Various phenotypes of short stature with heterozygous IGF-1 receptor (IGF1R) mutations.

Type 1 insulin-like growth factor receptor (IGF1R) plays an important role in normal fetal and postnatal growth. Over 30 pathogenic variants of IGF1R have been identified in patients with short stature. Yet, 20 years after the first report, a variety of phenotypes remain poorly defined. We analyzed the genetic and clinical data and responses to GH therapy in 11 patients using results from questionnaires. Eight of the 11 patients have already been reported in previous articles, and all of the identified mutations were heterozygous. The patients exhibited various phenotypes. At least two patients did not meet the criteria for GH treatment for small for gestational age (SGA) short stature, and two more patients showed lower serum IGF1 levels. Nine of the 11 patients had thin upper lips. Five patients with heterozygous IGF1R treated with GH exhibited similar height gains to those reported in previous Japanese studies on SGA short stature, which also led to extremely high serum IGF1 levels. Patients with short stature due to IGF1R mutations exhibit various phenotypes. Their presentation at diagnosis may be indistinguishable from common short stature. More specific clinical scoring that considers elevated IGF1 levels after GH treatment is needed to better detect IGF1R mutations.

Evaluation of the clinical performance of noninvasive prenatal testing at a Japanese laboratory.

AIM: We aimed to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of noninvasive prenatal testing (NIPT) in high-risk pregnant women. METHODS: Pregnant women who underwent GeneTech NIPT, the most commonly used NIPT in Japan, between January 2015 and March 2019, at Japan NIPT Consortium medical sites were recruited for this study. The exclusion criteria were as follows: pregnant women with missing survey items, multiple pregnancy/vanishing twins, chromosomal abnormalities in the fetus other than the NIPT target disease, and nonreportable NIPT results. Sensitivity and specificity were calculated from the obtained data, and maternal age-specific PPV and NPV were estimated. RESULTS: Of the 45 504 cases, 44 263 cases fulfilling the study criteria were included. The mean maternal age and gestational weeks at the time of procedure were 38.5 years and 13.1 weeks, respectively. Sensitivities were 99.78% (95% confidence interval [95% CI]: 98.78-99.96), 99.12% (95% CI: 96.83-99.76), and 100% (95% CI: 88.30-100) for trisomies 21, 18, and 13, respectively. Specificities were more than 99.9% for trisomies 21, 18, and 13, respectively. Maternal age-specific PPVs were more than 93%, 77%, and 43% at the age of 35 years for trisomies 21, 18, and 13, respectively. CONCLUSION: The GeneTech NIPT data showed high sensitivity and specificity in the detection of fetal trisomies 21, 18, and 13 in high-risk pregnant women, and maternal age-specific PPVs were obtained. These results could provide more accurate and improved information regarding NIPT for genetic counseling in Japan.

Post-Traumatic West Syndrome due to Abusive Head Trauma in Two Infants with Different Brain Imaging Findings.

Abusive head trauma (AHT), commonly known as shaken baby syndrome, is a cranial injury of infants and young children. AHT is an important cause of morbidity and mortality in young children, particularly those younger than 12 months of age. We describe two patients who developed West syndrome, which is a severe epilepsy syndrome composed of the triad of infantile spasms, hypsarrhythmia on electroencephalography, and developmental arrest or regression, possibly attributable to AHT. Case 1 was a 5-month-old boy presented with generalized convulsive status epilepticus when a babysitter had cared for him. Brain magnetic resonance imaging (MRI) exhibited a subdural hemorrhage with diffuse brain edema and a midline shift highly suggestive of AHT. He developed West syndrome at the age of 10 months. Case 2 was a 6-month-old girl presented infantile spasms and diagnosed with West syndrome. Although she had poor weight gain due to inadequate care by her mother, there were no history of trauma, no cutaneous finding, and no developmental delay. Brain MRI performed when West syndrome was diagnosed revealed contusional tears highly suggestive of AHT. The MRI finding indicated that contusional tears had occurred 1~2 months before the development of West syndrome. There are no reports of West syndrome due to contusional tears. AHT may be an important risk factor for postnatal West syndrome. It is noteworthy that evidence of AHT was found only after West syndrome onset, as in Case 2. The onset of West syndrome may contribute to the finding that AHT had occurred earlier.

A severe case of Menkes disease with repeated bone fracture during the neonatal period, followed by multiple arterial occlusion.

Menkes disease (MD) is a lethal infantile neurodegenerative disorder with X-linked inheritance, characterized by progressive neurodegenerative symptoms caused by pathogenic variants in the ATP7A. Early diagnosis and treatment are important, although the diagnosis is difficult prior to 2 months of age. We present an unusually severe case of MD with skull fractures at the birth and repeated fractures during the neonatal period, with further examinations leading to diagnosis. The patient died due to hemorrhagic shock, due to multiple arterial occlusion despite initiation of copper-histidine therapy in early infancy. Bone fracture at birth and multiple arterial occlusion are very rare findings in MD. This unusual and severe presentation emphasizes the importance of early diagnosis and treatment. A congenital bone fracture should be considered as a possible presentation of MD, especially in cases without birth complications.

Cornelia de Lange syndrome in diverse populations.

Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.

Classification of factors involved in nonreportable results of noninvasive prenatal testing (NIPT) and prediction of success rate of second NIPT.

OBJECTIVE: To evaluate the reasons for nonreportable cell-free DNA (cfDNA) results in noninvasive prenatal testing (NIPT), we retrospectively studied maternal characteristics and other details associated with the results. METHODS: A multicenter retrospective cohort study in pregnant women undergoing NIPT by massively parallel sequencing (MPS) with failed cfDNA tests was performed between April 2013 and March 2017. The women's data and MPS results were analyzed in terms of maternal characteristics, test performance, fetal fraction (FF), z scores, anticoagulation therapy, and other details of the nonreportable cases. RESULTS: Overall, 110 (0.32%) of 34 626 pregnant women had nonreportable cfDNA test results after an initial blood sampling; 22 (20.0%) cases had a low FF (<4%), and 18 (16.4%) cases including those with a maternal malignancy, were found to have altered genomic profile. Approximately half of the cases with nonreportable results had borderline z score. Among the women with nonreportable results because of altered genomic profile, the success rate of retesting using a second blood sampling was relatively low (25.0%-33.3%). Thirteen (11.8%) of the women with nonreportable results had required hypodermic heparin injection. CONCLUSIONS: The classification of nonreportable results using cfDNA analysis is important to provide women with precise information and to reduce anxiety during pregnancy.

Current status of non-invasive prenatal testing in Japan.

AIM: The purpose of this study was to report the 3-year experience of a nationwide demonstration project to introduce non-invasive prenatal testing (NIPT) of maternal plasma for aneuploidy, and review the current status of NIPT in Japan. METHODS: Tests were conducted to detect aneuploidy in high-risk pregnant women, and adequate genetic counseling was provided. The clinical data, test results, and pregnancy outcomes were recorded. We discuss the problems of NIPT on the basis of published reports and meta-analyses. RESULTS: From April 2013 to March 2016, 30 613 tests were conducted at 55 medical sites participating in a multicenter clinical study. Among the 30 613 women tested, 554 were positive (1.81%) and 30 021 were negative (98.1%) for aneuploidy. Of the 289, 128, and 44 women who tested positive for trisomies 21, 18, and 13, respectively, and underwent definitive testing, 279 (96.5%), 106 (82.8%), and 28 (63.6%) were determined to have a true-positive result. For the 13 481 women with negative result and whose progress could be traced, two had a false-negative result (0.02%). The tests were performed on the condition that a standard level of genetic counseling be provided at hospitals. CONCLUSION: Here, we report on the 3-year nationwide experience with NIPT in Japan. It is important to establish a genetic counseling system to enable women to make informed decisions regarding prenatal testing. Moreover, a welfare system is warranted to support women who decide to give birth to and raise children with chromosomal diseases.

A survey on awareness of genetic counseling for non-invasive prenatal testing: the first year experience in Japan.

The purpose of this study is to summarize the results from a survey on awareness of genetic counseling for pregnant women who wish to receive non-invasive prenatal testing (NIPT) in Japan. As a component of a clinical study by the Japan NIPT Consortium, genetic counseling was conducted for women who wished to receive NIPT, and a questionnaire concerning both NIPT and genetic counseling was given twice: once after pre-test counseling and again when test results were reported. The responses of 7292 women were analyzed. They expressed high satisfaction with the genetic counseling system of the NIPT Consortium (94%). The number of respondents who indicated that genetic counseling is necessary for NIPT increased over time. Furthermore, they highly valued genetic counseling provided by skilled clinicians, such as clinical geneticists or genetic counselors. The vast majority (90%) responded that there was sufficient opportunity to consider the test ahead of time. Meanwhile, women who received positive test results had a poor opinion and expressed a low-degree satisfaction. We confirmed that the pre-test genetic counseling that we conducted creates an opportunity for pregnant women to sufficiently consider prenatal testing, promotes its understanding and has possibilities to effectively facilitate informed decision making after adequate consideration. A more careful and thorough approach is considered to be necessary for women who received positive test results.

A case of Guillain-Barré syndrome with meningeal irritation.

Here, we report a 5-year-old girl with Guillain-Barré syndrome who presented with a chief complaint of pain in the extremities, which was followed by neck stiffness. Bladder dysfunction was found, which required catheterization. Magnetic resonance imaging revealed marked enhancement of the nerve roots in the cauda equina on T1-weighted imaging after gadolinium injection, and nerve conduction studies led to a diagnosis of Guillain-Barré syndrome. Her symptoms improved after intravenous immunoglobulin therapy, but her neck stiffness remained 16 days after admission. Four weeks after admission, she could walk without support. As patients with signs of meningeal irritation may be diagnosed with other diseases, such as meningitis, it is important to recognize atypical cases of pediatric Guillain-Barré syndrome to achieve early diagnosis and treatment.

Heterozygous nonsense mutations near the C-terminal region of IGF1R in two patients with small-for-gestational-age-related short stature.

OBJECTIVE: The type I insulin-like growth factor I receptor (IGF1R) plays an important role in growth. We aimed to evaluate the detailed mechanism underlying the effect of IGF1R on human growth. PATIENTS AND METHODS: We have performed sequence analysis of IGF1R in 55 patients with SGA short stature in Japan, since 2004, and identified novel heterozygous nonsense mutations in 2 patients: an 8-year-old Japanese boy (case 1), with a birthweight of 2228 g (-3·3 SDS) and height of 46 cm (-2·1 SDS), and a 3-year-old Japanese girl (case 2), with a birthweight of 2110 g (-3·0 SDS) and height of 44·3 cm (-2·8 SDS). Both patients had a short stature (-3·2 SDS, -3·1 SDS). We determined the protein expression of mutated IGF1R, assessed the effect of the endoplasmic reticulum-associated degradation (ERAD) pathway on mutated IGF1R, assessed the dominant-negative effect of IGF1R and performed quantitative RT-PCR analysis of IGF1R mRNA expression in whole blood cells. RESULTS: Two novel heterozygous nonsense mutations (case 1: p.Q1250X and case 2: p.W1249X) were identified. Although these mutations did not affect blood IGF1R mRNA levels, they significantly decreased the expression of IGF1R protein in transiently transfected cells. Treatment with the proteasome inhibitor MG132 showed significantly increased IGF1R protein. CONCLUSIONS: Heterozygous nonsense mutations affecting the C-terminal region (p.Q1250X, p.W1249X) of IGF1R decreased the expression of IGF1R through the ERAD pathway. Our study revealed the importance of the C-terminal region and the dosage of this receptor for growth.

Increased protein stability of CDKN1C causes a gain-of-function phenotype in patients with IMAGe syndrome.

Mutations in the proliferating cell nuclear antigen (PCNA)-binding domain of the CDKN1C gene were recently identified in patients with IMAGe syndrome. However, loss of PCNA binding and suppression of CDKN1C monoubiquitination by IMAGe-associated mutations hardly explain the reduced-growth phenotype characteristic of IMAGe syndrome. We demonstrate here that IMAGe-associated mutations in the CDKN1C gene dramatically increased the protein stability. We identified a novel heterozygous mutation, c.815T>G (p.Ile272Ser), in the CDKN1C gene in three siblings manifesting clinical symptoms associated with IMAGe syndrome and their mother (unaffected carrier). PCNA binding to CDKN1C was disrupted in the case of p.Ile272Ser, and for two other IMAGe-associated mutations, p.Asp274Asn and p.Phe276Val. Intriguingly, the IMAGe-associated mutant CDKN1C proteins were fairly stable even in the presence of cycloheximide, whereas the wild-type protein was almost completely degraded via the proteasome pathway, as shown by the lack of degradation with addition of a proteasome inhibitor, MG132. These results thus suggested that the reduced-growth phenotype of IMAGe syndrome derives from CDKN1C gain-of-function due to IMAGe-associated mutations driving increased protein stability.

Influence of premature rupture of membrane on the cerebral blood flow in low-birth-weight infant after the delivery.

Cerebral white matter injury, usually called periventricular leukomalacia (PVL), is the most common form of injury to preterm infants that is associated with adverse motor and cognitive outcomes. Intrauterine infection may be an important etiological factor in PVL, and premature rupture of the membranes (PROM) can be identified antepartum. In order to investigate the pathophysiology of cerebral white matter injury induced by PROM, the cerebral blood flow (CBF) of the internal carotid artery and the vertebral artery was measured by neck ultrasonography. The CBF was determined in 84 low-birth-weight infants with gestational ages ranging from 24 to 35 weeks, including 71 infants without PROM and 13 infants with PROM. The mean blood flow velocity and diameter of each vessel were measured on postnatal days 0-70. The intravascular flow volume was determined by calculating the mean blood flow velocity and the cross-sectional area. The mean blood pressures were recorded, and the ejection fraction was determined. The total cerebral blood flow (CBF) was significantly lower in infants with PROM than in infants without PROM from day 10 to day 70. The ejection fraction was significantly higher in infants with PROM than in infants without PROM on days 0, 5, 10, 21, and 42. There was no difference in the mean blood pressure between infants with PROM and infants without PROM. The results of the present study suggest that PROM may decrease cerebral blood flow after the birth.