Sumie Yamashita

A novel mutation (296 del G) of the SOX9 gene in a patient with campomelic syndrome and sex reversal

The human SOX9 gene is responsible for the campomelic syndrome (CMPS) and sex reversal. This gene encodes a transcription factor containing a DNA binding domain homologous to the SRY high mobility group (HMG) domain. A novel mutation of SOX9, i.e. a single G deletion in one allele at nt 296 from A of the first ATG in the open reading frame, was identified in a patient with CMPS with sex reversal. The deletion resulted in a frameshift mutation upstream of the HMG box and a stop codon 30 bp downstream of the HMG box. The predicted truncated SOX9 protein contained 108 amino acids instead of the 509 amino acids of the normal SOX9 protein, removing nearly 80% of the SOX9 protein, including the HMG and the C‐terminal transactivation domain. Most patients with CMPS reported previously died within the neonatal period. Our findings that the patient has survived, although has been in daily need of mechanical ventilation support for 5 years and 3 months despite a severely impaired SOX9 protein, do not support a linear relationship between the type of mutation and severity of the clinical outcome.

A case of autosomal dominant osteopetrosis type II with a novel TCIRG1 gene mutation

Abstract Osteopetrosis is a rare genetic disorder characterized by increased bone mineral density (BMD) due to osteoclast failure. T-cell immune regulator 1 (TCIRG1) plays crucial roles on osteoclast function, and its mutation causes autosomal recessive osteopetorosis. However, mutations in TCIRG1 have never been identified in autosomal dominant osteopetrosis (ADO). A 3-year-old boy was first presented to the clinic because of spontaneous radius and femur fractures. He has optic atrophy. The areal BMD at the lumbar spine was 1274 g/cm2 (233% of normal). Laboratory tests revealed no remarkable abnormal findings, including anemia, except for extremely elevated serum tartrate-resistant acid phosphatase-5b (14,600 mU/dL). Radiographically, the skull base, pelvis, and vertebrae showed a focal sclerosis. Genetic analysis revealed a novel de novo heterozygous missense mutation (His242Arg). Taken together with the mutation, his mild clinical features were diagnosed as ADO. This case implies that TCIRG1 could become a genetic candidate for ADO in addition to malignant forms such as ARO.

Transient neonatal hyperinsulinism with adaptation disorders: a report of three cases

Abstract Transient hyperinsulinism can occur in neonates following exposure to perinatal stress, such as intrauterine growth restriction and birth asphyxia. However, little is known about its pathophysiology and clinical manifestations. We report three neonatal cases of transient severe hyperinsulinism complicated with cardiopulmonary problems, thrombocytopenia, and marked erythroblastosis at birth. All cases showed signs of placental insufficiency, indicating that chronic hypoxia and malnutrition during fetal development might be associated with characteristic clinical features after birth. Perinatal stress-associated hyperinsulinism can be regarded as a systemic syndrome characterized by cardiopulmonary and hematological problems due to fetal chronic hypoxia.

Rapid screening method to detect mutations in CYP21, the gene for 21-hydroxylase

To facilitate a rapid and practical molecular diagnosis of 21-hydroxylase deficiency (21-OHD), we developed a polymerase chain reaction (PCR) test in which only the 21-OH gene (CYP21) is amplified. We applied the test to diagnose 23 patients with salt-wasting type of 21-OHD. The upstream and downstream sequences of CYP21 have been specifically amplified by using a primer set containing the 8-bp deletion sequence of exon 3, which is distinct from its pseudogene CYP21P. The amplified PCR products were further subjected to mutation detection by restriction analysis: E1PL by AciI, I2g by PstI, E63a by DraIII, E7VL by ApaLI, E8non by PstI, and E8RW by AciI. To detect delections and/or gene conversions occurring on exon 3, we used the method described by Rumsby and Honour [1990: J Med Genet 27:676-678]. Our method is able to elucidate 8 common CYP21 mutations by using only 3 primer pairs and 4 restriction enzymes. The overall detection ratio of abnormal haplotypes by this method was over 95%, indicating that our method is practical and useful, particularly for carrier detection.

Intraday glucose fluctuation is common in preterm infants receiving intermittent tube feeding

We previously reported on three preterm infants with blood glucose abnormalities after reaching full enteral feeding. Recently, it has been shown that clinically stable preterm infants may have large fluctuations in blood glucose after the establishment of enteral nutrition. We hypothesized that intraday glucose fluctuation is a common finding in preterm infants, but improves at term post‐conceptual age. This report describes a case series.

Expiratory CO2 as the first sign of successful ventilation during neonatal resuscitation

Three‐lead electrocardiography and expired CO2 monitoring were used during positive pressure ventilation of seven non‐intubated newborns (gestational age, 31–37 weeks; birthweight, 1503–2885 g). In all cases, adequate CO2 (>15 mmHg) was detected prior to the achievement of stable heart rate (>100 beats/min). The delay between detection of adequate CO2 and improvement of bradycardia ranged from 8 to 73 s (median, 15 s). Inadequate expired CO2 during positive pressure ventilation indicates airway obstruction or poor aeration of the newborn lungs. Thus, positive expiratory CO2 can be the first recognizable sign of successful ventilation during neonatal resuscitation.

Japanese growth prediction model for prepubertal children with growth hormone deficiency

Abstract Background: Individual responses to growth hormone (GH) treatment are variable, and efficacy should be judged in each individual patient. Objective: The aim of this study was to develop a prediction model for the growth response of GH treatment in Japanese prepubertal children with GH deficiency. Patients and methods: Pediatric patients with GH deficiency were enrolled. Auxological measurements, markers of GH status, and markers of bone metabolism were measured at baseline and at 3 and 6 months after the start of GH treatment. Correlations with height velocity (HV) at 36 months of GH treatment were calculated. Prediction models were evaluated by multiple regression analysis. Results: The model, which combined the parameters of HV at 3 months, insulin-like growth factor-binding protein 3, standard deviation score, and pyridinoline at 3 months, best predicted HV at 36 months. Conclusions: This model can accurately predict the first 3 years of growth response after 3 months of GH replacement therapy in prepubertal Japanese children.

Fetal Erythroblastosis May Be an Indicator of Neonatal Transient Hyperinsulinism

Background: Small for gestational age and birth asphyxia are associated with neonatal transient hyperinsulinism (THI). Some newborns with THI showed marked erythroblastosis on admission to our neonatal intensive care unit. Objective: This study was designed to test our hypothesis that fetal erythroblastosis may be a risk factor for developing THI. Methods: The records of all babies admitted to our neonatal intensive care unit within 24 h of birth between January 2010 and May 2014, and who were born after 34 weeks of gestation, were retrospectively reviewed. Hyperinsulinism was diagnosed as hypoglycemia concomitant with high serum insulin in babies requiring >6 mg/kg/min intravenous glucose and THI as hyperinsulinism without maternal diabetes or genetic disorders. The following three possible risk factors for THI were evaluated: (1) birth weight z-score, (2) 1-min Apgar score and (3) absolute nucleated red blood cell (aNRBC) count on admission. Results: Of 705 infants, 8 were diagnosed with THI. Multivariate logistic regression analysis revealed that the aNRBC count was the most significant risk factor for THI. The median aNRBC count was 181/µl (interquartile range 0-538/µl), and 8 of 71 infants (11.3%) having an aNRBC count >1,413/µl (90th percentile in this study) had THI. The aNRBC counts in the 8 cases with THI were significantly higher than those in the 5 cases with hyperinsulinism caused by maternal diabetes or genetic disorders. Conclusions: This study showed that the aNRBC count was strongly associated with subsequent THI. Fetal erythroblastosis, characterized by chronic fetal hypoxia, may be an indicator of perinatal stress sufficient to cause THI.