Pronounced and early acne in Apert's syndrome: a case successfully treated with oral isotretinoin

ARTICLE

An unusual case of widespread acne unresponsive to treatment with early onset in a child with Apert's syndrome is presented. The patient eventually responded to oral isotretinoin therapy.

The morphological profile of the sebaceous glands and the expression of proliferative markers and androgen receptors were evaluated in seboblasts and sebocytes using morphological, ultrastructural and immunohistochemical techniques.

There were no significant differences in staining for proliferative markers and nuclear expression of androgen receptors in the glands from the patient and four healthy controls. Our results support the view that acne in Apert's syndrome is not sustained by abnormalities of the sebaceous glands demonstrable with conventional morphological techniques, and that it does not depend on an increased expression of androgen receptors.

Key words: acne, acrocephalosyndactyly, androgen receptors, Apert's syndrome, isotretinoin.

Apert's syndrome ­ acrocephalosyndactyly type 1 ­ is an autosomal dominant disease with a sporadic incidence estimated at 1 in 160,000 live births [1]. It is characterised by syndactyly of fingers and toes and craniofacial abnormalities as a consequence of the premature obliteration of the craniofacial sutures [2].

Hermann et al. and Solomon et al. first reported the association between Apert's syndrome and moderate-to-severe acne involving the face, chest, back and forearms [3, 4].

We describe an unusual case of disseminated and unresponsive acne with early onset in a child with Apert's syndrome and report the results of an immunohistochemical and ultrastructural investigation of the sebaceous glands.

Case report

In April 1997, a 7-year-old white child with Apert's syndrome was referred to our Department for treatment of severe acne that had started at the age of six. Pubertal maturation stage was SMR 1 using Tanner's method (absence of pubic hair and presence of prepubertal penis and testicles). The patient exhibited the following abnormalities typical of Apert's syndrome: brachycephalic skull, flattened occiput, prominent forehead, retrognathia of the upper jaw, prognathia of the lower jaw, proptosis and ocular hypertelorism. The nose was short and broad; the hands, completely syndactylic at birth, had been partially separated surgically into semblances of fingers. Soft-tissue union joined all toes of both feet. Acne was prominent on the neck, chest, shoulders and back with numerous comedones, papules and pustules. The lesions did not improve with oral erythromycin therapy (1 g/day for 2 months) and local therapy with clindamycin phosphate, erythromycin, azelaic acid and benzoyl peroxide.

The patient returned in January 1998: the cutaneous lesions were greatly worsened with predominance of papules, pustules and small cysts also involving the lower jaw (Fig. 1a). Blood sedimentation rate, anti-streptococcal titre, reactive C protein, immunoelectrophoresis, plasma cortisol, testosterone, androstenedione, 17-OH-progesterone, dehydroepiandrosterone and dehydroepiandrosterone sulphate, and sex hormone-binding globulin were all normal.

The patient was started on a 24-week course of oral isotretinoin with an initial dose of 0.5 mg/kg/day in the first 12 weeks rising to 0.8 mg/kg/day in the remaining 12 weeks. Complete clearance of the cutaneous lesions was observed at 20 weeks. Severe skin dryness was the only adverse effect during treatment. After four years the patient is still free of acne (Fig. 1b).

Histopathology

Biopsies of involved and uninvolved skin were collected from the patient's back to investigate the descriptive diagnosis of acne vulgaris and were compared with back skin specimens from four preadolescent males in advanced SMR1 stage without clinical signs of hormonal abnormalities, two with and two without acne. All specimens were analyzed by light, ultrastructural and immunohistochemical techniques. KONTRON IBAS analyser and CAS 200 were used to evaluate morphometry and nuclear immunolabelling for androgen receptors of the sebaceous glands.

Statistical differences between obtained data were determined according to z test, p < 0.05 was regarded as indicating statistical significance.

Histopathology showed a typical closed comedone-type acne with a morphological aspect similar to that observed in the two control subjects affected by acne. The morphological profile of the pilosebaceous apparatus and the ultrastructural aspect of sebocytes were similar in the patient and the four healthy subjects.

Immunohistochemical analysis of mature sebocytes from all specimens showed a strong reaction for anti-EMA antibodies (DAKO-EMA, E29), but not for anti-Ki67 (clone MIB-1, DAKO) or anti-PCNA antibodies (CLONE PC-10, DAKO). By contrast, undifferentiated sebocytes were immunolabelled only with anti-Ki67 and anti-PCNA antibodies. Androgen receptors were consistently seen in nuclei of peripherally located undifferentiated sebocytes and in some differentiating sebocytes. At morphometry, the nuclear area immunoreactive for androgen receptors was similar in the patient and the four controls (Fig. 2a-b).

No significant differences in nuclear androgen receptor expression between patient and controls were evident (Table I).

Discussion

Little is known about the pathogenesis of acne in Apert's syndrome.

Several different, not mutually exclusive, hypotheses have been advanced. Based on the prevalent involvement of trunk, arms and thighs, rather than the face, and on the observation that the eruption is persistently monomorphic and unresponsive to antibiotic therapy in the usual dosage range, Steffen hypothesised that this is not true acne but rather an "acneiform eruption" developing on an inherited abnormality of the pilosebaceous apparatus [2, 5].

Linking acne pathogenetically to premature epiphyseal closure, which is the basic inherited disorder of acrocephalosyndactyly, Henderson and co-workers also hypothesised that an altered end-organ androgen metabolism might be responsible for both disorders [6].

The results of our study confirm the lack of overexpression of androgen receptors in the sebaceous glands reported in this syndrome [6]. Indeed, sebocytes from the patient and the four controls exhibited a similar proportion of positive nuclear areas. The patient's sexual hormone profile was normal. Likewise, no increased proliferative activity of sebaceous glands was demonstrated.

Conventional morphological techniques did not detect abnormalities in the pilosebaceous units of the patient.

Further studies are needed to provide new insights into the mechanism of androgen influence on sebaceous glands in Apert's syndrome.

As regards acne management in these patients, the few reports published to date indicate oral isotretinoin as the most effective therapy [1, 7-9].

To our knowledge, this is the first time oral isotretinoin has been used in a 7-year-old child with the syndrome and widespread acne with complete resolution of cutaneous lesions and no recurrence at four years.

References

1. Parker TL, Roth JG, Esterly NB. Isotretinoin for acne in Apert Syndrome. Pediatric Dermatol 1992; 9: 298-300.

2. Steffen C. The acneiform eruption of Apert's syndrome is not acne vulgaris. Am J Dermatopathol 1984; 6: 213-20.

3. Hermann J, Pallister PD, Opitz JM. Craniosynostosis and craniosynostosis syndromes. Rocky Mountain Med J 1969; 66: 45-56.

4. Solomon LM, Fretzin D, Pruzansky S. Pilosebaceous abnormalities in Apert's syndrome. Arch Dermatol 1970; 102: 381-5.

5. Steffen C. Acneiform eruption in Apert's syndrome, acrocephalosyndactyly. Arch Dermatol 1982; 118: 206-8.

6. Henderson CA, Knaggs H, Clark A, Highet AS, Cunliffe WJ. Apert's syndrome and androgen receptor staining of the basal cells of sebaceous glands. Br J Dermatol 1995; 132: 139-43.

7. Downs AMR, Condon CA, Tan R. Isotretinoin therapy for antibiotic-refractory acne in Apert's syndrome. Clin Exp Dermatol 1999; 24: 461-3

8. Krunic AL, Vesic SA, Goldner B, Novak A, Clark RE. Ectrodactyly, soft-tissue syndactyly, and nodulo-cystic acne: coincidence or association? Ped Derm 1997; 14: 31-5.

9. Robinson D, Wilms NA. Successful treatment of the acne of Apert syndrome with isotretinoin. J Am Acad Dermatol 1989; 21: 315-6.