A 20-month-old boy is referred to a paediatric endocrine clinic for evaluation.
Background:
- Born 35+4 weeks (maternal hypertension); neonatal intensive care unit for 24 days (respiratory support); no hypoglycaemia or seizures
- Neonatal magnetic resonance imaging (MRI): bilateral frontal polymicrogyria, hypoplastic corpus callosum, periventricular cystic change, enlarged infundibulum, possible ectopic posterior pituitary
- Developmental delay: not walking or talking at 20 months
- Height, weight and occipitofrontal circumference (OFC) all >99th centile since infancy – persistent rather than accelerating
- Genital exam normal: testes descended
Q1. This toddler has been referred due to persistent overgrowth and macrocephaly. What differential diagnoses may you consider?
Differential diagnosis
- Structural hypothalamic–pituitary abnormality (eg, hamartoma, Rathke cleft cyst, developmental anomaly)
- Congenital neurodevelopmental disorder or in-utero infection (e.g. congenital CMV infection)
- Congenital overgrowth syndrome (eg, Sotos, Weaver)
Q2. What further investigations would you like to perform?
Investigation | Frequency |
Auxology: height, weight, OFC | Every review (6-monthly) |
Pituitary screen: cortisol, prolactin, thyroid function tests (TFTs), insulin-like growth factor (IGF)-1, luteinising hormone/follicle-stimulating hormone (LH/FSH), testosterone | Repeat annually if normal, or sooner if clinically indicated |
Chromosomal microarray and Fragile X testing | Once, at baseline |
Neurology review with interval MRI | As advised by neurology (eg, annually until diagnosis is established) |
Developmental assessment | Ongoing |
Q3. Results of the investigations are shown below. Six months on from these, at age 2 years 9 months, height velocity had accelerated to 16.6 cm/yr putting height at +5.6 SDS. Looking back, is there anything in the previous investigations that might warrant further consideration?
Test | Result | Comment |
Testosterone | 1.1 nmol/L | Reference <0.8 nmol/L (prepubertal); mild elevation |
LH / FSH | Not obtained | Insufficient sample volume |
Prolactin | 315 mU/L | Mildly elevated |
Cortisol | 620 nmol/L | Adequate |
TFTs | thyroid-stimulating hormone mildly elevated, free thyroxine normal | – |
- The testosterone of 1.1 nmol/L at 26 months was detectable outside the recognised mini-puberty window, which in boys typically resolves by around 12 months of age
- A measurable testosterone beyond this window is not physiologically expected and should raise the question of evolving central precocious puberty (CPP). Unfortunately, in this case, the sample for gonadotropins was insufficient.
Q4. With this in mind, what would you examine and how would this examination influence the working differential?
With unexplained accelerating height velocity, androgen-driven growth must be considered, even in the context of an overgrowth clinical picture. An examination for both central and peripheral drivers of androgen excess is essential:
- Testicular volume and symmetry – bilateral, symmetrical enlargement usually points to gonadotropin-dependent (central) puberty; asymmetrical or unilateral enlargement raises suspicion of a primary testicular issue
- Genital staging – pubic hair, axillary hair, stretched penile length
- Skin – café-au-lait macules (McCune-Albright syndrome), hyperpigmentation (adrenal pathology)
- Abdominal examination – for adrenal or hepatic mass (hCG-secreting germ cell/hepatic tumours, androgen-secreting adrenal tumours)
- Blood pressure – hypertension can accompany some congenital adrenal hyperplasia variants (eg, 11β-hydroxylase deficiency)
In this case, the findings of the examination revealed a testicular volume of 6 mL bilaterally, stretched penile length: ~5 cm, and Tanner staging of G2, P1, A1. Skin and abdominal examination were unremarkable. Blood pressure was normal.
The testicular volume of greater than or equal to 4 mL is indicative of precocious puberty.
Q5. What investigations confirmed the diagnosis, and what did they show?
Investigation | Result | Interpretation |
Gonadotropin-releasing hormone (GnRH) stimulation test | Baseline LH <1 U/L; 20 min LH 22.1 U/L; 60 min LH 18.6 U/L | Pubertal (LH dominant) response* |
Bone age X-ray | 5 yrs 9 mths | Advanced ~3 years, consistent with sustained sex steroid exposure |
Tumour markers | Alpha-foetoprotein normal; β-human chorionic gonadotropin (hCG) negative | No biochemical evidence of an hCG-secreting germ cell tumour |
Testicular ultrasound | Right 2.7 mL, left 2.1 mL; no focal lesion | Symmetrical, structurally normal testes – enlargement is gonadotrophin-driven, rather than a primary testicular issue. Nb, testicular volumes on ultrasound are commonly significantly lower than clinical measurements by orchidometer |
Adrenal androgens / inhibin B | Normal / mildly raised | No peripheral androgen source; inhibin B in keeping with early Sertoli cell activation |
Dedicated pituitary MRI | Stable appearances. No hypothalamic–pituitary lesion | Congenital abnormalities persist but there are no structural lesions driving precocious puberty |
Trio whole genome sequencing | De novo heterozygous pathogenic variant in NSD1 gene | Chromosomal microarray and Fragile X testing were negative, prompting trio whole genome sequencing. This confirmed an underlying diagnosis of Sotos syndrome. |
*A peak LH ≥5 U/L (assay-dependent) with LH exceeding FSH is generally accepted as diagnostic of gonadotrophin-dependent (central) puberty. Cut-offs vary by assay platform (modern immunochemiluminescent assays generally use lower thresholds than older radioimmunoassay methods) so local assay-specific reference ranges should be applied. This patient’s peak LH of 22.1 U/L is several-fold above threshold, with the typical early (20-minute) peak
Based on these investigations, the diagnosis was confirmed to be idiopathic CPP, with an underlying diagnosis of Sotos syndrome, confirmed by whole-genome sequencing. Notably, obesity-associated or constitutional causes of rapid growth are not typically accompanied by macrocephaly; the persistence of OFC above the 99th centile since infancy in this child was suggestive of an underlying structural or syndromic cause.
Q6. What are the management priorities?
The current management priorities are control of CPP, in order to:
- Suppress the hypothalamic–pituitary–gonadal axis
- Halt progression of secondary sexual characteristics
- Slow bone maturation
- Preserve adult height potential.
For CPP, GnRH analogues are the mainstay of treatment.
GnRH analogues work by delivering continuous, rather than pulsatile, stimulation to the GnRH receptor. This paradoxically desensitises the pituitary, suppressing LH and FSH secretion and reducing sex steroid production. Several depot preparations exist internationally (eg, 1-, 3- and 6-monthly leuprolide acetate; a 12-monthly histrelin implant), though not all are licensed in the UK. Slow-release triptorelin pamoate remains the most widely used UK preparation.
Treatment was commenced at 2 years 11 months with intramuscular slow-release triptorelin pamoate 11.25 mg every 12 weeks. By age 3.5 years: height velocity fell from 16.6 to ~6.5 cm/yr; bone age progression also slowed.
Q7. With the clinical picture stable, are there any modifications to treatment you might consider?
- 12-weekly triptorelin is effective, but carries a real burden: injection-site pain, inflammatory reactions, frequent hospital attendance, and disruption to nursery/school
- Extended-interval triptorelin embonate 22.5 mg given every 24 weeks is increasingly used in the UK
- A UK multicentre retrospective cohort study of 44 children with CPP found equivalent efficacy and tolerability between the 24- and 12-weekly regimens, with reduced treatment burden and potential cost savings
- Treatment was switched to the 24-weekly regimen in May 2024; suppression has been maintained since
Conclusion
- CPP in boys under 3 years is rare and warrants full investigation to exclude intracranial pathology
- A detectable testosterone outside the mini-puberty window is not physiological and should prompt consideration of evolving CPP
- Height velocity acceleration can be the next clue – always examine testicular volume, even without pubic or axillary hair
- CPP is a recognised, but uncommon, manifestation of Sotos syndrome
- Extended-interval triptorelin embonate (22.5 mg, ~24-weekly) maintains suppression while roughly halving injection frequency – a meaningful benefit for very young children on long-term therapy.
- Varughese R, Lake L, Kothayan B, et al. Efficacy of 24-weekly vs 12-weekly decapeptyl SR treatment in central precocious puberty: a UK multicentre retrospective cohort study. J Clin Endocrinol Metab 2026; dgag096. doi: 10.1210/clinem/dgag096. https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgag096/8510261
- Latronico AC, Roberts SA, Alonzo M, et al. Central precocious puberty: an Endocrine Society clinical rractice guideline. J Clin Endocrinol Metab 2026; dgag168 doi:10.1210/clinem/dgag168 https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgag168/8697368
- Carel JC, Eugster EA, Rogol A, et al. Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children. Pediatrics 2009;123: e752–e762. https://publications.aap.org/pediatrics/article-abstract/123/4/e752/71373/Consensus-Statement-on-the-Use-of-Gonadotropin
- Ocansey S, Cole TRP, Rahman N, et al. Sotos Syndrome. 2004 Dec 17 [updated 2025 Jun 5]. In: Adam MP, Bick S, Mirzaa GM, et al, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 20301652. https://www.ncbi.nlm.nih.gov/books/NBK1479/
