Non-familial Case Research Articles

A Non-familial Case of SCA-42 Variant in Indian Subcontinent

A Non-familial Case of SCA-42 Variant in Indian Subcontinent

Autosomal recessive spastic paraplegias types 7 and 76

Introduction. Since 2017, the Research Centre for Medical Genetics has been conducting the first clinical and molecular study in Russia of a heterogeneous spastic paraplegia group based on the MPS high throughput sequencing method. Our group of molecularly diagnosed SPGs (types with known genes) includes 122 families with 22 SPG types. This article continues the publication series on the study results. The study aimed to determine the proportion and analyze the clinical, molecular, and genetic characteristics of two autosomal recessive forms, SPG7 and SPG76, in a group of identified SPGs. Materials and methods. We assessed three non-inbred Russian families: two with SPG7 (a non-familial and a familial case) and one with SPG76 (a non-familial cases). Molecular genetic methods included massive parallel sequencing (MPS) panel for spastic paraplegia, Sanger sequencing, and multiplex ligation-dependent probe amplification (MLPA)). Results. SPG7 was detected in 2 families and accounted for 1.6% of the entire SPG group and 8.7% of the autosomal recessive subgroup (less than in several other studies). The compound heterozygous genotypes in both families included the most frequent mutation in the SPG7 gene, c.1529C>T (p.Ala510Val); the allelic mutation in one case was a 4-exon deletion not previously described, while the other was a known mutation, c.228T>C (p.Ile743Thr). Despite a similar age at onset (end of the 3 rd –4 th decade), the symptoms were different: ‘uncomplicated’ spastic paraplegia in the non-familial case, while in the affected brothers prevailed ataxia; in both families, brain MRI showed cerebellar atrophy. The SPG76 case is a rare one, especially in a non-inbred family, and the first in Eastern Europe. A total of 28 families, mostly inbred, have been described worldwide. Two new mutations were found in the CAPN1 gene in the compound heterozygous state: c.398_399insAGTGGTTCCGCCGGCC (p. Arg133Glnfs*39) and c.1535G>A (p.Arg512His). Clinical features of the 30-year-old patient were typical, with onset at 20 years of age, spastic paraplegia and ataxia, and without brain MRI abnormalities. Conclusion. The range of autosomal recessive SPGs in Russian patients includes both common and very rare forms occurring in non-inbred families. Of the 5 mutations found in the SPG7 and CAPN1 genes, 3 have not been previously described. Our observations demonstrate the close relationship between spastic paraplegia and ataxia and the significance of MPS and MLPA technologies in the diagnostics of SPG. For citation: Rudenskaya G.E., Kadnikova V.A., Ryzhkova O.P., Demina N.A., Sharkova I.V., Polyakov A.V. [Autosomal recessive spastic paraplegias types 7 and 76]. Annals of clinical and experimental neurology 2021; 15(2): 13–20. (In Russ.) DOI: http://dx.doi.org/10.25692/ACEN.2021.2.2

Nonfamilial Multiple Trichoepithelioma: Few and Far Between.

Trichoepithelioma is a rare benign adnexal tumor which may be of solitary nonfamilial type or multiple familial trichoepitheliomas. Here, we describe a rare presentation of nonfamilial case of trichoepithelioma in a 50-year-old female with multiple skin colored facial papules and nodules over the face, upper back, and extremities.

Case report on cherubism: non-familial variant

Introduction: Cherubism is a rare, non-neoplastic, self-limiting, fibro-osseous disease, characterized by painless expansion of the maxilla, mandible or both. It usually develops in the first and second year of life. The radiographic appearance presentation is ordinarily bilateral, multilocular appearance in the mandible. To the best of our knowledge, very few cases (less than ten) of non-familial cherubism have been reported in the English literature. Objective: To describe non-familial case of cherubism in a 10-year-old child. Materials and methods: The current case was clinically, radiographically and histopathologically analysed for confirmatory diagnosis. Results: H & E stained section showed vascular and cellular stroma containing numerous multinucleated giant cells. Conclusion: Correlating radiographically and histopathologically the case was finally diagnosed as non-familial variant of cherubism.

Postpubertal Nonfamilial Cherubism and Teeth Transposition

Cherubism is a rare, nonneoplastic, fibro-osseous disease. It is an autosomal-dominant disorder in which the normal bone is replaced by cellular fibrous tissue and immature bone. It is genetically inherited, although many nonfamilial cases have been reported. Cherubism is a bone disease clinically characterized by bilateral, painless enlargements of the jaws. The mandible is the most severely affected craniofacial component, in which uncontrolled growth of the malady deteriorates the aesthetic balance of the face. A malocclusive and abnormal dentition, worse in the mandible, can be seen. Histopathologically, numerous randomly distributed multinucleated giant cells and vascular spaces within a fibrous connective tissue stroma with or without eosinophilic collagen perivascular cuffing were apparent. The appearance of the affected children is normal at birth. Between the ages of 2 and 7 years, swellings within the mandibular body or tuberosities of maxilla appear. This article relates to a postpubertal nonfamilial cherubism case that was noticed with multiple radiolucencies in radiographic examination and its effects on teeth.

Screening for germline DND1 mutations in testicular cancer patients

Although several observations suggest that a strong genetic predisposition to developing testicular germ cell tumors (TGCT) exists, no associated, highly penetrant germline mutations have been identified so far. In the 129/Sv mouse strain, a germline mutation in the DND1 gene has been shown to strongly increase the TGCT risk. We screened 272 men with TGCT (89% sporadic cases, 11% familial) for germline mutations in the human homologue of DND1. A single nucleotide substitution c.657C > G (p.Asp219Glu) was observed in a non-familial case of testicular embryonal carcinoma. The variant was also present in the patient’s asymptomatic father and two brothers, but not observed in 210 control chromosomes. The wild type DND1 allele was not lost in the patient’s tumor. In silico analysis of the variant predicts it to be non-pathogenic. We conclude that germline DND1 mutations are unlikely to contribute significantly to human testicular germ cell tumor susceptibility. The role of human DND1 in normal physiology and disease, however, is still virtually unknown and it therefore warrants further research.

Clinical and molecular features of familial and sporadic cases of von Hippel‐Lindau disease from Mexico

von Hippel-Lindau disease (VHL) is an uncommon autosomal dominant condition predisposing to the development of tumours in a variety of body organs and caused by germline mutations in VHL, a tumour suppressor gene located on 3p. Up to 60% of VHL patients show ocular involvement with retinal hemangioblastoma being the most common observed lesion. In this study, we describe the clinical and genetic characteristics of two familial and one apparently non-familial case of VHL ascertained at our institution. Clinical evaluation included ophthalmologic examination and imaging exams for tumours identification; molecular analysis consisted of PCR amplification of the complete VHL gene coding sequence (three exons) and automated nucleotide sequencing. A total of eight affected subjects were demonstrated to carry a causative mutation in VHL. Affected subjects from family #1 had a c.245G > C change, predicting a p.R82P substitution, affected individuals from family #2 were shown to have a c.266T > C change, leading to a p.L89P missense substitution, whereas the apparently non-familial case had a c.298-299insA mutation. One subject from family #2 was a non-penetrant carrier. No ocular anomalies were found in two adult affected subjects carrying the p.L89P mutation. Considerable interfamilial and intrafamilial clinical variability as well as one instance of non penetrance were recorded in these VHL disease cases. Three different mutations were demonstrated, including the c.298-299insA one base insertion, which has been previously described in two unrelated families from our country. Although additional studies are needed, our data suggest that this insertion could be a 'founder' mutation.

UNERTAN SYNDROME: REVIEW AND REPORT OF FOUR NEW CASES

The aim of this study was to describe additional patients (n= 3) exhibiting the Unertan syndrome (UTS), resident in rural areas of Canakkale. The 8th and 9th families with the UTS, with a total of 16 members affected, have not been previously characterized. A single, non-familial case (Bayramic, Canakkale) occurred during early childhood after an infection with a high fever. Three cases of familial UTS were located in another village in Canakkale. All cases exhibited the three key symptoms of the UTS: (1) walking on all four extremities, (2) primitive language (only sounds), and (3) rudimentary intelligence. Magnetic resonance imaging showed mild vermial hypoplasia in the non-familial case, while there was cerebellar and vermial hypoplasia with a flattened cerebral cortex in the familial cases. Dexterity of the fingers was normal. The man from the latter family was fond of dragging a wooden box after fastening a string around his belt. The collective observations and clinical findings suggest two etiologies for the UTS: (1) genetic, via autosomal recessive transmission and (2) viral, likely the poliovirus affecting the cerebro-cerebellar structures. At a minimum, vermial hypoplasia is suggested to cause fully developed UTS. The subjects could stand upright and even walk bipedally, despite difficulties in balance (ataxia), but they preferred quadrupedal walking. The main difficulty with gait was maintaining a dynamic-asymmetric lateral balance and initiation of the first step during standing. Apparently, a quadrupedal gait in an adult is a developmental regression with absence of the higher control mechanisms for asymmetric lateral balance during bipedal walking. It is suggested that these individuals exhibit ancestral traits; the quadrupedal gait with rudimentary intelligence and primitive speech resulting from viral infections and/or genetic damage may cause devolution (reverse evolution), a manifestation of an experiment of nature as well as experimental studies in animal models. The results support the notion of punctuated evolution, in contrast to Darwin's theory of graded evolution. Dragging a wooden box using a string wrapped around the belt may also be an example of reverse evolution with regard to tool making, illuminating the very long-lasting period before the invention of the wheel. Herein, there has been no intent to insult or injure these individuals affected by the UTS; rather, this is an endeavor to better understand the mystery of human evolution. Go to the publisher's online edition of International Journal of Neuroscience for the following free supplemental resource: video clips.

Fine mapping and identification of a candidate gene SSH1 in disseminated superficial actinic porokeratosis.

Disseminated superficial actinic porokeratosis (DSAP) is an uncommon autosomal dominant chronic keratinization disorder, characterized by multiple superficial keratotic lesions surrounded by a slightly raised keratotic border. Thus far, although two loci for DSAP have been identified, the genetic basis and pathogenesis of this disorder have not been elucidated yet. In this study, we performed a genome-wide linkage analysis in three Chinese affected families and localized the gene in an 8.0 cM interval defined by D12S330 and D12S354 on chromosome 12. Upon screening 30 candidate genes, we identified a missense mutation, p.Ser63Asn in SSH1 in one family, a frameshift mutation, p.Ser19CysfsX24 in an alternative variant (isoform f) of SSH1 in another family, and a frameshift mutation, p.Pro27ProfsX54 in the same alternative variant in one non-familial case with DSAP. SSH1 encodes a phosphatase that plays a pivotal role in actin dynamics. Our data suggested that cytoskeleton disorganization in epidermal cells is likely associated with the pathogenesis of DSAP.

A Missense Mutation in the SH3BP2 Gene on Chromosome 4p16.3 Found in a Case of Nonfamilial Cherubism

Cherubism is a rare hereditary multilocular cystic disease of the jaws, characterized by its typical appearance. Although nonfamilial cases have been reported, it is difficult to distinguish nonfamilial cherubism from central giant cell granuloma. Recent studies have revealed the point mutations in the SH3BP2 gene on chromosome 4p16.3 in cherubism families. In this article, the SH3BP2 gene in nonfamilial cherubism was examined.A 21-year-old Japanese woman with nonfamilial cherubism.Genomic DNA was purified from a blood sample obtained from the patient and used for direct sequencing. In addition, a sample of the lesion, resected during surgery, was used for histologic and immunohistochemical purposes.Genomic DNA sequencing found a Pro418Arg mutation in the SH3BP2 gene of the patient. In a histochemical analysis, the multinucleated giant cells proved to be strongly positive for PGM-1, KP-1, and tartrate-resistant acid phosphatase and faintly positive for osteopontin.The missense mutation Pro418Arg was identified in the SH3BP2 gene from a nonfamilial case of cherubism. DNA diagnosis may play a significant role in the identification of cherubism.

Nevoid basal cell carcinoma syndrome: report of an aggressive case with ethmoid sinus invasion

Nevoid basal cell carcinoma syndrome, also referred to as Gorlin–Goltz syndrome, is a rare autosomal dominant disorder characterized by multiple basal cell carcinomas, jaw cysts, palmar or plantar pits, ectopic calcification of the falx cerebri, and various skeletal developmental abnormalities. A minority of basal cell carcinomas demonstrate aggressive behavior and involve the craniofacial bones in nevoid basal cell carcinoma syndrome. A non-familial case of nevoid basal cell carcinoma syndrome with a basal cell carcinoma of the eyelid invading to the ethmoid sinus is reported.

Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas

Background: Paragangliomas are rare and highly heritable tumours of neuroectodermal origin that often develop in the head and neck region. Germline mutations in the mitochondrial complex II genes, SDHB, SDHC,...

ケルビズムの１例

Cherubism is an uncommon disease in Japan that was first described by Jones as a familialmultilocular cystic disease of the jaws. The disease is classified as a non-neoplastic bone lesion in the World Health Organization histological typing of odontogenic tumors, but diagnostic criteria have notbeen established.We report a non-familial case of cherubism in a 10-year-old boy. The patient clinically showed fullness of the cheeks, slightly upturned eyes, and multiple swellings of the submandibular and cervical lymphnodes. Intraorally, there was bilateral bone expansion from the mandibular first molar region to the ascendingramus. The right first molar was dislocated laterally and the left first molar was unerupted.Radiographically, multilocular radiolucent lesions were found bilaterally from the mandibular firstmolar region to the coronoid process. In addition, there were unilocular radiolucent lesions from the maxillary molar region to the tuberosity on both sides. Biopsy specimens obtained from the mandibular lesionswere diagnosed as giant cell granuloma. The patient is being examined periodically with no treatment. The lesions have shown no evidence of growth for 16 months.

A Sporadic Case of Congenital Hypotrichosis Simplex of the Scalp: Difficulties in Diagnosis and Classification

Hereditary hypotrichosis simplex of the scalp is a genotrichosis characterized by a hair defect limited to the scalp in the absence of other ectodermal or systemic abnormalities. Only large pedigrees consistent with autosomal dominant transmission have been described to date. In this article the clinical and scanning electron microscopy findings of a nonfamilial case of congenital scalp hypotrichosis simplex are reported. In some patients the diagnosis of sporadic hypotrichosis simplex of the scalp should be considered after ruling out all other possible causes of congenital and hereditary hypotrichosis.

Recurrence of the T666M Calcium Channel CACNA1A Gene Mutation in Familial Hemiplegic Migraine with Progressive Cerebellar Ataxia

Familial hemiplegic migraine (HM) is an autosomal dominant migraine with aura. In 20% of HM families, HM is associated with a mild permanent cerebellar ataxia (PCA). The CACNA1A gene encoding the alpha1A subunit of P/Q-type voltage-gated calcium channels is involved in 50% of unselected HM families and in all families with HM/PCA. Four CACNA1A missense mutations have been identified in HM: two in pure HM and two in HM/PCA. Different CACNA1A mutations have been identified in other autosomal dominant conditions: mutations leading to a truncated protein in episodic ataxia type 2 (EA2), small expansions of a CAG trinucleotide in spinocerebellar ataxia type 6 and also in three families with EA2 features, and, finally, a missense mutation in a single family suffering from episodic ataxia and severe progressive PCA. We screened 16 families and 3 nonfamilial case patients affected by HM/PCA for specific CACNA1A mutations and found nine families and one nonfamilial case with the same T666M mutation, one new mutation (D715E) in one family, and no CAG repeat expansion. Both T666M and D715E substitutions were absent in 12 probands belonging to pure HM families whose disease appears to be linked to CACNA1A. Finally, haplotyping with neighboring markers suggested that T666M arose through recurrent mutational events. These data could indicate that the PCA observed in 20% of HM families results from specific pathophysiologic mechanisms.

White sponge nevus presenting in the esophagus — case report and literature review

White sponge nevus (WSN) is a rare inherited disorder which usually presents as non-painful white plaques primarily involving the buccal mucosa, gingiva and palate. Extra-oral lesions most often occur in the esophagus or anogenital area but almost invariably follow the development of typical buccal lesions. We present a non-familial case in which the first manifestation of the disease was in the esophagus in the absence of oral lesions. This sequence of events has not previously been reported in the literature. The cytohistological and electron microscopical appearances which allow the recognition and differentiation of WSN from other conditions presenting as esophageal white lesions are discussed.

Nonfamilial Turcot Syndrome Presenting with Astrocytoma

A nonfamilial case of Turcot syndrome (glioma-polyposis syndrome) is described. A 16-year-old male with no siblings first developed a frontal astrocytoma, and was later found to have colonic polyposis with adenocarcinoma. The family history was negative for the syndrome, but his parents were first cousins.

Dermochondrocorneal Dystrophy (François' Syndrome)

Dermochondrocorneal dystrophy (François' syndrome) is an extremely rare disorder characterized by firm, nodular lesions involving the hands and the face; osteochondrodystrophy of the peripheral extremital bones, resulting in limitation of movement; and corneal dystrophy marked by white or brownish opacities. A nonfamilial case of dermochondrocorneal dystrophy was studied in a 45-year-old woman who had severe involvement of the gingival and palatal mucous membranes.

Obligatory bimanual associated movements: Report of a non-familial case in an otherwise normal left-handed boy

Amongst the abnormal synkinesias, bilateral and obligatory associated movements affecting predominantly the hands comprise a group of movement disorders which we have divided into: (1) those occurring as an autosomal dominant hereditary condition; (2) those occurring in the presence of disease of the central nervous system, including congenital abnormalities of the cervical region; and (3) rare, sporadic cases in otherwise healthy individuals. A left-handed patient falling into the last group is reported, in whom detailed neuropsychological assessment was also undertaken. Recalling the normal bimanual synkinesias of childhood, some of the mechanisms implicated in the production of pathological bimanual synkinesias are discussed: the effect of structural lesions within the central nervous system, defects in motor inhibition and the role of sensory afferent information, the part played by the commissures and abnormal motor pathways, the question of handedness, the relationship to mirror writing, and cerebral dominance have all been considered relevant, but from increasing evidence available from experimental work on primates the possible role of direct corticomotoneuronal connections is emphasised.

Mutation and childhood cancer: a probabilistic model for the incidence of retinoblastoma.

The incidences of some childhood cancers have been shown to fit a two-mutation hypothesis for cancer initiation. According to this hypothesis, the first mutation can be either germinal or somatic while the second is always somatic. A probabilistic model involving the mean number of tumors per genetically susceptible individual is developed as a function of age and is compared with age incidence data for retinoblastoma. The change in the mean number of tumors with time is interpreted in terms of the growth of retinal cells. In patients who are not genetically susceptible, the times of occurrence of the first and second somatic mutations can be inferred from a comparison of familial and non-familial unilateral case incidences. The total incidences of hereditary and nonhereditary forms of retinoblastoma are related to germinal and somatic mutation rates. The even distribution of certain childhood cancers throughout the world suggests that their incidences are determined by spontaneous mutation rates rather than by local environmental mutagenic carcinogens.