The NALCN channelosome regulates the resting membrane potential through sodium leak currents, influencing cellular excitability. Genetic variants in NALCN and UNC80, a subunit of the NALCN channelosome, cause ultra-rare and severe neurodevelopmental disorders. Autosomal dominant congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) syndrome is associated with gain-of-function (GOF) variants in NALCN. Infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) 1 syndrome is associated with biallelic variants in NALCN and IHPRF 2 syndrome with biallelic variants in UNC80, both resulting in a loss-of-function (LOF). This study aims to expand the phenotypes associated with these syndromes, exploring potential genotype-phenotype associations. This is a cross-sectional study including patients with pathogenic or likely pathogenic variants in NALCN and UNC80. Phenotypes were evaluated through a structured interview, questionnaires, and review of medical records. Associations between variants, clinical features, and syndromes were analyzed. Fifty-one patients were included (34 with CLIFAHDD, 9 with IHPRF 1, 8 with IHPRF 2; 3 months-27 years; 37.3% female). All exhibited neurodevelopmental delay, more severe in patients with LOF variants (p = 0.019). Neurodevelopmental regression was observed in 29.4% of patients with CLIFAHDD syndrome, associated with the onset of ataxia (70%). Patients with CLIFAHDD had more severe respiratory symptoms at birth (11.7% orotracheal intubation). Distal arthrogryposis (76.5%), episodic ataxia (41.2% of ambulatory patients), and paroxysmal dystonia (11.7%) were exclusively diagnosed in patients with CLIFAHDD. Patients with LOF variants presented more frequently with failure to thrive (88.2%, p = 0.001), central sleep apnea (CSA, 64.7%, p < 0.001), and epilepsy (70.6%, p < 0.001). Epilepsy was associated with more severe cognitive delays (p = 0.016) and was refractory in 58.8% of patients. Earlier seizure onset was associated with refractory epilepsy (p = 0.014). Patients with CLIFAHDD and premature death, epilepsy, or paroxysmal dystonia carried variants within NALCN pore domains. This study provides an in-depth clinical characterization of NALCN-related and UNC80-related disorders. Distal arthrogryposis, episodic ataxia, and paroxysmal dystonia were diagnosed in patients with CLIFAHDD while failure to thrive, CSA, and epilepsy were associated with LOF variants. We suggest potential genotype-phenotype associations, formulating hypotheses for validation in future studies with larger cohorts.

Freeman-Burian syndrome is a rare craniofacial syndrome surrounded by fake news. This situation shows the strong connection between the quality of a literature search and clinical reasoning displayed in patient care, especially in care of patients with rare conditions.

Congenital Contractures of Limbs and Face, Hypotonia, and Developmental Delay (CLIFAHDD) syndrome is a recently described type of distal arthrogryposis which unlike other subtypes is associated with developmental delay and various neurologic presentation. Epilepsy and ataxia have been reported. We add paroxysmal dyskinesia to the clinical spectrum. Understanding the molecular mechanism can help developing targeted therapy in future. This study resulted in identification of a novel variant in NALCN gene leading to autosomal dominant CLIFAHDD syndrome. Our patient presented with a form of nonepileptic paroxysmal dyskinesia. This is a new phenotype that has not been described previously.

Early child development is a critical stage of life that influences social, educational and health outcomes worldwide. A few years after Zika epidemic, families of children born with congenital Zika syndrome (CZS) continue to face uncertainties when it comes to the development of their children. The present study sought to analyse the developmental trajectories of a subset of children born with CZS in the first 24 months of life. Thirty-five children with CZS were assessed with the Bayley-III Scales at 12 and 24 months of age from November 2016 to December 2018 in a rehabilitation centre in Brazil. Inclusion criteria included children with established diagnosis of CZS. Exclusion criteria included the presence of arthrogryposis, prematurity, irregular follow-up, clinical complications or other causes of microcephaly. Children born with CZS who evolved with cerebral palsy (CP) were classified according to the Gross Motor Function Classification System (GMFCS) at 2 years of age. At 12 months of age mean composite scores on the Bayley cognitive, communication and motor scores were 57.71 (SD 7.11), 57.94 (SD 14.34) and 49.26 (7.20), respectively. At 24 months of age, composite scores were 57.43 (SD 7.11), 53.60 (SD 12.29) and 48.83 (7.76). In addition, 31 (88.57%) out of 34 children diagnosed with CP were classified as GMFCS levels IV and V. Zika virus congenital infection is a risk factor for functional impairments across all developmental domains having a direct and substantial negative impact in early child development.