Patients with geleophysic dysplasia are not always geleophysic

We report on two boys with facial anomalies, small hands and feet, joint contractures, thick skin, unusual tiptoe gait and lysosome-like inclusions in the hepatocytes, compatible with a diagnosis of geleophysic dysplasia (GD). One of them also had fibrosis and fatty degeneration of the liver. In both, the facial appearance was different and neither had short stature nor progressive cardiac valvular disease. These clinical findings, consistent with a mild form of GD, support the notion that this disorder may have a broader spectrum than initially suspected. Am. J. Med. Genet. 72:85–90, 1997. © 1997 Wiley-Liss, Inc.     

Geleophysic dysplasia: 7-year follow-up study of a patient with an intermediate form

Geleophysic dysplasia (MIM *231050) is a rare autosomal recessive disorder, characterized by short stature with short limbs, brachydactyly, joint contractures, and a good-natured facial appearance. Infiltration of liver and cardiac leaflets has been reported in some patients. Based on the clinical picture and the detection of lysosome-like inclusions in hepatocytes, tracheal mucosa, chondrocytes, and skin fibroblasts, the underlying cause of the conditions is considered to be a generalized lysosomal storage defect. We report on a new case born to consanguineous parents, first observed at age 8 months, and for whom a 7-year follow-up is available. Am. J. Med. Genet. 86:82–85, 1999. © 1999 Wiley-Liss, Inc.     

Encephalocraniocutaneous lipomatosis (ECCL): neuroradiological findings in three patients and a new association with fibrous dysplasia

Encephalocraniocutaneous lipomatosis (ECCL) is a rare neurocutaneous syndrome characterized by involvement of tissues of ectodermal and mesodermal origin such as skin, eye, adipose tissue, and brain. Since 1970, when Haberland and Perou had described the first patient, 54 cases of ECCL have been reported in literature. We report on three new boys with ECCL. In addition to their typical dermal, ocular and central nervous system anomalies, one of them had a spheno-ethmoidal osseous lesion. Histopathological evaluation confirmed the benign nature of the lesion and was consistent with fibrous dysplasia. The aim of our study is to review clinical records and brain imaging studies of these three new patients with ECCL and compare these findings with those reported in literature to better define the phenotypic spectrum and radiological findings in ECCL.     

Electron microscopic findings in skin biopsies from patients with infantile osteopetrosis and neuronal storage disease

Infantile osteopetrosis with neuronal storage disease is a rare lysosomal storage disorder. It is an autosomal recessive disease that is associated with mutations in the OSTM1 and chloride channel ClCN-7genes. So far mutations in the OSTM1 gene have been identified in only 8 patients. To date, the clinical and morphological features of nine patients with infantile osteopetrosis with neuronal storage have been reported, but no ultrastructural findings of skin have been described in these patients. Skin biopsy is a cost-effective tool for the diagnosis of lysosomal storage disease. The purpose of this report is to define the ultrastructure of affected cells seen in skin biopsies of 2 boys whose mutation of OSTM1 has been characterized. The children presented in infancy with severe osteopetrosis and neurological deficiencies whose predominant symptoms were marked cerebral atrophy, decreased myelinization, and severe central nervous system involvement. Because of the difficulties in distinguishing this disorder from some lysosomal storage diseases such as mucopolysaccharidosis that have both neurological and skeletal abnormalities, the authors elected to examine skin biopsies from these children. Ultrastructural examination revealed the presence of swollen unmyelinated axons containing spheroids, reduced numbers of myelinated axons, and the presence of secondary lysosomes in Schwann cells containing lipofuscin. This study demonstrates that electron microscopy of skin biopsy is a useful diagnostic method to identify patients with clinical features of osteopetrosis with neuronal storage disease.     

A chinese boy with geleophysic dysplasia caused by compound heterozygous mutations in ADAMTSL2

Geleophysic dysplasia, belonging to the group of acromelic dysplasia, is a rare genetic disease. Two genes, FBN1 and ADAMTSL2, were known to be linked to this disorder. The disorder presents as extreme short stature, short limbs, small hands and feet, stubby fingers and toes, joint stiffness, toe walking, skin thickening, progressive cardiac valvular thickening and characteristic facial features, including a round face with full cheeks. Here, we report the first Chinese case with geleophysic dysplasia type 1 based on clinical and genetic features. The boy was admitted because of severe physical growth retardation and mild motor retardation. Comprehensive medical evaluations were performed including metabolic studies, endocrine function examination, bone X-rays and echocardiography. Much delayed bone age and geleophysic dysplasia were found. Targeted next-generation sequencing was used to detect genetic mutations associated with skeletal dysplasia. Sanger sequencing was used to confirm the mutations in the patient. PCR amplification, cloing, and sequencing was used to determine the de novo mutation origin. Two compound heterozygous mutations were confirmed in the ADAMTSL2 gene of the patient. The c.340G > A (p.Glu114Lys) mutation was a de novo heterozygous mutation, and our results suggested that it was located on the paternal allele. While the c.234-2A > G inherited from his mother was a novel pathogenic heterozygous splicing mutation. Growth hormone deficiency had been observed in the patient. His growth velocity was improved by growth hormone supplementation. In conclusion, we have identified a novel splicing mutation of ADAMTSL2 carried by a Chinese boy with geleophysic dysplasia type 1. The patient was treated effectively with growth hormone supplementation.     

Abstract Digest—The Cutting Edge

Abstract

This paper describes a rapid protocol for iliac crest biopsies with embedding in LR White plastic to facilitate diagnosis of osteomalacia. Sections were cut and stained for light and electron microscopy using traditional staining methods with minor modifications. Total processing time was within three days. (The J Histotechnol 13:125, 1990)     

Cleidocranial dysplasia: Clinical,endocrinologic and molecular findings in 15 patients from 11 families

Cleidocranial dysplasia (CCD) is an autosomal dominant disorder characterized by skeletal anomalies such as delayed closure of the cranial sutures, underdeveloped or absent clavicles, multiple dental abnormalities, short stature and osteoporosis. RUNX2, encoding Runt DNA-binding domain protein important in osteoblast differentiation, is the only known gene related to the disease and identified as responsible in 70% of the cases. Our clinical evaluations revealed that short stature present at a rate of 28.6%, osteoporosis at a rate of 57.1% and osteopenia at 21.4%. In this study, RUNX2 sequencing revealed nine different variations in 11 families, eight being pathogenic of which one was novel gross insertion (c.1271_1272ins20) and one other being predicted benign in frame gross deletion (c.241_258del).     

Electron microscopic findings suggestive of focal and segmental glomerulosclerosis in patients with steroid-resistant nephrotic syndrome

Distinction between minimal change disease and unsampled Focal Segmental Glomerulosclerosis is a challenging concept in kidney biopsy of patients with nephrotic syndrome with minimal histopathological findings. This study was performed to compare electron microscopic findings in patients with steroid-resistant nephrotic syndrome with minimal histopathological abnormalities and cases with Focal Segmental Glomerulosclerosis. This Cohort study was conducted in Cancer Institute, Imam Khomeini Hospital Complex, Tehran, Iran. Twenty patients with steroid-resistant nephrotic syndrome and minimal changes on the light microscopic study were selected as case group. Similarly, 20 patients with Focal Segmental Glomerulosclerosis were selected as the control group. Ultrastructural findings were re-evaluated and scored qualitatively (0–3+). In patients with minimal changes on light microscopic evaluation, clinical course of the disease was followed after 5 years. Mean ages of the patients (8 women and 12 men) in case and control groups were 12.9 and 15.9 years, respectively (p > 0.05). There was no significant difference in number of examined glomeruli and sampling from cortico–medullary junction area between the groups. The mean percentage of sclerotic glomeruli in control group was 15.4%. Tubular atrophy and interstitial fibrosis were more frequent in control patients. Podocyte proliferation, GBM duplication (involving more than 10% of capillary walls), and moderate to severe multifocal expansion of mesangial matrix were significantly more obvious in FSGS patient samples (p < 0.05). No statistically significant difference was found in severity of cytoplasmic vacuolization, GBM wrinkling and splitting between the groups. Most of (80%) the patients with minimal changes improved during the 5-year follow-up. Generally, we concluded that Podocyte proliferation, GBM remodeling, and moderate to severe mesangial matrix expansion are the most reliable findings on electron microscopic examination in favor of FSGS.     

Mucolipidosis type IV: Clinical manifestations and natural history

The clinical manifestations and psychomotor development of five patients with mucolipidosis IV (MLIV) from three Ashkenazi-Jewish families are reported. The presenting symptoms were hypotonia, developmental delay, corneal clouding, and puffy eyelids. Four of the patients had convergent strabismus and none progressed beyond a developmental age of 15 months. One patient died of aspiration at 17 years while the oldest patient entered puberty at 20 years, developed a coarse face at 30 years, and is now 32 years old. Histopathological studies in four patients showed storage changes characteristic of MLIV.     

Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL): Clinical and radiological findings in a guatemalan patient

We report on a patient of Guatemalan descent whose physical and radiological findings are consistent with a diagnosis of spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL). This is a rare, autosomal recessive skeletal dysplasia with short limbs, severe scoliosis, high dorsal kyphoscoliosis, and joint hypermobility. Most described patients with SEMDJL are from the Afrikaans-speaking communities of South Africa. Patients with SEMDJL have an oval face, prominent eyes, and blue sclerae. Our patient's height and weight were below the fifth centile. She had prominent eyes with blue sclerae, a narrow, high-arched palate, pectus carinatum, severe scoliosis, and hyperextensibility and instability of most joint, with limited extension and supination of her elbows. A review of her roentgenograms showed severe scoliosis, poorly developed ischial, iliac, and pubic bones, a “bat-like” appearance of the iliac bones, “dysplastic” acetabulum, minimal metaphyseal and epiphyseal abnormalities at the knees, deformation of the proximal femoral metaphyses, and generalized brachydactyly of the hands and feet. This disorder may be more common than previously thought, and the diagnosis should be considered in any child with a dwarfing considered in any child with a dwarfing condition and joint laxity. © 1995 Wiley-Liss, Inc.     

Allergic dermatoses associated with chronic opisthorchiasis during antihelminthic therapy

We studied skin biopsy specimens from patients with allergic dermatoses associated with opisthorchiasis. Structural changes in the epidermis and derma were presented by degenerative and destructive changes in epitheliocytes with a pronounced membranolytic component, hemodynamic disturbances in the derma, disorganization of the connective tissue, and progressive fibrosis. Combination therapy including antihelmintic drug produced a positive effect, which was associated with induction of regenerative processes in basal epidermal cells, stabilization of the basal membrane, and normalization of the dermoepidermal junction. Our findings indicate that opisthorchiasis plays an important role in the pathogenesis of allergic dermatoses.     

Spondylo-meta-epiphyseal dysplasia (SMED), short limb-hand abnormal calcification type: Further expanding the mutational spectrum and dental findings of three new patients

Genetic skeletal disorders are clinically and genetically heterogeneous group of disorders that affect the normal development, growth, and maintenance of the human skeleton. Spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type (SMED-SL/AC; MIM# 271665) is a rare autosomal recessive genetic skeletal disorder characterized by distinctive facial features, disproportionate short stature, vertebral, metaphyseal, and epiphyseal abnormalities. This unique phenotype is caused by biallelic loss-of-function variants in Discoidin domain receptor 2 gene (DDR2, MIM# 191311). To date, only 10 pathogenic variants (six missense, two nonsense, one deletion, and one splice site) in DDR2 have been reported in patients with SMED-SL/AC. Dental anomalies related to skeletal dysplasia can include various abnormalities in the number, shape, and position of teeth in the jaw, as well as enamel hypoplasia and dentinogenesis imperfecta. Although abnormal dentition has previously been reported, orodental findings were described in only six patients with SMED-SL/AC. This study aimed to define the clinical, dental, radiological, and molecular findings of three new SMED-SL/AC patients from three unrelated families. Three DDR2 variants, two of which were novel, were detected with the aid of Sanger sequencing. Interestingly, one of the patients was diagnosed with Wilson's disease (WD) during the follow-up, a co-occurrence that has never been reported in patients with SMED-SL/AC so far.     

Psoriasis concomitant with chronic opisthorchiasis: ultrastructural changes in cell populations of gastroduodenal mucosa

Pathological changes based on degeneration of epithelial structures predominantly with preserved typical cell differentiation, but with unstable epithelial secretory function were detected in biopsy specimens of gastroduodenal mucosa from patients with psoriasis associated with chronic opisthorchiasis. The progress of the disease led to atrophy of glandular components and augmented stromal sclerosis. The compensatory adaptive reactions were realized via hyperplasia and hyperfunction of preserved glandulocytes, appearance of mix-cells with polypotent secretory cycle, and high functional activity of capillaries.     

Electron Microscopic Findings in Skin Biopsies from Patients with Danon Disease

Danon disease is a rare lysosomal disorder. It is due to deficiency of lysosomal-associated protein-2. In human LAMP-2 gene is located at chromosome region Xq24. Danon disease is characterized by hypertrophic cardiomyopathy, skeletal myopathy, mental retardation and retinopathy. To date, the morphological characterization of Danon disease has been limited to endomyocardial and skeletal muscle biopsies. In the current study we demonstrated that electron microscopy of a more accessible tissue, skin biopsies, is a useful method in the diagnosis of Danon disease.     

Galactosialidosis associated with IgA nephropathy: morphological study of renal biopsy

Galactosialidosis is an autosomal recessive lysosomal disease associated with a deficiency of β-galactosidase and neuraminidase. Described herein is the case of a young adult who had been diagnosed with galactosialidosis at 8 years of age. At the age of 30 years, proteinuria and hematuria appeared and the patient underwent a renal biopsy 1 year later. Light microscopy of the kidney sections indicated fine granular contents in the cytoplasm of glomerular endothelial and epithelial cells, arteriolar smooth muscles and proximal tubular epithelial cells on periodic acid silver–methenamin (PAM) stain. Electron microscopy of these cells indicated enlarged, smooth endoplasmic reticulum and lysosomes containing 150 nm-wide rods with a fine lattice structure at 66 Å periodicity. Moreover, electron-dense deposits were located in the paramesangial area. Immunofluorescence staining indicated diffuse and global anti-human IgA and C3-positive staining as a mesangial pattern. Given these findings this patient was therefore diagnosed with both galactosialidosis and IgA nephropathy. This is the first report to describe light and electron microscopy observations of storage materials in the kidneys in young/adult galactosialidosis.     

Chronic myelocytic leukemia: ultrastructural histopathology of bone marrow from patients in the chronic phase

We investigated the ultrastructural changes in the hematopoietic microenvironment of the bone marrow obtained from 15 untreated patients with chronic myelocytic leukemia (CML) in the chronic phase by transmission and scanning electron microscopy using the cryofracture technique. Examination of the unde-calcified bone marrow specimens confirmed extensive hyperplastic granulopoiesis. In the stroma, fat cells were scarce or absent. Macrophages were increased and scattered throughout the marrow. The cytoplasm contained abundant cellular debris and crystals of the Charcot-Ley den type. Slender reticular cells were inconspicuously located between proliferating myeloid cells. A few foci of fibrosis were occasionally observed. The sinus endothelium generally retained its continuity, and no features suggesting complete deterioration of the sinus were evident. However, certain alterations in the sinus wall were noted in the process of leukemia cell migration. Many cells migrated trans-cellularly into the circulation through transient large openings in the sinus endothelium.     

Clinical findings in 12 patients with MPS IV A (Morquio''s disease)

Odontoid dysplasia in the absence or presence of atlanto-axial instability was found in all cases. In general, this correlated well with the overall clinical severity of the condition and illustrates the importance of careful follow-up of these patients. Symptoms or signs of cervical cord compression merit further investigation. Proven compromise of the upper cervical cord is an indication for posterior fusion of the upper cervical spine.