Clinical characteristics.

Aymé-Gripp syndrome is classically defined as the triad of bilateral early cataracts, sensorineural hearing loss, and characteristic facial features in combination with neurodevelopmental abnormalities. The facial features are often described as "Down syndrome-like" and include brachycephaly, flat facial appearance, short nose, long philtrum, narrow mouth, and low-set and posteriorly rotated ears. Hearing loss is often congenital. Other features may include postnatal short stature, seizure disorder, nonspecific brain abnormalities on head imaging, skeletal abnormalities, and joint limitations. A subset of individuals have been found to have pericarditis or pericardial effusion during the neonatal or infantile period. All affected individuals have had developmental delay, but the degree of cognitive impairment is extremely variable. Other features including gastrointestinal and endocrine abnormalities, ectodermal dysplasia (i.e., nail dystrophy and mammary gland hypoplasia), dental anomalies, and chronic glomerulopathy with proteinuria have been reported in rare affected individuals.

Diagnosis/testing.

The diagnosis of Aymé-Gripp syndrome is established in a proband with cataracts, sensorineural hearing loss, and suggestive facial features and a heterozygous pathogenic variant in a specific region of MAF identified by molecular genetic testing.

Management.

Treatment of manifestations: Treatment is symptomatic and ideally involves multidisciplinary care. Hearing aids or cochlear implant for sensorineural hearing loss; surgical intervention and eye glasses for cataracts and refractive errors, respectively; physical therapy for milder joint limitations; hip replacement for those with chondrolysis; standard therapy for developmental delay / cognitive impairment, seizure disorder, scoliosis, congenital heart defects / pericardial issues, oligodontia, and hypothyroidism.

Surveillance: Dental evaluation every six months; assessment for new neurologic manifestations, progressive joint restriction in major joints, and developmental and educational needs at each visit; clinical examination for scoliosis at each visit until skeletal maturity; at least annual audiology and ophthalmology evaluations; assessment of thyroid function as clinically indicated.

Genetic counseling.

Aymé-Gripp syndrome is inherited in an autosomal dominant manner. Almost all individuals reported to date have been simplex cases (i.e., a single occurrence in a family) resulting from a de novo pathogenic variant. Once the causative genetic alteration has been identified in the proband, parental testing may be offered. Each child of an individual with Aymé-Gripp syndrome has a 50% chance of inheriting the MAF pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in an affected family member is known.

Suggestive Findings

Aymé-Gripp syndrome should be suspected in individuals with the following major and minor clinical features and imaging findings.

Major clinical features

• Distinctive facial features (Figure 1), often described as similar to those seen in individuals with Down syndrome, including:
  • Brachycephaly
  • Flat facial appearance
  • Short nose
  • Long philtrum
  • Narrow mouth
  • Dental abnormalities (small, abnormally shaped teeth)
  • Low-set and posteriorly rotated ears
• Sensorineural hearing loss
• Cataracts
• Developmental delay / intellectual disability
• Short stature

Figure 1.

Individuals with a molecularly confirmed diagnosis of Aymé-Gripp syndrome with characteristic facial features including midface retrusion, high forehead, flat nasal bridge, long philtrum, and thin vermillion of the upper lip Individual 1 shown (more...)

Minor clinical features

• Seizures (variable, from febrile seizures to epilepsy)
• Congenital radioulnar synostosis
• Pericardial effusion
• Mammary gland hypoplasia
• Ectodermal abnormalities (sparse scalp hair, dystrophic nails)

Imaging findings

• Congenital radioulnar synostosis
• Radial head subluxation
• Chondrolysis of the hip (in a young adult)
• Carpal/tarsal long bone defects

Establishing the Diagnosis

The diagnosis of Aymé-Gripp syndrome is established in a proband with cataracts, sensorineural hearing loss, and suggestive facial features AND a heterozygous pathogenic (or likely pathogenic) variant in a specific region of MAF identified by molecular genetic testing (see Table 1 and Molecular Genetics).

Note: Per ACMG 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. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

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

Gene-targeted testing requires that the clinician determine which gene is likely involved, whereas genomic testing does not. Because the phenotype of Aymé-Gripp syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Aymé-Gripp syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Individuals with Aymé-Gripp syndrome frequently have the triad of bilateral early cataracts, sensorineural hearing loss, and dysmorphic features that are often described as "Down syndrome-like" facies [Gripp et al 1996, Aymé & Philip 1997, Amudhavalli et al 2018, Niceta et al 2020]. To date, 21 affected individuals from 19 families have been reported [Amudhavalli et al 2018, Alkhunaizi et al 2019, Niceta et al 2020]. Clinical features in these individuals are summarized in Table 2.

Characteristic facial features. Dysmorphic facial features typically include brachycephaly (~80%), flat facial profile, midface retrusion, short nose, long philtrum, thin vermilion of the upper lip, and small mouth. Other features include widely spaced eyes, broad/sparse eyebrows, long philtrum, and high anterior hairline.

Audiologic manifestations. Early-onset or congenital sensorineural hearing loss has been reported in all but one affected individual. One affected mother was noted to have normal hearing as an adult [Alkhunaizi et al 2019].

• Hearing loss is frequently bilateral and often diagnosed early in childhood.
• Hearing loss can vary from mild to severe, with a few affected individuals requiring hearing aids or cochlear implant.

Ophthalmologic manifestations. Almost all affected individuals reported have congenital or early-onset cataract as a presenting feature. Cataract can be noted as early as infancy to as late as adolescence or even adulthood.

• One affected individual, age 18 months at presentation, had bilateral retinal hemorrhage and optic disc anomaly [Amudhavalli et al 2018].
• One affected individual was reported to have bilateral cataracts diagnosed at age 14 months. This individual developed aphakic glaucoma and went blind at age two years [Alkhunaizi et al 2019].
• Two affected parents were reported to have cataracts extracted after age 40 years [Javadiyan et al 2017, Alkhunaizi et al 2019].

Growth. Most affected individuals have mild-to-moderate short stature, with height 1.25-2 SD below the mean for age. Short stature usually develops postnatally, with birth length in the normal range. Weight and head circumference are typically within normal ranges for all age groups.

Intellectual development. Both speech and gross motor delays have been reported. Some affected individuals have been diagnosed with an autism spectrum disorder. Developmental delay has been reported in all but one affected individual, but the degree of intellectual impairment is highly variable. For example, an affected mother and son had only mild learning delays and were both able to complete secondary education [Javadiyan et al 2017], whereas an affected individual age 29 years was nonverbal and used sign language to communicate [Amudhavalli et al 2018]. One parent found to have a pathogenic MAF variant was reported to have normal development and no history of learning difficulties, and graduated from university with a bachelor's degree.

Neurologic manifestations

• Seizures have been reported in 15 of 21affected individuals, with five having febrile seizures [Amudhavalli et al 2018]. The age of onset ranges from age six months to 12 years in reported individuals.
• Nonspecific brain abnormalities such as ventriculomegaly, Chiari 1 malformation, obstructive hydrocephalus, empty sella, and cerebral atrophy have been noted in slightly more than half of individuals who have undergone brain imaging. One individual was reported to have calcifications of the basal ganglia [Alkhunaizi et al 2019].

Joint and skeletal manifestations. Joint manifestations, ranging from congenital radioulnar synostosis with forearm shortening to mild restriction in the range of motion, have been reported in most affected individuals. For an in-depth analysis of the skeletal features seen in Aymé-Gripp syndrome, see the review by Niceta et al [2020].

• Congenital radioulnar synostosis, radial head subluxation, and shortened forearm as individual findings or in various combinations are the most common joint manifestations.
• Clino/campto/brachydactyly, pectus excavatum, scoliosis without vertebral anomalies, delayed skeletal maturation and carpal/tarsal bone defects, short fourth metatarsal, and hip joint chondrolysis have also been reported.
• Coronal craniosynostosis requiring surgical repair is reported as a rare feature.
• One affected individual was reported to have early fusion of the growth plates, spontaneous fractures, and exostosis [Niceta et al 2020].
• Some affected adults have required hip replacement for hip joint chondrolysis.

Cardiac manifestations

• At least eight of 21 individuals have been noted to have pericarditis or pericardial effusion during the neonatal or infantile period:
  • Four affected individuals presented in the neonatal period with cardiac murmurs for which echocardiogram was performed, revealing pericardial effusion [Amudhavalli et al 2018, Niceta et al 2020].
  • One of these affected infants had persistent effusion and underwent effusion aspiration and eventually a pericardial window.
• Atrial septal defect and patent ductus arteriosus have been reported in a single individual each.

Ectodermal manifestations

• Bilateral mammary gland hypoplasia may be seen in females.
• Hair. Sparse scalp hair has been reported in both children and adults. Mild-to-moderate premature hair loss has been seen in some affected adults.
• Nails. Dystrophic or double nails (rudimentary or accessory nails that grow on top of an existing nail) have been observed [Javadiyan et al 2017, Niceta et al 2020].
• Dental abnormalities may include small teeth, abnormally shaped teeth, and/or oligodontia, present in slightly fewer than half of affected individuals

Hypothyroidism was identified in three of 15 affected individuals. Hypothyroidism was not congenital in nature but was diagnosed in childhood and responded to thyroid hormone replacement therapy. Other endocrine abnormalities have rarely been documented.

Rare manifestations may include the following:

• Hiatal hernia and diaphragmatic hernia
• Transient hematuria
• Proteinuria and/or microalbuminuria (reported as a late-onset feature)
• Glomerulonephropathy
• Nephrotic syndrome (which did not recur after treatment with prednisone)

Genotype-Phenotype Correlations

MAF has an N-terminal transactivation domain and a C-terminal DNA binding domain (see Molecular Pathogenesis).

• Pathogenic variants causing Aymé-Gripp syndrome occur at serine, threonine, and proline residues in the N-terminal transactivation domain [Niceta et al 2015].
• A subset of pathogenic variants in the C-terminal DNA binding domain have been associated with isolated congenital cataracts [Anand et al 2018] (see Genetically Related Disorders).

Penetrance

For this disorder, penetrance is felt to be 100%; however, there is variability in presentation as illustrated by a report from Javadiyan et al [2017] and Alkhunaizi et al [2019] in which an affected mother had a substantially milder phenotype than her child.

Prevalence

This disorder is rare and exact prevalence estimates are unknown. Only 21 individuals representing 19 families have been reported in the literature.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Aymé-Gripp syndrome, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment of this disorder is symptomatic and ideally involves multidisciplinary care, which may include an ophthalmologist, otolaryngologist, developmental and behavior specialist, speech therapist, occupational therapist, physiotherapist, orthopedist, endocrinologist, cardiologist, and neurologist, depending on the affected person's specific needs.

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

Aymé-Gripp syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with Aymé-Gripp syndrome have the disorder as the result of a de novo MAF pathogenic variant.
  The proportion of cases caused by a de novo pathogenic variant is approximately 90% in families in which both the mother and father of the proband were available for analysis [Niceta et al 2015, Javadiyan et al 2017, Amudhavalli et al 2018].
• In two families reported to date, a proband with Aymé-Gripp syndrome had the disorder as the result of an MAF pathogenic variant inherited from his mildly affected mother [Javadiyan et al 2017, Alkhunaizi et al 2019].
• Molecular genetic testing is recommended for the parents of a proband who has an identifiable MAF pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, the pathogenic variant was most likely de novo in the proband. Another possible explanation is germline mosaicism in a parent. Though theoretically possible, no instances of a proband inheriting a pathogenic variant from an apparently unaffected parent with germline (or somatic) mosaicism have been reported.
• Although almost all individuals with Aymé-Gripp syndrome represent simplex cases (i.e., the only affected individual in the family), the family history may appear to be negative due to failure to recognize features of the disorder in mildly affected family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

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 has the MAF pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• If the MAF pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the MAF pathogenic variant but appear to be clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population because of the possibility of a very mild phenotype in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with Aymé-Gripp syndrome has a 50% chance of inheriting the MAF pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the MAF pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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 or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the MAF pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

MAF encodes transcription factor Maf (MAF), a basic leucine zipper (b-ZIP) containing transcription factor of the AP1 family [Niceta et al 2015]. The MAF 373-amino-acid protein is important in lens and eye development but also controls multiple physiologic processes during embryonic development, including chondrocyte and skin cell differentiation. MAF is phosphorylated by GSK3 [Niceta et al 2015].

MAF has a C-terminal extended homology region, a b-ZIP domain mediating DNA binding, and an N-terminal transactivation domain required for transcriptional and regulatory activity [Niceta et al 2015]. MAF pathogenic variants causing Aymé-Gripp syndrome specifically reported to date affect residues located within the GSK3 recognition motifs at the N-terminal transactivation domain, including: p.Ser54, p.Ser57, p.Thr58, p.Pro59, p.Thr62, p.Pro63, p.Ser66, p.Pro69 (see also Genotype-Phenotype Correlations).To date, the most frequently affected residue is p.Pro59: p.Pro59His has been reported in three unrelated individuals, p.Pro59Leu in two unrelated individuals, and p.Pro59Arg in two related individuals.

Impaired phosphorylation of the GSK3 binding sites affects MAF ubiquitination, and in turn, this impairs protein degradation [Niceta et al 2015]. Pathogenic variants in this domain are postulated to disrupt dimerization, protein stability, and function, resulting in the syndromic phenotype [Anand et al 2018].

Revision History

• 6 February 2020 (ma) Review posted live
• 7 March 2019 (sma) Original submission

Literature Cited

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