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A: Patient 2 at 3 years of age. The paired twin nevi (telangiectatic nevus and nevus anemicus) are easily seen in the left cheek; (B and C) note the same vascular malformations at 13 years of age, which is minimally faded due to the natural history of the nevi and to the therapeutic effects of laser treatment performed shortly after 3 years of age; (D) similar vascular lesions are noticeable in the inner mucous membranes of the left mouth.
Source publication
Introduction:
Mucopolysaccharidosis (MPS) represent a heterogeneous group of inheritable lysosomal storage diseases in which the accumulation of undegraded glycosaminoglycans (GAGs) leads to progressive damage of affected tissues. The typical symptoms include organomegaly, dysostosis multiplex, mental retardation and developmental delay. Definitiv...
Contexts in source publication
Context 1
... birth, multiple, patched, erythematous, and port-wine stains were noted on the left hemi-face. At 3 years (Fig. 6A) of age, she was referred to a dermatology laser clinic for treatment of the vascular malformations. She underwent laser treatment with partial and temporary improvement of the left facial vascular ...
Context 2
... referred to our institution because of frequent (daily-to-weekly), brief (several minutes) episodes of headaches without a predominant localization. She fully recovered from these bouts after resting without treatment. On examination, her growth parameters were within the 50th centile. The facial vascular malformation was only minimally reduced (Fig. 6B), and consisted of a telangiectatic vascular nevus involving her left cheek. In addition, multiple, large, patches of varying sizes and shapes distinctly paler in the inner areas surrounded by dotted erythematous adjacent skin and smaller satellite paler macules were present in the same area of the left face (Fig. 6C). Enhancement of ...
Context 3
... was only minimally reduced (Fig. 6B), and consisted of a telangiectatic vascular nevus involving her left cheek. In addition, multiple, large, patches of varying sizes and shapes distinctly paler in the inner areas surrounded by dotted erythematous adjacent skin and smaller satellite paler macules were present in the same area of the left face (Fig. 6C). Enhancement of the paler inner-dotted areas and satellite macules was demonstrated upon stroking (or applying heat or cold) to the involved and adjacent skin, which became erythematous, consistent with the diagnosis of a nevus anemicus. These lesions were also recorded in the inner mucosa of the mouth (Fig. 6D) and in the left ear and ...
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... in the same area of the left face (Fig. 6C). Enhancement of the paler inner-dotted areas and satellite macules was demonstrated upon stroking (or applying heat or cold) to the involved and adjacent skin, which became erythematous, consistent with the diagnosis of a nevus anemicus. These lesions were also recorded in the inner mucosa of the mouth (Fig. 6D) and in the left ear and left retro-auricular region. Her parents declined a skin biopsy. Routine blood and urinalysis including coagulation tests were within nor- mal limits. A full ophthalmologic examination was negative. An ECG, EEG, and ultrasound of the heart and internal organs were normal. Skull X-rays showed mild-to-moderate ...
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... that ''lesions adopting these shapes may show areas of normal tissue within the patch, inter- mingled with involved areas, leading to a somewhat reticular pattern with preserved irregular borders''. This pattern is similar to the reticular pattern encountered in large areas in Patient 1 (see Figs. 1-3), and, to a lesser extent in Patient 2 (see Fig. 6B-C). These reticular patterns likely led to the initial misdiagnosis of cutis marmorata telangiectatica congenita (CMTC or Van Lohuzein syndrome) in Patient 1 that, despite the lesions, lacked the lilaceous banding in a livedoid pattern with areas of skin atrophy, which is typical of the CMTC [Eerola et al., 2002[Eerola et al., , ...
Citations
... In lysosomal storage disorders, such as mucopolysaccharidoses, skeletal abnormalities known as dysostosis multiplex often accompany macrocephaly. These abnormalities may include dolichocephaly, facial deformities, thoracic abnormalities, proximally pointed metacarpals, and broad, bullet-shaped phalanges [8,83,84,98,116]. Beta-thalassemia evolves with macrocephaly, alongside "tower skull" due to ectopic hematopoiesis, lateral malar prominence, kyphosis, and decreased spinal height, sausage-like fingers and sometimes hypercoagulability, leg ulcers, and vascular changes [67,[117][118][119]. ...
Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals.
... In the second and more severe case, patients display cognitive impairment, developmental delay and progressive neurocognitive regression in addition to somatic manifestations [4]. These symptoms are frequently paralleled by CNS anatomical defects: indeed, patients may present focal or diffuse white matter lesions, progressive demyelination and hydrocephalus [5]. CNSrelated abnormalities frequently arise by 4 years of age but can be anticipated to the first year of age in rapidly progressing cases, making MPS II a disease with paediatric onset [6]. ...
... Moreover, Dcc mutations have been associated with human neuro-pathologies such as Congenital Mirror Movement (CMM) and Developmental Split-Brain syndrome in which patients display defects in the axons of the cortico-spinal tract, anomalies in commissure fasciculation and partial agenesis of the corpus callosum [12]. This structure is a thick fascicle of commissural fibres involved in hemispheres communication and represents one of the most frequently affected CNS structures in MPS II patients [5]. ...
Most of the patients affected by neuronopathic forms of Mucopolysaccharidosis type II (MPS II), a rare lysosomal storage disorder caused by defects in iduronate-2-sulfatase (IDS) activity, exhibit early neurological defects associated with white matter lesions and progressive behavioural abnormalities. While neuronal degeneration has been largely described in experimental models and human patients, more subtle neuronal pathogenic defects remain still underexplored. In this work, we discovered that the axon guidance receptor Deleted in Colorectal Cancer (Dcc) is significantly dysregulated in the brain of ids mutant zebrafish since embryonic stages. In addition, thanks to the establishment of neuronal-enriched primary cell cultures, we identified defective proteasomal degradation as one of the main pathways underlying Dcc upregulation in ids mutant conditions. Furthermore, ids mutant fish-derived primary neurons displayed higher levels of polyubiquitinated proteins and P62, suggesting a wider defect in protein degradation. Finally, we show that ids mutant larvae display an atypical response to anxiety-inducing stimuli, hence mimicking one of the characteristic features of MPS II patients. Our study provides an additional relevant frame to MPS II pathogenesis, supporting the concept that multiple developmental defects concur with early childhood behavioural abnormalities.
... Essential steps in the substitution process include apoptosis of hypertrophic chondrocytes, resorption of mineralized ECM, and homing of blood vesselassociated progenitor cells producing bone, marrow stroma, and marrow adipose tissue (16,21). Accordingly, available studies on the mechanisms underlying the abnormal retention of cartilage observed in MPS IH endochondrally formed bone (12)(13)(14)(22)(23)(24) are mainly focused on the effects of GAG accumulation on this sequence of events (10,14,25). Recent evidence, however, demonstrates that endochondral ossification is a more complex phenomenon in which specific chondrocyte subsets escape death and undergo a phenotypic shift that leads to the direct remodeling of cartilage into other skeletal tissues (26)(27)(28)(29). ...
Dysostosis multiplex is a major cause of morbidity in Hurler syndrome (mucopolysaccharidosis type IH [MPS IH], OMIM #607014) because currently available therapies have limited success in its prevention and reversion. Unfortunately, the elucidation of skeletal pathogenesis in MPS IH is limited by difficulties in obtaining bone specimens from pediatric patients and poor reproducibility in animal models. Thus, the application of experimental systems that can be used to dissect cellular and molecular mechanisms underlying the skeletal phenotype of MPS IH patients and to identify effective therapies is highly needed. Here, we adopted in vitro/in vivo systems based on patient-derived bone marrow stromal cells to generate cartilaginous pellets and bone rudiments. Interestingly, we observed that heparan sulphate accumulation compromised the remodeling of MPS IH cartilage into other skeletal tissues and other critical aspects of the endochondral ossification process. We also noticed that MPS IH hypertrophic cartilage was characterized by dysregulation of signaling pathways controlling cartilage hypertrophy and fate, extracellular matrix organization, and glycosaminoglycan metabolism. Our study demonstrates that the cartilaginous pellet-based system is a valuable tool to study MPS IH dysostosis and to develop new therapeutic approaches for this hard-to-treat aspect of the disease. Finally, our approach may be applied for modeling other genetic skeletal disorders.
... There are eleven different types of enzyme deficiencies, which are associated with seven different types of MPS (MPSI, II, III, IV, VI, VII, IX). 1 Type IV MPS, also known as Morquio syndrome is a rare lysosomal storage disorder which consists of MPS IV A, which results from mutations in galactose-6-sulfatase genes, and MPS IV B, which results from beta-galactosidase deficiency. 2,3 This enzyme defect is acquired in an autosomal recessive mannerdue to the mutation in GALNS gene. ...
Mucopolysaccharidosis (MPS) IVA, or Morquio syndrome, is a rare lysosomal storage disorder characterized by skeletal dysplasia. It is caused due to deficiency in the enzyme N-acetylgalactosamine-6-sulfatase (GALNS), which results from an autosomal recessive mutation in the GALNS gene. The frequency of this mutation is equivalent in men and women. Here in, we present the case of Morquio syndrome, in a male child of twin gestation with poor antenatal and natal history. The peculiar presentations are those of skeletal deformities, coarse facial features, recurrent respiratory tract infections, and a history of NICU admission for meconium aspiration syndrome. This case is unique because, despite a negative family and prenatal history, and one of the twins being unaffected which adds to its appeal. Later, on biochemical and radiological investigations, he was diagnosed with mucopolysaccharidoses IVA and ultimately managed him supportively.
... 10). 26 Mucolipidosis Mucolipidosis (ML) is autosomal recessive lysosomal storage disorder that results in development of abnormal cell architecture and inclusion of intracytoplasmic bodies within the mesenchymal cells, particularly fibroblasts. Resultant overflow of lysosomal enzymes is seen into the serum/CSF/urine. ...
Skeletal dysplasias or osteochondrodysplasias comprise a large heterogeneous group of genetic disorders and possess significant overlap on imaging, which adds to the dilemma of the reporting radiologist. These entities are routinely evaluated with a detailed skeletal survey and hand radiographs form a crucial part of a complete survey. Certain conditions have characteristic imaging findings that enable a diagnosis be made on hand radiograph alone. Additionally, hand radiographs may also demonstrate findings that may be suggestive of a particular diagnosis/differential diagnoses and would warrant further assessment for proving the same. We aim to demonstrate the use of hand radiographs in diagnosis of various such entities through this review. Although they cannot replace a complete skeletal survey in the diagnosis, hand radiographs performed for other indications might alert a radiologist to the diagnosis of an unsuspected skeletal dysplasia.
... The diagnosis of MPS VI is made through urine GAG analysis, enzyme studies in cultured fibroblasts, or genetic analysis. Imaging plays an important role in detecting the disease, with skeletal abnormalities, kyphoscoliosis, and atlantoaxial instability suggestive features on radiography and echocardiography used to evaluate cardiac anomalies [14]. CT can assess the entire airway in patients, while MRI of the head and neck can be useful for detecting hydrocephalus or cervical cord compression [15]. ...
MUCOPOLYSACCHARIDOSIS TYPE VI, ALSO KNOWN AS MAROTEAUX-LAMY SYNDROME IS A RARE GENETIC DISORDER THAT IMPAIRS THE BODY'S ABILITY TO BREAK DOWN GLYCOSAMINOGLYCANS, LEADS TO VARIOUS SYMPTOMS SUCH AS SKELETAL ABNORMALITIES, JOINT STIFFNESS, VISION AND HEARING PROBLEMS, AND HEART AND LUNG COMPLICATIONS. WE REPORT A CASE OF A 15-YEAR-OLD FEMALE PATIENT WITH MAROTEAUX-LAMY SYNDROME, PRESENTING WITH DECREASED HEIGHT, SQUINTING, AND DIFFICULTY WALKING. IMAGING STUDIES REVEALED SEVERAL SKELETAL ABNORMALITIES, AND THE PATIENT'S ACTUAL BONE AGE CORRESPONDED TO THAT OF A THREE-YEAR-OLD FEMALE. ENZYME REPLACEMENT THERAPY AND PHYSIOTHERAPY LED TO CONSIDERABLE IMPROVEMENT IN MOBILITY, DISEASE PROGRESSION, AND BONE GROWTH. THIS CASE REPORT EMPHASIZES THE IMPORTANCE OF EARLY DIAGNOSIS AND TREATMENT IN MANAGING MAROTEAUX-LAMY SYNDROME
... Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage diseases caused by a deficiency of glycosaminoglycan (GAG) catalytic enzymes, previously termed mucopolysaccharides [1][2][3]. As a result, there is an accumulation of unprocessed or partly degraded GAGs in lysosomes and in extracellular space, leading to chronic and progressed cell degeneration of affected tissues, including central nervous system, heart, respiratory system, bones, and joints [1][2][3][4][5][6][7]. ...
... Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage diseases caused by a deficiency of glycosaminoglycan (GAG) catalytic enzymes, previously termed mucopolysaccharides [1][2][3]. As a result, there is an accumulation of unprocessed or partly degraded GAGs in lysosomes and in extracellular space, leading to chronic and progressed cell degeneration of affected tissues, including central nervous system, heart, respiratory system, bones, and joints [1][2][3][4][5][6][7]. ...
... Mucopolysaccharidosis II was the first MPS defined clinically in humans, and it is the only MPS transmitted in an X-linked manner, with an estimated incidence of 1 in 250,000 individuals [2][3][4]. Clinically, MPS usually presents a chronic and progressive course, with musculoskeletal manifestations being common in all types. It has been reported that patients with MPS II have a prevalence of 80% for such manifestations [4,5,[7][8][9][10]. ...
Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage diseases caused by a deficiency of glycosaminoglycan (GAG) catalytic enzymes, resulting in an accumulation of unprocessed or partly degraded GAGs in different tissues, including bones and joints. Notably, skeletal and joint abnormalities may be the first complaint that prompts patients to seek medical attention, especially in the milder forms of the disease. To our knowledge, there are no prior imaging reports that have documented capsuloligamentous thickening in patients with MPS on MRI. In this study, we present four cases of patients with clinically and genetically confirmed diagnosis of type II MPS, encompassing seven MRI examination of different joints, including cervical spine, hip, wrist, knee, and shoulder. All of the patients were male, aged between 14 and 35 years, and exhibited varying degrees of joint stiffness in the clinical examination and carpal tunnel syndrome in cases of the wrist joint was affected. None of the patients had a history of surgical procedures on the affected joint, other metabolic or deposit diseases, or sports activity practice. The MRI revealed significant capsuloligamentous and retinaculum thickening, up to eight times greater than the normal capsular thickness reported in the literature.
... In the second and more severe case, patients display cognitive impairment, developmental delay and progressive neurocognitive regression in addition to somatic manifestations 4 . These symptoms are frequently paralleled by CNS anatomical defects: indeed, patients may present focal or diffuse white matter lesions, progressive demyelination and hydrocephalus 5 . CNS-related abnormalities frequently arise by 4 years of age but can be anticipated to the rst year of age in rapidly progressing cases, making MPS II a disease with paediatric onset 6 . ...
... Each time point was compared with matched DMSO condition. 5. Immuno uorescence and lysotracker staining on primary cell culture For immuno uorescence assays, primary cell cultures were xed with 2% PFA supplied with 1 mM CaCl 2 , 1 mM MgCl 2 and 4% sucrose for 10 min RT. ...
Most patients affected by neuronopathic forms of Mucopolysaccharidosis type II (MPS II), a rare lysosomal storage disorder, exhibit early neurological defects associated with white matter lesions and progressive behavioural abnormalities. While neuronal degeneration has been largely described in experimental models and human patients, more subtle neuronal pathogenic defects remains still underexplored. In this work we discovered that the axon guidance receptor Deleted in Colorectal Cancer (Dcc) is significantly dysregulated in the brain of ids mutant zebrafish since embryonic stages. In addition, thanks to the establishment of neuronal-enriched primary cell cultures from embryonic dissected brains, we identified defective proteasomal degradation as one of the main pathways underlying Dcc upregulation in ids mutant conditions. Furthermore, ids mutant fish-derived primary neurons displayed higher levels of polyubiquitinated proteins and P62, suggesting a wider defect in protein degradation. Finally, we show that ids larvae display atypical response to anxiety-like stimuli, hence mimicking one of the characteristic features of MPS II patients. Our study provides an additional relevant frame to MPS II pathogenesis, supporting the concept that multiple developmental defects concur to early childhood behavioural abnormalities.
... Inferior beaking of vertebrae in MPS type I and central beaking in MPS type 4 is evident on a lateral radiograph. 2 Other imaging findings include platyspondyly and widening of disk spaces, varus deformity of humerus with mildly hypoplastic epiphysis and proximal humeral notching, small scapula with glenoid cavities flattening, and thick and short clavicles. 2 Other characteristic imaging findings are discussed in ►Table 1. 2 Mucolipidoses: This group of disorders has overlapping imaging features with MPS. ...
... Inferior beaking of vertebrae in MPS type I and central beaking in MPS type 4 is evident on a lateral radiograph. 2 Other imaging findings include platyspondyly and widening of disk spaces, varus deformity of humerus with mildly hypoplastic epiphysis and proximal humeral notching, small scapula with glenoid cavities flattening, and thick and short clavicles. 2 Other characteristic imaging findings are discussed in ►Table 1. 2 Mucolipidoses: This group of disorders has overlapping imaging features with MPS. Apart from paddle-shaped ribs in CXR, other indicative findings include undermodeling of the long bones (humeri), and periosteal "cloaking" in long bones (►Fig. ...
... Inferior beaking of vertebrae in MPS type I and central beaking in MPS type 4 is evident on a lateral radiograph. 2 Other imaging findings include platyspondyly and widening of disk spaces, varus deformity of humerus with mildly hypoplastic epiphysis and proximal humeral notching, small scapula with glenoid cavities flattening, and thick and short clavicles. 2 Other characteristic imaging findings are discussed in ►Table 1. 2 Mucolipidoses: This group of disorders has overlapping imaging features with MPS. Apart from paddle-shaped ribs in CXR, other indicative findings include undermodeling of the long bones (humeri), and periosteal "cloaking" in long bones (►Fig. ...
Chest X-ray (CXR) is the most commonly used imaging modality. It is commonly used for respiratory or cardiac ailments; however, it is also used routinely as a part of skeletal surveys. In the case of suspected skeletal dysplasia, the viewer is alerted regarding the presence of some skeletal abnormality. But in case of a routine CXR performed for some other reason, it is not uncommon to miss subtle pointers of skeletal dysplasia. Sometimes routine CXR is the first pointer to alert a radiologist toward some generalized skeletal anomaly and therefore, initiate its proper evaluation by the skeletal survey.
... Here, we present a male patient confirmed with MPS I-H. A multidisciplinary approach enabled the rapid identification of radiological signs and symptoms, consis other cases presented in the literature (Figure 4) [12][13][14]. Latin American patients wi syndrome have a median age at onset, diagnosis, and first treatment of 1, 1.9, and respectively [14]. Conversely, our patient began his treatment at 10 months-old, 4 yea than the time reported in the literature. ...
... Here, we present a male patient confirmed with MPS I-H. A multidisciplinary medical approach enabled the rapid identification of radiological signs and symptoms, consistent with other cases presented in the literature (Figure 4) [12][13][14]. Latin American patients with Hurler syndrome have a median age at onset, diagnosis, and first treatment of 1, 1.9, and 5 years, respectively [14]. Conversely, our patient began his treatment at 10 months-old, 4 years earlier than the time reported in the literature. ...
Introduction:
Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease present in 1:100,000 newborns. Variants in the IDUA (alpha-L-iduronidase) gene decrease the enzyme activity for glycosaminoglycans metabolism. MPS I patients exhibit clinical manifestations that fall on the Hurler, Hurler-Scheie, and Scheie syndrome spectrum.
Case presentation:
We present a male Mexican patient with respiratory exacerbations requiring recurrent hospitalizations. He showed macrocephaly, coarse facies, hepatomegaly, umbilical hernia, and dorsal kyphosis. The sequencing of the IDUA gene revealed the following genotype: c.46_57del12/c.1205G>A. He received combined therapy with hematopoietic stem cell transplantation and enzyme replacement. Mexican case reports were analyzed to estimate the prevalence of the associated genetic variants.
Conclusion:
Despite the challenges of managing this rare disease in Mexico, our patient benefited from the combined therapy. The discrete clinical manifestations and prompt evaluation by a geneticist were crucial in establishing a diagnosis, enabling an early intervention by a multidisciplinary team. The combination of ERT before and after HSCT provided health benefits to our patient.
