Clinical characteristics.

HYAL2 deficiency is characterized by cardiac anomalies, cleft lip and palate (unilateral or bilateral), ophthalmic findings (including mild-to-severe myopia up to −16.75 diopters and increased risk of retinal detachment), hearing loss (typically conductive), and skeletal findings (including pectus excavatum and digital anomalies). Intellect is typically normal. To date, 17 individuals from seven families have been reported with HYAL2 deficiency.

Diagnosis/testing.

The diagnosis of HYAL2 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in HYAL2 identified by molecular genetic testing.

Management.

Treatment of manifestations: There is no cure for HYAL2 deficiency. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include care by specialists in pediatric cardiology and cardiac surgery and a multidisciplinary craniofacial team to coordinate timing and type of surgical interventions, manage issues with feeding and nutrition, and work with speech-language pathologists (regarding speech and communication issues) and audiologists (regarding hearing loss).

Surveillance: Members of the multidisciplinary care team will recommend intervals to monitor existing manifestations and the individual's response to supportive care.

Genetic counseling.

HYAL2 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an HYAL2 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 being unaffected and not a carrier. Once the HYAL2 pathogenic variants have been identified in an affected family member, carrier testing for relatives at risk and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

HYAL2 deficiency should be suspected in a proband with one or more of the following clinical findings in the absence of intellectual disability and a family history consistent with autosomal recessive inheritance.

Clinical findings

• Characteristic facial features (See Figure 1.)
• Congenital cardiac anomalies (including coarctation of the aorta, mitral/pulmonary valve atresia, hypoplastic left ventricle, tetralogy of Fallot, double outlet right ventricle, hypoplastic pulmonary and aortopulmonary arteries with agenesis of the ductus venosus)
• Cleft lip and palate (CLP), either unilateral or bilateral
• Ophthalmologic features including:
  • Mild-to-severe myopia (up to −16.75 diopters), which can be asymmetric. When myopia is severe, complications include myopic macular degeneration and increased risk of retinal detachment.
  • Cataracts (posterior subcapsular cataract and wedge-shaped cortical cataract), suggesting that the high myopia may be part of a hereditary vitreoretinal degeneration phenotype
  • Ptosis (mild to moderate, bilateral). It is not currently known whether this is stationary or progressive.
• Hearing loss. Typically conductive, diagnosed on newborn hearing screening or soon after birth and associated with CLP. Sensorineural hearing loss is described but rare.
• Skeletal findings (including pectus excavatum and digital anomalies such as broad halluces and thumbs)

Figure 1.

Photographs of individuals with HYAL2 deficiency. Key features include frontal bossing, hypertelorism, broad and flattened nasal tip, and auricular anomalies (cupped ears, overfolded helices, preauricular pit) in almost all individuals. Additional variable (more...)

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 HYAL2 deficiency is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in HYAL2 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of biallelic HYAL2 variants of uncertain significance (or of one known HYAL2 pathogenic variant and one HYAL2 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

HYAL2 deficiency is characterized by congenital cardiac anomalies, cleft lip and palate that can be unilateral or bilateral, distinctive ophthalmic findings (including mild-to-severe myopia up to −16.75 diopters and increased risk of retinal detachment), hearing loss that is typically conductive, and skeletal findings (including pectus excavatum and digital anomalies). Intellect is typically normal.

To date, 17 individuals from seven families have been identified with HYAL2 deficiency [Muggenthaler et al 2017, Fasham et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

Congenital cardiac anomalies range from the asymptomatic (left cor triatrium) to those likely to require surgical intervention in the first year of life. Many affected individuals have complex congenital cardiac malformations combining a number of the individual anomalies listed below.

• Ventricular septal defect (4 individuals)
• Tetralogy of Fallot (2 individuals)
• Aortic regurgitation (2 individuals)
• Hypoplastic left ventricle
• Coarctation of the aorta
• Mitral valve atresia
• Pulmonary valve atresia
• Aortic stenosis
• Pulmonary hypertension
• Double outlet right ventricle
• Persistent left superior vena cava
• Left cor triatrium

Cleft lip and palate. See Table 2.

Myopia, identified in all 11 reported individuals who had a formal eye examination, may be particularly severe (up to −16.75 diopters). It may be complicated by myopic macular degeneration (four individuals) with retinal detachment (two of the four). Additional ocular findings include two individuals with cataracts, suggesting that high myopia may be part of a hereditary vitreoretinal degeneration phenotype.

Pectus excavatum. See examples included in Figure 2.

Figure 2.

Digital anomalies and pectus excavatum in individuals with HYAL2 deficiency A, B. Broad, proximally placed thumbs in an eight-year-old Polish female

Digital anomalies, common as a group, are individually variable (see Figure 2) and include the following:

• Broad thumbs and/or halluces (6/17)
• Syndactyly of fingers or toes (5/17), most commonly bilateral toe 2-3 syndactyly
• Finger webbing
• Hypoplastic nails
• Fifth finger clinodactyly

Duodenal web has been observed in two individuals presenting with features of obstruction. It is not clear at this point if this is an infrequent feature of HYAL2 deficiency or coincidental.

Hearing loss. As would be expected in association with cleft lip and palate, hearing loss is usually conductive, can be unilateral or bilateral, and is of variable severity (mild to severe) and age of onset. In two individuals prelingual-onset static sensorineural hearing loss was reported; in one person this was bilateral, mild to severe, and mixed in one ear. In the other person this was bilateral, profound, and treated with cochlear implant [Fasham et al 2022].

Growth, including stature and head size, has to date been normal [Fasham et al 2022].

Other congenital anomalies. Bilateral extrarenal pelvises, congenital diaphragmatic hernia, and glabellar capillary nevus were described in one individual (Individual 4 in Fasham et al [2022]).

Bilateral cryptorchidism was described once [Fasham et al 2022].

Prognosis. The presence and severity of congenital cardiac anomalies primarily determine prognosis. Two sibs with severe complex congenital cardiac lesions died at age less than one year [Fasham et al 2022]. One, who died at age 10 days, had mitral valve atresia, hypoplastic left ventricle, double outlet right ventricle with pulmonary valve atresia, hypoplastic pulmonary and aortopulmonary arteries, and agenesis of the ductus venosus. The other, who died at age 10 months, had ventricular septal defect, atrial septal defect, persistent patent ductus arteriosus, pulmonary hypertension, and diaphragmatic hernia.

When congenital heart disease is absent or amenable to surgical treatment, survival does not seem impacted. The oldest reported individuals are ages 19 and 20 years.

Genotype-Phenotype Correlations

Although no genotype-phenotype correlations have been conclusively identified, the phenotypes reported in three individuals with a nonsense variant in trans with a missense variant suggests that nonsense variants may be associated with more severe congenital cardiac anomalies and severe myopia. These include the two sibs described in Clinical Description, Prognosis, who died during the first year of life due to severe cardiac anomalies, who were compound heterozygous for the HYAL2 variants p.Ser65Ter and p.Phe425Val, and a third individual who was compound heterozygous for the HYAL2 variants p.Arg277Cys and p.Arg295Ter and had coarctation of the aorta, ventricular septal defect, and severe myopic maculopathy [Fasham et al 2022].

Prevalence

To date 17 individuals from seven families with HYAL2 deficiency have been identified [Muggenthaler et al 2017, Fasham et al 2022]. Given that HYAL2 deficiency is a recently described condition, the exact prevalence is unknown. However, low prevalence of the phenotype and low numbers identified in cohorts of individuals with cleft lip and palate with or without other syndromic features suggests that HYAL2 deficiency is rare.

The HYAL2 variant c.443A>G (p.Lys148Arg) is a founder variant in individuals primarily of Indiana Amish ancestry. Seven of 266 individuals of Amish ancestry were found to be heterozygous for this variant [Muggenthaler et al 2017]. This variant was also found to have an allele frequency of 0.6% in the Anabaptist community (based on studies of more than 10,000 exomes from Amish and Mennonite individuals) [Fasham et al 2022].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with HYAL2 deficiency, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for HYAL2 deficiency.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists (see Table 5).

Surveillance

HYAL2 deficiency is primarily a developmental disorder and as such progressive complications are not expected. However, because the complications of congenital anomalies may become apparent with time, the evaluations summarized in Table 6 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

HYAL2 deficiency 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 an HYAL2 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an HYAL2 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 an HYAL2 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 being unaffected and not a carrier.
• Intrafamilial clinical variability has been observed among related individuals with HYAL2 deficiency (e.g., cleft palate and/or cardiac anomalies in some but not all affected family members) [Muggenthaler et al 2017, Fasham et al 2022].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with HYAL2 deficiency are obligate heterozygotes (carriers) for a pathogenic variant in HYAL2.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an HYAL2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the HYAL2 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 affected, are carriers, or are at risk of being carriers.
• Carrier testing for reproductive partners of known carriers could be considered, particularly if both partners are of the same ethnic background. An HYAL2 founder variant has been identified in individuals of Amish ancestry (see Table 7).

Prenatal Testing and Preimplantation Genetic Testing

Once the HYAL2 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

Hyaluronidase-2 (HYAL2) is proposed to act as a hyaluronidase enzyme, catalyzing the degradation of the high-molecular-weight glycosaminoglycan hyaluronan. HYAL2 undergoes complex post-translational modification before achieving its final topology as a mature GPI-anchored cell surface glycoprotein. The translational steps required to generate mature HYAL2 begin in the endoplasmic reticulum (ER), where even conservative amino acid substitutions may lead to ER-associated degradation and HYAL2 deficiency [Fasham et al 2022].

In silico three-dimensional homology modeling of HYAL2 missense variants using a crystal structure of HYAL1(2PE4) was undertaken by Fasham et al [2022] and predicted destabilization of protein folding in almost all instances. Analysis of immunoblotting, immunofluorescence, and glycosylation of variant / wild type human HYAL2 expressed in mouse embryonic fibroblasts was consistent with protein instability and a concomitant reduction or absence of mature HYAL2 at the cell surface.

Mechanism of disease causation. HYAL2 pathogenic variants may cause disease by one of the following mechanisms:

• Nonsense-mediated mRNA decay and loss of functional protein
• Missense variants that either:
  • Result in protein instability resulting in low total cell HYAL2 levels;
  • Disrupt the localization of HYAL2 resulting in low cell surface HYAL2 levels.

Author Notes

Further information on our work with the Amish community can be found at Windows of Hope Project.

Acknowledgments

First and foremost, the authors would like to thank the patients and their families as well as the collaborators who have been involved in defining this emerging multisystem disorder. We would particularly like to acknowledge Professor Barbara Triggs-Raine (University of Manitoba) and her group, especially Ms Promita Ghosh, without whom we would have been unable to begin to define the pathomechanism of the condition.

This work was in part supported by the Medical Research Council, Medical Research Foundation, Newlife Foundation for Disabled Children, GW4-CAT Wellcome Trust, Fondazione Bambino Gesù, Vite Coraggiose, the Natural Science and Engineering Research Council of Canada, Genomic Answers for Kids, National Center for Advancing Translational Sciences of the National Institutes of Health, Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania, the National Human Genome Research Institute / National Heart, Lung and Blood Institute, Baylor-Hopkins Center for Mendelian Genomics, and Solve-RD.

Revision History

• 21 September 2023 (bp) Review posted live
• 19 December 2022 (eb) Original submission

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