**Background:** Dihydropyrimidinase (DHP) deficiency is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants in the DPYS gene, affecting the second enzyme in the pyrimidine degradation pathway. This leads to accumulation of dihydrouracil (DHU) and dihydrothymine (DHT) and low levels of N-carbamyl-β-amino acids. Clinical features vary widely, from severe neurological and gastrointestinal involvement to asymptomatic cases. To date, 34 patients have been reported. This case adds a newly identified patient with severe neurological involvement, profound intellectual disability (ID), seizure disorder, movement disorder, spastic quadriplegia, and abnormal MRI findings, along with novel skeletal manifestations.
**Methods:** The patient is an 18-year-old male born at 36 weeks gestation to healthy, nonconsanguineous parents. Pregnancy was complicated by maternal preeclampsia and fetal bradycardia. Developmental delay and spasticity were first noted at ~9 months of age. At 3.5 years, rapid regression occurred, followed by convulsions and diagnosis of spastic quadriplegic cerebral palsy. Extensive biochemical and molecular testing was performed, including plasma amino acids, acylcarnitine profile, carnitine, methylmalonic acid, homocysteine, B12, mucopolysaccharide and oligosaccharide electrophoresis, lysosomal enzyme screening, urine organic acids, karyotype, CGH chromosomal microarray, MECP2 sequencing, and research-based whole-genome sequencing (WGS), all of which were negative. Whole-exome sequencing (WES) identified a homozygous variant in DPYS (c.502T>C; p.Tyr168His). Urine pyrimidine analysis showed extremely high levels of DHU (150.6; normal 3–58) and DHT (137.5; normal 0–2.4), mildly elevated thymine (2.5; normal 0–0.09), and normal uracil (9.5; normal 0–17), consistent with DHP deficiency. A literature review of 34 previously reported patients was conducted.
**Key Results:** The patient exhibited macrocephaly (>98th percentile), coarse facial features, low-set posteriorly rotated ears, short broad neck, widely spaced teeth, high-arched palate, inverted nipples, scoliosis, bilateral arthrogryposis, bony wrist deformities, and camptodactyly. Neurological examination revealed dystonia, spasticity, abnormal deep tendon reflexes, and ankle clonus. The patient was nonverbal, wheelchair-dependent, and profoundly cognitively impaired. Brain MRI at 16 years showed mild increase in FLAIR signal in parietal periventricular white matter with volume loss and periventricular leukomalacia. Osteoporosis was diagnosed (lumbar spine 0.57 g/cm², left total hip 0.53 g/cm²) and improved with bisphosphonate treatment (lumbar spine 0.83 g/cm², left total hip 0.75 g/cm²). Feeding difficulties required gastrostomy tube placement. Among 35 total patients (including this case), neurological abnormalities were most common: ID (46%), seizures (34%), hypotonia (26%), developmental delay (23%), movement disorder (11%), spastic quadriplegia (6%), and MRI abnormalities (14%). Gastrointestinal symptoms included feeding problems (23%), failure to thrive (17%), vomiting (9%), GERD (6%), dysphagia (3%), and gastritis (3%). Skeletal manifestations (scoliosis, arthrogryposis, bony deformities, osteoporosis) were reported only in this patient.
**Clinical Implications:** DHP deficiency is not detected by routine biochemical tests (amino acids, organic acids, acylcarnitines), making it likely underdiagnosed. Screening for pyrimidine degradation defects is crucial in patients with nonspecific neurological symptoms. Identifying DHP deficiency is important to prevent neurotoxicity from pyrimidine analog drugs like 5-fluorouracil (5-FU) in cancer treatment. This case expands the phenotype to include osteoporosis, scoliosis, arthrogryposis, and bony deformities, highlighting the need for regular screening for these complications. The novel DPYS variant (c.502T>C; p.Tyr168His) adds to the variant spectrum, and the case emphasizes the essential role of metabolic testing alongside next-generation sequencing for accurate diagnosis.