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- Multidisciplinary Outpatient Clinic of Neurocutaneous Diseases: Five-Year Experience of a Pediatric Tertiary Hospital in PortugalPublication . Rebelo, M; Francisco, T; Perry da Câmara, R; Pereira, A; Iraneta, A; Amorim, M; Paiva Lopes, MJ; Lopes da Silva, R; Cordeiro, AIIntroduction: Neurocutaneous syndromes (NCS) are a heterogeneous group of conditions with multiorgan involvement and diverse manifestations, evolving throughout life with significant morbidity. A multidisciplinary approach to NCS patients has been advocated, although a specific model is not yet established. The aim of this study was 1) to describe the organization of the recently created Multidisciplinary Outpatient Clinic of Neurocutaneous Diseases (MOCND) at a Portuguese pediatric tertiary hospital; 2) to share our institutional experience focusing on the most common conditions, neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC); 3) to analyze the advantages of a multidisciplinary center and approach in NCS. Methods: Retrospective analysis of 281 patients enrolled in the MOCND over the first five years of activity (October 2016 to December 2021), reviewing genetics, family history, clinical features, complications, and therapeutic strategies for NF1 and TSC. Results: The clinic works weekly with a core team of pediatricians and pediatric neurologists supported by other specialties as needed. Of the 281 patients enrolled, 224 (79.7%) had identifiable syndromes such as NF1 (n = 105), TSC (n = 35), hypomelanosis of Ito (n = 11), Sturge-Weber syndrome (n = 5), and others. In NF1 patients, 41.0% had a positive family history, all manifested café-au-lait macules, 38.1% neurofibromas with 45.0% being large plexiform neurofibromas. Sixteen were under treatment with selumetinib. Genetic testing was performed in 82.9% of TSC patients with pathogenic variants found in TSC2 gene in 72.4% patients (82.7% if considered contiguous gene syndrome). Family history was positive in 31.4%. All TSC patients presented hypomelanotic macules and fulfilled diagnostic criteria. Fourteen patients were being treated with mTOR inhibitors. Conclusion: Offering a systematic and multidisciplinary approach to NCS patients enables timely diagnosis, promotes a structured follow-up, and encourages discussion to outline management plans for optimal care to every patient, with significant impact on the quality of life of patients and families.
- TANGO2 Deficiency Disorder: Two Cases of Developmental Delay Preceding Metabolic CrisisPublication . Dias, JV; Carvalho, AA; Freixo, JP; Antunes, D; Martins, AA; Painho, T; Jacinto, SBackground: TANGO2 deficiency disorder is a rare genetic disease caused by biallelic defects in TANGO2 gene. Methods: We report the clinical phenotype of two children with TANGO2 deficiency disorder. Results: Patient 1 is a female child presenting with developmental delay and microcephaly during the second year of life, who evolved with severe cognitive impairment, facial dysmorphisms, spastic paraparesis, and atonic seizures. At age 13 years, she was hospitalized due to an episode of rhabdomyolysis complicated with cardiac arrhythmia and hypothyroidism. Patient 2 is a female child with dysmorphic facial features, cleft palate, and developmental delay who was diagnosed with DiGeorge syndrome. At age three years, she presented with an acute episode of severe rhabdomyolysis in the context of human herpesvirus 6 infection. After the resolution of this acute episode, she maintained recurrent muscle weakness with axial hypotonia and progressive spasticity of the lower extremities. In both patients, diagnosis of TANGO2 deficiency disorder was only confirmed after an acute metabolic crisis. Conclusions: A high index of suspicion for TANGO2 deficiency disorder is needed in patients with developmental delay or other neurological symptoms and episodic rhabdomyolysis.
- Perfil Genético da Surdez: Reabilitação Auditiva e Fatores Preditivos de PrognósticoPublication . Pereira, S; Nunes, S; Mariano, M; Sousa, H; Lavra, T; Kay, T; Barros, EObjetivos: Caracterizar a população com surdez de etiologia genética, a relação genótipo-fenótipo e fatores prognósticos na decisão de tratamento de reabilitação. Material e Métodos: Análise retrospetiva da população pediátrica referenciada da consulta de Reabilitação Auditiva à consulta de Genética Médica entre janeiro-2012 e dezembro-2017. Resultados: Foram encaminhadas 128 crianças e o estudo genético foi positivo em 47%. Os resultados foram sugestivos de haver correlação genótipo-fenótipo nas mutações do gene GJB2 (p=0,30), tendo este grupo etiológico sido o que obteve os melhores ganhos auditivos (p=0,57) e linguísticos (p=0,19) com a reabilitação. O estudo genético revelou alterações associadas a hipoacusia progressiva em seis doentes e identificou variantes que afetam o órgão de Corti, prevendo o desempenho com implante coclear (IC). Conclusões: A confirmação etiológica permite prever a evolução da hipoacusia, como observado no gene GJB2. Doentes com mutações nos genes expressos no labirinto membranoso, com preservação do gânglio espiral, apresentam bom prognóstico com IC.
- Caracterização de Crianças com Distúrbio do Espectro da Neuropatia Auditiva e sua ReabilitaçãoPublication . Mariano, M; Correia, I; Nunes, S; Cunha, I; Sousa, H; Kay, T; Barros, EObjectivos: Identificar e caracterizar os casos pediátricos de Distúrbio do Espectro da Neuropatia Auditiva (DENA) e analisar a sua reabilitação. Desenho do Estudo: Estudo observacional descritivo. Material e Métodos: Análise dos processos clínicos de 671 doentes avaliados em primeira consulta de reabilitação auditiva pediátrica entre 2012 e 2019. Dos 467 casos de hipoacusia sensorioneural, incluíram-se aqueles que apresentavam PEATC sem resposta ou com resposta marcadamente anormal e OEAs presentes e/ou limiares tonais desproporcionais aos resultados electrofisiológicos. Obtiveram-se 12 casos de DENA. Resultados: A prevalência de DENA foi 2,6%. A maioria dos casos apresentou factores de risco para hipoacusia. Os resultados audiométricos foram heterogéneos e flutuantes. Quatro crianças foram reabilitadas com prótese auditiva e três com implante coclear. Conclusões: O DENA é uma condição rara, associada a vários factores de risco e de diagnóstico e abordagem desafiantes. A reabilitação auditiva tem de ser personalizada e guiada pelo desempenho funcional da criança.
- A New ABCA3 Gene Mutation Presenting as Early Neonatal Surfactant DeficiencyPublication . Martins de Abreu, S; Oliveira Antunes, D; Abreu, FMutations of the ATP-binding cassette transporter A3 gene (ABCA3) causing the dysfunction of surfactant proteins are a well-established cause of interstitial lung disease. The clinical presentation is variable ranging from neonatal early death to mild forms of interstitial lung disease in the adult. We present the case of a newborn with early neonatal respiratory distress. The clinical and radiologic findings were compatible with interstitial lung disease. The disease progressed toward severe respiratory insufficiency and the patient died at the age of 3 years. A variant not yet described in the literature was found in the ABCA3 gene (c.4442C>T), in apparent homozygosity. Parental genetic studies revealed that only the father was a carrier for this variant. The quantitative study of the ABCA3 gene in our patient revealed a deletion affecting exon 32 and possibly 29. This report describes the phenotype of a new ABCA3 variant causing surfactant deficiency while also highlighting the importance of considering gene deletions in case of unconfirmed homozygosity.
- A Novel Variant of DeSanto-Shinawi Syndrome with Joint ManifestationsPublication . Branco, J; Amorim, M; Conde, Mvariable degrees of developmental delay and intellectual disability that were recently delineated as DeSanto- Shinawi syndrome (OMIM 616708). We describe a patient with DeSanto-Shinawi syndrome caused by a novel frameshift variant in WAC gene (NM_016628.4(WAC):c.1689del (p.Phe563Leufs*6)). As noted in cases previously reported, our patient phenotype included facial dysmorphism, intellectual disability, behavioral problems, feeding difficulties, hirsutism, constipation and astigmatism. She also had limited range of motion of joints since birth and Juvenile Idiopathic Arthritis diagnosed at eleven years old. Although in the last years some additional features were reported in DeSanto-Shinawi syndrome, joint manifestations have not been previously described. As limited range of motion of joints was reported since birth with no correlation with arthritis onset, it could be a new clinical feature. Polyarthritis in this patient can be only a coincidence, since there is a first degree relative with psoriasis, or might be related to WAC mutation. Indeed, WAC encodes a protein that plays a vital role in autophagy. It has already been demonstrated that WAC haploinsufficiency leads to increased autophagy and, according to different authors, increased autophagy may display a pathogenic role in several autoimmune disorders such as Rheumatoid Arthritis and Juvenile Idiopathic Arthritis. Thus, WAC haploinsufficiency may have contributed to autoimmune disorder in this patient.
- X-linked Hypophosphatemic Rickets: a New MutationPublication . Maio, P; Mano, L; Rocha, S; Baeta Baptista, R; Francisco, T; Sousa, H; Parente Freixo, J; Abranches, MPhosphopenic rickets may be caused by mutations in the PHEX gene (phosphate regulating endopeptidase homolog X-linked). Presently, more than 500 mutations in the PHEX gene have been found to cause hypophosphatemic rickets. The authors report a clinical case of a 4-year-old girl with unremarkable family history, who presented with failure to thrive and bowing of the legs. Laboratory tests showed hypophosphatemia, elevated alkaline phosphatase, normal calcium, mildly elevated PTH and normal levels of 25(OH)D and 1.25(OH)D. The radiological study showed bone deformities of the radius and femur. Clinical diagnosis of phosphopenic rickets was made and the genetic study detected a heterozygous likely pathogenic variant of the PHEX gene: c.767_768del (p.Thr256Serfs*7). This variant was not previously described in the literature or databases. Knowledge about new mutations can improve patient's outcome. Genetic analysis can help to establish a genotype-phenotype correlation.
- The Kidney Genetics Clinic: Delivering Precision Medicine for Kidney PatientsPublication . Calado, J; Barata, R; Lucas, R; Francisco, T; Gonçalves, R; Carrilho Ribeiro, N; Nolasco, FMolecular genetic testing in human traits has traditionally relied on affiliated academic facilities, been focused on specific phenotypes and supported by research funding. We report the experience of the Kidney Genetics Clinic (“consulta de Doenças Renais Hereditárias”) for the past 5 years, a period during which we have outsourced genetic testing. We evaluated the impact of molecular testing in patients’ care, but we also assessed disease‑specific imaging procedures and medicines provided. During the study period, 293 individuals were evaluated. Autosomal Dominant Polycystic Kidney Disease was the most frequent diagnosis (61.8%). In 125 patients, a genetic test was available, and for 76 of these (60.8%) a pathogenic/likely pathogenic variant was identified. Depending on the phenotype, the mutation detection rate ranged from 100% (Tuberous Sclerosis Complex) to 15.4% (Autosomal Dominant Tubulointerstitial Kidney Disease). The impact of genetic testing on patients’ diagnosis and treatments is discussed. Total kidney volume was calculated in 6 patients with Autosomal Dominant Polycystic Kidney Disease and the combined volume for selected angiomyolipoma monitored in 3 individuals with the Tuberous Sclerosis Complex. Currently, 4 patients are being treated with Everolimus/Votubia™, 3 with Eculizumab/Soliris™ and 2 with Tolvaptan/Jinarc™. Our results demonstrate the feasibility of genetic molecular testing in a clinical setting while relying on outsourced sites for gene testing. We emphasize that it was only because the Kidney Genetics Clinic was given the opportunity to look after several patients affected by the same specific orphan or rare diseases (cohort enrichment) that we were able to improve diagnostic skills and deliver personalized medicines.
- Targeted Next-Generation Sequencing Study in Familial ALS-FTD Portuguese Patients Negative for C9orf72 HREPublication . Gromicho, M; Coutinho, AM; Pronto-Laborinho, AC; Raposeiro, R; Tavares, J; Antunes, D; de Carvalho, MAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with clinical and etiological heterogeneity and a complex genetic contribution. Clinical, neuropathological, and genetic evidence revealed that ALS and frontotemporal dementia (FTD) are in part of a single disease continuum. Genetic causes have been identified in sporadic (SALS) and familial patients (FALS) and the recurrent genetic factor underlying ALS and FTD is the C9orf72 hexanucleotide repeat expansion (HRE). However, in our population, the concomitance of ALS and FTD cannot be explained by C9orf72 HRE in many FALS and SALS cases. Our aim is to further understand the genetic basis of ALS in Portuguese patients. 34 patients with FALS or SALS-FTD, negative for C9orf72 HRE, were screened for rare variants in a panel of 29 relevant genes by next-generation sequencing. We detected 15 variants in 11 genes, one classified as pathogenic in TARDBP, two as likely pathogenic in TARDBP and PRPH, and the others as variants of unknown significance (VUS). Gene variants, including VUS, were found in 41.2% FALS patients and 40% SALS-FTD. In most patients, no potential pathogenic variants were found. Our results emphasize the need to enhance the efforts to unravel the genetic architecture of ALS-FTD.
- Primary Hyperoxaluria type 1 – Two Case ReportsPublication . Ganhão, I; Borges, C; Amorim, M; Braga da Cruz, M; Nobre, S; Francisco, T; Cardoso, D; Abranches, MPrimary hyperoxaluria type 1 is a rare autosomal recessive inherited disease, caused by mutations in AGXT gene, with an estimated incidence of 1:100.000 live births per year in Europe. Over 50% present with end stage renal disease at diagnosis. Case reports: The first case is a 14‑year‑old boy, second child to consanguineous parents, with history of recurrent lithiasis and ureteral dilatation starting 5 years before. Urine/stone analysis revealed calcium oxalate monohydrate crystals and markedly elevated urine oxalate excretion. Genetic tests confirmed a mutation in AGXT gene, c.1151T>C, in homozygosity. Two years after, nephrocalcinosis was identified and glomerular filtration rate gradually declined. Oxalate deposition in solid organs was excluded and successful orthotopic liver transplantation was performed, with stabilization of glomerular filtration rate. The second case is a 16‑year‑old girl, with recurrent episodes of renal colic. At diagnosis, she had obstructive hydronephrosis, multiple kidney stones and an estimated glomerular filtration of 42.1mL/min/1.73m2. Metabolic study showed hypocitraturia and hyperoxaluria. With dietetic measures and irregular treatment, urine oxalate excretion remained high but renal function improved. Genetic tests confirmed the presence of two pathologic variants in AGXT gene: c.731T>C and c.1151T>C in compound heterozygous. Conclusions: Recurrent urolithiasis and nephrocalcinosis in children along with family history/consanguinity should raise the suspicion of Primary Hyperoxaluria type 1. Conservative treatment may increase renal survival. Effects of systemic oxalosis must be screened when glomerular filtration rate declines below 30‑50mL/ min/1.73m2, and sequential or combined liver and kidney transplantation should be considered.