Søvik and Boman Vitamin D-dependent rickets type 1 and phenylketonuria
investigation (e.g. nuclear scintigraphy) to locate an alter- References
native source of sepsis. Persisting ductal patency on longitu-
1. Park MK. Premature infants with patent ductus arteriosus. In:
dinal surveillance would probably have justified attempting Park MK, editor. Pediatric cardiology for practitioners. St
catheter-based interventional closure. Louis, MO: Mosby, 2002: 386.
An increasing awareness of this condition, together with 2. Thilen U, Astrom-Olsson K. Does the risk of infective
wider availability of high-resolution echocardiography, may endarteritis justify routine patent ductus arteriosus closure?
have important service considerations for infants managed Eur Heart J 1997; 18: 503–7.
outside tertiary centres (case 2). Management in this setting 3. Huggon IC, Qureshi SA. Is the prevention of infective
endarteritis a valid reason for closure of the patent arterial
could include access to a paediatrician with specific cardio-
duct? Eur Heart J 1997; 18: 364–6.
logical expertise (S. A. Quereshi & S. Hobbins, unpublished 4. Sullivan ID. Patent arterial duct – when should it be closed?
results) or to a paediatric-trained echocardiographer. A pro- Arch Dis Child 1998; 78: 285–7.
visional curriculum of appropriate training (S. A. Quereshi 5. Sadiq M, Latif F, ur-Rehman A. Analysis of infective
& S. Hobbins, unpublished results) and a defined model of endarteritis in patent ductus arteriosus. Am J Cardiol 2004;
networked service provision for outreach paediatric cardi- 93: 513–5.
ology (13) offer useful guidance in service delivery in this 6. Campbell M. Natural history of persistent ductus arteriosus. Br
Heart J 1968; 30: 4–13.
setting. N3, a fast broadband networking service part of the
7. Touroff AWS. The results of surgical treatment of patency of
U.K. National Programme for IT (NPfIT), may prove a useful the ductus arteriosus complicated by subacute bacterial
inexpensive adjunct. endarteritis. Am Heart J 1943; 25: 187–210.
8. Keys A, Shapiro MJ. Patency of the ductus arteriosus in adults.
CONCLUSIONS Am Heart J 1943; 25: 158–86.
9. Bilge M, Uner A, Ozeren A, Aydin M, Demirel F, Ermis B,
The preterm neonate with a haemodynamically insignificant
et al. Pulmonary endarteritis and subsequent embolisation to
PDA remains at risk of ductal endarteritis. For this pop- the lung as a complication of a patent ductus arteriosus—a case
ulation, the evaluation of a sepsis syndrome unresponsive report. Angiology 2004; 55: 99–102.
to conventional medical therapy should include a detailed, 10. Rivera IR, Moises VA, Brandao AC, Silva CC, Andrade JL,
targeted echocardiogram. We instigate this investigation if Carvalho AC. Patent ductus arteriosus and pulmonary artery
a sepsis syndrome persists and repeated blood culture re- endarteritis. Arq Bras Cardiol 1997; 69: 335–8.
11. Rangel-Abundis A, Badui E, Verdin R, Escobar CV, Enciso R,
mains positive 7 days postremoval of a central venous line,
Valdespino A. Spontaneous aneurysm of the patent ductus
or earlier if clinical assessment suggests the presence of an arteriosus with endarteritis. Arch Inst Cardiol Mex 1991; 61:
endarteritic/endocarditic process. 59–64.
12. Flapper WJ, Dixit AS, Murton MM. Infective aortitis
associated with the nonpatent remnant of a ductus arteriosus.
Ann Thorac Surg 2003; 76: 931–33.
We are grateful to Mr. David Moscrop (IT specialist, 13. Gibbs J. Paediatricians subspecialising in cardiology: clinical
Northampton General Hospital) for his expertise in prepar- governance, maintenance of expertise, and training. Arch Dis
ing Figure 1. Child 2006; 91: 878–9.
Co-occurrence of vitamin D-dependent rickets type 1 and phenylketonuria
Oddmund Søvik (firstname.lastname@example.org)1,3 , Helge Boman2,3
1.Department of Pediatrics, Haukeland University Hospital, N-5021 Bergen, Norway
2.Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, N-5021 Bergen, Norway
3.Department of Clinical Medicine, University of Bergen, Bergen, Norway
Genetics, Phenylketonuria, Vitamin D-dependent
Vitamin D-dependent rickets type 1 (VDDR1) was diagnosed in a 15-month-old girl with
well-controlled phenylketonuria (PKU). The patient was homozygous for the PAH mutation L249F.
Prof. Oddmund Søvik, Department of Pediatrics, The PAH and CYP27B1 genes are both located on the long arm of chromosome 12 and could
Haukeland University Hospital, possibly have been inherited from a common ancestor. The parents were not aware of any ancestral
5021 Bergen, Norway. relationship and the patient was compound heterozygous for two different CYP27B1 mutations
Tel: +47-55972304 |
Fax: +47-55975159 | (R389H and S416X). Her mutations were shown to originate from each of her four grandparents. In
Email: email@example.com Norway, the co-occurrence of PKU and VDDR1 is expected to occur by chance one to two times per
Received billion births.
11 December 2007; revised 18 January 2008;
accepted 22 January 2008. Conclusion: The extremely rare co-occurrence of VDDR1 and PKU requires careful genetic work-up and close
attention to family information, but the combined treatment of the two metabolic disorders may not create special
C 2008 The Author(s)/Journal Compilation C 2008 Foundation Acta Pædiatrica/Acta Pædiatrica 2008 97, pp. 663–672 665
Vitamin D-dependent rickets type 1 and phenylketonuria Søvik and Boman
Table 1 Serum values in an infant with co-occurrence of vitamin D-dependent
INTRODUCTION rickets type 1 and phenylketonuria
Vitamin D-dependent rickets type 1 (VDDR1; OMIM #
264700 http://www.ncbi.nlm.nih.gov/omim), also known Serum values∗ Pretreatment After 3.5 m After 8 m
as pseudo-vitamin D-deficiency rickets, is a rare autoso- Calcium, mmol/L (2.20–2.52) 2.18 2.34 2.42
mal recessive disorder characterized by low serum calcium Phosphate, mmol/L (1.30–2.30) 0.75 1.15 2.03
and phosphate, secondary hyperparathyroidism and low cir- Alkaline phosphatase, U/L (250–1000) 4900 3467 783
culating levels of 1.25 (OH) 2 vitamin D 3 . The disease is PTH, pmol/L (0.7–7.5) 163 63.8 5.0
caused by homozygosity for an abnormal CYP27B1 gene 25-OH vitamin D, nmol/L (25–130) 165 118 193
leading to deficiency of renal 25(OH) D1 -hydroxylase. 1, 25-(OH) 2 vitamin D, nmol/L (70–190) 30 89 –
We identified VDDR1 in an infant with previously known 24, 25-(OH) 2 vitamin D, nmol/L 1.8 2.7 6.4
(3–6% of 25OHD)
phenylketonuria (PKU; OMIM # 261600) due to low lev-
els of phenylalanine hydroxylase (PAH) activity. She was ∗
Reference values in parentheses; m = months; – = data not available.
homozygous for a rare PAH mutation. As the CYP27B1
and the PAH genes both are located on the long arm
of chromosome 12 (12q14.1 and 12q23.2, respectively,
http://www.ncbi.nlm.nih.gov/mapview), we hypothesized
that she might also be homozygous for a CYP27B1 muta-
tion, inherited from a common ancestor.
A 15-month-old girl with PKU was admitted to hospital
with pain in the lower extremities. Her PKU was diagnosed
through the National Newborn Screening Programme, and
she had since done well on a balanced diet with low pheny-
lalanine and adequate nutritional and vitamin contents.
Growth and development had been normal until the age
of 12 months when she showed difficulties with standing up
and discomfort when the parents touched her lower extrem-
ities. Physical examination showed a well-nourished child
with normal psychomotor development. Her height was
76 cm (10th centile). She resisted attempts to make her stand
up on her feet and showed discomfort with passive move- Figure 1 Family pedigree. The CYP27Bl and PAH loci are located on chromo-
some 12q. The location of the two loci is indicated on a schematic chromosomal
ments of her hips. There was reduced muscle tone in the
segment. The patient‘s grandparents were each heterozygous for a mutation in
lower extremities. There was palpable widening of the dis-
one of the two loci. A recombination has occurred between the two loci in both
tal radius and double malleolus sign at the ankles. X-ray parents, resulting in a patient with two autosomal recessive disorders.
examination showed classical signs of rickets with widen-
ing and irregular mineralization of the distal radial meta-
physes, giving them a frayed and cupped appearance. Bio-
chemical analyses were entirely compatible with vitamin mutation has been seen in several European populations
D dependent rickets type 1, based on a hydroxylation de- (PAH locus specific database, http://www.pahdb.mcgill.ca)
fect of 25OH-D3. She was treated with calcitriol 1 g daily, and was reported in two of 236 alleles in Norwegian PKU
and showed the expected clinical and biochemical improve- patients (1). The patient was also homozygous for 13 well-
ments (Table 1). Her height at the age of 8 years was 127 cm known intragenic single nucleotide polymorphisms (SNPs),
(25–50th centile). compatible with that the L249F mutation indeed could orig-
inate from a common ancestor. No work was done to further
elucidate this possibility. The CYP27B1 mutation R389H has
RESULTS AND DISCUSSION been described by Wang et al. (2), whereas we find no report
The patient’s Norwegian parents and grandparents were on the nonsense mutation S416X (TCA > TGA).
not aware of any ancestral relationship, and supplementary The probability for the combined occurrence of PKU and
genealogical studies gave no indications of common ances- VDDR1, which to our knowledge has not been reported be-
try. DNA was isolated from blood samples of the patient, fore, is very low. PKU occurs in Norway with a frequency of
her parents and from three available grandparents. Direct approximately one case in 13 000 live born. The frequency
sequencing of the entire coding regions and adjacent intron of VDDR1 in Norway is unknown, but probably less than
sequences of the PAH and CYP27B1 genes were performed. 1:100 000. Based on these estimates, one would expect to
The patient was homozygous for the PAH mutation L249F find VDDR1 in only 1 of 100 000 PKU patients, and the
and compound heterozygous for two different CYP27B1 combination of PKU and VDDR1 less than once in 1.3 ×
mutations (R389H and S416X; Fig. 1). The PAH L249F 109 births.
666 C 2008 The Author(s)/Journal Compilation C 2008 Foundation Acta Pædiatrica/Acta Pædiatrica 2008 97, pp. 663–672
Cohen et al. Bladder telangiectasis in ataxia-telangiectasia
The PAH and CYP27B1 loci are situated 45 Megabases and efficient treatment regimens, and the combined treat-
apart on the long arm of chromosome 12 (http://www. ment of the two metabolic disorders did not create special
ncbi.nlm.nih.gov/mapview). The finding of one mutation for problems.
the two disorders in each of four grandparents made it clear
that a crossing over had occurred during sex cell formation References
simultaneously in both the doubly heterozygous parents, re-
sulting in the patient with two autosomal recessive disorders. 1. Eiken HG, Knappskog PM, Boman H, Thune KS, Kaada G,
Motzfeldt K, et al. Relative frequency, heterogeneity and
The extremely rare co-occurrence of VDDR1 and PKU re-
geographic clustering of PKU mutations in Norway. Eur J Hum
quires careful genetic work-up and close attention to family Genet 1996; 4: 205–13.
information, and represents a considerable therapeutic bur- 2. Wang JT, Lin CJ, Burridge SM, Fu GK, Labuda M, Portale AA,
den. Fortunately, PKU and VDDR1 were both among the et al. Genetics of vitamin D 1alpha-hydroxylase deficiency in 17
relatively few inborn errors of metabolism with established families. Am J Hum Genet 1998; 63: 1694–702.
Bladder wall telangiectasis causing life-threatening haematuria
in ataxia-telangiectasia: a new observation
Jonathan M Cohen1,2 , Peter Cuckow3 , E Graham Davies (firstname.lastname@example.org)1,4
1.Department of Immunology, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK
2.Infectious Disease and Microbiology Unit, Institute of Clinical Health, 30 Guilford Street, London WC1N, 1EH, UK
3.Department of Urology, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK
4.Molecular Immunology Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
Dr Graham Davies, Department of Clinical
We report two cases of life-threatening haemorrhage from bladder telangiectasia in children with
Immunology, Great Ormond St Hospital,
Great Ormond St, London, WC1N 3JH, UK. ataxia-telangiectasia (A-T) who had been treated for lymphoma earlier in life. Whilst oculocutaneous
Tel: 020-7813-8121 | telangiectasiae are an almost universal ﬁnding in this syndrome, bladder wall telangiectasis has not
Fax: 020-7813-8552 |
been reported previously. Both teenagers presented with recurrent severe haematuria due to
extensive bladder telangiectasis. Recurrent haemorrhage was controlled with cystoscopic diathermy
3 December 2007; revised 29 January 2008; treatment. As A-T is a DNA repair disorder, it is possible that chemotherapy-mediated damage to the
accepted 1 February 2008. bladder mucosa prompted the development of clinically signiﬁcant telangiectasis in these patients.
Conclusion: We advocate early cystoscopy for A-T patients who develop haematuria to investigate the cause, and
cystodiathermy to pre-emptively treat developing lesions prior to haemodynamically signiﬁcant haemorrhage.
INTRODUCTION tasis in A-T patients. We describe the factors that may have
Ataxia telangiectasia (A-T) is a complex syndrome with neu- contributed to the development of the problem, the cysto-
rological, immunological, endocrinological, hepatic and cu- scopic findings and the treatment.
taneous manifestations (1–3). It is caused by mutations in
the ATM gene located on the long arm of chromosome 11 PATIENT 1
(2,4). The gene codes for a critical cell cycle checkpoint Patient 1 was 15 years old at the time of referral for in-
protein, and the mutations lead to extreme sensitivity to vestigation of his haematuria. He suffered from ataxia and
ionizing radiation, resulting in defective DNA repair and had bulbar telangiectasis clinically consistent with A-T. This
multiple chromosomal abnormalities (4). Typical clinical was further supported by findings of a raised serum alpha-
manifestations include progressive cerebellar ataxia, oculo- fetoprotein level and increased chromosomal radiation sen-
cutaneous telangiectasis, chronic sinopulmonary disease, a sitivity. He had evidence of associated immunodeficiency
high incidence of malignancy and variable humoral and cel- treated with immunoglobulin replacement therapy. He had
lular immunodeficiency (2). Most children are confined to been treated outside the United Kingdom for a Burkitt-type
a wheelchair due to neurological disease by 10–12 years of lymphoma at the age of 8. Records are not available of the
age. precise chemotherapeutic regimen that he received. He had
Here we report 2 A-T patients with life-threatening suffered recurrent chest infections and his sputum was
haemorrhagic telangiectasis of the bladder mucosa. Both known to be colonized with Pseudomonas aeruginosa,
patients had previously been treated for lymphoma, a rec- for which he received regular nebulized colomycin. He
ognized complication of A-T (5,6). The bleeding posed sig- had a poor nutritional status, with thin muscle bulk. He
nificant challenges in both investigation and treatment. To had suffered intermittent haematuria over the previous 2
our knowledge, this is the first report of bladder telangiec- years, becoming increasingly persistent and requiring blood
C 2008 The Author(s)/Journal Compilation C 2008 Foundation Acta Pædiatrica/Acta Pædiatrica 2008 97, pp. 663–672 667