SOPH and NBAS mutations

Specific instructions for discussion

 

The instruction for this discussion consists of 4 steps

 

1) Read the literature matrix that I have compiled and other relevant literatures regarding SOPH and NBAS mutations

*Please note that the information in the notes are not 100% correct. Please access their accuracy based on your professionality.

Literature matrix – articles that I have used so far

Research article Type of study & Summary Details (clinical presentations & labs; genetics; treatment outcomes)
[16]

2020, Yves Lacassie, Severe SOPH due to novel NBAS mutation in 27yo woman – Review of this pleiotropic, autosomal recessive disorder; mystery solved after two decades

Case report of a 27yo woman who p/w dwarfism, osteolysis, multiple skeletal disorders, immunodeficiency, DM and multiple secondary medical problems; her condition was considered unknown until exon sequencing revealed a founder NBAS mutation (C.5741G>A) that was heterozygous with a novel pathogenic NBAS variation (c.17C>A). –          Pt has a T-cell & NK cell lymphopenia

–          Despite IgG replacement therapy, the pt still requires frequent antibiotics tx due to different recurrent infections (cotrimoxazole every 72hrs)

–          She had menarche at 20yo

–          At 26 yo, she was dxed w/ premature ovarian failure – high FSH/LH with very low levels of E2 and AMH

 

–          c.17C>A mutation changes exon 1 that results in the creation of a premature translational stop signal

 

–          “This pt harbored variants in other genes besides NBAS, but none were judged to be related to this individual’s phenotype based on clinical data.”

 

 

 

Interesting genetic comparison worth mentioning as it is similar to our pt’s genes:

 

Interesting conclusion on renaming the syndrome:

[13]

2020, Anna Khoreva, Complex Multisystem Phenotype with immunodef a.w. NBAS mutations – Reports of 3 pts and review of literature

Case report of 3 pts w/ heterozygous mutations of the NBAS genes & focus on the immunological manifestations of NBAS deficiency –          NBAS mutations that are a/w severe liver phenotype were either a loss-of-function or missense mutations that are located in the N-terminal and in the middle part of the NBAS gene (c.409C>T, c.680A>C;1749G>A, c.809G>C;2926del, c.1018G>C;2674G>T, c.2819A>C, and c.2819A>C)

–          Figure2 depicts the presence of clinical manifestations w/ their associated mutation located along the NBAS gene

–          (taken from discussion 3rd par): “A large number of targets were shown to be downregulated in response to NBAS depletion. Among them were several genes that play a role in bone development and cholesterol biosynthesis. Defects in these processes can explain bone defects in patients with NBAS deficiency.”

–          As NBAS proteins also play a role in NMD (nonsense mediated decay) pathway, which are expressed in ganglion cells, squamous epidermal cells and in leukocytes, a defect would explain the clinical manifestations of optic atrophy, senile skin and abnormal leukocytes (hence the hypogammaglobulinemia and low T- and B-cells observed) leading to susceptibility to infections

–          Interestingly, NMD is shown to serve as a barrier to viral replication – without the suppression of viral proteins and their titers in host cells, this makes SOPH pts susceptible to viral infections (such as: HSV and EBV, where the latter is seen in our pt)

–          Clinical presentation of immunodeficiency remains an under-recognized feature in NBAS deficiency, hence requires further invetigation

[12]

2019, Silvia Ricci, Immunological features of neuroblastoma amplified sequence deficiency – report of the 1st case identified thru newborn screening for 1mary immunodeficiency & review of literature

Case report of a male newborn w/ focus on Immunological features & Literature review;

First case od NBAS disease detected by NBS (new born screening program) for 1mary immunodeficiency

–          The pt’s immunological impairment & a/w GI dysfunction (w/ absence of plasma cells in intestinal mucosa biopsy) predominates the clinical picture of the pt

–          Reduced NK cells, altered CD4+/CD8+ ratio & hyper-IgE are present in this pt (as well as previously reported); together w/ a complete absence of B cells makes this pt the most severe immune phenotype ever reported in NBAS deficiency

 

–          From figure2 – out of the 73 pts reported from literatures, 60% did not undergo immune characterization, while the 44% who did, presented a form of immunological impairment à this stresses the importance of newborn screening w/ TRECs & KRECs in order to screen for T-cell or B-cell lymphopenia in newborns

[11]

2019, Sahoko Ono, Novel neuroblastoma amplified NBAS mutation in japanese boy w. fever-triggered recurrent acute liver failure

Case report of a 3yo boy p/w fever-triggered ALF. WES & sanger sequencing reveal a novel compound heterozygous missense mutation in NBAS; his extra-hepatic manifestations were PH anomaly and short stature; he did not p/w optic atrophy, facial dysmorphism or skeletal dysplasia. –          Western blot analysis was performed that compared the pt’s NBAS protein and p31 protein levels – revealing a significant decreased level of p31 proteins (used to form SNARE complex w/ NBAS)

 

–          Interestingly, the pt’s younger brother also carries the same heterozygous mutations; he was started on early anti-pyretic therapy and has never experienced fever-triggered ALF / liver dysfunctions to date (currently 5yo)

–          Still required further investigations regarding the penetration & phenotype-genotype correlation in NBAS mutation diseases

–          Refer to figure4: It is proposed that the sites at amino acid positions 1-1035 is the p31 binding site (Our pt has 1 mutation in this region, while another mutation falls in position 1035-2371, which is proposed to interact with ZW10 and RINT1 – that are involved in cellular transport btwn Golgi & ER)

[15]

2019, Francesca Nucci, Oculofacial alterations in NBAS-SOPH like mutations – case report

Case report of a 5yo girl who was initially examined for dysmorphic features, mental delay, strabismus & high myopia. A genetic assessment then revealed a NBAS-SOPH like mutation (note the genetic variation was not present in the study, hence it was excluded from the above table) –          (consider including sth similar to this for conclusion): “Due to the heterogeneity of the expressions, a multispecialty (or: multidisciplinary) approach to each pt is recommended.”

–          Essential to ddx from other diseases w/ similar presentations of growth retardation + facial dysmorphism – i.e., CUL7 gene mutation that is responsible for the autosomal recessive 3-M syndrome

[10]

2019, Bjorn Fischer-Zirnzak, SOPH syndrome in 3 affected individuals showing similarities w. progeroid senile skin conditions in early infancy

Case study on 3 pts w/ connective tissue conditions a/w biallelic NBAS mutations – the discovery of PH anomaly in their peripheral blood samples, followed by sequencing clinched the dx –          The finding of PH anomaly verifies the dx of SOPH (“it was unequivocally proven” despite NBAS deficiency being able to manifest as an isolated RALF or a multisystem disorder like SOPH)

–          It is observed in pt 1 that the liver enzymes were persistently elevated even after infections have resolved – this indicates the constant damaging processes to the liver occurring in a phase w/o infection [also observed in 2017, Fanny Kortum’s pt]

–          Pt that was tx w/ IgG did not die (pt 3); in contrast, pt 1 presented similarly to [2015, Nuria Seggarra]’s pt, which was tx w/ IgG and did not report any further liver crises – may suggest that this therapy strengthened the immune system and prevented infections accompanied by fever that trigger the acute liver crisis

–          No correlation btwn NBAS mutations w/ severity of phenotype has been noted so far; but homozygous pts w/ the founding mutation was shown to have a comparable amount of remaining NBAS protein, indicating that the altered protein remains stable, hence no hepatic involvement was reported

–           The above point ties into the surviving pt 3, who has one of the founding mutated allele; in addition to his other truncating mutation that may have some residual functionality; together w/ IgG tx, in compound explains his long-term survival

 

–          Figure 3 d. Shows the interspecies alignment of NBAS gene. As it is highly conserved throughout evolution, it strongly suggests its importance of function.

[7]

2017, Fanny Kortum, ALF meets SOPH: Case report on an Intermediate phenotype

Case report of a 4yo girl w/ cardinal features of SOPH + infections and pyrexia preceded by elevated LFTs. –          Absence of severe liver problems (hyperammonemia, hypoglycemia, coagulopathy or hepatic encephalopathy) in individuals carrying NBAS missense founder mutation c.5741G>A (or p.Arg1914His); hence suggesting that they could have abnormal liver function, but are less prone to develop ALF

–          By far, no hepatic involvement has been reported in SOPH pts w/ the homozygous NBAS founder mutation (c.5741G>A), which is located in exon 45

 

–          ALF has been linked to SOPH as observed in the Yakut population

–          The clinical spectrum a/w NBAS mutation ranges from isolated ALF to a multisystem disorder (skeletal, immune & eye system)

 

–          [Christian Staufner, 2016] NBAS mutations in pts w/ severe hepatic phenotype tend to cluster in the first half of the encoded protein (95-1121 amino acids); however, this is also observed in pts w/ exon-spanning deletions affecting the c-terminal regions of the NBAS gene; although none of the ALF-associated mutations affecting the founder mutation at exon 45 (which is also located in the c-terminal region) has been reported

[14]

2016, Christian Staufner, Tobia Haack, RALF due to NBAS deficiency: Phenotypic spectrum, disease mechanism & therapeutic options

Rapid communication that analyzes the phenotype and medical histories of 14 pts w/ NBAS deficiency, where functional studies were performed on the pts’ fibroblasts –          Phenotypic spectrum of NBAS is wide-ranging: from isolated RALF to a multisystemic phenotype presentation of SOPH (interestingly no liver phenotype has been described in SOPH pts)

–          ALF crises are fatal – it was observed that: Antipyretic therapy and the induction of anabolism (glucose and parenteral lipids) effectively ameliorated the course of liver crisis

–          Some pts received carnitine during the crises

–          One pt had liver transplantation at 3yo and did not have liver crises since then

–          Thermal susceptibility of the syntaxin 18 complex is the basis of fever dependency of ALF episodes – as evidenced by pts’ fibroblasts showing an increased sensitivity to high temperature and a disturbed tethering of vesicles (hence, a defect of intracellular transport among ER & Golgi)

–          [Longman et al. 2013] NBAS is also thought to act as a mediator of the nonsense-mediated mRBA decay and modulate genes involved in cholesterol biosynthesis

–          As there is no specific laboratory marker, diagnosis relies on genetic testing; the analysis of NBAS protein levels via immunohistochemistry of liver biopsies or western blot analysis of fibroblasts may aid the diagnostic process

 

–          High comorbidity in NBAS deficiency points to an a/w pathologies like cardiomyopathy, renal failure or epilepsy

   
[4]

2015, Nuria Garcia Segarra, NBAS mutations cause a multisystem disorder involving bone, CT, liver, immune system and retina

Case report of 2 different children with NBAS mutations and their clinical presentations –          Refer to case report written on patient 1 when describing clinical findings, p/e and growth curve (pg. 2903)

–          Patient 1 – Immunological workup: Hypogammaglobulinemia, absent response to vaccinations, reduced NK cell count; Treated w/ weekly sc. Injections of immunoglobulins at age 11.5yo (this cleared up the pts infections w/ substantial improvement in his general health)

–           Observe how growth status is written: pg.2908 – “Her growth parameters at that time (5 years) were as follows: weight 12.3kg (1st centile), stature 91cm (-3.5 SD) and OFC 48.5cm (5th centile).

 

–          Refer to discussion section (1st paragraph) for functions of NBAS gene

–          [Longman et al. 2013] Knockdown NBAS in HeLa cells à upregulation of CCL20 and IL6R à which are chemokine and cytokine respectively [Zohlnhofer, 1992] facilitate liver inflammation and cytolysis

–          [Longman et al. 2013] noted NBAS deficiency w/ reduced degradation of IL6R à hence, hypersensitivity of liver cells to inflammatory cytokines (hence the rationale use of NSAIDs at onset of pyrexia to reduce liver inflammation in pts w. NBAS deficiency)

–          [Longman et al. 2013] NBAS knockout model showed upregulation of MGP, which is a negative regulator of bone formation – [Munroe, 1999] deficiency results in abnormal calcification of cardiac valves, ear pinnae and bronchial arches – this explains the phenotype of skeletal dysplasia in these patients (suggestive of disturbance in bone mineralization) evident by: delayed maturation of epiphyses, thin bones, underossified vertebrae

 

Why is our study important? (conclusion)

–          Underossification of cervical spine poses a danger to neurological complications, which should be assessed early in pts w/ NBAS deficiency

–          Our study highlights the clinical manifestations of NBAS deficiency, which aims to raise the awareness on the SOPH syndrome. We have also expanded the syndrome, highlighting clinical issues to be recognized early (cervical instability and immunodeficiency). Our observations also suggest possible molecular and pathogenic mechanisms to be researched and treat this disorder.

[5]

2015, Tobias B. Haack, Biallelic Mutations in NBAS cause recurrent acute liver failure with onset in infancy

Case series involving 11 pediatric patients with onset of recurrent ALF starting in infancy

 

NBAS structure and conservation of identified mutations mapped in figure 2

–          Proposed that acute liver disease was triggered by fever – genetic changes in NBAS may result in thermal susceptibility of syntaxin complex 18

–          Interestingly, the most common disease-causing mutation in CF (delta-F508-CFTR) also results in a temperature sensitive folding defect [Ward, 1995]

 

–          NBAS deficiency also results in the concomitant reduction of p31, hence both proteins are subunits of the same SNARE complex.

 

 

 

References:

 

1. Mégarbané A, Samaras L, Chédid R, Chouery E, Chrétien D, Caillaud C, et al. Developmental delay, dysmorphic features, neonatal spontaneous fractures, wrinkled skin, and hepatic failure: a new metabolic syndrome? Am J Med Genet A. 2008;146A(24):3198–201.
   
2. Maksimova N, Hara K, Nikolaeva I, Chun-Feng T, Usui T, Takagi M, et al. Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huët anomaly. J Med Genet. 2010;47(8):538–48.
   
3. Capo-Chichi J-M, Mehawej C, Delague V, Caillaud C, Khneisser I, Hamdan FF, et al. Neuroblastoma Amplified Sequence (NBAS) mutation in recurrent acute liver failure: Confirmatory report in a sibship with very early onset, osteoporosis and developmental delay. Eur J Med Genet. 2015;58(12):637–41.
   
4. Segarra NG, Ballhausen D, Crawford H, Perreau M, Campos-Xavier B, van Spaendonck-Zwarts K, et al. NBAS mutations cause a multisystem disorder involving bone, connective tissue, liver, immune system, and retina. Am J Med Genet A. 2015;167A(12):2902–12.
   
5. Haack TB, Staufner C, Köpke MG, Straub BK, Kölker S, Thiel C, et al. Biallelic mutations in NBAS cause recurrent acute liver failure with onset in infancy. Am J Hum Genet. 2015;97(1):163–9.
   
6. Park JW, Lee SJ. Foveal hypoplasia in short stature with optic atrophy and Pelger-Huët anomaly syndrome with neuroblastoma-amplified sequence (NBAS) gene mutation. J AAPOS [Internet]. 2017; Available from: http://dx.doi.org/10.1016/j.jaapos.2016.09.030
   
7. Kortüm F, Marquardt I, Alawi M, Korenke GC, Spranger S, Meinecke P, et al. Acute liver failure meets SOPH syndrome: A case report on an intermediate phenotype. Pediatrics. 2017;139(1):e20160550.
   
8. He TY, Zhang N, Xia Y, Luo Y, Li CR, Yang J. Short stature, optic nerve atrophy and Pelger-Huët anomaly syndrome with antibody immunodeficiency and aplastic anemia: a case report and literature review. Zhonghua Er Ke Za Zhi. 2017;55(12):942–6.
   
9. Li X, Cheng Q, Li N, Chang G, Ding Y, Li J, et al. SOPH syndrome with growth hormone deficiency, normal bone age, and novel compound heterozygous mutations in NBAS. Fetal Pediatr Pathol. 2018;37(6):404–10.
   
10. Fischer-Zirnsak B, Koenig R, Alisch F, Güneş N, Hausser I, Saha N, et al. SOPH syndrome in three affected individuals showing similarities with progeroid cutis laxa conditions in early infancy. J Hum Genet. 2019;64(7):609–16.
   
11. Ono S, Matsuda J, Watanabe E, Akaike H, Teranishi H, Miyata I, et al. Novel neuroblastoma amplified sequence (NBAS) mutations in a Japanese boy with fever-triggered recurrent acute liver failure. Hum Genome Var. 2019;6(1):2.
   
12. Ricci S, Lodi L, Serranti D, Moroni M, Belli G, Mancano G, et al. Immunological features of neuroblastoma amplified sequence deficiency: Report of the first case identified through newborn screening for primary immunodeficiency and review of the literature. Front Immunol. 2019;10:1955.
   
13. Khoreva A, Pomerantseva E, Belova N, Povolotskaya I, Konovalov F, Kaimonov V, et al. Complex multisystem phenotype with immunodeficiency associated with NBAS mutations: Reports of three patients and review of the literature. Front Pediatr. 2020;8:577.
   
14. Staufner C, Haack TB, Köpke MG, Straub BK, Kölker S, Thiel C, et al. Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts. J Inherit Metab Dis. 2016;39(1):3–16.
   
15. Nucci F, Lembo A, Farronato M, Farronato G, Nucci P, Serafino M. Oculofacial alterations in NBAS-SOPH like mutations: Case report. Eur J Ophthalmol. 2020;30(2):NP12–5.
   
16. Lacassie Y, Johnson B, Lay-Son G, Quintana R, King A, Cortes F, et al. Severe SOPH syndrome due to a novel NBAS mutation in a 27-year-old woman-Review of this pleiotropic, autosomal recessive disorder: Mystery solved after two decades. Am J Med Genet A. 2020;182(7):1767–75.
   

2) Explain the figure that I have created better

 

Some notes regarding our patient’s mutation:

  • Novel compound heterozygous mutations in the NBAS gene
  • Paternal mutation: c.5139-5T>G à An intron variant, identified as a splice-site mutation, which is located 5 nucleotides away from exon 43, where it is believed to interact with the ZW10 and RINT1 at the C-terminal. According to ClinVar (refer to master student’s ppt), despite the prediction that this variant disrupts the natural splice acceptor site of intron 42, another model predicts otherwise.
  • Maternal mutation: c.2203-2A>G à Identified as a splice-site mutation, present in introns, specifically 2 nucleotides away from exon 21, in which the mRNA region translates to proteins that play a role in the secretory pathway Sec39 domain as well as the interaction with p31 protein.
  • Both of the above alleles were not previously reported as a pathogenic nor a benign variant.

 

 

Figure: Gene and protein structures of NBAS and their mutations.

 

 

3) Read through the notes I have made

Notes: Comparison of NBAS mutations in SOPH pediatric patients from literatures & present study

Patient NBAS mutation Notable clinical features Notable investigations Management Outcome / Prognosis
This study 2020 Heterozygous

P: c.5139-5T>G

M: c.2203-2A>G

Facial dysmorphism; short stature; senile skin; hepatosplenomegaly; developmental delay Elevated LFTs with episodes of pyrexia and recurrent infections; Pancytopenia; Pelger-Huet anomaly; Renal function abnormalities; bone marrow aspiration shows myeloid hyperplasia; Antipyretic therapy; IVIG & IM Human thrombopoietic for thrombocytopenia; steroids given over the past year Undetermined
[13] Heterozygous

P: ex. 35-47 del.

M: c.5741G>A

Facial dysmorphism; short stature; senile skin; developmental delay; skeletal dysplasia; bone fractures; muscular hypotonia Elevated LFTs with episodes of pyrexia and recurrent infections; Hypogammaglobulinemia; low T-cells; low B-cells; Osteoporosis; Optic nerve atrophy; Pelger-Huet anomaly Regular IVIG Immunoglobulin replacement therapy; Bisphosphonates given to manage osteoporosis (1mg/kg every 4mos.), physical therapy & orthopedic recommendations Undetermined
Heterozygous

P: ex. 35-47 del.

M: c.5741G>A

Elevated LFTs with episodes of pyrexia and recurrent infections; Hypogammaglobulinemia; low T-cells; low B-cells; osteoporosis; Optic nerve atrophy; Pelger-Huet anomaly Undetermined
Heterozygous

P: c.1628_1629insA

M: c.5741G>A

Elevated LFTs with episodes of pyrexia and recurrent infections; RALF; Hypogammaglobulinemia; low T-cells; low B-cells; thrombocytopenia; osteoporosis; Optic nerve atrophy; Pelger-Huet anomaly Steroids given to manage immune thrombocytopenia; gastrostomy tube due to encephalopathy / development impairment; IVIG infusion dose 0.4g/kg/mo. & prophylactic co-trimoxazole Undetermined
[12] Homozygous

c.1948C>T

Facial dysmorphism; short stature; senile skin; small hands and feet (specifically brachydactyly); hepatosplenomegaly Elevated LFTs with episodes of pyrexia;

Absent KREC & normal TREC (crucial in formation of T- and B-cell receptors) – absent CD19+ cells, low CD8+ lymphocytes & NK cells; Hypogammaglobulinemia; Lymphocytopenia w/ hypereosinophilia & thrombocytopenia; Absent plasma cells & reduced T-cells in intestinal mucosa (hence immunodeficiency)

Regular IVIG Immunoglobulin replacement therapy & antimicrobial prophylaxis; corticosteroid therapy (observed improvements in GI, cutaneous manifestations of eczema & reduction of hypereosinophilia) Undetermined
[11] Heterozygous

P: c.1018G>C

M: c.2674G>T

Short stature; hepatomegaly; developmental delay Elevated LFTs with episodes of pyrexia and infections (2 ALF episodes); Elevated WBC w/ left shift; Severe coagulopathy (elevated PT, INR, APTT); Delayed bone maturation; Renal dysfunction (elevated Cre & BUN); Cytokine storm (elevated IL-6 & neopterin); bone marrow aspiration shows hypercellularity w/ hemophagocytosis; Pelger-Huet anomaly Early antipyretic therapy with acetaminophen & glucose infusion

 

Intensive treatment during liver crises: Plasmapheresis, hemodialysis, IV antibiotics, IVIG, glucose infusion

Undetermined
[10] Heterozygous

P: c.405G>A

M: c.5741G>A

Facial dysmorphism; short stature; senile skin; developmental delay; skeletal anomalies (ie, Wormian bones); Hepatomegaly Elevated LFTs with episodes of pyrexia and recurrent infections; ALF; Pelger-Huet anomaly Undetermined Deceased at 2yo 7mos from ALF;
Heterozygous

P: c.3158A>G

M: c.2950delA

Facial dysmorphism; short stature; senile skin; developmental delay; skeletal anomalies; Hepatomegaly Elevated LFTs with episodes of pyrexia and recurrent infections; ALF; Hypogammaglobulinemia Deceased at 26mos from ALF w/ signs of hepatic encephalopathy
Heterozygous

P: c.6564dupT

M: c.5741G>A

Facial dysmorphism; short stature; senile skin; developmental delay; skeletal anomalies Elevated LFTs with episodes of pyrexia and recurrent infections; Hypogammaglobulinemia; Optic nerve atrophy; Pelger-Huet anomaly Regular IVIG Immunoglobulin replacement therapy Undetermined; Last reported at 19yo
[9] Heterozygous

P: c.500_501delTT

M: c.5752A>C

Facial dysmorphism; short stature; small hands and feet (micromelia and brachydactyly) Elevated LFTs with episodes of pyrexia and recurrent infections; Low GH; slightly small pituitary gland; Hypogammaglobulinemia; reduced NK cells; mild abdominal aortic stenosis; optic atrophy; Pelger-Huet anomaly Standard management for acute respiratory infection Undetermined
[8] Heterozygous

M: c.5741G>A

P: c.6496-6497insA

Facial dysmorphism; short stature; senile skin; developmental delay; skeletal anomalies; hepatosplenomegaly Elevated LFTs with episodes of pyrexia and recurrent infections; Hypogammaglobulinemia; Elevated CD19 B cells; Bone marrow smear showed hypoplasia in erythroid cells; osteoporosis; optic atrophy; Pelger-Huet anomaly Antipyretic treatment to minimize liver damage; prophylactic antibiotic; Regular IVIG Immunoglobulin replacement therapy; extensive follow up in specialized departments; bisphosphonates to manage osteoporosis Undetermined
[7] Heterozygous

P: c.5714G>A

M: c.2827G>T

Facial dysmorphism; short stature; senile skin; small hands and feet (micromelia and brachydactyly); bone dystrophy; muscular hypotonia Elevated LFTs with episodes of pyrexia; Hypogammaglobulinemia; Reduced B lymphocytes; Delayed bone maturation; optic atrophy; Pelger-Huet anomaly Regular IVIG Immunoglobulin replacement therapy managed to stop recurrent infections (candida tonsilitis & HSV) Undetermined
[6] (undefined zygosity)

c.5741G>A

Facial dysmorphism; short stature; senile skin; bone dystrophy; hypotonia Elevated LFTs with episodes of pyrexia; optic atrophy; complete achromatopsia Undefined Undetermined
[4] Heterozygous: c.284C>T & c.850A>T Facial dysmorphism; short stature; senile skin; bone dysplasia; hepatomegaly Elevated LFT with episodes of pyrexia and recurrent infections; RALF early infancy; hypogammaglobulinemia; reduced NK cells; osteoporosis; small C1-C2 vertebrae causing cervical instability and myelopathy; optic atrophy; Pelger-Huet anomaly

 

Supportive management (Glucose infusion for hypoglycemia during pyrexia and liver crises); Mefenamic acid as antipyretic; weekly IVIG Immunoglobulin replacement therapy starting 11.5yo; Stabilization surgery to relieve compression of cervical spinal cord Undetermined
Heterozygous: c.409C>T & c.1186T>A Facial dysmorphism; short stature; senile skin; bone dysplasia; hepatomegaly; fractures Elevated LFT with episodes of pyrexia and recurrent infections; RALF early infancy; coagulopathy; hypogammaglobulinemia; leukopenia; osteoporosis; small C1-C2 vertebrae causing cervical instability and myelopathy; Pelger-Huet anomaly; Stabilization surgery to relieve compression of cervical spinal cord Undetermined
[2] Homozygous c.5741G>A Facial dysmorphism; short stature; senile skin; small hands and feet (micromelia and brachydactyly) Pelger-Huet anomaly of granulocytes; optic nerve atrophy; achromatopsia Undefined Undetermined

where: P = Paternal; M = Maternal

 

 

4) Use the information from my notes in step 3 and other relevant literatures to complete the following table.

 

This table serves to compare our study with other existing literatures. Please include details from 12 existing literatures. First row should be information about my study, which is the case report.

Table

  Study NBAS mutation Exons affected Notable clinical features Notable Investigations Management / Treatment Outcome / Prognosis
1. Our study            
2.              
3.              
4.              
5.              
6.              
7.              
8.              
9.              
10.              
11.              
12.              
13.              

 

 

 

 

 

 

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