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Novel ACLV1 Mutation Identified in Late Onset Hereditary Hemorrhagic Telangiectasia

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DOI: 10.4236/ijohns.2016.54027    1,498 Downloads   2,175 Views   Citations

ABSTRACT

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder with variable expressivity. We present a 62-year-old patient with a rare, late-onset disease course featuring a novel mutation in ACVRL1, a signal transducer in the TGFβ/BMP pathway.

Received 22 June 2016; accepted 15 July 2016; published 18 July 2016

1. Introduction

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder with variable expressivity frequently presenting with recurrent epistaxis at adolescence. Here, we present a patient (pt) with a rare, late- onset disease course featuring a novel mutation in ACVRL1, a signal transducer in the TGFβ/BMP pathway.

2. Case

62-year-old female who presented 08/26/15 with worsening episodic epistaxis, fatigue, dyspnea on exertion for 10 years. Physical exam revealed upper and lower distal extremity telangiectasias (Figures 1-3) along with numerous tongue lesions (Figure 4). Labs: HGB 9.4 g/dL (low), HCT 30.1% (low), MCV 78.7 fL (low), RDW 23%

Figure 1. Telangiectasia of right palm.

Figure 2. Telangiectasias left finger nails.

(high), Reticulocytes 112700 cells/uL (high), Ferritin 17 ng/mL (low). CMP, PT, PTT, & fibrinogen were normal. Esophagoduodenoscopy (EGD) revealed non-bleeding gastric antrum arteriovenous malformations (Figure 5). Colonoscopy was normal. Fiberoptic examination by otolaryngology revealed multiple telangiectasias in the nasal mucosa. CT chest abdomen and pelvis 10/1/14 lacked well-defined AV malformations. Targeted sequencing of the exons and exon-intron junctions of known HHT genes, ENG, ACVRL1, SMAD4, RASA1 and BMP9, returned a previously unreported missense mutation in ACVRL1, resulting in a c.998G > A nucleotide substitution and p. Ser333Asn amino acid alteration. The patient was a heterozygote for this alteration. Her final diagnosis is microcytic anemia due to chronic blood loss due to HHT related epistaxis. She was treated with oral iron and periodic ENT cauterizations with stabilization of symptoms and HGB (11.9 g/dL, 9/2/15).

3. Discussion

Hereditary Hemorrhagic Telangiectasia (HHT), or Osler-Weber-Rendu syndrome, was first described in the 19th

Figure 3. Telangiectasias of left great hallux.

Figure 4. Telangiectasias of the tongue.

century as a hereditary disorder with abnormal vascular structures that caused recurrent bleeding from mucosa throughout the body [1] . Rendu first differentiated this disease from hemophilia when he studied a 52-year-old man with a clinical and family history of anemia, recurrent epistaxis, and telangiectasias. Osler and Weber produced more case reports on similar patients later on that made hereditary hemorrhagic telangiectasia well known within the medical community [2] .

Figure 5. EGD showing gastric antrum AVM.

HHT affects various organs including the nose, skin, lung, brain, and gastrointestinal track. The most common and earliest clinical manifestation is epistaxis from telangiectasias in the nasal mucosa [3] . Over 90 percent of patients with HHT experience their first episode of epistaxis by the age of 21 [4] . Symptoms in the skin, lung, brain, and gastrointestinal track typically present later in the disease course. Common areas for telangiectasias to occur on the skin include the lips, tongue palate, fingers, face, or trunk [3] . Pulmonary arteriovenous malformations are the typical presentation of hereditary hemorrhagic telangiectasia in the respiratory tract. It is estimated that pulmonary arteriovenous malformations are seen in 5 to 15 percent of patients with hereditary hemorrhagic telangiectasia [5] . Neurological symptoms vary and include migraines, transient ischemic attacks, seizures, and hemorrhage [3] . Telangiectasias and hemorrhage are rare in the gastrointestinal track and typically are not symptomatic until the fifth or sixth decade if present. Liver involvement can also occur but is rarely seen [3] . Our patient presents with a late-onset variation of HHT. Epistaxis and other clinical manifestations did not appear until the sixth decade.

The incidence of HHT is approximated to be between 1:5000 and 1:8000. However, the disease is thought to be underreported due to the fact that most patients are unaware of their diagnosis [1] .

HHT is an autosomal dominant disorder displaying variable expressivity, locus heterogeneity, and allelic heterogeneity [6] . HHT is attributed to reduction or loss of function alleles in five genes, ENG, ACVRL1, MADH4, BMP9 and BMPR2, resulting in haploinsufficiency of the coded protein [1] [6] . These five genes are all involved in TGF-β signaling pathways responsible for the maintenance of cardiovascular homeostasis.

Other possible loci are currently under investigation [7] (Table 1).

Patients are separated into three major subtypes of HHT based on the affected gene, HHT1, HHT2, and juvenile polyposis-HHT overlap syndrome. HHT1 patients have a mutation in the ENG gene encoding the protein endoglin, a coreceptor for type I and II TGF-β pathways. HHT2 patients have a mutation in the ACLVR1 (activin receptor-like kinase 1) gene encoding ALK1, a type-1 receptor in the TGF-β superfamily. Mutations in these two genes account for ~99% of cases of HHT. The different HHT classification reflects differing natural histories, with HHT1 patients experiencing more severe GI bleeds and more frequent pulmonary arterial hypertension [8] . ~1% - 2% of HHT patients have a mutation in MADH4 that results in juvenile polyposis-HHT overlap syndrome [9] . MADH4 encodes Smad-4, a downstream transcription factor of ALK1. The remaining cases of HHT attributed to an identified gene account for <1% of total cases and are caused by mutations in GDF2/BMP9, a TFG-β ligand, and BMPR2, a type 2 TGF-β receptor [1] [6] [10] .

An unreported missense mutation in the exon 7 of ACVRL1 resulting in a p. Ser333Asn amino acid alteration is the suspected cause of this patient’s late-onset HHT (Table 2).

ALK1 acts in endothelial cells, where it functions as a regulator of the activation stage of angiogenesis, promoting endothelial cell proliferation and migration. TGF-β ligands, including BMP9, bind to a Type-2 TGF-β receptor, resulting in the phosphorylation of ALK1, or other Type-1 TGF-β receptor receptors. ALK1 subsequently phosphorylates Smad-1/5/8, causing dimerization with Smad-4 [11] . The Smad dimer then enters the nucleus where it acts as a transcription factor, regulating the transcription of angiogenesis genes such as VEGF. Reduced presence of endoglin, a coreceptor for ALK family of receptors, has been shown to decrease the activity of the ALK1 pathway, as well as the ALK5 pathway that counterbalances ALK1 activity by promoting cell

Table 1. Summary of genes causing HHT [6] [14] .

Table 2. Documented predicted pathogenic ACLVR-1 mutations according to the University of Utah HHT mutation database.

Quiescence [12] . In healthy individuals, increases in endoglin levels can be seen after episodes of vascular damage. Circulating endothelial cells of HHT patients display a decreased level of endoglin and dysfunctional ALK1 and ALK5 signaling pathways. Recent data suggests ALK1 may also play a role in regulating the resolution phase of angiogenesis, further expanding the mechanism behind HHT dysgenesis [13] .

4. Conclusion

Here we have a late-onset variation of HHT in the presence of a novel, suspected pathogenic mutation in ACVRL1. HHT patients typically present with recurrent nosebleeds by the age of 30 (90%), superficial telangiectasias by the age of 40 (67%) and GI bleeding starting in their 50s. This patient reported recurrent epistaxis onset in her late middle age and at the age of 62 did not complain of GI bleeds. Abdomen, pelvis and chest CT revealed an absence of visceral AVMs. A mutation occurring at the same nucleotide position, c.998, but resulting in a different amino acid change, has been found in multiple other HHT patients. The clinical presentation of these patients is unknown; however the presentation of our patient suggests that a c.998G > A missense mutation causes a late-onset HHT clinical presentation manageable with supportive care.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Patrick, C. , McIntyre, K. , Ramidial, J. , Joa, S. , Dinsukhlal Zaveri, V. and Hansra, D. (2016) Novel ACLV1 Mutation Identified in Late Onset Hereditary Hemorrhagic Telangiectasia. International Journal of Otolaryngology and Head & Neck Surgery, 5, 157-173. doi: 10.4236/ijohns.2016.54027.

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