Novel Mutation of the Perforin Gene and Maternal Uniparental Disomy 10 in a Patient With Familial Hemophagocytic Lymphohistiocytosis

Al-Jasmi, Fatma; Abdelhaleem, Mohamed; Stockley, Tracy L.; Lee, Kyong-Soon; Clarke, Joe T.R.

doi:10.1097/mph.0b013e31817580fd

Cited by 14 publications

(4 citation statements)

References 13 publications

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“…Indeed, in the case of PRF1 , genuinely “null” mutations are most commonly caused by nonsense or frame-shift mutations and in-frame deletions that completely abrogate function. By contrast, a careful genotype-phenotype analysis has revealed that only about 50% of missense mutations ever reported resulted in a complete loss of perforin function, either due to direct interference with a critical functional domain or unscheduled post-translational modifications such as glycosylation (30, 36). The remaining PRF1 missense mutations were more commonly associated with atypical presentations of FHL or with seemingly unrelated pathologies (immunoregulatory or otherwise) in older children, adolescents, and even adults, who did not necessarily presented with FHL at all (23, 37).…”

Section: Acute Presentations Of Perforinopathy – Fhlmentioning

confidence: 94%

Perforinopathy: A Spectrum of Human Immune Disease Caused by Defective Perforin Delivery or Function

Voskoboinik

Trapani

2013

Front. Immunol.

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Congenital perforin deficiency is considered a rare cause of human immunopathology and immune dysregulation, and classically presents as a fatal illness early in infancy. However, we propose that a group of related disorders in which killer lymphocytes deliver only partially active perforin or a reduced quantum of wild-type perforin to the immune synapse should be considered part of an extended syndrome with overlapping but more variable clinical features. Apart from the many rare mutations scattered over the coding sequences, up to 10% of Caucasians carry the severely hypomorphic PRF1 allele C272 > T (leading to A91V mutation) and the overall prevalence of the homozygous state for A91V is around 1 in 600 individuals. We therefore postulate that the partial loss of perforin function and its clinical consequences may be more common then currently suspected. An acute clinical presentation is infrequent in A91V heterozygous individuals, but we postulate that the partial loss of perforin function may potentially be manifested in childhood or early adulthood as “idiopathic” inflammatory disease, or through increased cancer susceptibility – either hematological malignancy or multiple, independent primary cancers. We suggest the new term “perforinopathy” to signify the common functional endpoints of all the known consequences of perforin deficiency and failure to deliver fully functional perforin.

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Section: Acute Presentations Of Perforinopathy – Fhlmentioning

confidence: 94%

Perforinopathy: A Spectrum of Human Immune Disease Caused by Defective Perforin Delivery or Function

Voskoboinik

Trapani

2013

Front. Immunol.

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“…Studies were excluded if they did not discuss nHLH ( n = 280); aggregated nHLH patient data with all ages ( n = 83); provided insufficient detail and/or data describing a case of nHLH ( n = 28); and for other reasons ( n = 8). Two‐hundred‐five cases of nHLH from 142 articles were included in our analysis 12–152 …”

Section: Resultsmentioning

confidence: 99%

“…In neonates, it is incredibly difficult to identify whether changes in alertness, feeding, tone, and breathing (e.g., apnea) are driven by CNS HLH or a consequence of systemic illness. Furthermore, thrombocytopenia is common and may predispose patients to bleeding; subdural hematoma and intracranial hemorrhage is a reported complication of nHLH 12,15,74,106 . Head imaging was reported in less than one‐fifth of total cases and less than one‐half of cases with potential CNS manifestations.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, thrombocytopenia is common and may predispose patients to bleeding; subdural hematoma and intracranial hemorrhage is a reported complication of nHLH. 12,15,74,106 Head imaging was reported in less than one-fifth of total cases and less than one-half of cases with potential CNS manifestations. Current reports suggest that CNS HLH may be underevaluated and underrecognized in neonates.…”

Section: Treatment and Outcomementioning

confidence: 99%

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Neonatal hemophagocytic lymphohistiocytosis: A meta‐analysis of 205 cases

Kranz,

Hahn,

Thompson

et al. 2024

Pediatric Blood & Cancer

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BackgroundNeonatal hemophagocytic lymphohistiocytosis (nHLH), defined as HLH that presents in the first month of life, is clinically devastating. There have been few large descriptive studies of nHLH.ObjectivesThe objective of this study was to perform a meta‐analysis of published cases of nHLH.MethodsA comprehensive literature database search was performed. Cases of HLH were eligible for inclusion if clinical analysis was performed at age ≤30 days. Up to 70 variables were extracted from each case.ResultsA total of 544 studies were assessed for eligibility, and 205 cases of nHLH from 142 articles were included. The median age of symptom onset was day of life 3 (interquartile range [IQR]: 0–11, n = 141). Median age at diagnosis was day of life 15 (IQR: 6–27, n = 87). Causes of HLH included familial HLH (48%, n = 99/205), infection (26%, n = 53/205), unknown (17%, n = 35/205), macrophage activation syndrome/rheumatologic (2.9%, n = 4/205), primary immune deficiency (2.0%, n = 5/205), inborn errors of metabolism (2.4%, n = 5/205), and malignancy (2.0%, n = 4/205). Fever was absent in 19% (n = 28/147) of all neonates and 39% (n = 15/38) of preterm neonates. Bicytopenia was absent in 26% (n = 47/183) of patients. Central nervous system (CNS) manifestations were reported in 63% of cases (n = 64/102). Liver injury (68%, n = 91/134) and/or liver failure (24%, n = 32/134) were common. Flow cytometry was performed in 22% (n = 45/205) of cases. Many patients (63%, n = 121/193) died within the period of reporting. Discernable values for HLH diagnostic criteria were reported between 30% and 83% of the time.ConclusionsEvaluation of nHLH requires rapid testing for a wide range of differential diagnoses. HLH diagnostic criteria such as fever and bicytopenia may not occur as frequently in the neonatal population as in older pediatric populations. Neurologic and hepatic manifestations frequently occur in the neonatal population. Current reports of nHLH suggest a high mortality rate. Future publications containing data on nHLH should improve reporting quality by reporting all clinically relevant data.

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Genomic Imprinting and Uniparental Disomy

Wang

2012

The Principles of Clinical Cytogenetics

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Novel Mutation of the Perforin Gene and Maternal Uniparental Disomy 10 in a Patient With Familial Hemophagocytic Lymphohistiocytosis

Cited by 14 publications

References 13 publications

Perforinopathy: A Spectrum of Human Immune Disease Caused by Defective Perforin Delivery or Function

Perforinopathy: A Spectrum of Human Immune Disease Caused by Defective Perforin Delivery or Function

Neonatal hemophagocytic lymphohistiocytosis: A meta‐analysis of 205 cases

Genomic Imprinting and Uniparental Disomy

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