Postaxial Acrofacial Dysostosis

A number sign (#) is used with this entry because of evidence that postaxial acrofacial dysostosis (POADS), also known as Miller syndrome, is caused by compound heterozygous mutation in the DHODH gene (126064) on chromosome 16q22.

Description

Miller syndrome, or postaxial acrofacial dysostosis, is a rare autosomal recessive disorder characterized clinically by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the postaxial elements of the limbs, coloboma of the eyelids, and supernumerary nipples (summary by Ng et al., 2010).

Clinical Features

Miller et al. (1979) described 3 patients with postaxial limb deficiency, cup-shaped ears, and malar hypoplasia, and reviewed other reported cases. An affected sib of one of the patients of Miller et al. (1979) was reported by Fineman (1981).

Donnai et al. (1987) reviewed 7 published cases and 3 personally observed and previously unreported cases. Malar hypoplasia and lower lid ectropion were found in all. Micrognathia was the rule and tended to improve with age. Cleft palate was present in 9 of 10 cases, cleft lip in only 2 cases. Seven of 10 patients had bilateral absence of the fifth digit, including the fifth metacarpal, and the others showed unilateral aplasia or hypoplasia of the fifth digit. Most had shortened forearms and radiologic evidence of ulnar hypoplasia. The fifth toes were absent in all cases and occasionally the third and fourth as well. Intelligence appeared to be normal. Autosomal recessive inheritance was considered possible. The parents of a single case were said to be distantly related.

Fryns and Van den Berghe (1988) described a single male case. The fifth digital rays were absent bilaterally in both the hands and feet. A cleft soft and hard palate and malar hypoplasia were present.

Chrzanowska et al. (1989) reported 2 unrelated patients who showed malar hypoplasia, ectropion of the lower lid, micrognathia, cup-shaped ears, and absence of the fifth digital rays of 4 limbs with or without associated anomalies of the forearms. Chrzanowska and Fryns (1993) provided follow-up on the second patient reported by Chrzanowska et al. (1989) and his family. Growth and intellectual development had been normal in the proband. The second pregnancy of his parents ended spontaneously in preterm delivery at 31 weeks' gestation, with the birth of twin boys, both of whom had the same postaxial limb deficiency in the form of absence of the fifth digital rays of all 4 limbs. Both died in the neonatal period. Acrania-anencephaly was present with exophthalmos, flat nose, and low-set ears.

Ogilvy-Stuart and Parsons (1991) described affected brother and sister. In addition to characteristic facial and limb defects, previously undescribed anomalies, including midgut malrotation, gastric volvulus, and renal anomalies, were recorded. Parental consanguinity was reported by Fineman (1981).

Vigneron et al. (1991) reported a case and suggested that the mandibulofacial dysostosis is similar to that of Treacher Collins syndrome (154500). The postaxial deficiency in the limbs distinguishes the disorder from Nager syndrome (154400), which has preaxial limb deficiency.

Giannotti et al. (1992) described what they called POADS (for postaxial acrofacial dysostosis syndrome) in male and female sibs. Pereira et al. (1992) reported an isolated case and a second affected child who was the sister of a boy previously reported by Richieri-Costa and Guion-Almeida (1989). Pereira et al. (1992) tabulated the main clinical features in sporadic and familial cases of this syndrome, which they referred to as the Genee-Wiedemann syndrome (Genee, 1969; Wiedemann, 1973).

Phenocopy

Ng et al. (2010) commented that the pattern of malformations observed in individuals with Miller syndrome is similar to that in individuals with fetal exposure to methotrexate. Methotrexate is a well-established inhibitor of de novo purine biosynthesis, and its antiproliferative actions and are thought to be due to its inhibition of dihydrofolate reductase and folate-dependent transmethylations. Accordingly, defects of both purine and pyrimidine biosynthesis appear to be capable of causing a similar pattern of birth defects. The authors suggested that functional polymorphisms in the DHODH or other genes encoding proteins in the de novo pyrimidine biosynthesis pathway might influence susceptibility to methotrexate embryopathy.

Molecular Genetics

In 4 affected individuals from 3 independent kindreds, Ng et al. (2010) captured and sequenced coding regions to a mean coverage of 40X and sufficient depth to call variants at approximately 97% of each targeted exome. Filtering against public SNP databases and 8 HapMap exomes for genes with 2 previously unknown variants in each of the 4 individuals identified a single candidate gene, DHODH (126064), which encodes a key enzyme in the pyrimidine de novo biosynthesis pathway. Sanger sequencing confirmed the presence of DHODH mutations in 3 additional families with Miller syndrome. Collectively, Ng et al. (2010) identified 11 different mutations in the DHODH gene in 6 kindreds with Miller syndrome by a combination of exome and targeted resequencing. Each parent of an affected individual was found to be a heterozygous carrier, and none of the mutations appeared to have arisen de novo. In the kindreds with affected sibs, none of the unaffected sibs were compound heterozygotes. None of the mutations were identified in 200 control chromosomes from unaffected individuals of matched geographic ancestry that were genotyped. Ten mutations were missense, 2 affecting the same codon, and 1 was a 1-bp indel that was predicted to cause a frameshift resulting in a termination codon 7 amino acids downstream. One mutation (126064.0001) was shared by 2 unrelated individuals with Miller syndrome who were of different self-identified geographic ancestry.

Ng et al. (2010) commented that the mechanism by which mutations in DHODH cause Miller syndrome was unclear. Dihydroorotate dehydrogenase catalyzes the conversion of dihydroorotate to orotic acid, an intermediate in the pyrimidine de novo biosynthesis pathway that is subsequently converted to uridine monophosphate (UMP) by UMP synthase.

Roach et al. (2010) analyzed the whole genome sequences of a family of 4, consisting of 2 sibs and their parents. Both of these sibs were reported by Ng et al. (2010) as affected with Miller syndrome. Family-based sequencing allowed Roach et al. (2010) to delineate recombination sites precisely, identify 70% of the sequencing errors (resulting in greater than 99.999% accuracy), and identify very rare single-nucleotide polymorphisms. They also directly estimated a human intergeneration mutation rate of approximately 1.1 x 10(-8) per position per haploid genome. Both offspring in the family have 2 recessive disorders: Miller syndrome, for which the gene was concurrently identified, and primary ciliary dyskinesia (608644), for which the causative genes have previously been identified. Roach et al. (2010) concluded that the family-based genome analysis enabled the authors to narrow the candidate genes for both of these mendelian disorders to only 4.

Animal Model

The classical rudimentary phenotype in Drosophila melanogaster, reported by T. H. Morgan (1910) and characterized by wing anomalies, defective oogenesis, and malformed posterior legs, is caused by mutations affecting the pyrimidine biosynthesis pathway. This is the same pathway affected by mutations in DHODH, which result in Miller syndrome (Ng et al., 2010).

History

Because of phenotypic similarities between Miller syndrome and Treacher Collins syndrome (154500), which is caused by mutations in the TCOF1 gene (606847), Splendore et al. (2002) screened the TCOF1 gene in 1 Miller syndrome patient, but found no mutations.