Context 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting This was a multicenter retrospective study using information collected from 3 predominant centers. Patients A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

Patients with rare diseases face health disparities and are often challenged to find accurate information about their condition. We aimed to use the best available evidence and community partnerships to produce patient education materials for congenital hypogonadotropic hypogonadism (CHH) and the olfacto-genital (Kallmann) syndrome (i.e., CHH and defective sense of smell), and to evaluate end-user acceptability. Expert clinicians, researchers and patients co-created the materials in a multi-step process. Six validated algorithms were used to assess reading level of the final product. Comprehensibility and actionability were measured using the Patient Education Materials Assessment Tool via web-based data collection. Descriptive statistics were employed to summarize data and thematic analysis for analyzing open-ended responses. Subsequently, translation and cultural adaption were conducted by clinicians and patients who are native speakers. Co-created patient education materials reached the target 6th grade reading level according to 2/6 (33%) algorithms (range: grade 5.9–9.7). The online survey received 164 hits in 2 months and 63/159 (40%) of eligible patients completed the evaluation. Patients ranged in age from 18 to 66 years (median 36, mean 39 ± 11) and 52/63 (83%), had adequate health literacy. Patients scored understandability at 94.2% and actionability at 90.5%. The patient education materials were culturally adapted and translated into 20 languages (available in Additional file 1). Partnering with patients enabled us to create patient education materials that met patient- identified needs as evidenced by high end-user acceptability, understandability and actionability. The web-based evaluation was effective for reaching dispersed rare disease patients. Combining dissemination via traditional healthcare professional platforms as well as patient-centric sites can facilitate broad uptake of culturally adapted translations. This process may serve as a roadmap for creating patient education materials for other rare diseases.

Lymphocytic hypophysitis (LH) is an autoimmune inflammatory infiltration of the pituitary gland, usually with a benign evolution. In rare circumstances the inflammatory process may extend beyond the pituitary and infiltrate the surrounding structures. We present a 42-year-old woman affected by an aggressive form of LH with extension to the cavernous sinus causing internal carotid artery occlusion and right sixth cranial nerve palsy. Prednisone therapy caused severe iatrogenic Cushing's syndrome, and the patient underwent transsphenoidal decompression. The histopathology report was consistent with LH. The patient was symptom free for a short period with reappearance of severe headache, diplopia, and hearing loss (middle ear inflammation) 3 months after surgery. Corticosteroids were reintroduced with the addition of azathioprine, but there was no regression of the pituitary mass. The patient was referred for stereotactic radiosurgery (SRS) using Gamma Knife (15 Gy to the margin). After 26 months, azathioprine was stopped, and the dose of prednisone was gradually tapered to 7.5 mg/day. Sellar magnetic resonance imaging showed regression of the pituitary mass. After follow-up for > 3 years after SRS, there was no clinical or radiologic evidence of the disease, but carotid arteries remained occluded. The patient developed secondary hypothyroidism and hypogonadism as consequences of SRS. An aggressive form of LH extending beyond the pituitary gland infiltrating surrounding structures is described. It was successfully treated with SRS after failure of transsphenoidal surgery and combined immunosuppressive therapy (prednisone, azathioprine). The review of the literature presents timely information concerning treatment with azathioprine and SRS of patients with an aggressive form of LH.

Pheochromocytomas and sympathetic paragangliomas are rare catecholamine-secreting tumours that represent very rare causes of intracerebral haemorrhage in the young, with only a few cases reported. A 32-year-old man presented to our emergency department because of sudden onset of severe headache. He had a six-month history of paroxysmal headache, palpitations, and sweating. During examination he became somnolent and developed left-sided hemiplegia. A computed tomographic (CT) scan of the brain showed a right temporoparietal haematoma. He was admitted to the Clinic for Neurosurgery and the haematoma was evacuated. The patient was comatose, on assisted respiration, with frequent hypertensive crises. An examination for possible secondary causes of hypertension was undertaken. Plasma metanephrine value was elevated (414 pg/mL, reference values < 90 pg/mL). Abdominal CT scans revealed a large mass (6 cm) in the right adrenal gland. After adequate control of the hypertension was achieved with nonselectivealpha- and beta-adrenergic blockers the tumour was excised. The histopathologic findings confirmed the diagnosis of pheochromocytoma. The genetic analysis demonstrated a duplication in exon 1 of the VHL gene. We reported a rare, potentially fatal complication of pheochromocytoma - an intracerebral haemorrhage. This case and review of similar rare cases in the literature illustrate the importance of early recognition of the characteristic symptoms of catecholamine excess in young patients with hypertension.

Background/Aim. Vitamin D deficiency is a well-established risk factor for bone disease, but emerging data suggest that altered vitamin D homeostasis may play a role in the development of type 2 diabetes mellitus (T2DM), dyslipidemia hypertension, and other cardiovascular diseases (CVD). The aim of this study was to investigate the prevalence of vitamin D deficiency in patients with T2DM with/without CVD, to correlate it with anthropometric and metabolic parameters and to determine the predictors of vitamin D deficiency. Methods. A total of 88 patients with T2DM (49 male/39 female, aged 61.0 ? 0.9 yrs, body mass index (BMI) 29.9 ? 0.4 kg/m2) and 67 patients (44 male/23 female, aged 63.6 ? 1.0 yrs, BMI 29.2 ? 0.5 kg/m2) with T2DM and CVD (myocardial infarction in 57 patients and angina pectoris in 10 patients) were included in this study. These patients were compared with 87 healthy subjects (35 male/52 female, aged 52.8 ? 1.4 yrs, BMI 27.2 ? 0.5 kg/m2). Weight, height, waist circumference and BMI were recorded in all patients. Also, total cholesterol, triglycerides, hemoglobin A1c (HbA1c) and 25-hydroxy-vitamin D [25(OH)D] levels were measured in all. According to 25(OH)D level, all subjects were divided into three categories: severe vitamin D deficiency (? 15 ng/mL), vitamin D insufficiency (15-20 ng/mL) and vitamin D sufficiency (20 ng/mL). We correlated vitamin D levels with anthropometric and metabolic status and determined the predictors of vitamin D deficiency. Results. Severe vitamin D deficiency was registered in 16.1% healthy subjects, in 21.6% patients with T2DM and in 26.9% patients with T2DM and CVD. Patients with T2DM who were vitamin D deficient had increased weight, waist circumference, cholesterol and triglyceride levels when compared with patients with T2DM who had sufficient vitamin D level. 25(OH)D levels correlated with BMI and waist circumference in all subjects, but did not correlate with metabolic parameters (lipids, HbA1c). The best predictors of vitamin D level in all subjects were weight, waist circumference and BMI. Conclusion. The high prevalence of vitamin D deficiency in patients with T2DM and particularly in patients with T2DM and CVD suggests that supplementation with vitamin D may be beneficial although there is still not sufficient evidence for recommending prescribing vitamin D.