Pediatric Nephrology (2019) 34:425–427
https://doi.org/10.1007/s00467-018-4037-9
CLINICAL QUIZ
Recurrent kidney stones in a child with Lesch-Nyhan syndrome: Answers
Natasha Ng 1 & Amrit Kaur 1 & Mohan Shenoy 1
Received: 9 July 2018 / Accepted: 24 July 2018 / Published online: 15 August 2018
# IPNA 2018
Keywords Lesch-Nyhan syndrome . Allopurinol . Purine metabolism
Discussion
Lesch-Nyhan syndrome is a rare X-linked genetic disorder
caused by an inborn error of nucleotide metabolism. The dis-
ease is characterised by abnormal metabolic and neurologic
manifestations. This includes hyperuricaemia and a distinctive
neuro-behavioural phenotype manifested by dystonia and be-
havioural symptoms, with possible subsequent self-mutilation
behaviour. The mutations can be localised to the HPRT1 gene
which encodes the enzyme hypoxanthine-guanine
phosphoribosyltransferase (HGPRT), a key molecule in-
volved in the recycling of purine bases (Fig. 1). Patients with
a partial enzyme deficiency (Lesch-Nyhan variants) display
an incomplete phenotype, varying dependent on residual
HPRT activity [1]. Patients with the most severe form of dis-
ease have virtually complete deficiency (less than 1.5% resid-
ual HPRT activity) and are typically affected by the classical
form of Lesch-Nyhan syndrome. Patients with partial enzyme
deficiency (at least 8% residual HPRT activity), also referred
to as Kelley-Seegmiller syndrome, have apparently normal
neurodevelopment and are only affected by hyperuricaemia.
A third group of patients with 1.5–8% residual HPRT activity
tend to manifest with hyperuricaemia and neuro-disability,
however, without self-mutilation behaviour [2].
A direct consequence of HGPRT enzyme deficiency is the
augmented degradation of free purines and consequently an
overproduction of the end-product uric acid. Deficiency in the
HGPRT enzyme also results in an increased de novo synthesis
of purines as an attempt to compensate for the decreased
recycling of purine bases. This compensatory process results
This refers to the article that can be found at https://doi.org/10.1007/
s00467-018-4035-y.
* Natasha Ng
natashang@doctors.org.uk
1
Royal Manchester Children’s Hospital, Manchester M13 9WL, UK
in an exacerbated effect of excess uric acid production [3].
Excess uric acid can lead to the precipitation of uric acid
crystals in joints and or the renal tract, causing urolithiasis
which may lead to urinary tract obstruction.
Xanthine is the least soluble product of purine degradation
produced by xanthine oxidase, an enzyme that catalyses the
conversion of hypoxanthine to xanthine and xanthine to uric
acid. Despite recent advancements in treatment, allopurinol
remains the treatment of choice, as evident by its efficacy in
controlling the overproduction of uric acid in patients with
Lesch-Nyhan syndrome [3–6]. Allopurinol acts by competi-
tively inhibiting the enzyme xanthine oxidase, hence reducing
the production of uric acid. This is however at the expense of
increasing the concentration of upstream precursor oxypurines
(xanthine and hypoxanthine), which are either excreted in
urine or recycled by HGPRT. Xanthine, which is ten times
less soluble in water than hypoxanthine, therefore results in
a tendency towards development of xanthine urolithiasis. In
addition, in the cases of complete or partial HGPRT deficien-
cy, the observed effect in which allopurinol decreases de novo
purine biosynthesis appears to be absent [3, 7, 8]. Hence, it has
also been postulated that the uninhibited conversion of gua-
nine to xanthine by guanine deaminase with allopurinol treat-
ment may have a role for the development of xanthine
urolithiasis.
Management
Management of xanthine urolithiasis in this patient involved
more aggressive hydration and urinary pH manipulation. We
recommended increasing his daily fluid intake to 2 L per day
and continuation of potassium citrate therapy as a strategy to
promote urinary alkalinisation. In addition, the dose of allo-
purinol was reduced to 6 mg/kg/day with the aim to achieve
high normal plasma urate levels.
The management of hyperuricaemia in Lesch-Nyhan syn-
drome remains a clinical challenge, as to date, there are no
426 Pediatr Nephrol (2019) 34:425–427

Fig. 1 Schematic representation of purine synthesis and degradation pathways. APRT adenine phosphoribosyl transferase, PRPP phosphoribosyl
pyrophosphate, HGPRT hypoxanthine-guanine phosphoribosyltransferase

current consensus guidelines for the optimal dosage of allopu- calculi in the presence of low serum and urine uric acid levels.
rinol to avoid overproduction of oxypurines. Pais et al. recom- Diagnosis can be challenging as xanthine calculi are radiolu-
mended the lowest possible allopurinol dose sufficient to cent on radiography and repeated computed tomography
maintain serum and urine uric acid levels in the upper refer- scans are not recommended in children. Biochemical analysis
ence range of normal as a strategy for minimising risk of of stone composition is the most direct method to facilitate
iatrogenic xanthine urolithiasis [5]. This was further supported early diagnosis and treatment. The natural history of the dis-
by an observational study conducted on 19 patients with ease remains unclear and prevention of long-term renal dis-
HPRT deficiency which concluded with recommendations ease is of paramount importance.
for dose adjustments for allopurinol to be made to obtain se-
rum uric acid levels greater than 450 μmol/L but below
700 μmol/L [9, 10]. Based on data extrapolated from this
Conclusion
observational study, it appears that most children with
Lesch-Nyhan syndrome require a dose of allopurinol ranging
This report emphasises the need for a high index of clinical
between 3 and 8 mg/kg per day.
suspicion for iatrogenic xanthine urolithiasis particularly in
In classical Lesch-Nyhan syndrome, where there is extreme
patients on high maintenance doses of allopurinol therapy.
overproduction of purines, an additional possibility for prevention
Biochemical analysis of renal calculi for stone composition
of xanthine calculi has been suggested by maximising the dose of
can be performed to aid diagnosis as shown in this case, the
allopurinol. The therapeutic goal from such an approach is to
change from uric acid to xanthine stones following allopurinol
achieve a shift in urinary hypoxanthine to xanthine ratio in favour
therapy. Prevention of xanthine urolithiasis involves adequate
of hypoxanthine, which is a more soluble product [11]. In addi-
hydration, urine alkalinisation and sequential measurements
tion, evidence from a study on the solubility of xanthine and
of serum urate levels to permit allopurinol dose titration.
hypoxanthine in biological fluids have demonstrated greater sol-
Further studies are still required to identify alternative urate-
ubility of xanthine in alkaline urine, with solubility levels of
lowering strategies which could avoid the accumulation of
50 mg/L and 130 mg/L in urinary pH 5 and 7 respectively.
upstream oxypurines.
Hence, urinary excretion of oxypurines can in effect be further
supported by measures which promote urinary alkalinisation [12].
Compliance with ethical standards
Xanthine urolithiasis is an extremely rare occurrence even
amongst patients with Lesch-Nyhan syndrome. Laboratory Conflict of interest The authors declare that they have no conflict
findings which may suggest the diagnosis include radiolucent of interest.
Pediatr Nephrol (2019) 34:425–427
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