Giovanni Maria Poggi

The de novo Q167K mutation in the POU1F1 gene leads to combined pituitary hormone deficiency in an Italian patient.

The POU1F1 gene encodes a transcription factor that is important for the development and differentiation of the cells producing GH, prolactin, and TSH in the anterior pituitary gland. Patients with POU1F1 mutations show a combined pituitary hormone deficiency with low or absent levels of GH, prolactin, and TSH. Fourteen mutations have been reported in the POU1F1 gene up to now. These genetic lesions can be inherited either in an autosomal dominant or an autosomal recessive mode. We report on the first Italian patient, a girl, affected by combined pituitary hormone deficiency. The patient was found to be positive for congenital hypothyroidism (with low TSH levels) at neonatal screening. Substitutive therapy was started, but subsequent growth was very poor, although psychomotor development was substantially normal. Hospitalized at 10 mo she showed hypotonic crises, growth retardation, delayed bone age, and facial dysmorphism. In addition to congenital hypothyroidism, GH and prolactin deficiencies were found. Mutation DNA analysis of the patients POU1F1 gene identified the novel Q167K amino acid change at the heterozygous level. The highly conserved Q167 residue is located in the POU-specific domain. No mutation was detected in the other allele. DNA analysis in the probands parents did not identify this amino acid substitution, suggesting a de novo genetic lesion. From these data it can be hypothesized that the Q167K mutation has a dominant negative effect.

Determinants of Vitamin D Levels in Italian Children and Adolescents: A Longitudinal Evaluation of Cholecalciferol Supplementation versus the Improvement of Factors Influencing 25(OH)D Status.

Objective. This paper aims to assess 25(OH)D levels in Italian children and adolescents identifying risk factors for 25(OH)D deficiency and to evaluate whether a normal 25(OH)D value can be restored in 25(OH)D-deficient patients. Methods. We evaluated 25(OH)D levels in 679 Italian children and adolescents (≤10, 11–20, 21–30, and >30 ng/mL were defined as severe deficiency, deficiency, insufficiency, and sufficiency, resp.). Of these, 365 25(OH)D-deficient were followed up for 1 year; 205 were treated with cholecalciferol (Arm A: 400 I.U.) and 160 by improving the environmental variables influencing 25(OH)D levels (Arm B). Results. At cross-sectional evaluation, 11.3% showed sufficiency, 30.0% insufficiency, and 58.7% 25(OH)D deficiency. Mean 25(OH)D was 19.08 ± 8.44 ng/mL. At the enrollment time (T 0), no difference was found between Arms A and B with respect to distribution and 25(OH)D levels. At end time (T 1) 26.0% (29.7% in Arm A versus 20.6% in Arm B) showed sufficiency, 38.4% (42.0% versus 34.4%) insufficiency, and 35.6% (28.3% versus 45.0%) 25(OH)D deficiency. Mean 25(OH)D level was 23.71 ± 6.83 ng/mL. Conclusions. Neither changes of lifestyle nor 400 I.U. cholecalciferol supplementation alone appears to be sufficient to restore adequate 25(OH)D levels.

Underestimation of Invasive Meningococcal Disease in Italy

Underestimation is attributable to misdiagnosis, especially in fatal cases, and use of insufficiently sensitive laboratory methods.

Vertical Hepatitis C Virus Transmission is not Related to Mother-Child Class-1 HLA Concordance

Mother-child human leukocyte antigen (HLA) diversity is protective for vertical transmission of some viruses. The aim of this study is to evaluate the role of mother-child HLA diversity on hepatitis C virus (HCV) vertical transmission. Forty consecutive HCV infected and 46 consecutive control uninfected children born to HCV-RNA positive mothers were evaluated for HLA class-1 type concordance with their mothers. No significant difference in the degree of HLA concordance was found between HCV infected and uninfected children both when A, B, C (p=0.30) and when only A and B alleles were evaluated (p=0.59). Mother-infant HLA concordance does not affect HCV vertical transmission.

Incidence and clinical significance of reactive thrombocytosis in children aged 1 to 24 months, hospitalized for community-acquired infections.

The aims of this study were to identify demographic, clinical and laboratory characteristics associated with reactive thrombocytosis useful for clinical management and to evaluate potential complications of this condition in a cohort of children selected for they young age as at high risk of reactive thrombocytosis. Retrospective analysis of medical records of 239 children among 902 aged 1–24 months, hospitalized during a 12-month period, and discharged with a diagnosis of infectious disease was performed. One hundred and nineteen children out of 239 (49.8%) presented thrombocytosis (>500 platelets × 109/L; normal range 150–499 × 109/L), 81/119 (68%) on admission. The incidences of thrombocytosis or extreme thrombocytosis (>1,000 × 109/L) were 13.2% (119/902) and 0.8% (7/902). Thrombocytotic children had higher counts of white blood cells and had been treated more frequently with steroids (36/82, 43.9% vs. 5/53, 9.4%; p = 5 × 10−5; relative risk 7.51, 95% confidence intervals 2.71–20.82). No significant difference was found in relation to sex, age, fever, C reactive protein level, diagnoses and antibiotic therapy. Two out of 239 (0.8%) enrolled children, both thrombocytotic and with other acquired risk factors, developed thrombosis. In conclusion, reactive thrombocytosis in children aged 1 up to 24 months is frequent and unrelated to markers of disease activity or degree of inflammation.

SEN virus co-infection among HCV-RNA-positive mothers, risk of transmission to the offspring and outcome of child infection during a 1-year follow-up.

Summary.  SEN is a newly discovered blood‐transmissible virus. Among its variants, SENV‐D and ‐H are most often associated with non‐A, ‐E hepatitis. Very little is known about the risk of vertical transmission of the virus. By using polymerase chain reaction with specific primers for SENV‐D and ‐H, we investigated the prevalence of SENV‐H and ‐D infection, the transmission rate of SENV infection and clinical features of SENV‐infected children in 89 hepatitis C virus (HCV)‐positive human immunodeficiency virus type 1‐negative mothers. SENV infection was found in 36 (40%) mothers, and SENV‐D was more frequent than SENV‐H infection (34/36, 94%vs 5/36, 14%, P < 0.01). No difference in SENV infection rates was found between injection drug user (IDU) mothers (17/51, 33%) and mothers with no risk for bloodborne infection (19/38, 50%, P = ns). SENV‐H infection was found only in IDU mothers and mothers with HCV genotype1b. Both SENV‐D and ‐H can be transmitted to the offspring with an overall rate of 47%. Vertical transmission of HCV does not facilitate SENV infection of the offspring. Among 17 SENV‐infected children, none was co‐infected with HCV. Maternal HCV genotype or viral load does not interfere with mother‐to‐infant transmission of SENV. Persistence of SENV infection was demonstrated in 100% of infected children after 1‐year follow‐up, but none had clinical evidence of liver disease.

Mutational spectrum in ten Italian patients affected by methylmalonyl-CoA mutase deficiency.

SummaryWe report seven novel mutations, including three amino acids substitutions (p.Glu286Lys, p.Cys560Tyr, p.Pro615Leu), two nonsense mutations (p.Arg31X, p.Glu 451X), one splicing defect (c.2125−1G >A), one small deletion (c.1758–1759delA) and nine previously described mutations identified in 10 unrelated Italian patients affected by mut MMA.

A coeliac child presenting with bleeding

Dear Editor, Atypical presentations of coeliac disease (CD) and unusual CD-associated autoimmune disorders can make the diagnosis of CD challenging. Here, we report the case of a young child presenting with bleeding and transient lupus anticoagulant positivity and diagnosed with lupus anticoagulant–hypoprothrombinemia syndrome (LAHS) and CD. A 3-year-old girl experienced fever, vomiting and mild diarrhoea. The symptoms disappeared spontaneously in 3 days. Four days later, she presented to the emergency department of our hospital with diffuse bruising, gingival bleeding and epistaxis. Physical examination was normal, showing only diffuse multiple subcutaneous haematomas. Growth parameters were normal (weight for height and height for age stable around 0 standard deviation). The child had no family history of haemorrhagic disease. Blood tests revealed coagulopathy (international normalized ratio 2, activated partial thromboplastin time 104 sec, control 25–35 sec). Haemoglobin, platelet count, liver function tests, cholesterol, triglycerides and albumin levels were within normal limits (Table 1). The child was admitted to the paediatric unit. On admission, a single dose of 10 mg intramuscular phylloquinone (vitamin K) was administered. Lupus anticoagulants (LAs) were detected by the prolongation of silica clotting time and dilute Russells viper venom time. IgG/IgM anticardiolipin antibodies, IgG/IgM b2-glycoprotein I and antinuclear antibodies were negative. C4 level was low (6 UI/mL, normal value 17–45), and C3d was normal (125 IU/mL, normal value 75–150). Further investigation of coagulation factor activities revealed low values for factors II, VIII, IX, XI, and XII and values within normal limits for V, VII and X (Table 1). Tissue transglutaminase IgA antibodies were markedly high (>200 AU/mL). Endomysial antibody testing was positive. The child was started on a gluten-free diet. The coagulopathy slowly resolved (Table 2). Three months after the admission, LAs were negative. The present report describes a 3-year-old child presenting with bleeding and diagnosed with LAHS and CD. This is the youngest patient with LAHS ever reported. LAHS, for the first time, was diagnosed in the context of CD. Lupus anticoagulant–hypoprothrombinemia syndrome is characterized by the presence of low prothrombin activity (PA), bleeding and positivity for LAs (1). Bleeding and low PA are related strictly. A typical pattern of coagulation factors depletion has been described during LAHS with low PA as well as of other factors such as factor VIII, IX, XI and XII (1). The same pattern was found in the patient described in the present report. Bleeding, during LAHS, is dependent on PA. Severe bleeding is more likely when PA is lower than 10% of normal, while mildly reduced activity is associated with milder symptoms and of shorter duration (1). Both bleeding and low PA are secondary to the presence of LA. LAs are immunoglobulins that interfere with in vitro coagulation tests and belong to a family of antibodies that are directed against different protein–phospholipid complexes. LAs are recognized risk factors for venous and arterial thrombosis. The pathophysiologic mechanism of LA causing thrombosis is still not known, and it is probably multifactorial. Among the different hypotheses, LA may promote thrombosis by inhibiting the action of the protein C and S complex, thereby eliciting resistance to activated protein C (2). The association between LA and bleeding is less known and recognized although Conley and Hartmann, in 1952, in their original and first description of LAs reported the association of a circulating anticoagulant in patients diagnosed with lupus erythematosus presenting with bleeding and not with thrombosis. Paediatric data showed that bleeding was more common in children positive for LA than thrombosis (10% versus 5%) (3). Bleeding associated with LA has been explained by the presence of phosphatidylserine-dependent antiprothrombin antiphospholipid antibodies (aPS/PT). It has been hypothesized that aPS/PT may form an immune complex with prothrombin, which is trapped and destroyed by the reticuloendothelial system with the consequent reduction in plasma prothrombin (1). The prognosis of LAHS depends on the presence or absence of underlying systemic diseases. In a recent revision of the paediatric literature among 27 children with LAHS, 40% were diagnosed with systemic lupus erythematosus and received specific treatment. Among the other patients without any underlying systemic disease, nearly 80% recovered spontaneously (1). In the patient described in the present report, CD was diagnosed. Bleeding in patients with CD has been associated with vitamin K deficiency as a consequence of severe Table 1 Results of blood tests on admission

Hydrocortisone malabsorption due to polyethylene glycols (Macrogol 3350) in a girl with congenital adrenal insufficiency

BackgroundPrimary adrenal insufficiency is relatively rare in children and, if unrecognized, may present with cardiovascular collapse, making it a potentially life-threatening entity.Case presentationThe proposita, 11 months old of age, was admitted for lethargy and severe dehydration. Blood pressure was 62/38 mm Hg, and biochemical measurements showed hyponatraemia, hypochloraemia, hyperkalaemia, and metabolic acidaemia. Renin activity was 1484 μU/mL; cortisol, 1.03 μg/dL (normal, 5-25 μg/dL); and corticotropin (ACTH), 4832 ng/L (normal, 9-52 ng/L). Adrenal deficiency was diagnosed, and replacement therapy with glucocorticoids and mineralocorticoids was initiated. After 40 days, ACTH was 797 ng/L.During follow-up, the patient started taking macrogol twice daily for constipation and experienced a significant increase in ACTH (3262 ng/L), which dropped to 648 ng/L when macrogol was stopped. After arbitrary reintroduction of macrogol, the child presented with hypoglycaemia, lethargy, weakness, and hypotonia; ACTH was 3145 ng/L. After again stopping macrogol, her ACTH was near normalized (323 ng/L).ConclusionHydrocortisone malabsorption may be caused by macrogol use. Because chronic constipation is frequently reported in children, the possibility that macrogol contributes to adrenal crisis should be taken in account.

Neuroblastoma Presenting with Acute Kidney Injury, Hyponatremic-Hypertensive-Like Syndrome and Nephrotic Proteinuria in a 10-Month-Old Child

Neuroblastoma is the most common extracranial solid tumor in childhood. Its presenting signs and symptoms may be highly variable, depending on the location of the primary tumor and its local or metastatic diffusion and, rarely, with paraneoplastic syndrome such as opsoclonus-myoclonus-ataxia syndrome and gastrointestinal disturbances, due to autoantibodies or to aberrant secretion of vasoactive intestinal peptide. Herein we describe a 10-month-old child with neuroblastoma presenting with a complex clinical picture characterized by acute kidney injury manifested by renal insufficiency and signs and symptoms of tubulointerstitial damage, with polyuria, polydipsia, glucosuria, aminoaciduria and hypochloremic metabolic alkalosis, and of glomerular damage with heavy proteinuria. Imaging study documented a suprarenal mass enveloping the aorta and its abdominal and renal ramifications and bilaterally renal veins. This clinical picture shows some analogies with the hyponatremic-hypertensive syndrome concerning the renovascular disease; however, in absence of systemic arterial hypertension, the heavy proteinuria and the polyuria could be explained by sectional increased intraglomerular pressure, due to local renal blood vessels constriction. Hypochloremic metabolic alkalosis probably developed because of local production of renin, responsible of renin-angiotensin-aldosterone system activation, but above all because of chloride loss through sweating. The long lasting dehydration, due to vomiting, sweating and polyuria, caused prolonged prerenal failure evolving in proximal tubular damage manifestations.