Carpal tunnel syndrome and finger deformities in children with mucopolysaccharidoses and mucolipidoses: a retrospective review of 52 patients.

This single-centre retrospective study reports our management of carpal tunnel syndrome in 52 children (103 hands) with mucopolysaccharidoses and mucolipidoses. All except one were bilateral. The median age at surgery was 4 years (range 1.5 to 12). The diagnosis of carpal tunnel syndrome was confirmed by an electromyogram (EMG) in all patients; 38% of these presented without any clinical signs. Surgical neurolysis was performed in all hands, combined with epineurotomy in 52 hands (50%) and flexor tenosynovectomy in 75 hands (73%). Surgery was bilateral in 98% of children (102 hands). The mean follow-up was 12 years (range 1 to 19) and the EMG was normalized in 78% of hands. Ten patients suffered recurrence, eight of whom required further surgery. Screening for carpal tunnel syndrome is essential for the management of children mucopolysaccharidoses and mucolipidoses. Surgical treatment should be carried out early with follow-up by EMG to detect recurrence.Level of evidence: IV.

The rare reason of pain in hip girdle: Mucolipidosis type 3 gamma.

BACKGROUND: Mucolipidosis type 3 gamma (ML-IIIγ) is an autosomal recessive, rare and slowly progressive lysosomal storage disease. Short stature, restricted joint mobility, thick skin, and flat face with mildly coarse features are major clinical findings. It usually manifests in the third year. With advancing age, claw hand deformities, carpal tunnel syndrome, and scoliosis may develop. Morbidity is determined mainly by skeletal involvement. N-acetyl glucosamine-1 phospotransferase enzyme is composed of 2α, 2ß and 2γ subunits. The active enzyme is essential in the transport of hydrolases to the lysosomes, via addition of mannose-6-phosphate in the Golgi apparatus. GNPTG gene encodes the γ2 subunits, and biallelic mutations cause ML-IIIγ. CASE: A previously healthy 14-year-old male patient had leg pain after the age of nine, and was admitted with short stature, mild coarse face, pectus deformity, digital stiffness, scoliosis, genu valgum and mitral valve prolapse. He did not have intellectual disability or corneal clouding. Radiographs showed irregularities in the acetabular roof and proximal epiphyses of the femur and irregularities in the end plates of vertebral bodies. A novel homozygous missense variant in the exon 5 of GNPTG, c.316G > T, confirmed the diagnosis of ML- IIIγ. Juvenile idiopathic arthritis (JIA), progressive pseudorheumatoid dysplasia (PPRD), ML-II, ML-IIIαß, galactosialidosis and mucopolysaccharidosis should be considered in the differential diagnosis. CONCLUSIONS: ML-IIIγ should be kept in mind in populations with high consanguineous marriage rates or with possible founder effect, in patients with short stature and skeletal destruction. Genetic tests should be planned for a definitive diagnosis.

Perioperative management of patients with Mucolipidosis II and III: Lessons from a case series.

Mucolipidosis (ML) II and III are complex lysosomal storage disorders characterized by progressive multisystem pathology which can pose challenges to the anesthetist and increase the risks associated with general anesthesia. We sought to review the management of patients with ML II and III undergoing anesthesia in our institution in order to better define recommendations for the preoperative assessment and optimization of these children. We further elected to analyze the conduct of anesthesia, intraoperative management, and perioperative complications that our patients had experienced in order to allow improved informed consent and anesthetic planning. We performed a retrospective examination of the medical notes of those patients who had undergone anesthesia in our institution to identify their clinical features, anesthetic technique, airway management, and perioperative complications. Five children underwent 11 episodes of anesthesia. Fiber-optic or videolaryngoscopy was utilized in six out of seven intubations, with four out of seven requiring a change from the method initially chosen to enable intubation. Four of the five patients had an abnormal echocardiogram. Three patients had radiological evaluation of their cervical spine, with two demonstrating abnormalities. One patient had changes suggesting instability at the atlantoaxial junction. Children and babies with ML II and III present multisystem challenges to the anesthetist. Multidisciplinary planning and assessment, followed by a discussion of risk, should proceed any elective surgery. These complex children should undergo elective anesthesia delivered by an experienced (pediatric) anesthetist in an appropriate tertiary center with on-site pediatric ENT and critical care support.

Hip disease in Mucopolysaccharidoses and Mucolipidoses: A review of mechanisms, interventions and future perspectives.

The hips are frequently involved in inheritable diseases which affect the bones. The clinical and radiological presentation of these diseases may be very similar to common hip disorders as developmental dysplasia of the hip, osteoarthritis and avascular necrosis, so the diagnosis may be easily overlooked and treatment may be suboptimal. Mucopolysaccharidosis (MPS) and Mucolipidosis (ML II and III) are lysosomal storage disorders with multisystemic involvement. Characteristic skeletal abnormalities, known as dysostosis multiplex, are common in MPS and ML and originate from intra-lysosomal storage of glycosaminoglycans in cells of the cartilage, bones and ligaments. The hip joint is severely affected in MPS and ML. Hip pathology results in limitations in mobility and pain from young age, and negatively affects quality of life. In order to better understand the underlying process that causes hip disease in MPS and ML, this review first describes the normal physiological (embryonic) hip joint development, including the interplay between the acetabulum and the femoral head. In the second part the factors contributing to altered hip morphology and function in MPS and ML are discussed, such as abnormal development of the pelvic- and femoral bones (which results in altered biomechanical forces) and inflammation. In the last part of this review therapeutic options and future perspectives are addressed.

Microvillous Inclusion Disease as a Cause of Protracted Diarrhea.

Microvillous inclusion disease (MVID), also known as congenital microvillus atrophy, was first described by Davidson et al. in 1978. Till date, only a handful of cases with MVID have been described in English literature. It is an autosomal recessive disorder with no sex predisposition and more commonly noted in countries with prevalent consanguineous marriages. These patients usually present with intractable secretory diarrhea in early days of life. The pathognomonic findings of MVID are villous atrophy along with the formation of intracellular microvillous inclusions on electron microscopy. Till date, no curative therapy exists, and prognosis mainly depends upon parenteral nutrition. Small bowel transplantation is one of the treatment options. Clinician and pathologist should consider the possibility of MVID in the differential diagnosis of chronic intractable diarrhea in an infant. Herein, authors are describing a case of intractable diarrhea with MVID phenotype diagnosed in a 3-mo-old male child who presented with intractable diarrhea in an outside hospital, and the diagnostic workup was performed by the authors on endoscopic biopsy sample.

Mucolipidosis type IV in a child.

Mucolipidosis type IV is a rare autosomal recessive lysosomal storage disorder with psychomotor developmental delay, visual impairment, and achlorhydria. A mutation in the MCOLN1 gene causes an alteration of the protein mucolipin-1 that results in the accumulation of lipids and proteins in cytoplasmic vacuoles derived from lysosomes. Visual impairment results mainly from corneal clouding and retinal degeneration. The involvement of the corneal epithelium has been proposed following clinical observation and confirmed by ultrastructural studies of the cornea. We present the case of a child of French Canadian origin affected by mucolipidosis type IV who showed abnormal optical coherence tomography imaging of the cornea, typical skin cell inclusions on electronic microscopy, and a novel pathogenic mutation.

The carpal tunnel syndrome in children.

INTRODUCTION: Carpal tunnel syndrome (CTS) in children represents a complex challenge for the hand surgeon because of its rarity, poor patient cooperation, frequently associated malformation syndromes and mental retard, atypical symptoms and nuanced and poor sensitivity of instrumental tests. The most frequently associated causes with the CTS in children are rare congenital malformations and diseases, requiring an overall assessment of the young patient and a high degree of suspicion for the potentially associated canalicular syndrome. On the other hand, the associated syndromes may be the main ally for a diagnosis that starts from the knowledge of the literature and the surgeon's suspicion by observing the child wailing. Early diagnosis and decompression treatment is mandatory. MATERIALS AND METHODS: The authors report a case series of 26 children and analyze the etiology and diagnostic algorithms. Patient assessment was based on complete clinical examination and medical history collection of these young patients with the involvement of the family and educators. RESULTS: In all 26 patients treated, along an average period of 23 months (minimum 12, maximum 30), no signs of recurrence or persistence of median nerve disturbances were recorded. CONCLUSIONS: In conclusion, we believe that anamnesis, a careful physical examination and analysis of instrumental examinations, should be accompanied by a thorough knowledge of rare diseases in the context of congenital malformations. The carpal tunnel syndrome, while well known and treated by each orthopedic surgeon, reveals a mysterious aspect in the context of the "fabulous" world of childhood illnesses, even more difficult than rare congenital diseases.

Left Main Coronary Artery Atresia in an Infant With Inclusion-Cell Disease.

A 2-month-old male with dysmorphic facies, neonatal thrombocytopenia, left congenital cataract, and long bone abnormalities became hypotensive with ST depression on induction of anesthesia for congenital cataract repair. Echocardiogram demonstrated decreased left ventricular function (ejection fraction 46%), mild mitral valve regurgitation (MR), and regional wall motion abnormalities. The left coronary artery could not be visualized. Subsequent cardiac catheterization confirmed atresia of the left main coronary artery. The patient underwent cardiac surgery with coronary artery bypass grafting of the left internal mammary artery to the left anterior descending coronary artery. His postoperative course was uncomplicated, his ventricular function normalized, and he was discharged home. Over the next few months, he developed progressive, severe MR refractory to medical management. Repeat cardiac catheterization revealed stenosis of the right proximal coronary artery, raising concern for progressive coronary involvement. In addition to dysmorphic features and failure to thrive, there were profound developmental delays and a finding of vacuolated lymphocytes on blood smear, which led to a diagnosis of mucolipidosis II (Inclusion [I]-cell disease). The patient was referred for mitral valve replacement, which was successful; however, ongoing respiratory issues attributed to the progression of I-cell disease led to a prolonged hospitalization with placement of a tracheostomy. Reports of coronary anomalies in patients with I-cell disease are rare. An association between mucopolysaccharidosis syndromes and coronary artery abnormalities has been established and is supported by this case report, highlighting the importance of considering the potential for coronary artery involvement with I-cell disease and other similar storage diseases.

Enfermedad por inclusión microvellositaria como causa de diarrea congénita severa: caso clínico / Microvillous inclusion disease as a cause of severe congenital diarrhea: case report

Las diarreas congénitas son patologías graves de baja frecuencia y alta mortalidad. Se manifiestan durante los primeros días o meses de vida con severa diarrea, generando insuficiencia intestinal y dependencia de nutrición parenteral. Se debe sospechar ante un recién nacido o lactante con pérdidas masivas hidroelectrolíticas, y se diagnostican utilizando parámetros clínicos, endoscópicos, histológicos y eventualmente genéticos. El tratamiento es de soporte, con reposición hidroelectrolítica intensa y nutricional. OBJETIVO: Presentar un caso de diarrea congénita, identificada como Enfermedad por Inclusión Microvellositaria, de presentación neonatal. CASO CLÍNICO: Paciente varón edad actual 3 años, hijo de padres consanguíneos, quien debutó a los 10 días de vida con diarrea secretora severa, requiriendo ingreso a unidad de paciente crítico y nutrición parenteral permanente. Inicialmente además con síndrome de Fanconi, que luego se recupera. Se confirmó la sospecha de Enfermedad de Inclusión Microvellositaria utilizando microscopia óptica, electrónica e inmunohistoquímica. Se obtuvo una favorable evolución utilizando nutrición parenteral total (NPT) a domicilio. CONCLUSIONES: Se presenta el primer caso conocido en Chile de un paciente con diarrea congénita por inclusión microvellositaria manejado y su evolución.

Congenital diarrheas correspond to a severe and low frequency digestive disease, with a high mortality. They start a few days or months after birth, leading to intestinal insufficiency and dependence on parenteral nutrition. It must be highly suspected in newborns or infants with diarrhea and severe electrolyte disorders. The diagnosis is based on clinical, endoscopic, histologic and eventually genetic findings. Treatment is supportive with intensive correction of electrolyte imbalances as well as parenteral nutrition. OBJECTIVE: To present a case report of congenital diarrhea identified as microvillous inclusion disease presenting in the neonatal period. CASE REPORT: Male patient currently 3 years of age, son of consanguineous parents. At 10 days of age presents a severe secretory diarrhea, requiring treatment in a critical care unit and parenteral nutrition. Initially he also presented with Fanconi syndrome, which improved afterwards. The suspicion of congenital microvillous inclusion was confirmed later by optic and electronic microscopy, and inmunohistochemistry. A succesful evolution was later achieved maintaining home parenteral nutrition after discharge. CONCLUSION: We present the first known case in Chile of congenital diarrhea due to microvillous inclusión disease and his evolution.

[Intestinal failure and transplantation in microvillous inclusion disease]. / Fracaso intestinal y trasplante en la enfermedad por inclusiones microvellositarias.

INTRODUCTION: Microvillous inclusion disease is a rare autosomal recessive condition, characterized by severe secretory diarrhea that produces a permanent intestinal failure and dependency on parenteral nutrition. It usually begins in the neonatal period, and the only treatment at present is intestinal transplantation. PATIENTS AND METHODS: A retrospective review was conducted on 6 patients (three males and three females) diagnosed with microvillous inclusion disease between 1998 and 2013. RESULTS: All debuted in the first month of life, with a median age of three days (range, 3-30 days), and had secretory diarrhea dependent on parenteral nutrition, with fasting fecal volume of 150-200ml/kg/day. Light microscopy of duodenal biopsy samples showed varying degrees of villous atrophy without cryptic hyperplasia, accumulation of PAS positive material in the cytoplasm of enterocytes brush border, and anti-CD10 immunostaining was suggestive of intracytoplasmic inclusions. Diagnostic confirmation was performed with electron microscopy. Two of them had a genetic study, and showed mutations in MYO5B gene. Three died and three are alive; two of them with an intestinal transplantation and the third waiting for a multivisceral transplantation.

Microvillous atrophy: atypical presentations.

OBJECTIVES: Microvillous inclusion disease (MVID) is a cause of intractable diarrhea in infancy. In its classic form, the disease is characterized by a severe persistent watery diarrhea starting within the first days of life. Parenteral nutrition and small bowel transplantation are the only known treatments for the affected children. Histologically, periodic acid-Schiff (PAS) staining shows accumulation of periodic acid-Schiff-positive staining material along the apical pole of enterocytes, whereas transmission electron microscopy exhibits microvillus inclusion bodies within the cytoplasm of enterocytes with rarefied and shortened microvilli and secretory granules. The objective of this work was to explore clinical, morphological, and genetic findings in cases of MVID with unusual presentations. METHODS: Clinical, histological, and genetic findings are reported for 8 cases of MVID with atypical presentation. RESULTS: The diarrhea started after several months in 3 cases. It was usually less abundant and 3 patients were weaned off parenteral nutrition. None required intestinal transplantation. Three patients experienced malformations, dysmorphy, sensory disabilities, and severe mental retardation. One had a hydrocephaly. Three patients had a cholestasis with low γ-glutamyl transferase levels. Light microscopy showed histological abnormalities consistent with MVID in all of the cases, but the lesions were sometimes focal or delayed. Transmission electron microscopy retrieved some criteria of MVID in 4 patients. Finally, 6 patients were homozygotes or compound heterozygotes for MYO5B mutations. CONCLUSIONS: This study extends the spectrum of MVID to less severe clinical presentations.

Intractable diarrhea of infancy: 10 years of experience.

OBJECTIVES: Intractable diarrhea of infancy (IDI), a group of prolonged diarrheal disorders, is difficult to diagnose and manage. We documented general features of patients and the causes of IDI. METHODS: The present retrospective study included 60 hospitalized patients with IDI ages 0 to 24 months during January 2000 to December 2010. Detailed history, laboratory and endoscopic findings, diagnoses, and clinical courses were reviewed. Descriptive analyses were used for statistical evaluation. RESULTS: The male/female ratio was 1.4. The median age at onset of diarrhea was 12 days. A total of 70% and 11% of patients were severely and moderately malnourished, respectively. Carbohydrate malabsorption (CM) and food allergies (n = 11, 18% for both) were the most frequent causes. A total of 16 of the patients (27%) did not have a specific diagnosis. The other diagnoses were infections (n = 5), immune-mediated disorders (IMD) (n = 6), congenital enterocyte defects (CED) (n = 3, 5%), short bowel syndrome (n = 2), cystic fibrosis (n = 2), intestinal pseudoobstruction (n = 1), congenital disorder of glycosylation (n = 1), abetalipoproteinemia (n = 1), and proprotein convertase (PC) 1 deficiency (n = 1). Stool calprotectin level was high in 10 of 19 patients with Crohn disease (n = 3, mean 1116 ± 851 mg/L), food allergy (n = 4, mean 516 ± 288 mg/L), and undefined etiology (n = 3, mean 616 ± 780 mg/L). The mean duration of hospitalization was 76 days. CONCLUSIONS: IDI is a heterogeneous group of diarrheal disorders. The most frequent causes were CM and food allergies in our study. Because high levels of calprotectin support inflammation, calprotectin levels may help to discriminate CED and inflammatory causes of IDI.

Histological, biochemical, and genetic characterization of early-onset fulminating sialidosis type 2 in a Korean neonate with hydrops fetalis.

Non-immune hydrops fetalis is the most severe presenting feature of lysosomal storage disorders. However, it is difficult to identify the underlying condition because the different lysosomal storage diseases share many clinical features. A neonate with hydrops fetalis is described here. A lysosomal storage disorder was first suspected when the placental biopsy showed the presence of macrophages containing numerous cytoplasmic vacuoles. Subsequent comprehensive diagnostic processes and biochemical and molecular genetics characterization revealed a rare genetic cause, namely sialidosis type 2. Liquid chromatography-mass spectrometry revealed increased amounts of bound sialic acid in the urine. Pathogenic NEU1 mutations were detected. This is the first case with sialidosis type 2 ever known in the Korean population, exhibiting its most severe manifestation.

MYO5B mutations in patients with microvillus inclusion disease presenting with transient renal Fanconi syndrome.

BACKGROUND AND OBJECTIVE: : Microvillus inclusion disease (MVID) is a rare congenital enteropathy associated with brush border atrophy and reduced expression of enzymes at the enterocytes' apical surface. MVID is associated with mutations in the MYO5B gene, which is expressed in all epithelial tissues. Whether organs other than the intestine are affected in MVID is unclear. We report 2 patients with MVID that developed renal Fanconi syndrome while receiving total parenteral nutrition. Renal Fanconi syndrome has been correlated to apical plasma membrane defects in kidney proximal tubular epithelial cells. The aim of the present study was to determine whether MYO5B mutations in these patients correlate with similar apical plasma membrane defects in renal tubular epithelial cells as observed in the intestine. METHODS: : Biopsies from kidney, duodenum, ileum, jejunum, and colon of 2 patients with MVID carrying MYO5B mutations and of age-matched controls were fixed in paraffin and analyzed with immunohistochemistry and transmission electron microscopy. RESULTS: : Structural defects of the brush border and apical recycling endosome organization are observed in enterocytes of all of the segments of the small intestine and colon. MYO5B mutations in patients with MVID with renal Fanconi syndrome do not correlate with aberrant apical plasma membrane morphology or altered apical recycling endosome organization in renal tubular epithelial cells. CONCLUSIONS: : MYO5B mutations have divergent effects on the apical membrane system in kidney and intestinal epithelial cells. Epithelial defects presented in MVID are therefore likely triggered by intestine-specific factors, the identification of which may provide new targets and open avenues for the development of alternative therapeutic strategies to combat this devastating disease.

Microvillous inclusion disease diagnosed by gastric biopsy.

Protracted diarrhea in neonates is uncommon and usually requires an intestinal biopsy for etiological diagnosis. Gastric biopsy has not been used in the routine diagnosis of this condition. We report the first documented patient with microvillous inclusion disease from India, where the diagnosis was established by a gastric biopsy.

Unusual pulmonary findings in mucolipidosis II.

We report undescribed pulmonary findings in a child with mucolipidosis II (ML-II). Children with ML-II bear significant pulmonary morbidity that may include extensive pulmonary fibrosis, persistent hemosiderosis as well as pulmonary airway excrescences as they reach preschool age.

Severe hypernatremic dehydration and metabolic acidosis due to neonatal intestinal microvillus inclusion disease.

Neonatal microvillus inclusion disease (MID) is a congenital secretory diarrhea diagnosed by morphological enterocyte abnormalities on histology. The secretory diarrhea associated with MID occurs within the first few hours of birth and is exacerbated by enteral feeding. Affected newborns will die of dehydration and acid-base disturbances if MID is not rapidly recognized and treated with massive intravenous fluid replacement and gut rest. We report a case of a 4-day-old neonate presenting with 18% weight loss, hypernatremic dehydration and metabolic acidosis. Despite aggressive fluid resuscitation (206 ml/kg for the first 24 h), the dehydration and metabolic acidosis were only minimally improved. The diapers were found soaked with clear, non-odorous fluid on repeated examinations. Persistent secretory diarrhea was suspected. Stool electrolytes analyses showed a high NaCl content typical of secretory diarrhea and intestinal biopsy with electron microscopy was diagnostic of MID.