Two cases of Legg-Perthes and intellectual disability in Tricho-Rhino-Phalangeal syndrome type 1 associated with novel TRPS1 mutations.

Tricho-Rhino-Phalangeal syndrome is a rare autosomal dominant genetic disorder caused by mutations in the TRPS1 gene. This malformation syndrome is characterized by distinctive craniofacial features including sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. In this report, we describe two patients with the physical manifestations and genotype of TRPS type I but with learning/intellectual disability not typically described as part of the syndrome. The first patient has a novel heterozygous two-base-pair deletion of nucleotides at 3198-3199 (c.3198-3199delAT) in the TRPS1 gene causing a translational frameshift and subsequent alternate stop codon. The second patient has a 3.08 million base-pair interstitial deletion at 8q23.3 (113,735,487-116,818,578), which includes the TRPS1 gene and CSMD3. Our patients have characteristic craniofacial features, Legg-Perthes syndrome, various skeletal abnormalities including cone shaped epiphyses, anxiety (first patient), and intellectual disability, presenting unusual phenotypes that add to the clinical spectrum of the disease.

Early initiation of enzyme replacement therapy for the mucopolysaccharidoses.

The mucopolysaccharidoses (MPS), a group of rare genetic disorders caused by defects in glycosaminoglycan (GAG) catabolism, are progressive, multi-systemic diseases with a high burden of morbidity. Enzyme replacement therapy (ERT) is available for MPS I, II, and VI, and may improve walking ability, endurance, and pulmonary function as evidenced by data from pivotal trials and extension studies. Despite these demonstrable benefits, cardiac valve disease, joint disease, and skeletal disease, all of which cause significant morbidity, do not generally improve with ERT if pathological changes are already established. Airway disease improves, but usually does not normalize. These limitations can be well understood by considering the varied functions of GAG in the body. Disruption of GAG catabolism has far-reaching effects due to the triggering of secondary pathogenic cascades. It appears that many of the consequences of these secondary pathogenic events, while they may improve on treatment, cannot be fully corrected even with long-term exposure to enzyme, thereby supporting the treatment of patients with MPS before the onset of clinical disease. This review examines the data from clinical trials and other studies in human patients to explore the limits of ERT as currently used, then discusses the pathophysiology, fetal tissue studies, animal studies, and sibling reports to explore the question of how early to treat an MPS patient with a firm diagnosis. The review is followed by an expert opinion on the rationale for and the benefits of early treatment.

Homozygosity for a novel truncating mutation confirms TBX15 deficiency as the cause of Cousin syndrome.

Cousin syndrome, also called pelviscapular dysplasia (OMIM 260660), is characterized by short stature, craniofacial dysmorphism, and multiple skeletal anomalies. Following its description in two sibs in 1982, no new cases have been observed until the observation of two unrelated cases in 2008 who were homozygous for frameshift mutations in TBX15. We investigated an adult individual with short stature, a complex craniofacial dysmorphism, malformed and rotated ears, short neck, elbow contractures, hypoacusis, and hypoplasia of scapula and pelvis on radiographs. We identified homozygosity for a novel nonsense mutation (c.841C>T) in TBX15 predicted to cause a premature stop (p.Arg281*) with truncation of the protein. This observation confirms that Cousin syndrome is a consistent and clinically recognizable phenotype caused by loss of function of TBX15.

Radial overgrowth after radial shortening osteotomies for skeletally immature patients with Kienböck's disease.

PURPOSE: We hypothesized that radial shortening osteotomy (radial shortening) for skeletally immature patients with Kienböck's disease would induce overgrowth of the radius. The purpose of this study was to determine the effect of radial shortening on radial growth in skeletally immature patients with Kienböck's disease and to clarify the relationship between the postoperative growth alterations and the clinical results. METHODS: Eight wrists of 8 skeletally immature patients with Kienböck's disease were treated with radial shortening. There were 3 boys and 5 girls, ranging in age from 11 to 18 (mean, 14) years old. All patients presented with open physis and negative ulnar variance. The length of the radial shortening equaled the amount of negative ulnar variance. Clinical assessment was based on the modified Nakamura scoring system. Radiographic assessment, including Lichtman's stages, ulnar variance, carpal height ratio, radial inclination, and volar tilt, was performed before surgery, immediately after surgery, and at follow-up. A difference in ulnar variance of more than 2 mm between these 3 measurements was considered to be overgrowth. Statistical comparisons were performed using paired t-tests. RESULTS: At a mean follow-up period of 69 months, the mean clinical score was 19.7 of 21 maximum points, with all wrists rated as excellent. Radiographically, no progression of Lichtman stage was found in any patient. At follow-up, the x-ray and magnetic resonance imaging findings indicated lunate revascularization in all patients. Four of the 8 had overgrowth in the operated radius. On the other hand, other radiographic parameters showed no significant changes at follow-up. The occurrence of postoperative radial overgrowth did not notably affect the clinical scores. CONCLUSIONS: The current results suggest the probability of overgrowth of the radius in skeletally immature patients with Kienböck's disease treated with radial shortening. The postoperative radial overgrowth after this osteotomy had no effect on clinical and other radiographic outcomes. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Segmental costovertebral malformation associated with lipomyelomeningocoele.

We describe 2 patients with segmental costovertebral malformation, a form of spondylocostal dysostosis, associated with tethering of the conus to a lipomyelomeningocoele. Such an association is rare. In both these patients the defects occurred sporadically. The relevant literature is reviewed.

Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis.

Pycnodysostosis is an uncommon human genetic disorder characterized by osteosclerosis of the skeleton, short stature, and bone fragility. The disease results from mutations in the cathepsin K gene, a lysosomal cysteine protease highly expressed in osteoclasts and crucial for the degradation of organic matrix from mineralized bone. Recently, interest has focused on a pharmaceutical inhibition of cathepsin K to prevent bone loss. However, little is known about the cellular activity or material quality of bone in pycnodysostosis. In the present study, transiliac bone biopsies from two affected individuals, aged 5 and 21 yr, were investigated using light microscopy, quantitative backscattered electron imaging, and small angle x-ray scattering. Results were compared with published age-matched reference data. The mutations in the cathepsin K gene of both patients were identified, including one novel defect. Both individuals had severe osteosclerosis, and their biopsies displayed multinucleated osteoclasts apposed to areas of demineralized matrix as well as bone-lining cells adjacent to this undigested collagen left over by osteoclasts. The homogeneity of the mineralized matrix was markedly disturbed due to large inclusions of mineralized cartilage residues. Histomorphometric evaluation showed a quantitative decrease in static parameters of bone formation. In contrast and despite deficient cathepsin K activity, osteoclastic parameters were close to normal range. At the nanostructural level, there was a marked increase in the mean thickness of the mineral particles, reflecting decreased bone remodeling. Examination of the trabecular structure revealed that the lamellae were highly disordered, which was also apparent from a poor alignment of mineral crystals oriented along the longitudinal axis of collagen fibrils. Taken together, these results strongly suggest that functional cathepsin K is important for balanced bone turnover, and enzyme deficiency results in a profound deterioration of bone quality with respect to trabecular architecture and lamellar arrangement, which is presumably the reason for bone fragility in pycnodysostosis.

Combined deficiency of beta-galactosidase and neuraminidase: natural history of the disease in the first 18 years of an American patient with late infantile onset form.

We describe the clinical findings over the first 18 years of a patient with a novel phenotype for galactosialidosis, the storage disease produced by the combined deficiency of beta-galactosidase and neuraminidase. Clinical findings in the first few months included somewhat unusual appearance and hepatosplenomegaly. Dysostosis multiplex was evident by age 2 1/2 years. Mitral and aortic valvular disease appeared over the next few years and cardiac disease has become the most important clinical problem. Foam cells were present in the bone marrow, and vacuolated lymphocytes were present in the peripheral blood smear. The patient had no neurological symptoms, cherry red spots, or intellectual deterioration during the first 18 years. Evidence presented elsewhere indicates that the basic defect in this late infantile form of galactosialidosis (as is thought to be true for the other forms of galactosialidosis) is a reduced amount of the 32 kDa phosphoglycoprotein which associates with beta-galactosidase and alpha-neuraminidase in lysosomes.

Ischiospinal dysostosis with cystic kidney disease: report of two cases.

Ischiospinal dysostosis (ISD) is a recently described entity characterized by ischial hypoplasia and spinal segmental anomalies. Nephroblastomatosis that may manifest radiologically as 'polycystic kidney disease' has been regarded as a syndromic constituent of ISD. We report two children with ISD associated with 'renal cystic disease'. One child had multiple renal cysts resembling radiologically adult polycystic kidney disease, leading to renal dysfunction, whereas the other a solitary renal cyst with normal renal function. Renal malformations in ISD may be variable, ranging from diffuse nephroblastomatosis to a solitary renal cyst.

[Spondylocostal dysostosis: a rare genetic disease]. / Dysostose spondylo-costale: une maladie génétique rare.

Spondylocostal dysostoses represent a group of very rare genetic disorders, characterised by vertebral and costal segmentation defects, sometimes accompanied by visceral malformations. The major gene involved is DLL3, on chromosome 19. A mutation may lead to a somitogenesis defect, with segmentation defect of axial skeleton and deformations. Depending on the nature of the mutation of DLL3, spondylocostal dysostosis is transmitted as an autosomal dominant (less severe) or autosomal recessive trait (often more severe, but non lethal). Spondylocostal dysostoses must not to be confused with the Jarcho-Levin spondylothoracic dysostosis, a severe, autosomal recessive syndrome. Its most typical aspect is the crab-like appearance of the rib cage leading to major respiratory disorders. Death, due to respiratory insufficiency, usually occurs before the age of two, most often during the first few months. At this time, guidelines for treatment do not exist. We report a case of spondylocostal dysosotosis in a patient born to consanguineous turkish parents, and review the clinical and genetic data on that group of skeletal disorders.

[Diagnosis and logopedic rehabilitation in mandibulofacial dysostosis: a case report]. / Diagnosi e riabilitazione logopedica della disostosi mandibolo-facciale: un caso clinico.

TCS is hereditary condition transmitted as an autosomal dominant with a high penetrance rate and variable expressivity. Over half the cases derives from new mutations. A pathological gene has been located on the chromosome 5, between locus 31 and 34 of the long arm. The clinical picture is dominated by mandible-facial impairment and by numerous associated deficits, among which a hearing deficit. Therapy requires plurispecialistic intervention, personalized according to each patients condition. The Authors report the case of a three-year-old girl with transmissive deafness and serious language retardation. The child successfully underwent logopedical therapy for three years. The Authors conclude affirming that very young patients with S. Treacher Collins-Franceschetti have a very good chance of being inserted into society furthermore improved by the absence lack of mental deficiency and by spontaneous improvement in physical appearance.

Spatiotemporal disorder in the axial skeleton development of the Mesp2-null mouse: a model of spondylocostal dysostosis and spondylothoracic dysostosis.

Spondylocostal dysostosis (SCDO) is a genetic disorder characterized by severe malformation of the axial skeleton. Mesp2 encodes a basic helix-loop-helix type transcription factor that is required for somite formation. Its human homologue, Mesp2, is a gene affected in patients with SCDO and a related vertebral disorder, spondylothoracic dysostosis (STDO). This work investigated how the loss of Mesp2 affects axial skeleton development and causes the clinical features of SCDO and STDO. We first confirmed, by three-dimensional computed tomography scanning, that Mesp2-null mice exhibited mineralized tissue patterning resembling the radiological features of SCDO and STDO. Histological observations and in situ hybridization probing for extracellular matrix molecules demonstrated that the developing vertebral bodies in Mesp2-null mice were extensively fused with rare insertions of intervertebral tissue. Unexpectedly, the intervertebral tissues were mostly fused longitudinally in the vertebral column, instead of exhibiting extended formation, as was expected based on the caudalized properties of Mesp2-null somite derivatives. Furthermore, the differentiation of vertebral body chondrocytes in Mesp2-null mice was spatially disordered and largely delayed, with an increased cell proliferation rate. The quantitative three-dimensional immunofluorescence image analyses of phospho-Smad2 and -Smad1/5/8 revealed that these chondrogenic phenotypes were associated with spatially disordered inputs of TGF-ß and BMP signaling in the Mesp2-null chondrocytes, and also demonstrated an amorphous arrangement of cells with distinct properties. Furthermore, a significant delay in ossification in Mesp2-null vertebrae was observed by peripheral quantitative computed tomography. The current observations of the spatiotemporal disorder of vertebral organogenesis in the Mesp2-null mice provide further insight into the pathogenesis of SCDO and STDO, and the physiological development of the axial skeleton.

Acrodysostosis associated with hypercalcemia.

An 18-year-old man was admitted to the clinic complaining of deterioration in the function of his hands and feet. The clinical examination revealed that his movements were clumsy and that he had disproportionally short limbs. In addition, he also had facial abnormalities of frontal bossing, hypertelorism, maxillary hypoplasia, broad low nasal bridge, short upturned nose with anteverted nostrils and triangular mouth. All extremities appeared short with stubby fingers and toes and with broad hands and wrinkling of the dorsal skin. Chromosomal analysis showed a normal (46, XY) karyotype. X-ray studies revealed broad, short metacarpals and phalanges with cone-shaped epiphyses and brachycdactyly and a diagnosis of peripheral dysostosis was confirmed by the characteristic radiographic appearance of the hands. Serum calcium and alkaline phosphatase levels were high, parathormone (PTH) was low, but 25 (OH) Vitamin D, albumin, and 24 hour urine calcium levels were in the normal range. Based on these findings, a diagnosis of acrodysostosis associated with hypercalcemia was made. To the best of our knowledge, this represents the first description of this syndrome.

Pulgarización en Síndrome de Nager. Caso clínico / Pollicization in Nager Syndrome. A case report

El tratamiento de las hipoplasias del pulgar, independientemente del síndrome clínico en el que estén incluidas, se basa en su severidad. La pulgarización, migración quirúrgica del índice hacia la posición del pulgar para sustituir su función, se reserva para los casos más severos. Presentamos el caso de un varón de 4 años de edad con Síndrome de Nager. Entre las características clínicas más significativas del caso destacamos: paladar hendido, microtia bilateral, fisura palpebral antimongoloide, hipoplasia malar, hipoplasia mandibular, coloboma del párpado inferior, así como hipoplasia severa bilateral de pulgares y ausencia parcial de tibia. Realizamos procedimiento de pulgarización en mano derecha sin complicaciones, con evolución satisfactoria. Tras 18 meses de seguimiento, el paciente presenta prensión esférica y cilíndrica adecuada, prensión lateral, así como oposición al quinto dedo (AU)

Treatment paradigm for a child with thumb deficiency or hypoplasia is based on severity, apart from other clinical features. Pollicization or surgical substitution of the thumb, most commonly using the index finger, is reserved for the most severe cases. We present the case of a 4-year-old male with Nager Syndrome. Among the most notable clinical characteristics we found: cleft palate, bilateral microtia, downslanting palpebral fissure, malar hypoplasia, mandibular hypoplasia, lower eyelid coloboma, partial tibial agenesis as well as bilateral hypoplastic/absent thumbs. Pollicization was performed for the right hand without complications. After 18 months follow-up, adequate cilyndrical and spherical grasp was achieved, as well as lateral prehension and opposition to fifth finger (AU)

Complete bilateral agenesis of the ilium in a 7-year-old ambulatory girl: case report.

STUDY DESIGN: A 7-year-old ambulatory girl with complete bilateral agenesis of the ilium is reported. OBJECTIVE: To document the clinical evolution and the spino-pelvic balance of a girl with bilateral agenesis of the ilium. SUMMARY OF BACKGROUND DATA: Scapuloiliac dysostosis is a rare focal skeletal dysplasia consisting in hypoplasia of ilium and scapula. METHODS: A 7-year-old girl with a short stature was referred to our clinic at 35 months of age for an asymptomatic lumbar hyperlordosis. She presented a waddling gait, and normal range of motion of her upper and lower limbs. The neurologic examination was within normal limits. RESULTS: Initial radiographs at 35 months of age showed complete bilateral agenesis of the ilium with preservation of the pubis, ischium, and sacrum, associated with a bilateral high hip dislocation. The lumbar lordosis and sacral slope were 89 degrees and 84 degrees, respectively. A radiographic skeletal survey also showed hypoplasia of both scapulae. At 7 years old, the girl was fully ambulatory, with a waddling gait and had no pain. The sacral slope and lumbar lordosis have increased to 97 degrees and 97 degrees, respectively. There was no evidence of spondylolisthesis. So far, the patient has required no treatment for her condition. CONCLUSION: This article reports a unique case of scapuloiliac dysostosis with complete bilateral agenesis of the ilium in an ambulatory girl. This case indicates that a functional gait is possible with bilateral congenital absence of the ilium, provided that there is adequate muscular support and normal neurologic function.

Phagocytosis of bone collagen by osteoclasts in two cases of pycnodysostosis.

Electron microscopic examination of bone biopsies obtained from two patients suffering from pycnodysostosis revealed that osteoclasts contained (sometimes large) cytoplasmic vacuoles filled with bone collagen fibrils. These vacuoles stained positive for acid phosphatase activity, thereby suggesting that bone matrix had been phagocytosed and subsequently exposed to hydrolytic enzymes of the lysosomal apparatus. Collagen-containing vacuoles were not observed in osteoclasts of individuals not suffering from this disease.

A new mutation in the skeletal ryanodine receptor gene (RYR1) is potentially causative of malignant hyperthermia, central core disease, and severe skeletal malformation.

Malignant hyperthermia susceptibility (MHS) and central core disease (CCD) have been shown to result from missense mutations in the ryanodine receptor gene of the skeletal muscle (RYR1). A 15-year-old patient who had spondylocostal dysostosis (SCD) developed an MH crisis during general anesthesia. The patient was characterized phenotypically by block vertebrae, vertebral fusion, short neck and thorax, fused ribs, craniofacial abnormalities, spina bifida occulta, and a diaphragmatic defect closed surgically in early infancy. The diagnosis MH susceptible (MHS) was confirmed by the in vitro contracture test (IVCT) on a muscle biopsy. Surprisingly, the histopathological investigation revealed the presence of CCD too. Molecular genetic investigation of the RYR1 gene was performed to search for known MH-related mutations. Cluster regions of the RYR1 gene, in which mutations have already been found, were examined by direct automated sequencing. In addition to the diagnosis MHS and CCD we were able to identify a novel RYR1 mutation in exon 46: 7358ATC > ACC, resulting in an Ile2453Thr substitution. This mutation was also present in the mother, in whom MH disposition and CCD were determined by muscle investigations. We suggest that the newly identified RYR1 mutation is closely associated with MH and CCD. A probable causative role of the RYR1 gene in SCD patients should be assessed by further genetic investigations.

A case of pycnodysostosis with growth hormone deficiency.

Pycnodysostosis is a skeletal dysplasia characterized by short stature. Treatment of pycnodysostosis with growth hormone (GH) has not been reported so far. We describe a case of pycnodysostosis with growth hormone deficiency in addition to low mean insulin-like growth factor 1 (IGF-1) concentration. Complete GH deficiency was determined by two pharmacological provocative tests (insulin and L-dopa). A good height-velocity response was obtained after GH replacement treatment. Pycnodysostosis with GH deficiency and replacement therapy have not been reported previously, to the best of our knowledge.