Atrichia, ichthyosis, follicular hyperkeratosis, chronic candidiasis, keratitis, seizures, mental retardation and inguinal hernia: a severe manifestation of IFAP syndrome?

ARTICLE

In the perplexing confusion of diseases characterised by congenital alopecia, the distinction between ichthyosiform conditions with congenital alopecia has been quite difficult and the same disease could be found reported under different names [1-4].

Congenital alopecia is rare, it may occur without associated defects [5], or may be accompanied by other symptoms, such as: papular lesions [3, 4, 7-9], mental retardation [4, 6, 10, 11], pseudo-anodontia [12, 13] etc.

Different ichthyosiform conditions with alopecia have been described [14-20], but congenital atrichia is seen only in a few of them [3, 4, 6-9, 13, 21-23].

A boy with multiple signs of ichthyosis follicular, alopecia photophobia (IFAP) syndrome, and some features of keratis, ichthyosis, deafness (KID) syndrome prompted us to analyse the differential diagnosis between these entities.

Case report

A 3 1/2 year-old boy had been referred for the evaluation of seizures and severe mental and growth retardation. He was the product of a 34-week uncomplicated pregnancy and delivery of a healthy 30-year-old woman with no history of prenatal use of alcohol, tobacco, or drugs. Birth weight was 1,400 g and length was 45 cm. At birth he was noted to have total alopecia and 'dry' skin; he also had a natal tooth. No respiratory distress or seizures were recorded during the neonatal period. His family history disclosed that his mother's first cousin has a son with a similar condition (Fig. 1).

On physical examination the patient was normally proportioned but weight, length, and head circumference were below the third percentile, bone age was also below chronological age. A large left inguinal hernia was present.

He showed no scalp and body hair, and eyebrows and eyelashes were likewise absent. A generalised lamellar desquamation, with slight underlying erythema was noted (Fig. 2). Thicker and darker scales were present over the scalp, knees, wrist and ankles (Fig. 3); on the trunk and limbs follicular hyperkeratosis was also observed (Fig. 4); a mild keratoderma on the palmar and plantar surface was present. Sweat-test revealed normal sweating. The boy had recurrent candidal infections on the perioral and napkin areas (Figs. 2, 5); his nails were dystrophic, onychia and paronychia due to candida were detected. Teeth were normal.

Ophthalmological examination disclosed marked photophobia, and complete absence of eyelashes was noted. On slit-lamp examination a vascularizing keratitis could be demonstrated.

Neurological examination revealed severe mental retardation with no focal signs. EEG recorded an abnormally slow background. MRI showed brainstem hyperintensity signals (heterotopias). Brainstem auditory-evoked-potential disclosed no abnormalities.

Cardiovascular evaluation was within normal limits.

Skin biopsies were obtained from the patient's scalp and abdomen. Scalp samples showed a normal granular layer with focal parakeratosis. Abortive hair follicles, no sebaceous glands but normal sweat glands were found within the dermis. A slight perivascular infiltrate with vascular dilatation was also seen; no infiltrate around hair follicles was observed (Fig. 6). Sections of the abdominal biopsy showed an epidermis with an acanthotic appearance and a normal granular layer. The dermal features were similar to those found in the scalp samples.

Respiratory infections, purulent otitis and conjunctivitis marked the patient's subsequent course. Results of routine blood screening, tuberculin skin test, and quantitative inmunoglobulin were unremarkable.

Discussion

Ichthyosis, follicular alopecia, photophobia (IFAP) was characterised as a disease entity by McLeod in 1909, although Lesser first used this term in 1885 [21]. Patients with this disease have a unique appearance because of the alopecia, photophobia and generalised follicular hyperkeratosis. In most cases teeth and nails were normal and no abnormalities in sweat production were reported. Sometimes hyperkeratoses over the elbows, knees and dorsal fingers, but no palmo-plantar hyperkeratoses were seen [1, 21, 25, 26]. Congenital absence of hair (congenital atrichia) is the most prominent clinical feature of IFAP syndrome [1, 21].

Follicular hyperkeratosis is evident in the first year of life; in most cases thornlike projections, giving the skin the feeling of a 'nutmeg-grater' were described [21, 25]. As we saw the child at three years of age this type of generalised skin change was no longer so remarkable. However, follicular hyperkeratosis was observed on the trunk and abdomen and hyperkeratotic plaques were found over the joints and scalp. In addition to the follicular involvement, mild generalised lamellar scaling with underlying erythema, as was found in our patient, has been reported [1].

Photophobia is the third major feature of IFAP syndrome; severe ophthalmological problems with progressive corneal vascularization can also occur [1]. Both features were observed in our patient.

Dystrophic nail changes have only been reported in few cases [1, 10, 22, 25, 26]. In this patient, dystrophic nails were seen in relationship with candidal infections but no increased susceptibility to candida has been recorded in IFAP syndrome [21-27].

Teeth are normal in this syndrome, as well as sweating and hearing. No alteration in dentition, sweating or hearing was noticed in our patient.

In previously reported cases [1, 21], as in this case, severe growth and motor retardation, and generalised seizures signal the syndrome. The neurological abnormalities enable us to differentiate between this entity and other similar conditions [17, 20, 28, 29]. Neuropathological findings showed an unusual deformation of the temporal lobes and olivocerebellar atrophy [26].

A large inguinal hernia was a feature of the case reported by Martino et al. [22] as well as in our case. This feature was also present in our patient's cousin and should be considered a feature to define future cases.

Other associated reported features were bronchial asthma, proneness to infections, hypohidrosis, congenital aganglionic megacolon, vertebral, renal and other anomalies [22]. The child reported here suffered from both asthma and proneness to infections. The predisposition to cutaneous candidasis seen in our case has not been observed in the other published cases.

Histologically, the ichthyotic skin showed acanthokeratosis with follicular plugging. A normal granular layer was reported [1, 21], excluding ichthyosis vulgaris and epidermolytic hyperkeratosis. The scalp samples revealed atrophic hair follicles with their bulbs located within a thinned dermis with absence of sebaceous glands [1, 25, 30]. In the present case focal parakeratosis with a normal granular layer was found. Rudimentary hair follicles, absence of sebaceous glands, slight vascular dilatation and a mild perivascular infiltrate without perifollicular inflammation were the main features within the dermis.

Most of the reported cases have been males, making the diagnosis of an X linked recessive disorder more probable. Our case has an affected male cousin. Cytogenetic and molecular studies did not uncover deletions in either case.

This disorder has been confused in the literature with several other conditions in which alopecia and follicular changes are the main features [2, 4, 6-9, 17, 18, 24]. We considered the KID syndrome for the main differential diagnosis.

The keratitis, ichthyosis, and deafness (KID) syndrome was described in 1915 by Burns, and rediscovered in 1968 by Schnyder [31]. In 1981 Skinner et al. [32] proposed the term KID to describe a combination of congenital alterations in the form of corneal vascularization, probably hyperkeratosis, and a neurosensory hearing defect [33]. Traupe suggested redefining the "I" in this syndrome for "ichthyosis-like hyperkeratosis" [34]. Children are affected at birth with erythroderma, although in most cases hyperkeratotic plaques localised on the face, elbows, knees, palms and soles, developed at one year of age. As far as the cutaneous changes are concerned our patient was never erythrodermic, no hyperkeratotic changes were found on the face, palms and soles, but he presented thick and dark squamous plaques on the scalp, knees, ankles and wrist.

IFAP and KID syndromes share similar ocular changes. A progressive vascularizing keratitis has been described in both syndromes; its expression can be variable, it is preceded by photophobia and can eventually lead to total blindness.

Bilateral congenital neurosensory hearing loss is an essential feature in the diagnosis of KID syndrome. In a review of 61 cases by Cáceres-Ríos et al. it was present in 100% of the cases [20].

Patients with this syndrome have an average intellectual ability, only slight psychomotor retardation has been reported, probably due to deafness and limited vision [35]; the physical growth was unaffected.

There are numerous reports on candidal infection in KID syndrome [20, 34-38], but we could not find a single case of IFAP syndrome with this type of cutaneous infection. This was a striking finding in the present patient.

Most cases of KID syndrome have been sporadic, the sex ratio is 1:1; males do not tend to be more severely affected than females, therefore X-linked recessive or X-linked dominant inheritance are unlikely. The general paucity of familial cases may be taken as an indication that this syndrome is due to an autosomal dominant gene and that most cases represent de novo mutations [20, 33, 39]. In the present case, a boy was affected and the family history revealed another alopecic boy, making the diagnosis of an X-linked recessive syndrome more likely.

There are difficulties in the differential diagnosis between this syndrome and keratosis follicularis spinulosa decalvans (KFSD) [18, 21, 24] because all share alopecia and skin changes. However in the IFAP syndrome there is true congenital atrichia, whereas in KFSD the follicular hyperkeratosis is not present at birth and the alopecia is not universal, it develops gradually as a result of follicular atrophoderma, hence the histological changes are quite different.

CONCLUSION

We believe our patient represents a new case of IFAP syndrome. Recurrent candidal infections made the diagnosis more difficult, since no other reported case of IFAP syndrome with chronic cutaneous candidiasis could be found.

Because IFAP and KID syndromes could share similar dermatological and ophthalmological features, and could be associated with cutaneous as well as systemic infections it is tempting to speculate that IFAP syndrome could represent a link between the heterogeneous group of ichthyosis and atrichias as was suggested by Traupe [1].

Article accepted on 7/10/99

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