Dyschromatosis ptychotropica: an unusual pigmentary disorderin a boy with epileptic encephalopathy and progressive atrophyof the central nervous systema novel entity?
Ingo Helbig & Regina Flster-Holst & Jochen Brasch & Ingrid Hausser &Andreas van Baalen & Hiltrud Muhle & Karsten Alfke & Almuth Caliebe &Ulrich Stephani & Rudolf Happle
Received: 9 June 2009 /Accepted: 5 August 2009 /Published online: 26 August 2009# Springer-Verlag 2009
Abstract The skin and the central nervous system are tissuesof common ectodermal origin and share a close ontogeneticrelationship. Genetic diseases primarily affecting both organsystems are regularly encountered in both dermatological andneurological settings. Here, we report on a boy with epilepticencephalopathy, severe intellectual disability, optic atrophy,and progressive cerebellar and supratentorial atrophy, remi-niscent of progressive encephalopathy with edema andhypsarrythmia (PEHO) syndrome displaying a previouslyundescribed dyschromatosis in the form of progressive
reticulate and mottled hyper- and hypopigmentation of theneck and the inguinal and axillary regions. We hypothesisedthat this combination of neurological and cutaneous findingshas a common aetiology and represents a novel recognisableentity. Because of the unusual dermatological findings, wesuggest the term dyschromatosis ptychotropica. Recognitionof further cases may help elucidate the aetiology of thiscondition and give insight into the pathophysiology of bothpigmentation disorders and epileptic encephalopathies.
Keywords Epileptic encephalopathy . Pigmentary disorder .
Dyschromatosis . Neurocutaneous syndrome
The concept of neurocutaneous disorders refers to aheterogeneous group of neurological disorders in whichrecognition primarily depends on visual diagnosis of theassociated dermatological findings. The central nervoussystem can be affected in such disorders in several differentways, including impairment of global neuronal function aswell as effects of dysplasias or vascular malformations.
Neurocutaneous disorders are frequently encountered in apaediatric neurological setting, and conditions such as tuberoussclerosis account for a large fraction of patients with West syn-drome or LennoxGastaut syndrome . Recognition of theunderlying disease is important for genetic counselling andbecause of the increasing pharmacological and surgical treat-ment options . Moreover, patients can be monitored forassociated malignancies once a diagnosis has been achieved.
In a sizeable subset of children with severe epilepsies,diagnosis cannot be made based on neurological andimaging findings alone, and recognisable cutaneous fea-tures are sometimes the decisive clue.
I. Helbig (*) :A. van Baalen :H. Muhle :U. StephaniDepartment of Neuropediatrics,University Medical Center Schleswig-Holstein,Kiel Campus, Arnold-Heller-Str. 3, Haus 9, 24105 Kiel, Germanye-mail: [email protected]
R. Flster-Holst : J. BraschDepartment of Dermatology,University Medical Center Schleswig-Holstein,Kiel Campus, Schittenhelmstr. 7, 24105 Kiel, Germany
I. HausserDepartment of Dermatology, University Hospital Heidelberg,Vostr. 2, 69115 Heidelberg, Germany
K. AlfkeDepartment of Neuroradiology,University Medical Center Schleswig-Holstein,Arnold-Heller-Str. 3, Haus 9, 24105 Kiel, Germany
A. CaliebeDepartment of Human Genetics,University Medical Center Schleswig-Holstein,Arnold-Heller-Str. 3, Haus 10, 24105 Kiel, Germany
R. HappleDepartment of Dermatology, Philipp University of Marburg,Deutschhausstr. 9, 35033 Marburg, Germany
Eur J Pediatr (2010) 169:495500DOI 10.1007/s00431-009-1046-5
In this case report, we present a 5-year-old boy withprogressive mixed hypo- and hyperpigmentation showingaffinity to the body folds. We suggest that this cutaneousfinding might help delineate a novel distinct neurocuta-neous syndrome, and we propose the term dyschromatosisptychotropica (ptychotropism = affinity to the body folds).
General medical history
The patient is the first child of unrelated healthy parents.Family history is unremarkable. The patient was conceivedby intracytoplasmic sperm injection and was born at38 weeks gestation with Apgar values of 9-10-10 followingan uneventful pregnancy. Birth weight was 3,470 g, length
was 50 cm, and head circumference was 37 cm (allmeasures 75th95th percentile). At the age of 3 months,convulsive nystagmus was noted. Hypsarrythmia was seenat the age of 4 months, and multifocal epileptiformdischarges on electroencephalogram have been noted since.The prominent seizure type represents series of myoclonicseizures aggravated by fever, which has been noted sinceinfancy and has persisted since. Developmental delay hasbeen prominent from the first year of life with secondarymicrocephaly (
absent, suggestive of polyneuropathy. With the exception ofoedema of hands and feet, the general physical examinationwas otherwise unremarkable. Ultrasound of the abdomenrevealed no evidence of hepatosplenomegaly, and electro-cardiogram was normal. The following investigations wereperformed and yielded normal results: complete bloodcount; liver and thyroid function tests; plasma urea,electrolyte, and creatinine levels; creatinine kinase; choles-terol and triglycerides; acylcarnitine profile; urine aminoacids, organic acids, vanillylmandelic acid, and homova-nillic acid; blood and cerebrospinal fluid (CSF) lactate; CSFcells, protein, and glucose; plasma and CSF amino acids(tandem mass spectroscopy); and serum transferrin isoformpattern. Array comparative genomic hybridisation (CGH),screening for mutations in ARX, and karyotyping of skinfibroblasts from different biopsy sites gave normal results.
MRI scans obtained at the age of 3.5 months and at 4 yearsand 3 months showed progressive cerebellar and supra-tentorial atrophy as well as optic atrophy (Fig. 1).
Dermatological, histological, and ultrastructural findings
Irregular minute hyper- and hypopigmented macules mea-suring 24 mm in diameter and giving rise to a partlyreticular and partly mottled dyschromatosis were initiallynoted on the neck and in the axillary and inguinal regions.Over time, these pigmentary anomalies increased inintensity and spread to neighbouring areas. By the age of4.5 years, extensive mottled hyper- and hypopigmentationcould also be seen on the trunk and the extremities, but apronounced affinity to the body folds was still discernible(Fig. 2). A punch biopsy was taken for histopathology from
Fig. 2 Clinical appearance ofthe pigmentary disorder.Photographs taken at the age of5 years showing hyper- andhypopigmented areas on theneck (a, b), in the axillary (c),and inguinal regions (d)
Eur J Pediatr (2010) 169:495500 497
a pigmented axillary site. The epidermis had a regularstructure with a normal granular layer and a normal stratumcorneum (Fig. 3). Staining for melanin revealed a markedpigmentation of the basal epidermal cell layer, and immu-nostaining for Langerhans cells and melanocytes (S-100,HMB-45, melan-A) showed a proper distribution of thesecells. The superficial dermis was unremarkable.
Ultrastructural analysis of tissue obtained by punchbiopsy from a hyperpigmented area revealed normalamounts of synthetically very active melanocytes containinghigh numbers of fully melanised melanosomes (Fig. 4), butno specific vacuolation pattern as found in other dyschro-matoses on histological and ultrastructural analysis ofhyperpigmented areas [6, 13]. In contrast, the melanosomalload of keratinocytes was variable and not as regularlypronounced as to be expected in hyperpigmented areas.
We report on a 5-year-old boy with progressive cerebellarand supratentorial atrophy, optic atrophy, severe intellectualdisability, epileptic encephalopathy, and an unusual pro-gressive mottled hypo- and hyperpigmentation.
Clinically, the neurological defects of our patientresembled PEHO syndrome (progressive encephalopathywith oedema, hypsarrythmia, and optic atrophy, OMIM260565), and our patient meets the proposed diagnosticcriteria (Table 1) . The peculiar cutaneous findings,however, have thus far not been reported in PEHO
syndrome, PEHO-like syndrome, or other epileptic ence-phalopathies. Extensive metabolic and genetic studies failedto identify abnormalities in our patient. Neuroimagingshowed progressive supra- and infratentorial atrophy inconjunction with optic atrophy, but no evidence of a knownneurocutaneous disorder. The diagnosis of PEHO syndromeis exclusively based on clinical features with broadinclusion criteria. None of the features arguing againstPEHO syndrome were present in our patient such ascongenital microcephaly, abnormal gyral formation inneuroradiological studies, predominating spasticity in in-fancy, reappearance of visual contact after cessation ofinfantile spasms, and hepatosplenomegaly or storagedisorder in histological studies. An autosomal recessivemode of inheritance is assumed in PEHO syndrome, but theunderlying genetic basis remains unknown. PEHO appearsto be endemic to Finland, with only few cases reportedfrom other countries.
Fig. 4 Ultrastructural analysis on a pigmented axillary site. Ultra-structural analysis obtained through punch biopsy from an axillaryhyperpigmented area showing regular ultrastructural features ofsynthetically active melanocytes containing many fully melanisedmelanosomes (7400). N nucleus, M melanocytes, K keratinocyte;arrows point to densely packed melanosomes
Fig. 3 Histopathology on a pigmented axillary site. Hematoxylin andeosin stain on a tissue sample obtained through punch biopsy from anaxillary skin region (120). Epidermis and superficial dermis show anormal structure. 1 cornified layer