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AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome(XIGIS)

MedGen UID:
862856
Concept ID:
C4014419
Disease or Syndrome
Synonym: Xia-Gibbs syndrome
SNOMED CT: AT-hook DNA binding motif containing 1-related intellectual disability, obstructive sleep apnea, mild dysmorphism syndrome (774068004); Xia Gibbs syndrome (774068004); AHDC1-related intellectual disability, obstructive sleep apnea, mild dysmorphism syndrome (774068004)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
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 heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): AHDC1 (1p36.11-35.3)
 
Monarch Initiative: MONDO:0014358
OMIM®: 615829
Orphanet: ORPHA412069

Disease characteristics

Excerpted from the GeneReview: Xia-Gibbs Syndrome
The main features of Xia-Gibbs syndrome (XGS), present in a majority of affected individuals, include delayed motor milestones, speech delay with severely limited or absent speech, moderate-to-severe cognitive impairment, hypotonia, structural brain anomalies, and nonspecific dysmorphic features. Other features may include sleep apnea, movement disorders (ataxia, tremors, and bradykinesias) that often become apparent in childhood or adolescence, short stature, seizures, eye anomalies, behavioral concerns, autism spectrum disorder, scoliosis, and laryngomalacia. [from GeneReviews]
Authors:
Varuna Chander  |  Michael Wangler  |  Richard Gibbs, et. al.   view full author information

Additional descriptions

From OMIM
Xia-Gibbs syndrome (XIGIS) is characterized by impaired intellectual development with absent or poor expressive language, obstructive sleep apnea, mild dysmorphic features, and brain abnormalities (Xia et al., 2014). Patients with XIGIS can have a broad clinical spectrum with multisystemic involvement in addition to neurologic manifestation (Ritter et al., 2018).  http://www.omim.org/entry/615829
From MedlinePlus Genetics
Xia-Gibbs syndrome is a neurological disorder characterized by weak muscle tone (hypotonia), mild to severe intellectual disability and delayed development. Expressive language skills (vocabulary and the production of speech) are particularly affected; children with this condition usually do not speak their first word, a milestone typically achieved within the first year, until age two or later, and some never learn to talk. Development of motor skills, such as crawling and walking, can also be delayed.

Other signs and symptoms of Xia-Gibbs syndrome vary among affected individuals. Additional neurological features include poor coordination and balance (ataxia) and seizures. Feeding problems and sleep abnormalities can also occur in people with the condition, and many affected individuals experience short pauses in breathing while they sleep (obstructive sleep apnea). In some people with Xia-Gibbs syndrome, imaging tests of the brain show abnormalities in the brain's structure. For example, the tissue connecting the left and right halves of the brain (the corpus callosum) can be abnormally thin.

Xia-Gibbs syndrome can also affect physical development. Growth is usually impaired, and many affected individuals are shorter than their peers. Side-to-side curvature of the spine (scoliosis) is also a common feature. Some people with Xia-Gibbs syndrome have unusual facial features, such as a broad forehead, low-set ears or ears that stick out, widely spaced eyes (hypertelorism), eye openings that slant up or down (upslanting palpebral fissures or downslanting palpebral fissures), a flat bridge of the nose, or a thin upper lip. Other, less-common abnormalities involving the bones and skin include premature fusion of certain skull bones (craniosynostosis), unusually loose (lax) joints, and loose skin.

Neurodevelopmental disorders can also occur in Xia-Gibbs syndrome. Some affected individuals have autism spectrum disorder, which is characterized by impaired communication and social interactions, or attention-deficit/hyperactivity disorder (ADHD). Other problems can include aggression, anxiety, poor impulse control, and self-injury.  https://medlineplus.gov/genetics/condition/xia-gibbs-syndrome

Clinical features

From HPO
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
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.
Small earlobe
MedGen UID:
334587
Concept ID:
C1842680
Finding
Reduced volume of the earlobe.
Protruding ear
MedGen UID:
343309
Concept ID:
C1855285
Finding
Angle formed by the plane of the ear and the mastoid bone greater than the 97th centile for age (objective); or, outer edge of the helix more than 2 cm from the mastoid at the point of maximum distance (objective).
Uplifted earlobe
MedGen UID:
344655
Concept ID:
C1856117
Anatomical Abnormality
An abnormal orientation of the earlobes such that they point out- and upward. That is, the lateral surface of ear lobe faces superiorly.
Snoring
MedGen UID:
20006
Concept ID:
C0037384
Sign or Symptom
Deep, noisy breathing during sleep, accompanied by hoarse or harsh sounds, is caused by the vibration of respiratory structures, especially the soft palate. This vibration results in sound due to obstructed air movement during breathing while sleeping.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
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.
Obstructive sleep apnea syndrome
MedGen UID:
101045
Concept ID:
C0520679
Disease or Syndrome
Obstructive sleep apnea is a common, chronic, complex disease associated with serious cardiovascular and neuropsychologic sequelae and with substantial social and economic costs (Palmer et al., 2003).
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.
Retrocerebellar cyst
MedGen UID:
335172
Concept ID:
C1845370
Finding
Simplified gyral pattern
MedGen UID:
413664
Concept ID:
C2749675
Finding
An abnormality of the cerebral cortex with fewer gyri but with normal cortical thickness. This pattern is usually often associated with congenital microcephaly.
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.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Delayed ability to sit
MedGen UID:
1368737
Concept ID:
C4476710
Finding
A failure to achieve the ability to sit at an appropriate developmental stage. Most children sit with support at 6 months of age and sit steadily without support at 9 months of age.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
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.
Congenital laryngomalacia
MedGen UID:
120500
Concept ID:
C0264303
Anatomical Abnormality
Laryngomalacia is a congenital abnormality of the laryngeal cartilage in which the cartilage is floppy and prolapses over the larynx during inspiration.
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.
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.
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).
Esotropia
MedGen UID:
4550
Concept ID:
C0014877
Disease or Syndrome
A form of strabismus with one or both eyes turned inward ('crossed') to a relatively severe degree, usually defined as 10 diopters or more.
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).

Professional guidelines

PubMed

Nguyen DB, Khirani S, Griffon L, Baujat G, Michot C, Marzin P, Rondeau S, Luscan R, Couloigner V, Pejin Z, Zerah M, Cormier-Daire V, Fauroux B
Am J Med Genet A 2021 Jul;185(7):2108-2118. Epub 2021 Apr 28 doi: 10.1002/ajmg.a.62236. PMID: 33908178
Yu W, Sarber KM, Howard JJM, Huang G, Hossain MM, Heubi CH, Lu X, Simakajornboon N
J Clin Sleep Med 2020 Jun 15;16(6):899-906. doi: 10.5664/jcsm.8358. PMID: 32043964Free PMC Article
Tirosh E, Tal Y, Jaffe M
Acta Paediatr 1995 Jul;84(7):791-4. doi: 10.1111/j.1651-2227.1995.tb13758.x. PMID: 7549299

Recent clinical studies

Etiology

Combs D, Edgin J, Hsu CH, Bottrill K, Van Vorce H, Gerken B, Matloff D, La Rue S, Parthasarathy S
J Clin Sleep Med 2023 Dec 1;19(12):2065-2073. doi: 10.5664/jcsm.10764. PMID: 37555595Free PMC Article
Ioan I, Weick D, Sevin F, Sanlaville D, De Fréminville B, Schweitzer C, Akkari M, Coutier L, Putois B, Plancoulaine S, Thieux M, Franco P
Sleep Med 2022 Dec;100:542-549. Epub 2022 Sep 20 doi: 10.1016/j.sleep.2022.09.009. PMID: 36308912
Abijay CA, Tomkies A, Rayasam S, Johnson RF, Mitchell RB
Otolaryngol Head Neck Surg 2022 Mar;166(3):557-564. Epub 2021 Jul 13 doi: 10.1177/01945998211023102. PMID: 34253070
Santoro JD, Del Rosario J, Osterbauer B, Gillett ES, Don DM
Sleep Med 2021 May;81:463-465. Epub 2021 Mar 26 doi: 10.1016/j.sleep.2021.03.018. PMID: 33865077
Skotko BG, Macklin EA, Muselli M, Voelz L, McDonough ME, Davidson E, Allareddy V, Jayaratne YS, Bruun R, Ching N, Weintraub G, Gozal D, Rosen D
Am J Med Genet A 2017 Apr;173(4):889-896. Epub 2017 Jan 26 doi: 10.1002/ajmg.a.38137. PMID: 28124477Free PMC Article

Diagnosis

Ioan I, Weick D, Sevin F, Sanlaville D, De Fréminville B, Schweitzer C, Akkari M, Coutier L, Putois B, Plancoulaine S, Thieux M, Franco P
Sleep Med 2022 Dec;100:542-549. Epub 2022 Sep 20 doi: 10.1016/j.sleep.2022.09.009. PMID: 36308912
Alma MA, Nijenhuis-Huls R, de Jong Z, Ulgiati AM, de Vries A, Dekker AD
Res Dev Disabil 2022 Oct;129:104302. Epub 2022 Jul 16 doi: 10.1016/j.ridd.2022.104302. PMID: 35853354
Yu W, Sarber KM, Howard JJM, Huang G, Hossain MM, Heubi CH, Lu X, Simakajornboon N
J Clin Sleep Med 2020 Jun 15;16(6):899-906. doi: 10.5664/jcsm.8358. PMID: 32043964Free PMC Article
Waters KA, Castro C, Chawla J
Int J Pediatr Otorhinolaryngol 2020 Feb;129:109763. Epub 2019 Nov 1 doi: 10.1016/j.ijporl.2019.109763. PMID: 31704574
Skotko BG, Macklin EA, Muselli M, Voelz L, McDonough ME, Davidson E, Allareddy V, Jayaratne YS, Bruun R, Ching N, Weintraub G, Gozal D, Rosen D
Am J Med Genet A 2017 Apr;173(4):889-896. Epub 2017 Jan 26 doi: 10.1002/ajmg.a.38137. PMID: 28124477Free PMC Article

Therapy

Combs D, Edgin J, Hsu CH, Bottrill K, Van Vorce H, Gerken B, Matloff D, La Rue S, Parthasarathy S
J Clin Sleep Med 2023 Dec 1;19(12):2065-2073. doi: 10.5664/jcsm.10764. PMID: 37555595Free PMC Article
Scheermeyer E, Harris M, Hughes I, Crock PA, Ambler G, Verge CF, Bergman P, Werther G, Craig ME, Choong CS, Davies PSW; PWS and OZGROW collaboration
Growth Horm IGF Res 2017 Jun;34:1-7. Epub 2017 Mar 24 doi: 10.1016/j.ghir.2017.03.001. PMID: 28427039
Crockett DJ, Ahmed SR, Sowder DR, Wootten CT, Chinnadurai S, Goudy SL
Int J Pediatr Otorhinolaryngol 2014 Oct;78(10):1731-4. Epub 2014 Aug 2 doi: 10.1016/j.ijporl.2014.07.034. PMID: 25130946
Rosen D
Clin Pediatr (Phila) 2010 Apr;49(4):381-3. Epub 2010 Jan 28 doi: 10.1177/0009922809351093. PMID: 20118082

Prognosis

Abijay CA, Tomkies A, Rayasam S, Johnson RF, Mitchell RB
Otolaryngol Head Neck Surg 2022 Mar;166(3):557-564. Epub 2021 Jul 13 doi: 10.1177/01945998211023102. PMID: 34253070
Waters KA, Castro C, Chawla J
Int J Pediatr Otorhinolaryngol 2020 Feb;129:109763. Epub 2019 Nov 1 doi: 10.1016/j.ijporl.2019.109763. PMID: 31704574
Howard JJM, Sarber KM, Yu W, Smith DF, Tikhtman RO, Simakajornboon N, Ishman SL
Laryngoscope 2020 Jul;130(7):1828-1835. Epub 2019 Oct 11 doi: 10.1002/lary.28325. PMID: 31603543Free PMC Article
Skotko BG, Macklin EA, Muselli M, Voelz L, McDonough ME, Davidson E, Allareddy V, Jayaratne YS, Bruun R, Ching N, Weintraub G, Gozal D, Rosen D
Am J Med Genet A 2017 Apr;173(4):889-896. Epub 2017 Jan 26 doi: 10.1002/ajmg.a.38137. PMID: 28124477Free PMC Article
Hill CM, Evans HJ, Elphick H, Farquhar M, Pickering RM, Kingshott R, Martin J, Reynolds J, Joyce A, Rush C, Gavlak JC, Gringras P
Sleep Med 2016 Nov-Dec;27-28:99-106. Epub 2016 Oct 22 doi: 10.1016/j.sleep.2016.10.001. PMID: 27938928

Clinical prediction guides

Combs D, Edgin J, Hsu CH, Bottrill K, Van Vorce H, Gerken B, Matloff D, La Rue S, Parthasarathy S
J Clin Sleep Med 2023 Dec 1;19(12):2065-2073. doi: 10.5664/jcsm.10764. PMID: 37555595Free PMC Article
Ioan I, Weick D, Sevin F, Sanlaville D, De Fréminville B, Schweitzer C, Akkari M, Coutier L, Putois B, Plancoulaine S, Thieux M, Franco P
Sleep Med 2022 Dec;100:542-549. Epub 2022 Sep 20 doi: 10.1016/j.sleep.2022.09.009. PMID: 36308912
Abijay CA, Tomkies A, Rayasam S, Johnson RF, Mitchell RB
Otolaryngol Head Neck Surg 2022 Mar;166(3):557-564. Epub 2021 Jul 13 doi: 10.1177/01945998211023102. PMID: 34253070
Santoro JD, Del Rosario J, Osterbauer B, Gillett ES, Don DM
Sleep Med 2021 May;81:463-465. Epub 2021 Mar 26 doi: 10.1016/j.sleep.2021.03.018. PMID: 33865077
Skotko BG, Macklin EA, Muselli M, Voelz L, McDonough ME, Davidson E, Allareddy V, Jayaratne YS, Bruun R, Ching N, Weintraub G, Gozal D, Rosen D
Am J Med Genet A 2017 Apr;173(4):889-896. Epub 2017 Jan 26 doi: 10.1002/ajmg.a.38137. PMID: 28124477Free PMC Article

Recent systematic reviews

Clements AC, Dai X, Walsh JM, Sterni LM, Prichett L, Boss EF, Seal SM, Ryan MA
Laryngoscope 2021 Apr;131(4):898-906. Epub 2020 Jul 27 doi: 10.1002/lary.28922. PMID: 33026674

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