Global developmental delay, osteopenia and ectodermal defect: A new syndrome

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Brain & Development 28 (2006) 155–161 www.elsevier.com/locate/braindev

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Global developmental delay, osteopenia and ectodermal defect: A new syndrome Raffaella Zannollia,*, Sabrina Buonia, Francesca Macuccia, Maria M. de Santib, Flavia Miraccoc, Mauro Pierluigid, Massimo Mognid, Paola Piombonie, Maria R Massafraf, Paolo Galluzzig, Walter Livih, Aldo Cuccial, Maria A. Margolliccia, Lucia Puccia, Palmino Saccoi, Massimo Molinellia, Alberto B. Burlinaj, James A. Swiftk, Michele Fimianil, Michele Zappellam, Clelia Miraccob a

b

Department of Paediatrics, Obstetrics and Reproductive Medicine, Section of Paediatrics, Policlinico Le Scotte, University of Siena, Siena, Italy Department of Human Pathology and Oncology, Section of Pathological, Anatomy and Istology, Policlinico Le Scotte, University of Siena, Siena, Italy c Department of Ophthalmology and Neurosurgery, Policlinico Le Scotte, University of Siena, Siena, Italy d Human Genetics Laboratory, Galliera Hospital, Genoa, Italy e Department of Pediatrics, Obstetrics and Reproductive Medicine, Section of Biology, University of Siena, Siena, Italy f Stazione Sperimentale per la Seta, Milano, Italy g Neuroradiology Unit, Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, Siena, Italy h Department of ENT, Policlinico Le Scotte, University of Siena, Siena, Italy i Department of Radiology and Ortophaedics, Policlinico Le Scotte, University of Siena, Siena, Italy j Department of Pediatrics, University Hospital Padua, Padua, Italy k Department of Human Anatomy and Cell Biology, University of Liverpool, Liverpool, UK l Department of Internal Medicine and Immunological Sciences, Section of Dermatological Sciences, University of Siena, Siena, Italy m Pediatrics Neuropsychiatric Unit, Azienda Ospedaliera Universitaria Senese, Policlinico Le Scotte, Siena, Italy Received 13 May 2005; received in revised form 19 June 2005; accepted 21 June 2005

Abstract Global developmental delay is a serious social problem. It is often unrecognized and the phenotypes are inadequately studied. To investigate the phenotypes of children with aspecific central nervous system (CNS) impairment (poor speech, maladaptive behavioral symptoms such as temper tantrums, aggressiveness, poor concentration and attention, impulsiveness, and mental retardation). Setting. Tertiary care hospital. Patients: Three children (two male siblings, and one unrelated girl). Methods: We used the results from clinical neurological evaluations; imaging and electrodiagnostic studies; metabolic and genetic tests; skin biopsies and bone mineral densitometry. All three children suffered from (A) global developmental delay, (B) osteopenia, and (C) identical skin defects. The skin ultrastructural abnormalities were [1] abnormal keratin differentiation, consisting of hyperkeratosis and granular layer thickening; [2] sweat gland abnormalities, consisting of focal, cytoplasmic clear changes in eccrine secretory cells; and [3] melanocyte abnormalities, with both morphological changes (reduced number and size without evident dendritic processes), and functional changes (defects in the migration of melanosomes in the keratinocytes). These patients present a previously unrecognized syndrome. We retain useful to report this new association, to be recognized, in the next future, as a specific key-sign of a well-defined genetic defect. q 2005 Elsevier B.V. All rights reserved. Keywords: Global developmental delay; Ectodermal defect; Osteopenia

1. Introduction * Corresponding author. Tel.: C39 0577 586514; fax C39 0577 586143. E-mail address: [email protected] (R. Zannolli).

0387-7604/$ - see front matter q 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2005.06.011

Developmental disabilities form a group of related chronic, early-onset disorders. They are estimated to affect 5–10% of children. Global developmental delay, a subset of this group, is defined as a significant delay in the

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development of two or more of the following: gross or fine motor skills, speech or language, cognition, social or personal skills, and activities of daily living [1]. A child with the clinical appearance of global developmental delay is not necessarily mentally retarded. However, a child with global developmental delay is a serious problem, both socially and within the family. This disorder is often unrecognized and its physical characteristics have been inadequately studied [2]. The aim of this study was to better define the phenotype of patients suffering from aspecific global developmental delay by applying a standard work up.

2. Methods 2.1. Patients The three patients (Fig. 1) were children who were referred to our clinic because of their poor speech and maladaptive behavioral symptoms, such as temper tantrums, aggressiveness, poor concentration and attention, and impulsiveness. All three patients had apparently healthy and nonconsanguineous parents, and were born at term after uneventful pregnancies. Their physical growth was normal, but delayed psychomotor development and behavioral problems were apparent at an early stage. Two were brothers (Sib 1, seven years old, and Sib 2, four years old) and one was an unrelated 5-year-old girl. All underwent a systematic evaluation, including clinical histories; medical, neurological and ophthalmologic examinations; and the special diagnostic tests listed below. Skin, teeth, nails, hair and sudation were examined for defects. The skin was illuminated with a Wood’s lamp to identify hypopigmented areas. Routine laboratory tests for blood, urine, serum zinc, and copper were performed. All the probands had thyroid function tests, electrocardiography,

cardiac ultrasound, genitourinary system and abdominal examinations. The local Ethical Committee approved the study. Parents provided informed consent. 2.2. List of special examinations (1) Mental performance. Mental retardation, disorders in learning, motor skills, communication, pervasive development, attention deficit, disruptive behavior, and tic were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders criteria [3]. Intelligence was quantified with the Wechsler Preschool Primary Scale of Intelligence. Patients with a specific language disorder were excluded. (2) Biochemistry. All probands had a metabolic workup that included plasma analysis for ammonia, lactate and pyruvate, biotinidase, amino acids, acylcarnitine profile, very long chain fatty acids, phytanic acid, and the sialotransferrin pattern, and urine analysis for amino acids, organic acids, oligosaccharides, mucopolysaccharides, purine, and pyrimidine [4]. (3) Bone metabolism. Calcium–phosphorus metabolism was examined by measuring serum calcium and phosphorus levels, 24-h calciuria and phosphaturia values, calcitonin, parathyroid hormone, vitamine D levels, and serum alkaline phosphatase; serum bone alkaline phosphatase (bone ALP) measured with the Tandem (R) Ostase assay [5]. Appendicular bone mineral density (BMD) was measured. (4) Skin biopsy. The skin of each proband was examined with a Wood’s lamp and an area of low pigmentation was selected for biopsy. Under local anesthetic, one skin specimen was taken with a 4 mm Biopsy Punch (Biopsy Punch, Suddeutsche Feinmechanik, Bruckenstrasse, D-63607 Wachtersbach), previously sterilized with ethylene oxide. Biopsies were analyzed using light and transmission electron microscopy. For light

Fig. 1. Sib 1, Sib 2, and the girl. Note the hypopigmented areas in the two siblings (images taken under the effect of Wood’s lamp). Details of the joint laxity in the girl.

Table 1 Evidential data for each subject CNS dysfunction

Brain MRI

EEG

Hair

Skin

Bone metabolism

Sib 1

–mental delay, IQ 67 –ADHD –Speech delay –Behavioral problems

Normal

Normal

–Abnormal shape –Unusual pigmentation

–Keratins: orthokeratotic hyperkeratosis –Granular layer: thickened –Sweat glands: focal cytoplasmic clear change –Melanocytes: reduced in size, not evident dendritic process –Melanosomes: compound, present in basal keratinocytes, absent in suprabasal keratinocytes

Osteopenia, Z-score !K1.1 Hypocalciuriaa

Sib 2

–ADHD –Speech delay –Behavioral problems

Normal

–Minimal paroxysmal Activity in the central regions

–Abnormal shape –Unusual pigmentation

–Keratins: orthokeratotic hyperkeratosis –Granular layer: thickened –Sweat glands: focal cytoplasmic clear change –Melanocytes: reduced in size, not evident dendritic process –Melanosomes: compound, present in basal keratinocytes, absent in suprabasal keratinocytes

Osteopenia, Z-score !K2.5 Hypocalciuriab

Unrelated girl

–Mental delay, IQ 67 –ADHD –Speech delay –Behavioral problems

Widening of the perivascular Virchow–Robin spaces

–Minimal diffuse paroxysmal activity

–Abnormal shape –Unusual pigmentation

–Keratins: orthokeratotic hyperkeratosis –Granular layer: thickened –Sweat glands: focal cytoplasmic clear change –Melanocytes: reduced in size, not evident dendritic process –Melanosomes: compound, present in basal keratinocytes, absent in suprabasal keratinocytes

Osteopenia, Z-score !K1.8 Hypocalciuria and hypophosphaturiac

Normal values are 100–300 mg/24 h for calciuria, and 350–800 mg/24 h for phosphaturia. a Sib 1. 24 h calciuria: 47 mg. b Sib 2. 24 h calciuria: 56 mg c Unrelated girl. 24 h calciuria: 9 mg; 24 h phosphaturia: 27 mg.

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Patient

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microscopy, the skin fragments were stained with hematoxylin and eosin, giemsa–orcein for elastic skin fibers, and with Warthin Starry (pH 3.2), Alcian blue and PAS for melanin, mucin and glycogen deposits. Melanocytes were examined by immunostaining with Melan-A (anti-MART 1, mAb, Oncogene Research Products, San Diego, CA) as a marker, and the granular cell layers were examined using the marker filaggrin (anti-Filaggrin, mAb; Biomedical Technologies, DBAItalia, Segrate, Milano, Italy). For light microscopy, the skin fragments were examined with a Philips 208 S transmission electron microscope at 100 kV.

audiometry and impedentiometry were performed on each subject. (6) Chromosome studies. Standard metaphase spreads, obtained from peripheral blood lymphocytes and from cultured fibroblasts obtained by skin biopsy were studied with trypsin-giemsa (GTG) banding and highresolution banding. At least 100 metaphases chromosomes were observed from lymphocyte or fibroblast cultures to detect mosaic aneuploidy or mosaic chromosomal structural rearrangements.

3. Results The skin margins of two naevocytic naevi, excised from two normal children aged nine and 11 years, were the control biopsies. All specimens were analyzed using both light microscopy and transmission electron microscopy. (5) Imaging and electrodiagnostic studies. Brain magnetic resonance imaging (MRI) was performed on all patients, using a 1.5 T unit (Philips Gyroscan ACS NT15, Netherlands). Electroencephalographic recordings (EEGs) were obtained from the scalp with a BQ 3200 ACQDV, System 2 series EEG machine. Tonal

Normal test results are not reported for brevity. Evidential data for each subject are presented in Table 1, and some of the phenotypic features are shown in Fig. 1. Briefly, all the probands suffered from a global developmental delay, consisting of aspecific speech/language and cognition deficiencies, poor social and personal performance, and difficulty with activities of daily living. Two patients were mildly mentally retarded (Sib 1 and the unrelated girl, both with IQs of 67). All presented with slight joint laxity, which was more evident in the girl. The girl also

Fig. 2. Light microscopy of the skin biopsies of Sib 1, Sib 2, and the unrelated girl compared with a normal control. In all the probands, note (A) the thickening of the filaggrin (the continuous granular layer); (B) the extensive cytoplasmic clear cell change in eccrine secretory cells; and (C) the absence of melanocytes dendritic processes. (A) was stained with streptavidin-biotin immunostaining, OM!1000, (B) was stained with hematoxylin and eosin, OM(1000, (C) was stained with Melan-A, OM!1000.

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presented minimal dysmorphisms (broad and prominent forehead, thick eyebrows, slight synophrys, epicanthal folds, broad nasal bridge, long philtrum, thin lips, micrognathia with type II malocclusion). Her hands showed slight clinodactyly (second, fourth and fifth finger). Moreover, she had a winged scapula, hyperlordosis and dorsum recurvatum. Her teeth showed an evident hypoplasia of the lower central and lateral incisors, which seemed conical and lengthened, and a slight enamel dysplasia of the upper central incisors. Skin examinations revealed several hypopigmented areas with irregular lips, evident only using a Wood’s lamp, in the two boys. The girl presented several hypopigmented areas on the thorax with irregular lips that were only evident using a Wood’s lamp, and hyperpigmented linear areas in axillary and inguinal regions (images not shown). Elsewhere, these had initially been thought to be from incontinentia pigmenti [#MIM 308300], but the mutation analysis for the NEMO gene [MIM *300248] was not consistent with this diagnosis. Although the hairs were crowded and apparently normal, microscopy showed impressive, nonspecific abnormalities, suggesting a general defect in hair development. Sib 1 had irregular local forms, hair shaft discontinuities, and longitudinal splits through the cuticle. Sib 2 had abrupt changes in cross-sectional shape, continuity and longitudinal invagination. The girl had irregular local form, with abrupt changes in cross-sectional shape and continuity, and longitudinal invaginations. EEGs were normal in Sib 1, but Sib 2 showed minimal paroxysmal activity in the central regions, and the girl had minimal diffuse paroxysmal activity. Brain MRIs were normal in the sibling boys; those for the girl showed symmetrical widening of the perivascular Virchow–Robin spaces, which was more evident in the parietal paratrigonal regions (images not shown). Echocardiography revealed a mild insufficiency of the mitral valve and a mild-tomoderate insufficiency of the tricuspid valve in the girl. Calcium-phosphorus metabolism showed low values of 24h calciuria in all three probands (Sib 1: 47 mg per 24 h; Sib 2: 56 mg per 24 h; girl: 9 mg per 24 h; the normal range is 100–300 mg per 24 h), and phosphaturia in the girl (27 mg per 24 h; normal, 350–800 mg per 24 h). Osteopenia was found in all the probands (Sib 1: Z score ! K1.1; Sib 2: Z score ! K2.5; girl: Z score ! K1.8). Skin biopsies in all three probands showed [1] orthokeratotic hyperkeratosis and a thickened granular layer (Fig. 2A); [2] sweat glands with focal cytoplasmic clear changes in eccrine secretory cells, which were not due to mucins or glycogen storage (Fig. 2B); [3] melanocytes without evident dendritic processes (Fig. 2C); [4] no melanosomes in the keratinocytes of the suprabasal layer (Fig. 3); and [5] numerous compound melanosomes in the keratinocytes of the basal layer (Fig. 3, details). The presence of chromosome mosaicisms aneuploidy or mosaic chromosomal structural rearrangements both in lymphocytes and skin fibroblasts

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Fig. 3. Transmission electron microscopy of the skin biopsies of Sib 1, Sib 2, and the girl (A–C and F), compared with a normal control (D, E). In all the probands, note melanosomes abnormalities: (A–C) absence of the melanosomes into the keratinocytes of the suprabasal layer; presence of some melanosomes lying free between suprabasal keratinocytes (arrows); (F) only compound melanosomes (head arrow) in the melanocyte cytoplasm (from Sib 1, detail). In the skin control, note (D–E) numerous melanosomes present both around the nucleous and in the cytoplasmic dendrites. A–C, OM!3500. D and E, OM!8900. F, OM!15000. bk, basal keratinocyte; d, dendrite; m, melanocyte; sk, suprabasal keratinocyte.

was excluded, in at least 100 metaphases chromosomes both for blood lymphocytes and for fibroblasts.

4. Discussion Three children with aspecific CNS impairment (poor speech, maladaptive behavioral symptoms such as temper tantrums, aggressiveness, poor concentration and attention, impulsiveness; two were mentally retarded) were selected

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for examination with a standardized work-up. Our examination showed that all three suffer from (A) global developmental delay, (B) osteopenia, and (C) identical skin defects. This is a previously unrecognized syndrome. The skin ultrastructural abnormalities included three main defects: [1] abnormal keratin differentiation, consisting of hyperkeratosis and granular layer thickening; [2] sweat gland abnormalities, consisting of focal cytoplasmic clear change in eccrine secretory cells; and [3] melanocytic and melanosomal abnormalities, consisting of both morphological changes (reduced numbers and size, without evident dendritic processes for melanocytes, and the abnormal presence of compound melanosomes), and functional changes (defective migration of the melanosomes in the keratinocytes of the suprabasal layer). The chance of hypomelanosis of Ito, when considering it as only ‘a description not a diagnosis’ [6], has been excluded for three main reasons: (a) no association between the skin lesions and Blaschko lines; (b) absence of chromosome abnormalities; (c) differences in skin pathology. Although there are several patterns in hypopigmentation/hyperpigmentation in hypomelanosis of Ito, including not following to Blaschko lines, and there is no constant findings on chromosomal patterns between hypopigmented and hyperpigmented area [7], the combination in skin pathology (i.e. [1] abnormal keratin differentiation, [2] sweat gland abnormalities, and [3] melanocytic and melanosomal abnormalities) we found is unique, arising a possibility of new genetic syndrome. We cannot explain the association of the skin structural defects from these patients with their CNS impairment, although a close relationship between the skin and the brain has been suggested [8]. How these ultrastructural defects relate to the larger population of children with global developmental delay of unknown origin is also unknown, although osteopenia is associated with ectodermal defects and CNS impairment [9–11]. We retain useful to report the new association hoping that this will be recognized, in the next future, as a specific key-sign of a well-defined genetic defect. More extensive comments on the structural findings are included in Appendix to help in identifying the particular markers for this syndrome.

5. Electronic database information URLs for data in this article are as follows. Online Mendelian Inheritance in Man (OMIM): http://www.ncbi. nlm..nih.gov./Omim/Center for Medical Genetics, Johns Hopkins University, Baltimore, MD, and the national Centre for Biotechnology Information, National Library of Medicine, Bethesda, MD: #308300 INCONTINENTIA PIGMENTI, BLOCH- SULZBERGER TYPE *300248 INHIBITOR OF KAPPA LIGHT POLYPEPTIDE GENE ENHANCER IN B CELLS, KINASE OF,

GAMMA; IKBKG *300337 HYPOMELANOSIS OF ITO; HMI.

Acknowledgements We thank Emanuele Bruni, Sergio Medaglini, Lucio Natale, Letizia Pellegrini, and Gian Paolo Vatti, for their help in patients management. This study was supported in part by grant provided by the University of Siena (Piano d’Ateneo per la Ricerca 2003, project entitled ‘Phenotype and genetics of subjects with CNS disease and atypical ectodermal dysplasia’). The founding source had no role in the study design, data collection, data interpretation, or writing of the report.

Appendix A: The structural defects The abnormalities consisted of three main defects. (1)Abnormalities in keratin differentiation. The involvement of keratin differentiation is not understood. It is well known that modifications in the corneum and granular layers are strictly correlated in many cutaneous disorders (spongiotic dermatitis, lichen planus, and psoriasis) and in genodermatosis (ichthyosis and its several variants, and palmoplantar keratoderma) [12]. However, these conditions are quite different from those seen in our cases. (2)Abnormalities in sweat glands. The focal cytoplasmic clear changes in the eccrine secretory cells of the sweat gland were not due to mucins or glycogen storage. These can occur in benign eccrine tumors [14] and in situations other than cancer, such as local or systemic skin inflammation and diabetes [13]. However, focal cytoplasmic clear changes have not been observed in the normal skin of healthy young adults or children [15]. (3)Abnormalities in melanocytes. The abnormalities found in this study included (a) melanocytes reduced in size without evident dendritic processes; (b) compound melanosomes; and (c) the absence of melanosomes from the keratinocytes of the suprabasal layer. (a)The reduction in melanocyte size, without evident dendritic processes. This abnormality is present in the hypomelanosis of Ito [MIM *300337], a term applied to individuals with skin hypopigmentation along the Blaschko lines [13]. We can rule out an hypomelanosis of Ito [MIM *300337] in our patients because the skin hypopigmentation was not distributed along the Blaschko lines, and because of the increased numbers of melanosomes and the presence of compound melanosomes. Melanosomes are reduced in number and smaller in the hypomelanosis of Ito [16]. In another condition that resembles our situation, nevus achromians [17], the melanocytes are normal in shape and size, and numbers are normal or slightly reduced. In our patients, they lacked dendritic processes and were smaller. The melanosomes are normal in nevus achromians, whereas

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those in our patients had compound morphologies (for more details, see next paragraph). (b)Compound melanosomes. Compound melanosomes can be observed in the keratinocytes of the basal layer, and in lower densities in the suprabasal layer, in the normal population [16]. The density was very high in our patients. Normal melanosomes are laminated vesicles, 0.7!0.3 mm in size, and appear to be derived from the Golgi apparatus [18]. Their well-known function is to package melanin and to transfer melanin in the keratinocytes of the basal and suprabasal layer, via dendrites of the melanocytes. The presence of macromelanosomes (i.e. vesicles up to about 6 mm in size), are present in several conditions, such as cafe au lait spots, Chediak–Higashi syndrome, xeroderma pigmentosum, LEOPARD syndrome, generalized and multiple lentigines, Becker’s melanosis, vitiligous achromia with malignant melanoma, and even in normal skin. These are quite different to the compound melanosomes observed in this study [19]. Compound melanosomes have multiple melanosomes grouped together within single membranebound bodies. (c)Absence of melanosomes from the keratinocytes of the suprabasal layer. Failure in the transfer of melanosomes to suprabasal keratinocytes is also seen in the hypopigmented areas of patients with tuberous sclerosis [20] and Hermansky–Pudlak syndrome [21], although these conditions differ clinically and in their pathologies from our patients. We do not know why we did not find melanosomes in the suprabasal keratinocytes. The molecular motors that allow melanosomes to move within melanocytes have been studied intensively, and important proteins, such as the kinesin superfamily, dynein-associated proteins, the GTPase Rab27a protein, and myosin Va [22], have been discovered. However, the pathways leading to late (stage III or IV) melanosomes containing the mature melanin pigments being transferred to the suprabasal keratinocytes are poorly understood [23].

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