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Autosomal dominant Robinow syndrome 1(DRS1)

MedGen UID:
1641736
Concept ID:
C4551475
Disease or Syndrome
Synonyms: Acral dysostosis with facial and genital abnormalities; Costovertebral segmentation defect with mesomelia (formerly); Covesdem syndrome (formerly); Fetal face syndrome; Robinow dwarfism; WNT5A-Related Robinow Syndrome, Autosomal Dominant
 
Genes (locations): DVL1 (1p36.33); WNT5A (3p14.3)
 
Monarch Initiative: MONDO:0024455
OMIM®: 180700

Disease characteristics

Excerpted from the GeneReview: Autosomal Dominant Robinow Syndrome
Autosomal dominant Robinow syndrome (ADRS) is characterized by skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly), genital abnormalities (in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism; in females: hypoplastic clitoris and labia majora), dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion), dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth), bilobed tongue, and occasional prenatal macrocephaly that persists postnatally. Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive delay. When present, cardiac defects are a major cause of morbidity and mortality. A variant of Robinow syndrome, associated with osteosclerosis and caused by a heterozygous pathogenic variant in DVL1, is characterized by normal stature, persistent macrocephaly, increased bone mineral density with skull osteosclerosis, and hearing loss, in addition to the typical features described above. [from GeneReviews]
Authors:
Maian Roifman  |  Han Brunner  |  Jamie Lohr, et. al.   view full author information

Additional descriptions

From OMIM
Robinow syndrome, a rare skeletal dysplasia syndrome, is characterized by dysmorphic features resembling a fetal face, mesomelic limb shortening, hypoplastic external genitalia in males, and renal and vertebral anomalies (summary by Roifman et al., 2015). For a discussion of genetic heterogeneity of Robinow syndrome, see RRS (268310).  http://www.omim.org/entry/180700
From MedlinePlus Genetics
Robinow syndrome is a rare disorder that affects the development of many parts of the body, particularly the skeleton. The types of Robinow syndrome can be distinguished by the severity of their signs and symptoms and by their pattern of inheritance: autosomal recessive or autosomal dominant.

Autosomal recessive Robinow syndrome is characterized by skeletal abnormalities including shortening of the long bones in the arms and legs, particularly the forearms; abnormally short fingers and toes (brachydactyly); wedge-shaped spinal bones (hemivertebrae) leading to an abnormal curvature of the spine (kyphoscoliosis); fused or missing ribs; and short stature. Affected individuals also have distinctive facial features, such as a broad forehead, prominent and widely spaced eyes, a short nose with an upturned tip, a wide nasal bridge, and a broad and triangle-shaped mouth. Together, these facial features are sometimes described as "fetal facies" because they resemble the facial structure of a developing fetus. Other common features of autosomal recessive Robinow syndrome include underdeveloped genitalia in both males and females, and dental problems such as crowded teeth and overgrowth of the gums. Kidney and heart defects are also possible. Development is delayed in 10 to 15 percent of people with this condition, although intelligence is usually normal.

Autosomal dominant Robinow syndrome has signs and symptoms that are similar to, but tend to be milder than, those of the autosomal recessive form. Abnormalities of the spine and ribs are rarely seen in the autosomal dominant form, and short stature is less pronounced. A variant form of autosomal dominant Robinow syndrome includes increased bone mineral density (osteosclerosis) affecting the bones of the skull in addition to the signs and symptoms listed above. This variant is called the osteosclerotic form of Robinow syndrome.  https://medlineplus.gov/genetics/condition/robinow-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).
Hydronephrosis
MedGen UID:
42531
Concept ID:
C0020295
Disease or Syndrome
Severe distention of the kidney with dilation of the renal pelvis and calices.
Renal duplication
MedGen UID:
488826
Concept ID:
C0266298
Congenital Abnormality
A congenital anomaly of the urinary tract, in which the kidney is duplicated and is drained via two separate renal pelves and ureters.
Hypoplastic labia majora
MedGen UID:
107566
Concept ID:
C0566899
Finding
Undergrowth of the outer labia.
Clitoral hypoplasia
MedGen UID:
336198
Concept ID:
C1844527
Finding
Developmental hypoplasia of the clitoris.
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.
Brachydactyly
MedGen UID:
67454
Concept ID:
C0221357
Congenital Abnormality
Digits that appear disproportionately short compared to the hand/foot. The word brachydactyly is used here to describe a series distinct patterns of shortened digits (brachydactyly types A-E). This is the sense used here.
Dislocated radial head
MedGen UID:
488814
Concept ID:
C0265563
Congenital Abnormality
A dislocation of the head of the radius from its socket in the elbow joint.
Broad thumb
MedGen UID:
140880
Concept ID:
C0426891
Finding
Increased thumb width without increased dorso-ventral dimension.
Mesomelia
MedGen UID:
107808
Concept ID:
C0549306
Congenital Abnormality
Shortening of the middle parts of the limbs (forearm and lower leg) in relation to the upper and terminal segments.
Small hand
MedGen UID:
108279
Concept ID:
C0575802
Finding
Disproportionately small hand.
Short middle phalanx of the 5th finger
MedGen UID:
322335
Concept ID:
C1834060
Anatomical Abnormality
Hypoplastic/small middle phalanx of the fifth finger.
Radial deviation of finger
MedGen UID:
322852
Concept ID:
C1836189
Finding
Bending or curvature of a finger toward the radial side (i.e., towards the thumb). The deviation is at the metacarpal-phalangeal joint, and this finding is distinct from clinodactyly.
Short palm
MedGen UID:
334684
Concept ID:
C1843108
Finding
Short palm.
Duplication of the distal phalanx of hand
MedGen UID:
336580
Concept ID:
C1849343
Finding
This term applies if one or more of the distal phalanges of the hand are either partially duplicated, depending on severity leading to a broad or bifid appearance of the phalanges, or completely duplicated.
Broad toe
MedGen UID:
351283
Concept ID:
C1865038
Finding
Visible increase in width of the non-hallux digit without an increase in the dorso-ventral dimension.
Rhizomelia
MedGen UID:
357122
Concept ID:
C1866730
Congenital Abnormality
Disproportionate shortening of the proximal segment of limbs (i.e. the femur and humerus).
Bifid distal phalanx of toe
MedGen UID:
867402
Concept ID:
C4021772
Anatomical Abnormality
Limited elbow extension and supination
MedGen UID:
870670
Concept ID:
C4025124
Finding
Clinodactyly
MedGen UID:
1644094
Concept ID:
C4551485
Congenital Abnormality
An angulation of a digit at an interphalangeal joint in the plane of the palm (finger) or sole (toe).
Right ventricular outlet tract obstruction
MedGen UID:
11245
Concept ID:
C0035619
Disease or Syndrome
An obstruction to the forward flow of blood in the outflow tract of the right ventricle.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
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).
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.
Inguinal hernia
MedGen UID:
6817
Concept ID:
C0019294
Finding
Protrusion of the contents of the abdominal cavity through the inguinal canal.
Umbilical hernia
MedGen UID:
9232
Concept ID:
C0019322
Anatomical Abnormality
Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Retrognathia
MedGen UID:
19766
Concept ID:
C0035353
Congenital Abnormality
An abnormality in which the mandible is mislocalised posteriorly.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Delayed skeletal maturation
MedGen UID:
108148
Concept ID:
C0541764
Finding
A decreased rate of skeletal maturation. Delayed skeletal maturation can be diagnosed on the basis of an estimation of the bone age from radiographs of specific bones in the human body.
Short long bone
MedGen UID:
344385
Concept ID:
C1854912
Finding
One or more abnormally short long bone.
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.
Wide anterior fontanel
MedGen UID:
400926
Concept ID:
C1866134
Finding
Enlargement of the anterior fontanelle with respect to age-dependent norms.
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.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Macroglossia
MedGen UID:
44236
Concept ID:
C0024421
Disease or Syndrome
Increased length and width of the tongue.
Dental crowding
MedGen UID:
11850
Concept ID:
C0040433
Finding
Changes in alignment of teeth in the dental arch
Delayed eruption of teeth
MedGen UID:
68678
Concept ID:
C0239174
Finding
Delayed tooth eruption, which can be defined as tooth eruption more than 2 SD beyond the mean eruption age.
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).
Persistence of primary teeth
MedGen UID:
75597
Concept ID:
C0266050
Disease or Syndrome
Persistence of the primary teeth beyond the age by which they normally are shed and replaced by the permanent teeth.
Bifid tongue
MedGen UID:
82731
Concept ID:
C0266111
Congenital Abnormality
Tongue with a median apical indentation or fork.
Gingival overgrowth
MedGen UID:
87712
Concept ID:
C0376480
Finding
Hyperplasia of the gingiva (that is, a thickening of the soft tissue overlying the alveolar ridge. The degree of thickening ranges from involvement of the interdental papillae alone to gingival overgrowth covering the entire tooth crown.
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Short lingual frenulum
MedGen UID:
604928
Concept ID:
C0426501
Finding
The presence of an abnormally short lingual frenulum.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Narrow palate
MedGen UID:
278045
Concept ID:
C1398312
Finding
Width of the palate more than 2 SD below the mean (objective) or apparently decreased palatal width (subjective).
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Long palpebral fissure
MedGen UID:
340300
Concept ID:
C1849340
Finding
Distance between medial and lateral canthi is more than two standard deviations above the mean for age (objective); or, apparently increased length of the palpebral fissures.
Triangular mouth
MedGen UID:
336578
Concept ID:
C1849341
Finding
The presence of a triangular form of the mouth.
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Flat face
MedGen UID:
342829
Concept ID:
C1853241
Finding
Absence of concavity or convexity of the face when viewed in profile.
Midface retrusion
MedGen UID:
339938
Concept ID:
C1853242
Anatomical Abnormality
Posterior positions and/or vertical shortening of the infraorbital and perialar regions, or increased concavity of the face and/or reduced nasolabial angle.
Short nose
MedGen UID:
343052
Concept ID:
C1854114
Finding
Distance from nasion to subnasale more than two standard deviations below the mean, or alternatively, an apparently decreased length from the nasal root to the nasal tip.
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.
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
Downturned corners of mouth
MedGen UID:
356471
Concept ID:
C1866195
Anatomical Abnormality
A morphological abnormality of the mouth in which the angle of the mouth is downturned. The oral commissures are positioned inferior to the midline labial fissure.
Orofacial cleft
MedGen UID:
472000
Concept ID:
C3266076
Congenital Abnormality
The presence of a cleft (gap, opening, or groove) in the oral cavity, including cleft of the upper lip and/or cleft of the palate. Cleft of the upper lip is visible as a groove or fissure in the lip, most frequently due to a congenital failure of the maxillary and median nasal processes to fuse. Cleft palate is characterized by a grooved depression or fissure in the roof of the mouth, most often resulting from a congenital failure of the palate to fuse properly. Clefts of the lip and palate can occur individually or together. It is preferable to code each defect separately.
Short hard palate
MedGen UID:
892925
Concept ID:
C4023918
Anatomical Abnormality
Distance between the labial point of the incisive papilla to the midline junction of the hard and soft palate more than 2 SD below the mean (objective) or apparently decreased length of the hard palate (subjective).
Nevus flammeus
MedGen UID:
65911
Concept ID:
C0235752
Congenital Abnormality
A congenital vascular malformation consisting of superficial and deep dilated capillaries in the skin which produce a reddish to purplish discolouration of the skin.
Sacral dimple
MedGen UID:
98428
Concept ID:
C0426848
Finding
A cutaneous indentation resulting from tethering of the skin to underlying structures (bone) of the intergluteal cleft.
Nail dysplasia
MedGen UID:
331737
Concept ID:
C1834405
Congenital Abnormality
The presence of developmental dysplasia of the nail.
Long eyelashes
MedGen UID:
342955
Concept ID:
C1853738
Finding
Mid upper eyelash length >10 mm or increased length of the eyelashes (subjective).
Proptosis
MedGen UID:
41917
Concept ID:
C0015300
Disease or Syndrome
An eye that is protruding anterior to the plane of the face to a greater extent than is typical.
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).

Recent clinical studies

Diagnosis

Zhang C, Mazzeu JF, Eisfeldt J, Grochowski CM, White J, Akdemir ZC, Jhangiani SN, Muzny DM, Gibbs RA, Lindstrand A, Lupski JR, Sutton VR, Carvalho CMB
Am J Med Genet A 2021 Dec;185(12):3593-3600. Epub 2020 Oct 13 doi: 10.1002/ajmg.a.61908. PMID: 33048444Free PMC Article
Danyel M, Kortüm F, Dathe K, Kutsche K, Horn D
Am J Med Genet A 2018 Apr;176(4):992-996. doi: 10.1002/ajmg.a.38635. PMID: 29575616
White J, Mazzeu JF, Hoischen A, Jhangiani SN, Gambin T, Alcino MC, Penney S, Saraiva JM, Hove H, Skovby F, Kayserili H, Estrella E, Vulto-van Silfhout AT, Steehouwer M, Muzny DM, Sutton VR, Gibbs RA; Baylor-Hopkins Center for Mendelian Genomics, Lupski JR, Brunner HG, van Bon BW, Carvalho CM
Am J Hum Genet 2015 Apr 2;96(4):612-22. Epub 2015 Mar 26 doi: 10.1016/j.ajhg.2015.02.015. PMID: 25817016Free PMC Article
Beiraghi S, Leon-Salazar V, Larson BE, John MT, Cunningham ML, Petryk A, Lohr JL
Clin Genet 2011 Jul;80(1):15-24. Epub 2011 May 16 doi: 10.1111/j.1399-0004.2011.01683.x. PMID: 21496006
Person AD, Beiraghi S, Sieben CM, Hermanson S, Neumann AN, Robu ME, Schleiffarth JR, Billington CJ Jr, van Bokhoven H, Hoogeboom JM, Mazzeu JF, Petryk A, Schimmenti LA, Brunner HG, Ekker SC, Lohr JL
Dev Dyn 2010 Jan;239(1):327-37. doi: 10.1002/dvdy.22156. PMID: 19918918Free PMC Article

Therapy

Gignac SJ, Hosseini-Farahabadi S, Akazawa T, Schuck NJ, Fu K, Richman JM
Hum Mol Genet 2019 Jul 15;28(14):2395-2414. doi: 10.1093/hmg/ddz071. PMID: 31032853Free PMC Article

Prognosis

Hosseini-Farahabadi S, Gignac SJ, Danescu A, Fu K, Richman JM
J Dent Res 2017 Oct;96(11):1265-1272. Epub 2017 Jun 29 doi: 10.1177/0022034517716916. PMID: 28662348
White J, Mazzeu JF, Hoischen A, Jhangiani SN, Gambin T, Alcino MC, Penney S, Saraiva JM, Hove H, Skovby F, Kayserili H, Estrella E, Vulto-van Silfhout AT, Steehouwer M, Muzny DM, Sutton VR, Gibbs RA; Baylor-Hopkins Center for Mendelian Genomics, Lupski JR, Brunner HG, van Bon BW, Carvalho CM
Am J Hum Genet 2015 Apr 2;96(4):612-22. Epub 2015 Mar 26 doi: 10.1016/j.ajhg.2015.02.015. PMID: 25817016Free PMC Article
Castro S, Peraza E, Barraza A, Zapata M
J Clin Ultrasound 2014 Jun;42(5):297-300. Epub 2013 Oct 22 doi: 10.1002/jcu.22103. PMID: 24151023

Clinical prediction guides

Danyel M, Kortüm F, Dathe K, Kutsche K, Horn D
Am J Med Genet A 2018 Apr;176(4):992-996. doi: 10.1002/ajmg.a.38635. PMID: 29575616
Hosseini-Farahabadi S, Gignac SJ, Danescu A, Fu K, Richman JM
J Dent Res 2017 Oct;96(11):1265-1272. Epub 2017 Jun 29 doi: 10.1177/0022034517716916. PMID: 28662348
White JJ, Mazzeu JF, Hoischen A, Bayram Y, Withers M, Gezdirici A, Kimonis V, Steehouwer M, Jhangiani SN, Muzny DM, Gibbs RA; Baylor-Hopkins Center for Mendelian Genomics, van Bon BWM, Sutton VR, Lupski JR, Brunner HG, Carvalho CMB
Am J Hum Genet 2016 Mar 3;98(3):553-561. Epub 2016 Feb 25 doi: 10.1016/j.ajhg.2016.01.005. PMID: 26924530Free PMC Article
White J, Mazzeu JF, Hoischen A, Jhangiani SN, Gambin T, Alcino MC, Penney S, Saraiva JM, Hove H, Skovby F, Kayserili H, Estrella E, Vulto-van Silfhout AT, Steehouwer M, Muzny DM, Sutton VR, Gibbs RA; Baylor-Hopkins Center for Mendelian Genomics, Lupski JR, Brunner HG, van Bon BW, Carvalho CM
Am J Hum Genet 2015 Apr 2;96(4):612-22. Epub 2015 Mar 26 doi: 10.1016/j.ajhg.2015.02.015. PMID: 25817016Free PMC Article

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