Phosphoserine aminotransferase deficiency diagnosed by whole-exome sequencing and LC-MS/MS reanalysis: A case report and review of literature.

BACKGROUND: Phosphoserine aminotransferase deficiency (PSATD) is an autosomal recessive disorder associated with hypertonia, psychomotor retardation, and acquired microcephaly. Patients with PSATD have low concentrations of serine in plasma and cerebrospinal fluid. METHODS: We reported a 2-year-old female child with developmental delay, dyskinesia, and microcephaly. LC-MS/MS was used to detect amino acid concentration in the blood and whole-exome sequencing (WES) was used to identify the variants. PolyPhen-2 web server and PyMol were used to predict the pathogenicity and changes in the 3D model molecular structure of protein caused by variants. RESULTS: WES demonstrated compound heterozygous variants in PSAT1, which is associated with PSATD, with a paternal likely pathogenic variant (c.235G>A, Gly79Arg) and a maternal likely pathogenic variant (c.43G>C, Ala15Pro). Reduced serine concentration in LC-MS/MS further confirmed the diagnosis of PSATD in this patient. CONCLUSIONS: Our findings demonstrate the importance of WES combined with LC-MS/MS reanalysis in the diagnosis of genetic diseases and expand the PSAT1 variant spectrum in PSATD. Moreover, we summarize all the cases caused by PSAT1 variants in the literature. This case provides a vital reference for the diagnosis of future cases.

Unilateral progressive anterior iris adhesions in Mowat-Wilson syndrome: a new ocular finding.

Ocular associations in Mowat-Wilson syndrome (MWS) are rare. Those involving the anterior segment are scarce in the literature. We describe a child with genetic confirmation of MWS that presented with acquired onset of unilateral anterior iris adhesions with no known trauma.

Novel compound heterozygous ATP1A2 variants in a patient with fetal akinesia/hypokinesia sequence.

ATP1A2 encodes a subunit of sodium/potassium-transporting adenosine triphosphatase (Na+ /K+ -ATPase). Heterozygous pathogenic variants of ATP1A2 cause familial hemiplegic migraine, alternating hemiplegia of childhood, and developmental and epileptic encephalopathy. Biallelic loss-of-function variants in ATP1A2 lead to fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, resulting in fetal death. Here, we describe a patient with compound heterozygous ATP1A2 variants consisting of missense and nonsense variants. He survived after birth with brain malformations and the fetal akinesia/hypokinesia sequence. We report a novel type of compound heterozygous variant that might extend the disease spectrum of ATP1A2.

Craniofacial and dental features in children aged 3-5 years with congenital Zika syndrome.

OBJECTIVE: Zika virus infection has been associated to congenital zika syndrome (CZS) in newborns and is characterized by microcephaly, central/axial motor and sensory dysfunction, dysphagia among other previously described severe health complications. CZS is usually diagnosed postpartum by evident/apparent neural development problems. Although there are some reports of craniofacial/dentition development in CZS, several clinical oral aspects are still unknown. This study describes some structural and functional characteristics of facial and cranial growth and deciduous dentition in CZS-affected children. MATERIAL AND METHODS: Some cranial, facial and dental characteristics were determined in 14 children with CZS aged 3-5 years and compared them against 12 apparently healthy children paired by age and gender. RESULTS: Fourteen CZS cases presented microcephaly, maxillary prognathism, altered facial thirds, asymmetric pupillary line, bruxism (p = 0.006), deep and anterior open bite and distal step decidual molar relationship (p = 0.031). CZS children cannot feed by themselves and most cannot walk and have not develop coordinated and intelligible language according to their chronological age. In contrast, controls presented normal skull features, have autonomous locomotion skills, speak intelligible language, feed by themselves, presented a harmonic intermaxillary relationship and have symmetrical facial thirds. CONCLUSION: Microcephaly, dysphagia, bruxism, mandibular retrognathia, altered facial proportions and malocclusion are the main craniofacial and oral features at CZS. CLINICAL RELEVANCE: The complications of CZS including those related with the face and the oral cavity are still being identified. This study revealed some cranial, facial and oral features in children affected by CSZ. Interdisciplinary rehabilitation protocols must address these syndromic features that could improve children and parents living conditions.

Case Report: short stature, kidney anomalies, and cerebral aneurysms in a novel homozygous mutation in the PCNT gene associated with microcephalic osteodysplastic primordial dwarfism type II.

We report the case of a boy (aged 3 years and 7 months) with severe growth failure (length: -9.53 SDS; weight: -9.36 SDS), microcephaly, intellectual disability, distinctive craniofacial features, multiple skeletal anomalies, micropenis, cryptorchidism, generalized hypotonia, and tendon retraction. Abdominal US showed bilateral increased echogenicity of the kidneys, with poor corticomedullary differentiation, and a slightly enlarged liver with diffuse irregular echotexture. Initial MRI of the brain, performed at presentation, showed areas of gliosis with encephalomalacia and diffused hypo/delayed myelination, and a thinned appearance of the middle and anterior cerebral arteries. Genetic analysis evidenced a novel homozygous pathogenic variant of the pericentrin (PCNT) gene. PCNT is a structural protein expressed in the centrosome that plays a role in anchoring of protein complexes, regulation of the mitotic cycle, and cell proliferation. Loss-of-function variants of this gene are responsible for microcephalic osteodysplastic primordial dwarfism type II (MOPDII), a rare inherited autosomal recessive disorder. The boy died at 8 years of age as a result of an intracranial hemorrhage due to a cerebral aneurism associated with the Moyamoya malformation. In confirmation of previously published results, intracranial anomalies and kidney findings were evidenced very early in life. For this reason, we suggest including MRI of the brain with angiography as soon as possible after diagnosis in follow-up of MODPII, in order to identify and prevent complications related to vascular anomalies and multiorgan failure.

Pyoderma gangrenosum in a patient with Dubowitz syndrome: a new comorbidity?

INTRODUCTION: Dubowitz syndrome is a rare genetic disease with only a few cases reported in the literature. It is characterized by growth retardation, microcephaly, facial dysmorphism and higher risk of developing cancer and cardiomyopathies. PG is an autoinflammatory disorder that causes painful ulcers to develop on the skin and has not been previously associated with Dubowitz syndrome. CASE PRESENTATION: The authors report the case of a 50-year-old female with Dubowitz syndrome who developed painful ulcerative lesions. An incisional biopsy was performed to rule out other diagnoses, and a subsequent clinical diagnosis of PG was made. The patient was treated with specialized wound dressings and oral glucocorticoids. The clinical picture improved consistently after 7 weeks of therapy. CONCLUSIONS: This case report, to the authors' knowledge, is the first to suggest a possible association between Dubowitz syndrome and PG and also to indicate an effective treatment.

Novel blended SNRPE-related spliceosomopathy phenotype characterized by microcephaly and congenital atrichia.

Variants in genes encoding core components of the spliceosomes are associated with craniofacial syndromes, collectively called craniofacial spliceosomopathies. SNRPE encodes a core component of pre-mRNA processing U-rich small nuclear ribonuclear proteins (UsnRNPs). Heterozygous variants in SNRPE have been reported in six families with isolated hypotrichosis simplex in addition to one case of isolated non syndromic congenital microcephaly. Here, we report a patient with a novel blended phenotype of microcephaly and congenital atrichia with multiple congenital anomalies due to a de novo intronic SNRPE deletion, c.82-28_82-16del, which results in exon skipping. As discussed within, this phenotype, which we propose be named SNRPE-related syndromic microcephaly and hypotrichosis, overlaps other craniofacial splicesosomopathies.

5q35 duplication syndrome: Narrowing the critical region on the distal side and further evidence of intrafamilial variability and expression.

The key features of patients with a microduplication 5q35.2q35.3 (including the NSD1 gene) are short stature, microcephaly, mild developmental delay, behavioral problems, digital anomalies and congenital anomalies of internal organs. This core phenotype can be viewed as the reversed phenotype of Sotos syndrome, which is caused by a microdeletion in the same chromosomal region or a pathogenic variant in the NSD1 gene, and includes tall stature and macrocephaly, developmental delay, and epilepsy. Here, we report on a patient and his mother, both with a 5q35.2q35.3 duplication, adding a fifth family to the recently published overview of 39 patients of Quintero-Rivera et al. Our patient had several congenital anomalies, intrauterine growth restriction with a persisting short stature, while his mother was only mildly affected with decreased growth parameters. In addition, he had hemophagogocytic lymphohistiocytosis (HLH) triggered by Haemophilus influenzae and was recently diagnosed with Ewing sarcoma. Our cases carry the smallest duplication published (ca 332 kb, arr[hg19] 5q35.2q35.3(176493106-176824785)x3) further narrowing the distal side of the critical region of the 5q35.2q35.3 duplication. Besides broadening the clinical phenotypic spectrum, our report indicates that the 5q35.2q35.3 microduplication also shows a large intra-familial variability and expression.

Os sentidos produzidos por cuidadoras escolares de crianças com SCZV / Los sentidos producidos por cuidadores escolares de niños con SCZV / The senses produced by school caregivers of children with SCZV

RESUMO. Este estudo, fundamentado na perspectiva da psicologia cultural-histórica sobre a pessoa com deficiência, teve por objetivo apreender a dimensão subjetiva da realidade (ou as mediações) das crianças com a Síndrome Congênita do Zika Vírus (SCZV) no contexto escolar de desenvolvimento e aprendizagem a partir dos sentidos produzidos por cuidadoras escolares. Para tal, foram realizadas entrevistas semiestruturadas com três cuidadoras escolares que trabalham em três creches pertencentes ao sistema de educação de ensino de Campina Grande/PB. Para análise dos dados, foi realizado o procedimento dos Núcleos de Significação, que visa à apreensão das contradições que constituem as produções de significação discursiva dos sujeitos participantes. Os resultados indicaram que as cuidadoras escolares priorizam a mediação pedagógica na relação estabelecida com as crianças com SCZV, embora não desconsiderem a instância do cuidado em termos das necessidades especiais relacionadas à integridade psicomotora que essas crianças apresentam. Ademais, foi evidenciado que as participantes salientam as potencialidades das crianças em detrimento da falta ou lesão gerada pela deficiência.

RESUMEN. Este estudio, basado en la perspectiva de la psicología cultural-histórica sobre las personas con discapacidad, tenía como objetivo apreciar la dimensión subjetiva de la realidad de los niños con Síndrome Congénito del Virus del Zika (SCVZ). en el contexto escolar del desarrollo y el aprendizaje de los significados producidos por los cuidadores escolares. Para ello, se realizaron entrevistas semiestructuradas con tres cuidadores escolares de guarderías diferentes que pertenecen al sistema educativo de Campina Grande/PB. Para el análisis de datos, se realizó el procedimiento de los núcleos de significación, cuyo objetivo es aprehender las contradicciones que constituyen las producciones de significado discursiva de los participantes. Los resultados indicaron que los cuidadores de la escuela dan prioridad a la mediación pedagógica en la relación establecida con los niños con SCVZ, aunque no descuidan la instancia de cuidado en cuanto a las necesidades especiales relacionadas con la integridad psicomotora que tienen estos niños. Además, se destacó que los participantes ponen de relieve el potencial de los niños en detrimento de la falta o lesión generada por la discapacidad.

ABSTRACT This study is based by the perspective of the cultural-historical psychology on people with disabilities, aimed to apprehend the subjective dimension of the reality (or mediations) of children with Congenital Zika Virus Syndrome (CZVS) on the school context development and learning from the senses produced by school children caregivers. For this reason, semi-structured interviews were conducted with three caregivers working in three daycare centers belonging to the teaching system of education in Campina Grande/PB. For data analysis, was performed the meaning core, which aims to apprehend the contradictions that constitute the productions of discursive meaning in the participating subjects. The results indicated that school caregivers prioritize the mediation in the relationship established with children CZVS, though not disregard the instance of care in terms of the special needs related to psychomotor integrity that these children have. Furthermore, it was evidenced that the participants emphasize the children's potentialities to the detriment of the lack or injury generated by the disability.

A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: a case report and literature review.

BACKGROUND: The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by variant. We reported a Chinese male newborn with a de novo variant in CASK gene. CASE PRESENTATION: We present an 18-day-old baby with growth retardation and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense variant c.764G > A of CASK gene. The variant changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect. CONCLUSIONS: In this paper, a de novo variant of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported. CASK variants cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

Clinical and molecular delineation of mandibulofacial dysostosis with microcephaly in six Korean patients: When to consider EFTUD2 analysis?

Mandibulofacial dysostosis with microcephaly (MFDM, OMIM#610536) is an extremely rare genetic syndrome characterised by microcephaly, external ear deformity, hearing loss, and distinct facial appearance, including zygomatic hypoplasia and micrognathia. Occasionally, various malformations in other internal organs, including oesophageal atresia or tracheoesophageal fistula, may lead to life-threatening situations. Haploinsufficiency of EFTUD2 is responsible for MFDM. Here, we present the phenotypic and genetic characteristics of six Korean children who were diagnosed with MFDM by molecular genetic testing. All but one patient had occipitofrontal circumferences below the -2.0 standard deviation score. Micrognathia was identified in all patients. A cleft palate (66.7%) and other facial dysmorphisms, including facial asymmetry (50%) and malar hypoplasia (50%), were also frequently observed. Hearing loss was observed in all patients along with one or more internal and external ear deformities, including ossicular anomalies, auditory canal stenosis, and microtia. Two patients (33.3%) had undergone surgery for tracheoesophageal fistula type C. Most patients were initially misdiagnosed as other better-known syndromes with overlapping characteristics, such as Treacher Collins or CHARGE syndrome. The first three patients were diagnosed using exome sequencing. However, after increased awareness of MFDM in the first three patients, MFDM was considered one of the initial differential diagnoses and could be diagnosed by target gene analysis in the remaining three cases. Thus, we recommend targeted EFTUD2 analysis as the initial workup for the rapid diagnosis of MFDM in patients with facial dysostosis, microcephaly, and otologic problems.

Oral manifestations of congenital Zika virus infection in children with microcephaly: 18-month follow-up case series.

AIMS: To describe oral manifestations in children born with microcephaly attributed to congenital Zika virus syndrome (CZS). METHODS: Data was collected in semiannual intervals from 2017 to 2019, by oral exams of the children and interview with caregivers at a Public Dental Center in Rio de Janeiro, Brazil. A single calibrated examiner performed clinical examinations. RESULTS: Of 38 eligible children, 34 were followed-up from 12 to 30 months of age, 20 boys and 14 girls. The mean age of emergence of their first primary tooth was 12.4 months (SD = 2.9). By 30 months of age only 14.7% (n = 5) had complete primary dentition. Alteration in the sequence of tooth emergence was observed in 41.1% (n = 14). Radiographic examination demonstrated dental agenesis (14.7% n = 5). Dental developmental alterations (38.2%, n = 13), enamel defects (14.7%, n = 5), eruption cysts/hematoma (23.5%, n = 8), gingival bleeding (55.8%, n = 19), narrow palate, and bruxism (64.7%, n = 22) were also observed. No child had dental caries. CONCLUSION: Children with microcephaly attributed to CZS presented oral manifestations early in life.

Biallelic TERT variant leads to Hoyeraal-Hreidarsson syndrome with additional dyskeratosis congenita findings.

Short telomere syndromes constitute a heterogeneous group of clinical conditions characterized by short telomeres and impaired telomerase activity due to pathogenic variants in the essential telomerase components. Dyskeratosis congenita (DC) is a rare, multisystemic telomere biology disorder characterized by abnormal skin pigmentation, oral leukoplakia and nail dysplasia along with various somatic findings. Hoyeraal-Hreidarsson syndrome (HHS) is generally an autosomal recessively inherited subgroup showing growth retardation, microcephaly, cerebellar hypoplasia and severe immunodeficiency. We here report on a consanguineous family from Turkey, in which a missense variant in the reverse transcriptase domain of the TERT gene segregated with short telomere lengths and was associated with full-blown short telomere syndrome phenotype in the index; and heterogeneous adult-onset manifestations in heterozygous individuals.

Microcephaly measurement in adults and its association with clinical variables

ABSTRACT OBJECTIVE To establish a microcephaly cut-off size in adults using head circumference as an indirect measure of brain size, as well as to explore factors associated with microcephaly via data mining. METHODS In autopsy studies, head circumference was measured with an inelastic tape placed around the skull. Total brain volume was also directly measured. A linear regression was used to determine the association of head circumference with brain volume and clinical variables. Microcephaly was defined as head circumference that were two standard deviations below the mean of significant clinical variables. We further applied an association rule mining to find rules associating microcephaly with several sociodemographic and clinical variables. RESULTS In our sample of 2,508 adults, the mean head circumference was 55.3 ± 2.7cm. Head circumference was related to height, cerebral volume, and sex (p < 0.001 for all). Microcephaly was present in 4.7% of the sample (n = 119). Out of 34,355 association rules, we found significant relationships between microcephaly and a clinical dementia rating (CDR) > 0.5 with an informant questionnaire on cognitive decline in the elderly (IQCODE) ≥ 3.4 (confidence: 100% and lift: 5.6), between microcephaly and a CDR > 0.5 with age over 70 years (confidence: 42% and lift: 2.4), and microcephaly and males (confidence: 68.1% and lift: 1.3). CONCLUSION Head circumference was related to cerebral volume. Due to its low cost and easy use, head circumference can be used as a screening test for microcephaly, adjusting it for gender and height. Microcephaly was associated with dementia at old age.

Síndrome congênita pelo vírus zika: análise das redes de apoio de pais / Síndrome congénito por el virus del zika: análisis de las redes de apoyo de padres / Congenital zika syndrome: analysis of parent support networks

Resumo Objetivo Compreender o papel das redes de apoio no cuidado de crianças acometidas pela Síndrome Congênita pelo Vírus Zika. Métodos Estudo qualitativo, realizado em Centro de Referência Estadual em Neurodesenvolvimento, no nordeste brasileiro, entre abril de 2017 e fevereiro de 2018. Participaram pais de crianças com microcefalia atendidos no local. Foram realizadas 18 entrevistas semiestruturadas, sendo três com pai e mãe e 15 somente com mães, totalizando 21 participantes. A amostra foi definida pelo critério de saturação e foi utilizada análise de conteúdo na modalidade temática. Resultados Os resultados são apresentados a partir das categorias de análise "rede informal" e "rede formal". A rede de apoio informal, especialmente os avós, exerceu importante suporte emocional e financeiro aos pais. As redes sociais virtuais se destacaram como espaço de compartilhamento de informações e experiências. Quanto à rede de apoio formal, as famílias estabeleceram vínculos mais fortes com profissionais da atenção especializada que ofertaram suporte técnico e acolhimento aos pais e às crianças. Já a atenção primária desempenhou mais o papel de encaminhamento para a atenção especializada. Foram relatados diferentes graus de resolutividade por parte dos municípios, em termos de programas, de atuação de gestores e de profissionais. Conclusão As redes informais e formais atuaram de modo complementar no tratamento e apoio às crianças com Síndrome Congênita pelo Vírus Zika. A inserção em diferentes redes informais possibilitou apoio social para enfrentar o impacto provocado pela doença. Apesar do investimento do Ministério da Saúde na atenção primária foi identificada fragilidade neste nível de atenção.

Resumen Objetivo Comprender el papel de las redes de apoyo en el cuidado de niños afectados por el síndrome congénito por el virus del zika. Métodos Estudio cualitativo, realizado en un Centro de Referencia Regional en Neurodesarrollo, en el nordeste brasileño, entre abril de 2017 y febrero de 2018. Participaron padres de niños con microcefalia atendidos en el lugar. Se realizaron 18 entrevistas semiestructuradas, de las cuales tres fueron con el padre y la madre y 15 solo con madres, un total de 21 participantes. La muestra fue definida por el criterio de saturación y se utilizó análisis de contenido en la modalidad temática. Resultados Los resultados se presentan a partir de las categorías de análisis "red informal" y "red formal". La red de apoyo informal, especialmente los abuelos, ejerció un importante soporte emocional y financiero para los padres. Las redes sociales virtuales se destacaron como un espacio para compartir información y experiencias. Respecto a la red de apoyo formal, las familias establecieron vínculos más fuertes con profesionales de la atención especializada, que ofrecieron soporte técnico y acogida a los padres y a los niños. Por otro lado, la atención primaria cumplió más el papel de derivar a la atención especializada. Se relataron diferentes niveles de resolución de problemas por parte de los municipios, en términos de programas, de actuación de gestores y de profesionales. Conclusión Las redes informales y formales actuaron de modo complementario en el tratamiento y apoyo a niños con síndrome congénito por el virus del zika. La inserción en diferentes redes informales permitió un apoyo social para enfrentar el impacto provocado por la enfermedad. A pesar de las inversiones en atención primaria del Ministerio de Salud, se identificó fragilidad en este nivel de atención.

Abstract Objective To understand the role of support networks in the care of children affected by Congenital Zika Syndrome. Methods This is a qualitative study, conducted at a State Reference Center on Neurodevelopment, in northeastern Brazil, between April 2017 and February 2018. Parents of children with microcephaly treated at the site participated. 18 semi-structured interviews were conducted, three with father and mother and 15 only with mothers, totaling 21 participants. The sample was defined by the saturation criterion and content analysis was used in the thematic modality. Results The results are presented from the categories of analysis "informal network" and "formal network". The informal support network, especially grandparents, exercised important emotional and financial support to parents. Virtual social networks stood out as a space for sharing information and experiences. Regarding the formal support network, the families established stronger bonds with specialized care professionals who offered technical support and care to parents and children. Primary care, on the other, played the role of referral to specialized care. Different degrees of resolution were reported by the municipalities, in terms of programs, the performance of managers and professionals. Conclusion Formal and formal networks acted in a complementary way in the treatment and support of children with Congenital Zika Syndrome. The insertion in different indirect networks allowed social support to face the impact caused by the disease. Despite the ministry of health's investment in primary care, fragility was identified in this level of care.

A 10-Year-Old Boy with Short Stature and Microcephaly, Diagnosed with Moyamoya Syndrome and Microcephalic Osteodysplastic Primordial Dwarfism Type II (MOPD II).

BACKGROUND Moyamoya syndrome is a rare cerebrovascular condition caused by blockage of the arteries of the basal ganglia. The Japanese word "moyamoya" means "a puff of smoke" which describes the appearance of the collateral compensatory vessels that develop over time. Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a rare genetic syndrome characterized by microcephaly and short stature. In up to 25% of patients with MOPD II, there is an association with moyamoya syndrome. This report is of a Syrian boy diagnosed with moyamoya syndrome and MOPD II. CASE REPORT A 10-year-old boy was referred to our pediatric endocrinology unit for short stature (-11.1 standard deviations). Exploration of the oral cavity showed dental malposition. Laboratory tests revealed mild thrombocytosis and hypernatremia. Glucagon-based growth hormone-stimulation testing revealed pathology, with growth hormone levels peaked at 30 minutes below 1 ng/ml. No abnormalities of carbohydrate metabolism or heart function were identified. Neuropsychological assessment found moderate to severe intellectual disability. Imaging studies showed osteoporosis, bilateral coxa vara, diffuse platyspondyly without scoliosis, malrotation of the left kidney, severe microcephaly with simplified convolution pattern, and moyamoya features with secondary brain atrophy. A genetic study identified a mutation in both alleles of the pericentrin (PCNT) gene, enabling the diagnosis of microcephalic osteodysplastic primordial dwarfism type II. CONCLUSIONS This case highlights the importance of identifying the cause of short stature in children and genetic syndromes that may be linked with other abnormalities. MOPDII associated with moyamoya syndrome was diagnosed by cerebrovascular imaging, which led to a multidisciplinary approach to management.

Feingold syndrome type 2 in a patient from China.

Feingold syndrome type 2 (FGLDS2, MIM614326) is a genetic congenital malformation syndrome, caused by germline heterozygous deletion of MIR17HG on chromosome 13q31, which is extremely rare worldwide. To date, less than 25 patients have been described in the literature. Here, we report on a 3-year-old girl presented with hip dysplasia, polysyndactyly of the left thumb, brachymesophalangy of the fifth digit, microcephaly, intellectual disability, and growth delay. This is likely to be the first case of Feingold syndrome type 2 ever discovered among Chinese population. Through genetic testing and pedigree analysis, she was identified to have a de novo 4.8-Mb microdeletion at chromosome 13q31.3-q32.1, encompassing MIR17HG, GPC5, and GPC6. Additionally, we detected two common compound heterozygous variants (c.919-2A>G and c.147C>G) in SLC26A4 encoding pendrin protein, as well as a novel heterozygous variant c.985_988del in COMP encoding cartilage oligomeric matrix protein. This case report aims to analyze the microdeletion and the three types of variant detected in the patient, and to explore the association between the genotype and phenotype in patients with Feingold syndrome type 2, which may contribute to further understanding and future diagnosis of this disorder.

High-throughput STELA provides a rapid test for the diagnosis of telomere biology disorders.

Telomere biology disorders are complex clinical conditions that arise due to mutations in genes required for telomere maintenance. Telomere length has been utilised as part of the diagnostic work-up of patients with these diseases; here, we have tested the utility of high-throughput STELA (HT-STELA) for this purpose. HT-STELA was applied to a cohort of unaffected individuals (n = 171) and a retrospective cohort of mutation carriers (n = 172). HT-STELA displayed a low measurement error with inter- and intra-assay coefficient of variance of 2.3% and 1.8%, respectively. Whilst telomere length in unaffected individuals declined as a function of age, telomere length in mutation carriers appeared to increase due to a preponderance of shorter telomeres detected in younger individuals (< 20 years of age). These individuals were more severely affected, and age-adjusted telomere length differentials could be used to stratify the cohort for overall survival (Hazard Ratio = 5.6 (1.5-20.5); p < 0.0001). Telomere lengths of asymptomatic mutation carriers were shorter than controls (p < 0.0001), but longer than symptomatic mutation carriers (p < 0.0001) and telomere length heterogeneity was dependent on the diagnosis and mutational status. Our data show that the ability of HT-STELA to detect short telomere lengths, that are not readily detected with other methods, means it can provide powerful diagnostic discrimination and prognostic information. The rapid format, with a low measurement error, demonstrates that HT-STELA is a new high-quality laboratory test for the clinical diagnosis of an underlying telomeropathy.