Mutations in the enzyme glutathione peroxidase 4 cause Sedaghatian-type spondylometaphyseal dysplasia.

BACKGROUND: Sedaghatian-type spondylometaphyseal dysplasia (SSMD) is a neonatal lethal form of spondylometaphyseal dysplasia characterised by severe metaphyseal chondrodysplasia with mild limb shortening, platyspondyly, cardiac conduction defects, and central nervous system abnormalities. As part of the FORGE Canada Consortium we studied two unrelated families to identify the genetic aetiology of this rare disease. METHODS AND RESULTS: Whole exome sequencing of a child affected with SSMD and her unaffected parents identified two rare variants in GPX4. The first (c.587+5G>A) was inherited from the mother, and the second (c.588-8_588-4del) was de novo (NM_001039848.1); both were predicted to impact splicing of GPX4. In vitro studies confirmed the mutations spliced out part of exon 4 and skipped exon 5, respectively, with both resulting in a frameshift and premature truncation of GPX4. Subsequently, a second child with SSMD was identified; although DNA from the child was not available, the two unaffected parents were found by Sanger sequencing to each carry the same heterozygous stop mutation in exon 3 of GPX4, c.381C>A, p.Tyr127* (NM_001039848.1). CONCLUSIONS: Our identification of truncating mutations in GPX4 in two families affected with SSMD supports the pathogenic role of mutated GPX4 in this very rare disease. GPX4 is a member of the glutathione peroxidase family of antioxidant defence enzymes and protects cells against membrane lipid peroxidation. GPX4 is essential for early embryo development, regulating anti-oxidative and anti-apoptotic activities. Our findings highlight the importance of this enzyme in development of the cardiac, nervous, and skeletal systems.

Simplified gyral pattern with cerebellar hypoplasia in Sedaghatian type spondylometaphyseal dysplasia: a clinical report and review of the literature.

We report on a patient with Sedaghatian type spondylometaphyseal dysplasia (SSMD) who presented with metaphyseal dysplasia, congenital atrioventricular block, simplified gyral pattern, hypogenesis of corpus callosum, and severe cerebellar hypoplasia. We want to emphasize that in this rare congenital lethal skeletal dysplasia with unknown etiology, central nervous system malformations might be a major component of the disorder and should be evaluated in detail to possibly uncover the underlying pathophysiology.

Assessment of different folic acid supplementation doses for low-birth-weight infants.

AIM: The adequacy of 50 mcg folic acid supplementation given to low-birth-weight babies was investigated. The folate levels of the mothers and infants, and breastmilk, and the optimum dose for folic acid supplementation were also investigated. MATERIAL AND METHODS: After obtaining blood from 141 low-birth-weight infants on the 1st day of life for serum and red cell folate levels, the infants were randomly allocated into three groups according to the folic acid supplement dose. Forty-six infants were given 25 µg/d folic acid, 39 were given 50 µg/d folic acid, and 44 were given 75 µg/d folic acid. Folic acid could not be given to 12 infants. Follow-up blood samples were obtained at the end of folic acid supplementation. Maternal samples for red cell and serum folate levels and breast milk folate levels were obtained within the first 48 hours and the samples for measuring breastmilk folate level were obtained on the 3rd day postnatally. The feeding modes of the infants, maternal folic acid intake, and details of neonate intensive care unit course were recorded. RESULTS: The mean birth weight and gestational age of the infants were found as 1788.2±478.4 g and 33.5±2.9 weeks, respectively. The mean serum and red cell folate levels on admission were found as 21.2±12.2 ng/mL and 922.7±460.7 ng/mL, respectively. The mean maternal serum and red cell folate levels and the mean breast milk folate levels were found as 12.3±7.5 ng/mL, 845.5±301.4 ng/mL, and 30.6±33.0 ng/m, respectively. The breast milk folate levels of mothers who were supplemented with folic acid during pregnancy were significantly higher compared with mothers who were not supplemented with folic acid (p<0.001). Infants who were supplemented with folic acid had higher follow-up serum folate levels compared with the basal level in all groups, but there was no statistically significant difference between the groups. CONCLUSION: This study showed that the folic acid doses of 25, 50, and 75 µcg/d affected serum folate levels similarly. We can conclude that the dose of 25 µcg/d is adequate for low-birth-weight infants.

A newborn with antenatal testis tortion.

Testis tortion in the newborn (especially antenatal testis tortion) is observed very rarely and constitutes 10-12% of childhood testis tortions. In testis tortion, firm and painless testicular tissue is palpated on physical examination. Doppler ultrasonography is a sensitive method in the diagnosis. In cases of neonatal testis tortion, the testis can be saved with appropriate surgical exploration in only 0-5% of the cases. Here, a newborn with antenatal testis tortion who underwent orchiectomy in the first day of life was presented.

Two cases of fetus in fetu.

Fetus in fetu (FIF) is a rare cause of abdominal mass in children. One of the malformed monozygotic diamniotic twins is located in the body of other twin. It is differentiated from teratoma by the presence of vertebral organization with limb buds and other organ systems. Diagnosis is based on radiologic findings. Surgical excision is the treatment of choice, leading to the complete removal of the mass. To our knowledge, less than 200 cases have been described in the literature. Herein, we report 2 cases of FIF, a newborn who was diagnosed antenatally and a three-and-half-year- old boy diagnosed with mediastinal FIF after admission for recurrent respiratory tract infections.