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Intellectual disability-brachydactyly-Pierre Robin syndrome

MedGen UID:
325196
Concept ID:
C1837564
Disease or Syndrome
Synonym: Robin sequence with distinctive facial appearance and brachydactyly
 
Monarch Initiative: MONDO:0012095
OMIM®: 608670
Orphanet: ORPHA364577

Definition

Intellectual disability-brachydactyly-Pierre Robin syndrome is a rare developmental defect during embryogenesis syndrome characterized by mild to moderate intellectual disability and phsychomotor delay, Robin sequence (incl. severe micrognathia and soft palate cleft) and distinct dysmorphic facial features (e.g. synophris, short palpebral fissures, hypertelorism, small, low-set, and posteriorly angulated ears, bulbous nose, long/flat philtrum, and bow-shaped upper lip). Skeletal anomalies, such as brachydactyly, clinodactyly, small hands and feet, and oral manifestations (e.g. bifid, short tongue, oligodontia) are also associated. Additional features reported include microcephaly, capillary hemangiomas on face and scalp, ventricular septal defect, corneal clouding, nystagmus and profound sensorineural deafness. [from ORDO]

Clinical features

From HPO
Facial capillary hemangioma
MedGen UID:
347662
Concept ID:
C1858545
Finding
Hemangioma, a benign tumor of the vascular endothelial cells with small endothelial spaces, occurring in the face.
Short finger
MedGen UID:
334977
Concept ID:
C1844548
Anatomical Abnormality
Abnormally short finger associated with developmental hypoplasia.
Clinodactyly of the 5th finger
MedGen UID:
340456
Concept ID:
C1850049
Congenital Abnormality
Clinodactyly refers to a bending or curvature of the fifth finger in the radial direction (i.e., towards the 4th finger).
Aplasia of the distal phalanx of the 5th toe
MedGen UID:
867723
Concept ID:
C4022112
Finding
Short digit
MedGen UID:
893063
Concept ID:
C4023124
Finding
One or more digit that appears disproportionately short compared to the hand/foot, whereby either the entire digit or a specific phalanx is shortened.
Aplasia of the distal phalanx of the 5th finger
MedGen UID:
870070
Concept ID:
C4024501
Anatomical Abnormality
Absence of the distal phalanx of the little (5th) finger.
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Congenital Abnormality
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Ventricular septal hypertrophy
MedGen UID:
138013
Concept ID:
C0344955
Finding
The dividing wall between left and right sides of the heart, thickens and bulges into the left ventricle.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
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.
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
A type of abnormal location of the ears in which the position of the ears is characterized by posterior rotation (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Cleft mandible
MedGen UID:
146346
Concept ID:
C0685786
Finding
Midline deficiency of the mandible and some or all overlying tissues.
Prominent metopic ridge
MedGen UID:
387953
Concept ID:
C1857949
Finding
Vertical bony ridge positioned in the midline of the forehead.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Microglossia
MedGen UID:
10029
Concept ID:
C0025988
Congenital Abnormality
Decreased length and width of the tongue.
Isolated Pierre-Robin syndrome
MedGen UID:
19310
Concept ID:
C0031900
Congenital Abnormality
Pierre Robin sequence is a craniofacial anomaly comprising mandibular hypoplasia, cleft secondary palate, and glossoptosis leading to life-threatening obstructive apnea and feeding difficulaties during the neonatal period (summary by Tan et al., 2013).
Bulbous nose
MedGen UID:
66013
Concept ID:
C0240543
Finding
Increased volume and globular shape of the anteroinferior aspect of the nose.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Short palpebral fissure
MedGen UID:
98067
Concept ID:
C0423112
Finding
Distance between the medial and lateral canthi is more than 2 SD below the mean for age (objective); or, apparently reduced length of the palpebral fissures.
Telecanthus
MedGen UID:
140836
Concept ID:
C0423113
Finding
Distance between the inner canthi more than two standard deviations above the mean (objective); or, apparently increased distance between the inner canthi.
Smooth philtrum
MedGen UID:
222980
Concept ID:
C1142533
Finding
Flat skin surface, with no ridge formation in the central region of the upper lip between the nasal base and upper vermilion border.
Underdeveloped nasal alae
MedGen UID:
322332
Concept ID:
C1834055
Congenital Abnormality
Thinned, deficient, or excessively arched ala nasi.
Tented upper lip vermilion
MedGen UID:
326574
Concept ID:
C1839767
Finding
Triangular appearance of the oral aperture with the apex in the midpoint of the upper vermilion and the lower vermilion forming the base.
Exaggerated median tongue furrow
MedGen UID:
335102
Concept ID:
C1845109
Finding
Increased depth of the median tongue furrow.
Broad forehead
MedGen UID:
338610
Concept ID:
C1849089
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations above the mean (objective); or apparently increased distance between the two sides of the forehead.
Exaggerated cupid bow
MedGen UID:
376842
Concept ID:
C1850629
Finding
More pronounced paramedian peaks and median notch of the Cupid's bow.
Everted lower lip vermilion
MedGen UID:
344003
Concept ID:
C1853246
Finding
An abnormal configuration of the lower lip such that it is turned outward i.e., everted, with the Inner aspect of the lower lip vermilion (normally opposing the teeth) being visible in a frontal view.
Prominent nasal bridge
MedGen UID:
343051
Concept ID:
C1854113
Finding
Anterior positioning of the nasal root in comparison to the usual positioning for age.
Short columella
MedGen UID:
341783
Concept ID:
C1857479
Finding
Reduced distance from the anterior border of the naris to the subnasale.
Long philtrum
MedGen UID:
351278
Concept ID:
C1865014
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.
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).
Long upper lip
MedGen UID:
462845
Concept ID:
C3151495
Finding
Increased width of the upper lip.
Submucous cleft soft palate
MedGen UID:
868770
Concept ID:
C4023175
Congenital Abnormality
A cleft of the muscular (soft) portion of the palate that is covered by mucous membrane. Soft-palate submucous clefts are characterized by a midline deficiency or lack of muscle tissue.
Oligodontia
MedGen UID:
904670
Concept ID:
C4082304
Congenital Abnormality
The absence of six or more teeth from the normal series by a failure to develop.
Thin eyebrow
MedGen UID:
924116
Concept ID:
C4281771
Finding
Decreased diameter of eyebrow hairs.
Cafe-au-lait spot
MedGen UID:
113157
Concept ID:
C0221263
Finding
Cafe-au-lait spots are hyperpigmented lesions that can vary in color from light brown to dark brown with smooth borders and having a size of 1.5 cm or more in adults and 0.5 cm or more in children.
Small nail
MedGen UID:
537942
Concept ID:
C0263523
Finding
A nail that is diminished in length and width, i.e., underdeveloped nail.
Synophrys
MedGen UID:
98132
Concept ID:
C0431447
Congenital Abnormality
Meeting of the medial eyebrows in the midline.
Oligohydramnios
MedGen UID:
86974
Concept ID:
C0079924
Pathologic Function
Diminished amniotic fluid volume in pregnancy.
Corneal opacity
MedGen UID:
40485
Concept ID:
C0010038
Finding
A reduction of corneal clarity.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Microphthalmia
MedGen UID:
10033
Concept ID:
C0026010
Congenital Abnormality
Microphthalmia is an eye abnormality that arises before birth. In this condition, one or both eyeballs are abnormally small. In some affected individuals, the eyeball may appear to be completely missing; however, even in these cases some remaining eye tissue is generally present. Such severe microphthalmia should be distinguished from another condition called anophthalmia, in which no eyeball forms at all. However, the terms anophthalmia and severe microphthalmia are often used interchangeably. Microphthalmia may or may not result in significant vision loss.\n\nPeople with microphthalmia may also have a condition called coloboma. Colobomas are missing pieces of tissue in structures that form the eye. They may appear as notches or gaps in the colored part of the eye called the iris; the retina, which is the specialized light-sensitive tissue that lines the back of the eye; the blood vessel layer under the retina called the choroid; or in the optic nerves, which carry information from the eyes to the brain. Colobomas may be present in one or both eyes and, depending on their size and location, can affect a person's vision.\n\nPeople with microphthalmia may also have other eye abnormalities, including clouding of the lens of the eye (cataract) and a narrowed opening of the eye (narrowed palpebral fissure). Additionally, affected individuals may have an abnormality called microcornea, in which the clear front covering of the eye (cornea) is small and abnormally curved.\n\nBetween one-third and one-half of affected individuals have microphthalmia as part of a syndrome that affects other organs and tissues in the body. These forms of the condition are described as syndromic. When microphthalmia occurs by itself, it is described as nonsyndromic or isolated.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVIntellectual disability-brachydactyly-Pierre Robin syndrome
Follow this link to review classifications for Intellectual disability-brachydactyly-Pierre Robin syndrome in Orphanet.

Professional guidelines

PubMed

Mouthon L, Busa T, Bretelle F, Karmous-Benailly H, Missirian C, Philip N, Sigaudy S
Am J Med Genet A 2019 Dec;179(12):2365-2373. Epub 2019 Sep 11 doi: 10.1002/ajmg.a.61359. PMID: 31509347
Rojnueangnit K, Jones JR, Basehore MJ, Robin NH
Am J Med Genet A 2014 Feb;164A(2):516-21. Epub 2013 Dec 5 doi: 10.1002/ajmg.a.36299. PMID: 24311527
Caouette-Laberge L, Bayet B, Larocque Y
Plast Reconstr Surg 1994 Apr;93(5):934-42. PMID: 8134485

Recent clinical studies

Etiology

Fleurance A, Poets C, Chalouhi C, Thouvenin B, Abadie V
Semin Fetal Neonatal Med 2021 Dec;26(6):101286. Epub 2021 Sep 20 doi: 10.1016/j.siny.2021.101286. PMID: 34561179
Karempelis P, Hagen M, Morrell N, Roby BB
Int J Pediatr Otorhinolaryngol 2020 Apr;131:109842. Epub 2019 Dec 30 doi: 10.1016/j.ijporl.2019.109842. PMID: 31927149
Poets CF, Koos B, Reinert S, Wiechers C
J Craniomaxillofac Surg 2019 Nov;47(11):1699-1705. Epub 2019 Aug 20 doi: 10.1016/j.jcms.2019.08.002. PMID: 31477439
de Martino M, Chiarugi A, Boner A, Montini G, De' Angelis GL
Drugs 2017 Aug;77(12):1295-1311. doi: 10.1007/s40265-017-0751-z. PMID: 28597358Free PMC Article
Caouette-Laberge L, Bayet B, Larocque Y
Plast Reconstr Surg 1994 Apr;93(5):934-42. PMID: 8134485

Diagnosis

Fleurance A, Poets C, Chalouhi C, Thouvenin B, Abadie V
Semin Fetal Neonatal Med 2021 Dec;26(6):101286. Epub 2021 Sep 20 doi: 10.1016/j.siny.2021.101286. PMID: 34561179
Kumps C, D'haenens E, Vergult S, Leus J, van Coster R, Jansen A, Devriendt K, Oostra A, Vanakker OM
Clin Genet 2021 Mar;99(3):449-456. Epub 2021 Jan 5 doi: 10.1111/cge.13901. PMID: 33340101
Cody JD, Sebold C, Heard P, Carter E, Soileau B, Hasi-Zogaj M, Hill A, Rupert D, Perry B, O'Donnell L, Gelfond J, Lancaster J, Fox PT, Hale DE
Am J Med Genet C Semin Med Genet 2015 Sep;169(3):265-80. Epub 2015 Aug 3 doi: 10.1002/ajmg.c.31446. PMID: 26235940
Lehalle D, Wieczorek D, Zechi-Ceide RM, Passos-Bueno MR, Lyonnet S, Amiel J, Gordon CT
Clin Genet 2015 Nov;88(5):405-15. Epub 2015 May 1 doi: 10.1111/cge.12596. PMID: 25865758
Caouette-Laberge L, Bayet B, Larocque Y
Plast Reconstr Surg 1994 Apr;93(5):934-42. PMID: 8134485

Therapy

Thieblemont C, Phillips T, Ghesquieres H, Cheah CY, Clausen MR, Cunningham D, Do YR, Feldman T, Gasiorowski R, Jurczak W, Kim TM, Lewis DJ, van der Poel M, Poon ML, Cota Stirner M, Kilavuz N, Chiu C, Chen M, Sacchi M, Elliott B, Ahmadi T, Hutchings M, Lugtenburg PJ
J Clin Oncol 2023 Apr 20;41(12):2238-2247. Epub 2022 Dec 22 doi: 10.1200/JCO.22.01725. PMID: 36548927Free PMC Article
Vollebregt AAM, Ebbink BJ, Rizopoulos D, Lequin MH, Aarsen FK, Shapiro EG, van der Ploeg AT, van den Hout JMP
J Inherit Metab Dis 2021 May;44(3):751-762. Epub 2021 Jan 25 doi: 10.1002/jimd.12342. PMID: 33330992Free PMC Article
Poets CF, Koos B, Reinert S, Wiechers C
J Craniomaxillofac Surg 2019 Nov;47(11):1699-1705. Epub 2019 Aug 20 doi: 10.1016/j.jcms.2019.08.002. PMID: 31477439
de Martino M, Chiarugi A, Boner A, Montini G, De' Angelis GL
Drugs 2017 Aug;77(12):1295-1311. doi: 10.1007/s40265-017-0751-z. PMID: 28597358Free PMC Article
Pasyayan HM, Lewis MB
Cleft Palate J 1984 Oct;21(4):270-6. PMID: 6595082

Prognosis

Schalk A, Cousin MA, Dsouza NR, Challman TD, Wain KE, Powis Z, Minks K, Trimouille A, Lasseaux E, Lacombe D, Angelini C, Michaud V, Van-Gils J, Spataro N, Ruiz A, Gabau E, Stolerman E, Washington C, Louie R, Lanpher BC, Kemppainen JL, Innes M, Kooy F, Meuwissen M, Goldenberg A, Lecoquierre F, Vera G, Diderich KEM, Sheidley B, El Achkar CM, Park M, Hamdan FF, Michaud JL, Lewis AJ, Zweier C, Reis A, Wagner M, Weigand H, Journel H, Keren B, Passemard S, Mignot C, van Gassen K, Brilstra EH, Itzikowitz G, O'Heir E, Allen J, Donald KA, Korf BR, Skelton T, Thompson M, Robin NH, Rudy NL, Dobyns WB, Foss K, Zarate YA, Bosanko KA, Alembik Y, Durand B, Tran Mau-Them F, Ranza E, Blanc X, Antonarakis SE, McWalter K, Torti E, Millan F, Dameron A, Tokita M, Zimmermann MT, Klee EW, Piton A, Gerard B
J Med Genet 2022 Oct;59(10):965-975. Epub 2021 Dec 15 doi: 10.1136/jmedgenet-2021-107751. PMID: 34930816Free PMC Article
Kumps C, D'haenens E, Vergult S, Leus J, van Coster R, Jansen A, Devriendt K, Oostra A, Vanakker OM
Clin Genet 2021 Mar;99(3):449-456. Epub 2021 Jan 5 doi: 10.1111/cge.13901. PMID: 33340101
Vollebregt AAM, Ebbink BJ, Rizopoulos D, Lequin MH, Aarsen FK, Shapiro EG, van der Ploeg AT, van den Hout JMP
J Inherit Metab Dis 2021 May;44(3):751-762. Epub 2021 Jan 25 doi: 10.1002/jimd.12342. PMID: 33330992Free PMC Article
Cody JD, Sebold C, Heard P, Carter E, Soileau B, Hasi-Zogaj M, Hill A, Rupert D, Perry B, O'Donnell L, Gelfond J, Lancaster J, Fox PT, Hale DE
Am J Med Genet C Semin Med Genet 2015 Sep;169(3):265-80. Epub 2015 Aug 3 doi: 10.1002/ajmg.c.31446. PMID: 26235940
Caouette-Laberge L, Bayet B, Larocque Y
Plast Reconstr Surg 1994 Apr;93(5):934-42. PMID: 8134485

Clinical prediction guides

Schalk A, Cousin MA, Dsouza NR, Challman TD, Wain KE, Powis Z, Minks K, Trimouille A, Lasseaux E, Lacombe D, Angelini C, Michaud V, Van-Gils J, Spataro N, Ruiz A, Gabau E, Stolerman E, Washington C, Louie R, Lanpher BC, Kemppainen JL, Innes M, Kooy F, Meuwissen M, Goldenberg A, Lecoquierre F, Vera G, Diderich KEM, Sheidley B, El Achkar CM, Park M, Hamdan FF, Michaud JL, Lewis AJ, Zweier C, Reis A, Wagner M, Weigand H, Journel H, Keren B, Passemard S, Mignot C, van Gassen K, Brilstra EH, Itzikowitz G, O'Heir E, Allen J, Donald KA, Korf BR, Skelton T, Thompson M, Robin NH, Rudy NL, Dobyns WB, Foss K, Zarate YA, Bosanko KA, Alembik Y, Durand B, Tran Mau-Them F, Ranza E, Blanc X, Antonarakis SE, McWalter K, Torti E, Millan F, Dameron A, Tokita M, Zimmermann MT, Klee EW, Piton A, Gerard B
J Med Genet 2022 Oct;59(10):965-975. Epub 2021 Dec 15 doi: 10.1136/jmedgenet-2021-107751. PMID: 34930816Free PMC Article
Vollebregt AAM, Ebbink BJ, Rizopoulos D, Lequin MH, Aarsen FK, Shapiro EG, van der Ploeg AT, van den Hout JMP
J Inherit Metab Dis 2021 May;44(3):751-762. Epub 2021 Jan 25 doi: 10.1002/jimd.12342. PMID: 33330992Free PMC Article
Zhang LX, Lemire G, Gonzaga-Jauregui C, Molidperee S, Galaz-Montoya C, Liu DS, Verloes A, Shillington AG, Izumi K, Ritter AL, Keena B, Zackai E, Li D, Bhoj E, Tarpinian JM, Bedoukian E, Kukolich MK, Innes AM, Ediae GU, Sawyer SL, Nair KM, Soumya PC, Subbaraman KR, Probst FJ, Bassetti JA, Sutton RV, Gibbs RA, Brown C, Boone PM, Holm IA, Tartaglia M, Ferrero GB, Niceta M, Dentici ML, Radio FC, Keren B, Wells CF, Coubes C, Laquerrière A, Aziza J, Dubucs C, Nampoothiri S, Mowat D, Patel MS, Bracho A, Cammarata-Scalisi F, Gezdirici A, Fernandez-Jaen A, Hauser N, Zarate YA, Bosanko KA, Dieterich K, Carey JC, Chong JX, Nickerson DA, Bamshad MJ, Lee BH, Yang XJ, Lupski JR, Campeau PM
Genet Med 2020 Aug;22(8):1338-1347. Epub 2020 May 19 doi: 10.1038/s41436-020-0811-8. PMID: 32424177Free PMC Article
Basart H, van Oers HA, Paes EC, Breugem CC, Don Griot JP, van der Horst CM, Haverman L, Hennekam RC
Am J Med Genet A 2017 Jan;173(1):54-61. Epub 2016 Sep 20 doi: 10.1002/ajmg.a.37968. PMID: 27649059
Utami KH, Winata CL, Hillmer AM, Aksoy I, Long HT, Liany H, Chew EG, Mathavan S, Tay SK, Korzh V, Sarda P, Davila S, Cacheux V
Hum Mutat 2014 Nov;35(11):1311-20. Epub 2014 Sep 23 doi: 10.1002/humu.22636. PMID: 25137640

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