FLNA mutations in surviving males presenting with connective tissue findings: two new case reports and review of the literature

Cannaerts, Elyssa; Shukla, Anju; Hasanhodžić, Mensuda; Alaerts, Maaike; Schepers, Dorien; Laer, Lut Van; Girisha, Katta M.; Hojsak, Iva; Loeys, Bart; Verstraeten, Aline

doi:10.1186/s12881-018-0655-0

Cited by 23 publications

(19 citation statements)

References 48 publications

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“…Given the X-linkage, phenotypic severity is highly variable in females depending on the exact FLNA variant and the impact of skewed X inactivation. In contrast, most male FLNA mutation carriers, especially those with OPD2 and MNS, die in utero or early antenatally [41,42]. We now add a new cohort of males surviving even into adulthood with FLNA missense mutations, expanding the spectrum of FLNA phenotypes to include males with syndromic PBS with OPDSD or those only with isolated PBS.…”

Section: Introductionmentioning

confidence: 99%

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

et al. 2020

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Background: Prune belly syndrome (PBS) is a rare, multi-system congenital myopathy primarily affecting males that is poorly described genetically. Phenotypically, its morbidity spans from mild to lethal, however, all isolated PBS cases manifest three cardinal pathological features: 1) wrinkled flaccid ventral abdominal wall with skeletal muscle deficiency, 2) urinary tract dilation with poorly contractile smooth muscle, and 3) intra-abdominal undescended testes. Despite evidence for a genetic basis, previously reported PBS autosomal candidate genes only account for one consanguineous family and single cases. Methods: We performed whole exome sequencing (WES) of two maternal adult half-brothers with syndromic PBS (PBS + Otopalatodigital spectrum disorder [OPDSD]) and two unrelated sporadic individuals with isolated PBS and further functionally validated the identified mutations. Results: We identified three unreported hemizygous missense point mutations in the X-chromosome gene Filamin ) in two related cases and two unrelated sporadic individuals. Two of the three PBS mutations map to the highly regulatory, stretch-sensing Ig19-21 region of FLNA and enhance binding to intracellular tails of the transmembrane receptor β-integrin 1 (ITGβ1). Conclusions: FLNA is a regulatory actin-crosslinking protein that functions in smooth muscle cells as a mechanosensing molecular scaffold, transmitting force signals from the actin-myosin motor units and cytoskeleton via binding partners to the extracellular matrix. This is the first evidence for an X-linked cause of PBS in multiple unrelated individuals and expands the phenotypic spectrum associated with FLNA in males surviving even into adulthood.

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Section: Introductionmentioning

confidence: 99%

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

et al. 2020

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“…The possibility of live birth of a severely affected male child is low but has been reported. 13 Dr. Virginia M. Pierce (Pathology): Dr. Kinane, would you tell us what happened with this patient?…”

Section: Gene Tic Scr Eeningmentioning

confidence: 99%

“…The most common manifestations include a neurologic disorder called periventricular heterotopia (a neuronal migration defect), seizure, thrombocytopenia, gastrointestinal dysmotility, poor growth, skeletal dysplasia, and hypermobility. 13 Different combinations of these findings may result in different types of FLNA-related disease; these differences are probably based on genetic variation. FLNArelated disease is frequently fatal in male patients.…”

Section: Connective-tissue Disordersmentioning

confidence: 99%

Case 28-2019: A 22-Year-Old Woman with Dyspnea and Chest Pain

et al. 2019

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A 22-year-old woman was seen in the pediatric pulmonary clinic of this hospital because of chest pain, cough, and dyspnea on exertion. The patient had been well until she was 2 months of age, when an episode of bronchiolitis occurred. After this episode, repeated respiratory illnesses characterized by wheezing and cyanosis developed, and she was hospitalized frequently. The patient was subsequently evaluated by a pediatric pulmonologist at this hospital. Examination revealed decreased breath sounds at the apex of the right lung, and chest radiography revealed findings suggestive of congenital lobar emphysema of the right upper lobe. A blood test for alpha 1-antitrypsin deficiency was negative. Transthoracic echocardiography revealed right ventricular dilatation and hypertrophy, mild pulmonary arterial hypertension, and a small patent ductus arteriosus. When the patient was 24 months of age, a right upper lobectomy, coil embolization for the patent ductus arteriosus, and a biopsy of the right middle lobe were performed. Dr. Mari Mino-Kenudson: Histopathological examination of lung specimens revealed lobar emphysema of the right upper and middle lobes that was characterized by the presence of fewer alveoli than the number typically seen in normal lung tissue and hyperinflation of the existing alveoli (Fig. 1A). The number of bronchioles in the peripheral emphysematous areas was disproportionately low relative to the number of pulmonary vessels, and the central bronchi had mucus plugs that may have obliterated the bronchial lumens (Fig. 1B). In the hilum, the central bronchi had mucus plugs that resulted in partial obstruction of the bronchial lumens, but the amount and contour of the bronchial cartilage were normal (Fig. 1C). No diagnostic findings were consistent with pulmonary hypertension. There are two possible causes of lobar emphysema in this case: obstruction (either

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“…The reason for such high mortality remains unclear, but early deaths in males could arise from hemorrhage 3 or cardiovascular malformation 10 but not from brain malformation. However, approximately 30 male patients whose FLNA variants are predicted to be partially loss-of-function or mosaic have been reported to date 11 . The Flna-null mouse model showed that they died at midgestation with widespread hemorrhage from abnormal vessels and truncus arteriosus 12 .…”

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confidence: 99%

“…Two independent male cases could support that FLNA variants can cause epileptic encephalopathy with no PVNH. Interestingly, seizures associated with PVNH1 patients (females and males) are typically adolescent-onset, and early infantile onset is uncommon 6 , 7 , 10 , 11 , 20 . Our patient started spasms at the age of 9 months, and other epileptic patients without PVNH had seizures before the age of 1 year (Table 1 ).…”

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confidence: 99%

Hemizygous FLNA variant in West syndrome without periventricular nodular heterotopia

et al. 2020

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Pathogenic FLNA variants can be identified in patients with seizures accompanied by periventricular nodular heterotopia (PVNH). It is unusual to find FLNA aberrations in epileptic patients without PVNH on brain imaging. We report a boy with cryptogenic West syndrome followed by refractory seizures and psychomotor delay. We performed whole-exome sequencing and identified a de novo missense variant in FLNA. It is noteworthy that this patient showed no PVNH. As no other pathogenic variants were found in epilepsy-related genes, this FLNA variant likely caused West syndrome but with no PVNH.

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FLNA mutations in surviving males presenting with connective tissue findings: two new case reports and review of the literature

Cited by 23 publications

References 48 publications

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

Case 28-2019: A 22-Year-Old Woman with Dyspnea and Chest Pain

Hemizygous FLNA variant in West syndrome without periventricular nodular heterotopia

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