ABSTRACT

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.

Introduction

Floating-Harbor syndrome [FHS, (MIM 136140)] is a rare condition characterised by short stature, delayed osseous maturation, language deficits, and a distinctive facial appearance. Mutations in the SRCAP gene which codes for SNF2-related CREBBP activator protein cause truncation of the SRCAP protein, leading to FHS.

To date, approximately 100 cases have been reported in medical literature. Poor awareness of the condition and the non-specific clinical symptoms of FHS make its diagnosis difficult and delayed. Only two cases of FHS have been reported in Korea (1, 2). Both patients had facial dysmorphism and intellectual disabilities, but one patient did not exhibit short stature (1) and the other did not experience early puberty (2). In this report, we describe the clinical features and molecular analysis of an 11 years and 5-month-old girl with an SRCAP mutation who presented with short stature, developmental language delay, dysmorphic facial features, and early puberty.

Case Report

The female patient was born at 38 weeks of gestation through normal vaginal delivery with a birth weight of 2840 g [-0.89, Korean standard deviation score (SDS)]. No perinatal complications were observed. Her mother had a height of 162.5 cm (0.29 SDS), and the father had a height of 174 cm (-0.08 SDS), resulting in a predicted adult height, calculated using mid-parental height, of 161.7 cm (0.13 SDS) (see Figure 1A). Moreover, there was a family history of short stature, as evidenced by the maternal grandmother’s recorded height of 155 cm (-1.21 SDS) (see Figure 1B). The patient had no other significant family history. She exhibited persistent short stature from birth and so chromosomal analysis was performed at the age of 10 months. However, only an inversion p11-q13 in chromosome 9, which could be interpreted as a normal mutation, was identified. At the age of 16 months, Noonan syndrome was suspected at another hospital because of her short stature and large ears. Subsequently, genetic testing for Noonan syndrome was performed, and no abnormalities were found. Due to the initial suspicion of a Noonan-like syndrome, recombinant growth hormone (rhGH) therapy was started at 4 years of age. At that time, her height was 83.4 cm (-4.63 SDS), her weight was 9.4 kg (-5.19 SDS), and her insulin-like growth factor 1 (IGF-1) level was 55.3 ng/mL (reference range: 43.8-239.7). The patient’s language development progressed slowly, and she commenced speech therapy at the age of five and was able to speak sentences at approximately six years of age. As the patient’s growth was tracked, there was a consistent pattern of lagging bone age progression. However, at the age of 8 years and 7 months, the bone age assessment exhibited a significant acceleration, revealing a bone age of 7 years and 9 months, a markedly rapid increase compared to prior assessments. Furthermore, during a follow-up physical examination conducted six months later, at the age of 9 years and 3 months, bilateral breast development was observed, indicating significant progression. Remarkably, within just one year, the bone age had advanced by 2 years and 3 months. In response to these developments, starting at the age of 9 years and 10 months, a gonadotropin-releasing hormone (GnRH) agonist was administered in combination with the rhGH therapy to suppress bone maturation.

At the age of 11 years and 5 months, she was transferred to our hospital to continue treatment for her short stature and early puberty. Her height was 131.5 cm (-2.59 SDS), and her weight was 28.4 kg (-2.0 SDS) (Figure 1A). During physical examination, several distinctive features were noted that differed from those of her parents. These included large ears, a short neck, a long nose with a narrow nasal bridge and wide nostrils, mild cubitus valgus, and clinodactyly. Breast development was well suppressed, and bone age was determined to be 11 years, which was six months less than her chronological age. In addition, there were no anomalies detected in her blood biochemistry or thyroid function tests.

We conducted targeted exome sequencing (TES) to identify the genetic causes of her persistent short stature and facial dysmorphism. DNA samples were obtained from peripheral blood leukocytes using the Chemagic^TM Magnetic Separation Module I method (PerkinElmer Chemagen, Baesweiler, Germany) with a DNA blood 200 mL kit. The G-Mendeliome panel (Celemics, Inc., Seoul, South Korea) was used for library preparation, and sequencing was performed using the DNBSEQ-G400 (MGI Tech Co., Ltd., Shenzhen, China), generating 2×100 bp paired-end reads. The sequence reads obtained were aligned to the reference sequence based on the public human genome build GRCh37/UCSC hg19 using BWA-mem (version 0.7.17). Duplicate reads were marked with biobambam2, and base quality recalibration and variant calling was performed using the Genome Analysis Toolkit (GATK, version 4.1.8). Annotation was performed using variant effect predictor (VEP101) and dbNSFP v4.1.

TES revealed a heterozygous variant, NM_006662.3: c.7303C>T, p (Arg2435Ter), in SRCAP (Figure 2). The pathogenicity of this mutation was assessed following the guidelines established by the American College of Genetics and Genomics. Based on the criteria PVS1, PM2, and PP5, this variant was classified as pathogenic. Furthermore, it was not detected in the Genome Aggregation Database (gnomAD). Consequently, we have determined that this is a pathogenic variant causing a non-sense mutation, leading to the conversion of the arginine residue into a stop codon.

These results confirmed the presence of the SRCAP mutation, which ultimately led to a diagnosis of FHS. Notably, no SRCAP variants were identified in the patient’s father, mother, or sister. The patient was maintained on a regimen of 45 mg/kg/day of rhGH, which had been consistently administered at another hospital. GnRH agonists were discontinued at the age of 12 years. The patient consulted a doctor for the assessment of hyperopia, strabismus, and conductive hearing loss, which may be present in FHS. However, the findings of this assessment were unremarkable. The echocardiogram showed favourable results, and renal ultrasound showed a difference in size between the two kidneys but no other abnormalities.

The patient is currently 13 years and 4 months old, with a height of 141.9 cm (-2.5 SDS) and a weight of 36.2 kg (-1.8 SDS). She is undergoing rhGH (60 mg/kg/day) therapy and receiving continuous speech therapy for delayed language development.

Discussion

In this report, we confirmed the presence of a heterozygous SRCAP variant using TES. The patient exhibited symptoms of short stature, developmental language delay, dysmorphic facial features, and early puberty.

FHS can present with symptoms resembling those seen in other genetic conditions. Noonan syndrome, 3M syndrome, Rubinstein-Taybi syndrome, and Silver-Russell syndrome must be differentiated from FHS. Noonan syndrome, which shares facial features and short stature with FHS, can be differentiated from FHS by a variety of physical abnormalities, including heart defects (3, 4). Further, unlike in FHS, patients with 3M syndrome typically exhibit a large head and normal intelligence and speech development, with the possibility of hypogonadism in affected men (5). For Rubinstein-Taybi syndrome, patients often display a round face, severe intellectual decline, and normal bone age (6). In Silver-Russell syndrome, there are different features, such as an asymmetric body, café-au-lait spots, and blue sclera (7). As these conditions can present with symptoms resembling those of FHS, accurate diagnosis and genetic testing by a specialist are necessary.

Only two cases of FHS have been reported in Korea. Both patients had facial dysmorphism and intellectual disabilities, but one patient did not have short stature (1), and the other did not have early puberty (2). Therefore, our patient was the first in Korea to receive concurrent rhGH therapy and GnRH agonist therapy because of a short stature and early puberty.

The pathogenesis of short stature in FHS is not completely understood. It has been argued that GH deficiency, GH neurosecretory dysfunction, and IGF-1 signalling defects may be related to FHS, yet the evidence is limited due to the rarity of cases and lack of extensive scientific research (8). Contrasting with these uncertainties, another study has shown that the effects of rhGH therapy on FHS are modest at best, suggesting that the major molecular pathology of FHS is not caused by reduced GH secretion or activity (9). This highlights the necessity for additional research into the pathological mechanisms. In recent literature summarizing the experiences of 22 patients with FHS who received rhGH therapy, no side effects were reported. Notably, except for four individuals, there was a meaningful increase in height SDS compared to before treatment (8). In our case, the patient received rhGH therapy (45-60 mg/kg/day) for more than eight years. The final recorded height of the patient was 141.9 cm (SDS=-2.5), and no adverse effect of rhGH therapy was reported. In our patient, the growth rate improved. Given the rarity of FHS, there is limited information on the outcome of long-term treatment with rhGH. Further studies are necessary to clarify the longitudinal growth pattern and the real effectiveness and safety of rhGH therapy.

Recent studies have suggested a potential association between FHS and early puberty (9). However, the mechanisms underlying early puberty in FHS are again poorly understood. Several cases of precocious puberty in FHS patients have been reported, and some patients have undergone treatment with GnRH agonists (10, 11, 12). Treatment for early puberty in FHS resembles that for other forms of precocious puberty; however, its effectiveness requires further investigation. Our patient exhibited signs of puberty at the age of 9 years and 10 months. The rapid onset of puberty prompted the initiation of GnRH agonist therapy. This treatment successfully suppressed bone maturation. In FHS patients having symptoms of short stature and early puberty, we speculate that GnRH agonist therapy could potentially delay bone maturation, thereby extending the duration of rhGH therapy.

At the initial diagnosis of FHS, the growth rate should be evaluated, and renal ultrasonography, blood pressure measurement, ophthalmic examination, hearing testing, dental examination, and genitourinary examination should be performed (8). For men, it is necessary to check for undescended testes. Orthopedic examination and evaluation of motor and language development are required for detecting hip dysplasia or other anomalies, as well as for genetic counselling.

Poor awareness of the condition and the non-specific clinical symptoms of FHS make its diagnosis difficult and often delayed. Patients with short stature, dysmorphic facial features, and developmental delays should undergo genetic investigation, including consideration of conditions such as FHS. In cases like ours, where FHS is accompanied by early puberty and short stature, rhGH therapy and GnRH agonist therapy may be beneficial.