Desensitization of two young patients with infantile-onset Pompe disease and severe reactions to alglucosidase alfa.

Pompe disease is a metabolic myopathy, due to deficiency of alpha glucosidase, with a wide clinical spectrum. Enzyme replacement therapy is the only available treatment to improve morbidity and mortality, especially in infantile-onset form. However, some patients experience infusion-associated reactions, which may restrict their access to this treatment. We report on two patients (respectively 12 and 3 months old) with infantile-onset Pompe disease and severe cardiomyopathy, that presented with severe reactions during infusion of enzyme replacement therapy and were successfully desensitized with a new individualized protocol. Our protocol, using microdilution and a premedication with antihistamines, corticosteroids, and tranexamic acid, seems safe and effective and it may allow the continuation of therapy in Pompe patients resulting in the reduction of morbidity and mortality related to this disease.

Clinical impact of the new SIAPEC-IAP classification on the indeterminate category of thyroid nodules.

BACKGROUND: The increasing frequency in the diagnosis of thyroid nodules has raised a growing interest in the search for new diagnostic tools to better select patients deserving surgery. In 2014, the major Italian Societies involved in the field drafted a new cytological classification, to better stratify pre-surgical risk of thyroid cancer, especially for the indeterminate category, split into TIR3A and TIR3B subclasses, associated to different therapeutic decisions. MATERIALS AND METHODS: This retrospective cross-sectional survey analyzed thyroid fine-needle aspiration biopsy performed at our outpatient clinic before and after the introduction of the new SIAPEC-IAP consensus in May 2014. RESULTS: 8956 thyroid nodules were included in the analysis: 5692 were evaluated according to the old classification and 3264 according to the new one. The new criteria caused the overall prevalence of TIR3 to increase from 6.1 to 20.1%. Of those, 10.7 and 9.4% were included in the TIR3A and TIR3B subgroups, respectively. Each of the 213 TIR3B nodules underwent surgery and 86 (40.4%) were diagnosed as thyroid cancer, while among the 349 TIR3A nodules, only 15 of the 60 that underwent surgery were found to be thyroid cancer. CONCLUSIONS: This analysis shows that the new SIAPEC-IAC criteria significantly increased the proportion of the overall TIR3 diagnosis. The division of TIR3 nodules into two subgroups (A and B) allowed a better evaluation of the oncologic risk and a better selection of patients to be referred to surgery.

Hypothyroidism and hyponatremia: data from a series of patients with iatrogenic acute hypothyroidism undergoing radioactive iodine therapy after total thyroidectomy for thyroid cancer.

PURPOSE: The aim of the present study was to evaluate the role of hypothyroidism as a cause of hyponatremia in a clinical model of iatrogenic acute hypothyroidism due to thyroid hormone withdrawal prior to ablative radioactive iodine (RAI) therapy after total thyroidectomy. METHODS: The study group consisted of 101 differentiated thyroid cancer (DTC) patients (77 women and 24 men). Plasma concentration of thyroid-stimulating hormone ([TSH]) and sodium ([Na+]) was evaluated before total thyroidectomy (pre[TSH] and pre[Na+]) and on the day of RAI therapy (post[TSH] and post[Na+]). RESULTS: The frequency of hypothyroidism-associated hyponatremia was 4 % (4/101). Pre[Na+] was significantly higher than post[Na+] (140.7 ± 1.6 vs 138.7 ± 2.3 mEq/L, p = 0.012). Moreover, a linear correlation was identified between pre[Na+] and post[Na+]. CONCLUSIONS: Iatrogenic acute hypothyroidism-related hyponatremia is uncommon. However, because of the significant reduction of [Na+] in the transition from euthyroidism to iatrogenic hypothyroidism, the value of pre[Na+] should be viewed as a parameter to be considered. Since it acts as an independent risk factor for the development of hyponatremia, patients with a pre[Na+] close to the lower limit of normal range may deserve a closer monitoring of [Na+].

Liver transplantation in defects of cholesterol biosynthesis: the case of lathosterolosis.

We report the outcome of liver transplantation (LT) in the only surviving patient with lathosterolosis, a defect of cholesterol biosynthesis characterized by high lathosterol levels associated with progressive cholestasis, multiple congenital anomalies and mental retardation. From her diagnosis at age 2 she had shown autistic behavior, was unable to walk unaided and her sight was impaired by cataracts. By age 7 she developed end-stage liver disease. After a soul-searching discussion within the transplantation team, she was treated with LT as this represented her only lifesaving option. At 1-year follow-up, her lathosterol levels had returned to normal (0.61 mg/dL from 13.04 ± 2.65) and her nutrition improved. She began exploring her environment and walking by holding onto an adult's hand and then independently. Her brain magnetic resonance imaging (MRI) had shown a normal picture at age 1, whereas a volume reduction of white matter with ex vacuo ventricular dilatation and defective myelinization were observed before transplant. At 5-year follow-up, a complete biochemical recovery, an arrest of mental deterioration and a stable MRI picture were achieved, with a return to her every day life albeit with limitations. Timely liver transplant in defects of cholesterol biosynthesis might arrest the progression of neurological damage.

Betamethasone therapy in ataxia telangiectasia: unraveling the rationale of this serendipitous observation on the basis of the pathogenesis.

Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive neurological dysfunction. To date, only supportive care aimed to halt the progressive neurodegeneration is available for the treatment. Recently, an improvement of neurological signs during short-term treatment with betamethasone has been reported. To date, the molecular and biochemical mechanisms by which the steroid produces such effects have not yet been elucidated. Therefore, a review of the literature was carried out to define the potential molecular and functional targets of the steroid effects in A-T. Glucocorticoids (GCs) are capable of diffusing into the CNS by crossing the blood-brain barrier (BBB) where they exert effects on the suppression of inflammation or as antioxidant. GCs have been shown to protect post-mitotic neurons from apoptosis. Eventually, GCs may also modulate synaptic plasticity. A better understanding of the mechanisms of action of GCs in the brain is needed, because in A-T during the initial phase of cell loss the neurological impairment may be rescued by interfering in the biochemical pathways. This would open a new window of intervention in this so far incurable disease.

Update on early cardiovascular and metabolic risk factors in children and adolescents affected with growth hormone deficiency.

Growth hormone (GH), in addition to promote linear growth during childhood, exerts a key role in several processes of substrate metabolism. Adults with untreated GH deficiency and adolescents who discontinued GH therapy at completion of growth, exhibit a cluster of cardiovascular risk factors such as impaired cardiac performance, alteration in body proportion with increased visceral fat, dyslipidemia and hypertension, that could place them at higher risk of cardiovascular morbidity. Although studies on adolescents and children are still scarce, there is evidence that early markers of cardiovascular disease can be already detected in untreated children with GH deficiency and that, as in adults, GH replacement therapy exerts a beneficial role on metabolic alterations. Untreated GH deficiency in childhood and adolescence seems to be associated with reduced cardiac size and impaired cardiac function, dyslipidemia, abnormalities in body composition and in peripheral inflammatory markers. GH replacement therapy exerts a beneficial effects on most of these alterations. Aim of this review is to summarize the current findings on the effects of GH deficiency and GH treatment on early cardiovascular risk factors in children and adolescents.

A simple ultrasound score for the identification of candidates to fine needle aspiration of thyroid nodules.

BACKGROUND: Cytological examination of fine needle aspirates (FNA) is the standard procedure for discriminating potentially malignant thyroid nodules to be referred to surgery. In a fraction of cases, ultrasound (US) examination could provide information theoretically sufficient to avoid FNA, when typical US features suggesting malignancies are lacking. AIM: The aim of this study was to construct a simple US score predicting malignant nodules so as to reduce the number of unnecessary FNA. SUBJECTS AND METHODS: In a series of 1632 consecutive patients undergoing US-guided FNA (1812 nodules), echostructure, echogenicity, margins, halo, microcalcification, and vascularization were assessed. RESULTS: At multivariate analysis, the following parameters showed a strong predictive value for positive cytology (Thy 4 and Thy 5, suspicious and diagnostic for malignancy, respectively, according to the Thyroid British Association): solid echostructure, irregular margins and hypoechogenicity [adjusted odd ratio (OR) 5.13 (1.58-16.66), 3.03 (1.70-5.39), 2.05 (1.17-3.57), respectively]. A 10-point Thyroid Risk Ultrasound Score (TRUS) was constructed on the basis of the adjusted OR. A TRUS≥6 identified malignant nodules with sensitivity and specificity of 73% and 65%, respectively. Among the patients with follicular lesions (Thy 3) and final diagnosis of carcinoma, about 65% had a TRUS≥6.0. CONCLUSIONS: The sensitivity of TRUS, although higher than that of other scores, could still be insufficient for the identification of patients who could avoid FNA in routine clinical practice, whereas its predictive value for Thy 3 lesions deserves further investigations.

Imaging of segmental testicular infarction: our experience and literature review.

PURPOSE: The purpose of this study was to evaluate the usefulness of the main methods of diagnostic imaging in patients with segmental testicular infarction (STI) for obtaining accurate clinical and therapeutic approaches. MATERIALS AND METHODS: Between January 2004 and January 2011, 798 patients were examined with colour Doppler ultrasound (CDUS) for disease of the scrotum. Fourteen patients with CDUS findings suspicious for STI were subjected to magnetic resonance imaging (MRI). In five patients, contrast-enhanced ultrasonography (CEUS) was performed. RESULTS: CDUS showed hypoechoic avascular areas suspicious for STI in 14 patients (1.75%). MRI confirmed the presence of predominantly hypointense lesions in T1- and T2-weighted sequences, with perilesional vasculature and no intrinsic contrast enhancement in 13 patients. In follow-up examinations, these abnormalities gradually decreased. This finding was confirmed in the five patients examined with CEUS. Only in one case did MRI reveal discrete intralesional contrast enhancement after injection of contrast medium, and the lesions appeared stable during the CDUS and MRI follow-up; this patient underwent orchiectomy, with a diagnosis of B-cell lymphoma. CONCLUSIONS: In our experience CDUS, CEUS and MRI proved indispensable for accurate clinical and therapeutic approaches in suspected STI.

Evaluation of the anterior pituitary function in the acute phase after spontaneous subarachnoid hemorrhage.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a potential cause of hypopituitarism. Most of the studies regarding the relationship between SAH and anterior pituitary function were retrospective and hormonal assessment was performed several months after SAH. AIM: To prospectively evaluate the prevalence of anterior pituitary hormone deficiencies in the acute phase after spontaneous SAH and their possible correlation with clinical and radiological parameters. METHODS: Pituitary function was tested in 60 patients within 72 h after spontaneous SAH. RESULTS: 56.9% of the patients showed at least one anterior pituitary hormone deficiency: gonadotropin and GH secretion failure represented the most prevalent hormonal deficiencies (33.3 and 22.0%, respectively), whereas ACTH and TSH deficiency was less frequent (7.1 and 1.8%, respectively). With the exception of secondary hypogonadism, the prevalence of other pituitary hormone deficiencies is in agreement with previous studies, which evaluated pituitary function on longterm follow up after SAH. No correlation was found between hypopituitarism and clinical status, as assessed with Hunt-Hess and Glascow Coma Scales. Moreover, no correlation was found between hypopituitarism and bleeding severity evaluated with Fisher's scale. CONCLUSIONS: We demonstrated a high prevalence of anterior pituitary hormone deficiencies acutely after SAH. Although part of GH and gonadotropin deficiencies might be a consequence of functional alteration due to SAH itself, the finding of low cortisol levels in this stressful condition strongly suggests the presence of true hypocortisolism. Therefore, an evaluation of pituitary function shortly after SAH might be useful to identify a subset of patients who deserve a more accurate follow-up.

Role of the cytopathologist during the procedure of fine-needle aspiration biopsy of thyroid nodules.

PURPOSE: This study aimed to conduct a diagnostic and cost-effective analysis of the cytopathology assistance in the ultrasound (US)-guided fine-needle aspiration biopsy (FNAB) for characterising thyroid nodules. MATERIALS AND METHODS: We reviewed the reports relative to 9061 US-guided FNABs for the histologic definition of the nature of thyroid nodules: 45.4% completed with the cytopathologist assistance and 54.6% by the radiologist alone. We also performed the cost-effectiveness analysis (CEA) of the procedure with and without the cytopathologist assistance. RESULTS: We found a significant positive correlation between the adoption/non-adoption of cytopathologist assistance and the number of indeterminate (TIR1) (Chi-square; z-score, Z = 10.22; critical value 5%, C = 1.96; p < 0.001). The cytopathologist's absence was correlated with the number of TIR 1 (Pearson correlation, product-moment correlation r = 0.059; critical value 5%, C = 0.008; p < 0.001). The total cost of the model's cytopathologist-assistance branch is 109.87€, while the total cost of the non-cytopathologist-assistance branch is 95.08€. CONCLUSION: The cytopathologist assistance resulted in fewer nondiagnostic results, thus excluding the procedure's repetition but involved a higher expense, mainly due to the professional cost of the pathologist's participation. These data may provide decision-makers in healthcare with a practical evidence based on the opportunity to include the cytopathologist assistance in the thyroid nodule's FNAB depending on the available resources and the population's expectance.

Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

The syndrome of inappropriate ADH secretion (SIADH), also recently referred to as the "syndrome of inappropriate antidiuresis", is an often underdiagnosed cause of hypotonic hyponatremia, resulting for instance from ectopic release of ADH in lung cancer or as a side-effect of various drugs. In SIADH, hyponatremia results from a pure disorder of water handling by the kidney, whereas external Na+ balance is usually well regulated. Despite increased total body water, only minor changes of urine output and modest edema are usually seen. Renal function and acid-base balance are often preserved, while neurological impairment may range from subclinical to life-threatening. Hypouricemia is a distinguishing feature. The major causes and clinical variants of SIADH are reviewed, with particular emphasis on iatrogenic complications and hospital-acquired hyponatremia. Effective treatment of SIADH with water restriction, aquaretics, or hypertonic saline + loop diuretics, as opposed to worsening of hyponatremia during parenteral isotonic fluid administration, underscores the importance of an early accurate diagnosis and careful follow-up of these patients.

Vitamin E supplementation improves neutropenia and reduces the frequency of infections in patients with glycogen storage disease type 1b.

BACKGROUND: Neutropenia and/or neutrophil dysfunction are part of glycogen storage disease type 1b (GSD1b) phenotype. Recent studies indicated that activation of apoptosis and increased reactive oxygen species are implicated in the pathogenesis of neutropenia in GSD1b. METHODS: We studied seven GSD1b patients over a 2-year-period to evaluate the efficacy of vitamin E, a known antioxidant, in preventing or improving the clinical manifestations associated with neutropenia and neutrophil dysfunction. Frequency and severity of infections, neutrophil counts and function, ileocolonoscopy and intestinal histology, were monitored. During the first year, patients did not assume vitamin E; during the second year of the study, vitamin E supplementation was added to their therapeutic regimens. RESULTS: During vitamin E supplementation, the mean values of neutrophil counts were significantly higher (p < 0.05) and neutrophil counts lower than 500/mm(3) were found less frequently (p < 0.05); the frequency and severity of infections, mouth ulcers and perianal lesions, was reduced (p < 0.05); ileocolonoscopy and histology showed a mild improvement. Vitamin E supplementation did not result in changes in neutrophil function. CONCLUSIONS: These results suggest that vitamin E supplementation might be beneficial in GSD1b patients and may alleviate disease manifestations associated with neutropenia.

Molecular and functional characterization of eight novel GAA mutations in Italian infants with Pompe disease.

We characterized 29 unrelated patients presenting with the severe form of Pompe disease (Glycogen Storage Disease Type II, acid maltase deficiency) and identified 26 pathogenic mutations divided over 28 different genotypes. Among the eight new mutations, five were exonic point mutations (c.572A>G, c.1124G>T, c.1202A>G, c.1564C>G and c.1796C>A) leading to codon changes (p.Y191C, p.R375L, p.Q401R, p.P522A and p.S599Y); two were intronic point mutations (c.-32-3C>A and c.1636+5G>C) affecting mRNA processing; one was a single base deletion (c.742delC) generating a truncated protein (p.L248PfsX20). A comprehensive evaluation, based on different methodological approaches, confirmed the detrimental effect of the eight mutations on the protein and its function. Structural alterations potentially induced by the five missense mutations were also predicted through visual inspection of the atomic model of the GAA protein, in terms of both function and spatial orientation of specific residues as well as disturbance generated by amino acid substitutions. Although the remarkable heterogeneity of the mutational spectrum in Pompe disease was already known, our data demonstrate and confirm the power of molecular and functional analysis in predicting the natural course of Pompe disease.

The sulfatase gene family.

During the past few years, molecular analyses have provided important insights into the biochemistry and genetics of the sulfatase family of enzymes, identifying the molecular bases of inherited diseases caused by sulfatase deficiencies. New members of the sulfatase gene family have been identified in man and other species using a genomic approach. These include the gene encoding arylsulfatase E, which is involved in X-linked recessive chondrodysplasia punctata, a disorder of cartilage and bone development. Another important breakthrough has been the discovery of the biochemical basis of multiple sulfatase deficiency, an autosomal recessive disorder characterized by a severe of all sulfatase activities. These discoveries, together with the resolution of the crystallographic structure of sulfatases, have improved our understanding of the function and evolution of this fascinating family of enzymes.

Myasthenia gravis in a patient affected by glycogen storage disease type Ib: a further manifestation of an increased risk for autoimmune disorders?

Glycogen storage disease type Ib (GSD Ib, OMIM 232220) is an inborn disorder of glucose metabolism, caused by mutations in the G6PT gene, encoding a glucose 6-phosphate transporter (G6PT). GSD Ib is mainly associated with fasting hypoglycaemia and hepatomegaly. Most GSD Ib patients also show neutropenia and neutrophil dysfunction and therefore are at risk of developing severe infections and inflammatory bowel disease (IBD). An increased risk for autoimmune disorders, such as thyroid autoimmunity and Crohn-like disease, has also been demonstrated, but no systematic study on the prevalence of autoimmune disorders in GSD Ib patients has ever been performed. We describe a 25-year-old patient affected by GSD Ib who developed 'seronegative' myasthenia gravis (MG), presenting with bilateral eyelid ptosis, diplopia, dysarthria, severe dysphagia, dyspnoea and fatigue. The repetitive stimulation of peripheral nerves test showed signs of exhaustion of neuromuscular transmission, particularly evident in the cranial area. Even in the absence of identifiable anti-acetylcholine receptor antibodies, seronegative MG is considered an autoimmune disorder and may be related to the disturbed immune function observed in GSD Ib patients.

Genetic screening for pheochromocytoma: should SDHC gene analysis be included?

PGL3 syndrome is caused by mutations in the SDHC gene. At present, only a few families affected by SDHC mutations have been reported in the literature and in each of them the clinical presentation was characterised by paragangliomas located only in the head and neck regions. No evidence of thoracic or abdominal catecholamine-secreting chromaffin tumours has been reported to date. We report the case of a 15-year-old girl with hypertension and a norepinephrine-secreting abdominal paraganglioma who was found to harbour a novel nonsense SDHC mutation, demonstrating that the clinical presentation of PGL3 syndrome can be more diverse than expected.

Steroid therapy in an alpha-dystroglycanopathy due to GMPPB gene mutations: A case report.

Alpha-dystroglycanopathies are a group of progressive and untreatable neuromuscular disorders, due to aberrant alpha-dystroglycan glycosylation. We describe the effects of a short-term cycle of corticosteroid therapy in a 9-year-old boy, affected by an alpha-dystroglycanopathy due to GMPPB gene mutations. The patient was affected by a congenital progressive muscular dystrophy since the first month of life, associated with psychomotor delay, seizures, and congenital bilateral cataracts. Despite physical therapy he had a progressive motor impairment. At the age of 9 years, he was treated with 0.75 mg/kg/day of prednisone for 3 months and showed improvements in muscle strength and function scores and creatine kinase reduction. When steroid therapy was discontinued he showed again clinical and biochemical deterioration. These data suggest that corticosteroid may be considered as a treatment for patients with alpha-dystroglycanopathies due to GMPPB mutations.

Upper airway obstructive disease in mucopolysaccharidoses: polysomnography, computed tomography and nasal endoscopy findings.

In mucopolysaccharidoses, upper airway obstruction has multiple causative factors and progressive respiratory disease may severely affect morbidity and mortality. In a cross-sectional study over 2 years we evaluated upper airway obstructive disease through overnight polysomnography, upper airway computed tomography and nasal endoscopy in 5 children and 6 adults with mucopolysaccharidoses of various types. Measurements of apnoea and apnoea-hypopnoea index, arousal index, and sleep efficiency were obtained through polysomnography. Retropalatal and retroglossal spaces were calculated through computed tomography, and the degree of adenoid hypertrophy was assessed through endoscopy. Apnoea index and apnoea-hypopnoea index were significantly higher in children than in adults with mucopolysaccharidoses (p = 0.03 and p = 0.03, respectively). Compared to healthy controls, retropalatal and retroglossal spaces were significantly smaller in children (p = 0.03 and p = 0.004, respectively) or adults with mucopolysaccharidoses (p = 0.004 and p = 0.004, respectively). All subjects had adenoid hypertrophy causing first-degree (36%) or second-degree (64%) obstruction at endoscopy. Overnight polysomnography, upper airway computed tomography and nasal endoscopy are useful tools for diagnosing obstructive sleep apnoea syndrome in mucopolysaccharidoses, and identifying the site and severity of airway obstruction.