Archives ofDisease in Childhood 1992; 67: 178-183

A clinical study of Noonan syndrome

M Sharland, M Burch, W M McKenna, M A Paton

AbstractClinical details are presented on 151 indi-viduals with Noonan syndrome (83 malesand 68 females, mean age 12-6 years). Poly-hydramnios complicated 33% of affectedpregnancies. The commonest cardiac lesionswere pulmonary stenosis (62%), and hyper-trophic cardiomyopathy (20%), with a normalechocardiogram present in only 12-5% of allcases. Significant feeding difficulties duringinfancy were present in 76% of the group.Although the children were short (50% with aheight <3rd centile), and underweight (43%with a weight <3rd centile), the mean headcircumference of the group was on the 50thcentile. Motor milestone delay was usual, thecohort having a mean age of sitting unsup-ported of 10 months and walking of 21months. Abnormal vision (94%) and hearing(40%) were frequent findings, but 89% of thegroup were attending normal primary orsecondary schools. Other associations in-cluded undescended testicles (77%), hepato-splenomegaly (50%), and evidence ofabnormal bleeding (56%). The mean age atdiagnosis of Noonan syndrome in this groupwas 9 0 years. Earlier diagnosis of this com-mon condition would aid both clinical man-agement and genetic counselling.

St George's HospitalMedical School,London, South WestThames RegionalGenetic ServiceM SharlandM A PattonDepartment ofCardiological SciencesM BurchW M McKennaCorrespondence and requestsfor reprints to:Dr M Sharland,South West Thames RegionalGenetic Service,St George's HospitalMedical School,Cranmer Terrace,Tooting, London SW17 ORE.Accepted 13 September 1991

Nine patients with a characteristic facies,valvular pulmonary stenosis, and short staturewere first reported by Dr Jacqueline Noonan in1963.1 Her subsequent paper described 19patients (12 males and seven females) with a

typical facies, congenital heart disease, andclinical features of Turner's syndrome withnormal chromosomes.2 These papers ended an

era of confused terminology surrounding theindividual with a Turner phenotype. Turneroriginally reported a series of older women withwebbed neck, short stature, cubitus valgus, andsexual infantilism in 1938.3 Ullrich had inde-pendently recognised both males and femaleswith a similar phenotype which he named statusBonnevie Ullrich, after Bonnevie's work on

mice.4 It was only after Ford et al had identifiedthe karyotype 45X in a patient with the diagnosisof Turner's syndrome that a clear division was

made between Turner's syndrome (45X, femaleonly) and Noonan syndrome (normal karyo-type, equal sex incidence).5 Considerable differ-ences between the two disorders are now welldocumented.

Recent excellent reviews of Noonan syn-drome have been produced and have commentedon areas of limited knowledge.6 These included

difficulty in making the clinical diagnosis, thelack of a diagnostic biochemical marker, noclear advice about management or outcome, andthe absence of simple recurrence risks in geneticcounselling. This study was undertaken in anattempt to answer some of these questions. Afurther aim was to identify pedigrees suitablefor linkage analysis, in an attempt to map thegene for Noonan syndrome.

MethodsConsultant paediatricians, paediatric cardio-logists, and clinical geneticists in the UK werecontacted and asked for names of patients undertheir care with Noonan syndrome. Permissionto approach over 400 individuals was obtained.The first 200 patients ascertained were thencontacted and invited to participate in theresearch. If the family was willing to help withthe project, all first degree relatives were askedto visit St George's Hospital for one day.Travelling expenses were paid if necessary in anattempt to remove a social class bias. Theascertained proband and all first degree relativesunderwent a standardised symptom review andclinical examination. Echocardiography andclinical photography were performed on all thefamily members. Blood was taken for DNAstudies. Further specific examinations wereperformed on different cohorts during theproject. These included abdominal ultrasound,orthoptic and ophthalmological examination,coagulation studies, and speech therapy assess-ment.

ResultsA clinical diagnosis of Noonan syndrome wasmade in a total of 151 individuals (83 males and68 females) derived from 123 families. The agerange of the patients was from one week to 60years (mean 12-6 years). Data were obtainedfrom family questionnaires, clinical examination,and specific investigations.

OBSTETRIC DATAThe mean gestational age at delivery was 39weeks. A clinical diagnosis of polyhydramnioshad been made in 43 of the 130 pregnancieswhose obstetric details were available (33%).The mode of delivery had been ascertained in149 pregnancies. A normal vaginal deliveryoccurred in 103 cases (69%), a forceps deliverywas performed in 13 cases (9%), and a caesareansection in 32 cases (21%). The birth weight wasavailable for 114 babies born at term (38-42

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weeks) and had a mean (SD) of 3450 (510) g.The majority of parents had recognised thattheir baby was generally oedematous at birth,and lost excessive weight over the first week oflife, but this was not possible to quantify.

CARDIAC DATACorrective cardiac surgery had been performedon 31 individuals at the time of the project. All151 probands had echocardiograms performed.The following data are also derived from echo-cardiograms performed by regional cardiacunits before corrective surgery. Pulmonarystenosis was detected in 93 cases (62%) and wasusually due to a dysplastic pulmonary valve.The pulmonary stenosis was an isolated lesionin 65 cases (43%), associated with an atrial,ventricular, or atrioventricular septal defect in20 cases (13%), and with hypertrophic cardio-myopathy in a further eight cases (6%). Hyper-trophic cardiomyopathy, including asym-metrical septal hypertrophy, was present in 20%of the study group. It was found as an isolatedlesion in 19 cases (13%), and in two cases wasassociated with a patent ductus arteriosus.Three children had undergone surgical myo-mectomy, and two further children had requiredcardiac transplantation for severe heart failurein infancy. Other cardiac findings includedisolated septal defects (nine cases) and mitralvalve prolapse (four cases). Only 19 individuals(12-5%) had normal echocardiograms.

FACIAL CHANGESThe predominant facial features of Noonansyndrome seen in this group were hypertelorism,down slanting palpebral fissures with higharched eyebrows, epicanthic folds, full upperlip, depressed nasal root with a wide nasal base,and low set ears with a thickened helix. Severeptosis (either unilateral or bilateral) was presentin 63 individuals (42%). Obvious webbing ofthe skin of the neck (excluding the commonapparent neck shortening) was present in only34 cases (23%). The characteristic facial changesof children with Noonan syndrome at varyingages are demonstrated in fig 1, 2, and 3.

FEEDING DIFFICULTIESFeeding histories were obtained in 144 cases.There were no significant feeding difficulties in35 cases (24%). Mild feeding problems (definedas the infant having a poor suck, with each feedtaking on average over an hour to complete)were reported in 21 cases (15%). Moderatefeeding difficulties (defined as a very poor suck,with slow feeding and recurrent vomiting withmost feeds) were reported in 54 cases (38%).Severe feeding problems (defined as requiringtube feeding for two weeks or longer in a terminfant) were found in 34 cases (24%).

DEVELOPMENTAL DATAThe age at which the child first sat unsupportedwas known in 126 cases, and had a mean (SD)age of 10 (4-5) months. The time of first

Figure I Child with Noonan syndrome aged 2years.

Figure 2 Child with Noonan syndrome aged 4years.

walking unsupported was available for 112cases, and had a mean (SD) age of 21 (10-2)months. The age at which the child could firsttalk in simple two word sentences was known in102 children, and had a mean (SD) age of 31(9-6) months.

Hearing tests had been performed on 146 ofthe group and hearing loss was reported in 58(40%). In the great majority this was due to

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Sharland, Burch, McKenna, Paton

Centile:

LII <3rdM 3rdE3 10th

a 25thE3 50th* 75th

Figure 4 Height compared with nortnal centiles: percentageoftotal group.

Figure 3 Child with Noonan syndrome aged 8years.

serous otitis media. Nerve deafness requiringhearing aids had been detected in five children(3%).

Tests of vision had been performed on 145individuals. These were reported as abnormal in80 (55%). Because of this high figure, a cohortof 52 consecutive individuals underwent fullorthoptic and ophthalmological evaluationduring the sudy day. Strabismus was detectedin 33 (63%) with 16 (31%) demonstratingamblyopia. Significant refractive errors (bothmyopia and hypermetropia) were present in 35(67%). Only three (6%) of the cohort had anormal eye examination.One hundred individuals were of school age

or older. Of these, 84 individuals either wereattending or had attended a normal primary orsecondary school. A further five childrenattended a school for the physically handi-capped. Only 11 children required schooling ata school for the educationally subnormal (11%).

GROWTHThe height, weight, and head circumferencedata were compared with normal centiles. Thedata were plotted on Tanner and Whitehousecharts and the closest centile was recorded. Theresults are shown for height (fig 4), weight (fig5), and head circumference (fig 6). Twelve ofthe study population were receiving biosynthe-tic growth hormone treatment at the time of thestudy, and growth data was utilised from beforethe treatment was commenced. Bone age(measured by the standard Greulich and Pylemethod) was assessed in 37 cases. The mean(SD) delay of the bone age behind chronologicalage was 2-0 (1-36) years.

Undescended testicles were detected in 64 outof 83 males (77%). Puberty was delayed in both

^~~~~~~~~~~~~~......-- ---- --- -- is E = = EE iiiEx::::::::::::::::::: Cen==EEEr 1z tile

\:::::::::::::::::::::::::::::::::::::: <== =-

< _ ED >~~~~~97th

Figure 6 Head circumference compared with normalcentiles: percentage oftotal group.

sexes. The mean (SD) age of menarche in 20women was 14-6 (1-17) years. In the menpuberty was reported as being significantlydelayed and prolonged, but accurate data werenot available retrospectively.

HISTORY OF BLEEDINGEasy bruising and bleeding were frequentlyreported by the study group. Bleeding historieswere defined as normal, mild, moderate, orseverely abnormal. Mildly abnormal bleedingwas defined as easy bruising, with raised bruises>5 cm in diameter occurring over the wholebody after minor trauma. Moderately abnormal

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bleeding was defined as major bruising occurringafter surgery (for example, orchidopexy orcardiac catherisation) or postoperative bleedinglasting for over 24 hours (for example, afterdental extraction). Major abnormal bleedingwas defined as a life threatening haemorrhagerequiring emergency blood transfusion. Anormal history was found in 63 cases (42%). Amildly abnormal history was given by 51 patients(34%), moderately abnormal by 32 patients(21%), and a severe haemorrhage had occurredin five patients (3%).

ABDOMENHepatosplenomegaly unexplained by cardiacfailure was a common clinical finding in thetotal group (26%). This was more prominent inyounger children and decreased with age. Therehad been no case of hepatic dysfunction associ.ated with the organomegaly. A further cohort of45 consecutive patients subsequently under-went abdominal ultrasound examination. Signi-ficant hepatosplenomegaly was detected in 23cases (51%) with renal abnormalities seen inonly five cases (11%). In one child of mono-zygotic twins, abdominal ultrasound revealed acholedochal cyst. An ultrasound of the secondtwin was normal.

ORTHOPAEDIC ABNORMALITIESThe classical sternal change seen in Noonansyndrome (pectus carinatus superiorly andpectus excavatum inferiorly) was present in 144out of 151 cases (95%). A thoracic scoliosis wasdetected in 20 individuals (13%) but in no casehad this required medical or surgical treatment.Other orthopaedic abnormalities includedtalipes equinovarus (12%), joint contractures(4%), radioulnar synostosis (2%), and cervicalspine fusion (2%).

NEUROMUSCULAR ABNORMALITIESSignificantly abnormal joint hyperextensibilitywas found in 75 cases (50%). Hypotonia wasalso a common clinical finding. Serum creatinekinase was measured in a cohort of 35 consecu-tive patients. All concentrations were in thenormal range for age and sex, and had a mean of60 5 IU/1.

Recurrent convulsions had occurred in 20individuals (13%). These were grand malseizures in 14 cases (9%), temporal lobe epilepsyin four cases (3%), and febrile convulsions intwo cases (1-5%). An unexplained peripheralneuropathy leading to distal weakness andaltered sensation was detected in three adultsand one child. Cervical cord compression hadbeen excluded in all cases, and investigation hadfailed to reveal any cause for the neurologicalfindings.

SKIN CHANGESA considerable range of ectodermal changeswas found. Ulerythema ophryogenes is asevere follicular keratosis previously noted to beassociated with Noonan syndrome.8 It occurs

predominantly on the extensor surfaces and theface, where it may lead to absent eyebrows.This particular dermatological appearance wasseen in 21 cases (14%). The hair in Noonansyndrome has previously been described aseither thick and curly or thin and sparse.9Normal hair was present in 91 cases (60%),thick and curly hair in 44 cases (29%), andsparse hair was present in 16 cases (11%). Themost useful skin sign was an extra prominenceon the pads of all fingers and toes (fetal pads),which was present in 101 cases (67%). Multiplelentigines (over 100 counted on the trunk) werepresent in five cases (3%).

OTHER ASSOCIATIONSAbnormalities in the lymphatic system were notcommon, apart from minor pedal lymphoedema.One case each was documented of lymphaticdysplasia on the lip,'0 a lymphatic cyst in theneck, and pulmonary lymphangiectasia. Hypo-thyroidism had been documented in six cases.Antimicrosomal thyroid antibodies weremeasured in 23 consecutive asymptomatic casesand were positive in seven (30%). Evidence of afurther autoimmune dysfunction was providedby one case each of vasculitis, vitiligo, andanterior uveitis. Evidence of a possible im-munodeficiency was suggested by frequent lowerrespiratory infections, and one case each of abrain abscess, bacterial endocarditis, andosteomyelitis. The differences in clinical pheno-type between individuals with and without anaffected first degree relative were studied usingx2 analysis of eight variables. No significantdifference was observed between the two groupswith respect to incidence of cardiac disease,developmental delay, epilepsy, or neck webbing.However, individuals without an affectedparent with Noonan syndrome, did have asignificandy increased incidence of short stature(p<0-01), skeletal abnormalities (p<0-01),hepatosplenomegaly (p<0-01), and sparse hair(p<O-Ol).

DiscussionThe incidence of Noonan syndrome in the UKpopulation is unknown. It may be the secondcommonest syndrome associated with congenitalheart disease after Down's syndrome. Previousreviews have suggested an incidence of betweenone in 1000 and one in 2000 of the population.6 7Considering the frequency and importance ofNoonan syndrome, surprisingly few clinicalstudies have been reported. A total of sixcomplete studies have been performed, givingdetails on some aspects of the phenotype in 216patients. 11-15

Short stature in Noonan syndrome has beenwell defined on retrospective data and centilecharts are available. 6 17 This study has demon-strated clearly that the growth reduction seen inNoonan syndrome is the same for both heightand weight. It is interesting, however, that thehead circumferences of this group were normallydistributed, as macrocephaly has been reportedpreviously.6 The high incidence of cardiacanomalies in this group may have been due to

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182 Sharland, Burch, McKenna, Paton

the continued reluctance to make a diagnosis ofNoonan syndrome in the absence of congenitalheart disease. Pulmonary stenosis has been thecommonest cardiac abnormality reported in allprevious studies, with a frequency between25-90%. Hypertrophic cardiomyopathy isincreasingly recognised by echocardiography,and its frequency in this group (20%) is twicethat previously reported in studies using angio-graphy. 3 A further important point to behighlighted from this study is the low incidenceof significant renal abnormalities in Noonansyndrome compared with Turner's syndrome. 18Musculoskeletal changes have been recognisedas an important component of the syndrome.However previous reports of an associationbetween Noonan syndrome and malignanthyperpyrexia have not been confirmed in thisseries. 19 20 Hypotonia and hyperextensibility inthe younger child probably explain much of theearly delay in motor milestones. Developmentaloutcome in the older child does not seem toconfirm earlier reports of frequent mentalretardation.2 11 12 Hopkins-Acos and Bunkermade the relevant point that speech delay maybe related to hearing loss in Noonan syn-drome,2' and serous otitis media was a commonfinding in the study group. Although specificlearning disabilities have been reported in a fewpatients,22 23 more detailed studies are needed.

Clinical differences were observed betweenapparently familial and sporadic cases ofNoonan syndrome. The apparently sporadiccases seen in this study were shorter with anincreased incidence of skeletal changes, hepato-splenomegaly, and sparse hair. Only oneprevious smaller study had reported differencesbetween sporadic and familial cases and hadnoted an increased frequency of developmentaldelay and short stature in the familial group."The most likely explanation for the clinicaldifferences noted between the two groups in ourstudy is selection bias, with a less severephenotype accepted for diagnosis in familialcases. However, it is also possible that thesefindings may represent evidence for hetero-geneity within Noonan syndrome.

DIAGNOSISThe differential diagnosis of the child withNoonan syndrome is considerable. It is importantin all cases to exclude Turner's syndrome andother chromosomal abnormalities which canmimick the Noonan syndrome phenotype, forexample trisomy 8p, trisomy 22 mosaicism, andsex chromosome rearrangements.2F26 A numberof teratogens in pregnancy produce a phenotypethat can overlap with Noonan syndrome andneed to be specifically inquired for, particularlyalcohol and primidone.27 28 Other syndromesthat combine facial changes with short statureor cardiac abnormalities may be confused withNoonan syndrome, for example William'ssyndrome or Aarskog's syndrome. Both of thesesyndromes are now well defined however,2932and recognition of the full phenotype of Noonansyndrome should readily allow accurate dis-crimination between them. Two other syn-dromes have been differentiated from Noonan

syndrome based on specific ectodermal changes.The association of multiple lentigines withpulmonary stenosis and deafness led to thedescription of leopard syndrome,33 while anemphasis on keratotic and other skin changesled to the separation of the cardiofaciocutaneoussyndrome.34 The frequent ectodermal changesseen in our study population suggests that thesetwo syndromes cannot at present justifiably beseparated from Noonan syndrome. Twoprevious attempts have been made to produce ascoring system that would be helpful in makingthe clinical diagnosis of Noonan syndrome. 14 35While both are useful research tools, neitherhave come to be widely used in clinical practice,and diagnosis still rests on clinical patternrecognition.The average age at diagnosis of Noonan

syndrome in this group was 9 0 years. The facialfeatures of Noonan syndrome alter with age,36and the easiest time to make the clinicaldiagnosis is in early childhood. A promptdiagnosis is important not only to allow recog-nition of treatable associations, but also toprovide genetic counselling to the family.

1 Noonan J A, Ehmke D A. Associated non cardiac malfor-mations in children with congenital heart disease. J Pediatr1963;63:468-70.

2 Noonan J. Hypertelorism with Turner phenotype. AmJ DisChild 1%8;116:373-80.

3 Turner HH. A syndrome of infantilism, congenital webbedneck, and cubitus valgus. Endocrinology 1938;23:566-74.

4 Ullrich 0. Turner's syndrome and status Bonnevie Ullrich.AmJr Hum Genet 1949;1:179-200.

5 Ford CE, Jones KW, Polani PE, de Almeida JC, Briggs JH.A sex chromosome anomaly in a case of gonadal dysgenesis(Turner's syndrome). Lancet 1959;i:71 1-3.

6 Mendez HMM, Opitz JM. Noonan syndrome: a review. AmJ Med Genet 1985;21:493-506.

7 Allanson JE. Noonan syndrome. J Med Genet 1987;24:9-13.8 Pierini DO, Pierini AM. Keratosis pilaris atrophicans faciei

(ulerythema ophryogenes): a cutaneous marker in theNoonan syndrome. BrJr Dermatol 1979;100:409-16.

9 Baraitser M, Patton MA. A Noonan like short staturesyndrome with sparse hair. J Med Genet 1986;23:161-4.

10 Evans DGR, Lonsdale RN, Patton MA. Cutaneous lymph-angioma and amegakaryocytic thrombocytopenia inNoonan syndrome. Clin Genet 1991;39:228-32.

11 Collins E, Turner G. The Noonan syndrome-a review ofthe clinical and genetic features of 27 cases. J Pediatr1973;83:941-50.

12 Char F, Rodriguez-Fernandez HL, Scott CI, BorgaonkarDS, Bell BB, Rowe RD. The Noonan syndrome-a clinicalstudy of forty five cases. Birth Defects: Original Article Series1972;8:110-8.

13 Nora JJ, Nora AH, Sinha AK. The Ullrich-Noonan syn-drome (Turner phenotype). Am J Dis Child 1974;127:48-55.

14 Duncan WJ, Fowler RS, Farkes LG, et al. A comprehensivescoring system for evaluating Noonan syndrome. AmJ MedGenet 1981;10:37-50.

15 Sanchez Cascos A. The Noonan syndrome. Eur Heart J1983;4:223-9.

16 Ranke MB, Heidemann P, Kunpfer C, Enders H, SchmaltzAA, Bierich JR. Noonan syndrome: growth and clinicalmanifestations in 144 cases. EurJ Pediatr 1988;148:22-07.

17 Witt DR, Kenna BA, Hall JG, Allanson JE. Growth curvesfor height in Noonan syndrome. Clin Genet 1986;30:150-3.

18 Lemli L, Smith DW. The XO syndrome: a study of thedifferential phenotype in 25 patients. J Pediatr 1963;63:577-87.

19 King JO, Denborough MA. Anaesthetic induced malignanthyperpyrexia in children. J Pediatr 1973;83:37-40.

20 Hunter A, Pinsky L. An evaluation of the possible associationof malignant hyperpyrexia with Noonan syndrome usingserum creatinine phosphokinase levels. J Pediatr 1975;96:412-5.

21 Hopkins-Acos P, Bunker K. A child with Noonan syndrome.J Speech Hear Disord 1979;44:494-503.

22 Money J, Kalus ME Jr. Noonan syndrome-IQ and specificdisabilities. Am J Dis Child 1979;133:846-50.

23 Wilson M, Dyson A. Noonan syndrome: speech and languagecharacteristics. J (Comnmun Disord 1982-15:347-52.

24 Burn J, Baraitser M, Hughes D, Soldanan-Garcia P, TaylorJE. Absent right atrioventricular connection, and doubleinlet ventricle due to an unbalanced familial 8:13 chromo-some translocation: a cautionary tale. Pediatr Cardiol1984;5:55-60.

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SM, Sergovich FR. Trisomy 22 mosaicism syndrome andUllrich-Turner stigmata. AmJI Med Genet 1986;23:739-49.

26 Batstone PJ, Faed MJW, Jung RT, Gosden J. 45,X/46,X dic(Y) mosaicism in a phenotypic male. Arch Dis Child1991;66:252-3.

27 Spiegel PG, Peckman WM, Rich BH, Verstaag CH, NelsonV, Dudnikov M. The orthopedic aspects of the fetalalcohol syndrome. Clin Orthop 1979;139:58-63.

28 Mytre SA, Williams R. Teratogenic affects associated withmaternal primidone therapy. J Pediatr 1981;99:160-2.

29 Aarskog D. A familial syndrome of short stature associatedwith facial dysplasia and genital abnormalities. J Pediatr1970;77:856-61.

30 Grier RE, Farrington FH, Kendig R, Mamones P. Autosomaldominant inheritance of the Aarskog syndrome. Am J MedGenet 1983;15:39-46.

31 Williams JCP, Barratt-Boyes BG, Lowe JB. Supravalvularaortic stenosis. Circulation 1961;24:1311-8.

32 Martin NDT, Snodgrass GJAI, Cohen RD. Idiopathicinfantile hypercalcaemia-a continuing enigma. Arch DisChild 1984;59:605-13.

33 Gorlin RJ, Anderson RC, Blow M. Multiple lentiginessyndrome. Am J Dis Child 1969;117:652-62.

34 Reynolds JF, Neri G, Herrmann JP, et al. New multiplecongenital anomalies/mental retardation syndrome withcardio-facio-cutaneous involvement-the CFC syndrome.Am J Med Genet 1986;25:413-27.

35 Preus M. Differential diagnosis of the Williams and theNoonan syndromes. Clin Genet 1984;25:29-34.

36 Allanson JE, Hall JG, Hughes HE, Preus M, Witt RD.Noonan syndrome: the changing phenotype. Am J MedGenet 1985;21:507-14.

Prolonged acute crying in a young childA diagnosis of infantile colic is usually not difficult as there is ahistory of recurrent crying, often at a set time of day, in anotherwise well baby. The child who presents with a first episode ofexcessive crying poses a different diagnostic problem. It is a fairlyfrequent cause of presentation to hospital casualty departmentsand diagnosis may be difficult. A study from the Children'sHospital in Denver, Colorado (Steven R Poole, Pediatrics 1991;88:450-5) gives some help in tackling this problem. Over a one yearperiod 56 children under 2 years of age were seen in theemergency department because of the recent onset of excesssivecrying without fever. Babies who stopped crying before or duringexamination did not have a serious cause for their crying. Thediagnosis was made by physical examination in 23 of the 56children, as a result of investigations in 11, and only at follow upin 22. In 10 the 'diagnosis' was 'idiopathic crying' and six werethought to have infantile colic. Ten had otitis media and the resthad a wide variety of final diagnoses ranging from getting tooexcited at a family reunion to being bitten by a brown reclusespider. The importance of detailed and complete examination ofthe skin and skeletal system is emphasised as is examination of theeyes. Three children had unexpected corneal abrasions and one anocular foreign body. Three had unexpected skeletal or intracranialtrauma and one a foreign body in the throat that had escaped thenotice of two doctors and was discovered by a third using alaryngoscope after the child had been noticed to wince onswallowing. Only one child proved to have a urinary infection.Investigation was dictated by clinical findings with only urinemicroscopy and culture being 'routine'.The child who presents with acute unexplained crying is a good

test of diagnostic mettle. Those who don't settle down in thecasualty department, home, or surgery, and in whom a diagnosisis not apparent after detailed examination should be admitted tohospital for continued observation until a diagnosis is made.

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