Melnick-Needles Syndrome (MNS; OMIM #309350) is a rare X-linked dominant osteochondrodysplasia caused by FLNA gain-of-function variants. It is characterized by short stature, facial dysmorphism, skeletal anomalies, and systemic complications. FLNA encodes Filamin A, a cytoskeletal protein with over 90 binding partners. Variants in FLNA cause a broad spectrum of disorders, among which MNS represents one of the most severe phenotypes. Despite increasing research on MNS, many aspects of its genetic and phenotypic spectrum remain unknown. In this work, we presented two Mexican cases with a diagnosis of MNS with different FLNA missense variants p.(Leu1193Pro) and p.(Ser1199Leu). In addition, we performed a comprehensive review of the literature about FLNA variants related to MNS. This study reinforced the genetic and phenotypic complexity of MNS, emphasizing the critical role of exon 22 variants in the pathogenesis of the disease.

SummaryA female child was admitted to our centre with the chief complaints of recurrent cough and cold and breathing difficulties since day 20 of birth, bowing of both legs for the last 3 years, inability to gain weight for the last 2 years and easy fatigue. She had dysmorphic features characteristic of Melnick-Needles syndrome (MNS). Her mother also had similar phenotypic features.Whole exome sequencing picked up a heterozygous, missense, pathogenic variant (c.3562G>A) in FLNA that results in the amino acid substitution of threonine for alanine at the codon 1188 (p.Ala1188Thr; ENST00000369850.10).MNS (OMIM: #309350) belongs to a class of five X-linked disorders called otopalatodigital spectrum disorders that have similar clinical characteristics. The multitude of symptoms in MNS indicates the critical role of FLNA in multisystem organogenesis. Variable expressivity in patients may be due to epigenetic modifications. Challenges in genetic counselling were encountered in this case, which could be resolved with multiple counselling sessions. The FLNA-related otopalatodigital (FLNA-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following allelic conditions: otopalatodigital syndrome type 1 (FLNA-OPD1), otopalatodigital syndrome type 2 (FLNA-OPD2), frontometaphyseal dysplasia (FLNA-FMD), Melnick-Needles syndrome (FLNA-MNS), and terminal osseous dysplasia (FLNA-TOD). In FLNA-OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In FLNA-OPD2, females are less severely affected than related affected males. Most males with FLNA-OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FLNA-FMD, females are less severely affected than related affected males who are hemizygous for the same allele. Males usually, but not always, demonstrate a skeletal dysplasia in association with hearing loss and, variably, joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In females with FLNA-MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. FLNA-MNS in males results in perinatal lethality in all known individuals. FLNA-TOD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the hand and feet, pigmentary defects of the skin, and recurrent digital fibromata. The diagnosis of an FLNA-OPD spectrum disorder is established in a male proband with characteristic clinical and radiographic features and a family history consistent with X-linked inheritance. Identification of a hemizygous pathogenic variant in FLNA by molecular genetic testing can confirm the diagnosis if clinical features, radiographic features, and/or family history are inconclusive. The diagnosis of an FLNA-OPD spectrum disorder is usually established in a female proband with characteristic clinical and radiographic features and a family history consistent with X-linked inheritance. Identification of a heterozygous pathogenic variant in FLNA by molecular genetic testing can confirm the diagnosis if clinical features, radiographic features, and/or family history are inconclusive. Treatment of manifestations: Surgical treatment may be required for hand and foot malformations. Monitoring, bracing, and surgical intervention as needed for scoliosis; physical therapy for contractures; cosmetic surgery may correct the fronto-orbital deformity; surgical correction for orthognathic deformities as needed; chest expansion surgery has been used to treat thoracic hypoplasia; continuous positive airway pressure and mandibular distraction can improve airway complications related to micrognathia; hearing aids for deafness; treatment of cardiac anomalies and cardiomyopathy per cardiologist and cardiac surgeon; treatment of oligohypodontia per orthodontist and/or dental surgeon; treatment of genitourinary anomalies per urologist; evaluation with anesthesiologist if intubation and ventilation are required due to laryngeal stenosis. Surveillance: Annual clinical evaluation for orthopedic complications including contractures and scoliosis; evaluation of bone mineral density in those with FLNA-FMD; monitor head size and shape with each clinical evaluation in infancy for craniosynostosis; annual clinical evaluation for apnea with polysomnography studies as indicated; annual audiology evaluation; dental evaluations every six to 12 months beginning with eruption of primary teeth. Evaluation of relatives at risk: Consider molecular genetic testing for the family-specific pathogenic variant in at-risk female relatives. FLNA-OPD spectrum disorders are inherited in an X-linked manner. If the mother of the proband has an FLNA pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected. Penetrance in males with an FLNA pathogenic variant leading to an FLNA-OPD spectrum disorder is complete (male sibs of a proband with FLNA-MNS or FLNA-TOD who inherit the pathogenic variant will be affected and generally die prenatally or perinatally). Females who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations. If the father of the proband has an FLNA pathogenic variant, he will transmit it to all his daughters and none of his sons. Once the FLNA pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for FLNA-OPD spectrum disorders are possible.

Melnick-Needles syndrome (MNS) is a rare X-linked dominant skeletal dysplasia caused by pathogenic FLNA variants, primarily affecting females due to male lethality. Characterised by severe craniofacial and skeletal abnormalities, MNS exhibits marked phenotypic variability influenced by skewed X-inactivation, somatic mosaicism, and variant-specific functional consequences. Recent advances in next-generation sequencing and ACMG-based variant classification have refined diagnosis, particularly for pathogenic variants in exon 22, yet genotype-phenotype correlations remain incompletely defined. Differential diagnosis within the otopalatodigital spectrum, including OPD1, OPD2, and Frank-Ter Haar syndrome, remains challenging due to overlapping features, necessitating comprehensive radiological and molecular evaluation. Clinical manifestations span craniofacial dysmorphism, thoracic hypoplasia, respiratory compromise, and multisystem involvement. Management requires interdisciplinary coordination encompassing respiratory support, orthognathic surgery, dental reconstruction, and monitoring for complications such as glaucoma and psychiatric comorbidities. Evidence for the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) and mandibular distraction techniques highlights surgical adaptability, though altered bone metabolism in MNS necessitates modified approaches. Rare associations with periventricular nodular heterotopia and bipolar disorder suggest a broader neurodevelopmental impact of FLNA dysfunction. Despite expanding clinical insight, the rarity of MNS limits population-level studies, constraining understanding of natural history and long-term outcomes. Future research must prioritise elucidating modifier genes, therapeutic targets such as antisense oligonucleotides, and prenatal detection strategies. A synthesis of genetic, clinical, and surgical domains is essential to optimise care pathways, improve prognosis, and inform genetic counselling for families affected by this phenotypically diverse and medically complex disorder.

Melnick-Needles syndrome (MNS) is a rare skeletal dysplasia that affects skeletal and connective tissue. Less than 70 cases of MNS reported in the literature. MNS had various clinical manifestations such as skeletal deformity, cortical bony sclerosis, facial abnormality, and urogenital symptoms. We presented a 5-year-old girl who referred to our orthopedic clinic with knee valgus deformity, spinal kyphoscoliosis, bilateral coxa valga, and humerus cortical irregularity. Based on some facial and skeletal feature, MNS was confirmed with genetic evaluation (heterozygote Filamin A genome). The diagnosis of MNS requires a thorough medical and family history, physical examination, and radiographic evaluation. Differential diagnoses for patients with skeletal and facial deformities like MNS include Camurati-Engelmann disease, cystinuria, Galloway-Mowat syndrome, Joubert syndrome, and mucopolysaccharidosis. Treatment for MNS patients with bony deformities without lethal conditions can be conservative, but corrective surgery may be necessary in some cases. MNS was a rare syndrome with common clinical manifestations such as limb and spine deformity. It is important to conduct a careful examination of any patient who presents with limb and skeletal deformity to the orthopedic clinic, as the disease may have some lethal clinical implications.

To explore the clinical and genetic characteristics of a fetus with Melnick-Needles syndrome (MNS). A fetus with MNS diagnosed at Ningbo Women and Children's Hospital in November 2020 was selected as the study subject. Clinical data was collected. Pathogenic variant was screened by using trio-whole exome sequencing (trio-WES). Candidate variant was verified by Sanger sequencing. Prenatal ultrasonography of the fetus had shown multiple anomalies including intrauterine growth retardation, bilateral femur curvature, omphalocele, single umbilical artery, and oligohydramnios. Trio-WES revealed that the fetus has harbored hemizygous c.3562G>A (p.A1188T) missense variant of the FLNA gene. Sanger sequencing confirmed that the variant was maternally derived, whilst its father was of a wild type. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be likely pathogenic (PS4+PM2_Supporting+PP3+PP4). The hemizygous c.3562G>A (p.A1188T) variant of the FLNA gene probably underlay the structural abnormalities in this fetus. Genetic testing can facilitate accurate diagnosis of MNS and provide a basis for genetic counseling for this family.