Context:P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available.Objective:The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort.Design:The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries.Results:We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17α-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 18 46,XX and seven of 12 46,XY individuals. Homozygosity for p.A287P was invariably associated with 46,XX DSD but normal genitalia in 46,XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles.Conclusions:We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing.

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Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/P carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands' cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (HO). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands' fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon HO exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/P transport to the development of skeletal and connective tissue.

Penetrating foreign bodies of different origins in the head and neck are rare and potentially dangerous injuries, which might pose problems for their detection, primary care, and final treatment. Depending on the severity of the underlying trauma, some injuries present a higher risk for the presence of foreign bodies. Minor wounds, including common lacerations, are likely to be contaminated with loose gravel debris or dental fragments, and need to be distinguished from severe wounds caused by impalement, shootings, stabbings, and explosions. Blast injuries resulting from terror attacks are challenging recent therapeutic concepts. Even though these injury patterns are uncommon, they carry the risk of impacted objects with dramatic consequences. Despite improving medical imaging techniques, detection remains a challenge as it is dependent on the material of the foreign body, the affected anatomical site, and the injury severity. Therefore, a detailed history of the circumstances leading to trauma is essential when foreign objects are not visible during clinical examination. Precise detection of the foreign body, its anatomical position, and the affected surrounding structures are vital, especially for impalement injuries of the head and neck area. Therefore, an interdisciplinary planning approach is essential prior to removal of the foreign object. Finally, tension-free anatomical adaptation of the corresponding structures is crucial for maintaining and restoring aesthetic and function. Here, we give an overview of the diagnosis and treatment of cases of foreign body injuries encountered in our department.