A Tangled Web: Dual Diagnosis of Hereditary Hemorrhagic
Telangiectasia and Familial Cerebral Cavernous Malformation
Management of complex vascular anomalies is rapidly evolving towards
addition of targeted therapies as we increase our understanding of the
various mutations identified in affected tissues. Few vascular anomalies
also have pathognomonic germline mutations. We describe a child with
dual diagnosis of hereditary hemorrhagic telangiectasia (HHT) and
familial cerebral cavernous malformation 1 (CCM1). Family history (FH)
revealed 4 affected generations. Importance of a thorough FH and genetic
counselors (GCs) key role in a comprehensive vascular anomalies program
is highlighted.
A 5-year-old boy developed right hemiparesis, facial droop, focal
seizures with generalization, and slurred speech. Brain Magnetic
Resonance Imaging (MRI) demonstrated a 2.5 cm left parietal
intraparenchymal hematoma with hemosiderin staining and surrounding
vasogenic edema. Numerous other foci of hemosiderin staining were
present, suggesting multiple cavernous malformations (Fig. 1A). He
received levetiracetam and steroids with resolution of neurological
deficits. FH (Fig. 2) at initial evaluation revealed an asymptomatic
35-year-old mother (III-6), maternal grandfather (II-7) with a “blip”
on brain MRI and history of nose bleeds, and maternal uncles with
epistaxis (III-7), frequent headaches (III-8), and “lesions” on spine
MRI (III-9). Patient’s 34-year-old father (III-5) was well with normal
annual chest X Ray screening required for his profession. Paternal
grandmother (II-5) stroked at age 5 years, had a brainstem vascular
lesion resected in young adulthood, and her brother (II-1) had brain
surgery at age 13 years. This great-uncle also has two children who have
cerebral vascular lesions on MRI (III-2, III-3). Paternal uncle (III-4)
had 8-10 brain “vascular lesions” being monitored. Paternal
grandfather (II-4) died from skin cancer at 38 years. Paternal
great-grandfather (I-1) had a seizure disorder at least throughout his
adulthood. No one had undergone genetic testing previously. Patient’s 11
and 9-year-old sisters were well. CCM and HHT genetic testing panels on
the proband revealed a heterozygous pathogenic variant
[c.1201_1204del (p. Gln40TThrfs*10)] in the KRIT1 gene and a
heterozygous likely pathogenic variant [c.598C>T (p.
Arg200Trp)] in the ACVRL1 gene, indicating dual diagnosis of CCM1 and
HHT. Subsequent family testing showed his mother, two maternal uncles,
and maternal grandfather have the ACVRL1 variant, and father, paternal
uncle and paternal grandmother have the KRIT1 variant. The
eleven-year-old sister has negative genetic testing, but the 9-year-old
possesses both variants (Fig. 2). Patient’s serial brain imaging showed
resolution of the large left frontoparietal subcortical bleed over time
and re-demonstrated multiple “cavernomas”. Spine MRI and pulmonary
arteriovenous malformation (AVM) screening by transthoracic contrast
echocardiography (TTCE) were negative. He does not have epistaxis or
oral-cutaneous telangiectasias. No neurosurgical or neuro-interventional
procedure are planned currently. His affected sister has multiple small
cerebral “cavernomas” with a large lesion in the right cerebellum
(Fig. 1B).
CCMs occur in the brain and spinal cord and consist of clustered,
enlarged capillary channels. They can occur sporadically in isolation,
or as part of familial CCM, an autosomal dominant disorder caused by
pathogenic variants in one of 3 known genes: KRIT1, CCM2, PDCD10.
Familial CCM is not a fully penetrant genetic condition and only 50% of
individuals will be symptomatic of seizures, cerebral hemorrhage,
headaches, or retinal “cavernomas”. Of the asymptomatic patients,
about 50% will have an identifiable CCM on imaging. The Angioma
Alliance has published consensus guidelines regarding diagnostic and
management strategies1. HHT is also an autosomal
dominant vascular disorder, causing AVMs in the brain, lungs, and liver,
as well as skin and mucosal telangiectasias. Unlike familial CCM, HHT is
nearly fully penetrant. It is caused most often by an alteration in one
of three genes: ACVRL1, ENG, or SMAD4. Diagnosis and management
guidelines are well established2. CCMs are classified
as venous malformations and HHT as an arteriovenous malformation
disorder, per the International Society for the Study of Vascular
Anomalies (ISSVA) classifiction3.
The estimated prevalence of HHT and familial CCM is 1/5000 to
1/10,0001,2 and chance of inheriting both is rare at
1/100,000 to 1/400,000. Our two pediatric patients are unique in that
they carry genes for both conditions, a first report of its kind.
Involvement of genetic counselors in our vascular anomalies program
allowed for establishment of a 4-generation pedigree, genetic
counseling, and testing for all family members as desired. Earlier
genetic diagnosis in the extended family could potentially have led to
timely diagnosis and preemptive screening with intervention for our
patient and other family members. The adult family members now diagnosed
with HHT or CCM1 have established with adult hematologists at our
Hemophilia Treatment Center (HTC). The HTC model of care with all its
resources is very applicable to comprehensive care of patients with HHT
and other vascular anomalies. Additionally, it provides for seamless
transition from pediatric to adult care and enables comprehensive care
for the whole family, as in our patient’s case. Large, deep posterior
fossa vascular lesions (Fig 1B) at risk for bleeding can be challenging
to manage by surgical or interventional approaches. In this context, we
note a recent publication demonstrating augmented mTOR signaling in CCM
endothelial cells and use of mTOR inhibitor Rapamycin in mouse models,
showing effective blocking of CCM formation4, with
hope for translation to targeted therapies in such patients.