The patient displayed an atypical presentation of CPP in CS, which is classically associated with delayed pubertal development. CPP, as defined by premature activation of the hypothalamic-pituitary-gonadal (HPG) axis before the age of 8 years in females, has a reported incidence of 1:5000-10,000. Typically, the primary concerns of CPP are short adult stature due to early epiphyseal fusion, incomplete psychosocial ability to handle early menarche and discrepancies between physical and emotional maturity . These concerns are heightened in a child with CPP and CS, which is already associated with short stature and intellectual disability.
Although the vast majority of CPP in girls is idiopathic, rarely, it can be associated with monogenic conditions, tumor formation or other cranial abnormalities . Recent recommendations advise against routine brain MRI in girls with CPP beginning after age 6, as literature reports cranial findings are discovered in a minority of cases of CPP, of which only 1.6% are actionable tumors requiring treatment .
As CPP is rare in CS, we propose children with CS presenting with borderline precocious puberty receive brain MRI. A 2003 literature review revealed 73.7% of CS patients receiving MRI displayed abnormal cranial findings at baseline, consistent with a report by Gripp, et al. of 27 out of 28 CS patients found to have brain MRI abnormalities [3, 10]. In the Gripp, et al. cohort, 96% of the patients displayed posterior fossa crowding with cerebellar tonsil herniation and 46% of the patients required neurosurgical intervention. In CS, posterior fossa crowding and cerebellar herniation is often progressive, suggesting brain growth leading to Chiari malformations and ventricular enlargement which may eventually require intervention. There are no specific guidelines for brain imaging in CS, but it has been suggested all CS patients have a baseline MRI at diagnosis and follow up as clinically indicated . The presented patient emphasizes the importance of MRI in CS, even with a relatively benign presentation of CPP without other pituitary dysfunction and initial denial of headaches.
The cause of CPP is uncertain for this patient. Increased intracranial pressure, which can be associated with Chiari I malformations and syrinxes, could contribute to early activation of the HPG axis . HRAS is involved in gonadotropin-releasing hormone receptor signaling, but given the high prevalence of delayed puberty associated with the HRAS p.Gly12Ser mutation, the mutation alone cannot account for CPP. Van der Kaay et al. suggests there may be unidentified genetic or environmental factors influencing the RAS-MAPK pathway in RASopathies, based on relatively frequent case reports of CPP. CS can also be associated with hypothalamic dysfunction, another factor potentially influencing the timing of pubertal development .
Standard assessment of pituitary hormones was challenging, as the patient was unable to attend morning appointments. Based on physical examination, LH and estradiol values were likely higher in the morning. There was no cortisol assessment but given the lack of pituitary malformation on MRI, apparently intact GH-IGF-1 axis and normal thyroid function tests, suspicion for central adrenal insufficiency was low. Her significant short stature was likely due to CS, as well as nutritional deficiencies associated with feeding difficulties during early childhood. It is also almost certain CPP led to rapid advancement in bone age between the ages of 8 years 0 months and 9 years 7 months and further impacted her ultimate adult stature.
While CPP is a rare occurrence in CS, the patient’s presentation emphasizes the importance of pubertal assessment in children with CS. It also highlights the high frequency of actionable intracranial abnormalities in CS patients and the need for brain imaging, particularly in the setting of CPP.