Mutations in the insulin receptor (INSR) gene underlie rare severe INSR-related insulin resistance syndromes (SIR), including insulin resistance type A, Rabson–Mendenhall syndrome and Donohue syndrome (DS), with DS representing the most severe form of insulin resistance. Treatment of these cases is challenging, with the majority of DS patients dying within the first two years of life. rhIGF-I (mecasermin) has been reported to improve metabolic control and increase lifespan in DS patients. A case report and literature review were completed. We present a case involving a male patient with DS, harbouring a homozygous mutation in the INSR gene (c.591delC). Initial rhIGF-I application via BID (twice daily) injection was unsatisfactory, but continuous subcutaneous rhIGF-I infusion via an insulin pump improved weight development and diabetes control (HbA1c decreased from 10 to 7.6%). However, our patient died at 22 months of age during the course of a respiratory infection in in Libya. Currently available data in the literature comprising more than 30 treated patients worldwide seem to support a trial of rhIGF-I in SIR. rhIGF-I represents a treatment option for challenging SIR cases, but careful consideration of the therapeutic benefits and the burden of the disease is warranted. Continuous application via pump might be advantageous compared to single injections.

Background: PTEN Hamartoma Tumor Syndrome (PHTS) is caused by germline autosomal-dominant mutations of the tumor suppressor gene PTEN. Subjects harbour an increased risk for tumor development, with thyroid carcinoma occurring in young children. Establishing a diagnosis is challenging, since not all children fulfill diagnostic criteria established for adults. Macrocephaly is a common feature in childhood, with cerebral MRI being part of its diagnostic workup. We asked whether distinct cMRI features might facilitate an earlier diagnosis. Methods: We retrospectively studied radiological and clinical data of pediatric patients who were presented in our hospital between 2013 and 2019 in whom PTEN gene mutations were identified. Results: We included 27 pediatric patients (18 male) in the analysis. All patients were macrocephalic. Of these, 19 patients had received at least one cMRI scan. In 18 subjects variations were detected: enlarged perivascular spaces (EPVS; in 18), white matter abnormalities (in seven) and less frequently additional pathologies. Intellectual ability was variable. Most patients exhibited developmental delay in motor skills, but normal intelligence. Conclusion: cMRI elucidates EPVS and white matter abnormalities in a high prevalence in children with PHTS and might therefore aid as a diagnostic feature to establish an earlier diagnosis of PHTS in childhood.

PTEN hamartoma tumor syndrome (PHTS) encompasses different syndromic disorders which are associated with autosomal-dominant mutations of the tumor suppressor gene PTEN. Patients are at high risk to develop benign and malignant tumors. Macrocephaly is a diagnostic feature, but there is a paucity of data on auxological development during childhood. Growth charts for height, weight and head circumference for PHTS do not exist yet. In this study, patient data for height, weight and head circumferences (HC) were collected from repeated medical exams or prevention check-up visits starting at birth. Growth charts were generated and compared to German reference data. Standard deviation scores (SDS) of HC, height and body mass index (BMI) were calculated. We included 23 pediatric patients (8 female, 15 male) with molecular proven PTEN gene mutation. Most male patients already demonstrated macrocephaly at birth (73%), whereas only one female patient had documented congenital macrocephaly. By the age of two years all patients exhibited a head circumference above the 97th percentile. Stratified for different age groups the median HC-SDSs were between +3.3 and +5.5 in male patients and between +2.9 and +4.1 in female patients. Height, weight and BMI measurements for both sexes were mostly within the normal range. We conclude that macrocephaly, but not height, weight or BMI, is useful in the identification of PHTS patients. The increased HC in PHTS patients develops early in life and is more pronounced in males than in females, which might explain the finding of a higher percentage of male PHTS patients diagnosed during childhood.

Background: Neonatal diabetes with congenital hypothyroidism (NDH) syndrome is a rare condition caused by homozygous or compound heterozygous mutations in the GLI-similar 3 coding gene GLIS3. Almost 20 patients have been reported to date, with significant phenotypic variability.Case presentation: We describe a boy with a homozygous deletion (exons 5-9) in the GLIS3 gene, who presents novel clinical aspects not reported previously. In addition to neonatal diabetes, congenital hypothyroidism and other known multi-organ manifestations such as cholestasis and renal cysts, he suffered from hyporegenerative anemia during the first four months of life and presents megalocornea in the absence of elevated intraocular pressure. Compensation of partial exocrine pancreatic insufficiency and deficiencies in antioxidative vitamins seemed to have exerted marked beneficial impact on several disease symptoms including cholestasis and TSH resistance, although a causal relation is difficult to prove. Considering reports on persistent fetal hemoglobin detected in a few children with GLIS3 mutations, the transient anemia seen in our patient may represent a further symptom associated with either the GLIS3 defect itself or, secondarily, micronutrient deficiency related to exocrine pancreatic deficiency or cholestasis.Conclusions: Our report expands the phenotypic spectrum of patients with GLIS3 mutations and adds important information on the clinical course, highlighting the possible beneficial effects of pancreatic enzyme and antioxidative vitamin substitutions on characteristic NDH syndrome manifestations such as TSH resistance and cholestasis. We recommend to carefully screen infants with GLIS3 mutations for subtle biochemical signs of partial exocrine pancreatic deficiency or to discuss exploratory administration of pancreatic enzymes and antioxidative vitamins, even in case of good weight gain and fecal elastase concentrations in the low-to-normal range.

We report a 15-year-old boy who developed aseptic meningitis 10 days after administration of the second dose of the COVID-19 vaccine BNT162b2. Although accompanying aphthous mouth ulcers resembling herpetic stomatitis initially led us to suspect an underlying viral infection, broad virological and microbiological screening did not identify any causative pathogen. Gonarthritis and skin lesions, which both developed within three days after admission, extended the clinical presentation eventually resembling an acute Behçet’s disease episode. This is the first description of a juvenile patient with aseptic and pathogen-negative meningitis occurring in close temporal association with vaccination against COVID-19, along with a few previously reported adult patients with isolated meningitis and a further case with meningitis and an accompanying Behçet’s disease-like multisystem inflammation episode as seen in our patient. With billions of individuals being vaccinated worldwide so far and only a few cases of aseptic pathogen-negative meningitis reported in close temporal relation, causality is unclear. However, aseptic meningitis should be kept in mind in the differential diagnosis of patients with persistent or delayed onset of headache and fever following COVID-19 vaccination.

Context: Monocarboxylate transporter 8 (MCT8) deficiency is a rare X-chromosomal inherited disease leading to severe cognitive impairment, muscular hypotonia, and symptoms of peripheral thyrotoxicosis. Experimental approaches aiming to functionally rescue mutant MCT8 activity by the chemical chaperone phenylbutyrate (PB) demonstrated promising effects in vitro for several MCT8 missense mutations. Objective: The objective was to evaluate biochemical and clinical effects of PB in doses equivalent to those approved for the treatment of urea cycle disorders in a boy with MCT8 deficiency due to a novel MCT8 missense mutation c.703G>T (p.V235L). Results: During a treatment period of 13 months, PB led to a significant decrease of elevated thyrotropin and triiodothyronine (T3) serum concentrations, while free thyroxine (fT4) increased. The weight z-score of the toddler remained remarkably stable during the treatment period. Neurodevelopmental assessments (BSID-III) revealed a slight increase of gross motor skills from developmental age 4 to 6 months. However, increasing liver enzyme serum activities and accumulation of phenylacetate in urine led to treatment interruptions and dose alterations. In vitro analyses in MDCK1 cells confirmed the pathogenicity of MCT8 p.V235L. However, while PB increased expression of the mutant protein, it did not rescue T3 transport, suggesting a PB effect on thyroid function tests independent of restoring MCT8 activity. Conclusion: In a clinical attempt of PB treatment in MCT8 deficiency we observed a significant improvement of thyroid hormone function tests, tendencies toward body weight stabilization and slight neurodevelopmental improvement. Hepatotoxicity of PB may be a limiting factor in MCT8 deficiency and requires further investigation.