Germline mosaicism in X-linked periventricular nodular heterotopia

Periventricular nodular heterotopia (PNH) is a disorder of cortical development [1]. PNH is a term used to describe the collections of neurons lining the lateral ventricles that have failed to migrate normally to form the cerebral cortex [1]. It is a clinically and genetically heterogeneous group of disorders [2]. Mutations in the filamin A gene (FLNA) result in an X-linked dominant form of this disorder [3]. Mutations in FLNA leading to protein truncation are the predominant cause of the PNH phenotype [2, 4]. Most affected females present with seizures and normal to mildly impaired cognitive function [2, 5]. FLNA-associated PNH may also be associated with other cerebral malformations as well as extra-cerebral features [6]. The condition typically results in prenatal lethality or a more severe phenotype in males although paternal transmission has been documented in the literature [2, 7‐9].

Mutations in FLNA are associated with a wide spectrum of disorders including the otopalatodigital syndrome (OPD) spectrum disorders [10]. The phenotypes of these disorders are clinically distinct from FLNA-associated PNH and result from mutations that conserve the reading frame [10]. FLNA post-zygotic mutations and germline mosaicism have been reported in the OPD spectrum disorders [10].

We present the first documented evidence for germline mosaicism in a family with two sisters with FLNA-associated PNH due to a loss of function mutation in FLNA and clinically unaffected parents.

The index patient, a 38 year old female, was born after an uneventful pregnancy and delivery. Shortly after delivery she was found to have an ectopic 3rd kidney and a patent ductus arteriosus which required surgical closure at 18 months of age. Her development was normal with no history of seizures, meningitis, encephalitis or major head trauma. She was noted to have thrombocytopenia at age 23 years after complaints of unexplained weight loss. Bone marrow aspiration did not reveal any abnormalities. She continues to have easy bruising and prolonged bleeding time. She had her first seizure at 24 years with no evidence of any precipitating factors. Her neurologic examination was normal. Brain magnetic resonance imaging (MRI) revealed bilateral multiple and diffuse PNH (Figure 1). She has episodic headache with photophobia and phonophobia. An echocardiography at age 32 years revealed a mildly dilated aortic root and ascending aorta with mild aortic regurgitation.The second patient, a younger sister of the index case, is now 36 years of age. Her medical history is relevant for migraine headaches with visual aura. Her neurologic examination was normal and her EEG did not show any interictal abnormalities. An MRI of the brain shows heterotopic gray matter of both hemispheres (Figure 2). Her echocardiogram was normal.

The parents are a healthy nonconsanguineous couple. The mother is now 56 years. She is of English, Irish, and Belgian ethnic background. Her past medical history is unremarkable. Her brain MRI does not show evidence of PNH. The father is now 58 years. He is of Ukrainian and Polish ethnic background. His past medical history is unremarkable. His brain MRI does not show evidence of PNH.

It is possible that either parent is also somatic mosaic for this FLNA mutation as Sanger sequencing may not detect low levels of mosaicism [11]. Furthermore, mutation detection in the parents was limited to peripheral lymphocytes. Somatic mosaicism has been reported in males and females with FLNA-PNH. All individuals in these studies had PNH identified on brain MRI although clinically they may have been asymptomatic [8, 9, 12]. Somatic and germline mosaicism was reported in a male with a deleterious splice site mutation in FLNA [9]. In contrast to our family however, this individual had PNH identified on brain MRI and had other clinical features consistent with the FLNA-PNH phenotype [9].

In view of this case report, germline mosaicism should be considered in counseling families where there is an isolated case of FLNA-associated PNH and neither parent has any clinical, radiographic or molecular evidence of FLNA-associated PNH. Despite the apparent low risk of recurrence in such cases, prenatal testing should be considered for subsequent pregnancies.

Written informed consent was obtained from the patient for publication of the case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.