**Background:** Raine syndrome (MIM #259775) is a rare autosomal recessive disorder caused by mutations in the FAM20C gene, which encodes a Golgi casein kinase essential for bone mineralization and regulation of fibroblast growth factor 23 (FGF23). Two phenotypes exist: lethal (severe, early death) and non-lethal (milder, longer survival). Approximately 70 cases have been reported, with a prevalence of 1/100,000. This report presents a compound heterozygous newborn with severe Raine syndrome from non-consanguineous parents.
**Methods:** A 4-day-old male infant born at 37 weeks via C-section to a healthy non-consanguineous couple (mother 19 years, G2P2A0; father 21 years) was evaluated. The couple had previously lost a male child at 4 months with similar features. Prenatal screening (NIPT) was normal, but fetal ultrasound showed polyhydramnios and fetal distress. At birth, the patient had abnormal breath sounds, cyanosis, multiple congenital anomalies, birth weight 3500 g, length 52 cm, head circumference 35 cm, and Apgar scores of 5 at 1 and 5 minutes. Mechanical ventilation was initially unsuccessful due to choanal atresia and pulmonary hypoplasia but later succeeded. A tracheostomy was performed in the first month. Imaging included chest X-ray (showing multiple bone calcifications), abdominal ultrasound (mild bilateral pyelectasis), cranial CT (periventricular calcifications, cerebral atrophy, hypoplastic corpus callosum), and 3D brain CT (enlarged anterior fontanelle). Echocardiography showed borderline contractility. Ophthalmological exam revealed hyperemic conjunctivitis, bilateral palpebral edema, and mild corneal edema. Biochemical evaluation showed elevated PTH (54.72 pg/mL; reference 5.7–34), low vitamin D (16.10 ng/mL; reference 30–65), and normal calcium (2.14 mmol/L; reference 1.90–2.60). Genetic testing included cytogenetic analysis (normal 46,XY), MLPA for craniofacial genes (no deletions/duplications), and next-generation sequencing using a Skeletal Disorders Panel (358 genes) with targeted parental sequencing.
**Key Results:** The patient was a compound heterozygote for two FAM20C variants: a pathogenic missense variant c.1135G>A (p.Gly379Arg) inherited from the mother, and a likely pathogenic nonsense variant c.1291C>T (p.Gln431*) inherited from the father. The c.1135G>A variant is absent in gnomAD, predicted damaging by SIFT (score 0.001), disease-causing by Mutation Taster, and pathogenic by ACMG and VarSome. MutPred2 predicted changes in metal binding and transmembrane protein, loss of disulfide linkage at C378 (score 0.916, p≤0.05). The c.1291C>T variant causes a premature stop, is absent in gnomAD, 1000 Genomes, and Ensembl, classified as pathogenic by VarSome and likely pathogenic by ACMG, and disease-causing by Mutation Taster. MutPred-LOF predicted alterations in iron binding (p=0.0001), catalytic site (p=0.00023), PPI hotspot (p=0.0007), sulfation (p=0.003), and signal helix (p=0.005). Clinically, the patient displayed craniofacial dysmorphism (wide-open anterior fontanelle 5/6 cm, trigonocephaly, frontal bossing, severe proptosis, depressed nasal bridge, small nose with narrow nares, bilateral choanal atresia, large earlobe, prominent antitragus, small triangular mouth, microretrognathia, superior mouth cleft, inferior lip pseudo cleft, low-set ears, short neck, narrow thorax, bilateral bowed tibia), opisthotonos, diminished muscle tone and reflexes, and developmental delay. At nearly one year, weight was 6500 g and height 68 cm; the patient required nasogastric feeding and tracheostomy, with frequent hospitalizations for respiratory infections and failure to thrive.
**Clinical Implications:** This case expands the genotypic spectrum of Raine syndrome by reporting compound heterozygous variants (c.1291C>T and c.1135G>A) in a non-consanguineous family. The c.1135G>A variant has been previously reported in one lethal homozygous case and one non-lethal case, suggesting an association with severe phenotypes. The patient's survival beyond one year despite severe respiratory compromise and neurological deficits underscores the importance of aggressive supportive care (tracheostomy, nutritional support) and early genetic diagnosis. Genetic counseling is crucial for families with a history of similar features, as recurrence risk is 25% for autosomal recessive inheritance. The findings also highlight the need for continued investigation into genotype-phenotype correlations and potential targeted therapies.