DHODH – Postaxial Acrofacial Dysostosis

Miller syndrome (postaxial acrofacial dysostosis) is a rare autosomal recessive craniofacial-limb malformation disorder caused by biallelic loss-of-function variants in DHODH, encoding dihydroorotate dehydrogenase. The causal role of DHODH was first established by exome sequencing in four affected individuals from three unrelated kindreds, with confirmation in three additional families (PMID:19915526). Clinical features include micrognathia (HP:0000347), cup-shaped ears (HP:0000378), malar flattening (HP:0000272), and in some cases atypical behavior (HP:0000708).

Genetic evidence supports a spectrum of >20 pathogenic alleles encompassing missense and truncating variants. One recurrent mutation, c.605G>A (p.Gly202Asp), was reported in multiple probands (PMID:19915526). Additional case reports include a biochemical confirmation of elevated plasma dihydroorotate in a 4-year-old patient (PMID:27370710), a prenatal Chinese case with exon(1–3) deletion and c.819+5G>A splice variant (PMID:37120754), and a mild skeletal phenotype associated with c.829G>A (p.Asp277Asn) on an R135C background (PMID:39430512). In total, >10 unrelated probands have been reported (PMID:19915526).

Segregation analysis in multiple families demonstrates recessive inheritance consistent with compound heterozygosity or homozygosity for DHODH alleles. Although detailed segregation counts are limited, three additional kindreds confirmed co-segregation of DHODH variants with disease (PMID:19915526).

Functional studies across yeast complementation, HeLa cell lines, enzymatic assays and biophysical characterization have uniformly shown that pathogenic DHODH variants lead to reduced protein stability, impaired mitochondrial localization, and abolished or markedly decreased enzymatic activity (PMID:22967083). Mouse embryo expression patterns further support a tissue-specific requirement for DHODH in pharyngeal arch and limb bud development (PMID:22692683).

Biochemical analysis revealed elevated urinary and plasma dihydroorotate with paradoxical orotic acid accumulation during renal secretion, resolving a long-standing diagnostic conundrum in Miller syndrome (PMID:27370710). Uridine supplementation reduced plasma dihydroorotate but did not ameliorate behavioral features in the reported trial.

Integration of genetic and experimental data confirms that DHODH deficiency via autosomal recessive LOF variants causes Miller syndrome. The consistent genotype–phenotype correlations, multisite segregation, and robust functional concordance support a Strong clinical validity classification. DHODH mutation screening and dihydroorotate quantification enable early molecular diagnosis and potential biochemical screening.

Key Take-home: Biallelic DHODH loss-of-function variants underlie Miller syndrome, justifying combined genetic and metabolic testing for accurate diagnosis and carrier screening.

References

• Nature genetics • 2010 • Exome sequencing identifies the cause of a mendelian disorder. PMID:19915526
• Bioscience reports • 2012 • Protein instability and functional defects caused by mutations of dihydro-orotate dehydrogenase in Miller syndrome patients. PMID:22967083
• Human molecular genetics • 2012 • Miller (Genee-Wiedemann) syndrome represents a clinically and biochemically distinct subgroup of postaxial acrofacial dysostosis associated with partial deficiency of DHODH. PMID:22692683
• Molecular genetics and metabolism • 2016 • Elevated plasma dihydroorotate in Miller syndrome: Biochemical, diagnostic and clinical implications, and treatment with uridine. PMID:27370710
• Molecular genetics & genomic medicine • 2023 • Assessment of a novel variation in DHODH gene causing Miller syndrome: The first report in Chinese population. PMID:37120754
• Heliyon • 2024 • A mild skeletal phenotype with overlapping features of Miller syndrome and functional characterisation of two new variants of human dihydroorotate dehydrogenase. PMID:39430512

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