Blood Res 2021; 56(2):
Published online June 30, 2021
https://doi.org/10.5045/br.2021.2020308
© The Korean Society of Hematology
Correspondence to : Ali Al Ahmari, M.D.
Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11211, Saudi Arabia
E-mail: aahmari@kfshrc.edu.sa
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background
Our study was designed to investigate the frequencies and distributions of familial hemophagocytic lymphohistiocytosis (FHL) associated genes in Saudi patients.
Methods
FHL associated gene screening was performed on 87 Saudi patients who were diagnosed with hemophagocytic lymphohistiocytosis (HLH) between 1995 and 2014. The clinical and biochemical profiles were also retrospectively captured and analyzed.
Results
Homozygous mutations and mono-allelic variants were identified in 66 (75.9%) and 3 (3.5%) of the study participants, respectively. STXBP2 was the most frequently mutated gene (36% of patients) and mutations in STXBP2 and STX11 accounted for 58% of all FHL cases and demonstrated a specific geographical pattern. Patients in the FHL group presented at a significantly younger age than those belonging to the unknown-genetics group (median, 3.9 vs. 9.4 mo; P=0.005). The presenting clinical features were similar among the various genetic groups and the 5-year overall survival (OS) was 55.4% with a 5.6 year median follow-up. Patients with PRF1 mutations had a significantly poorer 5-year OS (21.4%, P =0.008) and patients undergoing hematopoietic stem cell transplant (72.4%) had a significantly better 5-year OS (66.5% vs. 0%, P =0.001).
Conclusion
Our study revealed the predominance of the STXBP2 mutations in Saudi patients with FHL. A genetic diagnosis was possible in 80% of the cohort and our data showed improved survival in FHL patients who underwent hematopoietic stem cell transplant.
Keywords Hemophagocytic lympho-histiocytosis, Genetic mutation, PRF1, UNC13D, STX11, STXBP2
Hemophagocytic lymphohistocytosis (HLH) is a life–threatening immune disorder associated with widespread lymphocyte and hemophagocytic infiltration of the vital organs and an overwhelming activation of the T-lymphocytes and macrophages [1]. There are two different types of HLH: primary HLH (pHLH) also known as inherited HLH [2] and secondary or acquired HLH (sHLH) [3]. pHLH includes familial HLH (FHL) and primary immunodeficiency-associated HLH. FHL is an autosomal recessive, life-threatening condition characterized by a defective immune response. Molecular evaluations have revealed a diverse pathogenesis for FHL. There are five FHL sub-types (FHL-1 to 5), separated according to genetic mutation caused by germline pathogenic variants in the
A total of 87 pediatric Saudi patients diagnosed with HLH between January 1995 and December 2014 at the King Faisal Specialist Hospital and Research Centre (KFSHRC) in Riyadh, Saudi Arabia, were enrolled in this study. All patients met the HLH-2004 diagnostic criteria as described by the Histiocyte Society [6]. Clinical data including demographic characteristics, family history, and treatment outcomes were obtained through the review of their medical records and the patients were treated according to either the HLH-1994 or HLH-2004 protocol. A written informed consent to obtain blood samples or to use stored DNA samples was obtained from each patient or their parent. A waiver for this consent was granted by the Research Advisory Committee of our institution in the case of samples from deceased patients. This study was approved by our hospital’s IRB and funded by King Abdulaziz City for Science and Technology, Saudi Arabia.
Blood samples from parents, patients and/or their siblings were collected when available at the time of diagnosis. For expired patients or for those who had undergone HSCT by the time of this study, DNA specimens were collected from the HLA typing lab. DNA was isolated from peripheral blood leukocytes using standard genomic DNA purification methods.
PCR and direct sequencing were used to identify the germline pathogenic variants in both the exons and splicing regions of
ACMG/AMP guidelines and literature evidence were used to support the interpretation of the impact of the sequence variants identified in this study [7]. All novel variants of uncertain significance (VUSs) as identified by ACMG/AMP were further analyzed using four
We used the HLH diagnostic criteria established by the Histiocyte Society [6]. Central Nervous System (CNS) involvement was defined as the development of neurological signs and/or symptoms, abnormal cerebrospinal fluid (pleocytosis and/or elevated protein), and neuroradiological findings [8]. In our study, patients harboring pathogenic variants in
IBM-SPSS version 20.0 (IBM, Armonk, USA) was used for all statistical analyses. Pearson’s chi-square test was used to determine whether there was a difference in qualitative variables between groups and OS was estimated using Kaplan-Meier survival analysis and compared using an appropriate test. The results were considered statistically significant at
Of the 87 patients analyzed, 62 (71.3%) were categorized as FHL, 7 (8.0%) as non-FHL group, and 18 (20.7%) as part of the unknown-genetics group. The median age at presentation was 0.45 years (range, 0–8.5 yr). Patients in the FHL group presented at a significantly younger age than those with unknown-genetics or non-FHL disease (median, 0.3 vs. 0.8 vs. 3.2 yr, respectively;
Table 1 Frequency of FHL-associated gene mutations by age (N=87).
Age at disease onset | N (%) | FHL groups | Negative genetic mutations (%) | |||||
---|---|---|---|---|---|---|---|---|
Total (%) | ||||||||
0≤3 mo | 28 (32.2) | 3 (10.7) | 7 (25.0) | 2 (7.1) | 10 (35.7) | 22 | 6 (21.4) | - |
3 mo≤1 yr | 35 (40.2) | 3 (8.6) | 3 (8.6) | 6 (17.1) | 16 (45.7) | 28 | 5 (14.3) | 2 (5.7) |
1 yr≤2 yr | 10 (11.5) | - | 1 (10.0) | 4 (40.0) | 1 (10.0) | 6 | 3 (30.0) | 1 (10.0) |
2 yr≤14 yr | 14 (16.1) | 1 (7.1) | 1 (7.1) | 4 (28.6) | - | 6 | 4 (28.6) | 4 (28.6) |
Total | 87 | 7 | 12 | 16 | 27 | 62 (71.3) | 18 | 7 |
Table 2 Clinical and laboratory characteristics, CNS involvement at presentation and clinical outcome for patients in different HLH groups.
FHL (N=62) | Non-FHL (N=7) | Unknown-genetics (N=18) | Total (N=87) | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Age at onset | 0.008 | 0.002 | ||||||||
≤12 mo | 50 (80.6%) | 2 (28.6%) | 11 (61.1%) | 63 (72.4%) | 8 (50.0%) | 10 (83.3%) | 26 (96.3%) | 6 (85.7%) | ||
>12 mo | 12 (19.4%) | 5 (71.4%) | 7 (38.9%) | 24 (27.6%) | 8 (50.0%) | 2 (16.7%) | 1 (3.7%) | 1 (14.3%) | ||
Age at onset in years, median (range) | 0.3 (0–6.9) | 3.2 (0.7–6.0) | 0.8 (0–8.5) | 0.4 (0–8.5) | 0.005 | 1.0 (0.1–5.2) | 0.2 (0.1–5.9) | 0.3 (0.0–1.2) | 0.2 (0.0–6.9) | 0.028 |
Gender (M/F) | 39/23 | 5/2 | 8/10 | 52/35 | 0.318 | 12/4 | 7/5 | 18/9 | 2/5 | 0.208 |
Consanguinity | 48/61 (78.7%) | 5/6 (83.3%) | 11/16 (68.8%) | 64/83 (77.1%) | 0.667 | 12 (75%) | 11 (91.7%) | 21 (77.8 %) | 4/6 (66.7%) | 0.575 |
Symptoms at presentation | ||||||||||
Fever | 61 (98.4%) | 6 (85.7%) | 17 (94.4%) | 84 (96.6%) | 0.108 | 16 (100%) | 11 (91.7%) | 27 (100%) | 7 (100%) | 0.306 |
Splenomegaly | 62 (100%) | 7 (100%) | 16 (89%) | 85 (97.7%) | 0.080 | 16 (100%) | 12 (100%) | 27 (100%) | 7 (100%) | - |
Hepatomegaly | 60 (96.8%) | 6 (85.7%) | 16 (88.9%) | 82 (94.3%) | 0.162 | 15 (93.8%) | 12 (100%) | 26 (96.3%) | 7 (100%) | 1.0 |
Skin rash | 2 (3.2%) | 0 (0%) | 2 (11.1%) | 4 (4.6%) | 0.444 | 1 (6.2%) | 0 (0%) | 1 (3.7 %) | 0 (0%) | 1.0 |
Jaundice | 24 (38.7%) | 0 (0%) | 6 (33.3%) | 30 (34.5%) | 0.147 | 4 (25.0%) | 4 (33.3%) | 13 (48.1 %) | 3 (42.9%) | 0.501 |
Pancytopenia | 49/54 (90.7%) | 6 (85.7%) | 15/16 (93.8%) | 70/77 (90.9%) | 0.670 | 12/13 (92.3%) | 9/11 (81.8%) | 22/24 (91.7%) | 6/6 (100%) | 0.759 |
Hyperbilirubinemia | 33 (53.2%) | 3 (42.9) | 11 (61.1%) | 47 (54.0%) | 0.726 | 6 (37.5%) | 9 (75.0%) | 15 (55.6%) | 3 (42.9%) | 0.253 |
High liver enzymes | 27/47 (57.4%) | 3/6 (50%) | 7/12 (58.3%) | 37/65 (56.9%) | 1.0 | 9/13 (69.2%) | 2/9 (22.2%) | 14/19 (73.7%) | 2/6 (33.3%) | 0.035 |
Hypertriglyceridemia | 24/48 (50.0%) | 3/4 (75.0%) | 7/11 (63.6%) | 34/63 (54.0%) | 0.596 | 7/14 (50.0%) | 7/11 (63.6%) | 8/17 (47.1%) | 2/6 (33.3%) | 0.692 |
Hyperferitinemia | 43/53 (81.1%) | 3/4 (75.0%) | 15/16 (93.8%) | 61/73 (83.6%) | 0.426 | 13/14 (92.9%) | 7/11 (63.6%) | 17/22 (77.3%) | 6/6 (100%) | 0.194 |
Coagulopathy | 22/51 (43.1%) | 2/6 (33.3%) | 4/13 (30.8%) | 28/70 (40.0%) | 0.778 | 3/11 (27.3%) | 5/11 (45.5%) | 10/23 (43.5%) | 4/6 (66.7%) | 0.501 |
Seizures | 6 (9.7%) | 0 (0.0%) | 1 (5.6%) | 7 (8.0%) | 1.0 | 2 (12.5%) | 1 (8.3%) | 3 (11.1%) | 0 (0.0 %) | 1.0 |
CNS involvement | 26/35 (74.3%) | 3/5 (60.0%) | 6/12 (50.0%) | 35/52 (67.3%) | 0.248 | 9/11 (81.8%) | 3/5 (60.0%) | 9/13 (69.2%) | 5/6 (83.3%) | 0.778 |
Hemophagocytosis | 37/53 (69.8%) | 5 (71.4%) | 9/13 (69.2%) | 51/73 (69.9%) | 1.0 | 11/14 (78.6%) | 7/11 (63.6%) | 16/22 (72.7%) | 3/6 (50.0%) | 0.588 |
Reactivation | 12 (19.4%) | 0 (0.0%) | 5 (27.8%) | 17 (19.5%) | 0.353 | 3 (18.8%) | 2 (16.7%) | 6 (22.2%) | 1/7 (14.3%) | 1.0 |
HSCT | 44 (71.0%) | 4 (57.1%) | 15 (83.3) | 63 (72.4%) | 0.372 | 12 (75%) | 7 (58.3%) | 24 (88.9%) | 1 (14.3%) | 0.001 |
Patient status (alive/dead) | 38/24 | 4/3 | 11/7 | 53/34 | 1.0 | 10/6 | 10/2 | 16/11 | 2/5 | 0.142 |
Five-year OS | 55.3±6.9% | 47.6±22.5% | 57.1±12.5% | 55.4±5.8% | 0.971 | 47.4±16.0% | 80.8±12.2% | 57.4±9.7% | 21.4±17.8% | 0.008 |
Median follow-up (yr, range) | 5.5 (0.1–20.9) | 4.5 (0.1–8.8) | 5.7 (0.7–11.8) | 5.6 (0.1–20.9) | - | 5.0 (0.2–11.6) | 5.2 (0.4–14.4) | 7.3 (0.3–20.9) | 6.0 (0.1–6.0) | - |
Five-year OS for patients undergoing HSCT | 66.4±7.4% | 75.0±21.7% | 64.6%±12.9% | 66.5±6.2% | 0.984 | |||||
Five-year OS for non-HSCT patients | 0.0±0.0% | 0.0±0.0% | 0.0%±0.0% | 0.0±0.0% | - | |||||
One-year OS for non-HSCT patients | 62.3±12.2% | 66.7±27.2% | 66.7±27.2% | 63.8±10.3% | 0.971 |
Abbreviations: CNS, central nervous system; HSCT, hematopoietic stem cell transplant; OS, overall survival.
The analysis of the 87 patients in this cohort revealed a total of 20 pathogenic variants in seven different genes in 69 patients (79.3%), including eight previously reported variants and 12 novel variants (Table 3, Supplementary Figs. 1–5). Among the 12 novel variants, five were frame shift mutations, resulting in stop/gain or splicing site variants causing a loss of protein function and identified as likely to be pathogenic according to the ACMG/AMP guideline. The remaining seven missense variants were interpreted as having uncertain significance using the ACMG guideline due to the lack of functional evaluation. Given this we went on to evaluate these variants using four computational prediction tools. Among the seven missense variants, six were identified as deleterious by all four prediction tools while only one variant (c.1034 C>T, p. Thr345Met) was identified as deleterious in only three tools. In addition, our clinical data showed that all of these missense variants were unique to the patients and none were detected in unaffected family members. Moreover, these seven missenses variants were absent in the 250 healthy controls used in this study. In addition, 77% patients presented with parental consanguinity and 53% of these patients had affected siblings. Taken together these data strongly imply that these seven missense variants are likely to be pathogenic. However, functional studies are required to confirm the pathogenicity of these variants (Supplementary Table 1).
Table 3 HLH-associated genetic mutations (N=69).
Gene | Nucleotide change | Amino acid change | Mutation type | Novelty | N of Patients | Age at onset (mo), median, range | Patient status (alive/dead) | Reference |
---|---|---|---|---|---|---|---|---|
c.673C>T | p.(Arg225Trp) | Missense | Reported | 1 | 83.9 | 0/1 | Stepp | |
c.1122G>A | p.(Trp374*) | Nonsense | Reported | 3 | 2.6 (0–6.0) | 1/2 | Balta | |
c.50delT | p.(Leu17ArgfsTer34) | Frameshift | Reported | 2 | 2.7 (2.3–3.0) | 0/2 | Trizzino | |
c.1081A>T | p.(Arg361Trp) | Missense | Reported | 1 | 11.4 | 0/1 | Gadoury-Levesque | |
c.1484T>G | p.(Val495Gly) | Missense | Novel | 1 | 72.4 | 1/0 | This study, Supplementary Fig. 1C | |
c.3047_3048insC | p.(Glu1017ArgfsTer8) | Frameshift | Novel | 6 | 2.4 (1.9–11.6) | 4/2 | This study, Supplementary Fig. 1A | |
c.3053C>A | p.(Ala1018Asp) | Missense | Novel | 2 | 2.6 (1.9–3.3 ) | 2/0 | This study, Supplementary Fig. 1D | |
c.2019C>G | p.(Tyr673*) | Nonsense | Novel | 1 | 15.1 | 1/0 | This study, Supplementary Fig. 1B | |
c.766C>T | p.(Arg256*) | Nonsense | Reported | 2 | 1.9 (1.6–2.1) | 2/0 | Zur Stadt | |
c.862T>C | p.(Trp288Arg) | Missense | Novel | 1 | 0.43 | 0/1 | This study, Supplementary Fig. 2 | |
c.1430C>T | p.(Pro477Leu) | Missense | Reported | 24 | 3.7 (0.8–14.2) | 16/8 | zur Stadt | |
c.1034C>T | p.(Thr345Met) (monoallelic) | Missense | Novel | 2 | 7.2 (5.3–9.0) | 0/2 | This study | |
c.601_602ins C | p.(Gln140ProfsTer46) | Frameshift | Novel | 1 | 16.9 | 1/0 | This study, Supplementary Fig. 3 | |
c.690G>A | p.(Gln230Ala) (monoallelic) | Missense | Novel | 1 | 9.5 | 0/1 | This study | |
c.173T>C | p.(Leu58Pro) | Missense | Reported | 14 | 12.1 (0.7–63.6) | 9/5 | Zur Stadt | |
c.4637C>T | p.(Ala1546Val) | Missense | Novel | 1 | 10.9 | 0/1 | This study, Supplementary Fig. 4C | |
c.9560+1G>C | Splice site | Splice site | Novel | 1 | 46.9 | 1/0 | This study, Supplementary Fig. 4B | |
c.9044+1G>T | Splice site | Splice site | Novel | 2 | 59.9 (47.0–72.9) | 2/0 | This study, Supplementary Fig. 4A | |
c.400A>C | p.(Lys134Gln) | Missense | Novel | 2 | 12.0 (8.0–16.0) | 1/1 | This study, Supplementary Fig. 5 | |
c.1190insA | p. (Ile397Asnfs Ter405) | Frameshift | Reported | 1 | 39.3 | 0/1 | Aguilar |
Of the 69 patients harboring pathogenic variants, 65 (94.2%) carried homozygous variants, 25 (36%) in
In the 7 patients presenting with mutations in non-classical FHL genes, two novel mutations were detected in the
These patients were assumed to have HLH based on the presence of consanguinity, familial recurrence or disease reactivation. The 18 patients with unknown-genetic etiology presented with a median age at disease onset of 0.7 years (range, 0–8.53) with a median survival of 3.8 years (range, 0.7–11.8). A history of affected family members and consanguinity was observed in 7 (40%) and 11 of the 18 (68.7%) patients, respectively. CNS involvement and disease reactivation were observed in 6 of 12 (50%) and 5 (27.8%) patients, respectively (Table 2).
Identification of population specific genetic markers for HLH is very important as it allows early recognition of HLH and facilitates earlier HSCT as well as the screening of family donors for HLH. Although FHL is a very rare disorder, it is relatively common in the Saudi population, likely because of the frequent consanguineous marriages in this population. The spectrum of HLH gene mutations in this population is unknown. This is, to our knowledge, the first report to comprehensively describe the mutations present in FHL-associated genes and their clinical characteristics in the Saudi population. FHL is usually diagnosed during infancy or early childhood. Our analysis revealed a median age at diagnosis of FHL of 0.4 years, with 79% of the patients being infants. In fact, only 4.8% of our FHL patients presented with disease onset at over 5 years of age which is comparable to the incidence rates recorded by the International Histiocyte Society which reports that approximately 5% of patients are affected after 5 years of age [9]. Previous studies have reported that adolescents and even older adults may have a genetic predisposition to HLH [10-13]. Our findings confirmed that
Table 4 Distribution of FHL-associated gene mutations by ethnicity including the Saudis [19, 37].
Gene | Caucasian (%) | Hispanic (%) | Black (%) | Turkish (%) | German (%) | Saudi (%) |
---|---|---|---|---|---|---|
20 (28) | 41 (73) | 44 (98) | 14 (48.3) | 3 (42.9) | 7 (11.7) | |
35 (48) | 10 (18) | 0 | 6 (20.7) | 4 (57.1) | 10 (16.7) | |
1(2) | 4 (7) | 0 | 6 (20.7) | 0 | 16 (26.7) | |
16 (22) | 1 (2) | 1 (2) | 3 (10.3) | 0 | 27 (45.0) | |
Total | 72 | 56 | 45 | 29 | 7 | 60 |
Of the five different
There is growing evidence that monoallelic variants can also contribute to FHL. In the Cetica
CNS involvement at the time of diagnosis was relatively common in our patient cohort, which agrees with most of the available literature. Although it is a well-known fact that CNS involvement has a negative effect on FHL prognosis [8], we did not find any differences between the survival rates of patients with and without CNS involvement in different FHL groups. Overall, 24 (27.6%) of our patients died from disease progression prior to HSCT at a median duration of 9.7 months with the majority of these fatalities presenting with
In conclusion, our study demonstrates the unique FHL profile in the Saudi population and highlights the tribal and geographical patterns of
*This study was supported by a grant from the Kingdom of Saudi Arabia National Science, Technology and Innovation Plan’s Strategic Technologies Grant (10-Bio1351-20) from the King Abdul-Aziz City for Science and Technology (Riyadh, Kingdom of Saudi Arabia).
No potential conflicts of interest relevant to this article were reported.
Blood Res 2021; 56(2): 86-101
Published online June 30, 2021 https://doi.org/10.5045/br.2021.2020308
Copyright © The Korean Society of Hematology.
Ali Al Ahmari1,5, Osama Alsmadi2,6, Atia Sheereen2, Tanziel Elamin2, Amal Jabr2, Lina El-Baik2, Safa Alhissi2, Bandar Al Saud3, Moheeb Al-Awwami4, Ibrahim Al Fawaz1,5, Mouhab Ayas1,5, Khawar Siddiqui1, Abbas Hawwari2,7
1Department of Pediatric Hematology/Oncology, 2Section of Immunogenetics, Department of Genetics, Research Center, 3Department of Pediatric Allergy/Immunology, 4Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, 5College of Medicine, AlFaisal University, Riyadh, Saudi Arabia, 6Cell Therapy, Applied Genomics, King Hussein Cancer Center, Amman, Jordan, 7King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City Hospital, Al-Ahsa, Saudi Arabia
Correspondence to:Ali Al Ahmari, M.D.
Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh 11211, Saudi Arabia
E-mail: aahmari@kfshrc.edu.sa
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background
Our study was designed to investigate the frequencies and distributions of familial hemophagocytic lymphohistiocytosis (FHL) associated genes in Saudi patients.
Methods
FHL associated gene screening was performed on 87 Saudi patients who were diagnosed with hemophagocytic lymphohistiocytosis (HLH) between 1995 and 2014. The clinical and biochemical profiles were also retrospectively captured and analyzed.
Results
Homozygous mutations and mono-allelic variants were identified in 66 (75.9%) and 3 (3.5%) of the study participants, respectively. STXBP2 was the most frequently mutated gene (36% of patients) and mutations in STXBP2 and STX11 accounted for 58% of all FHL cases and demonstrated a specific geographical pattern. Patients in the FHL group presented at a significantly younger age than those belonging to the unknown-genetics group (median, 3.9 vs. 9.4 mo; P=0.005). The presenting clinical features were similar among the various genetic groups and the 5-year overall survival (OS) was 55.4% with a 5.6 year median follow-up. Patients with PRF1 mutations had a significantly poorer 5-year OS (21.4%, P =0.008) and patients undergoing hematopoietic stem cell transplant (72.4%) had a significantly better 5-year OS (66.5% vs. 0%, P =0.001).
Conclusion
Our study revealed the predominance of the STXBP2 mutations in Saudi patients with FHL. A genetic diagnosis was possible in 80% of the cohort and our data showed improved survival in FHL patients who underwent hematopoietic stem cell transplant.
Keywords: Hemophagocytic lympho-histiocytosis, Genetic mutation, PRF1, UNC13D, STX11, STXBP2
Hemophagocytic lymphohistocytosis (HLH) is a life–threatening immune disorder associated with widespread lymphocyte and hemophagocytic infiltration of the vital organs and an overwhelming activation of the T-lymphocytes and macrophages [1]. There are two different types of HLH: primary HLH (pHLH) also known as inherited HLH [2] and secondary or acquired HLH (sHLH) [3]. pHLH includes familial HLH (FHL) and primary immunodeficiency-associated HLH. FHL is an autosomal recessive, life-threatening condition characterized by a defective immune response. Molecular evaluations have revealed a diverse pathogenesis for FHL. There are five FHL sub-types (FHL-1 to 5), separated according to genetic mutation caused by germline pathogenic variants in the
A total of 87 pediatric Saudi patients diagnosed with HLH between January 1995 and December 2014 at the King Faisal Specialist Hospital and Research Centre (KFSHRC) in Riyadh, Saudi Arabia, were enrolled in this study. All patients met the HLH-2004 diagnostic criteria as described by the Histiocyte Society [6]. Clinical data including demographic characteristics, family history, and treatment outcomes were obtained through the review of their medical records and the patients were treated according to either the HLH-1994 or HLH-2004 protocol. A written informed consent to obtain blood samples or to use stored DNA samples was obtained from each patient or their parent. A waiver for this consent was granted by the Research Advisory Committee of our institution in the case of samples from deceased patients. This study was approved by our hospital’s IRB and funded by King Abdulaziz City for Science and Technology, Saudi Arabia.
Blood samples from parents, patients and/or their siblings were collected when available at the time of diagnosis. For expired patients or for those who had undergone HSCT by the time of this study, DNA specimens were collected from the HLA typing lab. DNA was isolated from peripheral blood leukocytes using standard genomic DNA purification methods.
PCR and direct sequencing were used to identify the germline pathogenic variants in both the exons and splicing regions of
ACMG/AMP guidelines and literature evidence were used to support the interpretation of the impact of the sequence variants identified in this study [7]. All novel variants of uncertain significance (VUSs) as identified by ACMG/AMP were further analyzed using four
We used the HLH diagnostic criteria established by the Histiocyte Society [6]. Central Nervous System (CNS) involvement was defined as the development of neurological signs and/or symptoms, abnormal cerebrospinal fluid (pleocytosis and/or elevated protein), and neuroradiological findings [8]. In our study, patients harboring pathogenic variants in
IBM-SPSS version 20.0 (IBM, Armonk, USA) was used for all statistical analyses. Pearson’s chi-square test was used to determine whether there was a difference in qualitative variables between groups and OS was estimated using Kaplan-Meier survival analysis and compared using an appropriate test. The results were considered statistically significant at
Of the 87 patients analyzed, 62 (71.3%) were categorized as FHL, 7 (8.0%) as non-FHL group, and 18 (20.7%) as part of the unknown-genetics group. The median age at presentation was 0.45 years (range, 0–8.5 yr). Patients in the FHL group presented at a significantly younger age than those with unknown-genetics or non-FHL disease (median, 0.3 vs. 0.8 vs. 3.2 yr, respectively;
Table 1 . Frequency of FHL-associated gene mutations by age (N=87)..
Age at disease onset | N (%) | FHL groups | Negative genetic mutations (%) | |||||
---|---|---|---|---|---|---|---|---|
Total (%) | ||||||||
0≤3 mo | 28 (32.2) | 3 (10.7) | 7 (25.0) | 2 (7.1) | 10 (35.7) | 22 | 6 (21.4) | - |
3 mo≤1 yr | 35 (40.2) | 3 (8.6) | 3 (8.6) | 6 (17.1) | 16 (45.7) | 28 | 5 (14.3) | 2 (5.7) |
1 yr≤2 yr | 10 (11.5) | - | 1 (10.0) | 4 (40.0) | 1 (10.0) | 6 | 3 (30.0) | 1 (10.0) |
2 yr≤14 yr | 14 (16.1) | 1 (7.1) | 1 (7.1) | 4 (28.6) | - | 6 | 4 (28.6) | 4 (28.6) |
Total | 87 | 7 | 12 | 16 | 27 | 62 (71.3) | 18 | 7 |
Table 2 . Clinical and laboratory characteristics, CNS involvement at presentation and clinical outcome for patients in different HLH groups..
FHL (N=62) | Non-FHL (N=7) | Unknown-genetics (N=18) | Total (N=87) | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Age at onset | 0.008 | 0.002 | ||||||||
≤12 mo | 50 (80.6%) | 2 (28.6%) | 11 (61.1%) | 63 (72.4%) | 8 (50.0%) | 10 (83.3%) | 26 (96.3%) | 6 (85.7%) | ||
>12 mo | 12 (19.4%) | 5 (71.4%) | 7 (38.9%) | 24 (27.6%) | 8 (50.0%) | 2 (16.7%) | 1 (3.7%) | 1 (14.3%) | ||
Age at onset in years, median (range) | 0.3 (0–6.9) | 3.2 (0.7–6.0) | 0.8 (0–8.5) | 0.4 (0–8.5) | 0.005 | 1.0 (0.1–5.2) | 0.2 (0.1–5.9) | 0.3 (0.0–1.2) | 0.2 (0.0–6.9) | 0.028 |
Gender (M/F) | 39/23 | 5/2 | 8/10 | 52/35 | 0.318 | 12/4 | 7/5 | 18/9 | 2/5 | 0.208 |
Consanguinity | 48/61 (78.7%) | 5/6 (83.3%) | 11/16 (68.8%) | 64/83 (77.1%) | 0.667 | 12 (75%) | 11 (91.7%) | 21 (77.8 %) | 4/6 (66.7%) | 0.575 |
Symptoms at presentation | ||||||||||
Fever | 61 (98.4%) | 6 (85.7%) | 17 (94.4%) | 84 (96.6%) | 0.108 | 16 (100%) | 11 (91.7%) | 27 (100%) | 7 (100%) | 0.306 |
Splenomegaly | 62 (100%) | 7 (100%) | 16 (89%) | 85 (97.7%) | 0.080 | 16 (100%) | 12 (100%) | 27 (100%) | 7 (100%) | - |
Hepatomegaly | 60 (96.8%) | 6 (85.7%) | 16 (88.9%) | 82 (94.3%) | 0.162 | 15 (93.8%) | 12 (100%) | 26 (96.3%) | 7 (100%) | 1.0 |
Skin rash | 2 (3.2%) | 0 (0%) | 2 (11.1%) | 4 (4.6%) | 0.444 | 1 (6.2%) | 0 (0%) | 1 (3.7 %) | 0 (0%) | 1.0 |
Jaundice | 24 (38.7%) | 0 (0%) | 6 (33.3%) | 30 (34.5%) | 0.147 | 4 (25.0%) | 4 (33.3%) | 13 (48.1 %) | 3 (42.9%) | 0.501 |
Pancytopenia | 49/54 (90.7%) | 6 (85.7%) | 15/16 (93.8%) | 70/77 (90.9%) | 0.670 | 12/13 (92.3%) | 9/11 (81.8%) | 22/24 (91.7%) | 6/6 (100%) | 0.759 |
Hyperbilirubinemia | 33 (53.2%) | 3 (42.9) | 11 (61.1%) | 47 (54.0%) | 0.726 | 6 (37.5%) | 9 (75.0%) | 15 (55.6%) | 3 (42.9%) | 0.253 |
High liver enzymes | 27/47 (57.4%) | 3/6 (50%) | 7/12 (58.3%) | 37/65 (56.9%) | 1.0 | 9/13 (69.2%) | 2/9 (22.2%) | 14/19 (73.7%) | 2/6 (33.3%) | 0.035 |
Hypertriglyceridemia | 24/48 (50.0%) | 3/4 (75.0%) | 7/11 (63.6%) | 34/63 (54.0%) | 0.596 | 7/14 (50.0%) | 7/11 (63.6%) | 8/17 (47.1%) | 2/6 (33.3%) | 0.692 |
Hyperferitinemia | 43/53 (81.1%) | 3/4 (75.0%) | 15/16 (93.8%) | 61/73 (83.6%) | 0.426 | 13/14 (92.9%) | 7/11 (63.6%) | 17/22 (77.3%) | 6/6 (100%) | 0.194 |
Coagulopathy | 22/51 (43.1%) | 2/6 (33.3%) | 4/13 (30.8%) | 28/70 (40.0%) | 0.778 | 3/11 (27.3%) | 5/11 (45.5%) | 10/23 (43.5%) | 4/6 (66.7%) | 0.501 |
Seizures | 6 (9.7%) | 0 (0.0%) | 1 (5.6%) | 7 (8.0%) | 1.0 | 2 (12.5%) | 1 (8.3%) | 3 (11.1%) | 0 (0.0 %) | 1.0 |
CNS involvement | 26/35 (74.3%) | 3/5 (60.0%) | 6/12 (50.0%) | 35/52 (67.3%) | 0.248 | 9/11 (81.8%) | 3/5 (60.0%) | 9/13 (69.2%) | 5/6 (83.3%) | 0.778 |
Hemophagocytosis | 37/53 (69.8%) | 5 (71.4%) | 9/13 (69.2%) | 51/73 (69.9%) | 1.0 | 11/14 (78.6%) | 7/11 (63.6%) | 16/22 (72.7%) | 3/6 (50.0%) | 0.588 |
Reactivation | 12 (19.4%) | 0 (0.0%) | 5 (27.8%) | 17 (19.5%) | 0.353 | 3 (18.8%) | 2 (16.7%) | 6 (22.2%) | 1/7 (14.3%) | 1.0 |
HSCT | 44 (71.0%) | 4 (57.1%) | 15 (83.3) | 63 (72.4%) | 0.372 | 12 (75%) | 7 (58.3%) | 24 (88.9%) | 1 (14.3%) | 0.001 |
Patient status (alive/dead) | 38/24 | 4/3 | 11/7 | 53/34 | 1.0 | 10/6 | 10/2 | 16/11 | 2/5 | 0.142 |
Five-year OS | 55.3±6.9% | 47.6±22.5% | 57.1±12.5% | 55.4±5.8% | 0.971 | 47.4±16.0% | 80.8±12.2% | 57.4±9.7% | 21.4±17.8% | 0.008 |
Median follow-up (yr, range) | 5.5 (0.1–20.9) | 4.5 (0.1–8.8) | 5.7 (0.7–11.8) | 5.6 (0.1–20.9) | - | 5.0 (0.2–11.6) | 5.2 (0.4–14.4) | 7.3 (0.3–20.9) | 6.0 (0.1–6.0) | - |
Five-year OS for patients undergoing HSCT | 66.4±7.4% | 75.0±21.7% | 64.6%±12.9% | 66.5±6.2% | 0.984 | |||||
Five-year OS for non-HSCT patients | 0.0±0.0% | 0.0±0.0% | 0.0%±0.0% | 0.0±0.0% | - | |||||
One-year OS for non-HSCT patients | 62.3±12.2% | 66.7±27.2% | 66.7±27.2% | 63.8±10.3% | 0.971 |
Abbreviations: CNS, central nervous system; HSCT, hematopoietic stem cell transplant; OS, overall survival..
The analysis of the 87 patients in this cohort revealed a total of 20 pathogenic variants in seven different genes in 69 patients (79.3%), including eight previously reported variants and 12 novel variants (Table 3, Supplementary Figs. 1–5). Among the 12 novel variants, five were frame shift mutations, resulting in stop/gain or splicing site variants causing a loss of protein function and identified as likely to be pathogenic according to the ACMG/AMP guideline. The remaining seven missense variants were interpreted as having uncertain significance using the ACMG guideline due to the lack of functional evaluation. Given this we went on to evaluate these variants using four computational prediction tools. Among the seven missense variants, six were identified as deleterious by all four prediction tools while only one variant (c.1034 C>T, p. Thr345Met) was identified as deleterious in only three tools. In addition, our clinical data showed that all of these missense variants were unique to the patients and none were detected in unaffected family members. Moreover, these seven missenses variants were absent in the 250 healthy controls used in this study. In addition, 77% patients presented with parental consanguinity and 53% of these patients had affected siblings. Taken together these data strongly imply that these seven missense variants are likely to be pathogenic. However, functional studies are required to confirm the pathogenicity of these variants (Supplementary Table 1).
Table 3 . HLH-associated genetic mutations (N=69)..
Gene | Nucleotide change | Amino acid change | Mutation type | Novelty | N of Patients | Age at onset (mo), median, range | Patient status (alive/dead) | Reference |
---|---|---|---|---|---|---|---|---|
c.673C>T | p.(Arg225Trp) | Missense | Reported | 1 | 83.9 | 0/1 | Stepp | |
c.1122G>A | p.(Trp374*) | Nonsense | Reported | 3 | 2.6 (0–6.0) | 1/2 | Balta | |
c.50delT | p.(Leu17ArgfsTer34) | Frameshift | Reported | 2 | 2.7 (2.3–3.0) | 0/2 | Trizzino | |
c.1081A>T | p.(Arg361Trp) | Missense | Reported | 1 | 11.4 | 0/1 | Gadoury-Levesque | |
c.1484T>G | p.(Val495Gly) | Missense | Novel | 1 | 72.4 | 1/0 | This study, Supplementary Fig. 1C | |
c.3047_3048insC | p.(Glu1017ArgfsTer8) | Frameshift | Novel | 6 | 2.4 (1.9–11.6) | 4/2 | This study, Supplementary Fig. 1A | |
c.3053C>A | p.(Ala1018Asp) | Missense | Novel | 2 | 2.6 (1.9–3.3 ) | 2/0 | This study, Supplementary Fig. 1D | |
c.2019C>G | p.(Tyr673*) | Nonsense | Novel | 1 | 15.1 | 1/0 | This study, Supplementary Fig. 1B | |
c.766C>T | p.(Arg256*) | Nonsense | Reported | 2 | 1.9 (1.6–2.1) | 2/0 | Zur Stadt | |
c.862T>C | p.(Trp288Arg) | Missense | Novel | 1 | 0.43 | 0/1 | This study, Supplementary Fig. 2 | |
c.1430C>T | p.(Pro477Leu) | Missense | Reported | 24 | 3.7 (0.8–14.2) | 16/8 | zur Stadt | |
c.1034C>T | p.(Thr345Met) (monoallelic) | Missense | Novel | 2 | 7.2 (5.3–9.0) | 0/2 | This study | |
c.601_602ins C | p.(Gln140ProfsTer46) | Frameshift | Novel | 1 | 16.9 | 1/0 | This study, Supplementary Fig. 3 | |
c.690G>A | p.(Gln230Ala) (monoallelic) | Missense | Novel | 1 | 9.5 | 0/1 | This study | |
c.173T>C | p.(Leu58Pro) | Missense | Reported | 14 | 12.1 (0.7–63.6) | 9/5 | Zur Stadt | |
c.4637C>T | p.(Ala1546Val) | Missense | Novel | 1 | 10.9 | 0/1 | This study, Supplementary Fig. 4C | |
c.9560+1G>C | Splice site | Splice site | Novel | 1 | 46.9 | 1/0 | This study, Supplementary Fig. 4B | |
c.9044+1G>T | Splice site | Splice site | Novel | 2 | 59.9 (47.0–72.9) | 2/0 | This study, Supplementary Fig. 4A | |
c.400A>C | p.(Lys134Gln) | Missense | Novel | 2 | 12.0 (8.0–16.0) | 1/1 | This study, Supplementary Fig. 5 | |
c.1190insA | p. (Ile397Asnfs Ter405) | Frameshift | Reported | 1 | 39.3 | 0/1 | Aguilar |
Of the 69 patients harboring pathogenic variants, 65 (94.2%) carried homozygous variants, 25 (36%) in
In the 7 patients presenting with mutations in non-classical FHL genes, two novel mutations were detected in the
These patients were assumed to have HLH based on the presence of consanguinity, familial recurrence or disease reactivation. The 18 patients with unknown-genetic etiology presented with a median age at disease onset of 0.7 years (range, 0–8.53) with a median survival of 3.8 years (range, 0.7–11.8). A history of affected family members and consanguinity was observed in 7 (40%) and 11 of the 18 (68.7%) patients, respectively. CNS involvement and disease reactivation were observed in 6 of 12 (50%) and 5 (27.8%) patients, respectively (Table 2).
Identification of population specific genetic markers for HLH is very important as it allows early recognition of HLH and facilitates earlier HSCT as well as the screening of family donors for HLH. Although FHL is a very rare disorder, it is relatively common in the Saudi population, likely because of the frequent consanguineous marriages in this population. The spectrum of HLH gene mutations in this population is unknown. This is, to our knowledge, the first report to comprehensively describe the mutations present in FHL-associated genes and their clinical characteristics in the Saudi population. FHL is usually diagnosed during infancy or early childhood. Our analysis revealed a median age at diagnosis of FHL of 0.4 years, with 79% of the patients being infants. In fact, only 4.8% of our FHL patients presented with disease onset at over 5 years of age which is comparable to the incidence rates recorded by the International Histiocyte Society which reports that approximately 5% of patients are affected after 5 years of age [9]. Previous studies have reported that adolescents and even older adults may have a genetic predisposition to HLH [10-13]. Our findings confirmed that
Table 4 . Distribution of FHL-associated gene mutations by ethnicity including the Saudis [19, 37]..
Gene | Caucasian (%) | Hispanic (%) | Black (%) | Turkish (%) | German (%) | Saudi (%) |
---|---|---|---|---|---|---|
20 (28) | 41 (73) | 44 (98) | 14 (48.3) | 3 (42.9) | 7 (11.7) | |
35 (48) | 10 (18) | 0 | 6 (20.7) | 4 (57.1) | 10 (16.7) | |
1(2) | 4 (7) | 0 | 6 (20.7) | 0 | 16 (26.7) | |
16 (22) | 1 (2) | 1 (2) | 3 (10.3) | 0 | 27 (45.0) | |
Total | 72 | 56 | 45 | 29 | 7 | 60 |
Of the five different
There is growing evidence that monoallelic variants can also contribute to FHL. In the Cetica
CNS involvement at the time of diagnosis was relatively common in our patient cohort, which agrees with most of the available literature. Although it is a well-known fact that CNS involvement has a negative effect on FHL prognosis [8], we did not find any differences between the survival rates of patients with and without CNS involvement in different FHL groups. Overall, 24 (27.6%) of our patients died from disease progression prior to HSCT at a median duration of 9.7 months with the majority of these fatalities presenting with
In conclusion, our study demonstrates the unique FHL profile in the Saudi population and highlights the tribal and geographical patterns of
*This study was supported by a grant from the Kingdom of Saudi Arabia National Science, Technology and Innovation Plan’s Strategic Technologies Grant (10-Bio1351-20) from the King Abdul-Aziz City for Science and Technology (Riyadh, Kingdom of Saudi Arabia).
No potential conflicts of interest relevant to this article were reported.
Table 1 . Frequency of FHL-associated gene mutations by age (N=87)..
Age at disease onset | N (%) | FHL groups | Negative genetic mutations (%) | |||||
---|---|---|---|---|---|---|---|---|
Total (%) | ||||||||
0≤3 mo | 28 (32.2) | 3 (10.7) | 7 (25.0) | 2 (7.1) | 10 (35.7) | 22 | 6 (21.4) | - |
3 mo≤1 yr | 35 (40.2) | 3 (8.6) | 3 (8.6) | 6 (17.1) | 16 (45.7) | 28 | 5 (14.3) | 2 (5.7) |
1 yr≤2 yr | 10 (11.5) | - | 1 (10.0) | 4 (40.0) | 1 (10.0) | 6 | 3 (30.0) | 1 (10.0) |
2 yr≤14 yr | 14 (16.1) | 1 (7.1) | 1 (7.1) | 4 (28.6) | - | 6 | 4 (28.6) | 4 (28.6) |
Total | 87 | 7 | 12 | 16 | 27 | 62 (71.3) | 18 | 7 |
Table 2 . Clinical and laboratory characteristics, CNS involvement at presentation and clinical outcome for patients in different HLH groups..
FHL (N=62) | Non-FHL (N=7) | Unknown-genetics (N=18) | Total (N=87) | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Age at onset | 0.008 | 0.002 | ||||||||
≤12 mo | 50 (80.6%) | 2 (28.6%) | 11 (61.1%) | 63 (72.4%) | 8 (50.0%) | 10 (83.3%) | 26 (96.3%) | 6 (85.7%) | ||
>12 mo | 12 (19.4%) | 5 (71.4%) | 7 (38.9%) | 24 (27.6%) | 8 (50.0%) | 2 (16.7%) | 1 (3.7%) | 1 (14.3%) | ||
Age at onset in years, median (range) | 0.3 (0–6.9) | 3.2 (0.7–6.0) | 0.8 (0–8.5) | 0.4 (0–8.5) | 0.005 | 1.0 (0.1–5.2) | 0.2 (0.1–5.9) | 0.3 (0.0–1.2) | 0.2 (0.0–6.9) | 0.028 |
Gender (M/F) | 39/23 | 5/2 | 8/10 | 52/35 | 0.318 | 12/4 | 7/5 | 18/9 | 2/5 | 0.208 |
Consanguinity | 48/61 (78.7%) | 5/6 (83.3%) | 11/16 (68.8%) | 64/83 (77.1%) | 0.667 | 12 (75%) | 11 (91.7%) | 21 (77.8 %) | 4/6 (66.7%) | 0.575 |
Symptoms at presentation | ||||||||||
Fever | 61 (98.4%) | 6 (85.7%) | 17 (94.4%) | 84 (96.6%) | 0.108 | 16 (100%) | 11 (91.7%) | 27 (100%) | 7 (100%) | 0.306 |
Splenomegaly | 62 (100%) | 7 (100%) | 16 (89%) | 85 (97.7%) | 0.080 | 16 (100%) | 12 (100%) | 27 (100%) | 7 (100%) | - |
Hepatomegaly | 60 (96.8%) | 6 (85.7%) | 16 (88.9%) | 82 (94.3%) | 0.162 | 15 (93.8%) | 12 (100%) | 26 (96.3%) | 7 (100%) | 1.0 |
Skin rash | 2 (3.2%) | 0 (0%) | 2 (11.1%) | 4 (4.6%) | 0.444 | 1 (6.2%) | 0 (0%) | 1 (3.7 %) | 0 (0%) | 1.0 |
Jaundice | 24 (38.7%) | 0 (0%) | 6 (33.3%) | 30 (34.5%) | 0.147 | 4 (25.0%) | 4 (33.3%) | 13 (48.1 %) | 3 (42.9%) | 0.501 |
Pancytopenia | 49/54 (90.7%) | 6 (85.7%) | 15/16 (93.8%) | 70/77 (90.9%) | 0.670 | 12/13 (92.3%) | 9/11 (81.8%) | 22/24 (91.7%) | 6/6 (100%) | 0.759 |
Hyperbilirubinemia | 33 (53.2%) | 3 (42.9) | 11 (61.1%) | 47 (54.0%) | 0.726 | 6 (37.5%) | 9 (75.0%) | 15 (55.6%) | 3 (42.9%) | 0.253 |
High liver enzymes | 27/47 (57.4%) | 3/6 (50%) | 7/12 (58.3%) | 37/65 (56.9%) | 1.0 | 9/13 (69.2%) | 2/9 (22.2%) | 14/19 (73.7%) | 2/6 (33.3%) | 0.035 |
Hypertriglyceridemia | 24/48 (50.0%) | 3/4 (75.0%) | 7/11 (63.6%) | 34/63 (54.0%) | 0.596 | 7/14 (50.0%) | 7/11 (63.6%) | 8/17 (47.1%) | 2/6 (33.3%) | 0.692 |
Hyperferitinemia | 43/53 (81.1%) | 3/4 (75.0%) | 15/16 (93.8%) | 61/73 (83.6%) | 0.426 | 13/14 (92.9%) | 7/11 (63.6%) | 17/22 (77.3%) | 6/6 (100%) | 0.194 |
Coagulopathy | 22/51 (43.1%) | 2/6 (33.3%) | 4/13 (30.8%) | 28/70 (40.0%) | 0.778 | 3/11 (27.3%) | 5/11 (45.5%) | 10/23 (43.5%) | 4/6 (66.7%) | 0.501 |
Seizures | 6 (9.7%) | 0 (0.0%) | 1 (5.6%) | 7 (8.0%) | 1.0 | 2 (12.5%) | 1 (8.3%) | 3 (11.1%) | 0 (0.0 %) | 1.0 |
CNS involvement | 26/35 (74.3%) | 3/5 (60.0%) | 6/12 (50.0%) | 35/52 (67.3%) | 0.248 | 9/11 (81.8%) | 3/5 (60.0%) | 9/13 (69.2%) | 5/6 (83.3%) | 0.778 |
Hemophagocytosis | 37/53 (69.8%) | 5 (71.4%) | 9/13 (69.2%) | 51/73 (69.9%) | 1.0 | 11/14 (78.6%) | 7/11 (63.6%) | 16/22 (72.7%) | 3/6 (50.0%) | 0.588 |
Reactivation | 12 (19.4%) | 0 (0.0%) | 5 (27.8%) | 17 (19.5%) | 0.353 | 3 (18.8%) | 2 (16.7%) | 6 (22.2%) | 1/7 (14.3%) | 1.0 |
HSCT | 44 (71.0%) | 4 (57.1%) | 15 (83.3) | 63 (72.4%) | 0.372 | 12 (75%) | 7 (58.3%) | 24 (88.9%) | 1 (14.3%) | 0.001 |
Patient status (alive/dead) | 38/24 | 4/3 | 11/7 | 53/34 | 1.0 | 10/6 | 10/2 | 16/11 | 2/5 | 0.142 |
Five-year OS | 55.3±6.9% | 47.6±22.5% | 57.1±12.5% | 55.4±5.8% | 0.971 | 47.4±16.0% | 80.8±12.2% | 57.4±9.7% | 21.4±17.8% | 0.008 |
Median follow-up (yr, range) | 5.5 (0.1–20.9) | 4.5 (0.1–8.8) | 5.7 (0.7–11.8) | 5.6 (0.1–20.9) | - | 5.0 (0.2–11.6) | 5.2 (0.4–14.4) | 7.3 (0.3–20.9) | 6.0 (0.1–6.0) | - |
Five-year OS for patients undergoing HSCT | 66.4±7.4% | 75.0±21.7% | 64.6%±12.9% | 66.5±6.2% | 0.984 | |||||
Five-year OS for non-HSCT patients | 0.0±0.0% | 0.0±0.0% | 0.0%±0.0% | 0.0±0.0% | - | |||||
One-year OS for non-HSCT patients | 62.3±12.2% | 66.7±27.2% | 66.7±27.2% | 63.8±10.3% | 0.971 |
Abbreviations: CNS, central nervous system; HSCT, hematopoietic stem cell transplant; OS, overall survival..
Table 3 . HLH-associated genetic mutations (N=69)..
Gene | Nucleotide change | Amino acid change | Mutation type | Novelty | N of Patients | Age at onset (mo), median, range | Patient status (alive/dead) | Reference |
---|---|---|---|---|---|---|---|---|
c.673C>T | p.(Arg225Trp) | Missense | Reported | 1 | 83.9 | 0/1 | Stepp | |
c.1122G>A | p.(Trp374*) | Nonsense | Reported | 3 | 2.6 (0–6.0) | 1/2 | Balta | |
c.50delT | p.(Leu17ArgfsTer34) | Frameshift | Reported | 2 | 2.7 (2.3–3.0) | 0/2 | Trizzino | |
c.1081A>T | p.(Arg361Trp) | Missense | Reported | 1 | 11.4 | 0/1 | Gadoury-Levesque | |
c.1484T>G | p.(Val495Gly) | Missense | Novel | 1 | 72.4 | 1/0 | This study, Supplementary Fig. 1C | |
c.3047_3048insC | p.(Glu1017ArgfsTer8) | Frameshift | Novel | 6 | 2.4 (1.9–11.6) | 4/2 | This study, Supplementary Fig. 1A | |
c.3053C>A | p.(Ala1018Asp) | Missense | Novel | 2 | 2.6 (1.9–3.3 ) | 2/0 | This study, Supplementary Fig. 1D | |
c.2019C>G | p.(Tyr673*) | Nonsense | Novel | 1 | 15.1 | 1/0 | This study, Supplementary Fig. 1B | |
c.766C>T | p.(Arg256*) | Nonsense | Reported | 2 | 1.9 (1.6–2.1) | 2/0 | Zur Stadt | |
c.862T>C | p.(Trp288Arg) | Missense | Novel | 1 | 0.43 | 0/1 | This study, Supplementary Fig. 2 | |
c.1430C>T | p.(Pro477Leu) | Missense | Reported | 24 | 3.7 (0.8–14.2) | 16/8 | zur Stadt | |
c.1034C>T | p.(Thr345Met) (monoallelic) | Missense | Novel | 2 | 7.2 (5.3–9.0) | 0/2 | This study | |
c.601_602ins C | p.(Gln140ProfsTer46) | Frameshift | Novel | 1 | 16.9 | 1/0 | This study, Supplementary Fig. 3 | |
c.690G>A | p.(Gln230Ala) (monoallelic) | Missense | Novel | 1 | 9.5 | 0/1 | This study | |
c.173T>C | p.(Leu58Pro) | Missense | Reported | 14 | 12.1 (0.7–63.6) | 9/5 | Zur Stadt | |
c.4637C>T | p.(Ala1546Val) | Missense | Novel | 1 | 10.9 | 0/1 | This study, Supplementary Fig. 4C | |
c.9560+1G>C | Splice site | Splice site | Novel | 1 | 46.9 | 1/0 | This study, Supplementary Fig. 4B | |
c.9044+1G>T | Splice site | Splice site | Novel | 2 | 59.9 (47.0–72.9) | 2/0 | This study, Supplementary Fig. 4A | |
c.400A>C | p.(Lys134Gln) | Missense | Novel | 2 | 12.0 (8.0–16.0) | 1/1 | This study, Supplementary Fig. 5 | |
c.1190insA | p. (Ile397Asnfs Ter405) | Frameshift | Reported | 1 | 39.3 | 0/1 | Aguilar |
Table 4 . Distribution of FHL-associated gene mutations by ethnicity including the Saudis [19, 37]..
Gene | Caucasian (%) | Hispanic (%) | Black (%) | Turkish (%) | German (%) | Saudi (%) |
---|---|---|---|---|---|---|
20 (28) | 41 (73) | 44 (98) | 14 (48.3) | 3 (42.9) | 7 (11.7) | |
35 (48) | 10 (18) | 0 | 6 (20.7) | 4 (57.1) | 10 (16.7) | |
1(2) | 4 (7) | 0 | 6 (20.7) | 0 | 16 (26.7) | |
16 (22) | 1 (2) | 1 (2) | 3 (10.3) | 0 | 27 (45.0) | |
Total | 72 | 56 | 45 | 29 | 7 | 60 |