Context:Autosomal-recessive mutations in the growth hormone receptor (GHR) are the most common causes for primary growth hormone insensitivity (GHI) syndrome with classical GHI phenotypically characterized by severe short stature and marked insulin-like growth factor (IGF)-I deficiency. We report three families with dominant-negative heterozygous mutations in the intracellular domain of the GHR causing a nonclassical GHI phenotype.Objective:To determine if the identified GHR heterozygous variants exert potential dominant-negative effects and are the cause for the GHI phenotype in our patients.Results:All three mutations (c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C) are predicted to result in frameshift and early protein termination. In vitro functional analysis of variants c.964dupG and c.920_921insTCTCAAAGATTACA (c.920_921ins14) suggests that these variants are expressed as truncated proteins and, when coexpressed with wild-type GHR, mimicking the heterozygous state in our patients, exert dominant-negative effects. Additionally, we provide evidence that a combination therapy of recombinant human growth hormone (rhGH) and rhIGF-I improved linear growth to within normal range for one of our previously reported patients with a characterized, dominant-negative GHR (c.899dupC) mutation.Conclusion:Dominant-negative GHR mutations are causal of the mild GHI with substantial growth failure observed in our patients. Heterozygous defects in the intracellular domain of GHR should, therefore, be considered in cases of idiopathic short stature and IGF-I deficiency. Combination therapy of rhGH and rhIGF-I improved growth in one of our patients.

Objective: To determine clinical features, etiology and risk factors in term and near term newborns with severe hyperbilirubinemia. Methods: During ten years period (2000 - 2009), infants of ≥ 35 gestational weeks who received phototherapy were evaluated retrospectively. The study population was divided into two groups and clinical features, etiology and risk factors were compared. Group 1 defined by those who had bilirubin level ≥25 mg/dl (severe hyperbilirubinemia) and group 2 defined by bilirubin level <25 mg/dl. Results: During the study period 1335 babies were evaluated. Severe hyperbilirubinemia was found in 137 (10.3%) patients. Total serum bilirubin level was 29.7±4.7 mg/dl in group 1 and 18.9±3.5 mg/dl in group 2. Pathological weight loss, vaginal delivery and supplementary feeding were identified as significant risk factors for development of severe hyperbilirubinemia (p <0.001, p <0.001 and p = 0.04, respectively). The time at recognition of jaundice by family and postnatal age at admission were significantly higher in group 1. The ratios of previous sibling received phototherapy and being the second child or after were found higher in group 1. Conclusion: Pathological weight loss, vaginal delivery and supplementary feeding were determined as risk factors for development of severe hyperbilirubinemia. The newborns with severe hyperbilirubinemia had late recognition of jaundice and admission to hospital by their families.

Objectives Enzyme replacement therapy (ERT) with alglucosidase alfa (rhGAA) has changed the fatal course of infantile Pompe disease, however, development of anti rhGAA antibodies and infusion-associated reactions (IAR) restrict the tolerability and effectiveness of the treatment. Case presentation We describe a successful concomitant immune tolerance induction (ITI) and desensitization protocols in a cross-reactive immunologic material (CRIM) negative 7-month-old male patient. At the age of 5 months and eighth dose of the ERT, the patient developed IAR and his rhGAA specific IgE was negative however, his rhGAA specific IgG titer was as high as 12,800. ITI therapy to suppress antibody formation and a desensitization protocol was devised to be given concomitantly. At the end of 5-week therapy, his fatigue and weakness improved profoundly and a control antidrug antibody level decreased at 800. At the time of the patient’s follow up, he was still on ERT with desensitization at the age of 15 months without any reactions. Conclusions This is the first report in the literature applying concomitant ITI and desensitization protocols in a CRIM negative infantile-onset Pompe disease patient successfully, hence the importance of the case.

Objectives Fructose 1,6 bisphosphatase (FBPase) deficiency is a rare autosomal recessively inherited metabolic disease. It is encoded by FBP1, and the enzyme catalyzes the hydrolysis of fructose-1,6-bisphosphate to fructose 6-phosphate. Patients with recurrent episodes of metabolic acidosis, hypoglycemia, hypertriglyceridemia, and hyperketonemia are present. Methods In this study, we describe the clinical, biochemical, and molecular genetic features of six unrelated Turkish patients from six different families who were genetically diagnosed with FBPase deficiency in our clinic between 2008 and 2020. Their clinical and laboratory data were collected retrospectively. Next-generation sequencing (NGS) was performed for the molecular genetic analysis. Results All patients were hospitalized with recurrent hypoglycemia and metabolic acidosis episodes. Three out of six patients were presented in the neonatal period. The mean age at diagnosis was 26 months. NGS revealed a known homozygous gross deletion including exon 2 in three patients (50%), a known homozygous c.910_911dupTT pathogenic variant in one patient (16%), a novel homozygous c.651_653delCAGinsTAA likely pathogenic variant, and another novel homozygous c.705+5G>A splice site variant. Leukocyte FBPase analysis detected no enzyme activity in the patient with homozygous c.705+5G>A splice site variant. Conclusions We identified two novel mutations in this study. One of them is a splice site mutation which is five bases downstream of the exon, and the other one is an indel mutation. Both of the splice site and indel mutations are exceedingly rare in FBP1, and to the best of our knowledge, there are second splice site and indel variants reported in the literature. Exon 2 deletion is the most common mutation consistent with the previous reports in Turkish patients. FBPase is a frequent cause of hypoglycemia and metabolic acidosis, and the widespread use of molecular genetic analysis would contribute to the enlightenment of advanced genetic factors and possible genotype/phenotype correlation.

Objectives Familial hyperphosphatemic tumoral calcinosis is a rare disorder characterized by hyperphosphatemia with recurrent ectopic periarticular calcifications, in addition to other visceral and vascular manifestations, without any inflammatory or neoplastic disorder. The available treatment strategies are limited. Here we report an eight year old female patient with recurrent lesions under the chin, and bilateral hips which are painful and improving of the size of the lesions and hyperphosphatemia. Case presentation The patient was started to the treatment with peroral acetazolamide however the lesion did not regress but a new lesion appeared then we added sevelamer and topical sodium thiosulfate treatment for three months. After the three months of the combination treatment the lesions, there were no pain, no hyperphospahtemia regression/disappearance of the lesions. Conclusions This combination treatment or topical sodium thiosulfate use only may be a novel treatment strategy for the patients prospective controlled trials are needed.