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Autosomal dominant Robinow syndrome 2(DRS2)

MedGen UID:
897039
Concept ID:
C4225363
Disease or Syndrome
Synonyms: DRS2; ROBINOW SYNDROME, AUTOSOMAL DOMINANT 2
 
Gene (location): DVL1 (1p36.33)
 
Monarch Initiative: MONDO:0014591
OMIM®: 616331

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 description

From OMIM
Robinow syndrome is a skeletal dysplasia characterized by distinctive facial features, including midface hypoplasia, hypertelorism, a short nose, and a broad mouth, known collectively as 'fetal facies.' Additional features include mesomelic dwarfism, macrocephaly, gingival hypertrophy, dental malocclusion, genital hypoplasia, and brachydactyly (summary by Bunn et al., 2015). Additionally, increased skull bone density and appendicular osteosclerosis are present in patients with DRS2 (White et al., 2015; Bunn et al., 2015). For a discussion of genetic heterogeneity of Robinow syndrome, see RRS (268310).  http://www.omim.org/entry/616331

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).
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.
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.
Short distal phalanx of finger
MedGen UID:
326590
Concept ID:
C1839829
Finding
Short distance from the end of the finger to the most distal interphalangeal crease or the distal interphalangeal joint flexion point. That is, hypoplasia of one or more of the distal phalanx of finger.
Partial duplication of the phalanx of hand
MedGen UID:
869692
Concept ID:
C4024120
Anatomical Abnormality
A partial duplication, depending on severity leading to a broad or bifid appearance, affecting one or more of the phalanges of the hand. As opposed to a complete duplication there is still a variable degree of fusion between the duplicated bones.
Partial duplication of thumb phalanx
MedGen UID:
909031
Concept ID:
C4082168
Anatomical Abnormality
A partial duplication, depending on severity leading to a broad or bifid appearance, affecting one or more of the phalanges of the thumb. As opposed to a complete duplication there is still a variable degree of fusion between the duplicated bones.
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).
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).
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.
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.
Mixed hearing impairment
MedGen UID:
102336
Concept ID:
C0155552
Disease or Syndrome
A type of hearing loss resulting from a combination of conductive hearing impairment and sensorineural hearing impairment.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
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.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Camptodactyly
MedGen UID:
195780
Concept ID:
C0685409
Congenital Abnormality
The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers or toes cannot be extended to 180 degrees by either active or passive extension.
Calvarial osteosclerosis
MedGen UID:
340927
Concept ID:
C1855657
Finding
An increase in bone density affecting the calvaria (roof of the skull).
Thickened calvaria
MedGen UID:
346823
Concept ID:
C1858452
Finding
The presence of an abnormally thick calvaria.
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.
Wide mouth
MedGen UID:
44238
Concept ID:
C0024433
Congenital Abnormality
Distance between the oral commissures more than 2 SD above the mean. Alternatively, an apparently increased width of the oral aperture (subjective).
Dental malocclusion
MedGen UID:
9869
Concept ID:
C0024636
Anatomical Abnormality
Dental malocclusion refers to an abnormality of the occlusion, or alignment, of the teeth and the way the upper and lower teeth fit together, resulting in overcrowding of teeth or in abnormal bite patterns.
Dental crowding
MedGen UID:
11850
Concept ID:
C0040433
Finding
Changes in alignment of teeth in the dental arch
High forehead
MedGen UID:
65991
Concept ID:
C0239676
Finding
An abnormally increased height of the forehead.
Abnormality of the dentition
MedGen UID:
78084
Concept ID:
C0262444
Finding
Any abnormality of the teeth.
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.
Cleft soft palate
MedGen UID:
98471
Concept ID:
C0432098
Congenital Abnormality
Cleft of the soft palate (also known as the velum, or muscular palate) as a result of a developmental defect occurring between the 7th and 12th week of pregnancy. Cleft soft palate can cause functional abnormalities of the Eustachian tube with resulting middle ear anomalies and hearing difficulties, as well as speech problems associated with hypernasal speech due to velopharyngeal insufficiency.
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).
Triangular mouth
MedGen UID:
336578
Concept ID:
C1849341
Finding
The presence of a triangular form of the mouth.
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).
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).
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.
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.
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

Etiology

Schwartz DD, Fein RH, Carvalho CMB, Sutton VR, Mazzeu JF, Axelrad ME
Am J Med Genet A 2021 Dec;185(12):3576-3583. Epub 2020 Sep 21 doi: 10.1002/ajmg.a.61854. PMID: 32954672
Kaissi AA, Kenis V, Shboul M, Grill F, Ganger R, Kircher SG
J Investig Med High Impact Case Rep 2020 Jan-Dec;8:2324709620911771. doi: 10.1177/2324709620911771. PMID: 32172608Free PMC Article

Diagnosis

Smith CM, Guinon K, Bachir S, Tise CG
Prenat Diagn 2024 Aug;44(9):1119-1122. Epub 2024 Jul 9 doi: 10.1002/pd.6632. PMID: 38982229
Cammarata-Scalisi F, Avendaño A, Callea M
Arch Argent Pediatr 2018 Dec 1;116(6):437-444. doi: 10.5546/aap.2018.eng.437. PMID: 30457727
Nagasaki K, Nishimura G, Kikuchi T, Nyuzuki H, Sasaki S, Ogawa Y, Saitoh A
Am J Med Genet A 2018 Mar;176(3):739-742. Epub 2018 Jan 31 doi: 10.1002/ajmg.a.38623. PMID: 29383834
Tamhankar PM, Vasudevan L, Kondurkar S, Yashaswini K, Agarwalla SK, Nair M, Ramkumar TV, Chaubal N, Chennuri VS
J Clin Res Pediatr Endocrinol 2014;6(2):79-83. doi: 10.4274/Jcrpe.1233. PMID: 24932600Free PMC Article
Butler MG, Wadlington WB
Clin Genet 1987 Feb;31(2):77-85. doi: 10.1111/j.1399-0004.1987.tb02773.x. PMID: 3549067Free 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
Parıltay E, Hazan F, Ataman E, Demir K, Etlik Ö, Özbek E, Özkan B
J Pediatr Endocrinol Metab 2016 Sep 1;29(9):1111-4. doi: 10.1515/jpem-2015-0482. PMID: 27544718
Lv D, Luo Y, Yang W, Cao L, Wen Y, Zhao X, Sun M, Lo WH, Zhang X
J Hum Genet 2009 Jul;54(7):422-5. Epub 2009 May 22 doi: 10.1038/jhg.2009.48. PMID: 19461659

Clinical prediction guides

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
Lv D, Luo Y, Yang W, Cao L, Wen Y, Zhao X, Sun M, Lo WH, Zhang X
J Hum Genet 2009 Jul;54(7):422-5. Epub 2009 May 22 doi: 10.1038/jhg.2009.48. PMID: 19461659

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