Ichthyosis Follicularis, Alopecia, and Photophobia(IFAP) Syndrome: Clinical and NeuropathologicalObservations in a 33-Year-Old Man

K. Keyvani,1 W. Paulus,1 H. Traupe,3 F. Kiesewetter,4 C. Cursiefen,5 W. Huk,6 K. Raab,7 U. Orth,8A. Rauch,2 and R.A. Pfeiffer2*1Department of Neuropathology, Friedrich Alexander Universitat Erlangen-Nurnberg, Erlangen, Germany2Institute of Human Genetics, Friedrich Alexander Universitat Erlangen-Nurnberg, Erlangen, Germany3Department of Dermatology, Westfalische Wilhelms Universitat, Munster, Germany4Department of Dermatology, Friedrich Alexander Universitat Erlangen-Nurnberg, Erlangen, Germany5Department of Ophthalmology, Friedrich Alexander Universitat Erlangen-Nurnberg, Erlangen, Germany6Department of Neuroradiology, Friedrich Alexander Universitat Erlangen-Nurnberg, Erlangen, Germany7Cnopfsche Kinderklinik, Nuremberg, Germany8Institute of Human Genetics, University of Hamburg, Hamburg, Germany

The syndrome of ichthyosis follicularis, alo-pecia, and photophobia (IFAP) is an uncom-mon neuroichthyosis described in only 10males so far. We report on a man with con-genital ichthyosis and alopecia with appar-ently normal development in early infancy.Photophobia and generalized myoclonic-astatic seizures began during or after thefirst year of age and were associated withprogressive impairment of motor skills andmental abilities. He died at 33 years of age.Neuropathological findings showed an un-usual deformation of the temporal lobes andolivocerebellar atrophy. Cytogenetic andmolecular studies did not uncover deletionsin either Xp22.2 to 3 or in Xq27.3 to qter. Am.J. Med. Genet. 78:371–377, 1998.© 1998 Wiley-Liss, Inc.

KEY WORDS: IFAP syndrome; ichthyosisfollicularis; alopecia; photo-phobia; olivocerebellar atro-phy

INTRODUCTION

The syndrome of ichthyosis follicularis, alopecia, andphotophobia (IFAP)[Traupe, 1989] seems to have beenrecognized first by MacLeod [1909] in three brotherspresenting with ‘‘ichthyosis follicularis, baldness andtrachoma.’’ Since then it has been reported in only 10patients from 8 families when stringent diagnostic cri-

teria are applied. All patients have been males andbecause in one family two maternal brothers wereprobably affected [Martino et al., 1992], X-linked inher-itance was proposed (MIM 308205).We report on theclinical and autopsy findings in a sporadic case of thisrare disease.

CLINICAL REPORT

The patient was born in 1963. He was the first ofthree children of normal nonconsanguineous parents.Paternal age was 40, maternal age 33. The father andone of his brothers had had dry skin since childhoodbut did not require continuous treatment. The mater-nal family history is unremarkable.

The patient was born after uneventful pregnancyand delivery. Birth weight was 2,900 g. He was admit-ted to hospital shortly after birth because of dry scalingskin, and lack of scalp and brow hairs and eyelashes.The skin was erythematous and shiny and the provi-sional diagnosis of ‘‘congenital ichthyosis’’ was made.All other clinical findings were normal at that time.

Around the age of 1 year tonic-clonic seizures andphotophobia were first noted. Routine clinical findingswere again normal. Measurements were normal. From2 years on these findings were repeatedly confirmed.Electroencephalograms (EEGs) were abnormal andshowed diffuse spikes. According to medical recordsand the parents’ observations his psychomotor devel-opment was normal during the first 2 years (Fig. 1A–C), but mental and motor retardation were progres-sively manifest thereafter.

Clinical files on the patient after the age of 6 yearsdescribe myoclonic-astatic grand mal seizures, ataxiaof posture and gait, pseudobulbar paresis with impair-ment of swallowing, and loss of vision. Speech and so-cial behavior were severely impaired. Buhler-Hetzerscore at the age of 6 years was 28, indicating a devel-

*Correspondence to: Prof. R.A. Pfeiffer, Institute of Human Ge-netics, Schwabachanlage 10, D–91054 Erlangen, Germany.

Received 27 February 1998; Accepted 22 April 1998

American Journal of Medical Genetics 78:371–377 (1998)

© 1998 Wiley-Liss, Inc.

opmental age of 1.8 years. The EEG showed general-ized but also focal hypersynchronous discharges andirregular spike-wave complexes, with enhancementover right precentral and left occipital areas.

From the age of 10 years on he was unable to walkand had to be tube fed. He was considered blind buthearing apparently was preserved. He started speak-ing normally but later his vocabulary was reduced to afew words. Social contacts were limited to single famil-iar persons.

From the age of 14 years on he resided in an insti-

tution for severely handicapped persons. Until hisdeath at the age of 33 he was hospitalized for infec-tions, pneumonias, and grand mal seizures which oc-curred at least once a week. An ophthalmological examat the age of 25 years noted corneal scars, discrete al-terations of the pigmentary epithelium in the macula,and alterations in the fundus compatible with severemyopia.

At 26 years of age magnetic resonance imaging of thebrain with T2 and T1 weighted images showed sym-metric dilatation of both lateral ventricles probably

Fig. 1. The patient at age 15 months (A) showing alopecia and age 33months (B) appearing ‘‘not disabled but rather cheerful and venturesomelike other kids’’(parental statement, 1998). C: The patient shortly prior tohis death at age 33 years.

372 Keyvani et al.

Fig. 2. Magnetic resonance images (left,middle) T2 weighted (TR/T 4 3.0 4 /90), and(right) sagittal T1 weighted (TR/TE 4 0.2/15(1.5 Tesla). Marked generalized atrophymost prominent in the white matter, brain-stem, and cerebellum without changes of sig-nal intensity. Motion artefacts.

Fig. 3. Neuropathological abnormalities. Macroscopical examination shows deformed temporal lobes tapered to basal (A), slightly enlarged lateralventricles as a sign of mild inner atrophy (B), and cerebellar atrophy (C). Histological analysis of the cerebellum (D) shows loss of Purkinje cells, markedatrophy of the granular cell layer (G), an increase in the number of Bergmann glia (B), and single dystopic Purkinje cells (arrow); (W, white matter).

IFAP Syndrome 373

secondary to degeneration of the surrounding whitematter. The subarachnoid spaces of both Sylvian fis-sures including the basal temporopolar cisterns wereremarkably dilated, less so the subarachnoid spacesover both hemispheres, which were pronounced in thefrontoparietal regions. The most severe changes werefound in the posterior fossa with extensive atrophy ofthe brain stem and the cerebellum. There was nochange of signal intensity suggesting a diffuse or focalalteration of the brain parenchyma (Fig. 2).

A light and electron microscopic study of peripheralnerve and muscle at the same age showed mild non-specific degenerative and regenerative changes. Therewas no indication of a lysosomal or peroxisomal disor-der. This was also true for the skin biopsy.

During his life numerous metabolic deficiencies wereexcluded, such as mitochondrial defects (normal lactatein urine, serum, cerebrospinal fluid, muscle), peroxi-somal disorders (normal very long fatty chain acids andphytanic acid), lysosomal deficiencies (lymphocytes, fi-broblasts: GM1 and GM2 gangliosidosis, Krabbe dis-

ease, MPS VII, a-fucosidosis, a-mannosidosis, muco-lipidoses II and III, metachromatic leukodystrophy),neuronal ceroid-lipofuscinosis, as well as metabolic ab-normalities of aminoacids and uric acid.

The lymhocyte karyotype was normal. A submicro-scopic deletion in Xp22.3 was not detectable by fluores-cent in situ hybridization with DNA probes STS, KALand DXS1140 (Oncor, Heidelberg, Germany). Molecu-lar deletion screening in the regions Xp22.2 to 3 withintragenic sequence tagged sites (STS, KAL) as well asflanking markers and of Xq27.3 to Xqter with polymor-phic CA repeats with an average of 1 to 5 cM coveringa physical distance of about 10 and 12 Mbp, respec-tively, were negative.

AUTOPSY FINDINGS

The patient was 142 cm tall and weighed 35 kg. Headcircumference was 52 cm with alopecia totalis. Therewere flexion contractures of elbow, hand, finger, hip,and knee joints, double-S-formed scoliosis and club

TABLE I. Survey of Published IFAP Syndrome Cases Compared With the Present Case*

MacLeod[1909]

(3 cases)

Zeligman andFleisher [1959]

(2 cases)

Freire-Maiaand Pinheiro

[1984]

Eramo et al.[1985]

(2 cases)Hamm et al.

[1991]

Sex Males Males Male Males MaleShort stature − − + In cases 1: + +Skeletal

anomalies− − Platyspondylisis;

kyphosis− −

Muscles − − − − Hypotonia

Skin/hair Alopecia;ichthyiosiformhyperkeratosis

Alopecia;ichthyosisfollicularis

Alopecia;ichthyosisfollicularis

Alopecia;ichthyosisfollicularis; lackof sebaceousglands

Alopecia;ichthyosisfollicularis;lack ofsebaceousglands

Nails − − Dystrophic − Dystrophic

Teeth − − − − −Ears − − + − −

Photophobia + + − + +Seizures − − + In case 1: + +Mental

retardation− In case 1: + + − +

Brain − In case 1: X-ray:intracranialcalcification

− − −

Recurrentrespiratoryinfections

− − − In case 1: + −

Otheranomalies

− In case 1:umbilical hernia;horizontalnystagmus;conjunctivitis;anisocytosis

Hypohydrosis;megacolon;anemia

In case 1: asthma Atopicmanifestations;cryptorchidism

Chromosomalconstitution

? ? ? ? Normal, karyo-type; 46, XY

374 Keyvani et al.

feet. The nails were grossly normal. The ears werelarge and abnormally shaped. Both testes showed in-terstitial fibrosis and tubular atrophy with nodularSertoli cell hyperplasia. The kidneys showed oligemictubulopathy with osmotic nephrosis as a terminal pro-cess. Pulmonary findings were compatible with recur-rent, partly consolidated, suppurative bronchopneumo-nia with fibrinous pleuritis and pleural adhesions.Acute exacerbating bronchopneumonia was consideredthe cause of death.

Dermatopathological Findings

There was atrichosis. Sections from the scalp, ven-tral and dorsal thorax, inguinal region, toe and finger-nail were stained with hematoxylin and eosin, para-amino salicylic acid (PAS), and Van Gieson stain. Themain histopathological findings were compact follicu-lar hyperkeratosis, rare and small hair follicles, andthin epidermis with diminished but preserved granular

layer. Sebaceous glands were almost completely lack-ing. In addition, two superficial spreading melanomaswere found in the right inguinal region and on theback, respectively. Apart from a parakeratosis of thenail matrix no other abnormalities were seen.

Ophthalmopathological FindingsBoth eyes were enucleated 25 hours after death and

fixed in 2% paraformaldehyde. Paraffin-embedded pu-pil-optic disc sections were cut and stained with hema-toxylin and eosin. The right eye was 28 mm long, theleft 29 mm. Axial myopia was associated with a poste-rior staphyloma in both eyes. The cornea showed a su-perficially located avascular stromal scar. Bowman’slayer and the epithelial basement membrane were de-fective in this area. The optic nerve was not atrophic.

Neuropathological FindingsThe brain was fixed in 10% buffered formaldehyde

for 2 weeks. A total of 18 different brain regions were

TABLE I. (Continued)

Martinoet al.[1992]

Presentcase

Schinzel[1980]

van Gelderen[1982]

Rothe et al.[1990]

(2 cases)

Male Male Female Male Females+ + + + −

Platyspondylisis;kyphosis

Scoliosis; club feet Kyphoscoliosis; flexioncontracture of elbows;hip/knee dislocation;syndactyly; fusion ofvertebrea, etc.

Kyphoscoliosis;dislocation of hips;fusion of vertebrae;radio-ulnarsynostosis, etc.

−

− Flexion contracture ofextremities

− Flexion contracture ofextremities

−

Aopecia; ichthyosisfollicularis

Alopecia; ichthyosisfollicularis; lack ofsebaceous glands;melanoma

Alopecia; ichthyosiformhyperkeratosis

Alopecia Alopecia;ichthyosisfollicularis;angular cheilitis

Dystrophichyperconvex

Parakeratosis Dysplastic − −

Enamel dysplasia − − Enamel dysplasia −Large Large and dysplastic Large, hypoplastic Large In case 1: hearing

deficit+ + − − ++ + − − −+ + + + −

CCT: enlarged lateralleft ventricle andsubarachnoid space

Olivocerebellar atrophy;temporal lobemalformation; innercerebral atrophy;microcalcifications

CCT: microcephaly Microcephaly andturricephaly

−

+ + − − −

One hydronephroticenlarged kidney;inguinal hernia;congenitalaganglionicmegacolon; atopicmanifestation;hypohydrosis

Tubular atrophy; nodularSertoli cell hyperplasia

− No testes could bepalpated

In case 1: gingivalhypertrophy

Normal, karyotype:46, XY

Normal, karyotype:46, XY

Normal, karyotype:46, XX

? Normal karyotype:46, XX

*The last three cases share some but not all the anormalities with IFAP.

IFAP Syndrome 375

cut and embedded in paraffin. Histological sectionswere stained with hematoxylin and eosin, Bodian andKluver-Barrera stains. Immunohistochemical stainswere performed with antisera against glial fibrillaryacidic protein, ubiquitin, and phosphorylated tau(clone AT8). The monoclonal antibody Ki-M1P wasused to detect microglia.

The brain weighed 976 g. Both temporal lobes werepeculiarly deformed and tapered to basal (Fig. 3A). Thecoronal sections revealed slightly enlarged lateral ven-tricles (Fig. 3B). The corpus callosum and both opticalnerves seemed to be narrowed but they were not dis-colored. The cerebellum was small with a tough consis-tency (Fig. 3C). On parasagittal sections shrinkage ofthe folia and widened interfolial sulci of anterior andposterior lobes were encountered.

Microscopically, the cerebellar cortex showed anearly complete loss of Purkinje cells and a markedatrophy of the granular cell layer associated with anincrease in the number of Bergmann glia. Further-more, single dystopic Purkinje cells and gliosis wereencountered in the white matter of the cerebellum (Fig.3D). Marked neuronal loss and gliosis were also seen inthe inferior olivary nuclei. The pontine and dentatenuclei appeared well preserved. The neocortex showednormal architecture in all the examined regions. Therewere some perivascular microcalcifications in the semi-oval center and even more in the basal ganglia. The endfolium of the hippocampus demonstrated mild neuro-nal loss and astrogliosis and microgliosis. No demyelin-ation was found throughout the white matter of thecerebrum and the cerebellum. Immunohistochemistryfor ubiquitin and phosphorylated tau demonstrated nocytoplasmic inclusions in the neurons of glial cells ofthe pons, the dentate nucleus, or cerebral cortex. Dis-seminated intravascular coagulation was seen in a fewsmall cerebral blood vessels.

DISCUSSION

The ichthyosis follicularis, alopecia, and photophobia(IFAP) syndrome [Traupe, 1989] comprises spiny fol-licular hyperkeratosis, marked alopecia (atrichia), andphotophobia often associated with corneal vasculariza-tion and scars. Only a few similar cases have been pub-lished so far, and a few additional cases share some butnot all typical findings and raise diagnostic problems.

Apparently the syndrome was first described in 1909by MacLeod who reported on a family in which three offive boys were affected. He was struck by the peculiarassociation of severe follicular hyperkeratosis present-ing on the scalp, the extensor surfaces of the limbs, andthe abdomen, with complete baldness in this family.The boys had been referred to him because they suf-fered from ‘‘trachoma.’’ A definite and reliable familyhistory is lacking, but apparently the disorder had notoccurred in other relatives. MacLeod pointed out thatin addition to the follicular lesions the skin was ‘‘dryand harsh from the presence of fine scaliness’’ andthus, even according to current classifications, a diag-nosis of ichthyosis was fully justified. ‘‘Trachoma,’’probably subsequent to vascularizing keratitis, wasnoted in the patients at birth or soon after, while onset

of the keratotic lesions was not before the age of 2 andthe baldness developed from 7 years on. MacLeod alsoperformed a histopathological study of the follicularhorny lesions. The published illustrations show typicalfollicular plugs and in the interfollicular skin a moder-ately hyperkeratotic epidermis and a preserved or evenincreased granular layer and marked orthokeratosis.These histopathologic findings clearly exclude autoso-mal dominant ichthyosis vulgaris which is also oftenassociated with prominent follicular keratosis in child-hood [Traupe, 1989].

Despite this early report by an eminent author andthe very striking clinical appearance, the disorder fellinto oblivion until Zeligman and Fleisher [1959] ob-served two boys with follicular ichthyosis, alopecia, andphotophobia. Eramo et al. [1985] reported on two otherpatients with this unique pattern of abnormalities.Further cases of IFAP syndrome were discussed byFreire-Maia and Pinheiro [1984], Hamm et al. [1991],and Martino et al. [1992]. Patients with IFAP syn-drome are surveyed in Table I. Findings that are oftenbut not invariably present include retardation ofgrowth and psychomotor development [Zeligman andFleisher, 1959; Freire-Maia and Pinheiro, 1984; Hammet al., 1991; Martino et al., 1992], chill-like seizuresaccompanied by fever [Eramo et al., 1985; Hamm et al.,1991; Martino et al., 1992], a tendency to infection of-ten associated with bronchial asthma [Eramo et al.,1985; Martino et al., 1992], and skeletal abnormalities[Freire-Maia and Pinheiro, 1984; Martino et al., 1992].Transient or even long-lasting nail dystrophies havebeen reported by Hamm et al. [1991], Freire-Maia andPinheiro [1984], and Martino et al. [1992]. In two pa-tients congenital aganglionic megacolon was present[Freire-Maia and Pinheiro, 1984; Martino et al., 1992].Despite many common findings in published IFAP syn-drome cases, this review shows obvious variability ofclinical manifestations (Table I). It remains to be de-termined whether this variability represents differentgenetic entities, different phenotypes of the same ge-notype, or the expression of a contiguous gene defect.

Presently, the genetic basis of IFAP syndrome is un-clear. An X-linked inheritance is probable because allreported patients are males. An association betweenX-linked ichthyosis and microdeletions or a contiguousgene defect in the chromosome regions Xp22.2 to 3 andXq28 was suggested previously [Herrell et al., 1995;Paige et al., 1994; Traupe et al., 1992]. However, wewere not able to detect a deletion in these regions withcommercial probes in our patient.

For differential diagnosis, a remarkably similar syn-drome has to be taken into account that was reportedin two daughters of a man who presented with alopeciaand follicular keratosis from early childhood [Rothe etal., 1990] thus suggesting autosomal dominant inheri-tance. IFAP syndrome was proposed to be pathogeneti-cally related to this hereditary mucoepithelial dyspla-sia [Rothe and Lucky, 1995]. Indeed, this diseaseshares keratosis follicularis involving scalp, trunk, andextensor aspects of the arms and legs and noncicatri-cial alopecia with IFAP syndrome while other defectssuch as scaling between the hair follicles, and true ich-thyosis are absent. Dry perianal rashes and moist er-

376 Keyvani et al.

ythematous rashes around the mouth were not noted inany cases of IFAP syndrome in contrast to the casesreported by Rothe et al. [1990]. Two other cases re-ported by van Gelderen [1982] and Schinzel [1980] alsoshare abnormalities with IFAP syndrome but can bedistinguished by the absence of ichthyosis follicularis[van Gelderen, 1982] and photophobia [Schinzel, 1980;van Gelderen, 1982]. The observations listed in Table Iwere quoted for their similarity with IFAP syndrome,but due to the presence of abnormalities absent inIFAP syndrome (and vice versa) probably represent dif-ferent syndromes. This distinction is also true for otherknown neuroectodermal disorders such as KID (kera-titis, ichthyosis, and deafness) syndrome, Sjogren-Larsson syndrome, and Rud syndrome, which could beclassified as ‘‘neuroichthyoses.’’

The neuropathological abnormalities of IFAP syn-drome have not been reported so far. In our patientthey consist of olivocerebellar atrophy, a peculiar mal-formation of the temporal lobes, and mild inner cere-bral atrophy. These findings may, in part, explain theneurological symptoms of IFAP syndrome patients.The severe gait disturbance of our patient was prob-ably related to olivocerebellar atrophy. In contrast tothe more common variants of olivopontocerebellar at-rophy, the pontine nuclei were spared and cytoplasmicinclusions were absent in our case. Rather, the mor-phologic findings were similar to cerebello-olivary at-rophy, a genetically distinct disorder with autosomaldominant inheritance and beginning usually in thefourth or fifth decade of life [Subramony et al., 1996].Although some patients with cerebello-olivary atrophymay exhibit non-neurological symptoms such as hypo-gonadism [Eadie, 1975], the three key symptoms ofIFAP syndrome (i.e., ichthyosis follicularis, alopecia,and photophobia) have never been described in thesepatients, suggesting that the pathogenesis of neurode-generation is different in IFAP syndrome and in cer-ebello-olivary atrophy. On the other hand, the morpho-logic appearance of cerebellar anomalies sporadicallyencountered in patients with ichthyosis or alopecia isdifferent from that of our patient [Hsu et al., 1988,Munoz et al., 1997]. Whether the peculiar macroscopicmalformation of the temporal lobes was related to epi-lepsy remains uncertain, since no ‘‘dysplastic’’ abnor-malities were seen in the temporal neocortex. The mildAmmon’s horn sclerosis has to be regarded as a conse-quence rather than a cause of epilepsy. Progressivecognitive decline was apparently related to cerebral at-

rophy, but corresponding histological abnormalities,such as demyelination or marked neuronal loss, werenot observed.

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