El-Hattab-Alkuraya Syndrome

Clinical characteristics.

El-Hattab-Alkuraya syndrome is characterized by microcephaly (often early onset and progressive); severe-to-profound developmental delay; refractory and early-onset seizures; spastic quadriplegia with axial hypotonia; and growth deficiency with poor weight gain and short stature. Characteristic findings on brain imaging include cerebral atrophy that is disproportionately most prominent in the frontal lobes; ex vacuo ventricular dilatation with notable posterior horn predominance; brain stem volume loss with flattening of the belly of the pons; and symmetric under-opercularization. Neurologic involvement is progressive, with significant morbidity and mortality.

Diagnosis/testing.

The diagnosis of El-Hattab-Alkuraya syndrome is established in a proband by identification of biallelic pathogenic variants in WDR45B on molecular genetic testing.

Management.

Treatment of manifestations: Standardized treatments for seizures, spasticity, mobility, feeding issues, and ocular manifestations; developmental services and educational interventions for developmental delay and intellectual disability.

Surveillance: Monitor for changes in seizures, tone, movement disorders, nutrition, and safety of oral intake at each visit. Monitor development, educational needs, behavior, vision, and hearing annually or as needed.

Genetic counseling.

El-Hattab-Alkuraya syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a WDR45B pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the WDR45B pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

El-Hattab-Alkuraya syndrome should be considered in individuals with the following clinical, imaging, and family history findings.

Clinical findings

• Progressive microcephaly
• Developmental delay
• Early-onset, refractory seizures
• Spastic quadriplegia
• Growth deficiency (poor weight gain, short stature)

Imaging findings on brain MRI

• Cerebral atrophy with disproportionate atrophy of the frontal lobes
• Ex vacuo ventricular dilatation with posterior horn predominance
• Brain stem volume loss with flattening of the belly of the pons
• Symmetric under-opercularization

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of El-Hattab-Alkuraya syndrome is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in WDR45B identified by molecular genetic testing (see Table 1).

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 biallelic WDR45B variants of uncertain significance (or of one known WDR45B pathogenic variant and one WDR45B variant of uncertain significance) does not establish or rule out a diagnosis.

Molecular genetic testing in a child with developmental delay may begin with exome sequencing, a multigene panel, or chromosomal microarray analysis. Note: Single-gene testing (sequence analysis of WDR45B) is rarely useful and typically NOT recommended.

• 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 intellectual disability (ID) multigene panel, with the additional advantage that exome sequencing includes genes recently identified as causing ID whereas some multigene panels may not. 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.
• A multigene panel that includes WDR45B and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. 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. (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.

Clinical Description

El-Hattab-Alkuraya syndrome is characterized by congenital and progressive microcephaly, developmental delay, seizures, spastic quadriplegia, associated brain imaging findings, and progressive neurologic involvement with significant morbidity and mortality. To date, 22 individuals with biallelic pathogenic variants in WDR45B have been identified [Najmabadi et al 2011, Anazi et al 2017, Suleiman et al 2018, Almannai et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

Microcephaly. The majority of affected individuals had progressive microcephaly. Most individuals had congenital microcephaly (in those with a known birth head circumference). Microcephaly was identified prenatally in some individuals [Najmabadi et al 2011, Anazi et al 2017, Suleiman et al 2018, Almannai et al 2022].

Developmental delay. All individuals had severe-to-profound development delay. Individuals with loss-of-function WDR45B variants were profoundly delayed and unable to ambulate or communicate. Two sibs homozygous for a WDR45B missense variant were severely delayed but showed slow acquisition of some skills, and regression was not evident by ages four and 14 years. The two sibs were able to follow simple commands and speak a few monosyllables. Ambulation was achieved by age 30 months in the older sib, but had not been achieved by age four years in the younger sib.

Seizures. Refractory, early-onset seizures were reported in most individuals. The most common seizure type was generalized tonic-clonic. Other reported seizure types included myoclonic and focal. Seizures were refractory and required at least two anti-seizure medications (ASMs) in most individuals. Responses to ASMs were variable, with no particular ASM being more effective.

Spastic quadriplegia. Most individuals had spastic quadriplegia that was associated with axial hypotonia.

Growth deficiency. Poor weight gain was reported in most individuals. Feeding and swallowing problems were commonly observed. Method of feeding was reported for three individuals, who all required gastric tube feeding. Most affected individuals with loss-of-function variants are expected to require tube feeding given the extent of neurologic involvement. Short stature was reported in ten of 12 affected individuals for whom measurements were available.

Ocular manifestations. Most individuals have poor visual tracking; one individual was diagnosed with cortical blindness. Optic atrophy was reported in two individuals, and two other individuals were reported to have strabismus.

Nonspecific dysmorphic features were reported in most individuals. The most common reported features were thick, highly arched eyebrows, large ears, bitemporal narrowing, and long philtrum.

Common neuroradiographic findings include:

• Cerebral atrophy with disproportionate atrophy of the frontal lobe
• Giant cisterna magna
• Corpus callosum thinning
• Brain stem volume loss with flattening of the belly of the pons
• Ex vacuo ventricular dilatation with posterior horn predominance pattern of the ventriculomegaly
• Symmetric under-opercularization
• Dysplastic hippocampi
• Cerebellar atrophy
• Cervical spine atrophy

Other. One individual had behavioral issues including aggression and self-harming behavior.

Prognosis. Five individuals are deceased at the time of this report. The age of death ranged from two to 15 years; mean age of death was 7.9 years. When reported, the most common cause for death was aspiration pneumonia.

Genotype-Phenotype Correlations

The number of affected individuals is insufficient to establish genotype-phenotype correlations. However, two sibs homozygous for missense variant c.674G>A had milder clinical features; only one sib had seizures, and neither sib had characteristic brain MRI findings or spastic quadriplegia [Almannai et al 2022].

Nomenclature

El-Hattab-Alkuraya syndrome may also be referred to as WDR45B-related neurodevelopmental disorder based on the dyadic naming approach proposed by Biesecker et al [2021] to delineate mendelian genetic disorders.

Prevalence

The exact prevalence is unknown, but El-Hattab-Alkuraya syndrome appears to be rare, with only 22 individuals reported to date. Most affected individuals are of Arab ancestry.

Evaluations Following Initial Diagnosis

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

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in neurology, nutrition, ophthalmology, clinical genetics/metabolism, developmental pediatrics, speech-language therapy, occupational therapy, physical therapy, and audiology.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 5 are recommended.

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

El-Hattab-Alkuraya syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a WDR45B pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a WDR45B pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a WDR45B pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, individuals with El-Hattab-Alkuraya syndrome are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a WDR45B pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the WDR45B pathogenic variants in the family.

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 young adults who are carriers or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the WDR45B pathogenic variants have 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

WDR45B encodes for WD (tryptophan-aspartic acid) repeat-containing protein 45B, a member of the WIPI protein family. This protein family plays an important role in autophagy [Bakula et al 2017].

Mechanism of disease causation. Loss of function

Revision History

• 29 September 2022 (sw) Review posted live
• 5 August 2022 (ma) Original submission

Literature Cited

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