Family Phenotypic Profile in Hereditary Hemorrhagic Telangiectasia: Genotype-Phenotype Correlation in the Pediatric Population

doi:10.21203/rs.3.rs-4685890/v1

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Family Phenotypic Profile in Hereditary Hemorrhagic Telangiectasia: Genotype-Phenotype Correlation in the Pediatric Population

https://doi.org/10.21203/rs.3.rs-4685890/v1

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Hereditary Hemorrhagic Telangiectasia (HHT) is a rare, hereditary, autosomal dominant vascular disease, characterized by arteriovenous malformations (AVM), mucocutaneous telangiectasias and epistaxis.

The management of pediatric patients is currently based on limited literature.

The aim of our study is to evaluate whether the severity of HHT in affected children could be compared to their parents ‘phenotype, sharing the same genetic variants.

We collected data about 11 pediatric patients and their parents with a confirmed diagnosis of HHT, from the medical records of Fondazione Policlinico Universitario A. Gemelli IRCCS (Rome, Italy).

Starting from the analysis of the genotype-phenotype correlations among pediatric patients and their affected parents, we found that in three families (33,3%) the HHT presentation was similar between affected adults and affected siblings. In six families (67,7%) HHT phenotype was different between parents and children, being frequently more severe in parents rather than in children. Our results revealed a series of evidence confirming that HHT has variable phenotypic expressiveness.

Hereditary Hemorrhagic Telangiectasia

pediatrics

genotype-phenotype correlation

anemia

ACVRL1

ENG

HHT

Hereditary Hemorrhagic Telangiectasia (HHT) or Rendu-Osler disease is a rare, hereditary, autosomal dominant vascular disease (overall prevalence between 1/5000 and 1/8000 individuals). It is characterized by abnormal angiogenesis leading to the development of arteriovenous malformations (AVM) and mucocutaneous telangiectasias, with epistaxis being the most frequent manifestation [1–5].

The management of pediatric patients, as outlined in the Second International Guidelines [6], is based on available literature [7–10] that presents the limits of a rare disease. According to expert panel, HHT pediatric patients should be tested for iron deficiency and anemia just in case of recurrent bleeding and/or symptoms of anemia, with hemoglobin targets individualized on patients (depending on symptoms, severity of HHT-related bleeding, previous iron supplementation, comorbidity). As regard to pulmonary AVMs, the expert panel recommends screening in children at the time of presentation and then every 5 years in asymptomatic patients; it may be performed with chest radiography and pulse oximetry or trans-thoracic contrast echocardiography, while lung CT remains a confirmatory test, if screening tests are positive. Large pulmonary AVMs (at least 3 mm in diameter) or AVMs causing hypoxemia are suitable for embolotherapy to avoid complications. Finally, brain VM should be screened at the time of presentation with MRI, representing the first-line screening to detect the presence of malformations and to determine the risk of hemorrhage. At the moment, there is no agreement if routinely screening for brain VMs asymptomatic children. Abdominal ultrasound for liver VMs screening is performed according to adult recommendations [6].

There is no data in current literature about a comparative analysis of phenotypic manifestations among patients belonging to the same family unit – i.e. sharing a common genotype.

Therefore, the aim of our study is to determine, by describing the genotype-phenotype correlation in children with HHT and in their parents, whether HHT phenotypes are comparable among parents and affected children.

We conducted a single-centre retrospective study on pediatric patients and their parents with a confirmed diagnosis of HHT. Data were collected between May 1, 2022, and May 31, 2023, from the medical records of Fondazione Policlinico Universitario A. Gemelli IRCCS (Rome, Italy).

Affected parents of pediatric patients were asked to respond to a standardized semi-structured questionnaire, facilitating further investigation into the phenotypic manifestations of the pathology.

Moreover, we conducted a standardized evaluation of all patients (including physical examination, medical history, laboratory and imaging tests performed) considering the following data:

Clinical phenotype, investigated through the evaluation of the presence or absence of epistaxis, telangiectasias, AVM (pulmonary, hepatic, cerebral, gastrointestinal), and major bleeding (one of the following criterion: past treatment for bleeding and/or iron deficiency anemia – iron infusion/ blood transfusion);
Hemoglobin, serum iron and ferritin values, analyzed for all pediatric and adult patients;
Diagnostic tests -if performed-, such as ENT (ear-nose-throat) target examination, ultrasonography of the abdomen, MRI of the abdomen, brain MRI, chest CT scan, echocardiography with bubble test;
Therapeutic interventions, such as iron infusions, laser ablation/cautery for epistaxis, embolizations, blood transfusions.

For “subjects with a defined diagnosis of HHT,” we mean those who had confirmation of the pathology by genetic testing [11].

Data were analyzed using GraphPad PRISM 9. Comparable variables were analyzed using Student’s t test/one way ANOVA. A 0,05 level of significance was considered for all statistical tests.

Editorial Policies and Ethical Considerations

The study protocol was approved by Ethical Committee of Università Cattolica del Sacro Cuore di Roma. All patients and/or their parents/legal guardians signed informed consent form.

Demographic and Clinical Characteristics

The pediatric population [Table 1] consists of eleven children aged between 0 and 20 years, including 6 boys and 5 girls, with an average age of 11.82 ± 5.51 years, as shown. Two couple of sibs are included (child 1A-1B and child 4A-4B). All patients (100%) have a positive family history of HHT. The clinical history of 10 patients (90.9%) – 5 males and 5 females – is characterized by the presence of epistaxis. In 4 patients (36.4%) – 2 males and 2 females – mucocutaneous telangiectasias were found, while AVM are present in 3 patients (27.3%) – 2 males and 1 female. In particular, pulmonary AVM were diagnosed in 3 patients (27.3%), hepatic AVM in 1 (9.1%), cerebral AVM in 2 (18.2%).

Table 1

Demographic and clinical characteristics of the population; statistically significant differences are marked with *
	Children	Adults
Mean age (years ± SD)	11,82 ± 5,51	47 ± 8,68
Sex (male/female ratio)	6/5	6/3
Epistaxis (N; %)	10/11; 90,9%	9/9; 100%
Mucocutaneous telangiectasias (N; %)	4/11; 36,4%	9/9; * 100%
Family history of HHT (N; %)	11/11; 100%	8/9; 88,9%
AVM (N; %)	3/11; 27,3%	5/9; 55,6%
Pulmonary AVM (N; %)	3/11; 27,3%	5/9; * 55,6%
Hepatic AVM (N; %)	1/11; 9,1%	2/9; * 22,2%
Cerebral AVM (N; %)	2/11; 18,2%	2/9; 22,2%

The adult population [Table 1] – i.e. affected parents who share the same genetic variant as pediatric patients – consists of 9 patients, including six males and three females, with an average age of 47 ± 8.68 years. Of these, 8 patients (88.9%) have a positive family history of HHT. In all patients (100%), epistaxis was found. 9 (100%) patients present mucocutaneous telangiectasias, while AVM are described in 5 patients (55.6%). In particular, pulmonary AVM were diagnosed in 5 patients (55.6%), hepatic AVM in 2 (22.2%), cerebral AVM in 2 (22.2%).

The diagnostic tests conducted in both populations are as follows:

ENT the physical examination (the exam of nose, lips, oral cavity for telangiectases), performed in 10 out of 11 (90.9%) children and 8 out of 9 (88.9%) adults;
Ultrasonography of the abdomen, conducted in 10 out of 11 (90.9%) children and in all 9 (100%) adults;
MRI of the abdomen, conducted in 1 out of 11 (9.1%) children and in 1 out of 9 (11.1%) adults;
Brain MRI, performed in 8 out of 11 (72.7%) children and 5 out of 9 (55.6%) adults;
Chest CT scan, performed in 3 out of 11 (27.3%) children and 5 out of 9 (55.6%) adults, when screening tests were positive [6];
Echocardiography with bubble test, performed in 4 out of 11 (36.4%) children and in 3 out of 9 (33.3%) adults.

Genetic Variants

All patients, children, and adults, have a genetic diagnosis. In 11 children, 3 (27.3%) have a ENG gene variant, and 8 (72.7%) have ACVRL1 variants. In 9 adults, 3 (33.3%) have an ENG variant, and 6 (66.7%) have ACVRL1 variants.

Laboratory Values

To assess the impact of bleeding on anemia and iron reserves, the following laboratory values were considered: hemoglobin, serum iron and ferritin.

Within the pediatric population, no patient (0%) reported hemoglobin values below the cutoff [12]. In the adult population, 2 patients (22.2%) reported hemoglobin values below the cutoff [13].

No pediatric (0%) patient reported lower serum iron values than the cutoff [12]. 2 adult patients (22%) reported lower serum iron values than the cutoff [13].

No pediatric patient (0%) reported ferritin values below the cutoff [12]. 3 (33.3%) adult patients reported ferritin values below the cutoff [13].

Therapeutic Interventions

Considering the therapeutic interventions (iron infusions, laser ablation/cautery for epistaxis, embolizations, blood transfusions) to which the pediatric population has been subjected, it appears that no child (0%) has ever needed transfusions for reasons related to HHT, while 2/11 children (18.2%) have had their AVM embolized.

Considering the therapeutic interventions to which the adult population has been subjected, it appears that 1/9 adult (11.1%) has resorted to transfusions and 4/9 (44.4%) to iron infusions due to HHT-related anemia. 3/9 adults (33.3%) have also had their AVM embolized.

Major Bleeding

A comparison between the number of children and adults who have experienced major bleeding in the oral and nasal cavity shows that no child (0%) has experienced such bleeding, and 4 adults (44.4%) have required Emergency Room access for this reason.

Genotype-Phenotype Correlation

Table 2 illustrates genotype-phenotype correlations among pediatric patients and their affected parents, considering the following clinical data for evaluating phenotypic expression:

Table 2

Genotype-phenotype correlation: child vs adult^†
Gene	Variant			AVMs (1/0)
ACVRL1	c.1435C > T	Family 1	Child 1A	0	0	0
			Child 1B	0	0	0
			Parent 1	0	0	0
	c.200G > A	Family 2	Child 2	0	0	0
	c.200G > A		Parent 2	0	1 (I)	1
	c.526-6C > G	Family 3	Child 3	0	0	0
	c.526-6C > G		Parent 3	1 (P-H-GI)	1 (I)	1
	c.230G > A	Family 4	Child 4A	1 (P-H-C)	0**	0
			Child 4B	1 (P)	0***	0
			Parent 4	0	0	0
	c.230G > A	Family 5	Child 5	0	0	0
	c.230G > A		Parent 5	1 (H)	0	0
	c.1120C > T	Family 6	Child 6	0	0	0
	c.1120C > T		Parent 6	0	0	0
ENG	c.893del	Family 7	Child 7	0	0	0
	c.893del		Parent 7	1 (P)	1 (T, I, E)	1
	c.298del	Family 8	Child 8	0	0	0
	c.298del		Parent 8	1 (P-H-C)	1 (E)	0
	c.1A > G	Family 9	Child 9	1 (P-C)	0	0
	c.1A > G		Parent 9	1 (P-C)	1 (E)	1
^†Legend:
• AVM: P = pulmonary; H = hepatic; C = cerebral; GI = gastrointestinal;
• Treatments: T = transfusions due to HHT-related anemia; I = iron infusions due to HHT-related anemia; E = embolization.
**: 1 iron infusion due to favism comorbidity
***: 1 blood trasfusion due to favism comorbidity

Presence of AVM (pulmonary, hepatic, cerebral, gastrointestinal);
Treatments necessitated by the severity of anemia and/or AVM (iron infusions, laser ablation/cautery for epistaxis, embolizations, blood transfusions);
Major bleeding (one of the following criterion: past treatment for bleeding and/or iron deficiency anemia – iron infusion/ blood transfusion).

It follows that:

In family 1, with c.1435C > T variant in ACVRL1, no AVM, major treatments, or bleeding were recorded, neither in the parent nor in the two children.
In family 2, with c.200G > A variant in ACVRL1, no AVM, major treatment or bleeding was recorded in the child, while iron infusions and major bleedings in the parent were recorded.
In family 3, with c.526-6C > G variant in ACVRL1, no AVM, major treatments or bleeding was recorded in the child, while pulmonary, hepatic, and gastrointestinal AVMs, iron infusions, and major bleedings in the parent were recorded.
In family 4, with c.230G > A variant in ACVRL1, no AVM, major treatment or bleeding was recorded in the parent, while pulmonary, hepatic, and cerebral AVMs were recorded in one child and pulmonary AVMs in the other.
In family 5, with c.230G > A variant in ACVRL1, no AVM, major treatment or bleeding was recorded in the child, while hepatic AVMs were recorded in the parent.
In family 6, with c.1120C > T variant in ACVRL1, no AVM, major treatment or bleeding was recorded, neither in the parent nor in the child.
In family 7, with c.893del variant in ENG, no AVM, major treatment or bleeding was recorded in the child, while pulmonary AVMs, blood transfusions, iron infusions, embolizations and major bleedings in the parent were recorded.
In family 8, with c.298del variant in ENG, no AVM, major treatment or bleeding was recorded in the child, while pulmonary, hepatic, and cerebral AVMs and embolizations in the parent were recorded.
In family 9, with c.1A > G variant in ENG, pulmonary and cerebral AVMs were recorded in the child and pulmonary and cerebral AVMs, embolizations, and major bleedings were recorded in the parent.

Also, Table 2 illustrates the distribution of pulmonary, hepatic and cerebral AVM in the pediatric and adult population in relation to the genotype (ACVRL1 or ENG variants).

Out of a total of 8 children and 6 adults with ACVRL1 variants, 2 pediatric patients (25%) and 1 adult patient (16.7%) have pulmonary AVMs.

Out of a total of 3 children and 3 adults with ENG variants, 1 pediatric patient (33.3%) and 3 adult patients (100%) have pulmonary AVMs.

In 1 pediatric patient (12.5%) and no adult patient (0%) with ACVRL1 variants, cerebral AVM were found. Among patients with ENG variants, however, 1 child (33.3%) and 2 adults (66.7%) have cerebral AVMs.

Comparison with Literature

The analysis of the phenotypes of the pediatric population examined revealed a series of evidence confirming the literature. 90.9% of patients have epistaxis, that is confirmed to be the first symptom to manifest itself during childhood, which, however, rarely requires cauterization or other significant interventions to control bleeding [9], as demonstrated by the absence of major bleedings (0%) in the target population.

36.4% of pediatric patients have mucocutaneous telangiectasias, which, when compared to the prevalence of those in the adult population (100%), has their later presentation confirmed [9]. The same applies to AVMs, present in 27.3% of pediatric patients and 55.6% of adult patients.

The correlation of the phenotype characterized by the presence of pulmonary and cerebral AVMs with genotypes characterized by ENG and ACVRL1 variants is reported in Table 2. The increased frequency of pulmonary and cerebral AVMs in patients - both pediatric and adult - with ENG variants has been confirmed, as reported in literature [8]. However, as evidenced by the presence of cerebral AVMs in 1 pediatric patient (12.5%) with a ACVRL1 variant, it must be reiterated that the genotype alone cannot and must not guide the screening practices, as different AVMs are potentially present in all genotypes [8].

Analysis of Laboratory Values

Hemoglobin, serum iron, and ferritin below the respective cutoffs – as referred for age specific pediatric cut-off [12] - were not recorded for any pediatric patient. Moreover, none of these patients needed iron infusions or blood transfusions. These data strengthen published recommendations about blood test timeline both in adults and children with HHT [14]. An apparently normal value of hemoglobin in patients with pulmonary phenotype, as known, may depend on compensatory polycythemia. These patients, therefore, should be focused during the pubertal development period, due to the increase of iron requirement or increased loss – in post-menarche females.

Genotype-Phenotype Correlation

From the comparison of the phenotypes of the children with those of the parents with the same genotype (Table 2), despite the intrinsic limits linked to punctual considerations relative to a dynamic pathology, we have seen that, out of a total of 9 families analyzed, a similar clinical phenotype was recorded in 3 families (33.3%).

In this regard, the case of family 4 deserves to be reported. The history of this family began in 2018 with the suspicion of HHT in the eldest son following the finding of hypoxemia (SpO2 85%) and multiple pulmonary AVMs, 2 of which were treated with embolization. Further diagnostic investigations were simultaneously carried out in the father and in the second child, and both were found to be affected by HHT with c.230G > A variant in ACVRL1 (shared by all three family members). It is interesting to note that, with the same clinical score (3) assigned through the Curaçao criteria, we were faced with extremely different clinical pictures. The firstborn (20 years) presented epistaxis and the so called “lung phenotype”. The second son (16 years old) also presented epistaxis, but more severe, and, in addition to pulmonary AVMs, a hepatic AVM and a cerebral AVM – i.e. a mixed phenotype. On the other hand, the father (58 years) presented only epistaxis - less severe than in the children - and meager telangiectasias. Therefore, the difference in the phenotypic expression of the disease is evident, as, while it has no impact, if not small, on the quality of life of the father, it has a great impact on that of both children. The story of this family can help reminding that intra-familial phenotypic variation is well-established; in fact, most disease-causing mutations in ACVRL1, ENG, and SMAD4 are null alleles that result in haploinsufficiency [15]. Clinicians dealing with families with HHT should keep this peculiarity in mind and eventually address it to the families.

It is important to note that, in Italy, there is a National Health Care System providing a free screening and follow up program for rare diseases, including HHT. This program includes periodic abdominal ultrasound, that can be performed before the symptoms and/or signs of complications might appear.

Our study has some limitations that need to be addressed. This is a single center study including few patients, with observational aims. It follows that, when possible, statistical analysis has been performed, but limited by the sample size.

The results obtained so far show that it is not possible to talk about the overlap of phenotypes between parents and children suffering from HHT, which is confirmed as a hereditary disease with variable expressiveness. We confirm that present guidelines are valuable and, since complications themselves may represent the onset manifestation in pediatric patients, an early diagnosis is indispensable for their prevention.

Author Contribution

GE, GV and DFC conceived the idea for this manuscript. DFC, GV, PGC and CA recruited patients and collected the data. DFC and GV wrote the manuscript, with additional critical feedback provided by GE. All authors reviewed and discussed the results and contributed to the final manuscript.

Authorship

Di Foggia C and Giorgio V should be considered joint first author

Acknowledgements

This work was supported by no funding sources.

Conflict of interests

All authors declare no conflicts of interest.

Data Sharing and Data Accessibility

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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No competing interests reported.

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You are reading this latest preprint version

Family Phenotypic Profile in Hereditary Hemorrhagic Telangiectasia: Genotype-Phenotype Correlation in the Pediatric Population

Status:

Version 1

Abstract

INTRODUCTION

METHODS

Editorial Policies and Ethical Considerations

Demographic and Clinical Characteristics

Genetic Variants

RESULTS

Laboratory Values

Therapeutic Interventions

Major Bleeding

Genotype-Phenotype Correlation

DISCUSSION

Comparison with Literature

Analysis of Laboratory Values

Genotype-Phenotype Correlation

CONCLUSIONS

Declarations

Author Contribution

References

Additional Declarations

Status:

Version 1