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Miller syndrome(POADS)

MedGen UID:
120522
Concept ID:
C0265257
Disease or Syndrome
Synonyms: Genee-Wiedemann acrofacial dysostosis; Genee-Wiedemann syndrome; POADS; POADS syndrome; Postaxial Acrofacial Dysostosis; Postaxial acrofacial dysostosis (POADS) syndrome; Wildervanck-Smith syndrome
SNOMED CT: Miller syndrome (66038001); Postaxial acrofacial dysostosis syndrome (66038001)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): DHODH (16q22.2)
 
Monarch Initiative: MONDO:0009903
OMIM®: 263750
Orphanet: ORPHA246

Definition

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). [from OMIM]

Additional description

From MedlinePlus Genetics
Miller syndrome is a rare condition that mainly affects the development of the face and limbs. The severity of this disorder varies among affected individuals.

Children with Miller syndrome are born with underdeveloped cheek bones (malar hypoplasia) and a very small lower jaw (micrognathia). They often have an opening in the roof of the mouth (cleft palate) and/or a split in the upper lip (cleft lip). These abnormalities frequently cause feeding problems in infants with Miller syndrome. The airway is usually restricted due to the micrognathia, which can lead to life-threatening breathing problems.

People with Miller syndrome often have eyes that slant downward, eyelids that turn out so the inner surface is exposed (ectropion), and a notch in the lower eyelids called an eyelid coloboma. Many affected individuals have small, cup-shaped ears, and some have hearing loss caused by defects in the middle ear (conductive hearing loss). Another feature of this condition is the presence of extra nipples. Miller syndrome does not affect a person's intelligence, although speech development may be delayed due to hearing impairment.

Individuals with Miller syndrome have various bone abnormalities in their arms and legs. The most common problem is absent fifth (pinky) fingers and toes. Affected individuals may also have webbed or fused fingers or toes (syndactyly) and abnormally formed bones in the forearms and lower legs. People with Miller syndrome sometimes have defects in other bones, such as the ribs or spine.

Less commonly, affected individuals have abnormalities of the heart, kidneys, genitalia, or gastrointestinal tract.  https://medlineplus.gov/genetics/condition/miller-syndrome

Clinical features

From HPO
Cryptorchidism
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Abnormality of the kidney
MedGen UID:
78593
Concept ID:
C0266292
Congenital Abnormality
An abnormality of the kidney.
Micropenis
MedGen UID:
1633603
Concept ID:
C4551492
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Syndactyly
MedGen UID:
52619
Concept ID:
C0039075
Congenital Abnormality
Webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. Bony fusions are referred to as "bony" syndactyly if the fusion occurs in a radio-ulnar axis. Fusions of bones of the fingers or toes in a proximo-distal axis are referred to as "symphalangism".
Short thumb
MedGen UID:
98469
Concept ID:
C0431890
Congenital Abnormality
Hypoplasia (congenital reduction in size) of the thumb.
Hypoplasia of the radius
MedGen UID:
672334
Concept ID:
C0685381
Congenital Abnormality
Underdevelopment of the radius.
Hypoplasia of the ulna
MedGen UID:
395934
Concept ID:
C1860614
Congenital Abnormality
Underdevelopment of the ulna.
Abnormal foot morphology
MedGen UID:
1762829
Concept ID:
C5399834
Anatomical Abnormality
An abnormality of the skeleton of foot.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Postnatal growth retardation
MedGen UID:
395343
Concept ID:
C1859778
Finding
Slow or limited growth after birth.
Congenital hypertrophic pyloric stenosis
MedGen UID:
196010
Concept ID:
C0700639
Congenital Abnormality
Pyloric stenosis, also known as infantile hypertrophic pyloric stenosis, is an uncommon condition in infants characterized by abnormal thickening of the pylorus muscles in the stomach leading to gastric outlet obstruction. Clinically infants are well at birth. Then, at 3 to 6 weeks of age, the infants present with projectile vomiting, potentially leading to dehydration and weight loss.
Midgut malrotation
MedGen UID:
342335
Concept ID:
C1849706
Finding
Conductive hearing impairment
MedGen UID:
9163
Concept ID:
C0018777
Disease or Syndrome
An abnormality of vibrational conductance of sound to the inner ear leading to impairment of sensory perception of sound.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Cupped ear
MedGen UID:
335186
Concept ID:
C1845447
Congenital Abnormality
Laterally protruding ear that lacks antihelical folding (including absence of inferior and superior crura).
Congenital hip dislocation
MedGen UID:
9258
Concept ID:
C0019555
Disease or Syndrome
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Radioulnar synostosis
MedGen UID:
57861
Concept ID:
C0158761
Congenital Abnormality
An abnormal osseous union (fusion) between the radius and the ulna.
Supernumerary vertebrae
MedGen UID:
75583
Concept ID:
C0265681
Congenital Abnormality
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Finding
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Pectus excavatum
MedGen UID:
781174
Concept ID:
C2051831
Finding
A defect of the chest wall characterized by a depression of the sternum, giving the chest ("pectus") a caved-in ("excavatum") appearance.
Choanal atresia
MedGen UID:
3395
Concept ID:
C0008297
Congenital Abnormality
Absence or abnormal closure of the choana (the posterior nasal aperture). Most embryologists believe that posterior choanal atresia results from a failure of rupture between the 35th and 38th day of fetal life of the partition which separates the bucconasal or buccopharyngeal membranes. The resultant choanal atresia may be unilateral or bilateral, bony or membranous, complete or incomplete. In over 90 per cent of cases the obstruction is bony, while in the remainder it is membranous. The bony type of atresia is commonly located 1-2 mm. anterior to the posterior edge of the hard palate, and the osseous septum varies in thickness from 1 to 10 mm. In the membranous form of choanal atresia the obstruction usually occurs further posteriorly. In approximately one third of cases the atresia is bilateral.
Cleft upper lip
MedGen UID:
40327
Concept ID:
C0008924
Congenital Abnormality
A gap or groove in the upper lip. This is a congenital defect resulting from nonfusion of tissues of the lip during embryonal development.
Ectropion
MedGen UID:
4448
Concept ID:
C0013592
Disease or Syndrome
An outward turning (eversion) or rotation of the eyelid margin.
Conical tooth
MedGen UID:
82730
Concept ID:
C0266037
Congenital Abnormality
An abnormal conical form of the teeth, that is, a tooth whose sides converge or taper together incisally.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Eyelid coloboma
MedGen UID:
141737
Concept ID:
C0521573
Congenital Abnormality
A short discontinuity of the margin of the lower or upper eyelid.
Cleft palate
MedGen UID:
756015
Concept ID:
C2981150
Congenital Abnormality
Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).
Supernumerary nipple
MedGen UID:
120564
Concept ID:
C0266011
Congenital Abnormality
Presence of more than two nipples.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMiller syndrome
Follow this link to review classifications for Miller syndrome in Orphanet.

Professional guidelines

PubMed

Lonati D, Schicchi A, Crevani M, Buscaglia E, Scaravaggi G, Maida F, Cirronis M, Petrolini VM, Locatelli CA
Toxins (Basel) 2020 Aug 7;12(8) doi: 10.3390/toxins12080509. PMID: 32784744Free PMC Article
Wang Y, Zhang M, Chen L, Huang H, Xu L
Mol Genet Genomic Med 2020 Oct;8(10):e1446. Epub 2020 Aug 7 doi: 10.1002/mgg3.1446. PMID: 32767744Free PMC Article
Trainor PA, Andrews BT
Am J Med Genet C Semin Med Genet 2013 Nov;163C(4):283-94. Epub 2013 Oct 4 doi: 10.1002/ajmg.c.31375. PMID: 24123981Free PMC Article

Recent clinical studies

Etiology

Orozco Rodriguez JM, Wacklin-Knecht H, Knecht W
Nucleosides Nucleotides Nucleic Acids 2022;41(12):1337-1358. Epub 2022 Feb 20 doi: 10.1080/15257770.2022.2039393. PMID: 35184687
Orozco Rodriguez JM, Krupinska E, Wacklin-Knecht H, Knecht W
Nucleosides Nucleotides Nucleic Acids 2022;41(12):1318-1336. Epub 2022 Jan 30 doi: 10.1080/15257770.2021.2023749. PMID: 35094635
Duley JA, Henman MG, Carpenter KH, Bamshad MJ, Marshall GA, Ooi CY, Wilcken B, Pinner JR
Mol Genet Metab 2016 Sep;119(1-2):83-90. Epub 2016 Jun 14 doi: 10.1016/j.ymgme.2016.06.008. PMID: 27370710
Wieczorek D
Clin Genet 2013 Jun;83(6):499-510. Epub 2013 Apr 8 doi: 10.1111/cge.12123. PMID: 23565775
Fang J, Uchiumi T, Yagi M, Matsumoto S, Amamoto R, Saito T, Takazaki S, Kanki T, Yamaza H, Nonaka K, Kang D
Biosci Rep 2012 Dec;32(6):631-9. doi: 10.1042/BSR20120046. PMID: 22967083Free PMC Article

Diagnosis

Yang K, Fu LM, Chu XY, Zhang J, Chen WQ, Yan YS, Wang YP, Zhang DL, Yin CH, Guo Q
Mol Genet Genomic Med 2023 Jul;11(7):e2186. Epub 2023 Apr 30 doi: 10.1002/mgg3.2186. PMID: 37120754Free PMC Article
Sporrij A, Zon LI
Cell Cycle 2021 Aug;20(15):1455-1467. Epub 2021 Jul 19 doi: 10.1080/15384101.2021.1947567. PMID: 34281491Free PMC Article
Duley JA, Henman MG, Carpenter KH, Bamshad MJ, Marshall GA, Ooi CY, Wilcken B, Pinner JR
Mol Genet Metab 2016 Sep;119(1-2):83-90. Epub 2016 Jun 14 doi: 10.1016/j.ymgme.2016.06.008. PMID: 27370710
Klement KA, Black JS, Denny AD
J Craniofac Surg 2016 May;27(3):565-70. doi: 10.1097/SCS.0000000000002453. PMID: 26999694
Ku CS, Naidoo N, Pawitan Y
Hum Genet 2011 Apr;129(4):351-70. Epub 2011 Feb 18 doi: 10.1007/s00439-011-0964-2. PMID: 21331778

Therapy

Sporrij A, Zon LI
Cell Cycle 2021 Aug;20(15):1455-1467. Epub 2021 Jul 19 doi: 10.1080/15384101.2021.1947567. PMID: 34281491Free PMC Article
Duley JA, Henman MG, Carpenter KH, Bamshad MJ, Marshall GA, Ooi CY, Wilcken B, Pinner JR
Mol Genet Metab 2016 Sep;119(1-2):83-90. Epub 2016 Jun 14 doi: 10.1016/j.ymgme.2016.06.008. PMID: 27370710

Prognosis

Sporrij A, Zon LI
Cell Cycle 2021 Aug;20(15):1455-1467. Epub 2021 Jul 19 doi: 10.1080/15384101.2021.1947567. PMID: 34281491Free PMC Article
Rainger J, Bengani H, Campbell L, Anderson E, Sokhi K, Lam W, Riess A, Ansari M, Smithson S, Lees M, Mercer C, McKenzie K, Lengfeld T, Gener Querol B, Branney P, McKay S, Morrison H, Medina B, Robertson M, Kohlhase J, Gordon C, Kirk J, Wieczorek D, Fitzpatrick DR
Hum Mol Genet 2012 Sep 15;21(18):3969-83. Epub 2012 Jun 12 doi: 10.1093/hmg/dds218. PMID: 22692683

Clinical prediction guides

Carter H, Douville C, Stenson PD, Cooper DN, Karchin R
BMC Genomics 2013;14 Suppl 3(Suppl 3):S3. Epub 2013 May 28 doi: 10.1186/1471-2164-14-S3-S3. PMID: 23819870Free PMC Article
Fang J, Uchiumi T, Yagi M, Matsumoto S, Amamoto R, Takazaki S, Yamaza H, Nonaka K, Kang D
Biosci Rep 2013 Feb 5;33(2):e00021. doi: 10.1042/BSR20120097. PMID: 23216091Free PMC Article
Rainger J, Bengani H, Campbell L, Anderson E, Sokhi K, Lam W, Riess A, Ansari M, Smithson S, Lees M, Mercer C, McKenzie K, Lengfeld T, Gener Querol B, Branney P, McKay S, Morrison H, Medina B, Robertson M, Kohlhase J, Gordon C, Kirk J, Wieczorek D, Fitzpatrick DR
Hum Mol Genet 2012 Sep 15;21(18):3969-83. Epub 2012 Jun 12 doi: 10.1093/hmg/dds218. PMID: 22692683
Wang K, Li M, Hakonarson H
Nucleic Acids Res 2010 Sep;38(16):e164. Epub 2010 Jul 3 doi: 10.1093/nar/gkq603. PMID: 20601685Free PMC Article
Wang RY, Earl DL, Ruder RO, Graham JM Jr
Pediatrics 2001 Aug;108(2):E32. doi: 10.1542/peds.108.2.e32. PMID: 11483842

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