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Congenital muscular hypertrophy-cerebral syndrome(CDLS2)

MedGen UID:
315658
Concept ID:
C1802395
Disease or Syndrome
Synonyms: CDLS2; Cornelia de Lange syndrome 2; SMC1A-Related Cornelia de Lange Syndrome
SNOMED CT: Congenital muscular hypertrophy-cerebral syndrome (55016009); Bruch-de Lange syndrome (55016009)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Sources: HPO, OMIM
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Sources: HPO, OMIM
A mode of inheritance that is observed for dominant traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked dominant disorders tend to manifest very severely in affected males. The severity of manifestation in females may depend on the degree of skewed X inactivation.
 
Gene (location): SMC1A (Xp11.22)
 
Monarch Initiative: MONDO:0010370
OMIM®: 300590

Disease characteristics

Excerpted from the GeneReview: Cornelia de Lange Syndrome
Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. [from GeneReviews]
Authors:
Matthew A Deardorff  |  Sarah E Noon  |  Ian D Krantz   view full author information

Additional description

From OMIM
Cornelia de Lange syndrome is a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems. Affected individuals have dysmorphic facial features, cleft palate, distal limb defects, growth retardation, and developmental delay. About 4 to 6% of patients have mutations in the X-linked SMC1A gene, whereas about 60% have mutations in the NIPBL gene (608667) on chromosome 5p13 (CDLS1; 122470) (summary by Musio et al., 2006, Hoppman-Chaney et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of Cornelia de Lange syndrome, see 122470.  http://www.omim.org/entry/300590

Clinical features

From HPO
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.
Small hand
MedGen UID:
108279
Concept ID:
C0575802
Finding
Disproportionately small hand.
Short foot
MedGen UID:
376415
Concept ID:
C1848673
Finding
A measured foot length that is more than 2 SD below the mean for a newborn of 27 - 41 weeks gestation, or foot that is less than the 3rd centile for individuals from birth to 16 years of age (objective). Alternatively, a foot that appears disproportionately short (subjective).
Limited elbow movement
MedGen UID:
337930
Concept ID:
C1849955
Finding
Proximal placement of thumb
MedGen UID:
356033
Concept ID:
C1865572
Finding
Proximal mislocalization of the thumb.
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).
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract.
Cutis marmorata
MedGen UID:
78093
Concept ID:
C0263401
Disease or Syndrome
A reticular discoloration of the skin with cyanotic (reddish-blue appearing) areas surrounding pale central areas due to dilation of capillary blood vessels and stagnation of blood within the vessels. Cutis marmorata generally occurs on the legs, arms and trunk and is often more severe in cold weather.
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).
Intrauterine growth retardation
MedGen UID:
473406
Concept ID:
C1386048
Pathologic Function
Postnatal growth retardation
MedGen UID:
395343
Concept ID:
C1859778
Finding
Slow or limited growth after birth.
Gastroesophageal reflux
MedGen UID:
1368658
Concept ID:
C4317146
Finding
A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
Diminished mental function.
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.
Poor speech
MedGen UID:
341172
Concept ID:
C1848207
Finding
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
A broad category of disorders characterized by an impairment to the intelligence an individual possesses. These impairments can result from trauma, birth, or disease and are not restricted to any particular age group.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Brachycephaly
MedGen UID:
113165
Concept ID:
C0221356
Congenital Abnormality
An abnormality of skull shape characterized by a decreased anterior-posterior diameter. That is, a cephalic index greater than 81%. Alternatively, an apparently shortened anteroposterior dimension (length) of the head compared to width.
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.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Small hand
MedGen UID:
108279
Concept ID:
C0575802
Finding
Disproportionately small hand.
Short foot
MedGen UID:
376415
Concept ID:
C1848673
Finding
A measured foot length that is more than 2 SD below the mean for a newborn of 27 - 41 weeks gestation, or foot that is less than the 3rd centile for individuals from birth to 16 years of age (objective). Alternatively, a foot that appears disproportionately short (subjective).
Limited elbow movement
MedGen UID:
337930
Concept ID:
C1849955
Finding
Proximal placement of thumb
MedGen UID:
356033
Concept ID:
C1865572
Finding
Proximal mislocalization of the thumb.
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).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Brachycephaly
MedGen UID:
113165
Concept ID:
C0221356
Congenital Abnormality
An abnormality of skull shape characterized by a decreased anterior-posterior diameter. That is, a cephalic index greater than 81%. Alternatively, an apparently shortened anteroposterior dimension (length) of the head compared to width.
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).
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Synophrys
MedGen UID:
98132
Concept ID:
C0431447
Congenital Abnormality
Meeting of the medial eyebrows in the midline.
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
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.
Narrow forehead
MedGen UID:
326956
Concept ID:
C1839758
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations below the mean (objective); or apparently narrow intertemporal region (subjective).
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).
Low anterior hairline
MedGen UID:
331280
Concept ID:
C1842366
Finding
Distance between the hairline (trichion) and the glabella (the most prominent point on the frontal bone above the root of the nose), in the midline, more than two SD below the mean. Alternatively, an apparently decreased distance between the hairline and the glabella.
Thick eyebrow
MedGen UID:
377914
Concept ID:
C1853487
Finding
Increased density/number and/or increased diameter of eyebrow hairs.
Long eyelashes
MedGen UID:
342955
Concept ID:
C1853738
Finding
Mid upper eyelash length >10 mm or increased length of the eyelashes (subjective).
Prominent nasal bridge
MedGen UID:
343051
Concept ID:
C1854113
Finding
Anterior positioning of the nasal root in comparison to the usual positioning for age.
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.
Highly arched eyebrow
MedGen UID:
358357
Concept ID:
C1868571
Finding
Increased height of the central portion of the eyebrow, forming a crescent, semicircular, or inverted U shape.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Hirsutism
MedGen UID:
42461
Concept ID:
C0019572
Disease or Syndrome
Abnormally increased hair growth referring to a male pattern of body hair (androgenic hair).
Cutis marmorata
MedGen UID:
78093
Concept ID:
C0263401
Disease or Syndrome
A reticular discoloration of the skin with cyanotic (reddish-blue appearing) areas surrounding pale central areas due to dilation of capillary blood vessels and stagnation of blood within the vessels. Cutis marmorata generally occurs on the legs, arms and trunk and is often more severe in cold weather.
Synophrys
MedGen UID:
98132
Concept ID:
C0431447
Congenital Abnormality
Meeting of the medial eyebrows in the midline.
Low anterior hairline
MedGen UID:
331280
Concept ID:
C1842366
Finding
Distance between the hairline (trichion) and the glabella (the most prominent point on the frontal bone above the root of the nose), in the midline, more than two SD below the mean. Alternatively, an apparently decreased distance between the hairline and the glabella.
Thick eyebrow
MedGen UID:
377914
Concept ID:
C1853487
Finding
Increased density/number and/or increased diameter of eyebrow hairs.
Long eyelashes
MedGen UID:
342955
Concept ID:
C1853738
Finding
Mid upper eyelash length >10 mm or increased length of the eyelashes (subjective).
Highly arched eyebrow
MedGen UID:
358357
Concept ID:
C1868571
Finding
Increased height of the central portion of the eyebrow, forming a crescent, semicircular, or inverted U shape.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).

Recent clinical studies

Etiology

Srivastava S, Clark B, Landy-Schmitt C, Offermann EA, Kline AD, Wilkinson ST, Grados MA
J Autism Dev Disord 2021 May;51(5):1748-1758. doi: 10.1007/s10803-020-04617-x. PMID: 32809170
Gupta VS, Khan AM, Ebanks AH, Lally PA, Lally KP, Harting MT; Congenital Diaphragmatic Hernia Study Group.
J Pediatr Surg 2021 Apr;56(4):697-699. Epub 2020 Jun 11 doi: 10.1016/j.jpedsurg.2020.06.003. PMID: 32762940
Parma B, Cianci P, Decimi V, Mariani M, Provero MC, Funari C, Tajè S, Apuril E, Cereda A, Panceri R, Maitz S, Fossati C, Selicorni A
Am J Med Genet A 2020 Sep;182(9):2094-2101. Epub 2020 Jul 9 doi: 10.1002/ajmg.a.61749. PMID: 32648352
Groves L, Moss J, Crawford H, Nelson L, Stinton C, Singla G, Oliver C
J Neurodev Disord 2019 Jun 7;11(1):6. doi: 10.1186/s11689-019-9269-x. PMID: 31174462Free PMC Article
Santoro C, Apicella A, Casale F, La Manna A, Di Martino M, Di Pinto D, Indolfi C, Perrotta S
BMC Cancer 2016 Jun 13;16:365. doi: 10.1186/s12885-016-2402-2. PMID: 27291393Free PMC Article

Diagnosis

Srivastava S, Clark B, Landy-Schmitt C, Offermann EA, Kline AD, Wilkinson ST, Grados MA
J Autism Dev Disord 2021 May;51(5):1748-1758. doi: 10.1007/s10803-020-04617-x. PMID: 32809170
Avagliano L, Parenti I, Grazioli P, Di Fede E, Parodi C, Mariani M, Kaiser FJ, Selicorni A, Gervasini C, Massa V
Clin Genet 2020 Jan;97(1):3-11. Epub 2019 Nov 24 doi: 10.1111/cge.13674. PMID: 31721174
Sarogni P, Pallotta MM, Musio A
J Med Genet 2020 May;57(5):289-295. Epub 2019 Nov 8 doi: 10.1136/jmedgenet-2019-106277. PMID: 31704779Free PMC Article
Kline AD, Krantz ID, Bando M, Shirahige K, Chea S, Sakata T, Rao S, Dorsett D, Singh VP, Gerton JL, Horsfield JA, Calof AL, Katz O, Grados M, Raible S, Barañano K, Lyon G, Musio A, Carrico CS, Clemens DK, Caudill P, Massa V, McGill BE, Dommestrup A, O'Connor J, Haaland RE
Am J Med Genet A 2019 Jun;179(6):1080-1090. Epub 2019 Mar 15 doi: 10.1002/ajmg.a.61108. PMID: 30874362
Kline AD, Krantz ID, Deardorff MA, Shirahige K, Dorsett D, Gerton JL, Wu M, Mehta D, Mills JA, Carrico CS, Noon S, Herrera PS, Horsfield JA, Bettale C, Morgan J, Huisman SA, Moss J, McCleery J, Grados M, Hansen BD, Srivastava S, Taylor-Snell E, Kerr LM, Katz O, Calof AL, Musio A, Egense A, Haaland RE
Am J Med Genet A 2017 May;173(5):1172-1185. Epub 2017 Feb 12 doi: 10.1002/ajmg.a.38161. PMID: 28190301Free PMC Article

Therapy

El Hamichi S, Kon Graversen V, Gold AS, Berrocal AM, Murray TG
Optom Vis Sci 2021 Feb 1;98(2):104-108. doi: 10.1097/OPX.0000000000001639. PMID: 33617168
Mugheddu C, Dell'Antonia M, Sanna S, Agosta D, Atzori L, Rongioletti F
Dermatol Ther 2020 Jul;33(4):e13433. Epub 2020 Apr 29 doi: 10.1111/dth.13433. PMID: 32306513
Lei M, Liang D, Yang Y, Mitsuhashi S, Katoh K, Miyake N, Frith MC, Wu L, Matsumoto N
J Hum Genet 2020 Aug;65(8):667-674. Epub 2020 Apr 15 doi: 10.1038/s10038-020-0754-6. PMID: 32296131Free PMC Article
Gupta A, Naranje KM, Singh A, Pandita A, Gupta G, Mandal K, Pradhan M
Indian J Pediatr 2019 Jul;86(7):645-647. Epub 2019 Mar 16 doi: 10.1007/s12098-019-02908-5. PMID: 30879238
de Graaf M, Kant SG, Wit JM, Willem Redeker EJ, Eduard Santen GW, Henriëtta Verkerk AJM, Uitterlinden AG, Losekoot M, Oostdijk W
J Clin Res Pediatr Endocrinol 2017 Dec 15;9(4):366-370. Epub 2017 Jun 7 doi: 10.4274/jcrpe.4349. PMID: 28588001Free PMC Article

Prognosis

Gupta VS, Khan AM, Ebanks AH, Lally PA, Lally KP, Harting MT; Congenital Diaphragmatic Hernia Study Group.
J Pediatr Surg 2021 Apr;56(4):697-699. Epub 2020 Jun 11 doi: 10.1016/j.jpedsurg.2020.06.003. PMID: 32762940
Thanh DC, Ngoc CTB, Nguyen NL, Vu CD, Tung NV, Nguyen HH
Medicina (Kaunas) 2020 Feb 14;56(2) doi: 10.3390/medicina56020076. PMID: 32074972Free PMC Article
Latorre-Pellicer A, Ascaso Á, Trujillano L, Gil-Salvador M, Arnedo M, Lucia-Campos C, Antoñanzas-Pérez R, Marcos-Alcalde I, Parenti I, Bueno-Lozano G, Musio A, Puisac B, Kaiser FJ, Ramos FJ, Gómez-Puertas P, Pié J
Int J Mol Sci 2020 Feb 4;21(3) doi: 10.3390/ijms21031042. PMID: 32033219Free PMC Article
Gudmundsson S, Annerén G, Marcos-Alcalde Í, Wilbe M, Melin M, Gómez-Puertas P, Bondeson ML
Eur J Med Genet 2019 Jun;62(6):103526. Epub 2018 Aug 17 doi: 10.1016/j.ejmg.2018.08.007. PMID: 30125677
Decimi V, Parma B, Panceri R, Fossati C, Mariani M, Russo S, Gervasini CC, Cheli M, Cereda A, Selicorni A
Am J Med Genet A 2018 Sep;176(9):1865-1871. Epub 2018 Sep 21 doi: 10.1002/ajmg.a.40372. PMID: 30240081

Clinical prediction guides

Pablo MJ, Pamplona P, Haddad M, Benavente I, Latorre-Pellicer A, Arnedo M, Trujillano L, Bueno-Lozano G, Kerr LM, Huisman SA, Kaiser FJ, Ramos F, Kline AD, Pie J, Puisac B
Orphanet J Rare Dis 2021 Oct 30;16(1):458. doi: 10.1186/s13023-021-02082-y. PMID: 34717699Free PMC Article
Srivastava S, Clark B, Landy-Schmitt C, Offermann EA, Kline AD, Wilkinson ST, Grados MA
J Autism Dev Disord 2021 May;51(5):1748-1758. doi: 10.1007/s10803-020-04617-x. PMID: 32809170
Gupta VS, Khan AM, Ebanks AH, Lally PA, Lally KP, Harting MT; Congenital Diaphragmatic Hernia Study Group.
J Pediatr Surg 2021 Apr;56(4):697-699. Epub 2020 Jun 11 doi: 10.1016/j.jpedsurg.2020.06.003. PMID: 32762940
Latorre-Pellicer A, Ascaso Á, Trujillano L, Gil-Salvador M, Arnedo M, Lucia-Campos C, Antoñanzas-Pérez R, Marcos-Alcalde I, Parenti I, Bueno-Lozano G, Musio A, Puisac B, Kaiser FJ, Ramos FJ, Gómez-Puertas P, Pié J
Int J Mol Sci 2020 Feb 4;21(3) doi: 10.3390/ijms21031042. PMID: 32033219Free PMC Article
Groves L, Moss J, Crawford H, Nelson L, Stinton C, Singla G, Oliver C
J Neurodev Disord 2019 Jun 7;11(1):6. doi: 10.1186/s11689-019-9269-x. PMID: 31174462Free PMC Article

Recent systematic reviews

Bergeron M, Chang K, Ishman SL
Laryngoscope 2020 Apr;130(4):E122-E133. Epub 2019 Jul 13 doi: 10.1002/lary.28169. PMID: 31301187
Miura da Costa K, Saxena AK
Acta Paediatr 2018 Dec;107(12):2054-2058. Epub 2018 Jul 20 doi: 10.1111/apa.14476. PMID: 29949184
Livingstone DM, Smith KA, Lange B
Diving Hyperb Med 2017 Jun;47(2):97-109. doi: 10.28920/dhm47.2.97-109. PMID: 28641322Free PMC Article
Mulder PA, Huisman SA, Hennekam RC, Oliver C, van Balkom ID, Piening S
Dev Med Child Neurol 2017 Apr;59(4):361-366. Epub 2016 Dec 18 doi: 10.1111/dmcn.13361. PMID: 27988966
Richards C, Jones C, Groves L, Moss J, Oliver C
Lancet Psychiatry 2015 Oct;2(10):909-16. Epub 2015 Sep 1 doi: 10.1016/S2215-0366(15)00376-4. PMID: 26341300

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