ichthyosis follicularis, alopecia, and photophobia (ifap) syndrome: clinical and neuropathological...

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  • 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. 78:371377, 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. 1AC), 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, D91054 Erlangen, Germany.

    Received 27 February 1998; Accepted 22 April 1998

    American Journal of Medical Genetics 78:371377 (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 con

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