Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes.

BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.

mTOR mutations in Smith-Kingsmore syndrome: Four additional patients and a review.

Smith-Kingsmore syndrome (SKS) OMIM #616638, also known as MINDS syndrome (ORPHA 457485), is a rare autosomal dominant disorder reported so far in 23 patients. SKS is characterized by intellectual disability, macrocephaly/hemi/megalencephaly, and seizures. It is also associated with a pattern of facial dysmorphology and other non-neurological features. Germline or mosaic mutations of the mTOR gene have been detected in all patients. The mTOR gene is a key regulator of cell growth, cell proliferation, protein synthesis and synaptic plasticity, and the mTOR pathway (PI3K-AKT-mTOR) is highly regulated and critical for cell survival and apoptosis. Mutations in different genes in this pathway result in known rare diseases implicated in hemi/megalencephaly with epilepsy, as the tuberous sclerosis complex caused by mutations in TSC1 and TSC2, or the PIK3CA-related overgrowth spectrum (PROS). We here present 4 new cases of SKS, review all clinical and molecular aspects of this disorder, as well as some characteristics of the patients with only brain mTOR somatic mutations.

Abnormal bone turnover in individuals with low serum alkaline phosphatase.

The clinical spectrum of hypophosphatasia (HPP) is broad and variable within families. Along severe infantile forms, adult forms with mild manifestations may be incidentally discovered by the presence of low alkaline phosphatase (ALP) activity in serum. However, it is still unclear whether individuals with persistently low levels of ALP, in the absence of overt manifestations of HPP, have subclinical abnormalities of bone remodeling or bone mass. The aim of this study was to obtain a better understanding of the skeletal phenotype of adults with low ALP by analyzing bone mineral density (BMD), bone microarchitecture (trabecular bone score, TBS), and bone turnover markers (P1NP and ß-crosslaps). We studied 42 individuals with persistently low serum ALP. They showed lower levels of P1NP (31.4 ± 13.7 versus 48.9 ± 24.4 ng/ml; p = 0.0002) and ß-crosslaps (0.21 ± 0.17 versus 0.34 ± 0.22 ng/ml, p = 0.0015) than individuals in the control group. There were no significant differences in BMD, bone mineral content, or TBS. These data suggest that individuals with hypophosphatasemia have an overall reduction of bone turnover, even in the absence of overt manifestations of HPP or low BMD. We evaluated bone mineral density (BMD), bone microarchitecture, and bone turnover markers in patients with low serum levels of alkaline phosphatase. Our results show that these patients have low bone remodeling even in the absence of BMD abnormalities, thus supporting the recommendation of avoiding antiresorptives such as bisphosphonates in these subjects.

The role of CDKN2A/B deletions in pediatric acute lymphoblastic leukemia.

The CDKN2A/B genes in the 9p21 chromosomal region are frequently involved in human cancer, including pediatric acute lymphoblastic leukemia (ALL). These genes encode 3 proteins that belong to the RB1 and TP53 pathways and act as tumor suppressors by regulating the G1/S checkpoint of the cell cycle. The prognostic value of deletions in the CDKN2A/B locus in ALL is controversial in part due to the limitations of the methodologies used. Further studies with advanced technologies are needed for elucidation. Future studies would also highlight whether CDK4/CDK6 selective inhibitors might be useful therapies for children with these genetic aberrations.

A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies.

Pulmonary arterial hypertension (PAH) is a pathological condition characterized by a persistent and progressive elevation of pulmonary vascular resistance with devastating consequences if untreated. In the past recent years, several genes have been related to PAH, however, the molecular defect remains unknown in a significant proportion of patients with familial PAH (∼20%). During the past few years, we have observed that PAH shows a particular behavior in Iberian Gypsies, with more aggressive course and frequently affecting multiple members of the same family. We studied five Gypsy families in whom at least one individual from each family developed a severe form of PAH and in whom no mutation had been identified in the common genes. We applied SNP-array-based homozygosity mapping in three families and obtained, among others, one of which included the gene EIF2AK4, recently reported in patients with PAH from group-1' pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH). Subsequently, we sequenced EIF2AK4 and found a homozygous mutation in all five families: c.3344C>T(p.P1115L). The majority of our patients required early lung transplantation. Hence, this mutation appeared with a more severe phenotype than previously reported for other EIF2AK4 mutations. The finding of this novel mutation is important for genetic counseling and calculation of population recurrence risks.

Psychiatric polygenic risk as a predictor of COVID-19 risk and severity: insight into the genetic overlap between schizophrenia and COVID-19.

Despite the high contagion and mortality rates that have accompanied the coronavirus disease-19 (COVID-19) pandemic, the clinical presentation of the syndrome varies greatly from one individual to another. Potential host factors that accompany greater risk from COVID-19 have been sought and schizophrenia (SCZ) patients seem to present more severe COVID-19 than control counterparts, with certain gene expression similarities between psychiatric and COVID-19 patients reported. We used summary statistics from the last SCZ, bipolar disorder (BD), and depression (DEP) meta-analyses available on the Psychiatric Genomics Consortium webpage to calculate polygenic risk scores (PRSs) for a target sample of 11,977 COVID-19 cases and 5943 subjects with unknown COVID-19 status. Linkage disequilibrium score (LDSC) regression analysis was performed when positive associations were obtained from the PRS analysis. The SCZ PRS was a significant predictor in the case/control, symptomatic/asymptomatic, and hospitalization/no hospitalization analyses in the total and female samples; and of symptomatic/asymptomatic status in men. No significant associations were found for the BD or DEP PRS or in the LDSC regression analysis. SNP-based genetic risk for SCZ, but not for BD or DEP, may be associated with higher risk of SARS-CoV-2 infection and COVID-19 severity, especially among women; however, predictive accuracy barely exceeded chance level. We believe that the inclusion of sexual loci and rare variations in the analysis of genomic overlap between SCZ and COVID-19 will help to elucidate the genetic commonalities between these conditions.

[Severity of COVID-19 attributable to obesity according to BMI and CUN-BAE]. / Gravedad de COVID-19 atribuible a obesidad según IMC y CUN-BAE.

INTRODUCTION: Obesity is considered a risk factor in severe cases of COVID-19, which has been analysed using body mass index (BMI), an estimator that does not correlate adequately with body fat (BF) percentage. The aim of this study was to analyse the population attributable fraction to BF in severe forms of COVID-19 based on BMI and CUN-BAE. MATERIAL AND METHODS: Multicentre observational prevalence study. Sociodemographic information, personal history, BMI and CUN-BAE were collected in SARS-CoV-2 positive cases from the provinces of León and La Rioja. Logistic regression models were used to calculate odds ratios with their respective 95% confidence intervals adjusting for age and personal history, as well as the population attributable fraction to BF. RESULTS: Seven hundred eighty-five patients participated, 123 (15.7%) were severe. Age, obesity (both by BMI and CUN-BAE) and personal history were detected as risk factors. 51.6% of severe cases could be attributed to excess BMI and 61.4% to excess BF estimated according to CUN-BAE, with a higher underestimation of risk in women. CONCLUSIONS: Excess BF is a risk factor for severe forms of COVID-19 together with advanced age and the presence of cardiovascular, chronic respiratory or oncohematological diseases. BMI underestimates the risk especially in women, being CUN-BAE the predictor selected for its better estimation of the percentage of BF.

FOXL2 copy number changes in the molecular pathogenesis of BPES: unique cohort of 17 deletions.

Blepharophimosis Syndrome (BPES) is an autosomal dominant developmental disorder of the eyelids with or without ovarian dysfunction caused by FOXL2 mutations. Overall, FOXL2deletions represent 12% of all genetic defects in BPES. Here, we have identified and characterized 16 new and one known FOXL2 deletion combining multiplex ligation-dependent probe amplification (MLPA), custom-made quantitative PCR (qPCR) and/or microarray-based copy number screening. The deletion breakpoints could be localized for 13 out of 17 deletions. The deletion size is highly variable (29.8 kb - 11.5 Mb), indicating absence of a recombination hotspot. Although the heterogeneity of their size and breakpoints is not reflected in the uniform BPES phenotype, there is considerable phenotypic variability regarding associated clinical findings including psychomotor retardation (8/17), microcephaly (6/17), and subtle skeletal features (2/17). In addition, in all females in whom ovarian function could be assessed, FOXL2 deletions proved to be associated with variable degrees of ovarian dysfunction. In conclusion, we present the largest series of BPES patients with FOXL2 deletions and standardized phenotyping reported so far. Our genotype-phenotype data can be useful for providing a prognosis (i.e. occurrence of associated features) in newborns with BPES carrying a FOXL2 deletion.

Can we identify individuals with an ALPL variant in adults with persistent hypophosphatasaemia?

BACKGROUND: Hypophosphatasia (HPP) is an inborn error of metabolism characterized by low levels of serum alkaline phosphatase (ALP). Scarce evidence exists about features that should signal the potential association between hypophosphatasaemia and HPP in adults. The aim of this study is to estimate the prevalence of ALPL variants in subjects with persistent hypophosphatasaemia and determine the associated clinical and laboratory features. For this cross-sectional study, laboratory records of 386,353 subjects were screened by measurement of ALP activity. A total of 85 (0.18%) subjects with persistent hypophosphatasaemia (≥2 serum alkaline phosphatase-ALP-measurements ≤35 IU/L and none > 45 IU/L) were included (secondary causes previously discarded). ALPL genetic testing and a systematized questionnaire to retrieve demographic, clinical and laboratory data were performed. Descriptive analysis and logistic regression models were employed to identify the clinical and laboratory characteristics associated with ALPL variants. RESULTS: Forty subjects (47%) had a variant(s) in ALPL. With regard to clinical characteristics, the presence of an ALPL variant was significantly associated only with musculoskeletal pain (OR: 7.6; 95% IC: 1.9-30.9). Nevertheless, a trend to present more dental abnormalities (OR: 3.6; 95% IC: 0.9-13.4) was observed. Metatarsal stress fractures were also more frequent (4 vs 0; p < 0.05) in this group. Regarding laboratory features, median ALP levels were lower in subjects with ALPL variants (26 vs 29 IU/L; p < 0.005). Interestingly, the threshold of ALP levels < 25 IU/L showed a specificity, positive predictive value and positive likelihood ratio of 97.8, 94.4% and 19.8 to detect a positive ALPL test, respectively. CONCLUSIONS: In subjects with persistent hypophosphatasaemia -secondary causes excluded- one out of two presented ALPL variants. Musculoskeletal pain and ALP levels < 25 IU/L are associated with this variant(s). In this scenario, ALP levels < 25 IU/L seem to be very useful to identify individuals with the presence of an ALPL variant.

[Neonatal diabetes mellitus and KCNJ11 gene mutation: report of a family case]. / Diabetes mellitus neonatal y mutación del gen KCNJ11: presentación de un caso familiar.

Neonatal diabetes mellitus (NDM) is characterized by hyperglycemia within the first month of life and insulin dependence for at least two weeks. There are two types of NDM, transient (TNDM) and permanent (PNDM), which are genetically different. We report the case of two brothers who developed hyperglycemia without ketosis on the 18th day and 2 h of life, respectively. Thyroid function tests, abdominal ultrasound and karyotype where normal and there were no pancreatic antibodies. The first one required insulin therapy for the first 92 days of life and the second for 5 months. The mother developed gestational diabetes during both pregnancies and she was later diagnosed diabetes mellitus (without antibodies). They were studied for mutations in KCNJ11 gene (principally related to the permanent form). The three of them showed the E229K mutation (frequently associated with the transient form). A genetic study is essential in NDM to achieve the most accurate prognosis possible.

[Wolf-Hirschhorn syndrome. Description of a Spanish cohort of 51 cases and a literature review]. / Sindrome de Wolf-Hirschhorn. Descripcion de una cohorte española de 51 casos y revision de la bibliografia.

INTRODUCTION: Wolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome that gives rise to multiple congenital anomalies, caused by the loss of a distal portion of the short arm of chromosome 4 (4p16.3). It is characterised by its own peculiar facial phenotype, associated to growth problems, psychomotor retardation and epilepsy. AIMS: To establish a register of patients with WHS in Spain, describe their characteristics, determine the prevalence of epilepsy, estimate the degree of psychomotor retardation and perform a review of the literature in order to compare these data with those published to date. PATIENTS AND METHODS: In collaboration with the Spanish Wolf-Hirschhorn Syndrome Association, we contacted the families affected and collected data via forms endorsed by medical reports. RESULTS: The characteristics of 51 patients are described. Psychomotor retardation was considered the most severe in 37% of cases. Of the total sample, 88% presented epilepsy, and nearly all of them showed growth problems. The mean size of the deletion was 8.4 Mb, and the phenotype is displayed in photographs. Other clinical features reported were sensory alterations and nephrourological and cardiological pathologies. CONCLUSIONS: This study reports on the second largest cohort of patients with WHS with a genetic characterisation published to date. Many of the characteristics coincide with those described previously, with several exceptions, such as the degree of psychomotor retardation, which appears to be lower in the sample studied here.

TITLE: Sindrome de Wolf-Hirschhorn. Descripcion de una cohorte española de 51 casos y revision de la bibliografia.Introduccion. El sindrome de Wolf-Hirschhorn (SWH) es un sindrome de genes contiguos que provoca multiples anomalias congenitas, causado por la perdida de una porcion distal del brazo corto del cromosoma 4 (4p16.3). Se caracteriza por un fenotipo facial peculiar propio, asociado a problemas de crecimiento, retraso psicomotor y epilepsia. Objetivos. Realizar un registro de pacientes con SWH en España, describir sus caracteristicas, conocer la prevalencia de epilepsia, estimar el grado de retraso psicomotor y realizar una revision de la bibliografia para comparar estos datos con lo publicado hasta la fecha. Pacientes y metodos. En colaboracion con la Asociacion Española de Sindrome de Wolf-Hirschhorn se contacto con las familias afectadas y se realizo una recogida de datos mediante formularios corroborados por informes medicos. Resultados. Se describen las caracteristicas de 51 pacientes. El retraso psicomotor fue considerado grave en el 37% de los casos. El 88% presentaba epilepsia, y la practica totalidad, problemas de crecimiento. El tamaño medio de la delecion fue de 8,4 Mb y el fenotipo se expone en fotografias. Otra clinica descrita fueron alteraciones sensoriales y patologia nefrourologica y cardiologica. Conclusiones. Se describe la segunda cohorte en tamaño de pacientes con SWH publicada hasta la fecha con caracterizacion genetica. Muchas de las caracteristicas coinciden con lo ya descrito, salvo algunas, como el grado de retraso psicomotor, que parece ser menor en la muestra estudiada.

Severe axial anomalies in the oculo-auriculo-vertebral (Goldenhar) complex.

We have studied 4 infants with oculo-auriculo-vertebral (OAV) complex or Goldenhar "syndrome" who also had severe axial anomalies, including multiple vertebral segmentation errors affecting the thoracic and the lumbar spine. One of them presented a previously unreported pattern of vertebral and rib anomalies similar to spondylocostal dysostosis. Three patients had twins, and all 4 patients had other associated non-skeletal malformations which affected the midline, i.e., cleft lip and palate, esophageal atresia with tracheoesophageal fistula, and ventricular septal defect. The broad extent of the axial anomalies, the association with midline defects and twinning, and the combination in the same patient of two distinct conditions support the concept that OAV complex is a polytopic developmental field defect arising during blastogenesis.

Semilobar holoprosencephaly, coronal craniosynostosis, and multiple congenital anomalies: a severe expression of the Genoa syndrome or a newly recognized syndrome?

We report on a female newborn with holoprosencephaly, craniosynostosis, and multiple congenital anomalies including cloverleaf skull, Dandy-Walker malformation, bilateral microphthalmia, cleft soft palate, congenital scoliosis, hypoplastic nails and coarctation of aorta. Some of these features are consistent with the diagnosis of the Genoa syndrome, (MIM 601370) a rare autosomal recessive disorder recently described. The findings of other serious and previously undescribed malformations, however, raises the possibility of a newly recognized disorder.

Mulibrey nanism: three additional patients and a review of 39 patients.

We report on 3 patients with Mulibrey nanism (MN), or Perheentupa syndrome: the first 2 sibs from Argentina and a new patient from Spain. All 3 patients had growth failure, short stature, abnormal pigmentary retinal changes, and a J-shaped sella turcica. These findings are considered major criteria of MN. Two had pericardial constriction, which is a frequent and life-threatening abnormality in this syndrome. MN is a rare autosomal recessive condition. Reviewing the 39 patients described so far, we have classified the anomalies into the very frequent (present in more than 66%), frequent (in at least 25%), and not frequent. Identifying the anomalies specific to MN should help its early diagnosis and treatment.

Mitral and tricuspid valve rupture after moderate blunt chest trauma.

We present a patient with rupture of both atrioventricular valves in a previously healthy adult man who sustained a 5-foot fall. The mechanism of injury was such that it would not necessarily raise an adequate index of suspicion for valvular damage had valvular rupture not occurred. The usefulness of perioperative echocardiography is highlighted.

Research in two large pediatric residencies in Argentina.

PURPOSE: To obtain data about residents' research, knowledge of informatics, and proficiency in English in two pediatric residencies in Argentina. METHOD: Data collected in 1996 using a ten-item questionnaire were evaluated using EpiInfo software. Regression coefficients, odd ratios, and confidence intervals were calculated using logistic multivariate regression analysis (Hosmer-Lemeshow test). RESULTS: Of 249 residents surveyed, 227 (91.1%) answered the questionnaire. Of those, 224 (98.7%) thought that research during residency was useful; 63% believed that research should be required to obtain residency certification. One third of the respondents had presented at least one work or poster, or had published at least one research article. Among the two thirds who had not done so, the majority explained that they had been hindered by lack of mentors, time, or institutional support. Seventy-five percent of the respondents were reasonably proficient in English. A statistically significant association was found between knowledge of how to use statistical software and publication of papers (OR 4.5; 95% CI, 1.37-15.62; p < .003). CONCLUSION: The vast majority of respondents thought that research was useful and should be included in pediatric residency programs. Most thought that it should be required to obtain residency certification. If it is to be required, it should include trained, full-time mentors, time exclusively devoted to research, and courses in research methodology, informatics, and statistics.

Neurosyphilis in an eight-year-old child: usefulness of the SPECT study.

An 8-year-old boy with symptomatic late-onset congenital syphilis is reported. The child had been undertreated when he was 78 days of age, but his clinical and serologic follow-up did not occur until he was 3 years of age. At that time, he was asymptomatic, and cerebrospinal fluid disclosed not only hypercellularity but also a reactive Venereal Disease Research Laboratories test. Although he was then retreated at 4 years of age, he developed seizures. Cranial computed tomography and magnetic resonance imaging were normal, but two single photon emission computed tomography scans performed when he was 5 years of age and then 7 years of age demonstrated areas of hypoperfusion that closely agreed with the alterations on electroencephalograph. Brain single photon emission computed tomography was able to detect cerebral nervous system abnormalities in this young patient with neurosyphilis, whereas other image studies did not.