Clinical characteristics.

USP7-related Hao-Fountain syndrome is characterized by developmental delay in 100% of individuals, although intellectual disability is variable, with up to 50% of affected individuals having intellect in the normal range. Muscular hypotonia is also common; this tends to improve over time, but some affected individuals develop hypertonia. About two thirds of affected individuals have an abnormal/unsteady gait and about one quarter have contractures, most commonly involving large joints and joints of the lower extremities. Neuropsychiatric features can include autism, attention-deficit/hyperactivity disorder (ADHD), and behavioral issues such as stubbornness and compulsivity. Feeding difficulties are common and can require special feeding techniques, including use of a feeding tube. Gastroesophageal reflux disease, dysphagia, and hyperphagia have also been reported. Eye and vision issues (hyperopia, strabismus, nystagmus) are seen in more than 50% of affected individuals. About half of affected individuals have impaired bone mineralization, which can lead to fractures. Findings in fewer than 50% of individuals include epilepsy, sleep disturbance, hypogonadism, scoliosis, and hearing loss.

Diagnosis/testing.

The diagnosis of USP7-related Hao-Fountain syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in USP7 identified by molecular genetic testing.

Management.

Treatment of manifestations: Feeding therapy for poor weight gain / dysphagia; gastrostomy tube placement may be required for persistent feeding issues; consultation with a dietician when hyperphagia and/or obesity is present; adequate intake of Ca²⁺ and vitamin D for reduced bone mineral density. Standard treatment for developmental delay / intellectual disability, epilepsy, gastroesophageal reflux disease, diarrhea, constipation, eye issues, sleep disturbance, cryptorchidism, micropenis, hypothyroidism, growth hormone deficiency, adrenal insufficiency, and hearing loss.

Surveillance: At each visit, measure growth parameters; evaluate nutritional status and safety of oral intake; monitor for signs/symptoms of constipation and gastroesophageal reflux disease; monitor those with seizures; assess for new manifestations such as seizures, changes in tone, and gait abnormalities; monitor developmental progress and educational needs; monitor for scoliosis, contractures, mobility, and self-help skills; monitor for evidence of aspiration, respiratory insufficiency, and sleep disturbance (including for signs/symptoms of sleep apnea); monitor for signs and symptoms of puberty starting at about age seven years to the late teenage years. Annually, behavioral assessment for anxiety, ADHD, autism spectrum disorder, aggression, and self-injury; evaluate for hypothyroidism; audiology evaluation (in childhood). Assess bone mineral density every two years starting at age five years and then every three to five years in adulthood. Ophthalmology evaluation and endocrinologic tests for adrenal insufficiency as clinically indicated.

Genetic counseling.

USP7-related Hao-Fountain syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, individuals diagnosed with USP7-related Hao-Fountain syndrome inherited a pathogenic variant from a parent. Each child of an individual with USP7-related Hao-Fountain syndrome has a 50% chance of inheriting the pathogenic variant. Once the USP7 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

USP7-related Hao-Fountain syndrome should be considered in probands with the following clinical and brain MRI findings and family history.

Clinical findings

• Mild-to-severe developmental delay or intellectual disability

AND

• Any of the following features presenting in infancy or childhood:
  • Generalized hypotonia of infancy
  • Infant feeding difficulties
  • Moderate hyperphagia
  • Contractures (most commonly involving the large joints and the lower extremities)
  • Abnormal gait
  • Macrocephaly (rarely, microcephaly)
  • Seizures
  • Neurobehavioral/psychiatric manifestations, including autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or obsessive-compulsive behavior
  • Ophthalmologic involvement, such as hyperopia, strabismus, and/or nystagmus
  • Genitourinary anomalies, including cryptorchidism and/or micropenis in males

Brain MRI findings. Paucity of white matter, including thinning of the splenium and body of the corpus callosum

Family history. Because USP7-related Hao-Fountain syndrome 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 USP7-related Hao-Fountain syndrome is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in USP7 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology 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 GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous USP7 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 exome sequencing / genome sequencing [Manickam et al 2021, van der Sanden et al 2023]. Other options include use of a multigene panel. Note: Single-gene testing (sequence analysis of USP7, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An intellectual disability multigene panel that includes USP7 and other genes of interest (see Differential Diagnosis) is likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance 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. Given the rarity of USP7-related Hao-Fountain syndrome, some panels for intellectual disability may not include this gene. (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 intellectual disability multigene panel, with the additional advantage that exome sequencing includes genes recently identified as causing intellectual disability, whereas some multigene panels may not. To date, the majority of USP7 pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing. 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.

Epigenetic signature analysis / methylation array. A distinctive epigenetic signature (disorder-specific genome-wide changes in DNA methylation profiles) in peripheral blood leukocytes has been identified in individuals with USP7-related Hao-Fountain syndrome [van der Laan et al 2024]. Epigenetic signature analysis of a peripheral blood sample or DNA banked from a blood sample can therefore be considered to clarify the diagnosis in individuals with: (1) suggestive findings of Hao-Fountain syndrome but in whom no pathogenic variant in USP7 has been identified via sequence analysis or genomic testing; or (2) suggestive findings of Hao-Fountain syndrome and a USP7 variant of uncertain clinical significance identified by molecular genetic testing. For an introduction to epigenetic signature analysis click here.

Clinical Description

USP7-related Hao-Fountain syndrome is characterized by developmental delay / intellectual disability (mild to severe), hypotonia, and infantile feeding difficulties. Brain MRI anomalies, primarily affecting the white matter, are present in a majority of individuals. Contractures and genitourinary anomalies are present in a subset of affected individuals. However, none of these features are specific to USP7-related Hao-Fountain syndrome, and affected individuals exhibit broad variability.

To date, more than 250 individuals have been identified with a pathogenic variant in USP7 [Fountain et al 2019, Priolo et al 2022, van der Laan et al 2024, Wimmer et al 2024]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay and intellectual disability are common among affected individuals. Developmental delay affects both speech and motor milestones, with average ages of achieving these skills as follows [Wimmer et al 2024]:

• Independent sitting at age 12 months
• Crawling at age 15 months
• Independent walking at age 27 months
• First word at age 21 months
• Two-word sentences around age 33 months

The range of intellectual disability can be very broad, from severe intellectual disability (IQ <35) in several older individuals who are nonverbal to normal IQ (>70). The mean IQ is reported in the borderline range at 78.3.

Other neurodevelopmental features

• Hypotonia is one of the most frequent symptoms (73%-79% of affected individuals) and can be present from birth [Priolo et al 2022, Wimmer et al 2024]. The severity of the hypotonia improves with age in the majority of affected individuals. Spasticity has not been reported, but some severely affected individuals ultimately have muscular hypertonia.
• Abnormal/unsteady gait has been reported in 66% of affected individuals and may, in part, be secondary to hypotonia, balance problems, or contractures.

Neurobehavioral/psychiatric manifestations. About 72% of affected individuals have a clinical diagnosis of autism spectrum disorder. Attention-deficit/hyperactivity disorder is also a frequent feature. The following behaviors are occasionally seen:

• Impulsivity
• Compulsivity
• Stubbornness
• Temper tantrums
• Skin picking
• Aggressiveness and manipulative behavior (rare)

Epilepsy. Seizures are reported in 40% of affected individuals, although details on the onset and types of seizures observed are currently lacking [Wimmer et al 2024].

Respiratory/sleep. Sleep disturbances are reported in 47% of affected individuals, with sleep apnea reported in 29%. Approximately 70% of affected individuals have been reported to tire easily, and 64% show increased need for rest during the day (compared to sibs) [Wimmer et al 2024].

Neuroimaging. Abnormalities in brain MRI are nonspecific and can be found in 68%-73% of affected individuals. Recurring features may include general paucity of white matter and thinning of the corpus callosum. Additionally, shallow gyral patterns, dysmorphia of the ventricular system, and white matter hyperintensities have been reported.

Growth

• Stature can vary, with a mean around the 60th centile. However, 13%-30% of affected persons show growth restriction with short stature. Only two reported individuals had documented growth hormone deficiency, which required growth hormone supplementation (see Endocrinologic).
• Head size can also be variable but tends to be in the upper centiles with 35% of affected individuals having macrocephaly [van der Laan et al 2024]. Nonetheless, microcephaly can occur.

Gastrointestinal/feeding problems. The most frequent gastrointestinal symptoms are chronic constipation or diarrhea, hypothesized to be due to gut motility issues (although this requires further confirmation). Gastroesophageal reflux disease (GERD) occurs in 37%-50% of affected individuals.

• Infant feeding difficulties occurs in approximately 55% of affected children and can require special feeding techniques or use of a feeding tube [Fountain et al 2019, Wimmer et al 2024].
• In those with feeding difficulties, dysphagia can occur and can lead to increased risk of aspiration.
• Approximately 39% of affected individuals have hyperphagia or food-seeking behavior and about one quarter are obese.
• In some cases, prolonged neonatal jaundice has been reported. There is limited information on whether this is a conjugated or unconjugated hyperbilirubinemia.

Ophthalmologic involvement. Eye anomalies and vision issues are reported in 53%-65% of affected individuals. Features may include:

• Refractive errors, most frequently hyperopia
• Strabismus
• Nystagmus

Endocrinologic. Hypogonadism, typically consisting of cryptorchidism and/or micropenis in males, occurs in 25%-44% of males. To date, two affected females have been reported with hypogonadism, one of them showing delayed puberty [Fountain et al 2019]. In some affected individuals, growth hormone deficiency, hypothyroidism, or adrenal insufficiency has been described.

Musculoskeletal features

• Scoliosis or kyphosis occurs in 30% of affected individuals. Slight progression of the musculoskeletal symptoms due to severe hypotonia is possible.
• Joint contractures occur in about 24% of affected individuals [Fountain et al 2019, Priolo et al 2022, Wimmer et al 2024].
  • The contractures tend to occur in large joints and in the joints of the lower extremities, but other joints (e.g., shoulder, elbows, or smaller joints) can also be affected.
  • Joint contractures do not appear to be congenital but are also not reported to be progressive. However, in severely affected individuals markedly elevated muscle tone may be observed.
• Small hands and feet are seen in 25%-33% of affected individuals.
• Bone age is delayed in 30% of affected individuals and bone mineralization is impaired in 54% of affected individuals.
  • About 36% of individuals show a bone health index in the range of osteopenia (1-2.5 standard deviations [SD] below the mean) and 18% manifest osteoporosis (bone health index more than 2.5 SD below the mean).
  • Some affected individuals experience stress fractures or fractures after inadequate trauma [CP Schaaf, unpublished data].

Hearing. Approximately 15% of affected individuals have impaired hearing. This can include disturbances of sound conduction due to recurrent middle ear infections, non-progressive sensorineural hearing loss, and auditory processing issues.

Dental. Approximately 55% of affected individuals have dental issues. These include amelogenesis imperfecta, oligodontia, hyperdontia, decreased stability (early need of crowns, breaking after inadequate trauma), diastema, large frontal teeth, and widely spaced teeth [CP Schaaf, unpublished data].

Facial features. Dysmorphic facial features are found in 90% of affected individuals; however, there is no specific facial gestalt [Fountain et al 2019, Priolo et al 2022]. Frequently described dysmorphic features include a broad forehead, deeply set eyes, and a low-hanging columella

Prognosis. USP7-related Hao-Fountain syndrome represents a static condition and is not considered a progressive disease. It is unknown whether life span in USP7-related Hao-Fountain syndrome is abnormal. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported. Reduced life span may be caused by secondary complications, such as severe scoliosis leading to restrictive lung disease and/or pneumonia.

Genotype-Phenotype Correlations

Individuals who have a missense pathogenic variant that impacts the catalytic domain of ubiquitin carboxyl-terminal hydrolase 7 (the protein encoded by USP7) tend to have a more severe phenotype. They are affected by more of the associated symptoms, have more neonatal complications, and show a more severe developmental delay / intellectual disability phenotype. There is no known difference in phenotypic severity between missense pathogenic variants outside of the catalytic domain and pathogenic variants leading to loss of function [Wimmer et al 2024] (see Molecular Genetics).

Nomenclature

USP7-related Hao-Fountain syndrome may also be referred to as USP7-related neurodevelopmental disorder based on the dyadic naming approach proposed by Biesecker et al [2021] to delineate mendelian genetic disorders.

Prevalence

The prevalence of USP7-related Hao-Fountain syndrome is unknown. More than 250 individuals with this condition have been identified.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with USP7-related Hao-Fountain syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for USP7-related Hao-Fountain syndrome. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized 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

USP7-related Hao-Fountain syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most probands reported to date with USP7-related Hao-Fountain syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a de novo USP7 pathogenic variant.
• Rarely, individuals diagnosed with USP7-related Hao-Fountain syndrome inherited a USP7 pathogenic variant from a parent [Sun et al 2024; CP Schaaf, unpublished data]. Detailed phenotypic information on heterozygous parents is not currently available.
• Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• 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 gonadal (or somatic and gonadal) mosaicism [CP Schaaf, unpublished data].* 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 gonadal (germ) cells only.
    * A parent with somatic and gonadal mosaicism for a USP7 pathogenic variant may be mildly/minimally affected.

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 USP7 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• If the USP7 pathogenic variant found 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 possibility of parental gonadal mosaicism [CP Schaaf, unpublished data].

Offspring of a proband. Each child of an individual with USP7-related Hao-Fountain syndrome has a 50% chance of inheriting the USP7 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 USP7 pathogenic variant, the parent's family members may be at risk.

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 USP7 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 and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

USP7 encodes ubiquitin carboxyl-terminal hydrolase 7 (USP7), a ubiquitin-specific protease regulating the stability of various cellular proteins. It is involved in DNA damage response, transcription, epigenetic control of gene expression, immune response, and viral infection [Pozhidaeva & Bezsonova 2019]. It is assumed that the phenotype of USP7-related Hao-Fountain syndrome is caused by reduced complex formation between USP7, MAGE-L2, and TRIM27, leading to impaired protein recycling [Hao et al 2015]. Other functions of USP7 seem not to be sensitive to haploinsufficiency. USP7 consists of seven domains: an N-terminal TRAF-like domain, followed by the catalytic domain and five consecutive ubiquitin-like domains [Pozhidaeva & Bezsonova 2019, Nie et al 2022]. Missense pathogenic variants in the catalytic domain seem to lead to a more severe phenotype, assumed to lead to a dominant-negative effect [Wimmer et al 2024]. However, homozygous knockout of Usp7 is lethal in mice [Kon et al 2010].

Mechanism of disease causation. Loss of function in most cases; dominant-negative effect with rare missense pathogenic variants

Revision History

• 4 December 2025 (ma) Review posted live
• 14 February 2025 (cs) Original submission

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