Erratum: Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology.

[This corrects the article DOI: 10.1016/j.xhgg.2022.100102.].

A novel SYNJ1 homozygous variant causing developmental and epileptic encephalopathy in an Afro-Caribbean individual.

BACKGROUND: SYNJ1 encodes Synaptojanin-1, a dual-function poly-phosphoinositide phosphatase that is expressed in the brain to regulate neuronal synaptic vesicle dynamics. Biallelic SYNJ1 variants cause a spectrum of clinical manifestations, from early onset parkinsonism to developmental and epileptic encephalopathy. METHODS: Proband-only exome sequencing was used to identify a homozygous SYNJ1 pathogenic variant in an individual with epileptic encephalopathy. Sanger sequencing was used to confirm the variant. RESULTS: We present an Afro-Caribbean female who developed uncontrollable seizures shortly after birth, accompanied by developmental delay and severe generalized dystonia. She had homozygosity for a novel c.242-2A > G variant in SYNJ1 with both parents being heterozygous carriers. An older sister was reported to have had a similar presentation but was not examined. Both siblings died at an approximate age of 16 years. CONCLUSIONS: We report a novel pathogenic variant in SYNJ1 present in homozygosity leading to developmental and epileptic encephalopathy. Currently, there are only 4 reports describing 10 individuals with SYNJ1-related developmental and epileptic encephalopathy. This case expands the clinical knowledge and the allelic heterogeneity associated with SYNJ1 variants.

Children and the coronavirus disease 2019 pandemic: a Caribbean perspective.

This study aims to assess coronavirus disease 2019 (COVID-19) surveillance methods, health resources, vaccination coverage and income stratification and quantify burdens of disease and death in children and adolescents in the Caribbean. The investigation was a descriptive, cross-sectional study that included 15 Caribbean countries/territories and utilized surveys and secondary data sources. Quarantine and isolation measures were robust and surveillance strategies were similar. Pediatric specialists were available across the region, but few had designated pediatric hospitals or high-dependency units. There were more cases in children on islands with larger populations. Compared to high-income countries/territories, upper and lower middle-income countries/territories had higher disease burdens, fewer doctors and nurses per 1 000 population, lower bed capacities, and lower vaccination coverage. Child and adolescent cases ranged from 0.60% to 16.9%, compared with a global case rate of 20.2% in 2021. By August 2021 there were 33 deaths among children from Haiti, Jamaica, Trinidad and Tobago, and Barbados. The respective case fatality rates for 0-9-year-olds and 10-19-year-olds were 2.80 and 0.70 in Haiti, 0.10 and 0.20 in Jamaica, and 0.00 and 0.14 in Trinidad, compared with 0.17 and 0.1 globally. Overall COVID-19 incidence and mortality in children were consistent with global estimates. Limited resources have been offset by availability of pediatricians across the region, and minimally direct effects on children. Prioritization of admission of specific at-risk groups, training of first responders and vaccination campaigns targeting pregnant women and vulnerable children and adolescents could benefit countries with low vaccine coverage rates and limited resources.

El presente estudio tiene como objetivo evaluar los métodos de vigilancia, los recursos de salud, y la cobertura de vacunación y la estratificación de los ingresos, así como cuantificar las cargas de enfermedad y muerte de la enfermedad por coronavirus del 2019 (COVID-19) en niños, niñas y adolescentes en el Caribe. La investigación consistió en un estudio descriptivo y transversal que incluyó a 15 países o territorios del Caribe y empleó encuestas y fuentes de datos secundarios. Las medidas de cuarentena y aislamiento fueron sólidas, igual que las estrategias de vigilancia. Había especialistas pediátricos disponibles en toda la región, pero pocos designados en hospitales pediátricos o unidades de alta dependencia. Hubo más casos en pacientes pediátricos en las islas más pobladas. En comparación con los países y territorios de ingresos altos, los de ingresos medianos altos y medianos bajos presentaron una mayor carga de morbilidad, menos personal médico y de enfermería por 1 000 habitantes, menor capacidad de camas y menor cobertura de vacunación. Los casos de niños, niñas y adolescentes oscilaron entre 0,60% y 16,9%, en comparación con una tasa general de casos de 20,2% en el 2021. En agosto del 2021, hubo 33 muertes de pacientes pediátricos de Haití, Jamaica, Trinidad y Tabago y Barbados. Las tasas de mortalidad de los grupos etarios de 0 a 9 años y de 10 a 19 años fueron respectivamente de 2,80 y 0,70 en Haití; 0,10 y 0,20 en Jamaica; y 0,00 y 0,14 en Trinidad; en comparación con 0,17 y 0,1 a nivel mundial. La incidencia general de COVID-19 y la mortalidad en la población infantil fueron coherentes con las estimaciones mundiales. Se compensaron los recursos limitados con la disponibilidad de pediatras en toda la región y efectos directos mínimos en los niños. Priorizar la admisión de grupos específicos de riesgo, la capacitación de los equipos de respuesta inicial y las campañas de vacunación dirigidas a mujeres embarazadas y niños, niñas y adolescentes vulnerables podría beneficiar a los países con recursos limitados y bajas tasas de cobertura de vacunación.

Este estudo visa a avaliar os métodos de vigilância, recursos de saúde, cobertura vacinal e estratificação de renda relacionados à doença do coronavírus de 2019 (COVID-19) e quantificar a carga de morbimortalidade a ela atribuível em crianças e adolescentes no Caribe. Foi realizado um estudo descritivo e transversal que incluiu 15 países e territórios caribenhos e utilizaram-se levantamentos e fontes de dados secundárias. As medidas de quarentena e isolamento foram robustas, e as estratégias de vigilância foram semelhantes. Houve disponibilidade de especialistas pediátricos em toda a região, mas poucos países/territórios tinham hospitais pediátricos ou unidades semi-intensivas especificamente designados. Ocorreram mais casos em crianças nas ilhas com populações maiores. Em comparação com os países/territórios de alta renda, aqueles de renda média-alta e média-baixa apresentaram uma maior carga de morbidade, menos médicos e enfermeiros por 1 000 habitantes, menor capacidade de leitos e menor cobertura vacinal. De 0,60% a 16,9% dos casos ocorreram em crianças e adolescentes, contra uma média mundial de 20,2% em 2021. Até agosto de 2021, haviam ocorrido 33 óbitos de crianças em Barbados, Haiti, Jamaica e Trinidad e Tobago. Os respectivos índices de letalidade nas faixas etárias de 0-9 anos e de 10-19 anos foram 2,80 e 0,70 no Haiti, 0,10 e 0,20 na Jamaica e 0,00 e 0,14 em Trinidad, em comparação com 0,17 e 0,1 no âmbito mundial. Em geral, a incidência e a mortalidade por COVID-19 em crianças foram condizentes com as estimativas mundiais. Os recursos limitados foram compensados pela disponibilidade de pediatras em toda a região e pelos pouquíssimos efeitos diretos sobre as crianças. Priorização de grupos de risco específicos para internação, treinamento de socorristas e campanhas de vacinação dirigidas a gestantes e a crianças e adolescentes vulneráveis poderiam beneficiar países com baixos índices de cobertura vacinal e recursos limitados.

Children and the coronavirus disease 2019 pandemic: a Caribbean perspective

[ABSTRACT]. This study aims to assess coronavirus disease 2019 (COVID-19) surveillance methods, health resources, vaccination coverage and income stratification and quantify burdens of disease and death in children and adolescents in the Caribbean. The investigation was a descriptive, cross-sectional study that included 15 Caribbean countries/territories and utilized surveys and secondary data sources. Quarantine and isolation measures were robust and surveillance strategies were similar. Pediatric specialists were available across the region, but few had designated pediatric hospitals or high-dependency units. There were more cases in children on islands with larger populations. Compared to high-income countries/territories, upper and lower middle-income countries/territories had higher disease burdens, fewer doctors and nurses per 1 000 population, lower bed capacities, and lower vaccination coverage. Child and adolescent cases ranged from 0.60% to 16.9%, compared with a global case rate of 20.2% in 2021. By August 2021 there were 33 deaths among children from Haiti, Jamaica, Trinidad and Tobago, and Barbados. The respective case fatality rates for 0–9-year-olds and 10–19-year-olds were 2.80 and 0.70 in Haiti, 0.10 and 0.20 in Jamaica, and 0.00 and 0.14 in Trinidad, compared with 0.17 and 0.1 globally. Overall COVID-19 incidence and mortality in children were consistent with global estimates. Limited resources have been offset by availability of pediatricians across the region, and minimally direct effects on children. Prioritization of admission of specific at-risk groups, training of first responders and vaccination campaigns targeting pregnant women and vulnerable children and adolescents could benefit countries with low vaccine coverage rates and limited resources.

[RESUMEN]. El presente estudio tiene como objetivo evaluar los métodos de vigilancia, los recursos de salud, y la cobertura de vacunación y la estratificación de los ingresos, así como cuantificar las cargas de enfermedad y muerte de la enfermedad por coronavirus del 2019 (COVID-19) en niños, niñas y adolescentes en el Caribe. La investigación consistió en un estudio descriptivo y transversal que incluyó a 15 países o territorios del Caribe y empleó encuestas y fuentes de datos secundarios. Las medidas de cuarentena y aislamiento fueron sólidas, igual que las estrategias de vigilancia. Había especialistas pediátricos disponibles en toda la región, pero pocos designados en hospitales pediátricos o unidades de alta dependencia. Hubo más casos en pacientes pediátricos en las islas más pobladas. En comparación con los países y territorios de ingresos altos, los de ingresos medianos altos y medianos bajos presentaron una mayor carga de morbilidad, menos personal médico y de enfermería por 1 000 habitantes, menor capacidad de camas y menor cobertura de vacunación. Los casos de niños, niñas y adolescentes oscilaron entre 0,60% y 16,9%, en comparación con una tasa general de casos de 20,2% en el 2021. En agosto del 2021, hubo 33 muertes de pacientes pediátricos de Haití, Jamaica, Trinidad y Tabago y Barbados. Las tasas de mortalidad de los grupos etarios de 0 a 9 años y de 10 a 19 años fueron respectivamente de 2,80 y 0,70 en Haití; 0,10 y 0,20 en Jamaica; y 0,00 y 0,14 en Trinidad; en comparación con 0,17 y 0,1 a nivel mundial. La incidencia general de COVID-19 y la mortalidad en la población infantil fueron coherentes con las estimaciones mundiales. Se compensaron los recursos limitados con la disponibilidad de pediatras en toda la región y efectos directos mínimos en los niños. Priorizar la admisión de grupos específicos de riesgo, la capacitación de los equipos de respuesta inicial y las campañas de vacunación dirigidas a mujeres embarazadas y niños, niñas y adolescentes vulnerables podría beneficiar a los países con recursos limitados y bajas tasas de cobertura de vacunación.

[RESUMO]. Este estudo visa a avaliar os métodos de vigilância, recursos de saúde, cobertura vacinal e estratificação de renda relacionados à doença do coronavírus de 2019 (COVID-19) e quantificar a carga de morbimortalidade a ela atribuível em crianças e adolescentes no Caribe. Foi realizado um estudo descritivo e transversal que incluiu 15 países e territórios caribenhos e utilizaram-se levantamentos e fontes de dados secundárias. As medidas de quarentena e isolamento foram robustas, e as estratégias de vigilância foram semelhantes. Houve disponibilidade de especialistas pediátricos em toda a região, mas poucos países/territórios tinham hospitais pediátricos ou unidades semi-intensivas especificamente designados. Ocorreram mais casos em crianças nas ilhas com populações maiores. Em comparação com os países/territórios de alta renda, aqueles de renda média-alta e média-baixa apresentaram uma maior carga de morbidade, menos médicos e enfermeiros por 1 000 habitantes, menor capacidade de leitos e menor cobertura vacinal. De 0,60% a 16,9% dos casos ocorreram em crianças e adolescentes, contra uma média mundial de 20,2% em 2021. Até agosto de 2021, haviam ocorrido 33 óbitos de crianças em Barbados, Haiti, Jamaica e Trinidad e Tobago. Os respectivos índices de letalidade nas faixas etárias de 0-9 anos e de 10-19 anos foram 2,80 e 0,70 no Haiti, 0,10 e 0,20 na Jamaica e 0,00 e 0,14 em Trinidad, em comparação com 0,17 e 0,1 no âmbito mundial. Em geral, a incidência e a mortalidade por COVID-19 em crianças foram condizentes com as estimativas mundiais. Os recursos limitados foram compensados pela disponibilidade de pediatras em toda a região e pelos pouquíssimos efeitos diretos sobre as crianças. Priorização de grupos de risco específicos para internação, treinamento de socorristas e campanhas de vacinação dirigidas a gestantes e a crianças e adolescentes vulneráveis poderiam beneficiar países com baixos índices de cobertura vacinal e recursos limitados.

Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology.

Loss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important for epigenetic regulation of gene expression. PHF8-XLID is an under-characterized disorder with only five previous reports describing different PHF8 predicted loss-of-function variants in eight individuals. Features of PHF8-XLID include ID and craniofacial dysmorphology. In this report we present 16 additional individuals with PHF8-XLID from 11 different families of diverse ancestry. We also present five individuals from four different families who have ID and a variant of unknown significance in PHF8 with no other explanatory variant in another gene. All affected individuals exhibited developmental delay and all but two had borderline to severe ID. Of the two who did not have ID, one had dyscalculia and the other had mild learning difficulties. Craniofacial findings such as hypertelorism, microcephaly, elongated face, ptosis, and mild facial asymmetry were found in some affected individuals. Orofacial clefting was seen in three individuals from our cohort, suggesting that this feature is less common than previously reported. Autism spectrum disorder and attention deficit hyperactivity disorder, which were not previously emphasized in PHF8-XLID, were frequently observed in affected individuals. This series expands the clinical phenotype of this rare ID syndrome caused by loss of PHF8 function.

A novel unbalanced translocation between chromosomes 5p and 18q leading to dysmorphology and global developmental delay.

BACKGROUND: Individuals with various sized terminal duplications of chromosome 5p or terminal deletions of chromosome 18q have been described. These aberrations may cause congenital malformations and intellectual disability of varying severity. METHODS: Via an international collaborative effort, we obtained a cytogenetic diagnosis for a 5-year-old boy of Afro-Caribbean ancestry who has global developmental delay, dysmorphology, hypotonia, feeding difficulties, bilateral club feet, and intellectual disability. RESULTS: Conventional G-banded karyotyping showed additional chromatin of unknown origin on the long arm of chromosome 18. SNP microarray confirmed the loss of ~6.4 Mb from chromosome 18q: arr[hg19] 18q22.3-q23(71,518,518-77,943,115)x1. The source of the additional chromatin was determined from the microarray to be ~32 Mb from the short arm of chromosome 5 (arr[hg19] 5p13.3-p15.33(51,045-32,062,984)x3). The unbalanced translocation was verified by fluorescent in situ hybridization (FISH). Both parents are healthy and have normal karyotypes suggesting that this abnormality arose de novo in the proband, although gonadal mosaicism in a parent cannot be excluded. CONCLUSION: The combination of clinical features in this individual is most likely due to the partial deletion of 18q and partial duplication of 5p, which to our knowledge has not been previously described.

Children and the coronavirus disease 2019 pandemic: a Caribbean perspective / La población infantil y la pandemia de COVID-19: una perspectiva del Caribe / As crianças e a pandemia da doença do coronavírus de 2019: uma perspectiva do Caribe

ABSTRACT This study aims to assess coronavirus disease 2019 (COVID-19) surveillance methods, health resources, vaccination coverage and income stratification and quantify burdens of disease and death in children and adolescents in the Caribbean. The investigation was a descriptive, cross-sectional study that included 15 Caribbean countries/territories and utilized surveys and secondary data sources. Quarantine and isolation measures were robust and surveillance strategies were similar. Pediatric specialists were available across the region, but few had designated pediatric hospitals or high-dependency units. There were more cases in children on islands with larger populations. Compared to high-income countries/territories, upper and lower middle-income countries/territories had higher disease burdens, fewer doctors and nurses per 1 000 population, lower bed capacities, and lower vaccination coverage. Child and adolescent cases ranged from 0.60% to 16.9%, compared with a global case rate of 20.2% in 2021. By August 2021 there were 33 deaths among children from Haiti, Jamaica, Trinidad and Tobago, and Barbados. The respective case fatality rates for 0-9-year-olds and 10-19-year-olds were 2.80 and 0.70 in Haiti, 0.10 and 0.20 in Jamaica, and 0.00 and 0.14 in Trinidad, compared with 0.17 and 0.1 globally. Overall COVID-19 incidence and mortality in children were consistent with global estimates. Limited resources have been offset by availability of pediatricians across the region, and minimally direct effects on children. Prioritization of admission of specific at-risk groups, training of first responders and vaccination campaigns targeting pregnant women and vulnerable children and adolescents could benefit countries with low vaccine coverage rates and limited resources.

RESUMEN El presente estudio tiene como objetivo evaluar los métodos de vigilancia, los recursos de salud, y la cobertura de vacunación y la estratificación de los ingresos, así como cuantificar las cargas de enfermedad y muerte de la enfermedad por coronavirus del 2019 (COVID-19) en niños, niñas y adolescentes en el Caribe. La investigación consistió en un estudio descriptivo y transversal que incluyó a 15 países o territorios del Caribe y empleó encuestas y fuentes de datos secundarios. Las medidas de cuarentena y aislamiento fueron sólidas, igual que las estrategias de vigilancia. Había especialistas pediátricos disponibles en toda la región, pero pocos designados en hospitales pediátricos o unidades de alta dependencia. Hubo más casos en pacientes pediátricos en las islas más pobladas. En comparación con los países y territorios de ingresos altos, los de ingresos medianos altos y medianos bajos presentaron una mayor carga de morbilidad, menos personal médico y de enfermería por 1 000 habitantes, menor capacidad de camas y menor cobertura de vacunación. Los casos de niños, niñas y adolescentes oscilaron entre 0,60% y 16,9%, en comparación con una tasa general de casos de 20,2% en el 2021. En agosto del 2021, hubo 33 muertes de pacientes pediátricos de Haití, Jamaica, Trinidad y Tabago y Barbados. Las tasas de mortalidad de los grupos etarios de 0 a 9 años y de 10 a 19 años fueron respectivamente de 2,80 y 0,70 en Haití; 0,10 y 0,20 en Jamaica; y 0,00 y 0,14 en Trinidad; en comparación con 0,17 y 0,1 a nivel mundial. La incidencia general de COVID-19 y la mortalidad en la población infantil fueron coherentes con las estimaciones mundiales. Se compensaron los recursos limitados con la disponibilidad de pediatras en toda la región y efectos directos mínimos en los niños. Priorizar la admisión de grupos específicos de riesgo, la capacitación de los equipos de respuesta inicial y las campañas de vacunación dirigidas a mujeres embarazadas y niños, niñas y adolescentes vulnerables podría beneficiar a los países con recursos limitados y bajas tasas de cobertura de vacunación.

RESUMO Este estudo visa a avaliar os métodos de vigilância, recursos de saúde, cobertura vacinal e estratificação de renda relacionados à doença do coronavírus de 2019 (COVID-19) e quantificar a carga de morbimortalidade a ela atribuível em crianças e adolescentes no Caribe. Foi realizado um estudo descritivo e transversal que incluiu 15 países e territórios caribenhos e utilizaram-se levantamentos e fontes de dados secundárias. As medidas de quarentena e isolamento foram robustas, e as estratégias de vigilância foram semelhantes. Houve disponibilidade de especialistas pediátricos em toda a região, mas poucos países/territórios tinham hospitais pediátricos ou unidades semi-intensivas especificamente designados. Ocorreram mais casos em crianças nas ilhas com populações maiores. Em comparação com os países/territórios de alta renda, aqueles de renda média-alta e média-baixa apresentaram uma maior carga de morbidade, menos médicos e enfermeiros por 1 000 habitantes, menor capacidade de leitos e menor cobertura vacinal. De 0,60% a 16,9% dos casos ocorreram em crianças e adolescentes, contra uma média mundial de 20,2% em 2021. Até agosto de 2021, haviam ocorrido 33 óbitos de crianças em Barbados, Haiti, Jamaica e Trinidad e Tobago. Os respectivos índices de letalidade nas faixas etárias de 0-9 anos e de 10-19 anos foram 2,80 e 0,70 no Haiti, 0,10 e 0,20 na Jamaica e 0,00 e 0,14 em Trinidad, em comparação com 0,17 e 0,1 no âmbito mundial. Em geral, a incidência e a mortalidade por COVID-19 em crianças foram condizentes com as estimativas mundiais. Os recursos limitados foram compensados pela disponibilidade de pediatras em toda a região e pelos pouquíssimos efeitos diretos sobre as crianças. Priorização de grupos de risco específicos para internação, treinamento de socorristas e campanhas de vacinação dirigidas a gestantes e a crianças e adolescentes vulneráveis poderiam beneficiar países com baixos índices de cobertura vacinal e recursos limitados.

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.

Sickle cell disease in Grenada: Quality of life and barriers to care.

BACKGROUND: Grenada is a small, resource-limited Caribbean country with a high incidence of sickle cell disease (SCD). Since little is known about the challenges facing individuals living with SCD in the West Indies, we sought to assess barriers to healthcare and the impact of SCD on quality of life in Grenada. METHODS: Both adults aged 18+ (n = 19) and caregivers of children aged 2-17 (n = 26) completed validated survey measures regarding barriers to care and quality of life, along with a genetics knowledge questionnaire. Caregivers also completed a caregiver burden scale. Survey scores were calculated, and responses were analyzed for an association between demographic variables. RESULTS: The Barriers to Care Questionnaire, in which lower scores indicate more barriers, revealed that both adults (mean = 69.9) and children (mean = 75.5) with SCD experienced reduced access to care. The Adult Sickle Cell Quality of Life Measurement Information System indicated increased depression and loneliness in adults, with the lowest scores in the Emotional subscale. However, the Pediatric Quality of Life Inventory answered by caregivers of children with SCD showed the lowest scores in the Physical Functioning subscale. Further analysis using the Caregiver Burden Scale-Zarit Burden Interview revealed that 53.8% of caregivers of children with SCD indicated "little to no burden," which may reflect a difference in cultural expectations of a caregiver between high-income countries and Grenada. Finally, ~80% of respondents knew that SCD was a genetic condition; however, 61%-84% could not correctly indicate recurrence risks, demonstrating a need for additional education. CONCLUSION: These data provide new insights regarding the experience of living with SCD in Grenada and support the need for further investigations into specific barriers to healthcare delivery, which could also improve education and well-being for those affected by SCD in Grenada and in the broader Caribbean community.

Experiences with offering pro bono medical genetics services in the West Indies: Benefits to patients, physicians, and the community.

We describe our experiences with organizing pro bono medical genetics and neurology outreach programs on several different resource-limited islands in the West Indies. Due to geographic isolation, small population sizes, and socioeconomic disparities, most Caribbean islands lack medical services for managing, diagnosing, and counseling individuals with genetic disorders. From 2015 to 2019, we organized 2-3 clinics per year on various islands in the Caribbean. We also organized a week-long clinic to provide evaluations for children suspected of having autism spectrum disorder. Consultations for over 100 different individuals with suspected genetic disorders were performed in clinics or during home visits following referral by locally registered physicians. When possible, follow-up visits were attempted. When available and appropriate, clinical samples were shipped to collaborating laboratories for molecular analysis. Laboratory tests included karyotyping, cytogenomic microarray analysis, exome sequencing, triplet repeat expansion testing, blood amino acid level determination, biochemical assaying, and metabolomic profiling. We believe that significant contributions to healthcare by genetics professionals can be made even if availability is limited. Visiting geneticists may help by providing continuing medical education seminars. Clinical teaching rounds help to inform local physicians regarding the management of genetic disorders with the aim of generating awareness of genetic conditions. Even when only periodically available, a visiting geneticist may benefit affected individuals, their families, their local physicians, and the community at large.

Down syndrome on a small Caribbean island: an uphill battle to obtain services and care for affected individuals.

Most of the geographically isolated island nations in the Caribbean have small populations and low gross national product. As such, many lack important medical and community services. Difficulties are compounded when attempting to care for children with special needs and genetic disorders such as Down syndrome. International charitable organizations can help to provide much needed specialty medical care. Community associations can encourage local relationship building and education. Collaborative efforts with well-funded laboratories can help to deliver molecular characterization for individuals who have genetic disorders. With community and volunteer effort, a higher standard of care is obtainable in underserved communities.

A homozygous truncating NALCN variant in two Afro-Caribbean siblings with hypotonia and dolichocephaly.

NALCN encodes a sodium ion leak channel expressed in the nervous system that conducts a persistent influx of sodium ions to facilitate action potential formation. Homozygous or compound heterozygous loss of function variants in NALCN cause infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1; OMIM 615419). Through exome and Sanger sequencing, we found two siblings of Afro-Caribbean ancestry who are homozygous for a known NALCN pathogenic variant, p.Arg735Ter, leading to failure to thrive, severe hypotonia, and dolichocephaly. The older sibling died suddenly without a known etiology after evaluation but before molecular diagnosis. An international collaboration originating from a resource limited Caribbean island facilitated molecular diagnosis. Due to its small population, geographical isolation, and low socioeconomic status, the island lacks many specialty medical services, including clinical genetics. Descriptions of genetic disorders affecting individuals of Afro-Caribbean ancestry are rarely reported in the medical literature. Diagnosis of IHPRF1 is important, as individuals with biallelic pathogenic NALCN variants are severely affected and potentially are at risk for cardiorespiratory arrest. Additionally, knowing the pathogenic variants allows the possibility of prenatal or preimplantation genetic diagnosis.

Application of exome sequencing to diagnose a novel presentation of the Cornelia de Lange syndrome in an Afro-Caribbean family.

BACKGROUND: Cornelia de Lange syndrome (CdLS) comprises a recognizable pattern of multiple congenital anomalies caused by variants of the DNA cohesion complex. Affected individuals may display a wide range of phenotypic severity, even within the same family. METHODS: Exome sequencing and confirmatory Sanger sequencing showed the same previously described p.Arg629Ter NIPBL variant in two half-brothers affected with CdLS. Clinical evaluations were obtained in a pro bono genetics clinic. RESULTS: One brother had relatively mild proportionate limb shortening; the other had complete bilateral hypogenesis of the upper arm with absence of lower arm structures, terminal transverse defects, and no digit remnants. His complex lower limb presentation included long bone deficiency and a deviated left foot. The mother had intellectual disability and microcephaly but lacked facial features diagnostic of the CdLS. CONCLUSION: We describe a collaboration between a pediatrics team from a resource-limited nation and USA-based medical geneticists. Reports describing individuals of West Indian ancestry are rarely found in the medical literature. Here, we present a family of Afro-Caribbean ancestry with CdLS presenting with phenotypic variability, including unusual lower limb abnormalities. The observation of this novel family adds to our knowledge of the phenotypic and molecular aspects of CdLS.

Childhood-Onset Spinocerebellar Ataxia 3: Tongue Dystonia as an Early Manifestation.

Background: Dystonia is a relatively common feature of spinocerebellar ataxia 3 (SCA3). Childhood onset of SCA3 is rare and typically associated with either relatively large, or homozygous, CAG repeat expansions. Case report: We describe a 10-year-old girl with SCA3, who presented with tongue dystonia in addition to limb dystonia and gait ataxia due to a heterozygous expansion of 84 repeats in ATXN3. Discussion: Diagnosis of the SCAs can be challenging, and even more so in children. Tongue dystonia has not previously been documented in SCA3.

Identification of a de novo case of COL5A1-related Ehlers-Danlos syndrome in an infant in the West Indies leading to improved targeted clinical care.

A 1-year-old girl from an underserved community presented with irritability, pain, and delayed motor skills. Our genetics outreach program facilitated the diagnosis of Ehlers-Danlos syndrome masquerading as developmental delay after noting hyperextensible skin. Diagnosis for this family allows for state-of-the-art cardiac monitoring and appropriate symptomatic treatment for this rare disease.

Genetic diagnosis of Down syndrome in an underserved community.

It is a matter of course that in high-income countries, infants born with features suggestive of Down syndrome (DS) are offered genetic testing for confirmation of a clinical diagnosis. Benefits of a definitive diagnosis include an end to the diagnostic odyssey, informed prognosis, opportunities for caregiver support, inclusion to social support networks, and more meaningful genetic counseling. The healthcare experience for families of children born with DS in low- and middle-income nations is in stark contrast with such a level of care. Barriers to obtaining genetic diagnosis might include economic disparities, geographical isolation, and lack of access to health care professionals trained in genetic medicine. As part of a combined research and community outreach effort, we provided genetic testing for several patients with DS. These individuals and their families live on several resource-limited Caribbean islands and have either limited or virtually no access to medical genetics services. Within this group were three families with recurrent DS. Karyotype established that translocation events were not involved in the DS in any of these families. This information enabled genetic counseling to help family members understand their recurrent DS. A definitive diagnosis of DS is beneficial to families in resource-limited communities and may help to provide such families with genetic counseling, reassurance, and peace of mind.

Epilepsy care in the southern Caribbean.

Very little has been reported about the health resources available for patients with epilepsy in the five English-speaking southern Caribbean countries of Trinidad and Tobago, Barbados, Grenada, Saint Vincent and the Grenadines, and Saint Lucia. There is no comprehensive resource describing their health systems, access to specialty care, antiepileptic drug (AED) use, and availability of brain imaging and EEG. The purpose of this study was to profile epilepsy care in these countries as an initial step toward improving the standard of care and identifying gaps in care to guide future policy changes. In each southern Caribbean country, we conducted study visits and interviewed health-care providers, government health ministers, pharmacy directors, hospital medical directors, pharmacists, clinic staff, radiologists, and radiology and EEG technicians. Health-care providers completed extensive epilepsy care surveys. The five countries all have integrated government health systems with clinics and hospitals that provide free or heavily subsidized care and AEDs for patients with epilepsy. Only Trinidad and Tobago and Barbados, however, have neurology specialists. The three smaller countries lack government imaging and EEG facilities. Trinidad had up to one-year waits for public MRI/EEG. Government formularies in Grenada, Saint Vincent and the Grenadines, and Saint Lucia are limited to first-generation AEDs. One or more second-line agents are formulary in Trinidad and Barbados. Nonformulary drugs may be obtained for individual patients in Barbados. Grenada, Saint Lucia, and Saint Vincent and the Grenadines participate in an Organization of Eastern Caribbean States formulary purchasing system, which added levetiracetam following the survey. Newer generic AED formulations with the lowest risks for pregnancy malformation were not in use. In conclusion, patients with epilepsy in the southern Caribbean have excellent access to government clinics and hospitals, but AED choices are limited. Local medical providers reported that the major limitations in care were lack of specialty care, lack of imaging and EEG services, financial barriers to care, long wait times for care, and limited access to additional AEDs.

Characterization of tissue findings in bone marrow biopsy specimens with small monoclonal B-cell populations.

OBJECTIVES: Bone marrows (BMs) with incidentally identified, small monotypic B-cell populations (MBPs) were evaluated. METHODS: BM aspirates with MBPs representing 5% or less of total events by flow cytometry, less than 5.0 × 10(9)/L B cells in blood, and no history of lymphoma or MBP with a different phenotype from prior lymphoma were selected. Clinical, immunophenotypic, and histologic findings were evaluated. RESULTS: Forty-one of 3,052 BMs had MBPs at 5% or less of total events (median, 1%); 17 were females and 24 were males aged 30 to 87 years (median, 73 years). The MBPs were CD5- in 24, CD5+ resembling chronic lymphocytic leukemia (CLL) in 13, and CD5+ unlike CLL in four. Eighteen of 40 had lymphoid aggregates (LAs) with mostly T cells or a mixture of B and T cells, but three cases had B-cell-rich LAs. CONCLUSIONS: Unlike monoclonal B lymphocytosis in blood, MBPs in BMs were more commonly CD5-. Forty-five percent of BMs had LAs; none were interpreted as lymphoma, although three were suspicious for B-cell lymphoma.

Bone marrow involvement by subcutaneous panniculitis-like T-cell lymphoma: a report of three cases.

Subcutaneous panniculitis-like T-cell lymphoma is a rare subtype of cutaneous T-cell lymphoma. Virtually all cases are confined to the subcutaneous adipose tissue. In this report, we describe the first small series of subcutaneous panniculitis-like T-cell lymphoma (three patients) with bone marrow involvement. All patients presented with skin or soft tissue nodules, fever, and constitutional symptoms, and were diagnosed with subcutaneous panniculitis-like T-cell lymphoma based on the characteristic morphologic and immunophenotypic features of the subcutaneous lesions. Bone marrow core biopsies in these cases showed focal involvement by lymphoma with pathologic features similar to those seen in the diagnostic biopsies. Our observations suggest bone marrow involvement by subcutaneous panniculitis-like T-cell lymphoma does occur, and can be identified histologically and confirmed using standard immunohistochemistry. Our findings raise awareness of bone marrow involvement in this rare entity. However, the incidence and significance of bone marrow involvement in subcutaneous panniculitis-like T-cell lymphoma requires further evaluation.

Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies.

Post-transplant lymphoproliferative diseases (PTLD) are heterogeneous lymphoid disorders ranging from indolent polyclonal proliferations to aggressive lymphomas that complicate solid organ or hematopoietic transplantation. Risk factors for PTLD include viral infections, degree of immunosuppression, recipient age and race, allograft type, and host genetic variations. Clinically, extra-nodal disease is common including 10-15 % presenting with central nervous system (CNS) disease. Most PTLD cases are B cell (5-10 % T/NK cell or Hodgkin lymphoma), while over one-third are EBV-negative. World Health Organization (WHO) diagnostic categories are: early lesions, polymorphic, and monomorphic PTLD; although in practice, a clear separation is not always possible. Therapeutically, reduction in immunosuppression remains a mainstay, and recent data has documented the importance of rituximab +/- combination chemotherapy. Therapy for primary CNS PTLD should be managed according to immunocompetent CNS paradigms. Finally, novel treatment strategies for PTLD have emerged, including adoptive immunotherapy and rational targeted therapeutics (e.g., anti-CD30 based therapy and downstream signaling pathways of latent membrane protein-2A).