American Journal of Medical Genetics 118A:279–286 (2003)

Clinical Report

Noonan-Like Syndrome With Loose Anagen Hair:A New Syndrome?

Laura Mazzanti,1* Emanuele Cacciari,1 Alessandro Cicognani,1 Rosalba Bergamaschi,1

Emanuela Scarano,1 and Antonino Forabosco2

1Department of Pediatrics, University of Bologna, Bologna, Italy2Genetic Unit, Department of Morphological and Legal Sciences, University of Modena e Reggio Emilia, Modena, Italy

We present three children with short stature,the same facial phenotype, macrocephaly,enlarged cerebral spinal fluid spaces, shortneck with redundant skin, severe GH defi-ciency, mild psychomotor delay with atten-tion deficit/hyperactivity disorder (ADHD),mild dilatation of the pulmonary root intwo of them, and a unique combination ofectodermal abnormalities. Their appear-ance, not completely typical of Noonansyndrome, the behavioral phenotype, GHdeficiency, darkly pigmented and hairlessskin, and the unusual aspect of the hair,defined as loose anagen hair syndrome didnot fit any known condition. We postulatethat these children may represent a distinct,previously unreported syndrome that wewould name ‘‘Noonan-like syndrome withloose anagen hair’’. � 2003 Wiley-Liss, Inc.

KEY WORDS: Loose anagen hair; Noonansyndrome; CFC syndrome

INTRODUCTION

Noonan syndrome is a genetically heterogeneous con-dition comprising short stature, a typical facial pheno-type, short and webbed neck, pectus excavatum, andcongenital heart defect, most often pulmonary stenosisor hypertrophic obstructive cardiomyopathy.

The diagnosis can be difficult as the phenotype is veryvariable [Allanson et al., 1985;Mendez andOpitz, 1985],and in the absence of a biochemical marker, thediagnosis is based on clinical data and family history.

Approximately half of the patients are sporadic andmost of the reported familial cases are consistent withautosomal dominant inheritance (NS1 OMIM 163950).A gene for a dominant form of Noonan syndrome wasmapped on chromosome arm 12q in one large Dutchfamily [Jamieson et al., 1994]. Recently in this region agenecausingNoonansyndromewasclonedandsequenc-ed, andmissensemutations inPTPN11 genewere foundin about half the patients examined [Tartaglia et al.,2001].

A recessive form of Noonan syndrome was alsoreported [van der Burgt and Brunner, 2000] (NS2OMIM 605275). In addition, there are other conditionswith phenotypic similarities and ectodermal abnormal-ities, constituting a broad and causally heterogeneousgroup of entities. These include cardio-facio-cutaneous(CFC) (OMIM115150) syndrome,which differs from theNoonan syndrome on the basis of more ectodermalabnormalities and more severe mental retardation[Reynolds et al., 1986; Neri et al., 1987; Neri et al.,1991, Neri and Opitz, 2000] and neurofibromatosis-Noonansyndrome(NFNSOMIM601321) [Bahdauetal.,1996]. A Noonan syndrome-like condition with unusualhair was described by Baraitser and Patton [1986] butsubsequently included in CFC syndrome [Verloes andLe Merrer, 1992].

Easily pluckable, sparse, thin, slow growing, andgenerally silver-blond hair is a distinctive hair disorder,described originally by Zaun [1984] and Nodl [1986]and subsequently reported as a syndromic conditionthe ‘‘loose anagen hair syndrome’’ (LAH syndrome)(OMIM 600628) [Hamm and Traupe, 1989; Price andGummer, 1989; Lalevic-Vasic et al., 1990]. LAH syn-drome can be sporadic or familial. It is usually anisolated disorder and rarely occurs in association withother genetic conditions [Murphy et al., 1995; Tosti andPiraccini, 2002]. It has been described in two patientswith Noonan syndrome [Tosti et al., 1991; Tosti et al.,1997].

We studied these last two patients again and alsoanother one with the same condition, and we suggestthat they constitute a new condition distinct fromNoonan syndrome.

*Correspondence to: Dr. Laura Mazzanti, Clinica Pediatrica,Policlinico S.Orsola-Malpighi, Via Massarenti 11, 40138 Bologna,Italy. E-mail: laura@almadns.unibo.it

Received 7 March 2002; Accepted 22 July 2002

DOI 10.1002/ajmg.a.10923

� 2003 Wiley-Liss, Inc.

CLINICAL REPORTS

Patient 1

MGwas the 1st child of non-consanguineous parents,born at term after a normal pregnancy and delivery.Birth weight was 3,780 g. Birth length and OFC areunknown. At birth she had right clavicular fracture,parietal cephalohematoma, and a transient neonatalacidosis. At three months, a CT scan showed increasedsize of cerebral spinal fluid spaces. She had feedingdifficulties with recurrent vomiting, gastroesophagealreflux, and a hiatal hernia. At age three years she wastreatedwithL-tyroxine forhypothyroidismsecondary toa thyroiditis. At age 4½ years she was referred to ourattention for growth delay. Her height was 96.7 cm (3rdcentile), weight 14 kg (25th centile for height and age)and occipito-frontal circumference (OFC) 52 cm (>90thcentile) (Fig. 1).

Physical examination showed macrocephaly, highforehead, large eyes, epicanthic folds, mild palpebralptosis, broad and flat nasal bridge, anteverted nostrils,micro- and retrognathia, apparently low-set and poster-iorly angulated ears, high and narrow palate, short,broad neckwith redundant skin, posterior lowhair-line,pectus excavatumwithwidely spaced nipples, umbilicalhernia, slender arms and legs, broad finger tips, hyper-extensible joints, fine, dry, silver-blond, fine textured,

sparse hair, dry, hairless, and darkly pigmented skin,which was not present in the parents (Fig. 2).

The patient has been followed by us from the age offour years until her present age of 16 years.

She showed a mild psychomotor development delaywithdelayedverbal and languageabilities andattentionFig. 1. Patient 1: The patient at age 4½ years, frontal view.

Fig. 2. Patient 1: The patient at age 4½ years. a: Craniofacial appea-rance. b: Loose anagen hair in the lateral view.

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deficit hyperactivity disorder (ADHD). At 16 years, sheis attending high school with fair performance.

Karyotype at 400-GHG-bands was normal (46,XX).Echocardiography showed a mild dilation of the pul-monary bulb without signs of cardiopathy. Results ofophthalmologic and otorhinolaryngological evaluationswere normal. Roentgenograms of the skeleton werenormal; bone age was delayed (CA¼4, BA¼ 2 8=12 yrs).Pelvic echography was normal and thyroid echographyshowed a small left thyroid lobe. Hypothyroidism withantithyroid antibodies was confirmed, and growth hor-mone (GH) deficiency was diagnosed (GH peak <4 ng/ml after arginine and L-dopa tests; mean GH concen-tration <3 ng/ml during sleep test). GH therapy wasbegun. Adrenal function was normal. At 12.8 years ofage she experienced menarche and GH-therapy wasstopped. She reached a final height of 153 cm (above10th centile), a little below her target height (<25thcentile) (Figs. 3, 4). Since age nine years, OFC wasabove the 97th centile for height age. Dermatologicevaluation showed blond, fine, sparse, easily pluckablehair. The trichogram showed a striking prevalence ofanagen hairs devoid of sheaths, and loose anagen hair(LAH) syndrome was diagnosed.

Patient 2

DCF, a boy, was born at 39 weeks of gestation after anormal pregnancy and caesarian delivery. Birth weightwas 3,250 g (25th centile), length 48 cm (�25th centile).The parents were not consanguineous; themother had acavernous hemangioma of the left cheek and a goiterrequiring thyroid substitutive therapy. At birth he hadcyanosis, bradycardia, and transient neonatal myocar-diac ischemia. In the first years of life he had feedingproblems, recurrent atopic dermatitis, and food andinhalantallergies.For congenital hypotonia,he received

physiotherapy from the 4thmonth of life. At three yearsand one month he was referred for growth delay. Hisheight was at the 3rd centile (86.1 cm), weight 11.6 kg(25th centile for height and age), and OFC 52.9 cm(>97th centile for height and age) (Fig. 5).

Physical examination showed macrocephaly withdolichocephaly, high forehead, asymmetric face, upperand inversus epicanthic folds, ptosis and squint, lownasal bridge and anteverted nostrils, apparently low-setand folded ears with posterior angulation, high andnarrow palate, short neck with redundant skin, and lownuchal hairline; large chest with widely spaced nipples,umbilical hernia, slender arms and legs, terminal broa-dening fingers, hyperextensible joints; silver-blond, finetextured, and sparse hair easily pulled from the scalp;dry, hairless, darkly pigmented skin, and mild scoliosis(Fig. 6). Both the parents had very pale skin.

The patient has been followed by us from the age ofthree years until now (age 12 years). He initially showedmild psychomotor delay and ADHD with gradualimprovement; at age 10 years his IQ was 90.

Karyotype at 400-GHG-banding was normal (46,XY).Ophthalmological evaluation showed temporal pallorof the optic disc. Cardiac echography showed a smallASD (that closed spontaneously at 11 years), andminimal pulmonary bulb dilatation with a dysplasticpulmonary valve, without any sign of hemodynamic im-pairment. Results of abdominal and renal echographywere normal. At age three years he was GH-deficient(GH peak <4 ng/ml after arginine and L-dopa tests;mean GH concentration <3 ng/ml during sleep test)and he was begun on GH therapy. Adrenal functionwas normal. Bone age was delayed (CA¼ 3, BA¼1 5/12 years). Cerebral MRI showed a dilatation of thecisterna magna and pericerebellar spaces and a normalsellar area. Dermatologic evaluation showed blond, fine,sparse, easily pluckable hair. The trichogram showedpredominance of anagen hair devoid of sheaths. Adiagnosis of LAH syndrome was made; this improvedwith age. At auxological follow-up, height passed fromthe 3rd to the 10th centile (target height was below the25th centile), and OFC was always above the 97thcentile for height age. At 11 yrs and 10 months, heightwas 135.2 cm, weight 30.3 kg (50th centile for heightage), and OFC 58.5 cm (>97th centile for height age)(Figs. 4, 7).

Patient 3

The patient, a girl, was born at 37 weeks of gestationafter anormalpregnancyanddelivery.Birthweightwas2,980 g (50th centile), length 46 cm (10th–25th centile)and OFC 34.4 cm (>75th centile). The parents werenormal and not consanguineous, with unremarkablefamily history. At birth she developed hypocalcemia,hypomagnesemia, hypoglycemia, and hypotonia. Echo-encephalography at seven months showed intracranialhypertension and ventricular enlargement responsiveto medical therapy. MRI showed severe hydrocephalusthat worsened with age, and at age two years a ven-triculo-peritoneal shunt was placed. At 2 5/12 years shewas referred for growth delay: height was 70 cm (<3rdFig. 3. Patient 1: Facial appearance at 15 4/12 years, at final height.

Noonan-Like Syndrome With Loose Anagen Hair 281

Fig. 4. Height corves of the 3 patients.

282 Mazzanti et al.

centile),weight 7.8 kg (10th–25th centile), andOFCwas49.8 cm (>97th centile).

On physical examination, she hadmacrocephaly withdolichocephaly; a high and prominent forehead, upperand inversus epicanthic folds, mild ptosis and squint,low nasal bridge and anteverted nostrils, folded, poster-iorly angulated ears, high and narrowpalate; short neckwith redundant skin, large chest with pectus excava-tum, and widely spaced nipples; umbilical hernia;slender armsand legs, broadfingertips, hyperextensiblejoints; blond, fine textured, and sparse hair, easilypulled from the scalp; dry, hairless, darkly pigmentedskin (Fig. 8). Both the parents had pale skin.

The patient has been followed by us until now (age6½ years). There was initial psychomotor delay andirritability and ADHD that improved with age. Pre-sently, her mental age is only one year delayed forchronological age.

The karyotype at 400-GHG-banding was normal(46,XX). Ophthalmologic evaluation showed pale opticdiscs, nystagmus, and divergent squint. Findings oncardiac, abdominal, renal, and pelvic echography werenormal. Endocrinological examination showed GH-deficiency (GHpeak<4 ng/ml after arginine and L-dopatests), and she was begun on GH therapy. Adrenalfunction was normal. Bone age was delayed (CA¼3,BA¼ 1 5/12 years). At follow-up (4 1/12 years), cerebralMRI showedventriculomegaly, dilatation of the cisternamagna and pericerebellar spaces, Chiari malformation,and a normal sellar area. Dermatologic evaluation andtrichogram showed the presence of anagen hairs devoidof sheathswithout telogen hairs, and a diagnosis of LAHsyndrome was made. At auxological follow-up, herheight was below the 3rd centile, with gradual improve-ment, but the OFC remained above the 97th centile

for height age. At 6½ years her height is 103.9 cm (<3rdcentile), weight 16.9 kg (25th–50th centile), OFC53.1 cm (97th centile) (Fig. 4).

DISCUSSION

All three patients had short stature, the samecharacteristic craniofacial appearance with macroce-phaly, mild ptosis and epicanthic folds, short neck withredundant skin, widely spaced nipples, thin arms andlegs, enlarged spinal fluid spaces requiring a shunt inpatient 3, delayed bone age, GH deficiency, and mild

Fig. 6. Patient 2: The patient at 10 9/12 years. a: Frontal view: asymmetricface, folded ears. b: Loose anagen hair in the lateral view.

Fig. 5. Patient 2: Craniofacial appearance at 3 1/12 years.

Noonan-Like Syndrome With Loose Anagen Hair 283

psychomotor delay with ADHD. Two had amild dilationof the pulmonary root.

At first evaluation of patients 1 and 2, the clinicalfindings suggested Noonan syndrome, but at a subse-quent and more detailed evaluation, we also consideredthe CFC syndrome in the differential diagnosis. Thesesyndromes share short stature, the particular aspect ofthe ocular region, the ears, short neck with redundantskin, andhigh incidence of congenital cardiac defect, butthe cranial aspect withmacroencephaly, the ectodermalabnormalities (abnormally sparse, thin, and curly hair,hyperkeratotic skin lesions) [Borradori and Blanchet-Bardon, 1993], andmild or severeMR inmany cases aredistinguishing aspects of the CFC syndrome vs. theNoonan syndrome [Reynolds et al., 1986; Neri et al.,1987; Verloes et al., 1988; Neri et al., 1991; Neri andOpitz, 2000].

Fig. 8. Patient 3: The patient at six years. a: Frontal view. b: Looseanagen hair in the lateral view.

Fig. 7. Patient 2: Frontal view of the patient at 11 10/12 years.

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Our patients had some of the phenotypic manifesta-tions common to both conditions, i.e., the macrocephalyand ventriculomegaly characteristic of the CFC syn-drome, but a mild psychomotor delay more common toNoonan syndrome (Table I). In 46% of patients withNoonan syndrome, developmental and behavior diffi-culties are reported [Sarimski, 2000]. All of our patientshad the same developmental and behavioral phenotypewith mild psychomotor delay, irritability, and ADHD,which improved with age in all of them.

In 27% of Noonan syndrome cases, woolly or curlyhair is described without sparse growth; the CFC syn-drome hair is sparse and frequently curly or so ‘‘kinky’’as to be uncombable. All of our patients had short, blond,fine textured, sparse, and easily pluckable hair, and thetrichogram demonstrated the ‘‘loose anagen hair syn-drome’’ (OMIM 600628), characterized by a strikingprevalence of anagen hair and virtually completeabsence of telogen hair. In this condition, most of thehairs are in the anagen phase, the active growth phase,when hair fiber is produced. The loose anagen hair isdevoid of sheaths; the hair shafts are loosely anchored tothe follicle and are easily pulled out. In LAH syndrome,few or no hairs enter in the telogen phase, when thehair follicle is in a so-called resting state, probablybecause the hair shafts are lost during the anagenphase, before the end of the hair growth cycle [Hammand Traupe, 1989; Price and Gummer, 1989; Chapman

and Miller, 1996; Tosti and Piraccini, 2002]. Recently,some authors have suggested an involvement ofgenes for keratins in this condition [Chapalain et al.,2002].

The skin of all our patients was hairless and darklypigmented, different from that of their parents, who intwo of the three cases had very pale skin. It has tobe underlined that no patient had an impairment ofadrenal function.

The presence in all of our patients of the same facialphenotype, not completely typical of Noonan syndrome,the same characteristic craniofacial appearance withmacrocephaly, enlarged CSF spaces, short neck withredundant skin, GH deficiency, mild psychomotordelay with ADHD that improved with age, increasedskin pigmentation, and LAH did not allow us to diag-nose a known syndrome. Sporadic occurrence in allthree families suggests an autosomal dominant newcondition. We postulate a distinct, previously unre-ported syndrome that we would tentatively name‘‘Noonan-like syndrome with loose anagen hair’’.

ACKNOWLEDGMENTS

We thank J.M.Opitz for critical review of clinical dataand photographs, and the parents of our patients formaking the historical data available to us and permit-ting the description of their children.

TABLE I. Findings in Our Patients, Noonan Syndrome and CFC Syndrome

Findings Noonan syndrome CFC syndrome M.G. female D.C.F. male M.E. female

Skin and hairDark skin � þ þ þ þHyperkeratosis � þ þ þ þDermatitis/eczema � þ þ þ þSparse/absent scalp hair � þ þ þ þCurly hair � þ � � �Loose anagen hair � � þ þ þ

Head and neckMacrocephaly � þ þ þ þ

EyesPtosis þ þ þ þ þEpicanthal folds þ þ þ þ þ

NoseDepressed nasal bridge � þ þ þ þAnteverted nostrils � þ þ þ þ

Oral cavityHigh-arched palate þ þ þ þ þ

EarsApparently low-set ears þ þ þ þ �Retroverted ears þ þ þ þ þ

NeckBroad, short, webbed þ þ þ þ þ

ChestPectus excavatum þ þ þ � þ

CardiovascularPulmonic stenosis � þ � � �VSD/ASD/PDA � þ � þ �Pulmonary root dilatation � � þ þ �

Cerebral abnormalitiesDilated ventricles � þ þ þ þ

Mental retardation � � � � �Growth and developmentShort stature þ þ þ þ þDelayed bone age � þ þ þ þ

Noonan-Like Syndrome With Loose Anagen Hair 285

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