Wiedemann-Steiner syndrome in two patients from Portugal.

Wiedemann-Steiner syndrome (WSS) is a rare genetic disorder characterized by growth retardation, facial dysmorphism, hypertrichosis cubiti and neurodevelopment delay. It is caused by pathogenic variants in the KMT2A gene. This report describes two unrelated Portuguese patients, age 11 and 17 years, with a phenotype concordant with WSS and clinical and molecular diagnosis of WSS by the identification of two novel frameshift variants in the KMT2A gene. This work also highlights the presence of certain clinical features in patients with growth retardation and development delay and should draw attention to the diagnosis of WSS, when hirsutism, particularly hypertrichosis cubiti is present.

Genetic analyses in a cohort of Portuguese pediatric patients with congenital hypothyroidism.

Background Permanent primary congenital hypothyroidism (CH) can be caused by thyroid dysgenesis or dyshormonogenesis. A molecular genetic study is recommended in dyshormonogenesis, in syndromic hypothyroidism and when there is a family history of CH. The aim of this study was to identify a monogenic etiology for CH in selected individuals from a cohort of primary permanent CH. Methods From an initial cohort of 79 patients with permanent CH (3-19 years), 11 patients were selected for molecular analyses. Nine patients with dyshormonogenesis (normal in-situ gland or goiter) were screened for causative variants, by next-generation sequencing (NGS), in 28 genes known to be responsible for CH. One patient with a family history of CH was screened for the paired-box gene 8 (PAX8) gene and another patient with a syndromic CH was screened for the NKX2-1 gene. Results We found a monogenic basis of disease in eight patients, involving the thyroid peroxidase (TPO) gene (four patients), the thyroglobulin (TG) gene (two patients), and the PAX8 and NKX2-1 genes (one patient each). Two patients were heterozygotes, one harboring a variant in the TG gene and the other in the SLC5A5 gene. In one patient, we found no potential causative variants in any of the 28 genes screened. We described five novel variants: three in the TG gene, one in the NKX2-1 and one in the SLC5A5 gene, all of them classified as pathogenic. Conclusions In eight of the 11 screened patients, a monogenic disease was found. These results highlight the advantage of using an NGS panel and provide further data regarding the molecular basis of CH.

Mandibulofacial dysostosis with microcephaly: a syndrome to remember.

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare condition that causes abnormalities of the head and face. Other major extracranial malformations may also be found. The authors present a case of an MFDM in a 35 weeks newborn with antenatal growth restriction. The patient required resuscitation at birth and was diagnosed with oesophageal atresia with tracheoesophageal fistula at day 1. At physical examination he presented multiple congenital malformations including prominent forehead, plagiocephaly, low-set ears, malformed auricles, hypertelorism, downward-slanting eyes, micrognathia, everted lower lip, short neck, wide-spaced nipples and inguinal hernia. Imaging investigation showed dysplasia of the inner ear with agenesis of the vestibular-cochlear nerves and global cerebral atrophy. Analysis of the EFTUD2 gene revealed that the patient was a heterozygous carrier of a pathogenic mutation (c.831_832del[p.Lys277Asnsf*7]), which has not been previously described. This case illustrates the challenges faced in diagnosing and treating MFDM patients.

Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease.

OBJECTIVE: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype-phenotype correlation. METHODS: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. RESULTS: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype-phenotype correlation did not emerge. CONCLUSION: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.

Bilateral frontoparietal polymicrogyria: a novel GPR56 mutation and an unusual phenotype.

Loss of function of GPR56 causes a specific brain malformation called the bilateral frontoparietal polymicrogyria (BFPP), which has typical clinical and neuroradiological findings. So far, 35 families and 26 independent mutations have been described.We present a Portuguese 5-year-old boy, born from nonconsanguineous parents, with BFPP. This patient has a novel GPR56 mutation (R271X) and an unusual phenotype, because he presents hot water epilepsy.To the best of our knowledge, this is the first reported case of BFPP evolving hot water epilepsy.

Expanding the phenotype of IFAP/BRESECK syndrome: a new case with severe hypogammaglobulinemia.

The ichthyosis follicular with atrichia and photophobia syndrome (IFAP) is a rare X-linked multiple congenital malformation syndrome. Some male patients have additional features including brain anomalies, intellectual disability, ectodermal dysplasia, skeletal deformities, ear or eye anomalies and kidney dysplasia/hypoplasia (BRESEK syndrome) sometimes associated with Hirschsprung disease and cleft palate or cryptorchidism (BRESHECK syndrome). We report a 5 months-old male patient with the p.R429H mutation in MBTPS2 protein, which has been reported to be associated with the most severe phenotype of patients with IFAP/BRESHECK syndrome. This patient presented with a severe IFAP/BRESHECK phenotype including ichthyosis follicular, atrichia, photophobia, brain anomalies, global developmental delay, Hirschsprung disease and kidney hypoplasia. Additional features not previously reported in IFAP syndrome, include severe hypogammaglobulinemia and congenital rectourethral fistula.

Classic Ehlers-Danlos syndrome: case report and brief review of literature.

Easy bruising in children represents a diagnostic conundrum. Although trauma (accidental or not) and bleeding disturbances are the most common causes, other rarer etiologies should be considered in differential diagnosis. When a 4-year-old male patient presented with a history of bruising and hematomas after slight injuries, coagulopathy and physical abuse were suspected. However, the presence of skin hyperextensibility, generalized joint hypermobility, atrophic and "cigarette paper" scars, pes planus, piezogenic pedal papules, and similar clinical picture in the mother, maternal uncle and grandfather suggested a diagnosis of Ehlers-Danlos syndrome, classic type. Genetic study revealed a heterozygous variant (c.379C>T) in exon 3 of the COL5A1 gene, not previously described in the literature, confirming the clinical suspicion. The authors intend to draw attention to this rare and diagnostically challenging condition that should be correctly diagnosed for the early adoption of preventive measures.

Moyamoya vascular pattern in Alagille syndrome.

We describe a girl with Alagille syndrome and a moyamoya angiographic pattern on magnetic resonance angiography. She was referred for genetic consultation because of posterior embryotoxon and peripheral pulmonary stenosis. Her facial appearance was typical, but she had no cholestasis or vertebral involvement. A heterozygous duplication of one nucleotide (a c.715dupA mutation) not previously described was identified in exon 5 of the JAG1 gene. We review similar cases in the literature and possible pathophysiologic mechanisms (e.g., the Jagged 1 and Notch signaling pathway) of this association.

Sydenham's chorea in a family with Huntington's disease: case report and review of the literature / Coreia de Sydenham numa família com doença de Huntington: relato de caso e revisão da literatura

CONTEXT: Sydenham's chorea affects almost 30 percent of patients with acute rheumatic fever. It is more frequent in females and is rare in the first decade of life, and genetic vulnerability underlies it. Because of easy access to antibiotics, it is now rare in so-called developed countries. CASE REPORT: A 6-year-old boy with a family history of Huntington's disease, who was the only child of an unscreened and asymptomatic mother, was brought for a consultation because of migratory arthralgia, depressed mood, and rapid, abrupt and unintentional movements of his right arm and leg, that had evolved over a three-week period. On physical examination, he presented a grade III/VI systolic heart murmur and right-side choreic movements, giving rise to a deficit of active mobilization. Laboratory tests revealed elevated erythrocyte sedimentation rate (63 mm/h), C-reactive protein (25 mg/l) and antistreptolysin O titer (1,824 U/ml). Cardiovascular evaluation showed mild aortic insufficiency, moderate mitral insufficiency and a prolonged PR interval. A clinical diagnosis of Sydenham's chorea/acute rheumatic fever was made, and therapy consisting of penicillin, haloperidol, captopril and furosemide was instituted, with excellent results. CONCLUSION: In developed countries, Sydenham's chorea seems forgotten and, because of this, little is known about its clinical course and controversy surrounds the therapeutic options available. This occurrence of rheumatic chorea in a family with Huntington's disease highlights the importance of the differential diagnosis for the different forms of chorea.

CONTEXTO: A coreia de Sydenham surge em cerca de 30 por cento dos casos de febre reumática aguda. É mais frequente no sexo feminino, é rara na primeira década de vida e tem por base uma vulnerabilidade genética. Devido ao fácil acesso aos antibióticos, é uma doença rara atualmente nos países ditos desenvolvidos. RELATO DO CASO: Criança de seis anos, sexo masculino, com história familiar de coreia de Huntington, único filho de mãe assintomática e não rastreada, foi trazido à consulta por artralgias migratórias, humor deprimido e movimentos rápidos, abruptos e não intencionais dos membros superior e inferior direitos, com três semanas de evolução. Ao exame físico, apresentava um sopro cardíaco sistólico grau III/VI, e foram presenciados movimentos coreicos à direita, condicionando um défice de mobilização activa. Os exames laboratoriais mostraram aumento da velocidade de sedimentação (63 mm/h), proteína C-reativa (25 mg/L) e título de antiestreptolisina O (1.824 U/mL). O exame cardiovascular revelou insuficiência aórtica ligeira e insuficiência mitral moderada e aumento do intervalo PR. Foi feito o diagnóstico de coreia de Sydenham/febre reumática aguda, tendo sido instituída terapêutica com penicilina, haloperidol, captopril e furosemida, com excelente resultado. CONCLUSÃO: Nos países desenvolvidos, a coreia de Sydenham parece esquecida e, por isso, pouco se sabe quanto ao seu curso clínico e as opções terapêuticas disponíveis são controversas. A ocorrência de um caso de coreia reumática numa família com doença de Huntington realça a importância do diagnóstico diferencial das diferentes formas de coreia.