Floating-Harbor Syndrome
Summary
Clinical characteristics.
Floating-Harbor syndrome (FHS) is characterized by typical craniofacial features; low birth weight, normal head circumference, and short stature; bone age delay that normalizes between ages six and 12 years; skeletal anomalies (brachydactyly, clubbing, clinodactyly, short thumbs, prominent joints, clavicular abnormalities); severe receptive and expressive language impairment; hypernasality and high-pitched voice; and intellectual disability that is typically mild to moderate. Difficulties with temperament and behavior that are present in many children tend to improve in adulthood. Other features can include hyperopia and/or strabismus, conductive hearing loss, seizures, gastroesophageal reflux, renal anomalies (e.g., hydronephrosis / renal pelviectasis, cysts, and/or agenesis), and genital anomalies (e.g., hypospadias and/or undescended testes).
Diagnosis/testing.
The diagnosis is established by identification of a heterozygous SRCAP pathogenic variant in those with clinical findings of FHS.
Management.
Treatment of manifestations: Early intervention programs, special education, and vocational training to address developmental disabilities; communication rehabilitation with sign language or alternative means of communication; and behavior management by a behavioral specialist/psychologist with consideration of medication as needed. Referral to an endocrinologist for consideration of human growth hormone (HGH) therapy; however, data on use of HGH in FHS are limited. Standard treatment for refractive errors and strabismus, hearing loss, seizures, gastroesophageal reflux, and renal and genitourinary anomalies.
Surveillance: Close monitoring of growth, especially in the first year. Annual: ophthalmologic evaluation, hearing screening, blood pressure measurement, and assessment of renal function. Sonographic evaluation for renal cysts in teenage/adult years is indicated.
Genetic counseling.
FHS is inherited in an autosomal dominant manner. The majority of affected individuals have a de novo pathogenic variant. Each child of an individual with FHS has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis is possible for families in which the pathogenic variant has been identified.
Diagnosis
Suggestive Findings
Floating-Harbor syndrome (FHS) should be suspected in individuals with the following clinical and radiographic features.
Craniofacial appearance (see Figure 1)
Figure 1.
Facial appearance of a girl age 11 years with FHS (SRCAP pathogenic variant p.Arg2444Ter) A. Note triangular face with deep-set eyes; short philtrum; long nose with narrow bridge and broad base with low-hanging columella; and thin upper lip.
- Triangular face
- Deep-set eyes
- Short philtrum
- Wide mouth with a thin vermilion border of the upper lip
- Long nose with a narrow bridge, broad base, broad tip, and low-hanging columella
- Low-set ears
Other features
- Significant delay in bone age (≥-2 SD) with normalization between ages six and 12 years
- Skeletal anomalies. Brachydactyly, broad fingertips that give the appearance of clubbing, clinodactyly, short thumbs, prominent joints, clavicular abnormalities (see Figure 2)
- Short adult stature. 140-155 cm (see Figure 3)
Figure 2.
Dorsal (A) and palmar (B) view of the hands of the girl in Figure 1. Note clinodactyly, widened fingertips, and prominent joints.
Figure 3.
Frontal view of the girl in Figure 1. She has proportionate short stature with height <3rd centile.
Speech and language
- Dysarthria and verbal dyspraxia with phoneme imprecision
- Hypernasality
- High-pitched voice
- Severe receptive and expressive language impairment across all domains of function
Intellectual disability. All individuals have some degree of intellectual impairment and/or learning disability ranging from borderline normal to moderate intellectual disability.
Establishing the Diagnosis
The diagnosis of FHS is established in a proband with Suggestive Findings by identification of a heterozygous pathogenic variant in SRCAP on molecular genetic testing (see Table 1).
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, whereas genomic testing does not. Because the phenotype of FHS 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 with a phenotype indistinguishable from many other inherited disorders with short stature and/or intellectual disability are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of FHS, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.
Single-gene testing. Sequence analysis of SRCAP detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
A multigene panel that includes SRCAP and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost 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.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by short stature, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; 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.
Table 1.
Molecular Genetic Testing Used in Floating-Harbor Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| SRCAP | Sequence analysis 3 | 73/73 individuals 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Hood et al [2012], Le Goff et al [2013], Nikkel et al [2013], Dong et al [2014], Kehrer et al [2014], Nagasaki et al [2014], Seifert et al [2014], Amita et al [2016], Coughlin et al [2017], Singh et al [2017], Budisteanu et al [2018], Choi et al [2018], Milani et al [2018], Shields et al [2019]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
To date, large deletions that encompass SRCAP have not been associated with FHS phenotype [Author, personal communication] (see Genotype-Phenotype Correlations).
Clinical Characteristics
Clinical Description
Prior to the molecular characterization of Floating-Harbor syndrome (FHS) by Hood et al [2012], a number of reports included descriptions of individuals in whom the diagnosis of FHS could be questioned. This GeneReview only includes information on those 73 individuals with molecularly confirmed FHS (i.e., presence of a heterozygous SRCAP pathogenic variant) [Hood et al 2012, Le Goff et al 2013, Nikkel et al 2013, Dong et al 2014, Kehrer et al 2014, Nagasaki et a 2014, Seifert et al 2014, Amita et al 2016, Coughlin et al 2017, Singh et al 2017, Budisteanu et al 2018, Choi et al 2018, Milani et al 2018, Shields et al 2019]. The 41 females and 32 males range in age from eight months to 52 years.
FHS is frequently recognized in early childhood because of the characteristic facial features (Figure 1). Infants and younger children are often referred for assessment of poor growth or developmental (predominantly speech and language) delay.
Craniofacial features include triangular face, deep-set eyes, short philtrum, wide mouth with a thin vermilion border of the upper lip, long nose with a narrow bridge, broad base, broad tip, and low-hanging columella, and low-set ears.
The features become more pronounced with age, especially the length of the nose and the width of the nasal tip.
Intellect. Although gross motor and fine motor milestones are within normal limits, affected individuals typically have mild-to-moderate intellectual disability. A disorder of speech and language is the most severe disability. Most aspects of communication are affected; expressive language is most consistently and severely affected. Dysarthria and verbal dyspraxia with phoneme imprecision is most common, with absent speech in some individuals. Voice is described as hypernasal and high-pitched. The majority of affected children receive mainstream education with individualized educational plans. Regression of skills is not typical of FHS.
Behavior. Many individuals with FHS have temperament and behavior differences and difficulties: temper tantrums in infancy and attention-deficit/hyperactivity disorder spectrum with impulsivity, inattention, and restlessness at school age. Aggressive and violent outbursts can occur. Obsessive compulsive disorder and anxiety have been observed. Behavior problems are reported to improve in adulthood.
Growth. Short stature is a cardinal sign of FHS. The majority of individuals with FHS have low birth weight (from -3 SD to 0 SD) and normal head circumference (-2 SD to 0 SD). In the first years of life weight gain and linear growth are poor. A significant delay in bone age is reported (≥-2 SD) with normalization between ages six and 12 years. Average adult height is 140-155 cm.
Puberty. Early puberty has been reported; data are insufficient to determine the incidence in either gender.
Eye. Five of 73 individuals have been reported with hyperopia and eight of 13 with strabismus. One patient had anterior chamber abnormalities.
Hearing. Conductive hearing loss has been seen in eleven of 73 individuals with FHS. Cochlear abnormality has been observed in one of 73.
Neurologic. Seizures have been observed in seven of 73 individuals.
Gastrointestinal. Reflux can be severe, requiring G-tube feeding in some. Constipation and colonic strictures have been observed. One of 73 individuals had celiac disease; two had transient gluten intolerance.
Genitourinary. Renal and genitourinary anomalies can occur and include hypospadias and undescended testes, epididymal cysts, varicocele, and posterior urethral valves in boys. Hydronephrosis/renal pelviectasis and nephrocalcinosis, renal cysts, and renal agenesis have been observed. One adult of the 73 reported individuals developed polycystic kidney disease and end-stage renal disease.
Orthopedic. The body habitus is often stocky with a broad chest and short neck. Additional features include hand anomalies such as clinodactyly, brachydactyly, short thumbs, and broad fingertips that give the appearance of clubbing (Figure 2). Clavicular anomalies including pseudarthrosis and clavicular hypoplasia have been observed, as have short metacarpals, 11 pairs of ribs, kyphoscoliosis, prominent joints, dysplastic hips, and dislocated radial heads. Perthes disease has also been reported.
Dental. A number of individuals with FHS have dental problems (e.g., caries, microdontia, oligodontia, delayed loss of primary teeth) and orthodontic problems (e.g., maxillary retrusion, underbite).
Cardiac. Cardiac malformations are not usually a feature of FHS. Of 73 affected individuals one had mild aortic coarctation, one had mesocardia with persistent left superior vena cava, two had atrial septal defect, and one individual had tetralogy of Fallot.
Genotype-Phenotype Correlations
Pathogenic variants in exons 33 and 34 of SRCAP that are predicted to cause truncation of the protein (removing 3 C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact) result in the FHS phenotype.
Prevalence
The prevalence of FHS is not known. Seventy-three individuals with a heterozygous SRCAP pathogenic variant have been reported to date [Hood et al 2012, Le Goff et al 2013, Nikkel et al 2013, Dong et al 2014, Kehrer et al 2014, Nagasaki et a 2014, Seifert et al 2014, Amita et al 2016, Coughlin et al 2017, Singh et al 2017, Budisteanu et al 2018, Choi et al 2018, Milani et al 2018, Shields et al 2019].
The majority of individuals reported with FHS are of European origin, but FHS has also been diagnosed in individuals of Chinese, South American, South Asian, Japanese, and Korean background [Hood et al 2012, Nikkel et al 2013, Nagasaki et al 2014, Amita et al 2016, Singh et al 2017, Choi et al 2018]. Whether the occurrence of FHS is lower in nonwhite populations or the observed difference is the result of other factors is not known.
Differential Diagnosis
The distinctive facial features, bone age delay, and characteristic speech disability that make the diagnosis of Floating-Harbor syndrome (FHS) straightforward in early childhood become less distinct with age. Table 2 lists genes and associated conditions that should be considered in children in whom the diagnosis of FHS is suspected.
Table 2.
Other Genes of Interest in the Differential Diagnosis of Floating-Harbor Syndrome (FHS)
| Gene(s) 1 | Disorder | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/FHS | Distinguishing from FHS | |||
| CCDC8 CUL7 OBSL1 | Three M syndrome | AR |
|
|
| CREBBP EP300 | Rubinstein-Taybi syndrome | AD |
|
|
| FOXP2 | FOXP2 speech and language disorders | See footnote 2 |
| Absence of:
|
| Multiple etiologies 3 | Silver-Russell syndrome (SRS) | See footnote 3 |
|
|
AR = autosomal recessive; MOI = mode of inheritance; SRS = Silver-Russell syndrome; SD = standard deviation
- 1.
Genes are listed in alphabetic order.
- 2.
Recurrence risk for sibs of proband with a FOXP2 speech and language disorder depends on the causative genetic alteration.
- 3.
Silver-Russell syndrome (SRS) has multiple etiologies including: epigenetic changes that modify expression of genes in the imprinted region of chromosome 11p15.5, maternal UPD7, and (infrequently) autosomal dominant or autosomal recessive inheritance. When a proband has SRS as the result of paternal hypomethylation at IC1 or maternal UPD7, both parents are predicted to be unaffected, the risk to the sibs is not increased over that of the general population, and the risk to offspring is probably low.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Floating-Harbor syndrome (FHS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Floating-Harbor Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| Constitutional | Measurement of growth & plotting of growth parameters | Syndrome-specific charts are currently not available for children w/a SRCAP pathogenic variant. |
| Eyes | Ophthalmologic examination | |
| ENT | Audiology evaluation | (See Hereditary Hearing Loss and Deafness Overview for details of evaluation.) |
| Dental evaluation | ||
| Genitourinary |
| |
| Musculoskeletal | Orthopedic assessment | Evaluation for hip dysplasia & clavicular anomalies |
| Other | Multidisciplinary developmental evaluation | Incl assessment of gross & fine motor skills, speech/language, cognitive abilities, & vocational skills w/special attention to speech delay & anomalies |
| Consultation w/clinical geneticist &/or genetic counselor |
Treatment of Manifestations
Treatment includes the following:
- Early intervention programs, special education, and vocational training to address developmental disabilities
- Communication rehabilitation with sign language or alternative means of communication
- Behavior management strategies including referral to a behavioral specialist/psychologist and consideration of medication if needed
- Referral of the family to support groups and other resources
- Standard treatment for any of the following if identified:
- Refractive errors and strabismus
- Hearing loss
- Seizures
- Renal disease
- Cryptorchidism
- Orthopedic complications
- Dental problems
- Referral to an endocrinologist for consideration of human growth hormone (HGH) therapy. HGH therapy with modest response has been reported in three children with FHS. Caution is indicated as limited information about HGH therapy in FHS is available.
- Investigation for celiac disease if indicated by clinical features
Surveillance
Table 4.
Recommended Surveillance for Individuals with Floating-Harbor Syndrome
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Constitutional | Evaluation of growth | Close monitoring w/each visit, esp in 1st yr of life |
| Especially in individuals treated w/growth hormone | |
| Eyes | Ophthalmologic evaluation | Annual |
| ENT | Audiology evaluation | Annual; more frequent evaluation if history of multiple episodes of otitis media |
| Renal | Blood pressure measurement | Annual |
| Assessment of renal function incl plasma BUN & creatinine | Annual | |
| Standard monitoring for renal anomalies | Follow-up renal ultrasound if symptomatic | |
| Sonographic evaluation for renal cysts | In teenage/adult yrs as indicated by abnormalities on renal function tests &/or blood pressure measurement |
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Pregnancy Management
No specific pregnancy complications for the mother or the fetus have been observed in the two women with SRCAP pathogenic variants who had children with FHS.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.