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Leukocyte adhesion deficiency type II(LAD2; RHS; CDGIIc; CDG2C)

MedGen UID:
96022
Concept ID:
C0398739
Disease or Syndrome
Synonyms: CDG 2C; CDG IIc; Congenital disorder of glycosylation type 2C; CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIc; Leukocyte adhesion deficiency type 2; Rambam Hasharon syndrome; SLC35C1-CDG (CDG-IIc)
SNOMED CT: LAD - Leukocyte adhesion deficiency type 2 (234583001); Leukocyte adhesion molecule deficiency - type 2 (234583001); Sialyl-Lewis X defect (234583001); Leukocyte adhesion deficiency - type 2 (234583001); Congenital disorder of glycosylation type IIc (234583001)
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): SLC35C1 (11p11.2)
 
Monarch Initiative: MONDO:0009953
OMIM®: 266265
Orphanet: ORPHA99843

Definition

Congenital disorder of glycosylation type IIc (CDG2C) is an autosomal recessive disorder characterized by moderate to severe psychomotor retardation, mild dysmorphism, and impaired neutrophil motility. It is a member of a group of disorders with a defect in the processing of protein-bound glycans. For a general overview of congenital disorders of glycosylation (CDGs), see CDG1A (212065) and CDG2A (212066). Frydman (1996) contended that the neutrophil defect in CDG2C, which has been referred to as 'leukocyte adhesion deficiency type II' (LAD2), is a manifestation of the disorder and that there are no cases of 'primary' LAD II. Etzioni and Harlan (1999) provided a comprehensive review of both leukocyte adhesion deficiency-1 (LAD1; 116920) and LAD2. While the functional neutrophil studies are similar in the 2 LADs, the clinical course is milder in LAD2. Furthermore, patients with LAD2 present other abnormal features, such as growth and mental retardation, which are related to the primary defect in fucose metabolism. Delayed separation of the umbilical cord occurs in LAD1. For a discussion of genetic heterogeneity of LAD, see 116920. [from OMIM]

Clinical features

From HPO
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Inborn organic aciduria
MedGen UID:
66037
Concept ID:
C0241775
Finding
Excretion of non-amino organic acids in urine.
Oligosacchariduria
MedGen UID:
869388
Concept ID:
C4023815
Finding
Increased urinary excretion of oligosaccharides (low molecular weight carbohydrate chains composed of at least three monosaccharide subunits), derived from a partial degradation of glycoproteins.
Mucopolysacchariduria
MedGen UID:
870284
Concept ID:
C4024726
Finding
Excessive amounts of mucopolysaccharide in the urine.
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).
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).
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Intense feelings of nervousness, tension, or panic often arise in response to interpersonal stresses. There is worry about the negative effects of past unpleasant experiences and future negative possibilities. Individuals may feel fearful, apprehensive, or threatened by uncertainty, and they may also have fears of falling apart or losing control.
Autism
MedGen UID:
13966
Concept ID:
C0004352
Mental or Behavioral Dysfunction
Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996; Risch et al., 1999). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (see ASPG1; 608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008). Genetic studies in autism often include family members with these less stringent diagnoses (Schellenberg et al., 2006). Levy et al. (2009) provided a general review of autism and autism spectrum disorder, including epidemiology, characteristics of the disorder, diagnosis, neurobiologic hypotheses for the etiology, genetics, and treatment options. Genetic Heterogeneity of Autism Autism is considered to be a complex multifactorial disorder involving many genes. Accordingly, several loci have been identified, some or all of which may contribute to the phenotype. Included in this entry is AUTS1, which has been mapped to chromosome 7q22. Other susceptibility loci include AUTS3 (608049), which maps to chromosome 13q14; AUTS4 (608636), which maps to chromosome 15q11; AUTS6 (609378), which maps to chromosome 17q11; AUTS7 (610676), which maps to chromosome 17q21; AUTS8 (607373), which maps to chromosome 3q25-q27; AUTS9 (611015), which maps to chromosome 7q31; AUTS10 (611016), which maps to chromosome 7q36; AUTS11 (610836), which maps to chromosome 1q41; AUTS12 (610838), which maps to chromosome 21p13-q11; AUTS13 (610908), which maps to chromosome 12q14; AUTS14A (611913), which has been found in patients with a deletion of a region of 16p11.2; AUTS14B (614671), which has been found in patients with a duplication of a region of 16p11.2; AUTS15 (612100), associated with mutation in the CNTNAP2 gene (604569) on chromosome 7q35-q36; AUTS16 (613410), associated with mutation in the SLC9A9 gene (608396) on chromosome 3q24; AUTS17 (613436), associated with mutation in the SHANK2 gene (603290) on chromosome 11q13; AUTS18 (615032), associated with mutation in the CHD8 gene (610528) on chromosome 14q11; AUTS19 (615091), associated with mutation in the EIF4E gene (133440) on chromosome 4q23; and AUTS20 (618830), associated with mutation in the NLGN1 gene (600568) on chromosome 3q26. (NOTE: the symbol 'AUTS2' has been used to refer to a gene on chromosome 7q11 (KIAA0442; 607270) and therefore is not used as a part of this autism locus series.) There are several X-linked forms of autism susceptibility: AUTSX1 (300425), associated with mutations in the NLGN3 gene (300336); AUTSX2 (300495), associated with mutations in NLGN4 (300427); AUTSX3 (300496), associated with mutations in MECP2 (300005); AUTSX4 (300830), associated with variation in the region on chromosome Xp22.11 containing the PTCHD1 gene (300828); AUTSX5 (300847), associated with mutations in the RPL10 gene (312173); and AUTSX6 (300872), associated with mutation in the TMLHE gene (300777). A locus on chromosome 2q (606053) associated with a phenotype including intellectual disability and speech deficits was formerly designated AUTS5. Folstein and Rosen-Sheidley (2001) reviewed the genetics of autism.
Febrile seizure (within the age range of 3 months to 6 years)
MedGen UID:
3232
Concept ID:
C0009952
Disease or Syndrome
A febrile seizure is any type of seizure (most often a generalized tonic-clonic seizure) occurring with fever (at least 38 degrees Celsius) but in the absence of central nervous system infection, severe metabolic disturbance or other alternative precipitant in children between the ages of 3 months and 6 years.
Echolalia
MedGen UID:
8532
Concept ID:
C0013528
Mental or Behavioral Dysfunction
Echolalia is the automatic imitative repetition of sounds, words, or phrases in the absence of explicit awareness. The repeated words or phrases are typically odd or used in a non-social manner. These can be words or phrases that the affected individual has heard or invented.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
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.
Compulsive behaviors
MedGen UID:
109373
Concept ID:
C0600104
Mental or Behavioral Dysfunction
Behavior that consists of repetitive acts, characterized by the feeling that one "has to" perform them, while being aware that these acts are not in line with one's overall goal.
Autistic behavior
MedGen UID:
163547
Concept ID:
C0856975
Mental or Behavioral Dysfunction
Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.
Intellectual disability, progressive
MedGen UID:
337397
Concept ID:
C1846149
Mental or Behavioral Dysfunction
The term progressive intellectual disability should be used if intelligence decreases/deteriorates over time.
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Cellulitis
MedGen UID:
40174
Concept ID:
C0007642
Disease or Syndrome
A bacterial infection and inflammation of the skin und subcutaneous tissues.
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.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Bronchiolitis
MedGen UID:
14235
Concept ID:
C0006271
Disease or Syndrome
Inflammation of the bronchioles.
Periodontitis
MedGen UID:
45815
Concept ID:
C0031099
Disease or Syndrome
Inflammation of the periodontium.
Pneumonia
MedGen UID:
10813
Concept ID:
C0032285
Disease or Syndrome
Inflammation of any part of the lung parenchyma.
Neutrophilia
MedGen UID:
57729
Concept ID:
C0151683
Finding
Increased number of neutrophils circulating in blood.
Recurrent otitis media
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Reduction of neutrophil motility
MedGen UID:
870745
Concept ID:
C4025201
Finding
An abnormal reduction of the cell motility of neutrophils.
Abnormal circulating amino acid concentration
MedGen UID:
871177
Concept ID:
C4025653
Finding
The presence of an abnormal decrease or increase of one or more amino acids in the blood circulation.
Bulbous nose
MedGen UID:
66013
Concept ID:
C0240543
Finding
Increased volume and globular shape of the anteroinferior aspect of the nose.
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Widow peak
MedGen UID:
342891
Concept ID:
C1853486
Finding
Frontal hairline with bilateral arcs to a low point in the midline of the forehead.
Prominent fingertip pads
MedGen UID:
322758
Concept ID:
C1835807
Finding
A soft tissue prominence of the ventral aspects of the fingertips. The term "persistent fetal fingertip pads" is often used as a synonym, but should better not be used because it implies knowledge of history of the patient which often does not exist.
Abnormality of the integument
MedGen UID:
871273
Concept ID:
C4025761
Anatomical Abnormality
An abnormality of the integument, which consists of the skin and the superficial fascia.
Abnormal serum insulin-like growth factor 1 level
MedGen UID:
892647
Concept ID:
C4072896
Finding
An anomalous level of insulin-like growth factor 1 (IGF1) in the blood circulation.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Leukocyte adhesion deficiency type II in Orphanet.

Professional guidelines

PubMed

Etzioni A, Sturla L, Antonellis A, Green ED, Gershoni-Baruch R, Berninsone PM, Hirschberg CB, Tonetti M
Am J Med Genet 2002 Jun 15;110(2):131-5. doi: 10.1002/ajmg.10423. PMID: 12116250

Recent clinical studies

Etiology

Tahata S, Raymond K, Quade M, Barnes S, Boyer S, League S, Kumanovics A, Abraham R, Jacob E, Menon P, Morava E
Am J Med Genet A 2022 Jul;188(7):2005-2018. Epub 2022 Mar 26 doi: 10.1002/ajmg.a.62737. PMID: 35338746
Cooper N, Li YT, Möller A, Schulz-Weidner N, Sachs UJ, Wagner F, Hackstein H, Wienzek-Lischka S, Grüneberg M, Wild MK, Bein G, Marquardt T
Clin Immunol 2020 Dec;221:108599. Epub 2020 Sep 28 doi: 10.1016/j.clim.2020.108599. PMID: 32992000
Cagdas D, Yilmaz M, Kandemir N, Tezcan I, Etzioni A, Sanal Ö
J Clin Immunol 2014 Nov;34(8):1009-14. Epub 2014 Sep 21 doi: 10.1007/s10875-014-0091-7. PMID: 25239688
Gazit Y, Mory A, Etzioni A, Frydman M, Scheuerman O, Gershoni-Baruch R, Garty BZ
J Clin Immunol 2010 Mar;30(2):308-13. Epub 2010 Jan 23 doi: 10.1007/s10875-009-9354-0. PMID: 20099014
Becker DJ, Lowe JB
Biochim Biophys Acta 1999 Oct 8;1455(2-3):193-204. doi: 10.1016/s0925-4439(99)00071-x. PMID: 10571012

Diagnosis

Cooper N, Li YT, Möller A, Schulz-Weidner N, Sachs UJ, Wagner F, Hackstein H, Wienzek-Lischka S, Grüneberg M, Wild MK, Bein G, Marquardt T
Clin Immunol 2020 Dec;221:108599. Epub 2020 Sep 28 doi: 10.1016/j.clim.2020.108599. PMID: 32992000
Schneider M, Al-Shareffi E, Haltiwanger RS
Glycobiology 2017 Jul 1;27(7):601-618. doi: 10.1093/glycob/cwx034. PMID: 28430973Free PMC Article
Cagdas D, Yilmaz M, Kandemir N, Tezcan I, Etzioni A, Sanal Ö
J Clin Immunol 2014 Nov;34(8):1009-14. Epub 2014 Sep 21 doi: 10.1007/s10875-014-0091-7. PMID: 25239688
Gazit Y, Mory A, Etzioni A, Frydman M, Scheuerman O, Gershoni-Baruch R, Garty BZ
J Clin Immunol 2010 Mar;30(2):308-13. Epub 2010 Jan 23 doi: 10.1007/s10875-009-9354-0. PMID: 20099014
Durand G, Seta N
Clin Chem 2000 Jun;46(6 Pt 1):795-805. PMID: 10839767

Therapy

Cooper N, Li YT, Möller A, Schulz-Weidner N, Sachs UJ, Wagner F, Hackstein H, Wienzek-Lischka S, Grüneberg M, Wild MK, Bein G, Marquardt T
Clin Immunol 2020 Dec;221:108599. Epub 2020 Sep 28 doi: 10.1016/j.clim.2020.108599. PMID: 32992000
Lühn K, Marquardt T, Harms E, Vestweber D
Blood 2001 Jan 1;97(1):330-2. doi: 10.1182/blood.v97.1.330. PMID: 11133780
Marquardt T, Lühn K, Srikrishna G, Freeze HH, Harms E, Vestweber D
Blood 1999 Dec 15;94(12):3976-85. PMID: 10590041

Prognosis

Skurska E, Szulc B, Kreczko K, Olczak M
Int J Biochem Cell Biol 2024 Aug;173:106602. Epub 2024 Jun 4 doi: 10.1016/j.biocel.2024.106602. PMID: 38843991
Schneider M, Al-Shareffi E, Haltiwanger RS
Glycobiology 2017 Jul 1;27(7):601-618. doi: 10.1093/glycob/cwx034. PMID: 28430973Free PMC Article
Etzioni A, Gershoni-Baruch R, Pollack S, Shehadeh N
J Allergy Clin Immunol 1998 Aug;102(2):323-4. doi: 10.1016/s0091-6749(98)70104-6. PMID: 9723680

Clinical prediction guides

Skurska E, Szulc B, Kreczko K, Olczak M
Int J Biochem Cell Biol 2024 Aug;173:106602. Epub 2024 Jun 4 doi: 10.1016/j.biocel.2024.106602. PMID: 38843991
Sturla L, Rampal R, Haltiwanger RS, Fruscione F, Etzioni A, Tonetti M
J Biol Chem 2003 Jul 18;278(29):26727-33. Epub 2003 May 8 doi: 10.1074/jbc.M304068200. PMID: 12738772
Becker DJ, Lowe JB
Glycobiology 2003 Jul;13(7):41R-53R. Epub 2003 Mar 19 doi: 10.1093/glycob/cwg054. PMID: 12651883
Körner C, Linnebank M, Koch HG, Harms E, von Figura K, Marquardt T
J Leukoc Biol 1999 Jul;66(1):95-8. doi: 10.1002/jlb.66.1.95. PMID: 10410995
Kuijpers TW, Etzioni A, Pollack S, Pals ST
Int Immunol 1997 Apr;9(4):607-13. doi: 10.1093/intimm/9.4.607. PMID: 9138022

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