[Show abstract][Hide abstract] ABSTRACT: Background:
The 17q21.31 deletion syndrome phenotype can be caused by either chromosome deletions or point mutations in the KANSL1 gene. To date, about 60 subjects with chromosome deletion and 4 subjects with point mutation in KANSL1 have been reported. Prevalence of chromosome deletions compared with point mutations, genotype-phenotype correlations and phenotypic variability have yet to be fully clarified.
We report genotype-phenotype correlations in 27 novel subjects with 17q21.31 deletion and in 5 subjects with KANSL1 point mutation, 3 of whom were not previously reported.
The prevalence of chromosome deletion and KANSL1 mutation was 83% and 17%, respectively. All patients had similar clinical features, with the exception of macrocephaly, which was detected in 24% of patients with the deletion and 60% of those with the point mutation, and congenital heart disease, which was limited to 35% of patients with the deletion. A remarkable phenotypic variability was observed in both categories, mainly with respect to the severity of ID. Cognitive function was within normal parameters in one patient in each group. Craniosynostosis, subependymal heterotopia and optic nerve hypoplasia represent new component manifestations.
In KANSL1 haploinsufficiency syndrome, chromosome deletions are greatly prevalent compared with KANSL1 mutations. The latter are sufficient in causing the full clinical phenotype. The degree of intellectual disability (ID) appears to be milder than expected in a considerable number of subjects with either chromosome deletion or KANSL1 mutation. Striking clinical criteria for enrolling patients into KANSL1 analysis include speech delay, distinctive facial dysmorphism, macrocephaly and friendly behaviour.
Journal of Medical Genetics 10/2015; DOI:10.1136/jmedgenet-2015-103184 · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypertrichosis is defined as an excessive growth in body hair beyond the normal variation compared with individuals of the same age, race and sex and affecting areas not predominantly androgen-dependent. The term hirsutism is usually referred to patients, mainly women, who show excessive hair growth with male pattern distribution.
Hypertrichosis is classified according to age of onset (congenital or acquired), extent of distribution (generalized or circumscribed), site involved, and to whether the disorder is isolated or associated with other anomalies. Congenital hypertrichosis is rare and may be an isolated condition of the skin or a component feature of other disorders. Acquired hypertrichosis is more frequent and is secondary to a variety of causes including drug side effects, metabolic and endocrine disorders, cutaneous auto-inflammatory or infectious diseases, malnutrition and anorexia nervosa, and ovarian and adrenal neoplasms. In most cases, hypertrichosis is not an isolated symptom but is associated with other clinical signs including intellective delay, epilepsy or complex body malformations.
A review of congenital generalized hypertrichosis is reported with particular attention given to the disorders where excessive diffuse body hair is a sign indicating the presence of complex malformation syndromes. The clinical course of a patient, previously described, with a 20-year follow-up is reported.
Italian Journal of Pediatrics 08/2015; 41(1):55. DOI:10.1186/s13052-015-0161-3 · 1.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine genetic features of a pediatric uveal melanoma in a 6-year-old girl by array-based comparative genomic hybridization (a-CGH) and assess prognosis, and to search for constitutional copy number variations (CNVs) encompassing oncosuppressor genes.
High-resolution a-CGH was performed on genomic DNA from cancer cells and from peripheral blood cells. Histopathology and clinical staging of the tumor were simultaneously assessed.
Array-based CGH revealed no CNVs on tumor cells associated with poor prognosis; namely, no monosomy 3, losses of 1p, 6q, or 8p, and no gains of 8q. A unique genomic profile was observed, consisting mainly of partial terminal duplications affecting chromosomes 1, 4, 5, 9, 10, 11, 16, and 19, and complete trisomy of chromosomes 6, 7, and 20. The nonmetastatic tumor had predominantly epithelioid histology. No constitutional CNVs encompassing oncosuppressor genes were detected.
We report a very rare uveal melanoma characterized by low-risk genomic profile and poor prognostic histologic and clinical features. The child is relapse-free at 1-year follow-up. The unusual CNVs detected by a-CGH suggest specific pathogenic mechanisms.
European journal of ophthalmology 03/2015; 25(4). DOI:10.5301/ejo.5000600 · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MED13L haploinsufficiency has recently been described as responsible for syndromic intellectual disability. We planned a search for causative gene variants in seven subjects with intellectual disability and overlapping dysmorphic facial features such as bulbous nasal tip, short mouth and straight eyebrows. We found two de novo frameshift variants in MED13L, consisting in single-nucleotide deletion (c.3765delC) and duplication (c.607dupT). A de novo nonsense variant (c.4420A>T) in MED13L was detected in a further subject in the course of routine whole-exome sequencing. By analyzing the clinical data of our patients along with those recently described in the literature, we confirm that there is a common, recognizable phenotype associated with MED13L haploinsufficiency, which includes intellectual disability and a distinctive facial appearance. Congenital heart diseases are found in some subjects with various degree of severity. Our observation of cleft palate, ataxia, epilepsy and childhood leukemia observed in single cases broadens the known clinical spectrum. Haploinsufficiency for MED13L should be considered in the differential diagnosis of the 1p36 microdeletion syndrome, due to overlapping dysmorphic facial features in some patients. The introduction of massive parallel-sequencing techniques into clinical practice is expected to allow for detection of other causative point variants in MED13L. Analysis of genomic data in connection with deep clinical evaluation of patients could elucidate genetic heterogeneity of the MED13L haploinsufficiency phenotype.European Journal of Human Genetics advance online publication, 25 February 2015; doi:10.1038/ejhg.2015.19.
European journal of human genetics: EJHG 02/2015; 23(11). DOI:10.1038/ejhg.2015.19 · 4.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Classic clinical manifestations of HNPP are characterized by recurrent painless mononeuropathies, but a minority of patients presents with atypical clinical pattern, including CMT-like neuropathy, acute or chronic inflammatory demyelinating neuropathy-like polyneuropathy, carpal tunnel syndrome. Electrophysiological examination plays a central role in the diagnosis of HNPP, disclosing a non-uniform conduction slowing, more pronounced at entrapment sites.
Patients and Methods
We report clinical, electrophysiological and pathological findings from 73 patients with HNPP, coming from 53 unrelated families, followed in our Institute of Neurology over a 20-year period.
Typical presentation with recurrent multiple mononeuropathies was observed in 28/64 (44%) patients. In the remaining 36/64 (56%), we observed an atypical clinical presentation, characterized by generalized weakness and cramps; chronic ulnar neuropathy; carpal tunnel syndrome; chronic sensory polyneuropathy; Guillain-Barrè-like presentation; CMT-like presentation. Nine patients were asymptomatic for neuropathic symptoms. Nerve conduction studies showed in all cases a sensori-motor demyelinating polyneuropathy with conduction abnormalities preferentially localized at common entrapment sites. When performed, sural nerve biopsy disclosed focal thickenings of the myelin sheath in all patients.
About half of patients with HNPP from our cohort showed an atypical clinical presentation. Neurophysiological examination represents the main tool for a proper diagnosis.
Journal of the neurological sciences 06/2014; 341(1-2). DOI:10.1016/j.jns.2014.03.046 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several recently developed technologies, collectively known as next-generation sequencing (NGS), or massively parallel sequencing, are designed to gather data from large portions of the genome in a single experiment. Whole exome sequencing (WES) is a common implementation of NGS targeted to coding regions, or exons, where most disease causing mutations are believed to reside. As WES is becoming more cost effective, it is shifting from research to clinical applications, particularly for the diagnosis of rare genetic disorders of unknown etiology. NGS is also gaining ground in the specialized fields of pathology, prenatal diagnosis, and copy number detection. The large scope of NGS is raising important ethical and policy issues, such as reporting of incidental or secondary findings. In this review, these topics are discussed with specific focus on pediatrics, drawing examples from the study of intellectual disability and congenital heart disease.
[Show abstract][Hide abstract] ABSTRACT: Objective
Seizure disorder is one of the most relevant clinical manifestations in Wolf-Hirschhorn syndrome (WHS) and it acts as independent prognostic factor for the severity of intellectual disability (ID). LETM1, encoding a mitochondrial protein playing a role in K+/H+ exchange and in Ca2+ homeostasis, is currently considered the major candidate gene. However, whether haploinsufficiency limited to LETM1 is enough to cause epilepsy is still unclear. The main purpose of the present research is to define the 4p chromosome regions where genes for seizures reside.Methods
Comparison of our three unusual 4p16.3 deletions with 13 literature reports. Array-comparative genomic hybridization (a-CGH). Real-time polymerase chain reaction (RT-PCR) on messanger RNA (mRNA) of LETM1 and CPLX1. Direct sequencing of LETM1.ResultsThree unusual 4p16.3 deletions were detected by array-CGH in absence of a obvious clinical diagnosis of WHS. Two of these, encompassing LETM1, were found in subjects who never had seizures. The deletions were interstitial, spanning 1.1 Mb with preservation of the terminal 1.77 Mb region in one case and 0.84 Mb with preservation of the terminal 1.07 Mb region in the other. The other deletion was terminal, affecting a 0.564 Mb segment, with preservation of LETM1, and it was associated with seizures and learning difficulties. Upon evaluating our patients along with literature reports, we noted that six of eight subjects with terminal 4p deletions preserving LETM1 had seizures, whereas seven of seven with interstitial deletions including LETM1 and preserving the terminal 1 Mb region on 4p did not. An additional chromosome region for seizures is suggested, falling within the terminal 1.5 Mb on 4p, not including LETM1.SignificanceWe consider that haploinsufficiency not limited to LETM1 but including other genes acts as a risk factor for the WHS-associated seizure disorder, according to a comorbidity model of pathogenesis. Additional candidate genes reside in the terminal 1.5 Mb region on 4p, most likely distal to LETM1.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
[Show abstract][Hide abstract] ABSTRACT: To characterize epileptic phenotype, electroencephalography (EEG) features, and epileptic evolution in patients with ring 14 r(14) syndrome.
Twenty-two patients with ring chromosome 14 were enrolled in the study. We examined age at onset, seizure semiology and frequency at onset and at follow-up, drug responsiveness/resistance, and interictal/ictal EEG data. The degree of severity of the epileptic phenotype negatively influences child cognitive development.
The incidence of epilepsy in patients with r(14) syndrome is virtually 100%, characterized by early onset, polymorphic seizures, and drug-resistant seizures. In addition, we ascertained focal secondarily generalized epilepsy, seizure cluster tendency, frequent status epilepticus, and a rather typical epilepsy evolution. EEG abnormalities consisted of slow background activity with pseudoperiodic bursts of generalized slow waves in the early stage, focal frontotemporal or temporoposterior slow waves with multifocal spikes interposed, and unusual rhythmic fast recruiting posterior spikes followed by secondary generalization. The degree of severity of the epileptic phenotype negatively influences child cognitive development.
This study provides a more precise definition of seizure types, natural history, and drug responsiveness of r(14) syndrome, a highly epileptogenic chromosomal condition.
[Show abstract][Hide abstract] ABSTRACT: Low back pain (LBP) is a very common complaint in pregnancy. For this reason, it is often considered directly attributable to the pregnancy rather than a medical problem requiring diagnostic workup. Pregnancy-related LBP should be differentiated from the rare cases of LBP associated with serious spinal diseases. Hemangioblastoma is a vascular tumor of the central nervous system that very rarely can involve the spinal cord. Pregnancy can increase the growth of hemangioblastomas, leading to the appearance of neurologic symptoms.
To describe an unusual cause of LBP in pregnancy.
A case report.
A 38-year-old woman, with a history of surgical resection of a cerebellar hemangioblastoma at the age of 15 years, presented at 38 weeks of gestation with worsening LBP and numbness of the lower limbs. Diagnostic workup led to a diagnosis of spinal hemangioblastoma. The tumor was removed after cesarean section in the 39th week of gestation.
The detection of spinal hemangioblastoma resulted in a good outcome for both mother and infant.
This case emphasizes the main role of clinical evaluation in establishing the diagnostic workup, especially in pregnancy. Although LBP is commonly reported, this patient's medical history and the presence of clinical signs on neurologic examination suggested the need for further investigation.
The spine journal: official journal of the North American Spine Society 09/2013; 13(12). DOI:10.1016/j.spinee.2013.07.428 · 2.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mutations in the gene encoding fused-in-sarcoma (FUS) have been identified in a subset of patients with sporadic and familial
amyotrophic lateral sclerosis (ALS). Variants in the 3′ untranslated region (3′UTR) of FUS have also been reported in ALS patients, but their pathogenic role has not been assessed. We sequenced the whole 3′UTR of
FUS in 420 ALS patients who were negative for mutations in the currently known ALS genes and in 480 ethnically matched controls.
We detected four 3′UTR variants (c.*48 G>A, c.*59 G>A, c.*108 C>T and c.*110 G>A) in four sporadic and in one familial ALS
patients compared with none in controls (P = 0.02).We investigated whether these variants impaired FUS expression in primary fibroblast cultures from three patients
harbouring the c.*59 G>A, c.*108 C>T and c.*110 G>A variants, respectively. The pattern of FUS expression was also investigated
in fibroblasts from one ALS patient with FUS R521C mutation, in two ALS patients without mutations in the known ALS genes
and in four control individuals. By immunostaining and immunoblotting, large amounts of FUS were observed in both the cytoplasm
and nuclei of mutant 3′UTR FUS fibroblasts. In FUS R521C mutant fibroblasts, we observed a slight increase of FUS in the cytoplasm associated with a remarkable
loss of detection in nuclei. Our findings show that mutations in 3′UTR of FUS are overrepresented in ALS patients and result into translation de-regulation of FUS. Overexpression and mislocalization
of wild-type FUS likely contribute to ALS pathogenesis in these cases.
Human Molecular Genetics 07/2013; 22(23). DOI:10.1093/hmg/ddt328 · 6.39 Impact Factor