Floating-Harbor syndrome (FHS) is a rare neurodevelopmental disorder caused by truncating variants in the last two exons of the gene encoding the chromatin remodeler SRCAP. We used CRISPR-Cas9 genome editing to introduce a monoallelic c.7330C > T (p.Arg2444*) truncating mutation into a published WTC11 iPSC line containing a tetracycline-inducible NGN2 transgene. We characterised two independent lines that maintained a normal karyotype, pluripotency and the ability to differentiate in vitro into all three embryonic germ layers. These lines can be rapidly differentiated into cortical neurons through the addition of doxycycline, making them a useful model for understanding the pathogenic mechanisms underlying FHS.

Floating-Harbor syndrome (FHS) is a rare disorder characterized by facial dysmorphism, short stature, and delayed language development. We evaluated the clinical features and treatment outcomes of 10 Chinese children with FHS who received recombinant human growth hormone (rhGH) therapy or nutritional intervention. We retrospectively extracted the clinical features, height standard deviation score (SDS), genetic characteristics, and treatment outcomes from the medical records of 10 Chinese children with FHS. The treatment response was classified as good, moderate, or poor based on annual height SDS change and height velocity. All patients presented with short stature at diagnosis, distinct facial features, and non-specific skeletal abnormalities. All patients had delayed language development, feeding difficulties, intellectual disability, and diverse organ abnormalities. Whole-exome sequencing (WES) identified pathogenic or likely pathogenic variants in exon 34 of SRCAP, and eight mutations were identified, including three variants (c.7225dupG;p.Ala2409GlyfsTer34, c.7382delC;p.Pro2461GlnfsTer 14, and c.7255C > T;p.Gln2419Ter) that had not been previously reported in case reports. Eight patients were treated with rhGH, six of whom demonstrated good responses, one a moderate response, and one a poor response. One patient with a contraindication to rhGH treatment achieved meaningful height SDS improvement after nutritional therapy. Although FHS is a rare condition, we characterized its clinical features in a Chinese patient cohort. RhGH improved height in most patients, and nutritional optimization appeared to support growth in one child. • Floating-Harbor syndrome (FHS) is a rare genetic disorder characterized by facial dysmorphism and short stature, and it is often treated with growth hormone. The majority of documented cases of FHS have historically been concentrated within Western populations. The number of cases reported in Asian countries remains small. • We report three SRCAP variants that have not been previously documented in case reports among 10 Chinese children with FHS. Most children showed favorable short-term responses to recombinant human growth hormone, and one child demonstrated an improvement in height standard deviation score with structured nutritional therapy alone.

The genetic basis of autism spectrum disorder (ASD) is highly heterogeneous and continues to be elucidated through syndromic associations. Floating-Harbor Syndrome (FHS) is a rare genetic disorder caused by SRCAP mutations and is characterized by short stature, expressive language delays, and distinct craniofacial features. This report aims to present the diagnostic process and clinical challenges of a child diagnosed with both FHS and ASD. A 9-year-old boy presented with social communication difficulties, restricted interests, and sensory hypersensitivity. Psychometric testing demonstrated average intellectual functioning (. 94), while behavioral assessments revealed significant hyperactivity and behavioral dysregulation, in addition to severe autism as measured by the Childhood Autism Rating Scale (CARS). Based on DSM-5 criteria, he was diagnosed with ASD. Persistently elevated amylase and lipase levels prompted genetic evaluation, which confirmed FHS with an SRCAP mutation. This case underscores the diagnostic challenges of differentiating syndrome-specific features from true comorbid ASD when overlapping symptoms such as language delay and behavioral problems are present. These findings highlight the importance of comprehensive psychiatric and genetic evaluation in children with complex developmental profiles, and highlights the need for systematic screening for neurodevelopmental disorders in rare genetic syndromes.

Floating-Harbor syndrome (FHS) is a rare autosomal dominant genetic disorder characterized by proportionately short stature, lack of expressive language, and distinctive facial features, including a large nose, long eyelashes, deeply set eyes, and a triangular face. We present a case of an 11-year-old Korean girl who was initially suspected of having Noonan-like syndrome but was later diagnosed with FHS. The patient exhibited short stature, developmental language delay, dysmorphic facial features, and early puberty. Targeted exome sequencing revealed a heterozygous mutation, c.7303C>T (p.Arg2435Ter), in the SRCAP gene, confirming a diagnosis of FHS. She responded well to human recombinant growth hormone and gonadotropin-releasing hormone agonist, effectively suppressing bone maturation and improving her height standard deviation score from -4.6 to -2.4.

We present two CRISPR/Cas9-modified human iPSC lines with a heterozygous frameshift mutation (NM_006662.3:c.7300_7301insA) in the FLHS-locus of the SRCAP gene, which is associated with Floating-Harbor syndrome, a congenital neurodevelopmental disorder with symptoms including short stature and intellectual disability. The iPSCs express the pluripotency markers OCT4, SOX2, NANOG and TRA 1-60. They show differentiation into cells from all 3 germ layers, no chromosomal abnormalities and no off-target mutations in the tested regions. The mutation leads to a stop codon previously found in patients. Thus, either cell line can serve as disease-specific model for studying SRCAP in the context of FLHS. SRCAP-related Floating-Harbor syndrome (SRCAP-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, broad fingertips, clinodactyly, short thumbs, prominent joints, and 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, 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). The diagnosis is established in a proband with suggestive findings and a heterozygous SRCAP pathogenic variant identified by molecular genetic testing. Treatment of manifestations: Referral to an endocrinologist for consideration of human growth hormone (HGH) therapy; however, data on use of HGH in SRCAP-FHS are limited. Early intervention programs, special education, and vocational training to address developmental disabilities; communication rehabilitation with sign language or alternative means of communication; behavior management by a behavioral specialist / psychologist with consideration of medication as needed. Standard treatment for refractive errors, strabismus, hearing loss, seizures, gastroesophageal reflux, constipation, kidney and genitourinary anomalies, orthopedic, dental, and cardiac issues; family and social work support. Surveillance: Close monitoring of growth, especially in the first year of life. Bone age and evaluation for signs of early puberty as needed, especially in those on HGH. Monitor developmental progress and educational needs at each visit. Assess for seizures, gastroesophageal reflux, constipation, and manifestations of celiac disease at each visit. Annual behavioral assessment, ophthalmologic evaluation, audiology evaluation, blood pressure measurement, and assessment of kidney function. Monitor kidney anomalies per nephrologist. Kidney ultrasound to assess for cysts in teenage and adult years with follow up as needed. Orthopedic assessment for kyphoscoliosis and clinical manifestations of Perthes disease as needed. Dental evaluation every six months. SRCAP-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 SRCAP-FHS has a 50% chance of inheriting the pathogenic variant. Prenatal and preimplantation genetic testing are possible for families in which the pathogenic variant has been identified.