Elena Faleschini

Celiac disease in patients with sporadic and inherited cardiomyopathies and in their relatives

AIMS To investigate celiac disease (CD) and related co-morbidity in patients with familial and sporadic cardiomyopathy and in their relatives. METHODS AND RESULTS We screened anti-human-tissue-transglutaminase (IgA and IgG anti-h-tTG) and anti-endomysial antibodies (AEAs) in 238 consecutive adult patients with inherited or sporadic dilated cardiomyopathy (DCM), 418 relatives, and 2000 healthy blood donors. HLADQ2-DQ8 was tested in tTG-positive subjects. The IgA-tTG-positive patients with cardiomyopathy underwent duodenal biopsy. Twenty-six subjects were tTG-positive: five DCM patients (2.1%), two of 28 (7.1%) and three of 390 (0.7%) relatives with and without echocardiographic abnormalities respectively, and 16 controls (0.8%). Twenty-two of 26 subjects were AEA-positive, and 25 HLA-positive. Of the five patients with cardiomyopathy and biopsy-proven CD, four suffered iron-deficiency anaemia. Two CD-positive DCM patients and two tTG-positive relatives were from families with inherited disease in which CD did not co-segregate with DCM. CONCLUSIONS; The higher prevalence of CD in patients with sporadic or inherited DCM, and of tTG-positive serology in relatives with echocardiographic abnormalities, suggests that immune-mediated mechanisms are active in subsets of patients/families. However, gluten intolerance cannot be considered causative since CD seems to be associated but not co-segregated with DCM in familial cases.

Medium-term survival without haematopoietic stem cell transplantation in a case of IPEX: insights into nutritional and immunosuppressive therapy

Immunodysregulation, polyendocrinopathy, enteropathy, Xlinked (IPEX; OMIM 304930) is a severe disorder of immune development characterised by a usually fatal course in early childhood [6]. It is due to mutations in the FOXP3 gene (locus Xp11.23-q13.3) [2, 4, 9], leading to failure in immune tolerance. Haematopoietic stem cell transplantation (HSCT) is the only definitive therapy and, even if its success is inconstant, it is considered to be the treatment of choice for the disease [6, 8, 10]. On the other hand, just two cases have been reported as surviving the first decade with a severe form of the disease without HSCT [5, 7]. A 1-month-old male was referred to our department for a severe eczema (Fig. 1), intractable mucous diarrhoea and failure to thrive. Extensive investigations ruled out a severe combined immunodeficiency (SCID). Symptoms were controlled with intravenous immunoglobulin, cyclosporin A, steroids and total parenteral nutrition (TPN) (Fig. 2). During his second year of life, he developed autoimmune diabetes, autoimmune haemolytic anaemia (AHA), inflammatory interstitial pneumonia, alopecia and thyroiditis. Due to the unsatisfactory response to prednisone, oral betamethasone was prescribed, with a dramatically greater efficacy at an equipotent dosage. A bone marrow transplantation was refused by the parents. Flares of dermatitis, AHA and pneumonia occurred after every cold and required increasing doses of steroids, antibiotics and oxygen administration. Cyclosporin A (10 mg/kg/day) did not allow a reduction of steroids and the child developed a Cushing-like aspect. An experimental treatment with fludarabine followed by the infusion of autologous lymphocytes treated in vitro with vincristine and prednisone was repeated twice, allowing a prolonged reduction of steroid dosage (0.5–0.25 mg/day of betamethasone) and fairly good clinical improvement with less frequent and less intense reactivation of symptoms. At Eur J Pediatr (2007) 166:1195–1197 DOI 10.1007/s00431-006-0395-6

Maturity-Onset Diabetes of the Young with Necrobiosis Lipoidica and Granuloma Annulare

Abstract:  We describe a 12‐year‐old white girl with granuloma annulare localized to both ankles since she was five, necrobiosis lipoidica in the left pretibial region since she was ten, and a recent history of weakness, migraine, and weight loss. After initial evaluation, high fasting blood glucose levels and high hemoglobin A1c were found. The family history for non‐insulin‐dependent diabetes was suggestive of maturity‐onset diabetes of the young. Coexistence of necrobiosis lipoidica and granuloma annulare, together with a family history of non‐insulin‐dependent diabetes, the age of onset, and the absence of ketosis, are specific features making possible, a clinical diagnosis. Genetic confirmation may not be so easily accessible or necessary.

Sirolimus Therapy in Congenital Hyperinsulinism: A Successful Experience Beyond Infancy.

Congenital hyperinsulinism (CHI) due to diffuse involvement of the pancreas is a challenging and severe illness in children. Its treatment is based on chronic therapy with diazoxide and/or octreotide, followed by partial pancreatectomy, which is often not resolutive. Sirolimus, a mammalian target of rapamycin inhibitor, was reported to be effective in treating CHI in infants. We report here the case of an 8-year-old boy affected by a severe form of CHI due to a biallelic heterozygous ABCC8 mutation who responded to sirolimus with a dramatic improvement in his glucose blood level regulation and quality of life, with no serious adverse events after 6 months of follow-up. To the best of our knowledge, this is the first report of a successful intervention in an older child. It provides a promising basis for further studies comparing sirolimus with other treatments, particularly in older children.

A case of Rubinstein‐Taybi syndrome associated with growth hormone deficiency in childhood

Dear Editors, Rubinstein-Taybi syndrome (RTS) is a rare autosomal dominant disease. Point mutations or deletions of the cAMPresponse element-binding protein-BP (CREBBP) (50–60% of the cases) or the homologous gene E1A-binding protein (EP300) (5%) are involved in RTS. RTS patients show intellectual disability, distinctive clinical characteristics (such as broad and sometimes laterally deviated thumbs and halluces), short stature, and craniospinal and posterior fossa abnormalities. We describe the case of a girl delivered at term with mild perinatal asphyxia. At birth, weight and length were 2630 g ( 1 73 SDS) and 47 5 cm ( 1 34 SDS), respectively. A clinical diagnosis of RTS was performed in the first days of life because of broad thumbs and toes, downslating palpebral fissures and malpositioned ears with dysplastic helices. The molecular analysis showed a frameshift mutation of the CREBBP gene due to a duplication of 20 nucleotides (c.5838_5857dup20). This mutation, never described before, involves the exon 31 of the CREBBP gene and leads to a stop codon (p.Pro1953HisfsX30) with a resulting truncated protein of 1982 aminoacids (the wild-type protein is of 2442 aminoacids). In the following years, she showed growth impairment and development delay. She was referred to our attention at the age of 3 years because of short stature (86 5 cm, 2 1 SDS, 25–50° percentile following RTS growth charts). The growth velocity in the last year was 5 69 cm/year ( 1 67 SDS). The weight was between 10° and 25° percentile (between 25 and 50°pc following RTS growth charts). Tanner pubertal stage was Ph1 B1, and the bone age showed a delay of 2 years. Clinical examination showed features consistent with RTS and cutaneous neuromas. Cortisol levels at 8:00 a.m., thyroid, hepatic and renal functions were normal. Two arginine provocative tests for growth hormone (GH) secretion were performed. GH peak levels were 5 57 lg/l and 6 69 lg/l (n.v. >10 lg/l), respectively, revealing a GH deficiency. The IGF-1 levels were 22 27 nmol/l (n.v. 13 88– 32 75 nmol/l). A brain magnetic resonance (MRI) showed normal pituitary height (3 8 mm with a normal height range for age and sex of 4 25 0 68 mm) and volume, normal anatomy of the stalk, normal position of the posterior pituitary, and normal anatomy of the hypothalamic region. A thinning of the corpus callosum was evident. She started GH therapy (0 033 mg/kg/day) when she was 3 5 years old, with good improvement of growth velocity (the patient’s growth charts are shown in Fig. 1a and b). At last follow-up, the patient was 9 9 years old and her stature was 134 6 cm (+0 58 SDS according Italian charts and 90–97°percentile according RTS growth charts). At the present time, the GH dose is 0 022 mg/kg/day with a growth velocity of 6 95 cm/year (+1 90 SDS). Pubertal stage is Ph1 B1. IGF-1 levels are 49 38 nmol/l (n.v. 16 50–34 19 nmol/l). The bone age shows a retardation of 16 months. The thyroid function is normal. TSH levels are 3 35 mIU/l (n.v. 0 27–4 20 mIU/l), Ft4 levels are 13 64 pmol/l (n.v. 11 9–21 8 pmol/l), and Ft3 levels are 0 059 pmol/l (n.v. 0 027–0 070 pmol/l). She did not presented any side effects to GH therapy. In individuals with RTS, short stature is considered a classic feature of the syndrome and indirect measures of growth hormone secretion have been usually reported as normal. Therefore, these patients do not usually undergone dynamic testing to detect growth hormone deficiency. In literature, we found a single case report of RTS female patient with GH deficiency associated with a CREBBP frameshift mutation. The diagnosis of GH deficiency was performed when she was 11 years old. She was treated with GH therapy for 5 years with good improvement in growth velocity (reaching the 3° percentile of height for the normal population growth chart and the 75° percentile of height for the RTS growth chart) without any side effects. Interestingly, this patient presented also pituitary hypoplasia, Arnold Chiari malformation type 1 and double syringomyelic cavity. This fact underlines the possibility that GH deficiency could play a role in the short stature of RTS patients with CREBBP mutation and that the replacement therapy could lead to improvement of stature. Another RTS patient with GH deficiency and short stature is present in the population of Spena et al. and this patient showed a frameshift CREBBP mutation leading to a stop codon at aminoacid 107. Unfortunately, no more auxological data and information about a possible therapy are available. Herein, we report a precocious diagnosis of GH deficiency (performed when the patient was 3 5 years old) associated with a new CREBBP mutation. Our case report shows a GH replacement therapy started early in life in RTS patients with GH deficiency leading to an important improvement of stature (her height reached the 25° percentile according normal population and 90–97° percentile according RTS growth charts) without any side effects. Unlike the patient previously described, our patient did not present pituitary hypoplasia. The hypothesis of the linkage between short stature and GH deficiency in RTS patients with CREBBP mutations is supported by previous studies in mice and in vitro. cAMP-response element-binding protein (CREB) is one of the first transcription factors that showed an impact on somatic growth. CREB is required for the efficient production of GHRH in hypothalamus and GH in pituitary gland. In fact, CREBmutant mice present reduced postnatal growth consistent with dwarfism caused by GH deficiency. CREBBP, involved in RTS pathogenesis, is a nuclear factor named for its ability to bind CREB. It is possible that CREBBP mutations affect the CREB–CREBBP interaction, determining an impaired CREB-binding protein both at hypothalamic and at pituitary level, with consequent reduction in GH levels. In addition, at pituitary level, CREBBP interacts as cofactor with Pit-1. Pit-1 is an important transcription factor that promotes growth hormone and stimulates somatic growth. Therefore, an impairment of CREBBP/Pit-1 interaction could affect pituitary GH secretion. Considering all the GH secretion steps in whom CREBBP could be implicated, we suppose that in RTS patients without

Type 1 diabetes mellitus and celiac disease: usefulness of gluten-free diet.

We have read with interest the original article by Picarelli et al. [1] describing metabolic control and selected hemocoagulative/anticoagulant parameters in patients with isolated type 1 diabetes mellitus (T1DM) and in those affected by celiac disease (CD) too. According to our experience at Pediatric Endocrinology Unit of Trieste, we respectfully disagree with Picarelli’s conclusion and otherwise support the importance of a gluten-free diet (GFD). Picarelli et al. emphasize a better metabolic and glycolipidic control in patients with both DM1 and CD not following a GFD and suggest a protective role of CD in the prothrombotic state of DM1. In our opinion, their study has three critical points. First, all patients presented a glycosylated hemoglobin level (HbA1c)\7.5%. These inclusion criteria could be a selection bias that could influence the results. Second, in accord with literature, we believe that a single variable (glycosylated hemoglobin) is not sufficient to evaluate glycemic control: daily insulin dosages, hypoglycemia frequency, and glycemic variability should be also considered. Glycemic variability, specially, is considered an independent risk factor for complications [2]. Third, they do not analyze the effect of CD on the anthropometric variables nor investigate the presence of other autoimmunities. We followed up 74 patients with diabetes to evaluate the prevalence of celiac disease (CD) in a cohort of children with type 1 diabetes (T1DM) and to investigate the influence of CD on growth and metabolic control, before and after gluten-free diet (GFD). A total of 17 celiac-positive subjects (group 1) and 57 celiac-negative subjects (group 2) were examined. Data on growth and metabolic control were collected retrospectively at three different moments (diabetes diagnosis, CD diagnosis, and 6–12 months after a GFD was started). Prevalence of CD accounts for 13% of our cohort, which is comparable with prevalence in Picarelli’s cohort (13.8%). In most of cases (70%), screening test led to the diagnosis. In 70% of CD-positive patients, HbA1c levels were\8% before GFD (vs 54% of CD negative), but only in 42% of them after GFD. In CD-positive cases, good HbA1c levels were often associated with glycemic variability (65%) before GFD, while quite rarely after 6–12 months of diet (28.5%). These results allow us to suppose that before GFD was started, metabolic control was apparently good, but it really improved after GFD (reduction in glycemic variability). Besides, in our cohort, we observed that the co-occurrence of both disease compromises growth, and meanwhile, it improves after that GFD is started (BMI of CD-positive subjects rises from 46 percentile before GFD, to 54 after GFD, P \ 0.05). In our cohort, CD remains asymptomatic in the most of cases (70%), and then, the diagnosis would have been missed if the screening had not been performed, as confirmed by Picarelli’s study too. This result accords with literature [3–10] and supports importance of serological screening in diabetic population. In conclusion, we believe that serological screening is useful for diagnosing asymptomatic CD and GFD in CDpositive diabetic patients can allow growth and diabetes control comparable with patients with T1DM alone. P. Pascolo (&) E. Faleschini G. Tonini A. Ventura Institute for Child Health IRCCS Burlo Garofolo, Trieste, Italy e-mail: paolapascolo@gmail.com

Acute comitant esotropia secondary to idiopathic intracranial hypertension in a child receiving recombinant human growth hormone

Four days after symptom onset, 1 drop of 1% apraclonidine was placed in each eye. Pupil examination was conducted in both bright light and dark conditions, and reversal of anisocoria did not occur after 45 minutes. The patient returned 9 and 16 days after symptom onset, and repeat apraclonidine testing showed negative results. Further testing could not be conducted as the patient was lost to follow-up. Apraclonidine, a selective alpha-2 receptor agonist with weak alpha-1 receptor activity, has great potential to assist in the diagnosis of Horner syndrome. Interruption of the oculosympathetic pathway leads to upregulation of pupillary dilator muscle alpha-1 agonist receptors. This results in dilation of the affected, hypersensitive pupil in response to apraclonidine, while the normal pupil remains unchanged or may even constrict. It is not clear how much time must pass before hypersensitivity develops after Horner syndrome and when apraclonidine becomes a useful diagnostic tool. Several studies have found that apraclonidine compares favorably with cocaine for the diagnosis of Horner syndrome (Table 1). In all the patients in previous studies Horner syndrome was of relatively long duration (1 month or more) prior to testing. Brown et al. described 1 patient with a negative apraclonidine test. This patient was tested 9 years after diagnosis, had Horner syndrome of unknown etiology, and did not undergo confirmatory cocaine testing. Cocaine testing is not always practical in the clinical setting, and an equally efficacious alternative would benefit the clinician. Studies have shown that apraclonidine may represent a viable alternative. However, since apraclonidine depends upon the development of supersensitivity, it may require several weeks or months before one can depend upon a negative result. The patient presented here suffered from a potentially disabling or life-threatening carotid dissection. Her apraclonidine testing remained negative for 16 days after the onset of her disease. Our patient did not return for retesting with apraclonidine several months after onset of her Horner syndrome. It is possible that the false-negative test in the acute stage may have been persistently negative despite the passage of time. We would recommend caution in cases of acute and infantile Horner syndrome and suggest that cocaine testing remains the preferred method for diagnosis. Further study is required to determine the minimum time necessary for a positive apraclonidine test.

A Klinefelter boy with congenital adrenal hyperplasia: too much or too little androgens?

BackgroundThe simultaneous occurrence of Klinefelter Syndrome (KS) and Congenital Adrenal Hyperplasia (CAH) is an exceptional event: there are just three case reports (two children and a 51 years old man) describing males affected by both KS and 21OHD (21-hydroxylase deficiency) CAH, the first causing androgen deficiency, the latter leading to androgen excess.Case reportWe report the 4th case of association of KS and CAH in a young man with CAH with good androgen control and with normal secondary sex characteristics, whose Klinefelter syndrome was diagnosed because of reduced testicular volume. He was the first reported case of association of KS and CAH who started androgen replacement therapy in the pubertal age and whose pubertal development was described and followed up step by step.ConclusionIn a boy with CAH and small testicular volume, it’s important to consider that hypogonadism may be masked by the adrenal androgens excess and a karyotype should be performed once testicular adrenal rests have been ruled out.

Relapse and metastasis of atypical teratoid/rhabdoid tumor in a boy with neurofibromatosis type 1 treated with recombinant human growth hormone

Even though no increased recurrence rate seems to be reported in patients with brain tumors receiving recombinant human growth hormone (rhGH) replacement, in some patients multiple risk factors could put at higher risk for recurrence. In such cases, the decision to start rhGH therapy should be very cautious. A boy with neurofibromatosis type 1 developed an atypical teratoid/rhabdoid tumor (AT/RT) of right cerebellum, treated with surgery, radiotherapy, and chemotherapy. After 3 years of remission, he started rhGH for growth hormone deficiency, having a negative magnetic resonance imaging (MRI) scan. Ten weeks after starting therapy, the boy became symptomatic and MRI showed relapse of AT/RT in the right cerebellum and a new lesion in the brainstem. The boy died of progressive disease. In this case, the connection between AT/RT recurrence and the beginning of rhGH therapy, with a negative pretreatment MRI, cannot be excluded. Additional caution should be used for rhGH in patients with multiple risk factors.

Diagnosis of diabetes. What about cystic fibrosis

Kilpatrick and colleagues discuss measuring haemoglobin A1c to diagnose diabetes but did not mention diabetes related …