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Alkuraya-Kucinskas syndrome(ALKKUCS)

MedGen UID:
1634304
Concept ID:
C4693347
Disease or Syndrome
Synonyms: ALKKUCS; ALKURAYA-KUCINSKAS SYNDROME
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): BLTP1 (4q27)
 
Monarch Initiative: MONDO:0060631
OMIM®: 617822
Orphanet: ORPHA610569

Definition

ALKKUCS is an autosomal recessive severe neurodevelopmental disorder characterized by arthrogryposis, brain abnormalities associated with cerebral parenchymal underdevelopment, and global developmental delay. Most affected individuals die in utero or soon after birth. Additional abnormalities may include hypotonia, dysmorphic facial features, and involvement of other organ systems, such as cardiac or renal. The few patients who survive have variable intellectual disability and may have seizures (summary by Gueneau et al., 2018). [from OMIM]

Clinical features

From HPO
Small scrotum
MedGen UID:
141577
Concept ID:
C0455792
Finding
Apparently small scrotum for age.
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.
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Hand clenching
MedGen UID:
65994
Concept ID:
C0239815
Finding
An abnormal hand posture in which the hands are clenched to fists. All digits held completely flexed at the metacarpophalangeal and interphalangeal joints. In prenatal sonography of the fetal clenched hand, the index finger overlaps a clenched fist formed by the other digits. The proximal interphalangeal articulation of the index finger is flexed and ulnarly deviated, and the thumb is adducted.
Thumbs, congenital Clasped
MedGen UID:
98140
Concept ID:
C0431886
Congenital Abnormality
In the resting position, the tip of the thumb is on, or near, the palm, close to the base of the fourth or fifth finger.
Overlapping toe
MedGen UID:
182531
Concept ID:
C0920299
Anatomical Abnormality
Describes a foot digit resting on the dorsal surface of an adjacent digit when the foot is at rest. Initially clawing may be dynamic and only noticeable on walking. Over time the plantar plate tears, subluxation occurs at the metatarsophalangeal joint (MTPJ), and the deformity becomes permanent.
Overlapping fingers
MedGen UID:
252954
Concept ID:
C1446712
Finding
A finger resting on the dorsal surface of an adjacent digit when the hand is at rest.
Cutaneous syndactyly
MedGen UID:
396250
Concept ID:
C1861921
Congenital Abnormality
A soft tissue continuity in the A/P axis between two digits that extends distally to at least the level of the proximal interphalangeal joints, or a soft tissue continuity in the A/P axis between two digits that lies significantly distal to the flexion crease that overlies the metacarpophalangeal or metatarsophalangeal joint of the adjacent digits.
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).
Abnormal foot morphology
MedGen UID:
1762829
Concept ID:
C5399834
Anatomical Abnormality
An abnormality of the skeleton of foot.
Pericardial effusion
MedGen UID:
10653
Concept ID:
C0031039
Disease or Syndrome
Accumulation of fluid within the pericardium.
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).
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Seizure
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.
Atypical behavior
MedGen UID:
535345
Concept ID:
C0233514
Mental or Behavioral Dysfunction
Atypical behavior is an abnormality in a person's actions, which can be controlled or modulated by the will of the individual. While abnormal behaviors can be difficult to control, they are distinct from other abnormal actions that cannot be affected by the individual's will.
Lissencephaly
MedGen UID:
78604
Concept ID:
C0266463
Finding
A spectrum of malformations of cortical development caused by insufficient neuronal migration that subsumes the terms agyria, pachygyria and subcortical band heterotopia. See also neuropathological definitions for 2-, 3-, and 4-layered lissencephaly.
Cerebellar hypoplasia
MedGen UID:
120578
Concept ID:
C0266470
Congenital Abnormality
Cerebellar hypoplasia is a descriptive term implying a cerebellum with a reduced volume, but a normal shape and is stable over time.
Gray matter heterotopia
MedGen UID:
452349
Concept ID:
C0266491
Finding
Heterotopia or neuronal heterotopia are macroscopic clusters of misplaced neurons (gray matter), most often situated along the ventricular walls or within the subcortical white matter.
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.
Hypoplasia of the brainstem
MedGen UID:
334226
Concept ID:
C1842688
Finding
Underdevelopment of the brainstem.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Aplasia/Hypoplasia of the corpus callosum
MedGen UID:
354608
Concept ID:
C1861866
Finding
Absence or underdevelopment of the corpus callosum.
Cerebellar dysplasia
MedGen UID:
479952
Concept ID:
C3278322
Finding
Cerebellar dysplasia (abnormal growth or development) is defined by abnormal cerebellar foliation, white matter arborization, and gray-white matter junction. Cerebellar dysplasia is a neuroimaging finding that describes abnormalities of both the cerebellar cortex and white matter and is associated with variable neurodevelopmental outcome. Dysplasia may globally involve the cerebellum or affect only one cerebellar hemisphere. In addition, cerebellar dysplasia may be associated with cortical/subcortical cysts.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Oculomotor apraxia
MedGen UID:
483686
Concept ID:
C3489733
Disease or Syndrome
Ocular motor apraxia is a deficiency in voluntary, horizontal, lateral, fast eye movements (saccades) with retention of slow pursuit movements. The inability to follow objects visually is often compensated by head movements. There may be decreased smooth pursuit, and cancellation of the vestibulo-ocular reflex.
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.
Kinked brainstem
MedGen UID:
866721
Concept ID:
C4021068
Anatomical Abnormality
A kinked appearance of the brainstem, i.e., an exaggerated flexure.
Dandy-Walker syndrome
MedGen UID:
4150
Concept ID:
C0010964
Disease or Syndrome
Dandy-Walker malformation is defined by hypoplasia and upward rotation of the cerebellar vermis and cystic dilation of the fourth ventricle. Affected individuals often have motor deficits such as delayed motor development, hypotonia, and ataxia; about half have mental retardation and some have hydrocephalus. DWM is a heterogeneous disorder. The low empiric recurrence risk of approximately 1 to 2% for nonsyndromic DWM suggests that mendelian inheritance is unlikely (summary by Murray et al., 1985).
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
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.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Plagiocephaly
MedGen UID:
1825944
Concept ID:
C2081594
Finding
Asymmetric head shape, which is usually a combination of unilateral occipital flattening with ipsilateral frontal prominence, leading to rhomboid cranial shape.
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.
Arthrogryposis multiplex congenita
MedGen UID:
1830310
Concept ID:
C5779613
Disease or Syndrome
Multiple congenital contractures in different body areas.
Pleural effusion
MedGen UID:
10805
Concept ID:
C0032227
Disease or Syndrome
The presence of an excessive amount of fluid in the pleural cavity.
Edema
MedGen UID:
4451
Concept ID:
C0013604
Pathologic Function
An abnormal accumulation of fluid beneath the skin, or in one or more cavities of the body.
Cystic hygroma
MedGen UID:
60195
Concept ID:
C0206620
Neoplastic Process
A cystic lymphatic lesion of the neck.
Webbed neck
MedGen UID:
113154
Concept ID:
C0221217
Congenital Abnormality
Pterygium colli is a congenital skin fold that runs along the sides of the neck down to the shoulders. It involves an ectopic fibrotic facial band superficial to the trapezius muscle. Excess hair-bearing skin is also present and extends down the cervical region well beyond the normal hairline.
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).
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.
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).
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.
Hypermetropia
MedGen UID:
43780
Concept ID:
C0020490
Disease or Syndrome
An abnormality of refraction characterized by the ability to see objects in the distance clearly, while objects nearby appear blurry.
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).
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Hypotelorism
MedGen UID:
96107
Concept ID:
C0424711
Finding
Interpupillary distance less than 2 SD below the mean (alternatively, the appearance of an decreased interpupillary distance or closely spaced eyes).
Abnormality of eye movement
MedGen UID:
99227
Concept ID:
C0497202
Finding
An abnormality in voluntary or involuntary eye movements or their control.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAlkuraya-Kucinskas syndrome

Recent clinical studies

Diagnosis

Meszarosova AU, Lastuvkova J, Rennerova L, Hitka P, Cihlar F, Seeman P, Safka Brozkova D
Clin Dysmorphol 2020 Oct;29(4):197-201. doi: 10.1097/MCD.0000000000000335. PMID: 32657846
Kumar K, Bellad A, Prasad P, Girimaji SC, Muthusamy B
BMC Med Genet 2020 Jun 26;21(1):136. doi: 10.1186/s12881-020-01074-2. PMID: 32590954Free PMC Article

Prognosis

Wang C, Wang B, Pandey T, Long Y, Zhang J, Oh F, Sima J, Guo R, Liu Y, Zhang C, Mukherjee S, Bassik M, Lin W, Deng H, Vale G, McDonald JG, Shen K, Ma DK
Nat Commun 2022 Nov 10;13(1):6805. doi: 10.1038/s41467-022-34450-y. PMID: 36357390Free PMC Article
Chin HL, Lin S, Dalmann J, Modi B, Alderman E, Salman A, Del Bel KL, Lehman A, Turvey SE, Boerkoel CF
Eur J Med Genet 2022 Mar;65(3):104427. Epub 2022 Jan 19 doi: 10.1016/j.ejmg.2022.104427. PMID: 35063693

Clinical prediction guides

Wang C, Wang B, Pandey T, Long Y, Zhang J, Oh F, Sima J, Guo R, Liu Y, Zhang C, Mukherjee S, Bassik M, Lin W, Deng H, Vale G, McDonald JG, Shen K, Ma DK
Nat Commun 2022 Nov 10;13(1):6805. doi: 10.1038/s41467-022-34450-y. PMID: 36357390Free PMC Article
Chin HL, Lin S, Dalmann J, Modi B, Alderman E, Salman A, Del Bel KL, Lehman A, Turvey SE, Boerkoel CF
Eur J Med Genet 2022 Mar;65(3):104427. Epub 2022 Jan 19 doi: 10.1016/j.ejmg.2022.104427. PMID: 35063693

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