Hypogonadism and obesity are primary features of Bardet-Biedl syndrome (BBS). Obesity is also an associated factor of central precocious puberty (CPP). The present report describes the case of a girl (age, 7 years and 6 months), with clinical manifestations of precocious puberty, progressive obesity, postaxial polydactyly, retinal degeneration and intellectual disability. The patient visited the clinic for the first time due to early breast development and progressive obesity. After 8 months of follow-up, the bone age had advanced almost 3 years, and the gonadotropin-releasing hormone (GnRH) stimulation test showed results that had changed from indicating pseudo precocious puberty to CPP. Whole-exome gene sequencing showed that there were two heterozygous mutations in the BBS type 10 (
Bardet-Biedl syndrome (BBS) a rare autosomal recessive genetic disease with clinical manifestations that can affect multiple systems throughout the body, was first reported by Georges Bardet (
The incidence rate of retinal degeneration/dystrophy in patients with BBS is >90% (
Secondary BBS phenotypes include hepatic fibrosis, diabetes mellitus, neurological impairment, speech deficits, behavioral abnormalities, craniofacial dysmorphism, dental irregularities, developmental delay, hypertension, cardiovascular abnormalities, hearing loss and olfactory impairments (
In total, >500 cases of BBS have been reported globally, of which only 80 cases have been accurately diagnosed in China (
The present report describes the case of a girl (age, 7 years and 6 months) who was initially diagnosed with BBS due to early breast development and obesity, and gradually developed central precocious puberty (CPP) during follow-up. Whole-exome gene sequencing revealed new heterozygous mutations in the BBS type 10 (
The patient was a girl (age, 7 years and 6 months), with a height of 127.8 cm [+0.4 standard deviation score (SDS) girls, i.e. 0.4 SDs above average for girls this age] (
At 1 year and 3 months of age, the parents of the patient noticed rapid weight increase, with a height of 76.0 cm [-1 SDS girls (
At the first visit to the Department of Children's Health Care, Fifth People's Hospital of Foshan City in July 2020, the patient was 7 years and 6 months of age. A physical examination indicated the following: Blood pressure, 92/60 mmHg; height, 127.8 cm [+0.4 SDS girls (
The patient returned for another visit in January 2021, at 8 years and 2 months of age. The patient had experienced breast development and intermittent pain for 3 months. The following measurements were recorded: Height, 130.8 cm [+0.3 SDS girls (
In July 2020, at the time of the first visit, the patient's intelligence test score (Chinese-Wechsler Intelligence Scale for Children) was 75 (normal range: 85-115) (
Ultrasonography indicated that the patient's uterus and ovaries were in the prepubertal stage, and there was no adrenal and celiac ectopic hyperplastic disease. Additionally, the bone age was 10 years (
The gonadotropin-releasing hormone (GnRH) stimulation test showed that the peaks of FSH and LH, which were 5.66 IU/l and 1.23 IU/l (Reference range: peak of LH>5.0IU/l and LH/FSH>0.6), respectively, appeared at 60 min post-administration. The ratio of LH to FSH was 0.22. Peripheral blood lymphocyte karyotype showed a result of 46, XX (
According to all the aforementioned results, the patient was initially diagnosed with BBS and pseudo-precocious puberty. However, whole-exome gene sequencing was not performed, as it was too expensive for the parents. After 3 months of follow-up, the patient's breasts returned to Tanner stage B1.
In January 2021, at 8 years and 2 months old, the patient returned for another visit. This time, her hormones and biochemical data were still normal, and they were in the state of Tanner Stages 2 female. And her ovarian and adrenal function were also normal (
Furthermore, the bone age was 11 years (
Whole-exome gene sequencing was performed by the Guangzhou Daan Clinical Laboratory Center in Guangzhou, China). Genomic DNA from peripheral blood leukocytes, derived from the proband was extracted using a QIAamp DNA Blood Mini kit (cat. no. 51185; Qiagen, GmbH). Concentration was measure by Qubit 3.0. A total of 1 µg each genomic DNA sample was fragmented by sonication and purified to yield fragments of 200-300 bp. Paired-end adaptor oligonucleotides from Illumina, Inc. were ligated to the shared genomic DNA. A total of 500 nanograms of these tailed fragments were then hybridized to the probe library of the Sure Select Human All Exon V6 (Agilent; catalogue number: 51908864). The enrichment libraries were sequenced on the Illumina Novaseq 6000 sequencer (Illumina, San Diego, California) as 150-bp paired-end reads. Reads were aligned to the human reference genome (GRCh37/hg19) with the burrows-wheeler aligner (BWA) (
To avoid premature depletion of gonadal function, the patient's parents agreed to use GnRH analog (GnRHa) for CPP treatment. The initial dose was 3.75 mg subcutaneous injection, and the maintenance dose was subcutaneous injection 50-100 mg/kg every 4 weeks. The patient's height and sexual development will be fully assessed every 3 months. This treatment plan will last until the age of 11 or until the precocious puberty is well controlled.
The patient showed good intervention compliance and tolerance. So far, no unfavorable and unanticipated events have been observed. After 3 months of treatment with GnRHa, height and weight had increased to 132.0 cm [+0.2 SDS girls (
In May 2022, the patient was 9 years and 6 months old, and after receiving 15 months of treatment with GnRHa, height and weight measurements had increased to 138.6 cm [+0.26 SDS girls (
The final diagnosis in the present case was BBS10 and CPP. This is the first ever encounter of a patient with BBS10 and CPP in the Fifth People's Hospital of Foshan City.
The first visit of the patient was due to a rapid increase in body weight, but in fact, weight and BMI measurements did not change significantly from the beginning of pseudo-precocious puberty to CPP. A recent study showed that early-onset obesity enhanced paraventricular nucleus expression of serine palmitoyltransferase long chain base subunit 1 and advanced the maturation of the ovarian noradrenergic system (
Patients with precocious puberty often have secondary sex characteristic of mismatched gonadal development. However, the Tanner stage of the breast, and the uterus and ovaries of the present patient markedly lagged behind the development of bone age. We hypothesized that this may have been associated with the clinical features of BBS. Clinical manifestations included retinal degeneration, obesity, postaxial polydactyly and intellectual disability, which were in line with the characteristics of BBS10, except for renal abnormality. No adrenal gland diseases and germ cell tumors were found, and there was no chronic steroid use. The final whole-exome gene sequencing revealed that the c.1949del and c.1391C>G heterozygous mutations associated with the patient's clinical phenotype were located in the
To explain the cause of the CPP with BSS10, the literature was searched using the key words ‘precocious puberty’, ‘gonad dysplasia’, ‘Turner syndrome’, ‘Klinefelter syndrome’, ‘Kallmann syndrome’ and ‘Prader-Willi syndrome’ in Medline(
U-shaped gonadotrophin levels are present from birth to puberty in normal males, while the same pattern, but at markedly higher levels, is present in anorchid boys, indicating that the gonads serve a role in the negative feedback of gonadotrophins in childhood (
Another question is with regard to the manner in which precocious puberty then occurs in hypogonadotropic hypogonadism. No pathogenic allelic variants of genes known to cause monogenic CPP (KISS1 receptor, KiSS-1 metastasis suppressor, makorin ring finger protein 3 and δ like non-canonical Notch ligand 1) (
Central precocious puberty occurred in case of hypogonadotropic hypogonadis. Therefore, further clinical data and molecular biological evidence is required to confirm the etiology and mechanism of the present case.
The authors would like to thank Ms Liyu Yuan (Institute of Fashion Technology of Guangdong Polytechnic, Foshan China) for editing the figures associated with the manuscript.
All data generated or analyzed during this study are included in this published article.
HL, JH and IL were responsible for the study investigation. HL, JH, IL, RH and XS conceived and designed the study. HL wrote the original manuscript. HL, RH and XS reviewed and edited the manuscript. All authors read and approved the final manuscript. HL, JH and RH confirm the authenticity of all the raw data.
The experimental protocol was established according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of the Fifth People's Hospital of Foshan City (Foshan, China; approval no. 2021060704).
Written informed consent for publication of the case report was obtained from parents.
The authors declare that they have no competing interests.
Analysis of the peripheral blood lymphocyte karyotype showed a result of 46, XX.
Hormones and biochemical data in July 2020.
Parameter | Result | Reference range |
---|---|---|
Triglyceride, mmol/l | 1.70 | 0.56-1.70 |
Total cholesterol, mmol/l | 3.40 | 3.10-5.70 |
Fasting blood glucose, mmol/l | 5.40 | 3.90-6.10 |
Fasting insulin, mU/l | 15.40 | 3.00-25.00 |
Blood 17-hydroxyprogesterone, ng/ml | 0.76 | 0.33-2.97 |
α-fetoprotein, IU/ml | 1.10 | 0-20.00 |
β-human chorionic gonadotropin, mIU/ml | 2.00 | 0-10.00 |
Inhibin B, pg/ml | 11.20 | 0-43.91 |
Anti-Müllerian hormone, ng/ml | 2.20 | 0.05-10.40 |
Testosterone, nmol/l | 0.08 | <0.24-0.97 |
Estradiol, pmol/l | 99.80 | 37.00-88.00 |
FSH, IU/l | 3.51 | 1.00-10.80 |
LH, IU/l | 0.16 | 0.02-4.70 |
Free triiodothyronine, pmol/l | 5.80 | 3.50-6.60 |
Free thyroxine, pmol/l | 17.30 | 11.50-22.70 |
Thyroid-stimulating hormone, mIU/l | 3.87 | 0.64-6.27 |
FSH, follicle-stimulating hormone; LH, luteinizing hormone.
Hormones and biochemical data, January 2021.
Parameter | Result | Reference range |
---|---|---|
Blood 17-hydroxyprogesterone, ng/ml | 0.28 | 0.33-2.97 |
DHEA-S, µmol/l | 1.06 | 0.88-3.35 |
α-fetoprotein, IU/ml | 0.70 | 0-20.00 |
β-human chorionic gonadotropin, mIU | 3.10 | 0-10.00 |
Inhibin B, pg/ml | 7.20 | 0-43.91 |
Anti-Müllerian hormone, ng/ml | 4.40 | 0.05-10.40 |
Testosterone, nmol/l | 0.21 | <0.24-0.97 |
Estradiol, pmol/l | 81.30 | 37.00-88.00 |
FSH, IU/l | 1.47 | 1.00-10.80 |
LH, IU/l | 0.26 | 0.02-4.70 |
Free triiodothyronine, pmol/l | 5.30 | 3.50-6.60 |
Free thyroxine, pmol/l | 14.00 | 11.50-22.70 |
Thyroid-stimulating hormone, mIU/l | 5.23 | 0.64-6.27 |
DHEA-S, dehydroepiandrosterone-sulfate; FSH, follicle-stimulating hormone; LH, luteinizing hormone.