Melnick-Needles Syndrome Research Articles

Mutation of FLNA attenuating the migration of abdominal muscles contributed to Melnick-Needles syndrome (MNS) in a family with recurrent miscarriage.

Filamin A, encoded by the X-linked gene FLNA, links the cell membrane with the cytoskeleton and acts as a regulator of the actin cytoskeleton. Mutations in FLNA cause a large spectrum of congenital malformations during embryonic development, including Melnick-Needles syndrome (MNS). However, reports of MNS, especially in males, are rare, and the pathogenesis molecular mechanisms are not well understood. We found a family with two consecutive miscarriages of similar fetuses with multiple malformations. DNA was extracted from peripheral blood and tissues, and whole exome sequencing was performed for genetic analysis. Then, we created a C57BL/6 mouse with a point mutation by CRISPR/Cas-mediated genome engineering. The migration of primary abdominal muscle cell was detected by wound healing assay. The first fetus showed congenital hygroma colli and omphalocele identified by ultrasound at 12 wks; the second fetus showed hygroma colli and thoraco abdominoschisis at 12 wks, with a new hemizygous mutation c.4420G>A in exon 26 of the FLNA gene, which is predicted to cause an amino acid substitution (p.Asp1474Asn). The mother and grandmother were both present in the c.4420G>A heterozygous state, and the mother's healthy brother had wild-type FLNA. These FLNA-mutated mice exhibited a broader central gap between the rectus abdominis than the wild type (WT), similar to the midline structure dysplasia of the abdominal wall in the two fetuses. Wound healing assays showed the attenuated migration capacity of abdominal muscle cells in mice with mutated FLNA. Finally, we summarized the cases of MNS with FLNA mutation from the accessible published literature thus far. Our research revealed a mutation site of the FLNA for MNS and explored the mechanism of midline structure dysplasia in the abdominal wall of male patients, which could provide more evidence for the clinical diagnosis and genetic counseling of families with these disorders.

Melnick Needles Syndrome: Computed Imaging and Management Difficulties

Melnick Needles Syndrome: Computed Imaging and Management Difficulties

Surgical Management of Craniomaxillofacial Features in the Otopalatodigital Spectrum Disorders

Otopalatodigital syndrome spectrum disorders are caused by Filamin A (FLNA) gene mutations. Otopalatodigital syndrome spectrum disorders are a group of rare congenital skeletal dysplasia, with specific craniomaxillofacial features including otopalatodigital syndrome type 1 and type 2, Melnick-Needles syndrome, frontometaphyseal dysplasia, terminal osseous dysplasia with pigmentary defects. The authors describe cases of a young girl with Melnick-Needles syndrome and a young boy with frontometaphyseal dysplasia treated in the Oral and Maxillofacial Surgery Department. Both patients had FLNA gene mutation confirmed with molecular genetic analysis. The authors proposed a 4 step treatment of the malformations with good outcomes both aesthetically and functionally, without complication.

Two Rare Syndromic Syndactyly Cases in Neonates

Abstract Introduction Isolated findings of syndactyly are benign. However, syndactyly can be associated with rare syndromes that need to be diagnosed for further management and for genetic counseling. Methods We present two cases of syndromic syndactyly in neonates. The first case is a 13-day-old female neonate with dysmorphic features. The neonate had clinical features of prominent forehead, hypertelorism, widely separated sagittal and metopic sutures, down-slanting eyes, low set ears, depressed nasal bridge, micrognathia, cleft palate, pectus excavatum, brachydactyly, and syndactyly of the second to fourth fingers bilaterally in upper limbs and in lower limbs.The second case is a 10-day-old male neonate with dysmorphism in the form of cleft alveolar ridge and palate, hyperplastic frenula, hypoplastic alar cartilage, syndactyly of the left hand, clinodactyly of the left lower limb toes, and amniotic bands. Discussion Case 1 was diagnosed as otopalatodigital syndrome because of the characteristic clinical features. This is a rare syndrome associated with syndactyly that often goes undiagnosed. Otopalatodigital syndrome spectrum disorders comprise of four phenotypically related conditions: otopalatodigital syndrome types 1 and 2, frontometaphyseal dysplasia, and Melnick–Needles syndrome. As it is associated with x-linked inheritance, its severity is more in males.Case 2 was diagnosed to have orofaciodigital syndrome because of the characteristic clinical features. It is another rare syndrome associated with syndactyly having abnormalities in the development of the oral cavity, face, and digits along with intellectual disability and renal system impairment. Conclusion There are fewer publications on these syndromes as they are rare and diagnosis is difficult. Recognizing these syndromes is key to further management and for genetic counseling.

Melnick-Needles syndrome associated molecule, Filamin-A regulates dental epithelial cell migration and root formation

Abstract Background Filamin-A (FLNA) is one of the adaptor proteins binding to both integrin beta chain and actin filament. Several kind of mutation in human FLNA gene were observed in Melnick-Needles syndrome (MNS). However, the role of FLNA in tooth formation is still unknown. Matrials and methods We analyzed the tissue expression of FLNA during tooth development using immunostaining. The role of FLNA in cell migration was analyzed using a scratch assay. In addition, we analyzed the phenotype of teeth in patients with Mernick-Needles syndrome caused by FLNA gene abnormalities. Results FLNA expressed in inner and outer enamel epithelium in mouse tooth germ and also expressed in cervical region of dental epithelium. In postnatal stage, FLNA expressed in ameloblast and odontoblast layers. In rat dental epithelium cell line SF2, FLNA is localized at the boundary between cells and co-localized with the terminal region of F-actin filament. shRNA-FLNA transfected cells showed delayed cell migration and scratch closure compared with control cells. Analysis of actin fiber movement by time-lapse confocal microscopy showed slower fiber movement in shRNA-FLNA over expressing SF2 cells. Novel mutation in FLNA gene was observed in MNS with tooth anormaly. This patient showed tooth agenesis and short root in both primary and permanent dentition with thin enamel. Conclusion Taken together, these results suggest that filamin-A is play a key role for dental epithelium migration and root formation.

A family of Melnick-Needles syndrome: a case report

BackgroundMelnick-Needles syndrome (MNS) is an extremely rare osteochondrodysplasia caused by a mutation of FLNA, the gene encoding filamin A. MNS is inherited in an X-linked dominant manner. In this study, we describe three members of the same family with MNS, who exhibited different phenotypic severity despite having an identical FLNA gene mutation.Case presentationThe patient was 16 months old, with a history of delayed physical development, multiple upper respiratory infections and otitis media episodes. She was referred to our orthopedic clinic because of bowed legs and an abnormal plain chest radiograph. Both upper and lower extremities were bowed. Plain X-rays showed thoracolumbar kyphoscoliosis, with anterior and posterior vertebral scalloping, and thin, wavy ribs. Hypoplasia of the pubis and ischium, with bilateral coxa valga, were also noted. Target exome sequencing revealed a heterozygous mutation of FLNA, c.3578 T > C, p.Lys1193Pro, which confirmed the diagnosis of MNS. Her older sister and mother had minimal deformities of the axial and extremity skeleton, but genetic analyses revealed the same FLNA mutation as the patient. The mutation identified in this family has not been previously reported.ConclusionThis report illustrates the potential inherited nature of MNS and the phenotypic variability of clinicoradiologic characteristics. In patients with traits suggestive of MNS, a careful medical and family history should be obtained, and genetic testing should be performed for the patient, as well as all family members.

Rickets in a patient with melnick needles syndrome

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Familial Ebstein Anomaly: Whole Exome Sequencing Identifies Novel Phenotype Associated With FLNA.

Familial Ebstein anomaly is a rare form of congenital heart disease. We report 7 individuals among 2 generations of 1 family with Ebstein anomaly. This family was first reported in 1991 by Balaji et al in which family members were also reported to have a mild skeletal phenotype. The most likely mechanism of inheritance was concluded to be autosomal dominant. We sought to identify the genetic pathogenesis in this family using a next generation sequencing approach. Whole exome sequencing was performed in 2 cousins in this family using the Agilent SureSelect Human all Exon 51 Mb version 5 capture kit. Data were processed through an analytic in-house pipeline. Whole exome sequencing identified a missense mutation in FLNA (Filamin A), an actin-binding protein located at Xq28, mutations in which are associated with the skeletal phenotypes Frontometaphyseal dysplasia, Otopalatodigital, and Melnick-Needles syndrome, with X-linked periventricular nodular heterotopia and FG syndrome (Omim, 305450). Review of the phenotypes of those with the mutation in this family shows increased severity of the cardiac phenotype and associated skeletal features in affected males, consistent with X-linked inheritance. Although congenital heart disease is reported in families with mutations in FLNA, this is the first report of individuals being affected by Ebstein anomaly because of a mutation in this gene and details the concurrent skeletal phenotype observed in this family.

Otopalatodigital spectrum disorders: refinement of the phenotypic and mutational spectrum

Otopalatodigital spectrum disorders (OPDSD) constitute a group of dominant X-linked osteochondrodysplasias including four syndromes: otopalatodigital syndromes type 1 and type 2 (OPD1 and OPD2), frontometaphyseal dysplasia, and Melnick-Needles syndrome. These syndromes variably associate specific facial and extremities features, hearing loss, cleft palate, skeletal dysplasia and several malformations, and show important clinical overlap over the different entities. FLNA gain-of-function mutations were identified in these conditions. FLNA encodes filamin A, a scaffolding actin-binding protein. Here, we report phenotypic descriptions and molecular results of FLNA analysis in a large series of 27 probands hypothesized to be affected by OPDSD. We identified 11 different missense mutations in 15 unrelated probands (n=15/27, 56%), of which seven were novel, including one of unknown significance. Segregation analyses within families made possible investigating 20 additional relatives carrying a mutation. This series allows refining the phenotypic and mutational spectrum of FLNA mutations causing OPDSD, and providing suggestions to avoid the overdiagnosis of OPD1.

Maxillofacial Changes in Melnick-Needles Syndrome.

Background. Melnick-Needles Syndrome is rare congenital hereditary skeletal dysplasia caused by mutations in the FLNA gene, which codifies the protein filamin A. This condition leads to serious skeletal abnormalities, including the stomatognathic region. Case Presentation. This paper describes the case of a 13-year-old girl diagnosed with Melnick-Needles Syndrome presenting with different forms of skeletal dysplasia, such as cranial hyperostosis, short upper limbs, bowed long bones, metaphyseal thickening, genu valgum (knock-knee), shortened distal phalanges, narrow pelvis and shoulders, rib tapering and irregularities, elongation of the vertebrae, kyphoscoliosis, micrognathia, hypoplastic coronoid processes of the mandible, left stylohyoid ligament suggesting ossification, and dental development anomalies. Conclusion. Knowledge of this rare syndrome on the part of dentists is important due to the fact that this condition involves severe abnormalities of the stomatognathic system that cause an impact on the development of the entire face as well as functional and esthetic impairments.

Fetal phenotypes in otopalatodigital spectrum disorders.

Otopalatodigital spectrum disorders (OPDSD) include OPD syndromes types 1 and type 2 (OPD1, OPD2), Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). These conditions are clinically characterized by variable skeletal dysplasia associated in males, with extra-skeletal features including brain malformations, cleft palate, cardiac anomalies, omphalocele and obstructive uropathy. Mutations in the FLNA gene have been reported in most FMD and OPD2 cases and in all instances of typical OPD1 and MNS. Here, we report a series of 10 fetuses and a neonatally deceased newborn displaying a multiple congenital anomalies syndrome suggestive of OPDSD and in whom we performed FLNA analysis. We found a global mutation rate of 44%. This series allows expanding the clinical and FLNA mutational spectrum in OPDSD. However, we emphasize difficulties to correctly discriminate OPDSD based on clinical criteria in fetuses due to the major overlap between these conditions. Molecular analyses may help pathologists to refine clinical diagnosis according to the type and the location of FLNA mutations. Discriminating the type of OPDSD is of importance in order to improve the genetic counseling to provide to families.

PP05.6 – 2896: Genotype-phenotype correlations and counseling in carriers of Filamin A gene mutations

Objective Mutations in the X-linked gene Filamin A (FLNA) are known to be linked to a broad clinical phenotype ranging from otopalatodigital syndromes (OPD1, OPD2) to frontometaphyseal dysplasia, Melnick-Needles syndrome and periventricular nodular heterotopia (PVNH). In the present study we investigate the phenotype-genotype correlation in carriers of FLNA mutations in order to improve the counseling of these patients and their relatives. Methods Clinical and neuroloradiological data from 16 FLNA mutation carriers were collected through retrospective analysis of their hospital files and a standardized questionnaire sent to the referring physician. These data were reviewed by a neurologist, molecular geneticists and a clinical geneticist. Results Fifteen of the carriers were female, as expected in dominant X-linked disorders. Half of the carriers belonged to a mother-child pair, with the mother being diagnosed secondary to the diagnosis in the child. Four carriers had the clinical diagnosis of OPD and their mutations were clustered in exons 3 and 4, whereas the mutations associated with PVNH were scattered throughout the gene. Besides the PVNH other findings on brain MRI included mega cisterna magna, corpus callosum and white matter anomalies. Cardiac investigations revealed aortic valve insufficiency and dilatation of the aorta, even at young age. In the majority of the patients, the clinical work-up focused on the primary indications for FLNA mutation analysis whereby other organs were not systematically investigated. Conclusion Although a lot is already known on the manifestations caused by FLNA mutations, and phenotype-genotype correlations can be made to a certain extent, many patients could benefit from a more extensive work-up and follow-up. This will not only lead to further improvement of our knowledge and understanding of the FLNA-related disorders, but will also allow us to anticipate on certain complications.

Familial periventricular nodular heterotopia, epilepsy and Melnick–Needles Syndrome caused by a single FLNA mutation with combined gain-of-function and loss-of-function effects

BackgroundLoss-of-function mutations of the FLNA gene cause a neuronal migration disorder defined as X-linked periventricular nodular heterotopia (PNH); gain-of-function mutations are associated with a group of X-linked skeletal dysplasias designed...

Melnick-Needles syndrome の1例

Melnick-Needles syndrome の1例

Correction of Spine Deformity in Patients With Melnick-Needles Syndrome

Melnick-Needles syndrome (MNS) is a rare X-linked dominant disorder affecting the skeletal system and connective tissue. To date, < 70 cases with MNS have been documented. Although few reports in the literature have shown that these patients might develop kyphoscoliosis, there is no report regarding long-term follow-up of patients with MNS undergo spine surgery. The aim of this study is to describe 2 unique cases of MNS with long-term follow-up after instrumented posterior spinal fusion, multiple-level Ponte osteotomies, and pedicle subtraction osteotomies. A 17-year-old female patient (patient 1) was evaluated for the first time at our institution. She was diagnosed with MNS, severe kyphoscoliosis, and restrictive lung disease. After pulmonary function improvement, she underwent posterior spinal fusion. Halo-femoral traction with gradual weight increase was used a week before spinal surgery. Surgical correction of her spinal deformity was achieved through a hooks-and-wires construct. The second patient was an 18-year-old female (patient 2) who carried the diagnosis of MNS when she was first seen at our institution. She had a significant thoracolumbar junction kyphosis and gibbous. She also suffered from significant pulmonary disease with a stent in her right main stem bronchus. A posterior procedure consisting of multiple-level Ponte osteotomies and pedicle subtraction osteotomy at L2 was carried out. Eight- and 5-year follow-up of patients 1 and 2, respectively, demonstrated solid fusion, a well-maintained correction, and no evidence of implant breakage. The reported cases add to the literature of excellent long-term results of spinal deformity correction with instrumented posterior spinal fusion in patients with MNS. Patients with this condition should be closely monitored from early childhood for the development of spine deformity so that early referral to a spine surgeon can be made followed by appropriate treatment, if necessary.

Orthognathic surgery in Melnick–Needles-Syndrome. Case report and review of the literature

Melnick–Needles Syndrome (MNS) is a congenital syndrome associated with severe architectural disorder of the skeletal system that can cause significant effects on the craniofacial skeleton including poor aesthetics, impaired speech and masticatory problems. The authors report a case of a female patient who experienced masticatory constraint, hindered speech and functional problems related to a severe bite dysfunction due to the mandibular hypoplasia and the underlying bony architectural disorder associated with MNS. The patient underwent bilateral sagittal split osteotomy (BSSO) to correct her skeletal malocclusion and improve the characteristic aesthetics and speech. The inherent bony abnormalities with their altered collagen structure presented unique challenges to orthognathic surgery in this patient with an unpredictable bone healing process. In MNS patients a fragile trabecular bone structure and an increased bleeding tendency is thought to delay or forestall wound healing. The patient was treated successfully with BSSO and monocortical plate fixation following a well-established algorithm from orthodontic preparation to surgical protocol. A very satisfying outcome has been achieved, concerning functional rehabilitation and aesthetic improvement. A review of the literature revealed that little is known about bone regeneration and fracture healing in cases with MNS.

Structure of filamin A immunoglobulin-like repeat 10 from Homo sapiens.

Filamin A (FlnA) plays a critical role in cytoskeletal organization, cell motility and cellular signaling. FlnA utilizes different binding sites on a series of 24 immunoglobulin-like domains (Ig repeats) to interact with diverse cytosolic proteins and with cytoplasmic portions of membrane proteins. Mutations in a specific domain, Ig10 (FlnA-Ig10), are correlated with two severe forms of the otopalatodigital syndrome spectrum disorders Melnick-Needles syndrome and frontometaphyseal dysplasia. The crystal structure of FlnA-Ig10 determined at 2.44 Å resolution provides insight into the perturbations caused by these mutations.

Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu–Cheney syndrome

Serpentine fibula polycystic kidney syndrome (SFPKS; MIM600330) is a rare skeletal dysplasia that has polycystic kidneys and dysmorphic facies as additional defining phenotypic components. The nosological classification of this disease has been debated as the condition shares features common to other skeletal dysplasias such as Melnick Needles syndrome (MNS; MIM309350) and Hajdu-Cheney Syndrome (HCS; MIM102500). Here, two previously reported cases of SFPKS are presented with emphasis on their phenotypic evolution. With the recent discovery that HCS is caused by mutations in NOTCH2, DNA from the both cases was examined and both were found to have truncating mutations in exon 34 of NOTCH2. The phenotypic evolution of SFPKS and this molecular analysis strongly suggest that SFPKS is part of the phenotypic spectrum of HCS and should no longer be classified as a distinct disease entity.

Year in review 2010: Interstitial lung diseases, acute lung injury, sleep, physiology, imaging, bronchoscopic intervention and lung cancer

Year in review 2010: Interstitial lung diseases, acute lung injury, sleep, physiology, imaging, bronchoscopic intervention and lung cancer

Lung disease associated with periventricular nodular heterotopia and an FLNA mutation

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.