American Journal of Medical Genetics 135A:195–199 (2005)

Clinical ReportNovel Autosomal Recessive ProgressiveHyperpigmentation SyndromeUlrike Huffmeier,1* Ingrid Hausser,2 Andre Reis,1 and Anita Rauch1

1Institute of Human Genetics, Friedrich-Alexander University of Erlangen-Nuremberg, Germany2Hautklinik, University of Heidelberg, Germany

We present a family of Iraqui origin with threesiblings affected by a novel type of progressivehyperpigmentation syndrome. The generalizedinitially diffuse, later disseminated hyperpigmen-tation started in early infancy and increasedduring childhood. It also affected palms and soles,and the face but spared the cheeks. Additionalfeatures were dry, itchy and sunlight sensitiveskin, dystrophy of toe nails, hair loss, and myopia,but normal sweat glands. Light and electronmicroscopy showed signs of pigment incontinenceand compound melanosomes as well as fibrillarbodies. The occurrence of this entity in affectedsiblings from a consanguineous mating sug-gests autosomal recessive inheritance. Extensivereview of the literature showed no previousreport with this distinct combination of clinicaland microscopic findings.� 2005 Wiley-Liss, Inc.

KEY WORDS: hereditary skin disorder; consan-guinity; pigmentation; pigmentincontinence

INTRODUCTION

Generalized hyperpigmentation occurs as a primary defectof pigmentation, isolated or in combinationwith variable othermanifestations. It can also be a secondary feature of inbornerrors of metabolism and inflammatory diseases, as well asendocrinological disorders, such as Addison disease andhypercorticolism. We describe a family with a primary type ofprogressive generalized, disseminated hyperpigmentationwith additional manifestations that differ significantly fromother known conditions.

MATERIALS AND METHODS

Clinical Report

The family originated from Iraq, and the parents were firstcousins (Fig. 1). Three of their four children were affected. No

other family member had a similar skin disorder. Height was161.5 cm (3rd centile for Turkish men) in the father and154.7 cm (25–50th centile for Turkish women) in the mother.The remaining family history was unremarkable.

The oldest (IV.1) was a 15-year-old girl born about 2 weekspost term; her body creases were red. The mother notedabnormal hyperpigmentation proximal to the finger nails at 2weeks.Within the first year of life, she developed symmetrical,disseminated hyperpigmentation, most pronounced on thetrunk and sparing the face. Later, hyperpigmentation affectedthe palms, soles, and perioral and periorbital regions. Shecomplained that her skin was very dry and that sunlightresulted in pruritis. She also noted a white fluid emergingwhile cutting her nails. Childhood was remarkable for chronicdiarrhea, several instances of pneumonia, and acute hepatitistreated in Iraq. Episodic fever accompanied occipital hair lossat about age 11 years. In addition to myopia, her eyes wereirritable (itching and flushing). She also had unexplained earpain, which improved slightly following the extraction of somemolar teeth.

Examination at 15 years showed symmetrical, disseminatedhyperpigmentation (maximum size of a pinhead). Palmar,plantar, and mucosal surfaces were also involved. A highdensity of hyperpigmentation was found on the toes and dorsalside of the interphalangeal joints, with lower density on thecheeks. The toenails were dystrophic (thickened with creases),but fingernails had no major alterations. Her smaller toes hadblisters at the plantar and dorsal side. She had progressivehair loss, mainly in the occipital region (Fig. 2). Her heightwas 152.3 cm (3rd centile for German children, 3rd–10thcentile for Turkish girls), her weight was 53.1 kg (25–50th

Fig. 1. Pedigree of family with hyperpigmentation syndrome.

*Correspondence to: Dr. Ulrike Huffmeier, Institut fur Human-genetik, Schwabachanlage 10, 91054 Erlangen, Germany.E-mail: uhueffm@humgenet.uni-erlangen.de

Received 14 October 2004; Accepted 3 January 2005

DOI 10.1002/ajmg.a.30668

� 2005 Wiley-Liss, Inc.

centile), herhead circumferencewas52.5 cm (10–25th centile).Karyotype was normal.

The second (IV.2) was a 13-year-old healthy boy with shortstature only (139.5 cm, below 3rd centile for Turkish boys).

The third (IV.3) was an 8-year-old girl who developedhyperpigmentary changes at about 2 weeks. She wore glassesbecause she was nearsighted and had episodic diarrhea justlike her sister. During infancy, she needed a blood transfusion

Fig. 2. Distribution of hyperpigmentation: body in IV.1 (a) and IV.4(c) face in IV.3 (b) progression of hyperpigmentation mainly on the face andon the extremities with age; (d) hair loss in IV.1; (e) hyperpigmentation inperioral region and on tongue in IV.1; (f–h) progressive hyperpigmentationof feet from youngest child (h) to older girl (f) plantar involvement andblisters of the fourth and fifth toes in IV.1 (f) shortened fourth metacarpal,

particularly, on the right hand in IV.3 (g) progressive nail dystrophy in allthree patients; progressive hyperpigmentation of palms in IV.1 (i), IV.3 (j),and IV.4 (k) transverse palmar crease in IV.4 (k) progressive hyperpigmen-tation of fingers in IV.1 (l) and IV.4 (m) proximal to nails and aboveinterphalangeal joints in IV.1; hyperpigmentation of upper back in IV.3(n) diffuse to disseminated distribution of hyperpigmentation.

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due to an unexplained anemia. Head sweating with inflam-mation resulted in the avoidance of heat. In sunlight, shecomplained of itchy eyes and sensitive cheeks. Her skin wasless dry than her other affected siblings. Her hyperpigmenta-tionwas somewhat lighter and less dense and her face was lessaffected. However, distribution of hyperpigmentary spots andtoenail dystrophy were similar to those of her sister (Fig. 2).She had short fourth metacarpals, more severe on the righthand.One canine toothwasabsent, but the rest of her dentitionwas normal, as was her skeleton. Her height (126 cm), weight(28.8 kg), and head circumference (50 cm) were within thenormal range.

The fourth (IV.4)wasa4-year-old boywithhyperpigmentarychanges at 2weeks.He alsowore glasses andhad irritable eyesin sunlight. His face was slightly affected, his skin was verydry, and hyperpigmentation was more pronounced on histrunk; his extremities were mildly affected. Truncal hyper-pigmentation appearedmore diffusewith interspersed areas ofpale skin. He also had a hypopigmented macule of theabdomen, left-sided supernumerary nipple, and single palmar

crease on the left hand (Fig. 2).Hehad episodic pneumonia andupper airway infection.

Skin Biopsy

Skin biopsies were taken from hyperpigmented and hypo-pigmented areas of patient IV.1. They were prepared for lightand electron microscopy and tyrosinase activity with dihy-droxyphenylalanine (DOPA) reaction (Figs. 3, 4).

DISCUSSION

Manifestations of affected siblings were progressive, initiallydiffuse with later disseminated hyperpigmentation of the skin,palms, soles, and mucosa. The skin was dry and compact; thetoenails were dystrophic. Hair loss began during puberty;myopia and light sensitivity developed; and unexplaineddisorders as well as upper and lower respiratory infectionsoccurred during infancy. Other low frequency findings in dif-ferent siblings included blistering of the toes, absent canine

Fig. 2. (Continued)

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Fig. 4. Electron microscopy of skin biopsy; cells with more (a) and less (b) melanin; dihydroxyphenylalanine (DOPA)-reaction showing even primarymelanosomes in dark color (c) and labeled cisternae of dictyosomes of Golgi apparatus (d) melanophage in upper dermis (e) and fibrillary body beside tail ofmelanophage (f).

Fig. 3. Light microscopy of skin biopsy in hypopigmented (a) and hyperpigmented (b) areas. Arrows indicate sites of melanophages.

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tooth, brachymetacarpalism, supernumerary nipple, singlepalmar crease, transitory anemia, and heat intolerance despitenormal palmar sweat glands.

These abnormalities are compatible with the group of ecto-dermal dysplasias [Freire-Maia and Pinheiro, 1984], but thedistinct combination with progressive disseminated hyper-pigmentation found in our patients has not been describedpreviously. A rare type of hypohidrotic ectodermal dysplasiawith reticular pigmentation appearing around 2 years of ageand fading after puberty differs by its course as well as theseverity of dental involvement, palmoplantar keratoses, andnormal hair [Itin et al., 1993]. Other rare syndromes withhyperpigmentation also differ clinically and/ormicroscopically(see supplementary table online). Melanosis diffusa congenitadescribed byBraun-Falco et al. [1980] resembles the syndromedescribed here in age of onset and nail dystrophy. However,other manifestations are present and the histological findingsas well as the type of hyperkeratosis differ.

In two types of dyskeratosis, DKC1 mutations (X-linkedform) [Heiss et al., 1998] and hTR mutations (autosomaldominant form) [Vulliamy et al., 2001]may be good candidatesfor the novel form of progressive hyperpigmentation found inour family.

ACKNOWLEDGMENTS

WethankProf.WolfgangKuster, TOMESA-Fachklinik, BadSalzschlirf, and Prof. Heiko Traupe, Dermatology Depart-ment, University Clinic, Munster for helpful discussions.

REFERENCES

Braun-Falco O, Burg G, Selzle D, Schmoeckel C. 1980. [ Diffuse congenitalmelanosis ]. Hautarzt 31:324–327.

Freire-Maia N, Pinheiro M. 1984. Ectodermal dysplasias: A clinical andgenetic study. New York: Alan R. Liss.

Heiss NS, Knight SW, Vulliamy TJ, Klauck SM, Wiemann S, Mason PJ,Poustka A, Dokal I. 1998. X-linked dyskeratosis congenita is caused bymutations in a highly conserved gene with putative nucleolar functions.Nat Genet 19:32–38.

Itin PH, Lautenschlager S, Meyer R, Mevorah B, Rufli T. 1993. Naturalhistory of the Naegeli-Franceschetti–Jadassohn syndrome and furtherdelineation of its clinical manifestations. J Am Acad Dermatol 28:942–950.

VulliamyT,MarroneA,GoldmanF,DearloveA,BesslerM,MasonPJ,DokalI. 2001. The RNA component of telomerase is mutated in autosomaldominant dyskeratosis congenita. Nature 413:432–435.

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