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|Year : 2016
: 9 | Issue : 2 | Page
|Clinical and genetic challenges in a family with history of childhood polyp, aortopathy, and clinical diagnosis of hereditary hemorrhagic teleangiectasia (HHT)
Tanya Kadiyska1, Alexander Nossikoff2, Pencho Kratunkov3, Mary Hachmerian4, Ludmila Angelova4
1 Department of Medical Chemistry and Biochemistry, Genetic Medico-Diagnostic Laboratory Genica, Sofia Medical University, Sofia, Bulgaria
2 Department of Cardiology, University Hospital Lozenets, Sofia, Bulgaria
3 St. Ekaterina University Hospital, Sofia, Bulgaria
4 University Hospital “St. Marina”, Varna, Bulgaria
Click here for correspondence address and
|Date of Web Publication||29-Apr-2016|
| Abstract|| |
Hereditary hemorrhagic teleangiectasia (HHT) is a genetic disorder, characterized by abnormal vessel formation and arteriovenous malformations (AVMs). The so-called “Curaçao criteria” are most commonly employed for the purposes of clinical diagnosis. However, children may not exhibit the full magnitude of symptoms and the Curaçao criteria appear to be less sensitive in this setting. We describe a family, in which two members were clinically diagnosed with HHT and referred for genetic testing. As there were phenotypic features suggesting the high likelihood of combined syndrome of juvenile polyposis with hereditary hemorrhagic teleangiectasia (JPHT), we proceeded with genetic testing of SMAD4 gene as initial step, which revealed a novel frameshift mutation. This case shows the variety of challenges that clinicians and genetic laboratories may face in complex cases such as combined JPHT syndrome. Knowledge of the syndrome features is of paramount importance as they could frequently point at the most appropriate gene to be tested.
Keywords: Hereditary hemorrhagic teleangiectasia (HHT), juvenile polyposis, juvenile polyposis hereditary hemorrhagic teleangiectasia (JPHT), SMAD4
|How to cite this article:|
Kadiyska T, Nossikoff A, Kratunkov P, Hachmerian M, Angelova L. Clinical and genetic challenges in a family with history of childhood polyp, aortopathy, and clinical diagnosis of hereditary hemorrhagic teleangiectasia (HHT). Ann Pediatr Card 2016;9:176-8
|How to cite this URL:|
Kadiyska T, Nossikoff A, Kratunkov P, Hachmerian M, Angelova L. Clinical and genetic challenges in a family with history of childhood polyp, aortopathy, and clinical diagnosis of hereditary hemorrhagic teleangiectasia (HHT). Ann Pediatr Card [serial online] 2016 [cited 2020 Mar 31];9:176-8. Available from: http://www.annalspc.com/text.asp?2016/9/2/176/180674
| Introduction|| |
Hereditary hemorrhagic teleangiectasia (HHT; OMIM:187300), also known as Osler-Weber-Rendu, is a genetic disorder characterized by abnormal vessel formation and arteriovenous malformations (AVMs). The so-called “Curaçao criteria” are used for the purposes of clinical diagnosis and include epistaxis, teleangiectasias, visceral lesions, and family history (a first-degree relative with HHT). The presence of three criteria in a selected patient makes the diagnosis of HHT definite, and the presence of two criteria makes it possible or suspected. If less than two criteria are identified, the diagnosis is unlikely. A majority of the patients harbor mutations in either ENG or ACVRL genes. In 1-2% of the cases, mutations in SMAD4 gene have been described.
Juvenile polyposis syndrome (JPS; OMIM: #174900) is a distinct disorder characterized by multiple hamartomatous polyps, which might be caused by mutations in either BMPR1A gene or SMAD4 gene. Although HHT and JP are both uncommon; the combined syndrome of juvenile polyposis hereditary hemorrhagic teleangiectasia (JPHT; OMIM: #175050) has been reported and eventually characterized as related to SMAD4 mutations. The low prevalence of JPHT and the variability of clinical presentation make the diagnosis challenging and require a multidisciplinary approach.
There are some important clinical implications when JPHT overlap is suspected or SMAD4 has been identified in a particular patient:
- If genetic testing is considered in a patient with combined JPHT, it should initially target SMAD4 gene;
- Patients diagnosed with HHT and identified to carry SMAD4 mutations would benefit from endoscopy screening even if they do not have any history of polyposis;
- Patients diagnosed with JPS and then identified to carry SMAD4 mutations are likely to benefit from AVMs screening; and
- Patients carrying SMAD4 mutations may exhibit heart valve disease and aortic root dilation and therefore, may benefit from echocardiography screening.,
| Case Report|| |
We present a 7-year-old boy and his 32-year-old mother, both clinically diagnosed with HHT. The mother had suffered from recurrent spontaneous nosebleeds and rectal bleeds in her childhood. At the age of 11 years, she had a colonoscopy, revealing a solitary 2-mm polyp in the sigmoid colon, which was removed and described on histopathology as hyperplastic. Then, she was reviewed by the ear, nose, and throat (ENT) physician who described multiple teleangiectasias and mentioned HHT as a possible diagnosis. Since that age, she has not been suffering from any gastrointestinal symptom. At the age of 30 years, she suffered an ischemic stroke. Brain AVMs were not found on magnetic resonance imaging (MRI). The stroke was considered to be of embolic etiology. Transoesophageal echocardiography with agitated saline showed late left chamber opacification consistent with intrapulmonary shunt. Contrast-enhanced computed tomography (CT) scan revealed multiple lung AVMs.
Her only child was delivered via Cesarean section (C-section) 3 weeks prior to the expected day of delivery because of preeclampsia, weighing 2,000 g. The child was doing well until his sixth year, when he was admitted to the hospital due to breathlessness. Lung consolidation was suspected from the chest x-ray and significant desaturation was apparent from arterial blood gases. Finger clubbing, cyanosis, and microcytic anemia were documented. Inflammatory markers were negative. In the light of family history, the child had a contrast-enhanced CT scan of the thorax, which revealed one large fistula [Figure 1] and hundreds of small and peripherally located pulmonary AVMs [Figure 1]. The largest AVM and two smaller ones were successfully closed with Amplatzer vascular plugs but significant right-to-left shunt remained with 70% O2 saturation on pulse oximetry. The rest of the family members did not exhibit any HHT symptom, with the exception of the maternal father who has been suffering from recurrent epistaxis since childhood and was diagnosed with “dilated aorta and heart murmur.” At the time of referral, he was living abroad and not available for genetic testing. According to the Curaçao criteria, both the mother and the child had “definite” HHT with three of the four criteria present. The maternal father was considered to have “possible” HHT with two criteria present.
|Figure 1: Contrast-enhanced CT scan revealing one large pulmonary AVM (white arrows) and multiple small peripheral pulmonary AVMs (empty arrows)|
Click here to view
We discussed the possibilities and suggested SMAD4 genetic testing as the most appropriate to begin with. The mother signed informed consent. The study was conducted according to the World Medical Association Declaration of Helsinki.
SMAD4 genetic test revealed novel heterozygous frame-shift mutation (R531GfsX6) in exon 11, coding the C-terminus of the protein (MH2 domain), which is involved in the formation of mono- and heteromeric complexes between SMAD2 and SMAD4 proteins. This truncating mutation was leading to the synthesis of protein, 17 amino acids shorter than the wild type, which was likely to affect SMAD complex formation.
| Discussion|| |
We did not follow the classical recommendations for HHT genetic testing because we had several clues pointing at the high likelihood of SMAD4 mutation:
- The mother's colonic polyp, although solitary and not satisfying the criteria for JPS, the coincidence was suspicious,
- The lower gastrointestinal bleeds in HHT usually start at a much later age compared to JPHT syndrome,,
- Aortic dilatation has been described previously in SMAD4 mutation carriers,, and
- De novo cases are more common in SMAD4 mutation-positive patients compared to ENG and ALK1 mutations.,
Apart from identifying a novel SMAD4 mutation in the family, this case shows the variety of challenges faced in complex cases such as combined JPHT syndrome. The condition is rare, with low awareness and may have varying phenotypic expression even in a single family. Children may not exhibit the full magnitude of symptoms and the Curaçao criteria appear to be less sensitive in this setting. It may take years for a patient to be diagnosed with JPHT syndrome. It may be difficult to obtain a detailed medical history. Some relatives may not be available for testing. Syndrome features could point at the most appropriate gene to be tested. In our case, the SMAD4 mutation identification had several clinical implications, as we advised the mother to continue with the follow-up colonoscopies due to increased risk of colorectal cancer. We referred the child to a gastroenterologist who suggested initial screening colonoscopy to be performed at the age 15 years if asymptomatic as colorectal cancer is extremely uncommon in the pediatric age group. The maternal father was offered confirmatory genetic testing, which if positive would lead to targeted investigations such as colonoscopy and agitated saline echocardiogram.
The authors are grateful to the patients for participating in this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Department of Medical Chemistry and Biochemistry, Sofia Medical University, Sofia-1431, 2 Zdrave str., Sofia-1431
Source of Support: None, Conflict of Interest: None