Central precocious puberty in a 3 year-old girl with Phenylketonuria: a rare association?
© Lucaccioni et al.; licensee BioMed Central Ltd. 2014
Received: 11 November 2013
Accepted: 8 April 2014
Published: 28 April 2014
Central precocious puberty (CPP) and phenylketonuria (PKU) are two rare conditions, the latter being the rarer. To date, only one case featuring both these conditions has been reported, and hyperphenylalaninemia was assumed triggering CPP.
We present a 3.2 years old girl referred with a 12 months history of breast and pubic hair development, and vaginal discharge. Hyperphenylalaninemia had been identified by newborn screening and PKU subsequently confirmed by plasma amino acid and genetic analysis. Early dietary control of plasma phenylalanine had been excellent afterwards, resulting in phenylalanine concentrations consistently within the recommended range. Clinical scenario, hormonal assessment and imaging were in keeping with true idiopathic central precocious puberty. Treatment with long lasting gonadotropin-releasing hormone analogue led to regression of secondary sexual characteristics.
We describe for the first time CPP in a girl affected with PKU but with persistently well controlled blood phenylalanine concentrations. This finding is in contrast to a previous report which suggested persistently high phenylalaninemia levels as potential trigger for CPP in PKU patients. Our report, together with the lack of evidence in published cohort studies of children with PKU, strongly suggests this rare association is coincidental and independent of the presence of severe hyperphenylalaninemia.
KeywordsPrecocious puberty Phenylketonuria Hyperphenylalaninaemia Gonadotropin-realising hormone agonist treatment
True Central Precocious puberty (TCPP), also called GnRH-dependent precocious puberty, can be defined as true puberty, mediated by the hypothalamus, with the onset of secondary sexual characteristics before the age of eight in girls and nine in boys [1–4]. The estimated incidence of TCPP is 1:5.000-10.000 throughout the world  with a female:male ratio of between 3:1 and 23:1 . It is less common than, and should be differentiated from, other forms of sexual precocity such as premature thelarche and exaggerated adrenarche. Early activation of the hypothalamic-pituitary-gonadal axis (HPGA) in TCPP is mostly idiopathic, especially in girls [1–4]. However TCPP may be secondarily related to brain tumors (hamartoma especially), brain infections, congenital brain defects, cranial irradiation, insults and injuries to the brain or spinal cord (including cerebral palsy, hydrocephalus and brain ischemia) . Moreover TCPP has been widely described in association with learning disability syndromes, including Angelman, Kabuki make-up syndrome and other genetic conditions in which mental retardation is a key clinical feature [5–8]. Phenylketonuria (PKU) is an autosomal recessive disease caused by a deficient activity of Phenylalanine Hydroxylase (PAH), the enzyme which metabolizes Phenylalanine (Phe) to Tyrosine (Tyr). Deficiency of PAH results in tyrosine deficiency, hyperphenylalaninemia (HP) and accumulation of Phe in other body fluids . If left untreated or not appropriately controlled, patients may develop mental retardation, microcephaly and epilepsy due to the high sensitivity of the immature brain to pathological Phe concentrations. Insufficiently treated patients can also have behavioural problems and some may suffer from psychiatric illnesses . To our knowledge only one girl affected by HP has been described in the medical literature with associated TCPP . In their paper the authors highlight the poor control of serum Phe level due to their patient’s inadequate adherence to the low Phe diet and hypothesized that chronically elevated Phe concentrations were the trigger of TCPP. Since then, no other data supporting or rejecting this conjecture have been reported. We present the case of a three-year-old girl affected by severe PAH deficiency who was diagnosed with TCPP, and have compared her to the single case previously reported, pointing out differences and similarities.
Clinical and biochemical features in a girl with phenylketonuria presenting with sexual precocity aged 3 years
Ht corrected for MPH, SDS
Bone age, yr
Ht velocity, cm/y
Basal/Peak LH, U/l
Basal/Peak FSH, U/l
11.25 mg/12 weeks
11.25 mg/10 weeks
11.25 mg/10 weeks
11.25 mg/10 weeks
Phenylketonuria was first described by Asbjørn Følling in 1934 as one of the most common inherited metabolic disorders. The overall incidence of PKU in Europe and North America is 1:10.000-15.000 live births . It occurs, however, more frequently in certain areas such as Turkey (1:3.500-1:5.000), Ireland (1:4.500) or the West of Scotland (1:7.500) . Patients can be classified on the basis of residual enzyme activity as judged by peak blood Phe levels or, better, long-term phenylalanine tolerance. Phe-restricted diets with amino acid and micronutrient supplementation are highly effective in preventing irreversible brain damage and allow for a normal physical and cognitive development . The recommendations for acceptable safe blood Phe concentrations are to some extent age specific . Our patient has a severe enzyme deficiency with a low phenylalanine tolerance, increasing the risk for neurocognitive anomalies. Her parents achieved an excellent dietary control of Phe concentrations with subsequent normal neurodevelopment. To our knowledge, there is only one previous case reported in the literature  describing TCPP in a Turkish girl aged 7.5 years with severe PAH deficiency. While most countries represented in the medical literature have universal neonatal screening programs in place to avoid symptomatic PKU, classical PKU was diagnosed late in this patient at 2.5 years of age, indicating that she had been exposed to elevated Phe concentrations from birth. Moreover, satisfactory Phe concentrations could not be achieved in the girl because of poor adherence to dietary recommendations. The authors assumed that persistent poor dietary control could have prompted TCPP due to a premature activation of the HPGA by a toxic effect on the brain. Concerning this latter conjecture, there are currently insufficient data in the literature as to the incidence of TCPP in untreated or insufficiently treated individuals with PAH deficiency. However, expert opinion corroborated by a poll of the metabolic listserv “metab-l” suggests that this is an extremely rare occurrence. Our patient is the first case where idiopathic TCPP occurred under conditions of perfect dietary control. Since encountering TCPP in our patient we have performed a literature search to identify studies that describe the growth pattern of patients with PKU, but none of them focused on the timing of pubertal onset. Recent studies of larger cohorts of individuals on PKU diets have identified an increased prevalence of obesity and overweight towards adolescence in female subjects, with no specific records about precocious or early pubertal progression [17, 18]. Lack of evidence for different timing of pubertal onset in PKU patients compared with the general population corroborates our observation, and strongly supports the notion of a co-incidental association between PKU and TCPP. We can not entirely exclude, however, that significant anomalies in the onset and tempo of puberty in PKU patients might have been overlooked by previous population studies.
We conclude that TCPP is a rare coincidental event in children with PKU and can occur independently by the persistently high phenylalanine concentrations.
Written informed consent was obtained according to the parents of the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
Central precocious puberty
True central precocious puberty
Follicle stimulating hormone
The authors would like to thank the patient’s family.
- Grumbach MM, Styne DM: Puberty: Ontogeny, neuroendocrinology, physiology, and disorders. Williams Textbook of Endocrinology. Edited by: Wilson JD, Foster DW, Kronenberg HM, Larsen PR. 1998, Philadelphia: W.B. Saunders, 1509-1625. 9Google Scholar
- González ER: For puberty that comes too soon, new treatment highly effective. JAMA. 1982, 248: 1149-1151. 10.1001/jama.1982.03330100003001. 1155View ArticlePubMedGoogle Scholar
- Bridges NA, Christopher JA, Hindmarsh PC, Brook CG: Sexual precocity: sex incidence and etiology. Arch Dis Child. 1994, 70: 116-118. 10.1136/adc.70.2.116.View ArticlePubMedPubMed CentralGoogle Scholar
- Fahmy JL, Kaminsky CK, Kaufman F, Nelson MD, Parisi MT: The radiological approach to precocious puberty. Br J Radiol. 2000, 73: 560-567.View ArticlePubMedGoogle Scholar
- Raphaelson MI, Stevens JC, Elders J, Comite F, Theodore WH: Familial spastic paraplegia, mental retardation and precocious puberty. Arch Neurol. 1983, 40: 809-810. 10.1001/archneur.1983.04050120059008.View ArticlePubMedGoogle Scholar
- Kurosawa K, Kawame H, Okamoto N, Ochiai Y, Akatsuka A, Kobayashi M, Shimohira M, Mizuno S, Wada K, Fukushima Y, Kawawaki H, Yamamoto T, Masuno M, Imaizumi K, Kuroki Y: Epilepsy and neurological findings in 11 individuals with 1p36 deletion syndrome. Brain Dev. 2005, 27: 378-382. 10.1016/j.braindev.2005.02.004.View ArticlePubMedGoogle Scholar
- Ito N, Ihara K, Tsutsumi Y, Miyake N, Matsumoto N, Hara T: Hypothalamic pituitary complications in Kabuki syndrome. Pituitary. 2013, 16: 133-138. 10.1007/s11102-012-0386-8.View ArticlePubMedGoogle Scholar
- Young C, Wang PJ, Tsai WY, Shen YZ: Precocious puberty in a case with probable Angelman syndrome. Brain Dev. 1994, 16: 249-252. 10.1016/0387-7604(94)90080-9.View ArticlePubMedGoogle Scholar
- Waisbren SE, Noel K, Fahrbach K, Cella C, Frame D, Dorenbaum A, Levy H: Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab. 2007, 92: 63-70. 10.1016/j.ymgme.2007.05.006.View ArticlePubMedGoogle Scholar
- Brenton DP, Pietz J: Adult care in phenylketonuria and hyperphenylalaninaemia: the relevance of neurological abnormalities. Eur J Pediatr. 2000, 159 (Suppl 2): 114-120.View ArticleGoogle Scholar
- Büyükgebiz B, Eroğlu Y, Büy ukgebiz A: True precocious puberty associated with phenylketonuria. J Pediatr Endocrinol. 1994, 7: 361-363.PubMedGoogle Scholar
- Freeman JV, Cole TJ, Chinn S, Jones PR, White EM, Preece MA: Cross sectional stature and weight reference curves for the UK, 1990. Arch Dis Child. 1995, 73: 17-24. 10.1136/adc.73.1.17.View ArticlePubMedPubMed CentralGoogle Scholar
- Marshall WA, Tanner JM: Variations in pattern of pubertal changes in girls. Arch Dis Child. 1969, 44: 291-303. 10.1136/adc.44.235.291.View ArticlePubMedPubMed CentralGoogle Scholar
- Tanner JM, Whitehouse RH, Marshall WA, Healy MJR, Goldstein H: Assessment of skeletal maturity and prediction of adult height (TW2 method). 1983, London: Academic, 2Google Scholar
- Christ SE: Asbjørn Følling and the discovery of phenylketonuria. J Hist Neurosci. 2003, 12: 44-54. 10.1076/jhin.184.108.40.20688.View ArticlePubMedGoogle Scholar
- Woolf LI: Phenylketonuria in Turkey, Ireland and West Scotland. J Inherit Metab Dis. 1994, 17: 246-247. 10.1007/BF00711628.View ArticlePubMedGoogle Scholar
- Belanger-Quintana A, Martínez-Pardo M: Physical development in patients with phenylketonuria on dietary treatment: a retrospective study. Mol Genet Metab. 2011, 104: 480-484. 10.1016/j.ymgme.2011.08.002.View ArticlePubMedGoogle Scholar
- Burrage LC, McConnell J, Haesler R, O’Riordan MA, Sutton VR, Kerr DS, McCandless SE: High prevalence of overweight and obesity in females with phenylketonuria. Mol Genet Metab. 2012, 107: 43-48. 10.1016/j.ymgme.2012.07.006.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6823/14/38/prepub
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