Clinical characteristics.

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.

Diagnosis/testing.

The diagnosis of XGS is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in AHDC1 that is predicted to lead to a truncated protein, identified by molecular genetic testing

Management.

Treatment of manifestations: Treatment is symptomatic and can include: speech, occupational, and physical therapy; specialized educational programs depending on individual needs; standard treatment of behavioral concerns (ADHD, anxiety) and autism spectrum disorders; treatment of movement disorders by a neurologist familiar with movement disorders; standard treatment of seizures, feeding difficulties, gastroesophageal reflux disease, obstructive sleep apnea; stridor/disordered breathing, scoliosis, ophthalmologic/vision issues, and hearing loss; consideration of growth hormone therapy in those with short stature who also have growth hormone deficiency.

Surveillance: At each visit monitor growth and nutrition, occupational and physical therapy needs; assess for seizures, movement disorders, developmental progress, behavioral issues, gastrointestinal issues, respiratory issues, and family needs. Clinical assessment for scoliosis at each visit in childhood until skeletal maturity. Annual vision and hearing assessments. Measurement of growth hormone level in those with poor growth velocity.

Genetic counseling.

XGS is an autosomal dominant disorder typically caused by a de novo pathogenic truncating variant in AHDC1. The risk to other family members is presumed to be low, but parental testing should be done when possible to confirm that the variant is de novo. Once an AHDC1 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.

Suggestive Findings

XGS should be considered in individuals with the following clinical and brain MRI findings.

Clinical findings. Early-onset moderate-to-profound developmental delay (DD) or intellectual disability (ID) AND any of the following features presenting in infancy or childhood:

• Neurologic issues, including:
  • Generalized hypotonia of infancy
  • Epilepsy
  • Ataxia
  • Nystagmus
• Developmental issues, including:
  • Delayed motor milestones
  • Speech delay
  • Autism spectrum disorder (ASD)
• Respiratory issues, including:
  • Obstructive sleep apnea
  • Tracheomalacia
  • Laryngomalacia
• Scoliosis
• Short stature
• Strabismus
• Dysmorphic features (See Clinical Description.)

Brain MRI findings

• Thinning of the corpus callosum
• Posterior fossa cyst
• Delayed myelination

Family history. Because XGS is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of XGS is established in a proband with suggestive clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in AHDC1 that is predicted to lead to a truncated protein, identified by molecular genetic testing (see Table 1 and Molecular Genetics).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous missense AHDC1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with chromosomal microarray analysis (CMA). Other options include use of a multigene panel or exome/genome sequencing. Note: Single-gene testing (sequence analysis of AHDC1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An intellectual disability (ID) or developmental delay (DD) multigene panel that includes AHDC1 and other genes of interest (see Differential Diagnosis) limits identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. However, given the rarity of XGS, some panels for ID or DD may not include AHDC1, and this should be considered ahead of testing. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time; therefore, present inclusion of AHDC1 does not guarantee that the gene was included when a given individual underwent testing. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to an ID multigene panel ‒ with the added advantage that it includes genes recently identified as causing ID, whereas some multigene panels may not. Historically, trio whole-exome sequencing has been the genetic test that typically identifies de novo AHDC1 pathogenic variants that are predicted to lead to truncation of protein synthesis [Xia et al 2014, Yang et al 2015, García-Acero & Acosta 2017, Jiang et al 2018, Ritter et al 2018, Cheng et al 2019, Díaz-Ordoñez et al 2019, Murdock et al 2019, Yang et al 2019, Cardoso-Dos-Santos et al 2020, Gumus 2020, He et al 2020].
  Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

To date, approximately 280 individuals have been identified with a pathogenic variant in AHDC1 [Jiang et al 2018]. The striking features of XGS include delayed motor milestones, speech delay, cognitive impairment, hypotonia, structural brain anomalies, dysmorphic features, and sleep apnea, in addition to variable presentation of secondary features [Xia et al 2014, Yang et al 2015, García-Acero & Acosta 2017, Park et al 2017, Jiang et al 2018, Ritter et al 2018, Díaz-Ordoñez et al 2019, Cardoso-Dos-Santos et al 2020, Wang et al 2020, Khayat et al 2021b]. The following description of the phenotypic features associated with this condition is based on these published reports.

Developmental delay (DD) and intellectual disability (ID). Delayed developmental milestones have been reported in the first year in concert with generalized hypotonia.

• Motor development delay is usually accompanied by poor coordination and gait disturbances, typically starting in early childhood.
• The median age when walking begins is 2.5 years (range ~1.5-6 years) [Jiang et al 2018].
• The majority of affected individuals function in the moderate-to-severe range of intellectual disability, although individuals with mild intellectual disability have also been reported [Xia et al 2014].

Speech delay. All individuals with XGS have delayed speech and language development. Most are nonverbal or have very limited speech.

• In one study the average age of using a first word was 2.75 years and the median age for using two words together was 3.5 years [Jiang et al 2018].
• Language delay was more pronounced in males than females, with one small study of 20 affected individuals demonstrating that affected males were statistically significantly more likely to be nonverbal compared to affected females (p<.01) [Jiang et al 2018]. Expressive language development was more severely impaired than receptive language skills [Jiang et al 2018].

Autism spectrum disorder (ASD). About one third of affected individuals either have a clinical diagnosis of an ASD or were assessed for an ASD based on a "high risk" score on the M-CHAT [Jiang et al 2018, Khayat et al 2021b]. A female presenting with high-functioning autism spectrum without intellectual disability has been reported [Della Vecchia et al 2021]. This individual also had attention deficit, motor dyspraxia, and a disharmonic intelligence profile, with better verbal performance. Other reports of individuals with XGS who displayed autistic symptoms with poor social interaction, or who had been diagnosed with ASD, have been documented [Yang et al 2015, Díaz-Ordoñez et al 2019, Faergeman et al 2021, Mubungu et al 2021].

Behavioral problems. Yang et al [2015] reported one individual with aggression and self-injury and another with self-injurious behavior. Self-injurious behavior has also been reported in several other individuals with XGS [Jiang et al 2018, Díaz-Ordoñez et al 2019, Murdock et al 2019, Cardoso-Dos-Santos et al 2020, Faergeman et al 2021]. Other common behavioral problems reported in individuals with XGS include the following [Xia et al 2014, Jiang et al 2018, Murdock et al 2019, Cardoso-Dos-Santos et al 2020, Della Vecchia et al 2021, Faergeman et al 2021, Mubungu et al 2021]:

• Impulsiveness
• Anxiety
• Poor social interaction
• Sleep disturbances
• Attention-deficit/hyperactivity disorder (ADHD)

Behavioral issues in affected individuals is an ongoing active area of study. The degree of manifestation of these behavioral features is variable among individuals with XGS, and not all affected individuals will display these features.

Neurologic

• Abnormal muscle tone. Generalized hypotonia may be noted during the first months of life and typically does not improve significantly over time. Oral hypotonia has also been reported [Yang et al 2015, Jiang et al 2018, Ritter et al 2018, Gumus 2020].
• Movement disorders. Ataxia, tremors, and bradykinesia have been frequently associated with XGS, typically first noted in childhood or adolescence [Yang et al 2015, Murdock et al 2019].
• Seizures occur in about half of affected individuals and can range from generalized tonic-clonic seizures to absence seizures, including febrile seizures, atonic, sleep-related, and startle-induced atonic seizures [Xia et al 2014, Yang et al 2015, Murdock et al 2019, Cardoso-Dos-Santos et al 2020].
  • The median age of seizure onset is four years (range 9 months to ~12 years) [Jiang et al 2018].
  • Abnormal EEG recordings have been reported in about 50% of individuals. This can include capturing seizures on EEG, but could also include individuals with diffuse slowing or other EEG abnormalities.
  • Seizures typically respond to standard anti-seizure medication.

Neuroimaging. More than half of affected individuals have delayed myelination or hypomyelination on brain magnetic resonance imaging (MRI). Other findings in those studied have included hypoplasia of the corpus callosum, posterior fossa cysts, and dysmorphic sulci-gyri [Xia et al 2014, Yang et al 2015, Jiang et al 2018, Ritter et al 2018, García-Acero & Acosta 2017, Gumus 2020].

Growth and feeding issues. Many individuals with XGS have a history of growth problems including short stature (length and/or height >-2 SD) and feeding difficulties [Yang et al 2015].

• Most affected individuals have a normal birth weight but have poor postnatal growth due to feeding issues during infancy.
• Specific feeding problems may include difficulties with suck and swallowing, recurrent vomiting, and gastroesophageal reflux disease [Yang et al 2015, Jiang et al 2018, Ritter et al 2018, Gumus 2020].
• Growth hormone deficiency was revealed as the cause for short stature in two affected individuals, who eventually responded well to growth hormone replacement therapy [Cheng et al 2019].

Dysmorphic features. Nonspecific dysmorphic facial features are a common finding in affected individuals [Xia et al 2014, Yang et al 2015, García-Acero & Acosta 2017, Jiang et al 2018, Ritter et al 2018, Cardoso-Dos-Santos et al 2020] and generally include:

• Broad forehead
• Horizontal eyebrows
• Widely spaced eyes
• Downslanted or upslanted palpebral fissures
• Mild ptosis
• Depressed nasal bridge
• Low-set ears
• Thin vermilion of the upper lip
• Micrognathia
• Transverse palmar crease

Sleep apnea and respiratory abnormalities. Sleep apnea is present in about 45% of affected individuals and is mostly obstructive in nature [Xia et al 2014, Yang et al 2015, Jiang et al 2018, Ritter et al 2018, Cardoso-Dos-Santos et al 2020, Khayat et al 2021b].

• Sleep disturbance is also a common finding with some affected individuals reported to have abnormal breathing patterns, breath-holding episodes, and irregular breathing patterns at night.
• Many use respiratory support. CPAP, BiPAP, and supplementary oxygen have been used during sleep at night.
• Some affected individuals also have structural airway issues, including laryngomalacia and tracheomalacia. Surgical intervention may be pursued in some cases.
• These occurrences suggest the need for close monitoring of airway function and consideration of referral to pulmonology (see Management).

Scoliosis. Scoliosis is common.

• About one fifth of affected individuals who participated in a XGS registry had scoliosis (at ages 10~21 years) [Jiang et al 2018] ‒ significantly higher than the prevalence in the general population (i.e., 5%).
• Some individuals have required surgery for scoliosis.
• In a male age 55 years with XGS and loose soft skin, scoliosis was ascribed to connective tissue abnormalities [Murdock et al 2019].
• Timely identification, intervention, and management of scoliosis is recommended to prevent life-threatening complications [Murdock et al 2019, Goyal et al 2020] (see Management).

Eyes/vision. Strabismus has been described in more than half of individuals with XGS [Yang et al 2015, Jiang et al 2018, Ritter et al 2018, Gumus 2020].

• Some affected individuals have nystagmus, myopia, hyperopia, and/or ptosis.
• The severity of eye anomalies varies among individuals with XGS, with visual problems requiring correction and many affected individuals wearing glasses.

Hearing. Sensorineural hearing loss has been reported in one individual [Ritter et al 2018].

Other associated features

• Skin. Almost half of the individuals with XGS have an abnormality in the skin and in other connective tissues. Specifically, cutis aplasia and soft loose skin have been frequently reported [Ritter et al 2018, Murdock et al 2019].
• Craniosynostosis. Craniosynostosis has been reported in a few individuals with XGS. The type of sutures reported include coronal, bicoronal, and metopic [Yang et al 2015, Miller et al 2017, Gumus 2020].

Prognosis. It is unknown whether life span in Xia-Gibbs syndrome is abnormal. One reported individual is alive at age 55 years, demonstrating that survival into adulthood is possible [Murdock et al 2019]. Data on possible progression of behavior abnormalities or neurologic findings are still limited. Since many adults with DD or ID issues have not undergone advanced genetic or genomic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

Truncating pathogenic variants (frameshift or stop-gain) have been reported to span across the length of the gene.

• Truncating pathogenic variants that arise near the N terminus of the protein have been associated with a statistically significant higher risk of developing seizures and scoliosis [Khayat et al 2021b].
• Similarly, truncating pathogenic variants at the C terminus of the protein are less likely to be associated with the development of seizures or scoliosis.

Missense variants. There are at least ten individuals with clinical features of XGS who have de novo missense variants within AHDC1 that are presumed to be pathogenic (see Molecular Genetics) [Khayat et al 2021a].

Prevalence

The prevalence of XGS in the general population is estimated to be more than one in 80,000 live births with more than 270 individuals reported worldwide. Since many individuals with XGS may go undiagnosed due to lack of genomic testing (particularly in developing countries), the incidence may be greater than the current estimate.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Xia-Gibbs syndrome (XGS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Xia-Gibbs syndrome (XGS) is an autosomal dominant disorder typically caused by a de novo pathogenic truncating variant.

Risk to Family Members

Parents of a proband

• Most probands reported to date with XGS whose parents have undergone molecular genetic testing have the disorder as a result of a de novo AHDC1 pathogenic truncating variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to assess risk of recurrence.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [He et al 2020]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the AHDC1 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• If the AHDC1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. Sib recurrence due to presumed maternal germline mosaicism has been reported in one family [He et al 2020].

Offspring of a proband

• Each child of an individual with XGS has a 50% chance of inheriting the AHDC1 pathogenic variant.
• Individuals with XGS are generally not known to reproduce; however, most are not yet of reproductive age.

Other family members. Given that most probands with XGS reported to date have the disorder as the result of a de novo AHDC1 pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the AHDC1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

AHDC1 contains a total of seven exons with a single coding exon. Little is known about the normal function of the AHDC1 protein or how mutation of AHDC1 leads to the clinical features seen in individuals with XGS. The gene encodes a protein containing three AT-hooks, which likely function in DNA binding. In individuals with clinical features of XGS who have de novo missense variants in AHDC1, it is hypothesized that the missense variants are in regions that are predicted to be functional motifs [Khayat et al 2021a].

Mechanism of disease causation. The mechanism by which AHDC1 pathogenic variants result in XGS is unknown, with prior suggestions of both haploinsufficiency and dominant-negative effects [Khayat et al 2021b]. While loss-of-function (protein-truncation) pathogenic variants are consistent with either mechanism, Khayat et al [2021b] reported variable effects depending on the position of the truncating pathogenic variant, consistent with a dominant-negative effect. Further, pathogenic missense variants that result in XGS are expected to result in full-length protein products and are therefore more likely to act in a dominant-negative or other gain-of-function manner. Consequently, the available data support a dominant-negative model, but do not exclude the possibility of either haploinsufficiency (loss of function) or other gain-of-function mechanisms.

Author Notes

Varuna Chander, MS
PhD candidate, Molecular and Human Genetics
Baylor College of Medicine
[email protected]

Michael F Wangler, MD
Assistant Professor, Molecular and Human Genetics
Baylor College of Medicine
[email protected]
Web page: www.texaschildrens.org/find-a-doctor/michael-f-wangler-md

Richard A Gibbs, PhD
Wofford Cain Chair and Professor, Molecular and Human Genetics
Director, Human Genome Sequencing Center
Baylor College of Medicine
[email protected]
Web page: www.hgsc.bcm.edu/people/gibbs-r

David Murdock, MD, FACMG
Assistant Professor, Molecular and Human Genetics
Assistant Director, Human Genome Sequencing Center Clinical Laboratory
Baylor College of Medicine
[email protected]
Web page: www.hgsc.bcm.edu/people/murdock-d

Acknowledgments

We would like to thank all the family members participating in the AHDC1 Xia-Gibbs registry and their clinicians who have contributed to ongoing Xia-Gibbs syndrome research. Varuna Chander is supported by the training fellowship from the NLM Training Program in Biomedical Informatics & Data Science (T15LM007093).

Revision History

• 9 December 2021 (ma) Review posted live
• 21 June 2021 (dm) Original submission

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