Otopalatodigital syndrome type 2 (OPD2) is a rare, typically lethal X-linked congenital disorder associated with craniofacial, skeletal, and visceral malformations. Because of its rarity, each case provides valuable insights into neonatal care, genetic counseling, and anticipatory guidance. A male infant diagnosed prenatally with OPD2 after ultrasound revealed multiple anomalies, and genetic testing confirmed the pathogenic variant. The mutation was de novo, as there was no family history of X-linked inheritance. The infant exhibited cleft palate, skeletal deformities, omphalocele, thoracic hypoplasia, and additional brain and renal anomalies consistent with the lethal phenotype. Intensive neonatal care included respiratory support, nutritional interventions, and multidisciplinary consultations. Despite intensive medical management, the infant remained critically ill. Palliative care was introduced early after admission and played an important role in subsequently assisting with arranging the discharge of the infant home on hospice care. The infant survived 6 weeks postnatally, allowing meaningful time with his family. This case highlights the critical importance of prenatal genetic counseling, early anticipatory guidance, and shared decision making, with palliative care integrated as part of the care continuum. Neonatal nurse practitioners and NICU registered nurses are not only essential members of the multidisciplinary team but also serve as consistent advocates for the infant and the family. Their roles in care coordination, ongoing bedside support, and facilitation of compassionate, family-centered communication are vital in helping parents navigate the complex decisions and emotional challenges that accompany a lethal congenital diagnosis. 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.