contribute for a better characterization of the long-term course of these metabolic disorders and for the recognition of such diseases in older patients.

Critical role of Yp inversion in PRKX/PRKY-mediated Xp;Yp translocation in a patient with 45,X testicular disorder of sex development.

45,X testicular disorder of sex development (TDSD), previously known as 45,X maleness, with unbalanced Xp;Yp translocation is an extremely rare condition caused by concomitant occurrence of loss of an X chromosome of maternal origin and an aberrant Xp;Yp translocation during paternal meiosis. We identified a Japanese male infant with an apparently 45,X karyotype who exhibited chondrodysplasia punctata and growth failure. Cytogenetic analysis revealed a 45,X.ish der(X)t(X;Y)(p22.33;p11.2)(DXZ1+,SRY+) karyotype. Array comparative genome hybridization analysis showed a simple Xp terminal deletion involving SHOX and ARSE with the breakpoint just centromeric to PRKX, and an apparently complex Yp translocation with the middle Yp breakpoint just telomeric to PRKY and the centromeric and the telomeric Yp breakpoints around the long inverted repeats for the generation of a common paracentric Yp inversion. Subsequently, a long PCR product was obtained with an X-specific and a Y-specific primers that were designed on the assumption of the presence of a Yp inversion that permits the alignment of PRKX and PRKY in the same direction, and the translocation fusion point was determined to reside within a 246 bp X-Y homologous segment at the "hot spot A" in the 5' region of PRKX/PRKY, by sequential direct sequencing for the long PCR product. These results argue not only for the presence of rare 45,X-TDSD with Xp;Yp translocation, but also for a critical role of a common paracentric Yp inversion in the occurrence of PRKX/PRKY-mediated unbalanced Xp;Yp translocation.

Challenges of spine surgery in patients with chondrodysplasia punctata.

BACKGROUND: Chondrodysplasia punctata (CDP) is a common manifestation of an etiologically heterogenous group of disorders. There is very little data regarding the development and management of spinal deformity in patients with CDP. The purpose of this study was to present a multicenter series of CDP, to describe the surgical outcomes of spinal deformities in CDP patients and to emphasize important considerations that may influence choice of surgical treatment of spinal deformity in this patient population. METHODS: The medical records and spinal radiographs of patients with the diagnosis of CDP followed in 2 centers between 1975 and 2011 were retrospectively reviewed. Epiphyseal stippling was present on radiographs in all patients who fulfilled the clinical criteria. RESULTS: Among the 17 patients who were diagnosed with CDP, 13 had spinal deformities. The mean age at diagnosis of spinal deformity was 14.6 months (range, 1 wk to 9 y). Males and females were close to equally represented (10 males and 7 females). Twelve patients (92%) required surgery to correct spinal deformity. Patients were followed for a median of 8.4 years (range, 2.8 to 19.5 y). The total number of surgical procedures performed was 17 averaging 1.5 per patient. Four patients required >1 procedure. Eighty percent of the patients who required >1 surgical procedure were females with probable diagnosis of X-linked dominant CDP. Revision surgery was indicated in 50% of the patients treated with combined anterior and posterior fusion and 20% of the patients treated with posterior fusion alone. CONCLUSIONS: Spinal deformity in CPD patients may range from significant kyphoscoliosis to minimal deformity that does not require any treatment. For those patients in whom spine surgery was indicated, a high incidence of revision surgery and curve progression after fusion was recorded. Female patients with probable diagnosis of X-linked dominant CDP were more likely to require a second surgical procedure. Isolated posterior fusion showed less favorable results compared with combined anteroposterior fusion in terms of revision surgery. LEVEL OF EVIDENCE: Level IV-therapeutic study.

Progressive early-onset scoliosis in Conradi disease: a 34-year follow-up of surgical management.

BACKGROUND: Conradi-Hunermann syndrome (CHS) is a rare metabolic syndrome with several orthopaedic problems. Early-onset scoliosis is of great importance because of often rapidly progressive nature and high risk of postoperative complications. OBJECTIVES: To report the 34-year follow-up and outcome of a patient with CHS treated with combined anterior and posterior fusion without instrumentation. METHODS: All available clinical and radiographs of a female patient with CHS retrospectively reviewed. Overall health status, sagittal and coronal deformity, pulmonary function test, and outcome questionnaires were evaluated. RESULTS: Initial films at the age of 4 months showed a curve of 37 degrees from T6-T11 and a curve of 17 degrees from T11-L2. Thoracic kyphosis was measured at 43 degrees. Standing films at the age of 2 years and 2 months showed progression of both the curves to 50 and 66 degrees, respectively, and a significant spinal imbalance. The kyphosis also progressed to 57 degrees. She underwent a staged anterior inlay graft spinal fusion with autograft and allograft ribs from T8-L1 and posterior in situ fusion from T6-L1 with corticocancellous allograft. Solid radiographic fusion was observed 18 months after surgery. She was 36 years old at her latest follow-up, 34 years after surgery, with neutral clinical coronal and sagittal balance. No significant pain and respiratory complaint at moderate sports and normal daily life activity. "Vital capacity" and "total lung capacity" were 65% and 75%, respectively, of the normal. Thoracic curve of 35 degrees (T6-T11) and right thoracolumbar curve of 53 degrees from T11-L2 with a solid fusion fromT6-L1 with kyphosis measured over the fused area of 40 degrees were observed. Her overall mean Scoliosis Research Society-22 score was 3.68. She is an MBA graduate from a competitive school and currently works full-time. CONCLUSIONS: Although the treatment of early-onset scoliosis has significantly evolved over the past 3 decades, the traditional method of anterior release and fusion and staged in-situ posterior fusion posterior fusion with postoperative immobilization showed acceptable deformity correction and maintenance of the pulmonary function over the 34 years.

Condrodisplasia «punctata» rizomélica clásica: comunicación de dos casos con las formas grave y benigna de la afección / Classic rhizomelic chondrodysplasia punctata: report of 2 cases with two forms of the disease

La condrodisplasia punctata rizomélica clásica (RCDP) es una rara enfermedad multisistémica autosómica recesiva, debida a una alteración del metabolismo peroxisomal que determina una deficiencia de la biosíntesis de plasmalógenos y de la alfaoxidación del ácido fitánico. Se caracteriza por la presencia desde el nacimiento de un acortamiento proximal de las extremidades, calcificaciones periarticulares, dismorfia facial, retraso del desarrollo y mortalidad precoz. Se presentan dos casos de RCDP clásica, o tipo I, con las dos formas clínicas de presentación, grave o mortal y leve o benigna, en relación con la existencia de actividad enzimática residual, y se revisan sus principales aspectos clínicos(AU)

Classic rhizomelic chondrodysplasia punctata (CRCP) is a rare multisystem disease, autosomal recessive disorder. It is due because a peroxisomal metabolism alteration that determine deficiency of the plasmalogen biosynthesis and the alpha oxidation of phytanic acid. It is characterized by proximal shortening of the limbs, punctuate calcifications of the epiphyses, facial dysmorphia, developmental delay and early lethality. We present two cases of CRCP type I with two different forms of presentation, one severe and another one mild or bening, in relation with the residual enzyme activity and we revise the main clinical aspects(AU)

Specific entities affecting the craniocervical region: syndromes affecting the craniocervical junction.

INTRODUCTION: The craniocervical junction is a vital component in understanding the function of the human central nervous system. It is the threshold for major pathways affecting both brain and spinal cord function, and these structures are intricately housed in a network of bone, ligaments, and soft tissues. Abnormal development of any of these components may lead to altered structure, and therefore, altered function in the central nervous system. MATERIALS AND METHODS: We herein describe a set of genetic syndromes that commonly affect the craniovertebral junction and offer clinical examples from more than 6,000 patients who have been treated for these disorders. DISCUSSION: The syndromes described include Chiari type I malformation, Conradi syndrome, Goldenhar syndrome, Klippel-Feil syndrome, Larsen syndrome, Morquio syndrome, Pierre-Robin syndrome, spondyloepiphyseal dysplasia congenital and Weaver syndrome. The genetic mechanisms responsible for these disorders may offer unique insight into the developmental pathways and patterning in the musculoskeletal and cranial systems and may, ultimately, guide future diagnosis and treatment.

Chondrodysplasia punctata: case report and review of audiological and ENT features.

Chondrodysplasia punctata is a term referring to a clinically heterogeneous group of bone and cartilage dysplasias which cause characteristic epiphyseal stippling. The condition can involve the ear, nose and throat in diverse ways at many levels. We present a case of X-linked brachytelephalangic chondrodysplasia punctata, which illustrates the features of this condition particularly relevant to the audiological physician, otolaryngologist and neonatologist.

[Cervical spinal cord compression in chondrodysplasia punctata: report of two cases]. / Compresión de la médula cervical en la condrodisplasia punctata: presentación de dos casos.

AIM: To present two patients with chondrodysplasia punctata and cervical spine compression who had a chronic myelopathy. CASE REPORTS: The patients are a boy who was seen in our service at 13 years of age because of a progressive spastic quadriparesis since infancy and muscle spasm, and a girl, actually 15-year-old, who was studied by us since 2 years of age because of the same problem and moderate mental retardation. Magnetic resonance study disclosed narrowing of the spinal canal at the level of C1-C2 and C5-C6. Surgical decompression was performed in both cases. The case 2 also received physiotherapy, myorrelaxing medication and botulinum toxin treatments. The case 2 has short stature and intellectual level below normality. CONCLUSION: Chondrodysplasia punctata, that exhibits well defined clinical and radiological manifestations, is a disease that can present spinal cord compression during the first years of life. However, other pathological causes of still unknown origin may contribute to the progressive evolution and lack of recuperation of the problems derived of the spasticity as well as the mental retardation and the short stature.

Cervical spine stenosis and possible vitamin K deficiency embryopathy in an unusual case of chondrodysplasia punctata and an updated classification system.

We describe in this paper a patient with brachytelephalangic chondrodysplasia punctata (BCDP) who has multiple serious medical problems and striking physical abnormalities. These include cervical spine stenosis with resultant quadriplegia, severe nasal hypoplasia, and brachytelephalangy. Radiographs taken shortly after birth demonstrated extensive epiphyseal and vertebral stippling, and distal phalangeal hypoplasia. The pregnancy was complicated by maternal intestinal obstruction due to a small bowel carcinoma and probable malabsorption. The severity of the phenotype in this case may have been influenced by these maternal factors particularly vitamin K deficiency.

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.

Prenatal findings in chondrodysplasia punctata, tibia-metacarpal type.

Chondrodysplasia punctata, a skeletal dysplasia with craniofacial dysmorphism and joint contractures can occur with rhizomelia, mesomelia or both. The rhizomelic form is generally lethal, whereas one form of mesomelic chondrodysplasia punctata has been described that is associated with a presumably normal lifespan and intelligence. We describe a case of a fetus suspected prenatally of having rhizomelic chondrodysplasia punctata, who was subsequently diagnosed at 1.5 years of age to have the tibia-metacarpal form of chondrodysplasia punctata. The prenatal sonographic findings of second-trimester micromelic bone shortening and third-trimester proximal femoral stippling may be present in the rhizomelic form but are not specific to this condition.

X-linked dominant chondrodysplasia punctata with decreased dihydroxyacetone phosphate acyltransferase activity.

BACKGROUND: We examined an 18-month-old girl with typical clinical features of X-linked dominant chondrodysplasia punctata (CDPX2) with decreased activity of dihydroxyacetone phosphate acyltransferase (DHAP-AT), previously reported in CDPX2. On the other hand, steroid sulfatase, whose activity is deficient or decreased in X-linked ichthyosis and X-linked recessive chondrodysplasia punctata, has been reported to be normal in CDPX2, although all of these diseases have ichthyotic skin changes. OBJECTIVE: We measured the activity of DHAP-AT and steroid sulfatase of the patients fibroblasts to confirm the DHAP-AT abnormality in CDPX2. RESULTS: The DHAP-AT activity was remarkably reduced, but steroid sulfatase activity was within normal levels when compared with those of 2 healthy controls. CONCLUSION: The abnormal metabolism in plasmalogen synthesis in CDPX2 was confirmed. It is, however, unknown how the decreased DHAP-AT activity is related to the skin changes.

A 13-month-old boy with progressive genu valgum.

The following case illustrates the roentgenographic and clinical findings of a condition of interest to the orthopedic surgeon. Initial history, physical findings, and roentgenographic examinations are indicated below. The final clinical and differential diagnoses are presented on the following pages.

Síndrome de condrodisplasia punctata rizomélica: informe de un caso / Rhizomelic chondrodysplasia punctata syndrome

Se informa un caso de condrodisplasia punctata rizomélica. Esta es una displasia ósea poco frecuente; su diagnóstico es clínico y radiológico. Se trata de una afección de carácter autosómico recesivo, en la que hay alteración de los peroxisomas, caracterizada bioquímicamente por daño en la biosíntesis del plasmalógeno y del catabolismo del fitanato.

Influence of plasmalogen deficiency on membrane fluidity of human skin fibroblasts: a fluorescence anisotropy study.

The influence of plasmalogen deficiency on membrane lipid mobility was determined by measuring fluorescence anisotropy of trimethylammoniumdiphenylhexatriene (TMA-DPH) and diphenylhexatrienylpropanoylhydrazylstachyose (glyco-DPH) inserted in the plasma membranes of human skin fibroblasts deficient in plasmalogens. The cells used were from patients affected with cerebrohepatorenal (Zellweger) syndrome (CHRS) or rhizomelic chondrodysplasia punctata. Their plasmalogen content (0-5% of total phospholipid) is significantly reduced compared with that of control cells from healthy donors (13-15% of total phospholipid) or of CHRS fibroblasts supplemented with the plasmalogen precursor, hexadecylglycerol. Plasmalogen-deficient cells consistently showed lower fluorescence anisotropies of membrane-bound DPH fluorophores corresponding to higher membrane lipid mobilities as compared to controls. However, very similar lipid mobilities were found for sonicated aqueous dispersions of phospholipids extracted either from CHRS or control cells. Therefore, the differences observed with living cells are not due to differences in the overall physical properties of the membrane lipid constituents. Other phenomena such as lipid asymmetry and/or plasmalogen-protein interactions may be responsible for the effects observed in the biomembranes.

Peroxisomal dysfunction in chondrodysplasia punctata, rhizomelic type.

The rhizomelic type of chondrodysplasia punctata (RCDP) is recognizable at birth because of the typical phenotype and radiological features. Most patients die young, some survive until their teens but all are severely retarded. Recent studies showed RCDP to be a peroxisomal disorder. Peroxisomal investigations may be important in defining the prognosis for an individual patient, and are definitely of use in antenatal diagnosis.

Conradi-Hunerman syndrome. Case report.

Conradi-Hunerman syndrome, a variant of chondrodysplasia punctata, rarely presents with primary manifestations relevant to the head and neck surgeon. Usually, the disease is evidenced by malformation of the extremities, cataracts, cutaneous lesions, and an unusual facies. We have followed a child with Conradi-Hunerman syndrome for 7 years whose primary manifestation of the disease is respiratory compromise secondary to calcification of the laryngotracheobronchial tree. In addition, he has a conductive hearing loss thought to be secondary to ossicular chain fixation.

Peroxisomal disorders: clinical characterization.

The peroxisomal disorders can be divided into three classes: firstly, those in which the activity of only one single enzyme is reduced; secondly, those in which the activities of multiple peroxisomal enzymes are deficient and also the number of peroxisomes is reduced; and thirdly, those in which the activities of multiple peroxisomal enzymes are lacking and at the same time the number of peroxisomes is normal at least in liver tissue. The cerebro-hepato-renal syndrome of Zellweger is the prototype of peroxisomal disorders of the second group. Clinical distinction between Zellweger syndrome and neonatal adrenoleukodystrophy or infantile Refsum disease can be impossible. The clinical abnormalities that should give rise to suspicion for the presence of a peroxisomal disorder and urge the necessity of further biochemical studies are proposed.