Recombinant human growth hormone treatment of Floating-Harbor syndrome: a case report and literature review

Abstract

Background

Floating Harbor syndrome (FHS) is a rare genetic disorder with over 100 reported cases worldwide and less than 30 treated with recombinant human growth hormone (rhGH). This article reports the clinical characteristics of a child with FHS and the effect of rhGH on height increase.

Case summary

The patient in this case exhibits the most typical features of FHS. Whole exome sequencing (WES) detected a pathogenic variant (c.7303 C > T, p.R2435X) in the SRCAP gene of this patient, which is a denovo variant. Has good sensitivity to rhGH treatment. The literature review included 28 children who received rhGH treatment, most of whom showed an increase in height SDS without any adverse reactions.

Conclusion

For patients with characteristic clinical manifestations, the diagnosis of FHS should be considered, and further pathogenic gene sequencing analysis should be performed to assist in the diagnosis. The genetic characteristic is a heterozygous nonsense mutation of the SRCAP gene. rhGH treatment is an effective treatment method for FHS.

Introduction

FHS is a rare autosomal dominant genetic disorder characterized by short stature, facial deformities, delayed bone mineralization, speech disorders, and intellectual disabilities [1–3]. The SRCAP gene is located on chromosome 16p11.2. It is the pathogenic gene of FHS, which can encode multi-protein SNF2-related CBP activating protein (SRCAP), thereby affecting chromatin remodeling and gene expression [2, 4]. FHS has a genetic pattern caused by nonsense or frameshift mutations in exons 33 and 34 of the SRCAP gene, which are believed to produce C-terminally truncated SRCAP protein variants that lack an AT-hook motif with DNA binding activity and maybe the main negative factor triggering FHS attacks [5]. At present, there are only over 100 reported cases of FHS worldwide, and there are few treatment methods for these children. This leads to a lack of understanding of the disease, and case reports related to the treatment of the disease may increase our knowledge of the disease. Therefore, this article describes a boy with FHS who experienced delayed growth and development and all height increases after rhGH treatment. In addition, we have consulted relevant literature to understand this disease better.

Case report

Early disease manifestations and clinical history

The male patient is currently 5 years and 3 months old. Born at 38 weeks of gestation. His mother gave birth to her second child through cesarean section after her second pregnancy. His birth weight is 2900 g, his body length is 48 cm, and there are no birth injuries, asphyxia, or pathological jaundice.

At 6 months old, with the addition of complementary foods, the physical and intellectual development has been significantly lagging behind that of peers, especially in language development, but no relevant evaluation has been conducted. Vaccinate according to plan. The parents are not close relatives who got married. The father is 166 cm in height, the mother is 156 cm in height, and the sister is 13 years old and 157 cm in height. No similar patients have been found in the family.

At 9 months, the child was found to have delayed growth and development at the Children’s Health Department of Guangyuan Central Hospital, with a body length of 64.0 cm and a weight of 6.05 kg. Due to abnormal facial features, it is recommended that the higher-level hospital conduct further genetic testing and diagnose FHS. At the age of 2 years and 1 month, the patient sought medical attention due to developmental and intellectual disabilities. At that time, the examination showed a height of 73 cm (-4.7 SDS), weight of 8.6 kg, well-proportioned physique, good mental health, triangular face shape, deep eye sockets, high and wide nose bridge, large mouth and thin lips, rotated auricles, and wide thumb. Normal skin, no heart murmurs, no abdominal swelling, no abnormalities in external genitalia, no abnormalities in limb joints, normal muscle tone, and no pathological signs detected.

Laboratory examination

When a patient is 2 years old and 1 month old, bone age is 1.0 years old. Head MRI: No abnormalities were found on the plain scan of the skull, and no abnormalities were found on the plain scan of the pituitary gland. Abdominal ultrasound: No abnormalities were found in the liver, gallbladder, pancreas, spleen, and both kidneys, and no abnormalities were found in both adrenal glands. Cardiac ultrasound: No abnormalities found. Blood routine tests, liver and kidney function, blood sugar, thyroid function, insulin function, ferritin, alpha-fetoprotein, hepatitis B and serum IGF-1 level (172.0ng/ml) were both normal. After the first rhGH treatment, insulin-like growth factor 1 (IGF-1) levels fluctuated within the normal range (determined by Cao [6] et al.‘s study).

Imaging examination

X-ray film of left wrist joint : the bone age of left wrist bone was about 1 year old when the child was 2 years old and 1 month old, but the relevant image data and report could not be found because of the damage of hospital system. When the child was 3 years old, the bone age was 1 year and 3 months. The X-ray film is shown that the finger bones was short, the distal phalanges were prominent, the little finger was inwardly curved, and the middle phalanges of the little finger were irregularly shaped (Fig. 1).

Fig. 1.

X-ray film of left wrist joint

Genetic examination

Collect venous blood from patient for WES. The results showed that there was a heterozygous c.7303 C > T (p.R2435X) pathogenic mutation in the SRCAP gene of the patient. Sanger sequencing analysis of this region in the parent sample of the patient did not detect this mutation, indicating that it is a denovo mutation in the patient.

Diagnosis and diagnostic criteria

Diagnosis: Floating Harbor syndrome. Diagnostic criteria: The child exhibits most of the features of FHS, including a triangular face shape, deep eye sockets, wide nose bridge, large mouth and thin lips, posterior rotation of the auricle, and wide thumb. Language developmental disorders, intellectual disability, poor social skills, and SRCAP gene mutations.

Treatment method

The physical growth of the child was monitored regularly and the weight Z score (WAZ) and length Z score (HAZ) were calculated according to and by the World Health Organization reference standards for Height and Weight for children aged 0–18 years. After excluding contraindications, the patient began receiving rhGH treatment at the age of 2 years and 1 month. From the time the patient received treatment until the time of writing this article, the treatment lasted for 3 years and 2 months. The height increased from 73 cm (-4.79 SDS) to 100 cm (-2.46 SDS), the height increased by 27 cm. The weight increased from 8.6 kg (-3.17 SDS) to 16 kg (-1.39 SDS). The treatment is effective. At the age of 3 years and 1 month, the bone age was rechecked to be 2 years old. At the age of 5, parents reported significant language communication delay in the child but refused further evaluation. There were no significant adverse reactions or abnormal discomforts during the entire treatment period. However, the treatment was interrupted because the child was afraid of injection and did not cooperate with continuous treatment. The specific situation during the treatment is shown in Table 1; Fig. 2.

Table 1.

Follow-up data of child receiving rhGH treatment

Age (years, months)	Head circumference (cm)	Head circumference SDS	Heigh (cm)	Heigh SDS	Weight (kg)	Weight SDS	Daily rhGH dosage (IU)	rhGH dosage per unit weight (IU/kg·d)	IGF-1 (ng/ml)
9 M	41.9	-2.45	64	-3.56	6.05	-3.42	-	-	-
11 M	42.5	-2.54	65.6	-3.87	6.1	-3.81	-	-	-
1 Y 1 M	43.3	-2.37	66.8	-4.15	6.7	-3.43	-	-	-
1 Y 7 M	45.3	-1.65	71.5	-4.28	8.1	-2.90	-	-	-
1 Y 10 M	45.6	-1.76	73.5	-4.26	8.3	-3.09	-	-	-
2 Y 1 M	-	-	73	-4.79	8.6	-3.17	1	0.12	172.0
2 Y 4 M	-	-	76.6	-4.18	9.2	-2.76	1	0.11	-
2 Y 7 M	-	-	78.6	-4.07	10	-2.63	1.5	0.15	226.0
3 Y 1 M	-	-	84.3	-3.32	11	-2.40	1.5	0.14	276.0
3 Y 4 M	-	-	86.2	-3.20	11.7	-2.15	1.5	0.13	-
3 Y 9 M	-	-	88	-3.34	12.2	-2.20	1.5	0.12	-
4 Y 4 M	-	-	95.7	-2.27	14	-1.67	2	0.14	-
4 Y 7 M	-	-	95.7	-2.59	13.5	-2.14	2	0.15	-
4 Y 10 M	-	-	97.5	-2.49	14.5	-1.81	2	0.14	163.0
5Y	-	-	98.9	-2.40	14.5	-1.93	2.2	0.15	-
5 Y 3 M	-	-	100	-2.46	16	-1.39	Drug withdrawal	Drug withdrawal	-

Fig. 2.

Growth chart of the child’s head circumference, height, and weight. A: Head circumference growth chart; B: Height growth chart; C: Weight growth chart

Literature review

A search on PubMed using the keyword “Floating Harbor syndrome” revealed that there were over 100 reported cases of FHS worldwide. However, a search using the keywords “Floating Harbor syndrome” and “hormone” revealed that only over 20 cases were reported. This indicates that only a few children with FHS receive rhGH treatment. Most of them have pathogenic mutations in exon 34 of the SRCAP gene, while a few have mutations in exon 33. After rhGH treatment, FHS patients showed an increase in height SDS without any adverse reactions, but a small portion also showed ineffective rhGH treatment and adverse reactions. Short stature is a common characteristic among all children with FHS. The specific situation is shown in Table 2.

Table 2.

Mutations related to FHS in literature and this study

Number	Gender	SRCAP Mutation	Initial age of rhGH treatment (years, months)	Height at the initiation of rhGH reatmentSDS	Duration of rhGH treatment (years, months)	Height at last examination (SDS)	Height ΔSDS	References	Notes
1	Male	c.7330 C > T(p.Arg2444X)	3Y	-	1Y8 M	-	-	Li et al. [1]	The effect is not satisfactory
2	Male	c.7401delC (p.lle2468Phefs*7)	6 Y 8 M	-4.5	5 M	-3.6	0.9	Bo et al. [7]	-
3	Male	c.7330 C > T (p.Arg2444*)	4 Y 9 M	-3.1	8 Y 1 M	-1.1	2	Homma et al. [8]	-
4	Female	c.7303 C > T (p.Arg2435*)	4 Y 2 M	-3.4	2 Y 8 M	-2.6	0.8		-
5	Male	c.7262dupG (p.Arg2421fs)	7 Y 9 M	-3	2 Y 5 M	-2	1		-
6	Female	c.7330 C > T (p.Arg2444X)	10 Y 4 M	-2.1	4 Y 1 M	-2.5	-0.4		-
7	Female	c.7303 C > T (p.Arg2435Ter)	4 Y	-4.6	9 Y 4 M	-2.5	2.1	Jeon et al. [9]	-
8	Male	c.7219 C > T	2 Y 2 M	-4.2	3 Y 8 M	-3.16	1. 04	Yang et al. [3]	-
9	Male	c.7466 C > G (p.Ser2489*)	4 Y 5 M	-4.11	11 Y 10 M	-3.28	0.83	Turkunova et al. [4]	-
10	Male	c.7330 C > T(p.Arg2444Ter)	5 Y 2 M	-4.52	1 Y	-4.40	0.12	Zhang et al. [10]	-
11	Female	c.7330 C > T(p.Arg2444Ter)	2 Y	-3.62	1 M	-	-		-
12	Male	c.7245_7246delAT(p.Ser2416ArgfsTer26)	43 Y 10 M	-4.12	4 Y 2 M	-2.56	1.56		-
13	Female	c.7330 C > T(p.Arg2444Ter)	5 Y	-3.84	1 Y 7 M	-3.49	0.35		-
14	Male	c.7330 C > T(p.Arg2444Ter)	6 Y 6 M	-5.30	4 Y 3 M	-3.86	1.44		-
15	Male	c.7303 C > T(p.Arg2435Ter)	5 Y 2/12	-4.47	4 Y 3 M	-3.31	1.16		-
16	Female	c.7303 C > T(p.Arg2435Ter)	1 Y 5 M	-4.17	2 Y 2 M	-2.96	1.21		-
17	Female	c.7466 C > G(p.Ser2489Ter)	2 Y 3 M	-4.17	3 M	-3.81	0.36		-
18	Female	c.7330 C > T(p.Arg2444*)	8 Y	-3.33	4 Y 7 M	-2.7	0.63	Son et al. [11]	-
19	Female	-	5 Y 4 M	-3.84	1 Y 9 M	-2.59	1.25	Galli-Tsinopoulou et al. [12]	-
20	Female	-	3 Y 5 M	-3.11	5	-2.4	0.71	García et al. [13]	-
21	Female	-	5 Y 3 M	short stature	3 Y 7 M	-0.9	-	Wieczorek et al. [14]
22	Male	c.7330 C > T, p.R2444X	10 Y	-4.9	2 Y	-3.6	1.3	Nagasaki et al. [15]	Great side effects
23	Female	c.7395delA (p.Val2466Tyrfs*9)	3 Y	-	3 Y	-2	-	Seifert et al. [16]	The final height has increased
24	Female	c.7218dupT (p.Gln2407Serfs*36)	5 Y	-	9 Y	-1.8			The final height has increased
25	Female	c.6985 C > T (p.Arg2329*)	-	-	-	-1.7			The final height has increased
26	Female	-	10 Y 1 M	-2.23	7 Y 4 M	-1.20	1.03	Stagi et al. [17]	-
27	Female	-	9 Y 1 M	-2.8	1 Y 6 M	-1.9	0.9	Cannavòet al. [18]	-
28	Male	c.7303 C> T:p.R2435X	2 Y 1 M	-4.7	3 Y 2 M	-2.8	1.7	This case	-

Discussion

The FHS was first reported in 1973 and has reported more than 100 cases to date. Delayed speech development, short stature, and characteristic facial features (triangular face, deeply sunken eyes, long eyelashes, bulbous nose, wide columella, short stature, thin lips) are typical features of FHS [19, 20]. Short neck, low birth weight, skeletal abnormalities (short finger deformity, clubbed finger, oblique finger deformity, short thumb, joint protrusion, clavicle abnormality), voice with unusual hypernasal and high pitch, mild to moderate intellectual impairment are other inconsistent characteristics [19–21]. Some children with FHS may also exhibit hirsutism, posterior rotation low implant ear, celiac disease, hyperopia and/or strabismus, conductive hearing loss, epilepsy, dental abnormalities (malocclusion, dysplasia of teeth, excess teeth, underdevelopment of mandibular incisors, mandibular posterior deformities, small jaw deformities, and mandibular dysplasia), hypertension, gastroesophageal reflux, renal abnormalities (such as hydronephrosis/pyelonectasis, cysts, and/or hypoplasia), and genital abnormalities (such as hypospadias and/or undescended testicles) [19–22]. In this case report, we observed that the patient not only exhibited developmental delay, short stature, and characteristic facial features (triangular face shape, deep eye sockets, high and wide nasal bridge, largemouth, and thin lips), but also exhibited intellectual disability, posterior rotation of the auricle, and broad thumb.

FHS is caused by SRCAP mutations. The SRCAP gene consists of 34 exons that encode the SRCAP protein, which is abundant in the human nucleus and activates CREBBP, which is involved in regulating cell growth and division. CREBBP plays a key role in regulating cell growth, cell division, DNA repair, differentiation, cell death, and tumor inhibition [1, 19]. Thus, mutations in SRCAP that impair CREBBP function may be responsible for FHS. In addition, it has been reported that FHS mutation can affect the nuclear localization of SRCAP [23], and SRCAP has the effect of DNA terminal excision [24]. According to current reports, all FHS-causing variants have been mapped to the last two exons of SRCAP (exons 33 and 34), most of which are SRCAP exon 34 mutations, with very few SRCAP exon 33 mutations [1, 25, 26]. A mutation in exon 34 of the SRCAP gene was detected in this child: c.7303 C > T (p.R2435X), which is a denovo variant.

Children with FHS require early intervention programs, special education, and professional training to address growth and developmental disorders, behavioral management by a behavioral specialist or psychologist, and consideration of medication as needed [1]. In general, standardized treatment is usually given for problems such as vision, teeth, and kidney diseases [1]. Short stature is the most typical characteristic of FHS, and the birth size of FHS patients is usually normal, and the growth rate begins to slow down in infancy [11]. Literature has shown that the short stature of children with FHS is related to growth hormone deficiency, growth hormone neurosecretion dysfunction, and IGF-1 signal transduction defect [7]. For the treatment of short stature in children with FHS, GH therapy may be considered [1]. GH is a peptide hormone secreted by the anterior pituitary gland, which can promote the growth of bones, viscera, the nervous system, and the whole body. GH treatment can maintain IGF-1 at a high level, thus stimulating the proliferation and hypertrophy of growth plate chondrocytes. In many cases, growth plate chondrocytes will accelerate linear growth non-specifically. Thus, the defects of some other factors affecting the growth plate can be partially compensated [3, 7]. Bone age is an important factor in evaluating height, and multiple studies have found that rhGH treatment can improve the growth rate and height of children with FHS, but it can also lead to inappropriate acceleration of bone age [1, 11] Therefore, in order to better evaluate the benefits and side effects of rhGH treatment, it is important to assess the latest bone age even after stopping rhGH treatment and during follow-up. In our case report, after 3 years and 2 months of rhGH treatment, the child’s body length (height) increased from 73 cm (-4.7SDS) to 100 cm(-2.8SD), body length (height) increased by 27 cm, and body weight increased from 8.6 kg (-3.17) to 16 kg (-1.39). There were no obvious adverse reactions during treatment.

Conclusion

In general, FHS is extremely rare and easy to miss and misdiagnosed. For patients with characteristic clinical manifestations, the diagnosis of FHS should be considered, and further pathogenic gene sequencing analysis should be performed to assist with diagnosis. SRCAP is the only known pathogenic gene that can cause FHS. GH therapy is an effective treatment for FHS.

Author contributions

Qing He and Menghui Wu contributed to the conceptualization and design of this study. Menghui Wu critically revised the important knowledge content of the article. Qing He wrote the initial draft of the manuscript. All authors participated in the revision, read and approved the final version for submission.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Data availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study has been approved by the Human Ethics Committee of Guangyuan First People’s Hospital (ethics number GYYYLCYJ2023112812). The legal guardians of the patient have written informed consent to participate in the study. This study was conducted based on the Helsinki Declaration.

Consent for publication

Written informed consent was obtained from the patient’s legal guardian for the publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare no competing interests.