Open Access

A prospective observational study of associated anomalies in Hirschsprung’s disease

  • Alessio Pini Prato1Email author,
  • Valentina Rossi2, 1,
  • Manuela Mosconi1,
  • Catarina Holm1,
  • Francesca Lantieri3,
  • Paola Griseri4,
  • Isabella Ceccherini4,
  • Domenico Mavilio5, 6,
  • Vincenzo Jasonni1,
  • Giulia Tuo7,
  • Maria Derchi7,
  • Maurizio Marasini7,
  • Gianmichele Magnano8,
  • Claudio Granata8,
  • Gianmarco Ghiggeri9,
  • Enrico Priolo10,
  • Lorenza Sposetti10,
  • Adelina Porcu11,
  • Piero Buffa1 and
  • Girolamo Mattioli2, 1
Orphanet Journal of Rare Diseases20138:184

https://doi.org/10.1186/1750-1172-8-184

Received: 6 October 2013

Accepted: 21 November 2013

Published: 23 November 2013

Abstract

Background

Associated anomalies have been reported in around 20% of Hirschsprung patients but many Authors suggested a measure of underestimation. We therefore implemented a prospective observational study on 106 consecutive HSCR patients aimed at defining the percentage of associated anomalies and implementing a personalized and up-to-date diagnostic algorithm.

Methods

After Institutional Ethical Committee approval, 106 consecutive Hirschsprung patients admitted to our Institution between January 2010 and December 2012 were included. All families were asked to sign a specific Informed Consent form and in case of acceptance each patient underwent an advanced diagnostic algorithm, including renal ultrasound scan (US), cardiologic assessment with cardiac US, cerebral US, audiometry, ENT and ophthalmologic assessments plus further specialist evaluations based on specific clinical features.

Results

Male to female ratio of our series of patients was 3,4:1. Aganglionosis was confined to the rectosigmoid colon (classic forms) in 74,5% of cases. We detected 112 associated anomalies in 61 (57,5%) patients. The percentage did not significantly differ according to gender or length of aganglionosis. Overall, 43,4% of patients complained ophthalmologic issues (mostly refraction anomalies), 9,4% visual impairment, 20,7% congenital anomalies of the kidney and urinary tract, 4,7% congenital heart disease, 4,7% hearing impairment or deafness, 2,3% central nervous system anomalies, 8,5% chromosomal abnormalities or syndromes and 12,3% other associated anomalies.

Conclusions

Our study confirmed the underestimation of certain associated anomalies in Hirschsprung patients, such as hearing impairment and congenital anomalies of the kidney and urinary tract. Subsequently, based on our results we strongly suggest performing renal US and audiometry in all patients. Conversely, ophthalmologic assessment and cerebral and heart US can be performed according to guidelines applied to the general population or in case of patients with suspected clinical features or chromosomal abnormalities. This updated diagnostic algorithm aims at improving overall outcome thanks to better prognostic expectations, prevention strategies and early rehabilitation modalities. The investigation of genetic background of patients with associated anomalies might be the next step to explore this intriguing multifactorial congenital disease.

Keywords

HirschsprungPhenotypeObservational studyAssociated anomalies

Background

Hirschsprung’s disease (HSCR) is a congenital multifactorial developmental disorder of the enteric nervous system characterized by the absence of ganglion cells in the hindgut with variable distal bowel involvement. This is a rare disease, which occurs with an incidence of 1 into 5000 live births as a consequence of premature arrest of cranio-caudal migration of neural crest derived neuroblasts (NCN) in the hindgut, and is therefore regarded as a neurocristopathy [13]. The neural crest is one of the earliest organs to form within the developing embryo, during formation of the neural tube. Cells of the neural crest are pluripotential and follow migratory pathways depending on their axial level of origin. NCN differentiate into crucial cell types ancestors and participate in the development of various organs such as adrenal medulla, melanocytes, craniofacial cartilage and bone, smooth muscle, neuroendocrine cells and sympathetic and parasympathetic nervous systems, including the enteric nervous system [3, 4]. Alterations in any of the genes involved in the enteric nervous system development may interfere with the colonization process of NCN and represents a primary aetiology for HSCR [5, 6]. The major gene responsible for HSCR is RET, whose mutations are detected in up to 50% of familial and in 7-35% of sporadic cases [7]. RET is crucial for the embryologic development of the enteric nervous system but also of other organs, including kidneys and urinary tract [8]. So far, a number of other minor HSCR susceptibility genes have been identified in less than 5% of patients [7]. The involvement of heterogeneous genetic pathways and pluripotential cell lineage explains why HSCR disease can be associated to malformations basically involving all organs and system.

Associated anomalies have been detected in between 20% and 30% of HSCR patients according to literature [5, 9, 10]. In 2006, Moore SW performed a systematic review of 18 series with 4328 patients reported in the last forty years and suggested an average percentage of associated anomalies of 21.1%, ranging between 5% and 35% [10]. Similarly, Amiel J and co-workers reported a percentage of associated anomalies of around 30% [9]. Nonetheless, both Authors suggested a measure of underestimation [9, 10]. In accordance to these considerations, we recently demonstrated that Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) occur 4-folds more frequently than previously reported [8]. As a consequence, it comes clear that the exact clinical phenotype of HSCR patients is yet unknown and deserves definition to provide our patients with reliable prognostic expectations. A better knowledge of all associated anomalies in HSCR will also reveal undisclosed genetic implications that will improve the comprehension of HSCR pathophysiology. We therefore implemented a prospective observational cross-sectional study on 106 consecutive HSCR patients aimed at defining the percentage of associated anomalies and at subsequently implementing an up-to-date diagnostic algorithm.

Methods

All consecutive HSCR patients who were admitted to Giannina Gaslini Research Institute between January 2010 and December 2012 were eligible for this prospective observational cross-sectional study. Inclusion criterion was the presence of a reliable diagnosis of HSCR achieved with adequate pathological assessment [11]. Exclusion criteria were uncertain diagnosis and/or refusal to participate.

This study received Institution Review Board approval on the 15th of October 2009. After enrolment, patients and parents were interviewed to collect demographic data, personal and family history and any information regarding known associated anomalies. All families were asked to sign a specific Informed Consent form and in case of acceptance each patient underwent an advanced non-invasive diagnostic algorithm, including ultrasound scan (US) of the kidney and urinary tract, cardiologic assessment with cardiac US, audiometry and ENT assessment, ophthalmologic assessment, cerebral US (< 1 year-old), and further specialist investigations based on clinical features. All these non-invasive investigations were performed according to widely accepted guidelines. The following data were collected according to the Personal Data Protection Act:

  • Demographics

  • Personal and family history.

  • Length of aganglionosis [8].
    • ⃘ S-HSCR (aganglionosis extending up to the left descending colon).

    • ⃘ L-HSCR(aganglionosis extending beyond the splenic flexure, up to the ascending colon and/or caecum).

    • ⃘ TCSA (aganglionosis involving the whole colon).

    • ⃘ TIA (less than 20 cm of normoganglionic bowel).

  • Associated anomalies detected during the phenotype screening.

  • Other associated anomalies or syndromes not included in the phenotype screening.

Details of phenotype screening

Cakut screening

All patients underwent renal US + urinalysis and colture. In case of positive findings we applied widely accepted diagnostic guidelines to properly investigate the patients [8]. To perform renal US we used Philips iU 22 US scanner (Philips, DA Best, The Netherlands) equipped with convex and linear multiple frequency electronic transducers, similarly to the study already published by our study group in 2009 [8]. We also used the same criteria to define all possible CAKUT variants: renal agenesis, renal dysplasia-hypoplasia, hydronephrosis, vesicoureteric reflux, duplex collecting system, and horseshoe kidney [8].

Cardiovacular screening

The cardiovascular screening included personal medical history, physical examination, non invasive blood pressure measurement, a twelve lead electrocardiogram and echocardiogram. Detailed US was performed with a pulsed, continuous, and color-Doppler provided US system (Philips iE33), using a 5 or 8 MHz transducer. Echo-scan was done by a transthoracic approach with the patient in the supine and left decubitus position. Morphological variables were measured offline by two observers (G.T. and M.D.) who used the so called Z score for normalization of the cardiac structures dimensions to the body size [1214].

Cardiac anatomy was routinely assessed by a segmental approach that included the abdominal view, the subcostal short and long axis view, the apical four-chambers view, the parasternal short axis view at the level both of the papillary muscles and of the mitral valve, the parasternal long axis view and the suprasternal view. Two-dimensional echocardiographic measurements included the end-systolic diameter of the aortic annulus of the Valsalva sinuses and of the ascending aorta. These dimensions were measured from the parasternal long-axis view with the “inner edge convention”, which uses the innermost bright edge reflection as a contour. End-diastolic posterior wall thickness, left ventricular internal dimension and interventricular septal thickness were measured through the M-mode technique, which was performed also for calculating the shortening fraction. Diastolic ventricular function as well as valves function was assessed by both pulsed and continuous Doppler technique [1518].

Auditory and ent screening

We assessed the possible presence of audiologic risk factors as those indicated by the Joint Committee of Infant Hearing, including in-utero infections, craniofacial anomalies, physical findings suggesting syndromes known to include a sensorineural or permanent conductive hearing loss, neonatal intensive care (NICU) admission longer than 5 consecutive days, exposure to ototoxic medications, family history and prematurity [19]. The tests used for auditory screening depended on patients’ age and degree of cooperation. Hearing impairment (HI) was defined in case of hearing threshold higher than 20 dB. Deafness or unilateral anacusia were defined in case of complete absence of response to auditory stimuli [20]. Screening was conducted in a quiet room without visual and auditory distractions according to widely accepted standards [21].

  • From birth to 6 months of age - We used the Automated Auditory Brain System (AABR). This methodology measures cochlear response in the 1 to 4-kHz range with a broadband click stimulus in each ear. The automated screener provides a pass-fail report; no test interpretation by an audiologist is required. A “fail” report on an AABR implies a new non-automatic ABR test associated to ENT clinical assessment.

  • From 6 months to 3 years of age - We used the Visual Reinforcement Audiometry (VRA), a behavioural test measuring responses of the child to speech and frequency-specific stimuli presented through speakers or insert earphones.

  • From 3 years to 6 years of age - We used the Conditioned Play Audiometry (CPA) through earphones; in this test the child is conditioned to respond when stimulus tone is heard, such as to put a peg in a pegboard or drop a block in a box.

  • From 6 years of age onwards - We used the Conventional Audiometry (CA) in which the patient is instructed to raise a hand in case of stimulus is heard. Deafness or hearing impairment were defined and graded according to widely accepted international standards.

Ophtalmologic screening

We recorded detailed information regarding family history and any risk factors for visual impairment, including length of stay in NICU and gestational age and weight at birth. Methodology differed according to the age. Visual impairment (VI) was defined as uncorrected visual acuity (VA) < 20/50 and was assessed only in patients older than 36 months of age. In younger patients we addressed strabismus or other VA indirect measures.

  • Before 3 years of age, we performed only an objective evaluation due to the lack of child compliance. After a good visual inspection to exclude eye and eyelid malformations, anatomic abnormality, evident strabismus, anomalies of eye motility and head posture, we assessed:
    • ⃘ Anterior segment and pupillary evaluations. The anterior segment was evaluated using a handheld or stand-mounted slit lamp. Pupillary responses were tested with a hand light.

    • ⃘ Cycloplegic autorefraction and keratometry, with Plus Optix autorefractor (Plusoptix Inc., Atlanta, GA, USA) or Retinomax autorefractor, (Nikon, Melville, NY, USA). Refractory defects were defined and graded according to widely accepted international standards [22].

    • ⃘ Fundus with cycloplegia.

  • After 3 years of age, throughout adolescence and adulthood we also performed visual acuity assessment, orthoptist screening with distance acuity test, cover test, extrinsic ocular movements, prism test, and Lang-stereotest. Moreover, we also looked for the presence of amblyopia. In this age group we resorted to subjective components thanks to reasonably good patients’ compliance.

Patients were divided into three different age groups: younger than 3 (infants), between 3 and 6 (pre-school children), and older than 6 years of age (school children) to compare our results to literature data [2224].

Brain screening and definition

Studies were performed with convex and linear-array 7,5 MHz transducers via the anterior fontanel in coronal and sagittal planes. Further screening images were obtained via other supplemental fontanels (posterior and mastoid). The investigation was performed in all patients younger than 12 months and/or with adequate echoic windows. We assessed subarachnoid spaces, lobes, ventricles and midline structures to rule out major congenital malformations [25].

Other associated anomalies and syndromes

Further investigations were performed basing on clinical features detected during the first detailed physical examination aimed at ruling out major gross abnormalities, including skull and facial malformations, cleft lip or palate, gross skeletal malformations, skin pigmentation disorders, external genitalia abnormalities, neurodevelopmental delay, etc. All information regarding other associated anomalies or syndromes reported by parents or patients were recorded. In case of need, patients were investigated in details according to widely accepted standards of care. In particular, chromosome analysis, array-CGH or direct sequencing of targeted genes was performed basing on genetist’s suggestion after appropriate dysmorphology assessment.

Statistical analysis

Descriptive statistics were reported as percentages with 95% confidence interval (CI), when indicated, in case of categorical variables. Median and range was used for age, given the wide variability in our series. Differences in the frequencies of each categorical variable were evaluated by the Chi-square test. Comparison of continuous data was performed using the 2-tailed unpaired t test. In case of scant data or non-normal distribution, non parametric tests (Man-Whitney) were used. A p value lower than 0.05 was considered as statistically significant. Analyses were performed using Stata for Windows statistical package (release 9.0, Stata Corporation, College Station, TX).

Results

Demographics

Overall, 144 consecutive HSCR patients were admitted to the Department of Surgery of Giannina Gaslini Institute during the study period. One-hundred-and-six (106) patients met the inclusion criteria, were enrolled and underwent the entire phenotype screening during the study period. Median age was 2,4 year (range 3 months to 25 years). Male to female ratio was 3,4:1. Nineteen patients (17,9%) had ultralong HSCR (either TCSA or TIA), 8 (7,6%) had L- HSCR, and 79 (74,5%) had S- HSCR. A total of 112 associated anomalies were detected in 57,5% (95% CI, 48,0-66,5%) of the patients (61 out of 106) with a proportion that did not significantly differ either according to length of aganglionosis or gender (p = 0,8209 and 1,0000, respectively). Twenty-eight patients (26,4%) were already aware of their association when they were enrolled in the study (see Table 1 for details).
Table 1

Overall details of 106 HSCR who completed the screening during the study period

 

Overall, n (screened)

% (95% CI)

Patients, n

106 (106)

 

Median age

2,4

 

Male to female ratio

3,4:1

 

VI or ophthalmological issues

46 (106)

43,4% (95% CI, 34,4-52,9%)

CAKUT

22 (106)

20,7% (95% CI, 14,1-29,4%)

CHD

5 (106)

4,7% (95% CI, 2,0-10,6%)

HI or deafness

5 (106)

4,7% (95% CI, 2,0-10,6%)

CNS abnormalities

1 (43)

2,3% (95% CI, 0,4-12,1%)

Other associated anomalies

13 (106)

12,3% (95% CI, 7,3-19,9%)

Syndromes

9 (106)

9,4% (95%CI, 5,2-16,5%)

Down Syndrome

7 (106)

6,5% (95% CI, 3,2-13%)

Legend: Syndrome, Patients with known genetic abnormalities (i.e. Down Syndrome, Cat Eye, CCHS, etc.); VI = Visual Impairment; CAKUT, Congenital Anomalies of the Kidney and Urinary Tract; CHD, Congenital Heart Defect; HI, Hearing Impairment; CNS, Central Nervous System.

Ophtalmologic abnormalities or visual impairment

None of the patients was diagnosed with blindness. No major ocular abnormalities were detected in our series of patients. No family history of severe visual impairment (VI) or blindness was recorded. Refractive error or ophthalmologic issues were detected in 43,4% (95% CI, 34,4-52,9%) of the patients (Table 2 for details). Male to female ratio was 3,6:1. Five patients had chromosomal abnormalities and 1 had Congenital Central Hypoventilation Syndrome (CCHS) known to be at higher risk for VI. We observed the following phenotypes: hyperopia (29,2% of the overall series), astigmatism (26,4%), myopia (7,5%), strabismus (4,7%), amblyopia (4,7%), papilla abnormalities (1,9%), opaque iris (0,9%) and severe ptosis (0,9%). Twenty-eight patients were diagnosed during the phenotype screening. Ophthalmologic abnormalities were observed in 34% of the patients younger than 3, in 48% of those aged between 3 and 6 and in 54% of those older than 6 years of age. Overall percentage of VI was 9,4%.
Table 2

Ophthalmologic abnormalities in 46 patients

Pt

Sex

HSCR type

Age (m)

Ophthalmologic abnormality

Side

VI

Other anomalies

1

F

TCSA

146

Mild myopia

R

N

 

2

M

TCSA

12

Hyperopic astigmatism

B

N

 

3

M

TCSA

32

Moderate myopia

B

N

FMTC; CAKUT

4

M

TCSA

107

Hyperopic astigmatism

B

N

GH DEFICIENCY

5

F

TCSA

16

Hyperopic astigmatism

B

N

GUT ATRESIA

6

F

L-HSCR

11

Hyperopic astigmatism

B

N

 

7

F

L-HSCR

52

Severe hyperopic astigmatism

B

N

 

8

M

L-HSCR

30

Mixed astigmatism + opaque iris

B

N

ONDINE; CAKUT; CRYPTO; HI

9

M

L-HSCR

62

Hyperopic anisometropia + amblyopia + ptosis

L

Y

DOWN

10

F

S-HSCR

5

Hyperopia

B

N

 

11

M

S-HSCR

129

Hyperopic anisometropia + severe amblyopia

R

Y

CAKUT

12

F

S-HSCR

41

Hyperopia

B

N

 

13

M

S-HSCR

3

Hyperopic anisometropia

L

N

 

14

M

S-HSCR

37

Hyperopic astigmatism

R

N

 

15

M

S-HSCR

70

Hyperopic astigmatism

B

N

 

16

F

S-HSCR

26

Myopic astigmatic anisometropia

L

N

 

17

F

S-HSCR

30

Hyperopic astigmatism

B

N

 

18

M

S-HSCR

17

Hyperopic astigmatism

B

N

 

19

M

S-HSCR

4

Hyperopia

L

N

 

20

M

S-HSCR

133

Mixed astigmatism

B

N

FMTC

21

M

S-HSCR

5

Hyperopic astigmatism

B

N

 

22

M

S-HSCR

69

Hyperopic astigmatism

L

N

 

23

M

S-HSCR

76

Hyperopia

B

N

CAKUT

24

M

S-HSCR

26

Hyperopic astigmatism

B

N

CAKUT

25

M

S-HSCR

11

Hyperopic astigmatism

B

N

DOWN; CHD

26

M

S-HSCR

44

Hyperopic astigmatism + amblyopia

L

Y

 

27

M

S-HSCR

76

Hyperopic astigmatism

B

N

CAKUT; HI

28

F

S-HSCR

248

Myopia

B

N

CAKUT; HI

29

M

S-HSCR

16

Diverging strabismus

B

Y

CAT EYE; CHD; CAKUT; VI; EAR PIT

30

M

S-HSCR

3

Hyperopic astigmatism

B

N

 

31

M

S-HSCR

220

Mixed astigmatism

B

N

CAKUT

32

M

S-HSCR

54

Hyperopic astigmatism + mixed amblyopia

L

Y

 

33

M

S-HSCR

161

Myopic astigmatism

L

N

CRYPTO; HYPERTG

34

M

S-HSCR

288

Vertical strabismus

L

Y

OSTEOPOROSIS

35

M

S-HSCR

113

Myopic astigmatism

B

N

 

36

F

S-HSCR

290

Hyperopic astigmatism + strabismus

B

Y

DOWN; CHD; CAKUT

37

M

S-HSCR

77

Amblyopia

L

Y

 

38

M

S-HSCR

152

Severe myopia + converging strabismus

L

Y

DOWN; CHD

39

M

S-HSCR

109

Hyperopic astigmatism

B

N

ADHD

40

M

S-HSCR

154

Myopia

B

N

CAKUT; DYSLESSIA; CCA

41

M

S-HSCR

4

Hyperopic astigmatism

B

N

 

42

M

S-HSCR

101

Hyperopic astigmatism

B

N

 

43

M

S-HSCR

49

Hyperopia

B

N

CAKUT

44

M

S-HSCR

138

Hyperopic anisometropia

B

N

 

45

M

S-HSCR

142

Strabismus

B

Y

EARLY PUBERTY

46

M

S-HSCR

44

Hyperopic astigmatism

B

N

CAKUT

LEGEND: GH, Growth Hormone; ADHD, Attention Deficit Hyperactivity Disorder; CCA, Corpus Callosum Agenesis; B, Bilateral; L, Left; R, Right; VI, Visual impairment; Y, Yes; N, No.

Incidence of visual impairment was 9,4%.

Cakut

CAKUT were detected in 20,7% (95% CI, 14,1-29,4%) of the patients. Male to female ratio was 4,5:1. One patient had a clear familial history of CAKUT. We observed a total of 26 abnormalities with a slight right-sided preponderance (right to left ratio = 1,14:1) (Table 3 for details). Three patients had two or more co-existing CAKUT. Thirteen patients were diagnosed during the phenotype screening. In 7 patients CAKUT were symptomatic with urinary tract infections requiring medications (antibiotics either for treatment or prophylaxis) and long-term follow-up. Three patients required surgery.
Table 3

Details of 22 patients with CAKUT

ID

Sex

HSCR type

CAKUT

Side

Other anomalies

1

M

TIA

MCDK

R

 

2

F

TCSA

RH

B

HI

3

M

TCSA

RA

L

FMTC; VI

4

M

TCSA

VUR

B

 

5

M

L-HSCR

RH

R

ONDINE; CRYPTO; VI; HI

6

M

S-HSCR

RH

R

VI

7

M

S-HCSR

DCS

L

VI

8

M

S-HCSR

HN

B

VI

9

M

S-HCSR

HN

L

PALATE CLEFT

10

M

S-HSCR

VUR

R

EAR PIT

11

F

S-HCSR

RH + DCS

B

VI; HI

12

M

S-HCSR

RH

L

VI; HI

13

M

S-HCSR

VUR

B

CAT EYE; CHD; VI; EAR PIT

14

M

S-HSCR

RH

R

VI

15

F

S-HSCR

RH

B

 

16

M

S-HSCR

RH + HN

B

DOWN; CHD; VI

17

M

S-HSCR

VUR

R

 

18

M

S-HSCR

HN

B

VI; DISLESSIA; CCA

19

M

S-HSCR

HN

L

VI

20

M

S-HSCR

VUR + PUV + RH

R

 

21

F

S-HSCR

RH

R

VI

22

M

S-HSCR

VUR

L

DOWN; ATRESIA

Legend: TIA, Total Intestinal Aganglionosis; TCSA, Total colonic aganglionosis; L-HSCR, Aganglionosis extended between left transverse colon and the cecum; S-HSCR, Aganglionosis extending up to the splenic flexure; MCDK, Multicystic Dysplastic Kidney; RH, Renal hypoplasia; RA, Renal Asymmetry; HN, Hydronephrosis; VUR, Vesicoureteric Reflux; DCS, Duplex Collecting System; PUV, Posterior urethral valve; R, Right; B, Bilateral; L, Left; HI, Hearing impairment; FMTC, Familiar Medullary Thyroid Carcinoma; VI, Visual Impairment; CRYPTO, Cryptorchidism; CHD, Congenital Heart Disease; CCA, Corpus Callosum Agenesis.

Sixteen right and 14 left rental units were involved for a slight right side preponderance. Most of HSCR patients with CAKUT (17/22 = 77%) had further associated malformations.

Congenital heart diseases (CHD)

Major CHD were detected or confirmed during phenotype screening in 4,7% (95% CI, 2–10,6%) of the patients (Table 4 for details). Male to female ratio was 1,5:1. No positive family history was reported by any of the patients. CHD were represented by septal defects (either atrial or ventricular) in all patients but one. Four patients, all carrying chromosomal abnormalities, had severe CHD requiring surgical correction. In addition to the above-mentioned abnormalities, we detected ostium secundum type ASD in 4 patients and dilatation of the aortic sinus in 3. Those patients are being followed up in the long term. See Table 4 for details.
Table 4

Details of HSCR patients with CHD

Pt ID

Sex

Age (m)

HSCR type

Disease

Management

Other anomalies

1

F

12

TCSA

AC

Surgical intervention

TURNER

2

F

291

S-HSCR

ASD + VSD + MI

Surgical intervention

DOWN; CAKUT; VI

3

M

152

S-HSCR

ASD + VSD

Surgical intervention

DOWN; VI

4

M

15

S-HSCR

ASD + VSD

Surgical intervention

CAT EYE; CAKUT; VI; EAR PIT

5

M

3

S-HSCR

ASD + small VSD

F-UP

DOWN

 

M

26

S-HSCR

AS DIL.

F-UP

CAKUT; VI

 

M

52

L-HSCR

AS DIL.

F-UP

CAKUT; EAR PIT

 

M

134

S-HSCR

AS DIL.

F-UP

 
 

M

95

TCSA

ASD (OS)

F-Up

 
 

M

161

S-HSCR

ASD (OS)

F-Up

VI; IPERTG; CRYPTO

 

M

288

S-HSCR

ASD (OS)

F-Up

VI; OSTEOPOROSIS

 

M

40

S-HSCR

ASD (OS)

F-Up

DOWN

Legend: AC = Aortic Coarctation; ASD = Atrial Septal Defect; VSD = Ventricular Septal Defect; MI = Mitral Insufficiency; F-UP = Follow up; AS DIL. = Aortic Sinus Dilatation.

Five patients were diagnosed with major CHD (4.7%). Four patients required cardiac surgery. All patients with CHD suffered from chromosomal abnormalities (3 Down, 1 Cat Eye, and 1 Turner Syndrome). In addition to the above-mentioned abnormalities, we detected dilatation of the aortic sinus in 3 patients and ostium secundum type ASD in 4. All those patients are being followed up in the long term.

Hearing impairment (HI), deafness or ent anomalies

HI or deafness were reported in 4,7% (95% CI, 2–10,6%) of the patients with slight female preponderance. Two further patients (1,9%) had congenital preauricular fistulas (Ear pit) (Table 5 for details). No positive family history was reported by any of the patients. We observed the following HI: 3 sensorineural hypoacusia, 1 mixed sensorineural/conductive hypoacusia and 1 unilateral deaf. No bilateral involvement was reported. One patient had CCHS known to be potentially associated to HI. Four patients were diagnosed during the phenotype screening. In addition to the above-mentioned anomalies we could detect bilateral deep at frequencies higher than 8000 Htz in 3 patients and conductive HI in 12, mostly related to upper airways infections or mucous retention.
Table 5

Patients with hearing impairment, deafness or ENT anomalies

Pt

Sex

HSCR type

ORL disease

Side

Other anomalies

1

F

TCSA

Sensorineural hypoacusia

L

CAKUT

2

M

L-HSCR

Sensorineural hypoacusia

B

ONDINE; CAKUT; VI; TESTIS

3

F

S-HSCR

Sensorineural hypoacusia

B

 

4

M

S-HSCR

Preauricular fistula (Ear Pit)

L

CAT EYE; CAKUT; CHD; VI

5

M

S-HSCR

Anacusia

R

CAKUT; VI

6

M

S-HSCR

Preauricular fistula (Ear Pit)

L

CAKUT

7

F

S-HSCR

Mixed hypoacusia + conductive hearing loss

B

CAKUT; VI

Five patients (4.7%) had sensorineural hypoacusia or anacusia. Two further patients had minor ENT anomalies (Ear Pit). Six out of seven patients with auditory problems or ENT anomalies had other congenital abnormalities. Right to left ratio was 0,7:1 with slight left side preponderance.

Central nervous system abnormalities

Corpus callosum agenesis was detected in 2,3% (95% CI, 0,4-12,1%) of the patients (1 out of 43 HSCR patients who underwent cerebral US). No other major brain abnormalities were detected. We identified ventricle asymmetry or subarachnoid spaces dilatation in 7 patients (16%) all with left side involvement. Moreover, we detected a mild hydromielic spinal cavity in a patient who underwent MRI for other reasons and congenital thalamic calcifications of unclear aetiology in another.

Other associated anomalies

A further 18 associated anomalies have been detected in 12,3% (95% CI, 7,3-19,9%) of the patients from our series (12,3%). Amongst the various associated anomalies detected in our study outside the phenotype screening, endocrinologic and/or metabolic issues accounted for 4,7% of the patients (5/106), gastrointestinal abnormalities for 2,8% (3/106) and genital abnormalities and tumors (FMTC) for 1,9% each (2/106). One patient with severe developmental delay and one with corpus callosum agenesis underwent molecular genetic analysis of ZFHX1B/SIP1 to rule out Mowat-Wilson syndrome. See Table 6 for details.
Table 6

Other anomalies detected during the study

ID

Sex

HSCR type

Associated anomalies

Screening results

   

Chromosomal anomalies

 

1

F

TCSA

Down Syndrome

 

2

F

TCSA

Turner Syndrome

CHD

3

M

L-HSCR

Down Syndrome

VI

4

M

S-HSCR

Down Syndrome

CHD; VI

5

F

S-HSCR

Down Syndrome

CHD; CAKUT; VI

6

M

S-HSCR

Down Syndrome

CHD; VI

7

M

S-HSCR

Down Syndrome

 

8

M

S-HSCR

Down Syndrome

CAKUT

9

M

S-HSCR

Cat-Eye Syndrome

CHD; CAKUT; VI; HI

   

Metabolic issues

 

10

M

TCSA

GH deficiency

VI

11

M

S-HSCR

Familial Hyper-TG

VI

12

M

S-HSCR

Hypothyroidism

 

13

M

S-HSCR

Osteoporosis

VI

14

M

S-HSCR

Precocious Puberty

VI

   

Gastrointestinal abnormalities

 

15

F

TCSA

Gut Atresia

VI

16*

M

TCSA

Coeliac Disease

 

8

M

S-HSCR

Pancreas anularis

CHD; CAKUT

8

M

S-HSCR

Malrotation

CHD; CAKUT

   

Genital Abnormalities

 

17

M

L-HSCR

Cryptorchidism

CAKUT; HI; VI

11

M

S-HSCR

Cryptorchidism

VI

   

Tumors

 

18

M

TCSA

FMTC

CAKUT; VI

19

M

S-HSCR

FMTC

VI

   

Other Anomalies

 

16*

M

TCSA

Seizures

 

17

M

L-HSCR

Ondine Syndrome

CAKUT; HI; VI

20

M

S-HSCR

Cleft Palate

CAKUT

21*

M

S-HSCR

Dyslessia

CAKUT; VI; CCA

22

M

S-HSCR

ADHD

VI

Most of these anomalies were already known and occurred in association with other associated anomalies in a syndromic fashion.

Legend: FMTC = Familial Medullary Thyroid Carcinoma; ADHD, Attention Deficit Hyperactivity Disorder; CCHS, Congenital Central Hypoventilation Syndrome; CCA, Corpus Callosum Agenesis; * = Mowat-Wilson excluded.

Four patients had more than one associated anomaly detected outside the screening (pts number 8, 11, 16 and 17). The great heterogeneity of organs and systems is evident in our series of patients. Only 4 of these patients had no further anomalies detected during the study.

Syndromes

Chromosomal abnormalities or known syndromes (Down, Turner, Cat Eye, Congenital Central Hypoventilation Syndromes) have been detected in 9,4% (95% CI, 5,2-16,5%) of the patients (Table 6). The percentage of patients suffering from Down Syndrome in our series was 6,6% (95% CI, 3,2-13%). With regard to associated anomalies, syndromic HSCR patients proved to have a higher proportion of CHD compared to non-syndromic HSCR patients (p = 0,0001). Other associated anomalies have been detected more frequently in syndromic HSCR but the association proved not to be statistically significant (see Table 7 for details).
Table 7

Details of patients divided according to syndromic vs non-syndromic features

 

Syndromic, n (%, 95%CI)

Non-syndromic, n (%, 95% CI)

p

Patients, n

10 (9%, 5%-16%)

96 (91%, 83%-95%)

 

Median age

2,25

2,42

n.a.

Male to female ratio

2,33:1

3,57:1

0,6912

S-HSCR

6 (60%, 31%-83%)

73 (76%, 67%-83%)

0,2719

Other HSCR forms

4 (40%, 17%-69%)

23 (24%, 16%-33%)

VI

6 (60%, 31%-83%)

40 (41,7)

0,7918

CAKUT

4 (40%, 17%-69%)

18 (18,7)

0,2106

CHD

5 (50%, 24%-76%)

0 (0%, 0%-5%)

0,0001

HI

1 (10%, 18%-40%)

4 (4%, 2%-10%)

0,3968

CNS anomalies

0 (0%, 0%-33%)

1 (1%, 0,2%-57%)

1,000

OTHER

3 (30%, 11%-60%)

10 (10%, 6%-18%)

0,1044

Legend: n.a., Not assessed.

Although associated anomalies were encountered more frequently in syndromic patients, only CHD showed a statistically significant association.

Multiple associations

Thirty-one patients (29,2%) had ≥ 2 associated anomalies or chromosomal abnormalities. Twelve (11,3%) had ≥ 3 and 3 (2,8%) had ≥ 4. The latter patients all had known syndromes (Down, Cat Eye, and Congenital Central Hypoventilation Syndrome).

Discussion

This is the first prospective observational study aimed at defining the spectrum of possible phenotypes in a large cohort of HSCR patients. A reason why none previously addressed this issue probably relies on the rarity of the disease and on the difficulty to organize and perform such complex multidisciplinary prospective clinical assessments. In fact, literature reports regarding associated anomalies in HSCR are merely retrospective assessments of surgical series or systematic literature reviews [5, 9, 10].

The results of our study are remarkable and confirmed a measure of underestimation already suggested by some [5, 810, 26, 27]. In particular, we demonstrated that the percentage of associated anomalies is higher than expected with involvement of basically all organs and systems.

Delayed diagnosis or mild symptoms can explain the reason for such a discrepancy. In fact, refractive anomalies or visual impairment (VI), mild CAKUT or unilateral hearing impairment (HI) can be diagnosed with significant delay in the absence of specific screening programmes [8, 19, 28].

With regard to phenotype considerations, our study confirmed the high percentage of CAKUT in HSCR patients, as previously published [8]. In fact, despite some overlap of patients included in both studies (17% of cases), the percentage of associated CAKUT remained constantly high as well as the preponderance of hypoplasia, vesicoureteric reflux and hydronephrosis amongst detected malformations. Based on the results of our studies, we thus confirm that renal US should be included as a routine diagnostic investigation in all HSCR patients.

We could not detect any major ocular anomaly in our series of HSCR patients but nearly 10% of VI and more than 40% of refraction abnormalities. The latter are frequent in HSCR patients as well as in the general population. In 2009, the Baltimore Pediatric Eye Disease Study indicated in 0,7% the prevalence of myopia and nearly 9% that of hyperopia, in 1030 white Americans younger than 6 years of age [22]. Similarly, in 2011 the Sydney Pediatric Eye Disease Study examined 2461 children younger than 6 years of age and suggested an incidence of 6,4% of VI mostly due to refractive errors, amblyopia, and strabismus [23]. In 2008 Jobke and co-workers performed a population-based study on 516 German children, adolescent and young adults aged between 2 and 35 years and ended up with a prevalence of over 75% of emmetropia, nearly 20% myopia and 5% hyperopia [24]. Due to the heterogeneity of literature data regarding the general population, we can hardly determine the relative risk of HSCR patients of having refraction abnormalities. Nonetheless, based on embryologic considerations regarding the shared neural crest origin of enteric nervous system and specific ocular structures and on the relatively high percentage of patients with refractive errors and VI observed in our study, we strongly recommend to perform routine ophthalmologic assessments (as those performed in the general population) in order to early detect and prevent VI, in accordance to WHO suggestions [28, 29].

The prevalence of major or moderate CHD has been reported to be around 7,2 per 1000 live birth in the general population [30], whereas the proportion of CHD in HSCR patients has been reported to be around 5%, according to literature [5, 9, 10]. We could basically confirm these data (4,7% in our series). In particular, CHD detected during phenotype screening mostly occurred in patients with chromosomal abnormalities and were essentially represented by septal defects. This is in accordance with the embryologic role of NCN in the development of both enteric nervous system and cardiac outflow septation [31]. On the other hand, none of the patients presented conotruncal heart defects, whose pathogenesis is similarly related to the abnormal neural crest cell proliferation and migration [31]. The percentage of minor CHD or trivial lesions without clinical significance in our series accounted for another 6,6% of patients, well within literature ranges [30]. Based on these results we do suggest performing cardiac US only in the subpopulation of known or suspected syndromic HSCR patients.

In the general population, the incidence of HI in subjects without audiological risk factor is around 1,5‰, whereas that of subjects with audiological risk factors is 4,5% [32, 33]. With specific regard to HSCR patients, syndromic HI can be found in patients with Waardenburg-Shah type 4, due to mutations of SOX10 gene [5, 9, 10]. Of note in 1973 Skinner described 4 patients with congenital deafness and HSCR and suggested that this association could not be fortuitous but based on shared embryological background as only one case had known risk factors for HI (streptomycin administration) [34]. Based on these considerations and on the results of our study (4,7% of HI), we recommend that HSCR itself should be included amongst risk factors for HI. Subsequently HSCR patients should undergo specific audiologic screening programmes as those suggested by the Joint Committee of Infant Hearing in 2007 [19].

Although Moore reported a relatively high proportion of brain abnormalities in HSCR patients, we could only confirm a case of corpus callosum agenesis in a patient of ours who was already diagnosed with prenatal US [10, 26]. The child had no further syndromic features and a near-normal neurologic development (mild dyslexia). In our series of patients we could also detect some ventricle asymmetry and subarachnoid spaces dilatations that were found in less than 20% of cases, mostly on the left hand side. Of note, asymmetry between the sizes of the ventricles can be observed in up to 40% of healthy infants, being the left ventricle often larger than the right [25]. Based on these results and in accordance with literature data, we do not recommend performing routine cerebral US in all HSCR patients but only in those with clear syndromic features who have higher likelihood of carrying cerebral malformations (i.e. Mowat-Wilson Syndrome) [10, 26, 35].

Amongst other associated anomalies (Table 6) tumors were exclusively represented by FMTC, well known to be associated with specific genotypes at the RET gene locus in HSCR patients [7]. As expected, after testing for mutations of the RET gene (data not shown), we could verify that the two patients of our panel who are affected with HSCR + FMTC syndromic association are indeed carriers of the p.C609Y and p.Y791F mutations, respectively. These mutations have already been reported in association with this combined phenotype and also described as “Janus mutations” [36].

The percentage of anomalies that could have been tracked down retrospectively by notes reviews or questionnaire administration resembles that of literature reports [5, 9, 10]. In fact, 26,4% of patients was already aware of their association when they entered our screening programme. This aspect further confirms the reliability of our results and that a deeper clinical screening could have detected the missed associated anomalies (“the more you look for, the more you find”).

Besides providing a novel view on clinical associations and variable symptoms of HSCR disease in children, the present data prompt us to deepen into follow-up data from adults who were treated for HSCR, which are lacking at the moment. Indeed, we cannot exclude that additional organs or systems can be involved and become impaired later in adult life. Indeed, typical adulthood associated diseases have not been described yet and are unknown at the moment. For instance, association with specific cancers, nervous degeneration, intestinal chronic inflammation and/or other late-onset disorders cannot be ruled out and further investigation in an adult set of HSCR patients would be advisable.

Our Institution is known to be a referral centre for HSCR with an intrinsic subsequent risk of inclusion BIAS. This concern was confirmed by the higher than expected percentage of ultralong forms of the disease in our series (17,9%). Nonetheless, given the fact that the percentage and type of associated anomalies did not correlate to gender or length of aganglionosis, the results of our study maintained their strength. Furthermore, the percentage of Down Syndrome as well as the strong male preponderance observed in our series of patients are coherent with literature data and confirm that the results of our study are representative of the whole HSCR population [5, 9, 10].

The relatively small population of this observational study represents another potential limitation. As a consequence, the estimates we could provide have the intrinsic limitation of a wide variability and should be taken with care (see Tables 1 and 7 for details). Nonetheless, HSCR is a rare disease and the number of patients enrolled in such a relatively small time-span implies strong commitment and a multidisciplinary approach that deserve consideration.

It is evident that the implementation of a prospective multicentre research project is warranted. In fact, a larger series of patients could increase the strength of the results and possibly confirm the cost-effectiveness of this proposed diagnostic algorithm for a significant change in clinical practice for HSCR management (Figure 1).
Figure 1

Proposed diagnostic workup for patients with a reliable diagnosis of Hirschsprung’s disease. Algorithm changes according to the present of sure or suspected chromosomal abnormalities.

Conclusions

Based on the results of our study, we suggest performing US of the kidney and urinary tract as well as audiologic investigation in all cases, whereas heart US, cardiologic assessment, cerebral US and ophthalmologic assessment should be performed basing on clinical features and according to the standards of care adopted for the general population. On the other hand, all investigations should be considered for patients with known or suspected syndromes or chromosomal abnormalities in order to promptly apply specific prevention strategies, as we already suggested (i.e. preoperative prophylactic stoma and postoperative rectal irrigations in case of associated CHD) [37]. Figure 1 shows a suggested diagnostic algorithm. It includes early clinical genetic assessment in order to detect symptoms and signs suggestive of syndromes that would lead to further investigations.

Early diagnosis of associated anomalies provides more reliable prognostic expectations, prompt establishment of prevention strategies and implementation of adequate rehabilitation treatments. In accordance to our previous publication and to present results, we hypothesize that intestinal aganglionosis in HSCR patients represents the intestinal phenotype of a more complex syndrome driven by the interaction of neural crest maldevelopment and predisposing genetic background [5, 710, 29, 31]. The investigation of genetic background of individuals presenting with associated anomalies might be the next step to explore this intriguing multifactorial congenital disease.

Abbreviations

HSCR: 

Hirschsprung

NCN: 

neural crest derived neuroblasts

CAKUT: 

Congenital anomalies of the Kidney and Urinary Tract

US: 

Ultrasound scan

ENT: 

Ear nose and throat

NICU: 

Neonatal intensive care unit

HI: 

Hearing impairment

AABR: 

Automated auditory brainstem response

VRA: 

Visual reinforcement audiometry

CPA: 

Conditioned play audiometry

CA: 

Conventional audiometry

VI: 

Visual impairment

VA: 

Visual acuity

CCHS: 

Congenital central hypoventilation syndrome

CHD: 

Congenital heart disease.

Declarations

Acknowledgements

This research project was founded by the Italian Ministry of Health with Young Researcher Grant (Bando Giovani Ricercatori GR-2008-1135082) and Cinque per Mille and Ricerca Corrente funding. PG is supported by a Fellowship of Fondazione Veronesi. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Authors’ Affiliations

(1)
Department of Pediatric Surgery, Istituto Giannina Gaslini
(2)
DINOGMI, Università di Genova
(3)
Department of Health Science, Biostatistics Section, Università di Genova
(4)
UOC Medical Genetics, Istituto Giannina Gaslini
(5)
Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center
(6)
Department of Medical Biotechnologies and Translational Medicine, University of Milan
(7)
Cardiovascular Department, Istituto Giannina Gaslini
(8)
Radiology Unit, Istituto Giannina Gaslini
(9)
Nephrology Unit, Istituto Giannina Gaslini
(10)
Ophthalmology Unit, Istituto Giannina Gaslini
(11)
Otorhinolaryngology Unit, Giannina Gaslini Institute

References

  1. Puri P, Montedonico S: Hirschsprung’s disease: clinical features. Hirschsprung’s disease and allied disorders. Edited by: Holschneider A, Puri P. Berlin Heidelberg: Springer Verlag; 2008: 107-114.View ArticleGoogle Scholar
  2. Goldstein AM, Hofstra RM, Burns AJ: Building a brain in the gut: developmentof the enteric nervous system. Clin Genet. 2013, 83 (4): 307-316. 10.1111/cge.12054.PubMed CentralPubMedView ArticleGoogle Scholar
  3. Bolande RP: The neurocristopathies; a unifying concept of disease arising in neural crest maldevelopment. Hum Pathol. 1973, 5: 409-429.View ArticleGoogle Scholar
  4. Kuo BR, Erickson CA: Regional differences in neural crest morphogenesis. Cell Adh Migr. 2010, 4 (4): 567-585. 10.4161/cam.4.4.12890.PubMed CentralPubMedView ArticleGoogle Scholar
  5. Amiel J, Sproat-Emison E, Garcia-Barcelo M, Lantieri F, Burzynski G, Borrego S, Pelet A, Arnold S, Miao X, Griseri P, Brooks AS, Antinolo G, de Pontual L, Clement-Ziza M, Munnich A, Kashuk C, West K, Wong KK, Lyonnet S, Chakravarti A, Tam PK, Ceccherini I, Hofstra RM, Fernandez R: Hirschsprung disease consortium. Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet. 2008, 45 (1): 1-14.PubMedView ArticleGoogle Scholar
  6. Newgreen D, Young HM: Enteric nervous system: development and developmental disturbances, part 1. Pediatr Dev Pathol. 2002, 5 (3): 224-247.PubMedGoogle Scholar
  7. Lantieri F, Griseri P, Amiel J, Martucciello G, Ceccherini I, Romeo G, Lyonnet S: The molecular genetics of Hirschsprung’s disease. Hirschsprung’s disease and allied disorders. 3rd edition. Edited by: Holschneider A, Puri P. Berlin Heidelberg: Springer Verlag; 2008: 63-78.View ArticleGoogle Scholar
  8. Pini Prato A, Musso M, Ceccherini I, Mattioli G, Giunta C, Ghiggeri GM, Jasonni V: Hirschsprung disease and congenital anomalies of the kidney and urinary tract, a novel syndromic association. Medicine (Baltimore). 2009, 88 (2): 83-90. 10.1097/MD.0b013e31819cf5da.View ArticleGoogle Scholar
  9. Amiel J, Lyonnet S: Hirschsprung disease, associated syndromes, and genetics: a review. J Med Genet. 2001, 38 (11): 729-739. 10.1136/jmg.38.11.729.PubMed CentralPubMedView ArticleGoogle Scholar
  10. Moore SW: The contribution of associated congenital anomalies in understanding Hirschsprung’s disease. Pediatr SurgInt. 2006, 22 (4): 305-315.Google Scholar
  11. Martucciello G, Pini Prato A, Puri P, Holschneider AM, Meier-Ruge W, Jasonni V, Tovar JA, Grosfeld JL: Controversies concerning diagnostic guidelines foranomalies of the enteric nervous system: a report from the fourth InternationalSymposium on Hirschsprung’s disease and related neurocristopathies. J Pediatr Surg. 2005, 40 (10): 1527-1531. 10.1016/j.jpedsurg.2005.07.053.PubMedView ArticleGoogle Scholar
  12. Henry WL, Ware J, Gardin JM, Hepner SI, McKay J, Weiner M: Echocardiographic measurements in normal subjects. Growth related changes that occur between infancy and early adulthood. Circulation. 1978, 57: 278-285. 10.1161/01.CIR.57.2.278.PubMedView ArticleGoogle Scholar
  13. Daubeney PE, Blackstone EH, Weintraub RG, Slavik Z, Scanlon J, Webber SA: Relationship of the dimension of cardiac structure to body surface size: an echocardiographic study in normal infants and children. Cardiol Young. 1999, 9: 402-410.PubMedView ArticleGoogle Scholar
  14. Pettersen MD, Skeens ME, Humes RA: Regression equations for calculation of Z scores of cardiac structures in a large cohort of healthy infants, children, and adolescents: an echocardiographic study. J Am Soc Echocardiogr. 2008, 21: 922-934. 10.1016/j.echo.2008.02.006.PubMedView ArticleGoogle Scholar
  15. Devereux RB, Lutas EM, Casale PN, Kligfield P, Eisenberg RR, Hammond IW, Miller DH, Reis G, Alderman MH, Laragh JH: Standardization of M-Mode Echocardiographic left ventricular anatomic measurements. J Am Coll Cardiol. 1984, 4: 1222-1230. 10.1016/S0735-1097(84)80141-2.PubMedView ArticleGoogle Scholar
  16. Pearlman JD, Triulzi MO, King ME, Newell J, Weyman AE: Limits of normal left ventricular dimensions in growth and development: analysis of dimensions and variance in the two-dimensional Echocardiograms of 268 normal healthy subjects. J Am Coll Cardiol. 1988, 12: 1432-1441. 10.1016/S0735-1097(88)80006-8.PubMedView ArticleGoogle Scholar
  17. Nidorf SM, Picard MH, Triulzi MO, Thomas JD, Newell J, King ME, Weyman AE: New perspectives in the assessment of cardiac chamber during devolopment and adulthood. J Am Coll Cardiol. 1992, 19: 983-988. 10.1016/0735-1097(92)90282-R.PubMedView ArticleGoogle Scholar
  18. O’Leary PW, Durongpisitkul K, Cordes TM, Bailey KR, Hagler DJ, Tajik J, Seward JB: Diastolic ventricular function in children: a Doppler echocardiographic study establishing normal values and predictors of increased ventricular end-diastolic pressure. Mayo Clin Proc. 1998, 73: 616-628. 10.1016/S0025-6196(11)64884-2.PubMedView ArticleGoogle Scholar
  19. American Academy of Pediatrics, Joint Committee on Infant Hearing: Year 2007position statement: principles and guidelines for early hearing detection andintervention programs. Pediatrics. 2007, 120 (4): 898-921. ex 15.View ArticleGoogle Scholar
  20. Patel H, Feldman M: Universal newborn hearing screening. Pediatr Child Health. 2011, 16 (5): 301-310.Google Scholar
  21. Paludetti G, Conti G, DI Nardo W, DE Corso E, Rolesi R, Picciotti PM, Fetoni AR: Infant hearing loss: from diagnosis to therapy Official Report of XXIConference of Italian Society of Pediatric Otorhinolaryngology. Acta Otorhinolaryngol Ital. 2012, 32 (6): 347-370.PubMed CentralPubMedGoogle Scholar
  22. Giordano L, Friedman DS, Repka MX, Katz J, Ibironke J, Hawes P, Tielsch JM: Prevalence of refractive error among preschool children in an urban population: the baltimore pediatric eye disease study. Ophthalmology. 2009, 116 (4): 739-746. 10.1016/j.ophtha.2008.12.030.PubMed CentralPubMedView ArticleGoogle Scholar
  23. Pai AS, Wang JJ, Samarawickrama C, Burlutsky G, Rose KA, Varma R, Wong TY, Mitchell P: Prevalence and risk factors for visual impairment in preschool children. Ophthalmology. 2011, 118: 1495-1500. 10.1016/j.ophtha.2011.01.027.PubMedView ArticleGoogle Scholar
  24. Jobke S, Kasten E, Vorwerk C: The prevalence rates of refractive errors among children, adolescents and adults in Germany. Clin Ophthalm. 2008, 2 (3): 601-607.View ArticleGoogle Scholar
  25. Lowe LH, Bailey Z: State-of-the-art cranial sonography: part 2, pitfalls and variants. Am J Roentgenol. 2011, 196 (5): 1034-1039. 10.2214/AJR.10.6203.View ArticleGoogle Scholar
  26. Moore SW: Hirschsprung’s disease and the brain. Pediatric Surg Int. 2011, 27: 347-352. 10.1007/s00383-010-2807-y.View ArticleGoogle Scholar
  27. Ahola J, Koivusalo A, Sairanen H, Jokinen E, Rintala R, Pakarinen M: Increased incidence of Hirschsprung’s disease in patients with hypoplastic left heart syndrome- a common neural crest–derived etiology?. J Pediatr Surg. 2009, 44: 1396-1400. 10.1016/j.jpedsurg.2008.11.002.PubMedView ArticleGoogle Scholar
  28. Resnikoff S, Pascolini D, Mariotti S, Pokharel GP: Global magnitude of visual impairment caused by uncorrected refractive errors in 2004. Bull WHO. 2008, 86 (1): 63-70.PubMed CentralPubMedGoogle Scholar
  29. Creuzet S, Vincent C, Couly G: Neural crest derivatives in ocular and periocular structures. Int J Dev Biol. 2005, 49: 161-171. 10.1387/ijdb.041937sc.PubMedView ArticleGoogle Scholar
  30. Dolk H, Loane M, Garne E: European surveillance of congenital anomalies (EUROCAT) working group. Congenital heart defects in Europe: prevalence and perinatal mortality, 2000 to 2005. Circulation. 2011, 123 (8): 841-849. 10.1161/CIRCULATIONAHA.110.958405.PubMedView ArticleGoogle Scholar
  31. Scoll AM, Kirby ML: Signals controlling neural crest contributions to the heart. Wiley Interdiscip Rev Syst Biol Med. 2009, 1 (2): 220-227. 10.1002/wsbm.8.View ArticleGoogle Scholar
  32. Ghirri P, Liumbruno A, Lunardi S, Forli F, Boldrini A, Baggiani A, Berrettini S: Universal neonatal audiological screening: experience of the University Hospital of Pisa. Ital J Pediatr. 2011, 37: 16. 10.1186/1824-7288-37-16.PubMed CentralPubMedView ArticleGoogle Scholar
  33. Gaffney M, Green DR, Gaffney C: Newborn hearing screening and follow-up: are children receiving recommended services?. Public Health Rep. 2010, 125 (2): 199-207.PubMed CentralPubMedGoogle Scholar
  34. Skinner R, Irvine D: Hirschsprung’s disease and congenital deafness. J Med Genet. 1973, 10: 337-339. 10.1136/jmg.10.4.337.PubMed CentralPubMedView ArticleGoogle Scholar
  35. Glass HC, Shaw GM, Ma C, Sherr EH: Agenesis of the corpus callosum in California 1983–2003: a population-based study. Am J Med Genet A. 2008, 146A (19): 2495-2500. 10.1002/ajmg.a.32418.PubMed CentralPubMedView ArticleGoogle Scholar
  36. Arighi E, Popsueva A, Degl’Innocenti D, Borrello MG, Carniti C, Perälä NM, Pierotti MA, Sariola H: Biological effects of the dual phenotypic Janus mutation of ret cosegregating with both multiple endocrine neoplasia type 2 and Hirschsprung’s disease. Mol Endocrinol. 2004, 18 (4): 1004-1017. 10.1210/me.2003-0173.PubMedView ArticleGoogle Scholar
  37. Pini Prato A, Rossi V, Avanzini S, Mattioli G, Disma N, Jasonni V: Hirschsprung’s disease: what about mortality?. Pediatr Surg Int. 2011, 27 (5): 473-478. 10.1007/s00383-010-2848-2.PubMedView ArticleGoogle Scholar

Copyright

© Pini Prato et al.; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Advertisement