Elsevier

European Journal of Medical Genetics

Volume 54, Issue 1, January–February 2011, Pages 25-28
European Journal of Medical Genetics

Original article
Lung disease associated with periventricular nodular heterotopia and an FLNA mutation

https://doi.org/10.1016/j.ejmg.2010.09.010Get rights and content

Abstract

X-linked periventricular nodular heterotopia (PH) is a neuronal migration disorder caused by mutations in the gene encoding filamin A (FLNA). High phenotypic diversity, ranging from PH to otopalatodigital syndrome and frontometaphyseal dysplasia has been described in association with FLNA mutations. Extra-neurological features including cardiovascular abnormalities, coagulopathy, skeletal dysplasia and joint hypermobility have sometimes been described in patients with PH. Respiratory manifestations have not been associated with FLNA disorders with the exception of tracheal stenosis and pulmonary hypoplasia associated with frontometaphyseal dysplasia and Melnick–Needles syndrome. Here, we report on a male patient aged 6 years presenting with a mosaic nonsense mutation c.994delG within the FLNA gene, PH and severe congenital lung disease comprising bilateral atelectasis, lung cysts, tracheobronchomalacia, pulmonary arterial hypertension and long-term oxygen dependence; histology of resected lung showed panpulmonary emphysema with marked reduction of bronchial cartilage. Rare male patients with PH and FLNA mutations have already been reported, usually with early lethality. These observations suggest the possibility of a link between FLNA mutations and congenital lung disease. A prospective study of patients with PH and FLNA mutations would be helpful in order to test this hypothesis.

Introduction

Periventricular nodular heterotopia (PH) is a neuronal migration disorder characterized by the presence of uncalcified nodules of neurons ectopically situated along the surface of the lateral ventricles [5], [12], [13], [19]. Epilepsy of variable severity is the major clinical manifestation, predominantly starting in the second decade of life, and generally associated with normal to borderline intelligence [1], [2], [13]. The disorder is genetically heterogeneous. Mutations in the gene encoding filamin A (FLNA) have been demonstrated in patients with PH, especially females from pedigrees consistent with an X-linked dominant mode of inheritance [3], [5], [9], [13], [21]. The ADP-Ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2) gene on chromosome 20q13.13 has been implicated in rare autosomal recessive PH cases with microcephaly [22]. Other patients are reported as sporadic. From a study of 120 patients with either isolated or syndromic PH, Parrini et al. found a mutation in FLNA in 100% of familial cases with segregation of the trait consistent with an X-linked aetiology and 26% of sporadic patients with classical PH [16]. Mutations in FLNA have also been associated with a spectrum of skeletal dysplasias, the otopalatodigital spectrum disorders, which include Melnick–Needles syndrome and frontometaphyseal dysplasia [4], [5], [18], [21]. In addition to seizures, other neurological and extra-neurological features have been reported to be associated with PH and FLNA gene mutations, including cardiac anomalies (patent ductus arteriosus, aortic aneurysm, bicuspid aortic valve), an Ehlers–Danlos syndrome-like phenotype [13], [23], dyslexia [13], vasculopathy and/or coagulopathy with thrombocytopenia and, more rarely, stroke or vascular aneurysm [5], [13]. These features may be due to the abnormal interaction of filamin A with other proteins [5], [13], [17], [19]. Here, we report on a male with FLNA-related PH presenting with significant pulmonary disease, and suggest that these manifestations could be part of the clinical spectrum of FLNA mutations.

Section snippets

Patients, methods and results

The proband, a male, was 6 years old at the last examination. He was the third child of non-consanguineous Australian aboriginal parents. Birth was at term after a normal pregnancy, labour and delivery with Apgar scores of 9 at 1 min and 9 at 5 min and birth weight 3420 g (50th centile), birth length 50 cm (50th centile) and birth head circumference 37 cm (>90th centile). He presented at 3 months of age with a 6 week history of tachypnoea, weak cry, poor weight gain and hypotonia. Chest X-rays

Discussion

We report a male who from 3 months age had severe lung disease characterized by recurrent respiratory infections, bilateral lung atelectasis, lung cysts, tracheobronchomalacia, pulmonary arterial hypertension, asthma and long-term oxygen dependence; histology of resected lung showed panpulmonary emphysema with marked reduction of bronchial cartilage. Other clinical features were a patent ductus arteriosus requiring ligation and PH. FLNA sequencing showed a mosaic nonsense mutation c.994delG

Acknowledgements

This work was supported by GIS (projects no. 04/59 and 05/46) and from the Programme Hospitalier de Recherche Clinique national no. 04/07, the Institut des Maladies Rares, INSERM, the Ministère de l’Enseignement Supérieur et de la Recherche and the Ministère de la Santé. The experimental work was performed at the University of Otago, Dunedin, New Zealand. SR is supported by the Child Health Research Foundation of New Zealand.

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