SHORT REPORT
Dyschromatosis ptychotropica: an unusual pigmentary disorderin a boy with epileptic encephalopathy and progressive atrophyof the central nervous system—a novel entity?
Ingo Helbig & Regina Fölster-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
Introduction
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 Lennox–Gastaut syndrome [2]. Recognition of theunderlying disease is important for genetic counselling andbecause of the increasing pharmacological and surgical treat-ment options [8]. 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. Fölster-Holst : J. BraschDepartment of Dermatology,University Medical Center Schleswig-Holstein,Kiel Campus, Schittenhelmstr. 7, 24105 Kiel, Germany
I. HausserDepartment of Dermatology, University Hospital Heidelberg,Voßstr. 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) 169:495–500DOI 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).
Case report
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 75th–95th 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 (<3rd percentile), and at a consultation at theage of 4.5 years, the patient presented with severeintellectual disability. Speech was absent, while appropriatereactions to auditory stimuli could be elicited. Fixation andvisually evoked potentials were not present. The patientcould roll over from back to front and often assumed anopisthotonic posture when lying on the back. Upper andlower limbs were hypotonic, and deep tendon reflexes were
Fig. 1 Cranial MRIat 3.5 months and 4 years and3 months. Sagittal T1-weightedimages at 3.5 months (a) and at4 years and 3 months (b) show aprogressive cerebellar andcerebral atrophy. CoronalT2-weighted images at 4 yearsand 3 months (c) show atrophyof optic nerve and brain.Cerebellar atrophy (A, B) andoptic atrophy (C) is indicatedby arrows
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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 2–4 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)
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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.
Discussion
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) [14]. 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 (stratum corneum); 2 granular layer(stratum granulosum); 3 prickle cell layer (stratum spinosum); 4stratum reticulare
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The cutaneous findings in our patient do not resemblepreviously described disorders of pigmentation. Other syn-dromes characterised by hyperpigmentation and neurologicaldefects, such as incontinentia pigmenti or neurocutaneousmelanosis, are associated with distinct cutaneous features thatcan be easily distinguished from the dyschromatosis present inour patient.
Some additional conditions with reticulated or mottledhyperpigmentation have previously been described. Mottledhyperpigmentation in combination with microcephaly andintellectual disability is observed in macular bullous dystrophyof Mendes da Costa (OMIM 302000) [5, 12]. However,spontaneous blistering, a key feature of this X-linked recessivetrait, is notably absent in our patient, and the reticulatedhyperpigmentation as described in Mendes da Costa syn-drome is most prominent on the face and limbs, whereas thepigmentation abnormalities in our patients were most prom-inent in the nuchal, axillary, and inguinal folds. Conditionssuch as reticulate acropigmentation of Kitamura [3] andDowling–Degos disease (OMIM 179850) [9] can be excludeddue to the presence of hypopigmented macules. Naegeli–
Franceschetti–Jadassohn syndrome (OMIM 161000) [3] canbe ruled out because key features of this syndrome such asdiminished sweating, absence of teeth, and hyperkeratosis ofpalms and soles are not present. Moreover, these conditionsusually are not associated with epileptic encephalopathies.
Dyschromatoses are disorders of skin pigmentation inwhich cutaneous findings include both hyperpigmented andhypopigmented macules. Dyschromatosis universalishereditaria (DUH, OMIM 127500, 612715) and dyschro-matosis symmetrica hereditaria (DSH, OMIM 127400),also known as acropigmentation of Dohi, constitute the twomajor subtypes, which are predominantly encountered inJapan and other Asian ethnicities [15]. In DUH, pigmen-tation deficits are usually present within the first year of lifeand typically present with larger, irregular macules on thetrunk, the extremities, and the face. Neither the time ofoccurrence nor the pattern of distribution is compatible withthe skin findings in our patient. DSH has been found to beassociated with various neurological conditions of child-hood [10]. However, the absence of prominent acraldyspigmentation rules out DSH in our patient.
Necessary criteria for PEHO syndrome
1. Infantile, usually neonatal hypotonia
2. Seizure disorder manifesting with myoclonic jerks and infantile spasms
3. Profound psychomotor delay with severe hypotonia; absence of motor milestones and speech
4. Absence or early loss of visual fixation with atrophy of optic discs by 2 years of age; normalelectroretinogram, extinguished visual evoked potentials
5. Progressive brain atrophy, particularly in the cerebellum and brain stem; milder supratentorial atrophy
Supportive criteria for PEHO syndrome
1. Subtle dysmorphic features with bitemporal narrowing of forehead, epicanthic folds, short nose,orofacial hypotonia (open mouth), micrognathia, and tapering fingers
2. Oedema of face and limbs, especially in early childhood
3. Brisk tendon reflexes in early childhood
4. Abnormal brain stem auditory evoked potentials
5. Absent cortical responses of somatosensory evoked potentials
6. Slow nerve conduction velocities in late childhood
7. Dysmyelination in magnetic resonance imaging
Featuring not supportive of a diagnosis of PEHO syndrome
1. Microcephaly at birth
2. Evidence of brain malformation
3. Predominating spasticity in infancy
4. Reappearance of visual contact after cessation of infantile spasms
5. Hepatosplenomegaly or storage disorder in histological studies
Differential diagnosis in patients with suspected PEHO syndrome (compiled from various sources)
1. Joubert syndrome
2. Autosomal recessive cerebellar hypoplasia (Norman syndrome)
3. Olivopontocerebellar atrophy with spinal muscular atrophy
4. Mevalonic aciduria
5. Infantile neuronal ceroid lipofuscinosis (Batten disease)
6. Carbohydrate-deficient glycoprotein syndrome
Table 1 Clinical features ofPEHO syndrome and differentialdiagnoses (modified fromSomer 1993)
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Mosaicism is occasionally seen in patients with pigmen-tary disorders and neurological features. Hypomelanosis ofIto (OMIM 300337) was ruled out in the present casebecause of the symmetric and nonsegmental involvement.The pigmentary anomalies of our patient did not followBlaschko's lines or any other segmental pattern as usuallyseen in mosaic conditions. In particular, the various types ofcutis tricolor could be excluded because the areas of hyper-and hypopigmentation are much larger in these disorders,even in cutis tricolor parvimaculata [4, 7, 11]. Largestructural genomic aberrations such as a mosaic supernu-merary inv dup(15) chromosome, which was recentlyreported in a patient with mottled hyperpigmentation,intellectual disability, and epileptic seizures [1] could beexcluded by array CGH.
In summary, we report on a 5-year-old patient with aPEHO-like syndrome and a previously undescribed distinctdyschromatosis. Even though dermatological findings arenot considered exclusion criteria for PEHO, the distinctcutaneous dyschromatosis sets our patient apart fromclassical PEHO syndrome. While we cannot exclude thatdyschromatosis is a rare additional and as yet undescribedfeature of classical PEHO syndrome, we suggest that it mayconstitute a separate entity. Identification of further patientswith this condition may help delineate the clinical spectrumof this disorder and elucidate its molecular basis.
Conflict of interest We declare that we have no conflict of interest.
References
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