Acta Pdiatrica ISSN 08035253

LETTER TO THE EDITOR

Mycoplasma respiratory tract infection complicated by Stevens-Johnson

syndrome and surgical emphysema
Rakesh Amin (Rakesh.Amin@cmmc.nhs.uk), Elisa Smit, Guftar Shaikh, Philippa Rawling, Eliza Alexander
Royal Manchester Childrens Hospital, Hospital Road, Manchester, UK

Correspondence
Rakesh Amin, M.D., Royal Manchester Childrens Hospital,
Hospital Road, Manchester, M27 4HA, UK.
Tel: 0161 9222581 | Fax: 0161 9222583 |
E-mail: Rakesh.Amin@cmmc.nhs.uk
Received
20 August 2006; accepted 30 August 2006.
DOI:10.1111/j.1651-2227.2007.00088.x

Sir,
An 11-year-old girl presented with a 10-day history of a
vesicular rash on her extremities, lips and eyelids and purulent conjunctivitis followed by a cough, lethargy, pyrexia
and weight loss. Oxygen saturation in air was 89%, CRP
was 22 mg/L and white cell count was 11.5 10 9/l. Chest
X-ray showed bilateral patchy shadowing, thus a diagnosis
of atypical pneumonia was made and she was treated with
intravenous erythromycin and oxygen.
On day 5 of admission, she developed widespread target
lesions consistent with erythema multiforme. These lesions
subsequently ulcerated including extensive, painful intraoral lesions consistent with StevensJohnson syndrome.
On day 7, she became increasing short of breath, complained of chest pain and developed increasing oxygen
requirements. Examination revealed evidence of surgical
emphysema at her neck, shoulders and upper limbs, which
was confirmed by repeat chest X-ray (Fig. 1). A CT scan
showed extensive air trapping at the mediastinum, neck,
chest wall and axillae. In addition, air was evident in the
extradural space of the spinal canal.
Serology showed a rise of Mycoplasma titre from 1 out of
160 on day 3 of admission to 1 out of 640 on day 10. Blood
cultures, throat and skin swabs and herpes PCR serology
were negative. In view of the surgical emphysema, a gastrograffin swallow was performed and demonstrated no oesophageal perforation, indicating that the air leak was due
to bronchial erosion secondary to the StevensJohnson syndrome lesions.
Daily serial chest X-rays showed no mediastinal expansion, therefore she was treated conservatively for 14 days
with erythromycin, oxygen, pain relief and skin care.

472

Figure 1 Chest X-ray on day 7 of admission showing patchy, bilateral lung shading consistent with infection and also extensive air trapping at the mediastinum
and subcutaneous tissues, consistent with surgical emphysema.

Her oxygen requirement and surgical emphysema resolved

within 3 weeks.
We report a complication of StevensJohnson syndrome
resulting in significant morbidity but which resolved with
conservative management.


C 2007 The Authors/Journal Compilation 
C 2007 Foundation Acta Pdiatrica/Acta Pdiatrica 2007 96, pp. 472479

Letter to the Editor

Letter to the Editor

Comments on Lead neurotoxicity in children: is prenatal exposure more

important than postnatal exposure?
Joe M. Braun (jmbraun@unc.edu)1 , Bruce Lanphear2
University of North Carolina-Chapel Hill, Department of Epidemiology, Chapel Hill, USA
Cincinnati Childrens Environmental Health Center, Cincinnati Childrens Hospital Medical Center, Cincinatti, USA
Correspondence
Joe M. Braun, University of North Carolina-Chapel
Hill,Department of
Epidemiology McGavran-Greenberg Hall,
CB 7435 Chapel Hill, North Carolina 27599, USA.
Tel.: 919-951-8519 | Fax: 919-966-2089 |
Email: jmbraun@unc.edu
Received
11 October 2006; accepted 25 October 2006.
DOI: 10.1111/j.1651-2227.2007.00131.x

Sir,
Ronchetti et al. contrasts two different approaches to preventing lead associated neurotoxicity: remediation of lead
contaminated environments and providing women with micronutrient supplementation before and during pregnancy
to avoid mobilizing lead stores during pregnancy (1). The
authors conclude that because it is costly, difficult, and of
uncertain usefulness to perform environmental remediation
of lead exposures, that efforts should be made to study and
reduce prenatal lead exposure through nutritional and social
factors thus reducing its burden on childhood neurodevelopment. Reducing prenatal exposure to lead is desirable and
may diminish lead-associated neurodevelopmental deficits,
but it is not, by itself, adequate to protect children from the
adverse consequences of lead toxicity.
As noted by Ronchetti et al., there is considerable evidence that dietary deficiencies are associated with increases
in blood lead levels (2). The results are less convincing, however, that dietary supplementation with calcium or iron can
significantly reduce blood lead levels in children or adult
females (3,4). Thus, it is unwise to suggest that micronutrient supplementation is the only tenable solution to eliminate
lead-associated neurotoxicity in children.
In an otherwise excellent review, the authors erroneously
conclude that the majority of lead stores in children are derived from maternal and fetal stores of lead and that scientific data which allow us to decide whether, at the epidemiological level, prenatal or postnatal lead exposure is the main
neurotoxic event, are scarce. Although maternal stores are
clearly an important source of lead exposure during the first
6 months of life and undoubtedly contribute to lifetime
exposure the predominant source of childrens body lead
burden is from exposures to lead-contaminated paints, dust,
soil, cosmetics, pottery and water during the first 5 years of
life (5).
In addition, existing research suggests that chronic exposure to low-level lead exposure during early childhood is

a stronger predictor of lead-associated intellectual deficits

than prenatal exposure. Contrary to the authors argument,
although prenatal exposure is associated with intellectual
function in several prospective epidemiological studies, the
effect is diminished or absent after adjusting for postnatal
lead exposure. In a pooled analysis of 696 children from
seven prospective studies that had measures of both prenatal and postnatal blood lead concentration, we found that
concurrent blood lead concentration, but not prenatal blood
lead concentration, was a predictor of childrens intellectual
ability with both variables in the multivariable analysis (6).
It is critical to test and implement cost-effective solutions
to eliminate both prenatal and postnatal lead exposures to
prevent the adverse consequences of lead toxicity. Until we
eliminate all sources of environmental lead exposure we will
fail to protect children from the consequences of lead toxicity. Although it will be difficult to convince national agencies
to promulgate regulatory standards to reduce environmental sources of childhood lead exposure, it is not impossible. Indeed, contrary to widespread expectations, childrens
blood lead levels plummeted once leaded gasoline and other
environmental sources of lead exposure were reduced; it
is astounding what can be achieved when we promulgate
environmental health policy that is based on empirical research.

References
1. Ronchetti R, Van Den Hazel P, Schoeters G, Hanke W,
Rennezova Z, Barreto M, et al. Lead neurotoxicity in children:
Is prenatal exposure more important than postnatal exposure?
Acta Paediatr. 2006; 95: 459.
2. Mahaffey KR. Nutrition and lead: strategies for public health.
Environ Health Perspect 1995; 103(Suppl 6): 1916.
3. Rosado JL, Lopez P, Kordas K, Garcia-Vargas G, Ronquillo D,
Alatorre J, et al. Iron and/or zinc supplementation did not
reduce blood lead concentrations in children in a randomized,
placebo-controlled trial. J Nutr. 2006; 136: 237883.


C 2007 The Authors/Journal Compilation 
C 2007 Foundation Acta Pdiatrica/Acta Pdiatrica 2007 96, pp. 472479

473

Letter to the Editor

Letter to the Editor

4. Gulson BL, Mizon KJ, Korsch MJ, Taylor AJ. Low blood lead
levels do not appear to be further reduced by dietary
supplements. Environ Health Perspect 2006 Aug; 114:
118692.
5. Lanphear BP, Hornung R, Ho M, Howard CR, Eberly S, Knauf
K. Environmental lead exposure during early childhood. J

Pediatr 2002; 140: 407. Erratum in: J Pediatr 2002 Apr;

140(4): 490.
6. Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P,
Bellinger DC, et al. Low-level environmental lead exposure
and childrens intellectual function: an international pooled
analysis. Environ Health Perspect 2005; 113: 8949.

Lead neurotoxicity in children: is prenatal exposure more important than

postnatal exposure?
Roberto Ronchetti (roberto.ronchetti@ospedalesantandrea.it)1 , Peter van den Hazel2 ,Greet Schoeters3 , Wojtek Hanke4 , Zuzana Rennerova5 ,
Mario Barreto1 , Maria Pia Villa1
1.Department of Paediatrics, Second School of Medicine, University La Sapienza, Rome, Italy
2.Public Health Services Gelderland Midden, Arnhem, The Netherlands
3.Vlaamse Instelling voor Technologisch Onderzoek, Mol, Belgium
4.Department of Informatics and Statistics Medical University, Nofer Institute of Occupational Medicine, Lodz, Poland
5.Srobars Institute for Respiratory Diseases and Tuberculosis for Children, Dolny Smokovec, Vysoke Tatry, Slovak Republic

Correspondence
Professor Roberto Ronchetti, Clinica Pediatrica, Ospedale SantAndrea,
Via Grottarossa 1035/1039, 00189 Rome (RM), Italy.
Tel: +39-06-3377 5856 | Fax: +39-06-3377 5941 |
Email: roberto.ronchetti@ospedalesantandrea.it
Received
26 October 2006; revised 31 October 2006; accepted 9 November 2006.
DOI: 10.1111/j.1651-2227.2006.00144.x

Dear Sir,
We are pleased to see that our review raised the interest of
a recognized expert in the epidemiology of lead neurotoxicity, Dr. Lanphear, and of his co-author Dr. Braun. Our review
(a paper within the PINCHE EU Project, Workpackage of
Toxicology) reported evidence from the literature suggesting
that lead neurotoxicity may depend more on prenatal than
on postnatal exposure (1).
The writers first take issue with our statement that performing environmental remediation of lead exposure is
costly, difficult and of uncertain usefulness. In Europe, for
example, the general childhood population has measurable
mean blood lead levels ranging from 5 to 10
g/dL (Western
versus Eastern European countries) (1,2). These low levels
represent the results of concerted efforts on the part of regulatory authorities and most important, largely depend from
the withdrawal of alkyl leads from gasoline. Because most of
the lead neurotoxicity observed in children at the age of 7 is
already evident at a blood lead level less than 7.510
g/dL
and robust epidemiological data (3,4) found no evidence of
a lower threshold (children should have blood lead levels
near to zero), we find it somewhat hard to envisage the task
of reducing further and near to zero the environmental lead
exposure for all our children as being inexpensive, simple
and of undoubted usefulness.

474

The second point raised by Drs Lanphear and Braun is the

origin of lead stores in the newborn. In adult women twothirds (4575%) of blood lead comes from long-term lead
tissue stores (bone), a fact demonstrated by the studies on
natural lead isotopes partition in blood and urine and widely
accepted in the literature (57). Moreover, during pregnancy
bone resorption undergoes a physiological increase which
further increases the contribution of maternal bone lead deposits in the accumulation into the foetal skeleton of lead (7).
In this process lead simply follows the fate of calcium and if
the mother has high concentration of lead in her bone mineral deposits, the same concentration will be deposited in the
bones of the foetus. These metabolic exchanges take place
mainly during the last trimester of pregnancy when maternal
blood lead increases 25100% owing to high mobilization of
lead from bone deposits (7). Dietary supplementation with
calcium or other metabolites during this phase of pregnancy
can reduce blood lead levels in women: these studies therefore show that lead mobilization in pregnant women can be
reduced by means of calcium or other supplements (810).
These studies differ in concept from the studies cited in
the letter in which various types of dietary supplementation
failed to reduce blood lead levels in normal children aged 7
(11,12).


C 2007 The Authors/Journal Compilation 
C 2007 Foundation Acta Pdiatrica/Acta Pdiatrica 2007 96, pp. 472479

Letter to the Editor

Finally, in the excellent paper describing the pooled analysis of data from 1333 children and cited in the letter
(Lanphear et al., 2005) (4), blood lead levels were measured
at various times from birth (cord blood lead) to the moment
of IQ measurement at about 7 years (concurrent blood lead).
Both cord blood and concurrent blood lead levels were significantly associated with IQ at the age of 7. Even if IQs correlated more strongly with the concurrent blood lead than
with other blood lead measures the fact that cord blood
lead and blood lead measured in early childhood (6 months
to 2 years) or the average lifetime blood lead were each
highly correlated with IQ suggests that IQ loss could, at
least partially, arise from lead exposure in utero or in the
first months of life. Newborns normally have a negative lead
balance in the sense that, owing to bone turnover, they eliminate three times more than their dietary lead intake (6). We
therefore find it difficult to believe that lead neurotoxicity
already predicted by blood lead level at birth or early postnatally is a consequence of external contamination.
In conclusion, we believe that environmental measures
aimed to reduce lead exposure in children and in the
general population are always welcome, but their current
efficacy seems questionable. At the same time (and not as
an alternative) we need to focus our attention on the lead
bone deposits of the mother and their mobilization during
pregnancy. Scanty and preliminary results suggest that this
mobilization could be at least partly avoided through various
types of dietary supplementation (810) although precisely
how remains to be fully established.

Letter to the Editor

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

References
1.

Ronchetti R, Van Den Hazel P, Schoeters G, Hanke W,

Rennezova Z, Barreto M et al. Lead neurotoxicity: is prenatal
exposure more important than postnatal exposure? Acta
Paediatr 2006; 95(Suppl 95): 4549.

12.

SCOOP. Report of Task 3-2.11: Assessment of the dietary

exposure to arsenic, cadmium, lead and mercury of the
population of the EU Member States, March 2004. URL:
www.mhlw.go.jp/shingi/2004/08/dl/s0817-2k2.pdf.
Canfield RL, Henderson CR Jr., Cory-Slechta DA, Cox C,
Jusko TA, Lanphear BP. Intellectual impairment in children
with blood lead concentrations below 10 microg/dl. N Engl J
Med 2003; 348: 15l726.
Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P,
Bellinger DC, et al. Low-level environmental lead exposure
and childrens intellectual function: an international pooled
analysis. Environ Health Perspect 2005; 113: 8949.
Gulson BL, Jameson CW, Mahaffey KR, Mizon KJ, Korsch MJ,
Vimpani G. Pregnancy increases mobilization of lead from
maternal skeleton. J Lab Ciin Med 1997; 130: 5162.
Gulson BL, Pounds JG, Mushak P, Thomas BJ, Gray B, Korsch
MJ. Estimation of cumulative lead release (lead flux) from the
maternal skeleton during pregnancy and lactation. J Lab Clin,
Med 1999; 134: 63140.
Gulson BL, Mizon KJ, Palmer JM, Patison N, Law AJ, Korsch
MJ, et al. Longitudinal study of daily intake and excretion of
lead in newly born infants. Environ Res 2001; 85:
23245.
Jarakiraman V, Ettinger A, Mercado-Garcia AQ, Hu H,
Hernandez-Avila
M. Bone turnover and mineral metabolism in

the last trimester of pregnancy: effects of multiple gestation.

Obset Gynecol 1996; 88: 16873.
Hertz-Picciotti I, Schramm M, Watt-Morse M, Chantala K,
Anderson J, Osterloh J. Patterns and determinants of blood
lead during pregnancy. Am J Epidemiol 2000; 152: 82937.
Tellez-Rojo
MM, Hernandez-Avila M, Lamadrig-Figueroa H,
`
Smith D, Hernandez-Cadena
L, Mcrcado A et al. Impact of

bone lead and bone resorption on plasma and whole blood

lead levels during pregnancy. Am J Epidemiol 2004; 160:
66878.
Rosado JL, Lopez P, Kordas K, Garcia-Vargas G, Ronquillo D,
Alatorre J, et al. Iron and/or zinc supplementation did not
reduce blood lead concentrations in children in a randomized,
placebo-controlled trial. J Nutr 2006; 136: 237883.
Gulson BL, Mizon KJ, Korsch MJ, Taylor AJ. Low blood lead
levels do not appear to be further reduced by dietary
supplements. Environ Health Perspect 2006; 114: 118692.

Hypoglycaemia in an infant with severe pulmonary hypertension after

prenatal exposure to nimesulide: coincidence or side effect?
Monica Manganaro, Paola Papoff, Roberto Cicchetti, Elena Caresta, Corrado Moretti
Department of Pediatrics, Pediatric Intensive Care Unit, La Sapienza University of Rome, Rome, Italy

Keywords
Hypoglycaemia, Infant, Nimesulide
Correspondence
Paola Papoff, MD, Department of Pediatrics, PICU, Azienda Policlinico Umberto I,
Viale Regina Elena, 324, 00161 Rome, Italy.
Email: p.papoff@libero.it
Received
13 August 2006; revised 1 September 2006; accepted 19 September 2006.
DOI:10.1111/j.1651-2227.2006.00113.x


C 2007 The Authors/Journal Compilation 
C 2007 Foundation Acta Pdiatrica/Acta Pdiatrica 2007 96, pp. 472479

475

Letter to the Editor

Letter to the Editor

Sir,
Anecdotal evidence suggests that pulmonary hypertension may develop in infants who have been exposed to a
number of nonsteroidal anti-inflammatory drugs (NSAIDs)
in the third trimester of pregnancy. In a case-control
study, Alano and coworkers have demonstrated an independent association between the use of inhaled nitric oxide
and the presence of NSAIDs in the meconium of infants with severe pulmonary hypertension (1). By inhibiting prostaglandin formation, these agents can cause ductal
and pulmonary vessel constriction, increase pulmonary arterial smooth muscle thickness, and thus stimulate pulmonary
hypertension.
Nimesulide is a selective cyclo-oxygenase type-2 (COX-2)
inhibitor commonly used for pain relief but also prescribed
in pregnancies at risk of premature delivery or complicated
with polydramnios. In this setting, the use of this drug has
been associated with a number of complications in the foetus, such as renal failure and subsequent oligohydramnios,
and pulmonary hypertension if used at the end of pregnancy.
We report here on hypoglycaemia as a possibly rare neonatal complication of the maternal use of nimesulide, in an
infant who was prenatally exposed to this agent, in whom
the most striking signs were increased pulmonary arterial
pressure and prolonged lowered glucose levels.

CASE REPORT
This baby girl was born at 37 weeks gestation by elective caesarean section. Her birth weight was 3300 g. The pregnancy
was uneventful except for sciatica a week before delivery,
because of which nimesulide (100 mg twice a day) was prescribed. At 1 min her Apgar score was 7. Three min later, the
baby became pale, hypotonic and presented signs of respiratory distress. She was immediately ventilated and because of
persistent bradycardia was intubated and given epinephrine
and hydrocortisone. A blood gas analysis showed marked
metabolic acidosis (base excess 25), which was corrected
with sodium bicarbonate. On admission to our paediatric
intensive care unit, the baby appeared extremely hypotonic,
cyanotic and bradycardic. Epinephrine was administered
and mechanical ventilation was started in association with
nitric oxide (35 ppm) with the potential of pulmonary hypertension. Bedside echocardiography confirmed the clinical
suspicion of pulmonary hypertension, but also showed closure of ductus arteriosus, reduced contractility and marked
dilation of the right heart. A chest X-ray showed only mild
lung hypoexpansion but marked enlargement of the heart.
Surfactant was given and high frequency oscillatory ventilation was started. In addition, administration of 10% dextrose in water with calcium and sodium as well as empiric
antibiotics (amplital and nettacin) and phenobarbital treatment because of increased alertness were begun. The babys
condition rapidly improved, and five days later she was extubated. Serum creatinine remained 1.2 mg/dL for 3 days after
admission and then it returned to normal values. Urine output in the first day of life decreased to less than 1 mL/kg/h
but improved after furosemide. Blood tests (including cul-

476

tures) obtained on admission were negative or within normal

limits, except for arterial gas analysis and blood glucose levels. For 6 days after admission, we observed mild metabolic
acidosis (base excess 7 to 9) with slightly high lactate levels (3 to 4 mmoL/L) that required bicarbonate supplementation and hypotension, which was treated with dopamine
infusion. Similarly, the blood glucose level, which was above
the normal range on arrival, dropped to 37 mg/dL at 7 h of
life, and a bolus of 2 mL/kg 10% dextrose in water was given.
After 24 h, blood glucose levels were low again (39 mg/dL).
The rate of the dextrose infusion was gradually increased
up to 15 mg/kg/min, but glucose levels continued to stay between 40 and 50 mg/dL. Hydrocortisone (2.5 mg/kg 2 i.v.)
was then started and this treatment resulted in rapid stabilisation of glucose levels. No symptoms relating to hypoglycaemia were detected in this period. The rate of dextrose
infusion and hydrocortisone treatment was tapered after
6 days. Several causes of hypoglycaemia were investigated.
Immunoreactive insulin, cortisol, urinary organic acids,
plasma aminoacids and acylcarnitines were negative or
within normal range. An abdominal ultrasound performed
to exclude a pancreatic adenoma resulted negative. Renal
function tests were normal. The infant gained weight over
the coming weeks and was discharged home on the 18th
postnatal day. At the time of discharge, blood glucose level
was 86 mg/dL. An elective echocardiogram examination on
day 13 of life showed resolution of pulmonary hypertension
and marked regression of right ventricular dysfunction. A
magnetic resonance imaging of the brain showed no abnormalities on day 17 of life.

DISCUSSION
Although the adverse effects of NSAIDs most commonly
include gastrointestinal disturbances, renal dysfunction and
decreased platelet aggregation, there are some reports suggesting that these drugs may cause hypoglycaemia. In 1877,
Ebstein first advocated a better tolerance to carbohydrates in
patients receiving salicylates (2). Subsequently, several other
investigators reported that NSAIDs could ameliorate glucose clearance in diabetic subjects especially if assumed at
large doses. The mechanisms underlying the blood glucose
reducing effects of NSAIDs remain unclear. In vitro and in
vivo studies have suggested that prostaglandins might participate in the regulation of glucose homeostasis and it has
been speculated that decreased basal rates of hepatic glucose production, enhanced peripheral insulin sensitivity, and
decreased insulin clearance may explain hypoglycaemia in
treated subjects (3).
In neonates, indomethacin has been invariably reported
to cause a decrease in blood glucose levels when used for
closure of patent ductus arteriosus in preterm babies, and
increased glucose intake and hydrocortisone treatment have
been necessary to resolve hypoglycaemia in these infants (4).
Moreover, in a retrospective study, Hosono et al. showed
that an increase in glucose infusion rate might prevent the
occurrence of hypoglycaemia in preterm infants following
indomethacin therapy (5). In contrast, the evidence on a


C 2007 The Authors/Journal Compilation 
C 2007 Foundation Acta Pdiatrica/Acta Pdiatrica 2007 96, pp. 472479

Letter to the Editor

possible association of hypoglycaemia and the use of nimesulide is scanty. In the English literature we were able to
find only one report, by Yapakci et al., on a 3-year-old boy
who developed hypoglycaemia after ingestion of a high dose
of nimesulide. He also showed hypotension and metabolic
acidosis (6).
The coexistence of neonatal hypoglycemia and maternal
use of nimesulide is here reported for the first time. In the
neonate we have described, hypoglycaemia was associated
with prolonged and unexplained hypotension and metabolic
acidosis. These findings are similar to those previously reported by Yapakci after accidental ingestion of high dose
nimesulide. We speculate that in our patient a long exposure
to a full dose (100 mg twice a day) of nimesulide before birth
might have contributed to the occurrence of this uncommon
adverse effect. This hypothesis is supported by previous findings in adults showing that the effects on blood glucose levels
of NSAIDs depend on the amount of drug assumed and the
length of treatment.
In conclusion, based on the current knowledge we believe
that the possibility that our case represents an actual pathophysiological association rather than a mere coincidence
is plausible. Alertness to this possibility in infants born to
mothers who had been taking NSAIDs and early initiation

Letter to the Editor

of appropriate treatment should be considered to prevent

unwarranted evaluations and potential complications.

References
1. Alano MA, Ngougmna E, Ostrea EM Jr, Konduri GG. Analysis
of nonsteroidal antiinflammatory drugs in meconium and its
relation to persistent pulmonary hypertension of the newborn.
Pediatrics 2001; 107: 51923.
2. Ebstein W: Zur therapie des diabetes mellitus, insbesondere
uber die anwendung der salicylsauren natron bei demselben.
Berl Klin Wochenschr 1877; 24: 33740.
3. Hundal RS, Petersen KF, Mayerson AB, Randhawa PS,
Inzucchi S, Shoelson SE, et al. Mechanism by which high-dose
aspirin improves glucose metabolism in type 2 diabetes. J Clin
Invest 2002; 109: 13216.
4. Hosono S, Ohono T, Kimoto H, Nagoshi R, Shimizu M,
Nozawa M. Preventive management of hypoglycemia in very
low-birthweight infants following indomethacin therapy for
patent ductus arteriosus. Pediatr Int 2001; 43: 4658.
5. Hosono S, Ohno T, Ojima K, Kimoto H, Nagoshi R, Shimizu M,
et al. Intractable hypoglycemia following indomethacin therapy
for patent ductus arteriosus. Pediatr Int 2000; 42: 3724.
6. Yapaci E, Uysal O, Demirbilek H, Olgar S, Nacar N, Ozen H.
Hypoglycaemia and hypothermia due to nimesulide overdose.
Arch Dis Child 2001; 85: 510.

Is early identification of asymptomatic infants with mild CFTR genotypes

clinically useful?
C Colombo (carla.colombo@unimi.it)1 , D Costantini1 , MC Russo1 , L Claut1 , L Porcaro2 , R Nobili1
1.IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, CF Center
2.IRCCS Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, Molecular Genetic Laboratory, Milan, Italy

Correspondence
Carla Colombo, IRCCS Ospedale Maggiore
Policlinico,Mangiagalli e Regina Elena,
Department of Pediatrics, CF Center, Via
Commenda 9, I-20122 Milano, Italy.
Tel: +39 02 5503 2456 | Fax: +39 02 5503 2814 |
Email: carla.colombo@unimi.it
Received
24 July 2006; revised 27 September 2006;
accepted 13 November 2006.
DOI: 10.1111/j.1651-2227.2006.00142.x

Dear Sir,
We read with interest the paper by Padoan et al. (1) concerning identification of the 5T-12TG allele of the cystic
fibrosis transmembrane regulator (CFTR) gene in hypertrypsinaemic newborns. Their finding that this mutation was
the second most frequent allele in infants with biochemical
alterations suggestive of cystic fibrosis (CF) raises the important issue of the pathogenetic role and clinical significance
of this and other mild CFTR alleles (2).

We would like to report here the long term follow up of

the same subjects selected by the neonatal screening programme between October 1998 and October 2000 (Table 1)
and described in the paper as mild and atypical forms of
CF (3). All these 18 infants had been referred to the regional CF Centre in Milano where they underwent clinical examination, blood biochemistry, chest X-ray, sputum


C 2007 The Authors/Journal Compilation 
C 2007 Foundation Acta Pdiatrica/Acta Pdiatrica 2007 96, pp. 472479

477

Letter to the Editor

Letter to the Editor

Table 1 Follow-up data of 18 children with atypical CF identified by newborn screening

Genotype

Age at
first visit
Sex (years)

Age at
last visit
(years)

DF508/Y1032C
DF508/D1152H
DF508/D1152H
DF508/S1455X
DF508/R117L
DF508/F1074L
DF508/5T-12TG
D110E/D110E
R117H/5T-12TG
R347P/5T-12TG
R347P/D1152H
G542X/D614G
G542X/5T-12TG
R553X/L997F
D1152H/4382DelA

M
M
M
M
F
F
F
F
F
M
M
F
F
M
F

1.20
0.62
0.28
5.91
0.91
0.68
0.41
0.16
0.44
0.26
0.18
0.66
0.13
0.24
1.13

7.27
6.91
3.10
8.45
5.71
5.25
6.26
0.70
0.60
5.09
6.32
2.93
6.42
0.43
5.40

N1303K/5T-12TG
2183-AA>G/5T-12TG
2789 + 5G>A/S42F/
5T-12TG
Mean SD

F
F
F

0.23
0.35
0.36

5.96
6.35
7.08

0.79 1.32

5.01 2.43

Respiratory
symptoms

Weight
for age
z-score

Height
for age
z-score

None
None
Occasional bronchitis
Occasional bronchitis
Occasional bronchitis
None
None

0.08
3.19
0.05
0.53
0.38
0,09
1,61

0.75
1.70
0.39
0.57
0.33
0,55
0,95

None
None
Occasional bronchitis
Occasional bronchitis

0.62
1.41
0.58
0.46

Pneumonia, atelectasis
first year of life
Occasional bronchitis
Occasional bronchitis
Recurrent sinusitis

2.19

108
109
Not done
121
130
106.6
Not done
Lost at follow-up
Lost at follow-up
0.64
Not done
1.04
140.3
1.29
Not done
1.23
112.3
Lost at follow-up (adopted)
2.08
135

0.78
0.25
3.15

1.79
0.66
1.47

0.78 1.21

0.81 0.88

culture, abdominal ultrasound and fecal pancreatic elastase

determination.
At first visit all patients were in good clinical conditions
and were completely asymptomatic, with normal growth and
nutritional status; there was no biochemical and ultrasonographic evidence of pancreatic and liver involvement. Patients then entered an annual follow-up programme which
includes clinical evaluation, anthropometric measurements,
sputum culture, chest X-ray (when needed); pulmonary
function tests (FEV1, FVCX, FEF 2575) were determined
by means of spirometry in patients older than 5 years. At
each control visit z scores for weight-for-age and height-forage were calculated using the CDC-WHO reference values
(ANTHRO software program, version 1.01, 1990, Centres
for Disease Control and Prevention, Atlanta, Georgia, U.S.).
All patients were instructed to perform nasal washings; only
those found to have symptoms were put on preventive treatment with PEP mask and antibiotics were promptly given
when necessary.
Median duration of follow-up was 4.81 years (range 0.43
8.45 years); three children (one bearing L997F, that has recently been suggested to be a polimorphysm rather than a
CF disease-causing mutation) (4), were lost at follow-up after the first visit. As shown in the Table 1, anthropometric
parameters were satisfactory in all cases and mild respiratory
symptoms were reported by eight children. None developed
pancreatic and liver involvement and chronic Pseudomonas
aeruginosa infection. In the 11 children older than 5 years,
pulmonary function tests were normal or even above the predicted range for age. This may be the result of prompt and
adequate treatment of respiratory symptoms. In another series of children in whom intermediate sweat chloride results

478

FEV1
%

Sweat
chloride
(mmol/L)

FVC
%

FEF 2575
%

94
96

106
128

113
117
93.4

116
117
112.6

130.9

123.3

105.8

98.4

121

130

44/41
33
44/57
102/97
36/33/35
40/32
39/38/36
53/40
21/27/34
31
42
47/46/52
32/48
33/29
35

102.8
114.7
104.5

94.1
102.6
99.6

101.3
102.6
83.2

38/33/48
33/33/34
32/33/44

116.75 13.00

106.13 12.70

107.40 13.44

and mild CFTR genotype were detected because of respiratory symptoms at a mean age of 4.8 years, the respiratory
phenotype at follow up was relatively more severe than in
our patients (5).
Finally the sweat test was repeated in 14 patients (twice
in seven and three times in other seven); chloride concentrations persisted to be in the borderline range with the
only exception of the patient bearing the S1455X mutation,
who showed a pathologic chloride values on two occasions.
Indeed, this mutation has been associated with isolated
increased sweat chloride concentrations (6), hyponatremia
and metabolic alkalosis (7).
Two patients carrying the D1152H mutation showed radiological evidence of moderate lung involvement, with
occasional bronchitis and no pathological flora in the lungs;
this mutation is associated with a broad clinical spectrum,
with lung disease that may be evident from infancy and may
be quite severe in some adults (8). The only patient with early
development of CF pulmonary disease (D1152H/4382delA
genotype) complicated with right lobe atelectasis and
treated with antibiotic therapy, repeated bronchoscopy and
bronchoalveaolar lavage during the first year of life before being referred to our Center, has been thereafter in
good clinical condition, with normal pulmonary function
and without Pseudomonas infection at the age of
5.4 years.
Of the seven patients bearing 5T-12TG allele (one male,
six females), one was lost at follow-up after her second visit,
whereas of the six who remained compliant at the follow-up
programme, three complained of minimal respiratory symptoms and one of recurrent sinusitis. It has been recently reported that the 5T variant has a milder clinical consequence


C 2007 The Authors/Journal Compilation 
C 2007 Foundation Acta Pdiatrica/Acta Pdiatrica 2007 96, pp. 472479

Letter to the Editor

than previously estimated in females (2). Obviously we cannot exclude that congenital bilateral absence of the vas deferens (CBAVD) associated infertility may possibly occur in
the only one male patient of our cohort bearing this allele
(9).
Overall our data may give a contribution to the debate
about selection and identification of atypical forms of CF
by newborn screening. It has been recently pointed out that
a good screening programme should identify the maximum
number of cases that are likely to be severely affected, ensure that as many as possible of the missed cases are mildly
affected and detect as few unaffected carriers as possible
(10). On the other hand, an expert panel has recently recommended that newborn screening should report of any
abnormal result that may be associated with clinically significant conditions, including the definitive identification of
carrier status (11).
Despite the favourable follow-up data documented in this
small cohort of children bearing mild CFTR genotype, the
diagnostic dilemma in front of a screening positive infant
without CF symptoms and a borderline sweat test remains.
While awaiting for further long term follow-up information
that should permit to define the clinical phenotype associated with the 5T-12TG allele and other mild mutations, some
aspects need to be taken into account: first, the impact of the
diagnosis of mild or atypical CF on a growing up child has
not yet been assessed, and, second, the risk that parents of
asymptomatic children, regardless of their genotype, could
not cope with their childrens developing symptoms, maybe
as a defence against the sorrow of having an imperfect child
(12). Thirdly, financial issues also deserve consideration.

Letter to the Editor

2.

3.

4.

5.

6.

7.

8.

9.
10.
11.

References
1. Padoan R, Corbetta C, Bassotti A, Seia M. Identification of the
5T-12TG allele of the cystic fibrosis transmembrane

12.

conductance regulator gene in hypertrypsinaemic newborns.

Acta Paediatr 2006; 95: 8713.
Sun W, Anderson B, Redman J, Milunsky A, Buller A,
McGinniss MJ, et al. CFTR 5T variant has a low penetrance in
females that is partially attributable to its haplotype. Genet
Med 2006; 8: 33945.
De Boeck K, Wilschanski M, Castellani C, Taylor C, Cuppens
H, Dodge J, et al. Cystic Fibrosis:terminology and diagnostic
algorithms. Thorax 2006; 61: 62735.
Derichs N, Schuster A, Grund I, Ernsting A, Stolpe C,
Kortge-Jung S, et al. Homozygosity for L997F in a child with
normal clinical and chloride secretory phenotype provides
evidence that this cystic fibrosis transmembrane conductance
regulator mutation does not cause cystic fibrosis. Clin Genet
2005; 67: 52931.
Desmarquest P, Feldmann D, Tamalat A, Boule M, Fauroux B,
Tournier G, et al. Genotype analysis and phenotypic
manifestations of children with intermediate sweat chloride
results. Chest 2000; 188: 159197.
Salvatore D, Tomaiuolo R, Vanacore B, Elce A, Castaldo G,
Salvatore F. Isolated elevated sweat chloride concentrations in
the presence of the rare mutation S1455X: an extremely mild
form of CFTR dysfunction. Am J Med Genet A 2005; 133:
2078.
Epaud R, Girodon E, Corvol H, Niel F, Guigonis V, Clement
A, et al. Mild cystic fibrosis revealed by persistent
hyponatremia during the French 2003 heat wave, associated
with the S1455X C-terminus CFTR mutation. Clin Genet 2005
Dec; 68: 5523.
Mussaffi H, Prais D, Mei-Zahav M, Blau H. Cystic fibrosis
mutations with widely variable phenotype: the D1152H
example. Pediatr Pulmonol 2006 Mar; 41: 2504.
Cuppens H, Cassiman JJ. CFTR mutations and polymorphisms
in male infertility. Int J Androl 2004; 27: 2516.
Price JF. Newborn screening for cystic fibrosis: do we need a
second IRT? Arch Dis Child 2006; 91: 20910.
Newborn screening: toward a uniform screening panel and
system. http://mihb.hrsa.gov/screening/summary.htm
Farrel MH, Farrel PM. Newborn screening for cystic fibrosis:
ensuring more good than harm. J Pediatr 2003; 143: 707
12.


C 2007 The Authors/Journal Compilation 
C 2007 Foundation Acta Pdiatrica/Acta Pdiatrica 2007 96, pp. 472479

479