Valosin containing protein (VCP) mutations have been reported to present with a high degree of variability and can be present in patients even if they may have an initial normal work up. A 55-year-old woman was labeled a...Valosin containing protein (VCP) mutations have been reported to present with a high degree of variability and can be present in patients even if they may have an initial normal work up. A 55-year-old woman was labeled as "normal" and "pain medication seeking" after an unrevealing work up of clinical, laboratory, electrodiagnostic, radiographic, pathologic, and genetic testing. She continued to present with chronic neck pain, and had variable features of scapuloperoneal atrophy, which was also seen in her family. The patient and her family were found to have a known pathogenic c.464G>A, p.Arg155His (RH) mutation in the gene. Despite traditional thinking of attempting to localize neurological syndromes, mutations are difficult to localize as they can present with significant clinical heterogeneity including a scapuloperoneal syndrome with variable neuropathic and myopathic features.
Dihydropyrimidine dehydrogenase (DPD) is the major enzyme in the catabolism of 5-Fluorouracil (5-FU) and its prodrug capecitabine. We report a 65-year-old female with rectal adenocarcinoma who experienced severe toxiciti...Dihydropyrimidine dehydrogenase (DPD) is the major enzyme in the catabolism of 5-Fluorouracil (5-FU) and its prodrug capecitabine. We report a 65-year-old female with rectal adenocarcinoma who experienced severe toxicities secondary to standard dose 5-FU based chemotherapy. She was found to be heterozygous for rs371313778, c.2434G>A. This finding prompted restarting 5-FU at 50% dose reduction with further titration in subsequent cycles. We herein report the first case of rs371313778, c.2434G>A (p.Val812lle) polymorphism leading to severe 5-FU toxicities. The patient eventually completed a 6-month course of adjuvant treatment with modification of 5-FU dose.
Gorlin syndrome is mainly caused by pathogenic germline variants in the tumour suppressor genes and , both regulatory genes in the hedgehog pathway. However, the phenotypes of patients with and pathogenic variants see...Gorlin syndrome is mainly caused by pathogenic germline variants in the tumour suppressor genes and , both regulatory genes in the hedgehog pathway. However, the phenotypes of patients with and pathogenic variants seem to differ. We present a family with a frameshift variant in the gene c.954del, p.Asn319Thrfs42 leading to meningiomas and multiple basal cell-carcinomas.
Distal deletions and duplications of 3p are individually well-characterized chromosome abnormalities. Here, we report an inverted duplication of 3p with an adjacent terminal 3p deletion in a 17-month-old girl who had pre...Distal deletions and duplications of 3p are individually well-characterized chromosome abnormalities. Here, we report an inverted duplication of 3p with an adjacent terminal 3p deletion in a 17-month-old girl who had prenatal intrauterine growth restriction and cardiac defects. Other findings included hemangiomas, neutropenia, umbilical hernia, hypotonia, gross motor delay, microcephaly, and ptosis. Family history was noncontributory. Microarray analysis revealed a 5.37 Mb deletion of chromosome bands 3p26.1 to 3p26.3 and a 13.68 Mb duplication of 3p24.3 to 3p26.1. FISH analysis confirmed that the duplication was inverted. Upon literature review, only one postnatal patient and one second trimester pregnancy have been reported with this finding. Many of our patient's features are present in both 3p deletion and 3p duplication syndromes, including congenital heart disease, growth restriction, microcephaly, hypotonia, and developmental delay. Our patient has additional features not commonly reported in 3p deletion or duplication patients, such as aortic dilation, hemangiomas, and neutropenia. The identification of this patient contributes to additional understanding of features associated with concurrent deletion and inverted duplication in the distal 3p chromosome. This report may assist clinicians working with patients who have constellations of similar features or similar cytogenomic abnormalities.
We performed exome sequencing to evaluate the underlying molecular cause of a patient with bilateral conductive hearing loss due to multiple ossicular abnormalities as well as symphalangism of the fifth digits. This lead...We performed exome sequencing to evaluate the underlying molecular cause of a patient with bilateral conductive hearing loss due to multiple ossicular abnormalities as well as symphalangism of the fifth digits. This leads to the identification of a novel heterozygous start codon variant in the gene (c.2T>C:p.Met1?) that hinders normal translation of the noggin protein. Variants in lead to a spectrum of otologic, digit, and joint abnormalities, a combination suggested to be referred to as -related-symphalangism spectrum disorder (-SSD). Conductive hearing loss from such variants may stem from stapes footplate ankylosis, fixation of the malleoincudal joint, or fixation of the incus short process. In this case, the constellation of both stapes and incus fixation, an exceptionally tall stapes suprastructure, thickened long process of the incus, and enlarged incus body was encountered, leading to distinct challenges during otologic surgery to improve hearing thresholds. This case highlights multiple abnormalities to the ossicular chain in a patient with a start codon variant in . We provide detailed imaging data on these malformations as well as surgical considerations and outcomes.
We report a case of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) occurring in a 53-year-old female with Li Fraumeni syndrome (LFS) with a prior history of breast cancer. We present the clinical fea...We report a case of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) occurring in a 53-year-old female with Li Fraumeni syndrome (LFS) with a prior history of breast cancer. We present the clinical features, investigation, and management of this patient and potential mechanisms that could explain the increasing association of BIA-ALCL and LFS.
Lysosomal storage disorders (LSDs) collectively constitute a significant public health burden in developing countries. Commoner LSDs include Gaucher, Fabry, and Niemann-Pick disease (NPD), but many cases remain undiagnos...Lysosomal storage disorders (LSDs) collectively constitute a significant public health burden in developing countries. Commoner LSDs include Gaucher, Fabry, and Niemann-Pick disease (NPD), but many cases remain undiagnosed. With the high incidence of consanguineous marriages, South East Asian countries are expected to have high prevalence of these LSDs. Here we report 4 cases of NPD type A/B in 3 families presenting with hepatosplenomegaly and cytopenias including one family with two sibs having hypertension and mitral valve prolapse. The diagnosis of NPD was proven by mutation analysis with identification of novel mutations, including a novel 4 bp insertion mutation (C>CCTGG) in exon 2 of the gene. We also had two cases of NPD type C, confirmed on mutation analysis.
Monogenic Diabetes is relatively rare, representing only 1-2% of total diabetes cases; nevertheless, it is often misdiagnosed primarily as type 1 diabetes, leading to unnecessary insulin therapy and delayed recognition o...Monogenic Diabetes is relatively rare, representing only 1-2% of total diabetes cases; nevertheless, it is often misdiagnosed primarily as type 1 diabetes, leading to unnecessary insulin therapy and delayed recognition of affected family members. In the present article, we describe a case of a young, male patient who presented with hyperglycemia in the absence of ketosis and following genetic testing; he proved to harbor the loss-of-function p.Arg1353His (c.4058G>A) mutation in the gene, inherited from his mother. This mutation has been previously described in patients with Congenital Hyperinsulinism. Furthermore, different mutations in the gene have been linked with MODY 12, type 2, and gestational diabetes; however, to the best of our knowledge, this is the first report that associates this specific mutation with diabetes phenotype. -related diabetes is characterized by remarkable heterogeneity in terms of clinical presentation and therapeutic approach. Early diagnosis and individualized treatment are essential to achieving metabolic targets and avoiding long-term diabetes complications.
The -related syndrome is a rare X-linked neurodevelopmental condition that was first described in 2011. The disorder is caused by pathogenic variants in the gene located on chromosome X at position Xq28. Clinical featur...The -related syndrome is a rare X-linked neurodevelopmental condition that was first described in 2011. The disorder is caused by pathogenic variants in the gene located on chromosome X at position Xq28. Clinical features typically include severe psychomotor developmental delay, cardiac disease, dysmorphic features, postnatal growth failure, and hypotonia, although there is significant variability in the severity of the phenotype among affected individuals. We describe a 5-year-old female with the syndrome; massively parallel exome sequencing and analysis revealed the c.247C>T (p.Arg83Cys) pathogenic variant that has been previously reported in ten affected individuals. Ocular manifestations of the -related syndrome are not uncommon, although they have not been well characterized in literature reports. From a systematic review of previously published cases to date, ocular abnormalities are present in more than half of patients with the syndrome. Common ocular findings reported include astigmatism, hyperopia, cortical vision impairment, microphthalmia/anophthalmia, and hypertelorism. Our patient presented with growth restriction, dysmorphic features, and hypotonia. Ocular manifestations identified in this child include downslanting palpebral fissures, myopic astigmatism, nystagmus, and exotropia. We speculate that the type and severity of ocular defects present in individuals with the -related syndrome are dependent on the specific pathogenic variant involved.
The anomalies of X chromosome are classified as numerical or structural. Concomitant structural anomalies in this chromosome that associate partial loss of its long arm with duplications in its short arm are uncommon. On...The anomalies of X chromosome are classified as numerical or structural. Concomitant structural anomalies in this chromosome that associate partial loss of its long arm with duplications in its short arm are uncommon. Only a few cases have been published and in most of them the reported patients present ovarian dysfunction, tall stature, and overdosage of the SHOX gene with locus Xp22.33. Considering these reports, we evaluated the case of a woman with a deletion in the long arm of the X chromosome, premature ovarian failure, tall stature, and multiple arterial vascular disease. With the aim to find a relationship between karyotype and phenotype, we explored associated anomalies in Xp and certified the overdosage of the SHOX gene in this case by MLPA. Also, taking into account the fact that the gene locus of the angiotensin-converting enzyme type 2 (ACE2) is located in Xp, our goal was to investigate the influence of this gene in the development of cardiovascular disease. The detection of the gene product of ACE2 by ELISA was undetectable. We have proposed that cytogenetic anomalies in X chromosome could contribute to decrease this protein synthesis in this gender.
Pallister-Hall syndrome (PHS) is an extremely rare syndrome of unknown prevalence with autosomal dominant inheritance due to gene mutations classically characterized by the presence of a hypothalamic hamartoma and polyd...Pallister-Hall syndrome (PHS) is an extremely rare syndrome of unknown prevalence with autosomal dominant inheritance due to gene mutations classically characterized by the presence of a hypothalamic hamartoma and polydactyly. Additional diagnostic criteria include bifid epiglottis, imperforate anus, small nails, hypopituitarism, growth hormone deficiency, and genital hypoplasia. It is typically diagnosed in infancy and early childhood, presenting with seizures and/or precocious puberty due to the hypothalamic hamartoma, and with limb anomalies due to central polydactyly. Our patient had presented with polysyndactyly at birth. However, as this is not uncommon in infants and is usually as part of the sporadic, isolated form of polydactyly, no further work up was done. He then presented at age 16 years with a headache and subjective visual changes, with brain imaging revealing a hypothalamic hamartoma. He did not have a history of seizures or central precocious puberty. Genotyping revealed a pathogenic variant affecting the gene. We encourage all clinicians to consider PHS or an associated syndrome with a clinical finding of polydactyly. Further, as the natural history continues to reveal itself, this patient's presentation provides important new data to the broad phenotypic spectrum of PHS.
We report a heterozygous, 2,009 base pairs (bps) genomic DNA deletion within the gene that has not previously been reported in a case of type I hereditary angioedema (HAE). The patient is a 28-year-old Han Chinese femal...We report a heterozygous, 2,009 base pairs (bps) genomic DNA deletion within the gene that has not previously been reported in a case of type I hereditary angioedema (HAE). The patient is a 28-year-old Han Chinese female living in Hong Kong who has suffered from recurrent angioedema since adolescence, with increasing attack frequency as she entered adulthood; in the past, episodes occurred annually, but now occur every two to three months. The affected areas are not itchy and include common sites such as the left and right forearms, but without throat involvement. The patient also experiences epigastric pain. The patient's mother suffers from similar symptoms. A mutation in the serine protease inhibitor, clade G, member 1 () gene is associated with HAE. Patients with HAE type I commonly carry either a small deletion within or a truncated transcript. We performed a multiplex ligation-dependent probe amplification (MLPA) assay on our indexed patient. Our result suggests a 2,009 bps deletion spanning across exons 5 and 6 within . Although earlier literature has described other large DNA deletions encasing exons 5 and 6 in , these DNA rearrangements were larger in size between 4 and 6 kbps, and the breakpoint locations were generally not determined due to technical constraints (Pappalardo et al., 2000; Duponchel et al., 2001; Roche et al., 2005; Loules et al., 2018; and Göwein et al., 2008). Our report describes mapping of this 2,009 bps in . Using a combination of molecular techniques, we were able to confirm and locate this large heterozygous genomic DNA deletion that includes both exons 5 and 6 of .
Werner's syndrome (WS) is an autosomal recessive genetic disease, which is mainly characterized by scleroderma-like skin changes, juvenile cataracts, short stature, and signs of premature aging. We report a case of a 48-...Werner's syndrome (WS) is an autosomal recessive genetic disease, which is mainly characterized by scleroderma-like skin changes, juvenile cataracts, short stature, and signs of premature aging. We report a case of a 48-year-old male patient, who presents with cardinal signs of WS including high-pitched voice, sclerotic skin lesions mainly on feet, premature greying of scalp hair, bilateral cataracts, and "bird-like" facial appearance. In addition, the patient presents other clinical characteristics observed in patients with WS such as short stature, type 2 diabetes mellitus, hypogonadism, parental consanguinity, and a history of a sibling with similar clinical characteristics. gene sequencing identified the homozygous pathogenic variant NM_00553.4: c.2581C>T (NP_000544.2: pGln861Ter). This is the first case of WS reported in the Colombian population. We report this case to avoid misdiagnosis of this infrequent condition and allow timely identification of potential complications associated with premature aging, especially malignancies, cardiovascular and metabolic diseases.
8q22.2q22.3 microdeletion syndrome has been described in only seven patients. We present a new case from Colombia. The characteristics of this condition are developmental delay, microcephaly, seizures, and typical facial...8q22.2q22.3 microdeletion syndrome has been described in only seven patients. We present a new case from Colombia. The characteristics of this condition are developmental delay, microcephaly, seizures, and typical facial dysmorphism. We discuss the clinical phenotype of the patient presenting relevant findings like hearing loss and severe epilepsy and the possible relations between the phenotype and the genes involved in the microdeletion. We describe a female with developmental delay, microcephaly, epilepsy, severe short stature, impaired speech, facial dysmorphism, and congenital deafness. A minimal/maximal deletion of 5.238 Mb and 5.374Mb, respectively, at 8q22.2q22.3 was diagnosed using a genome-wide array. The clinical phenotype is similar to the others seven patients previously reported; however, the severity of epilepsy and the concomitant hearing loss is remarkable, characteristics previously observed independently in only two patients. The KCNS2 gene is located in the deleted regions (8q22.2). Therefore it is a possible candidate for explaining the complex neurologic phenotype.
Fujisawa T, Aizawa Y, Katsumata Y
… +13 more, Udo A, Ito S, Hatakeyama K, Hirose M, Miyama H, Nakajima K, Nishiyama T, Kimura T, Nitta M, Misumi K, Takatsuki S, Kosaki K, Fukuda K
A 62-year-old female had suffered from recurrent syncopal episodes triggered by physical and emotional stress since childhood. She had no family history of sudden death. An intensive examination could not detect any stru...A 62-year-old female had suffered from recurrent syncopal episodes triggered by physical and emotional stress since childhood. She had no family history of sudden death. An intensive examination could not detect any structural disease, and exercise stress testing provoked polymorphic ventricular ectopy followed by polymorphic ventricular tachycardia accompanied with syncope leading to a diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT). A genetic analysis with a next generation sequencer identified a homozygous W361X mutation in the gene. Careful history taking disclosed that her parents had a consanguineous marriage. Here we present a Japanese patient with a recessive form of CPVT.
The clinical effect of T118M variant of the PMP22 gene has been controversial. Several studies have suggested that it may be autosomal recessive, partial loss of function, or a benign variant. Here we report three cases...The clinical effect of T118M variant of the PMP22 gene has been controversial. Several studies have suggested that it may be autosomal recessive, partial loss of function, or a benign variant. Here we report three cases in further support that the T118M variant of the PMP22 gene is a partial loss of function variant. These three unrelated cases were heterozygotes with the T118M variant of the PMP22 gene. All three cases presented with painful peripheral neuropathy and varying degrees of Charcot-Marie-Tooth exam features. Electrophysiological studies revealed polyneuropathy with axonal and demyelinating features in one case, but there were minimal electrophysiological changes in the other two cases. We propose that the T118M variant can cause painful peripheral neuropathy, which may be an underrecognized feature of this variant.
Hereditary sensory and autonomic neuropathies (HSANs) are a clinically and genetically heterogeneous group of disorders involving various sensory and autonomic dysfunctions. The most common symptoms of HSANs include loss...Hereditary sensory and autonomic neuropathies (HSANs) are a clinically and genetically heterogeneous group of disorders involving various sensory and autonomic dysfunctions. The most common symptoms of HSANs include loss of sensations of pain and temperature that frequently lead to chronic ulcerations in the feet and hands of the patient. In this case study, we present the clinical features and genetic characteristics of two affected individuals from two unrelated Saudi families presenting mutilating sensory loss and spastic paraplegia. We employed homozygosity mapping and exome sequencing which is an efficient strategy to characterize the recessive genes, thus obtaining a rapid molecular diagnosis for genetically heterogeneous disorders like HSAN. Subsequently, a nonsense mutation (c.926 C>G; p.S309⁎) in was identified. In addition, we confirmed that the mutant FAM134B transcripts were reduced in these patients presumably disrupting the receptors of the degradative endoplasmic reticulum pathways that facilitate the autophagy processes.
GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder due to mutations in the lysosomal acid 3-galactosidase gene, . It is usually classified into three forms, infantile, juvenile, or adult, based on ag...GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder due to mutations in the lysosomal acid 3-galactosidase gene, . It is usually classified into three forms, infantile, juvenile, or adult, based on age at onset and severity of central nervous system involvement. Because of their broad clinical spectrum and their similarity to many other aetiologies, including inherited neurodegenerative and metabolic diseases, it is often difficult to diagnose such diseases. Recently, whole exome sequencing (WES) has become increasingly used when a strong hypothesis cannot be formulated based on the clinical phenotype. Here, we present three patients belonging to a consanguineous Moroccan family with a GM1-gangliosidosis with unusual clinical onset and atypical radiological presentation that had eluded diagnosis for over a decade. To identify the disease-causing mutation, we performed a whole exome sequencing and a chromosomal microarray genotyping in order to reduce the number of genetic variants to be interpreted, by focusing the data analysis only on the linked loci. The already known pathogenic missense mutation c.601G>A in (p.R201C) was found at homozygous state in the proband V.1 and at heterozygous state in his father IV.1. The mutation was validated by Sanger sequencing and segregated in all the family members according to a recessive mode of inheritance. Outside of the linked loci, we found the p.Ser272Thr mutation at heterozygous state in all the patients and their mother IV.2. This mutation was reported to cause pontocerebellar hypoplasia type 1C and could act as a modifying factor that exacerbates the brain atrophy of patients. Our study identified the first mutation in North Africa in patients with unexpected brain-MRI outcomes extending the clinical spectrum of the GM1-gangliosidosis.
Individuals with Sickle Cell Trait (SCT), generally considered a benign carrier state of hemoglobin S (HbAS), are thought to be at risk for exertional rhabdomyolysis and hematuria, conditions that can also be caused by v...Individuals with Sickle Cell Trait (SCT), generally considered a benign carrier state of hemoglobin S (HbAS), are thought to be at risk for exertional rhabdomyolysis and hematuria, conditions that can also be caused by various other acquired and inherited factors. We report an SCT positive service member with an exertional rhabdomyolysis event, recurrent hematuria with transient proteinuria, and episodic burning pain in the lower extremities. Clinical and genetic studies revealed the multifactorial nature of his complex phenotype. The service member was taking prescription medications known to be associated with exertional rhabdomyolysis. He carried a pathogenic mutation, p.V260E, reported in nephropathy and a new variant p.R838Q in , a gene involved in familial episodic pain syndrome. Results suggest that drug-to-drug interactions coupled with the stress of exercise, coinheritance of HbAS and p.V260E, and p. R838Q in contributed to exertional rhabdomyolysis, recurrent hematuria with proteinuria, and episodic pain, respectively. This case underscores the importance of comprehensive clinical and genetic evaluations to identify underlying causes of health complications reported in SCT individuals.
BACKGROUND: Birt-Hogg-Dubé syndrome is a genetic disorder characterized by skin fibrofolliculomas, cystic lung disease, and bilateral renal tumors. It has also been implicated in the formation of tumors in other organs,...BACKGROUND: Birt-Hogg-Dubé syndrome is a genetic disorder characterized by skin fibrofolliculomas, cystic lung disease, and bilateral renal tumors. It has also been implicated in the formation of tumors in other organs, particularly thyroid and colon. This case presents a young female presenting with only cystic lung disease and kidney tumors, identified as having a never before identified heterozygous mutation in the folliculin () gene which is the likely cause of her syndrome. CASE PRESENTATION: A 34-year-old female was found to have bilateral renal masses, 2.4 cm on the right and 7.6 cm on the left, as well as multiple, small cysts in the lungs. Chest imaging further characterized the lung cysts as being basilar predominant with the largest measuring 1.6cm. The left kidney mass was resected with a partial nephrectomy with final pathologic diagnosis of an oncocytoma. Genetic testing was undertaken as she did not have characteristic skin findings. A previously undescribed mutation in the gene (c.780-2A>G) was identified with no matches in the human genetic mutation database (HGMD). Review of that database identified over 160 separate mutations in the gene. Extensive history did not identify any family members who had similar disease processes suggesting that this could be a spontaneous mutation in the proband. CONCLUSIONS: This case highlights that the traditional view of Birt-Hogg-Dubé syndrome as having a strong familial component may be incorrect and that spontaneous mutation may be more common than previously thought. Also notable is the fact that this patient had no characteristically described fibrofolliculomas that traditionally are the hallmark of the condition. This case suggests that genetic testing should be obtained in all suspected cases of Birt-Hogg-Dubé syndrome as the patient may not present with the typical skin findings and may also present with no family history consistent with this disorder.