Central Precocious puberty in KBG syndrome with a pathogenic variant in ANKRD11
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
KBG syndrome is a rare genetic disorder characterized by short stature, macrodontia, distinctive facial features like triangular face, synophrys, prominent nasal bridge with anteverted nares, skeletal anomalies, and delayed development. This condition results from a heterozygous pathogenic variant in ANKRD11 gene. Although central precocious puberty (CPP) has been infrequently documented in patients with KBG syndrome, this case highlights its occurrence. Diagnosing CPP in the context of short stature presents a unique challenge. Here, we present the case of a Korean boy with CPP and short stature, ultimately diagnosed with KBG syndrome through the identification of a pathogenic ANKRD11 variant.
Case Presentation
The patient was born at 37weeks of gestation via cesarean section, weighing 2,600 gm(-1.07 SDS). He first presented to the clinic at 5.8 years of age with short stature (height: 102.4 cm, -2.70 SDS; weight: 16.1 kg, -2.21 SDS). Bone age (BA) was delayed by 1.8 years. Developmentally, he began speaking at 15 months and walking independently at 18 months. He failed his newborn hearing screening and was found to have approximately 80% hearing capacity by 18 months. After being lost to follow-up, he revisited at 10.8 years old with facial acnes and increased testicular volume (Tanner stage Gonad III). Physical examination revealed macrodontia of the upper central incisors, a triangular facial shape, a prominent nasal bridge, a long philtrum, and a thin upper lip vermilion. His height SDS had improved to -1.78 SDS (133 cm), with an advanced bone age gap of 16 months.
Diagnostic Workup
From the results of gonadotropin releasing hormone (GnRH) stimulation test, peak LH was 16.60 mIU/ml and basal testosterone was 2.54 ng/ml. Whole exome sequencing identified a pathogenic missense variant in the ANKRD11 gene, c.2197C>T (p.Arg733Ter).
Treatment and Management
The patient began treatment with a GnRH agonist combined with growth hormone (GH) therapy.
Outcome and Follow-Up
After 20 months of treatment, his height increased to 144.9 cm (-1.44 SDS), and his weight improved from -2.21 SDS to -0.66 SDS.
Discussion
ANKRD11 plays a role in chromatin modulation and influences growth by upregulating P21, a known cell cycle inhibitor. Its specific role in pubertal development has not yet been determined. This case draws attention to the importance of thorough clinical examination and radiological assessment and whole exosome sequencing.
Conclusion
The role of ANKRD11 in regulating the pace of pubertal development requires further clarification in the future. It is necessary to analyze additional cases of KBG syndrome in the future to uncover the specific conditions associated with clinical symptoms of precocious puberty.
KBG syndrome is a rare genetic disorder characterized by short stature, macrodontia, distinctive facial features like triangular face, synophrys, prominent nasal bridge with anteverted nares, skeletal anomalies, and delayed development. This condition results from a heterozygous pathogenic variant in ANKRD11 gene. Although central precocious puberty (CPP) has been infrequently documented in patients with KBG syndrome, this case highlights its occurrence. Diagnosing CPP in the context of short stature presents a unique challenge. Here, we present the case of a Korean boy with CPP and short stature, ultimately diagnosed with KBG syndrome through the identification of a pathogenic ANKRD11 variant.
Case Presentation
The patient was born at 37weeks of gestation via cesarean section, weighing 2,600 gm(-1.07 SDS). He first presented to the clinic at 5.8 years of age with short stature (height: 102.4 cm, -2.70 SDS; weight: 16.1 kg, -2.21 SDS). Bone age (BA) was delayed by 1.8 years. Developmentally, he began speaking at 15 months and walking independently at 18 months. He failed his newborn hearing screening and was found to have approximately 80% hearing capacity by 18 months. After being lost to follow-up, he revisited at 10.8 years old with facial acnes and increased testicular volume (Tanner stage Gonad III). Physical examination revealed macrodontia of the upper central incisors, a triangular facial shape, a prominent nasal bridge, a long philtrum, and a thin upper lip vermilion. His height SDS had improved to -1.78 SDS (133 cm), with an advanced bone age gap of 16 months.
Diagnostic Workup
From the results of gonadotropin releasing hormone (GnRH) stimulation test, peak LH was 16.60 mIU/ml and basal testosterone was 2.54 ng/ml. Whole exome sequencing identified a pathogenic missense variant in the ANKRD11 gene, c.2197C>T (p.Arg733Ter).
Treatment and Management
The patient began treatment with a GnRH agonist combined with growth hormone (GH) therapy.
Outcome and Follow-Up
After 20 months of treatment, his height increased to 144.9 cm (-1.44 SDS), and his weight improved from -2.21 SDS to -0.66 SDS.
Discussion
ANKRD11 plays a role in chromatin modulation and influences growth by upregulating P21, a known cell cycle inhibitor. Its specific role in pubertal development has not yet been determined. This case draws attention to the importance of thorough clinical examination and radiological assessment and whole exosome sequencing.
Conclusion
The role of ANKRD11 in regulating the pace of pubertal development requires further clarification in the future. It is necessary to analyze additional cases of KBG syndrome in the future to uncover the specific conditions associated with clinical symptoms of precocious puberty.