Το σύνδρομο Σμιθ-Μαγγίνις παρουσιάζει ξεχωριστά χαρακτηριστικά προσώπου, αναπτυξιακή υστέρηση, γνωστικά ελλείμματα και προβλήματα συμπεριφοράς.

Χαρακτηριστικά του συνδρόμου

Όψη του προσώπου

Πλατύ τετράγωνο σχήμα προσώπου, βραχυκεφαλία, προτεταμένο μέτωπο, σμιχτά φρύδια, ελαφρώς κυρτά βλέφαρα με ραγάδες, βαθουλωτά μάτια, πλατιά ρινική γέφυρα, υποπλασία του μεσαίου τμήματος του προσώπου, κοντή και πλατιά μύτη, μικρογναθία κατά τη βρεφική ηλικία που εξελίσσεται σε σχετικό προγναθισμό με την ηλικία και ιδιαίτερη όψη του στόματος με παχύ προεξέχον άνω χείλος. Με την πάροδο των ετών η όψη του προσώπου γίνεται πιο χαρακτηριστική και χονδροειδής, με συνεχιζόμενη υποπλασία του μεσαίου τμήματος του προσώπου, σχετικό προγναθισμό και πυκνά φρύδια που δίνουν μια κάπως άγρια όψη. Έχουν σημειωθεί περιπτώσεις οδοντικών ανωμαλιών, πιο συγκεκριμένα αγενεσία (συνήθως των προγόμφιων) και πρόσφατα ταυροδοντία.

Όπως συμβαίνει συχνά στα γενετικά σύνδρομα νοητικής υστέρησης, και στο σύνδρομο Σμιθ-Μαγγίνις οι γνωστικές και προσαρμοστικές ικανότητες ποικίλουν, με την πλειονότητα των ατόμων με σύνδρομο Σμιθ-Μαγγίνις να παρουσιάζουν ελαφρά έως μέτρια νοητική υστέρηση.

Κρανιοπροσωπικά / σκελετικά χαρακτηριστικά

* Βραχυκεφαλία
* Υποπλασία του μέσου τμήματος του προσώπου
* Ελαφρύς προγναθισμός
* Πλατύ, τετράγωνο πρόσωπο
* Προεξέχον και παχύ άνω χείλος
* Βαθουλωτά μάτια
* Μικρές και χοντρές παλάμες
* Οδοντικές ανωμαλίες (απουσία προγόμφιων, ταυροδοντία)

Ωτορινολαρυγγικές ανωμαλίες

* Ανωμαλίες μέσου ωτός και λάρυγγα
* Βραχνή, βαθειά φωνή

Νευρολογικά / Συμπεριφοριστικά χαρακτηριστικά

* Βλάβη γνωστικών λειτουργιών / αναπτυξιακή καθυστέρηση
* Γενική παθητικότητα / λήθαργος (κατά τη βρεφική ηλικία)
* Βρεφικός ελαττωμένος μυϊκός τόνος
* Ανεστραμμένος 24ωρος ρυθμός μελατονίνης
* Αυτοβλαπτικές συμπεριφορές
* Καθυστέρηση ομιλίας
* Αργά ανακλαστικά
* Συμπτώματα περιφερικής νευροπάθειας
* Λεκτική, αισθητηριακή και κινητική δυσλειτουργία (κατά την πρώτη παιδική ηλικία)

Συνήθη χαρακτηριστικά (50-75% των ατόμων με σύνδρομο Σμίθ-Μαγγίνις)

* Απώλεια ακοής
* Μικρό ανάστημα
* Σκολίωση
* mild vetriculomegaly of brain
* Προβλήματα τραχείας και βρόγχων
* Velopharyngeal insufficiency (VPI)
* Οφθαλμικές ανωμαλίες (ανωμαλίες ίριδας, microcornea)
* Ανωμαλίες στη φάση ύπου REM
* Υπερχοληστερολαιμία / Υπερτριγλυκεριδαιμία
* Δυσκοιλιότητα
* Μη φυσιολογικό ΗΕΓ χωρίς εμφανείς επιληπτικές κρίσεις

Λιγότερο συνήθη χαρακτηριστικά (25-50% των ατόμων με σύνδρομο Σμιθ-Μαγγίνις)

* Καρδιακές δυσπλασίες
* Ανωμαλίες στη λειτουργία του θυρεοειδούς
* Επιληπτικές κρίσεις
* Ανωμαλίες ανοσοποιητικού συστήματος (ιδιαίτερα χαμηλά επίπεδα ανοσοσφαιρίνης Α)

Σπάνια χαρακτηριστικά (<25% των ατόμων με σύνδρομο Σμιθ-Μαγκίνις)

* Νεφρικές ανωμαλίες και ανωμαλίες ουροποιητικού συστήματος
* Επιληπτικές κρίσεις
* Δυσπλασία αντιβραχίονα
* Χειλιοσχιστία
* Αποκόλληση αμφιβληστροειδή

Η αναπτυξιακή καθυστέρηση είναι εμφανής από την πρώτη παιδική ηλικία με την πλειονότητα των μεγαλύτερων παιδιών και των ενηλίκων να παρουσιάζουν ελαφρά εώς μέτρια νοητική υστέρηση. Γνωστικά παρατηρούνται αδυναμίες στον αλληλοδιάδοχο συλλογισμό [σκέψη σε βήματα] και στη βραχυπρόθεσμη μνήμη αλλά παράλληλα παρατηρείται ικανότητα μακροπρόθεσμης μνήμης και perceptual closure (δηλ. της διαδικασίας όπου ένα ένα μερικό οπτικό ερέθισμα γίνεται αντιληπτό ως ολόκληρο - τα μέρη ενός όλου).

Τα βρέφη με σύνδρομο Σμιθ-Μαγκίνις αντιμετωπίζουν προβλήματα στη λήψη τροφής, δεν αναπτύσσονται κανονικά, παρουσιάζουν υποτονικότητα, κοιμούνται πολύ ή χρειάζεται να τα ξυπνήσουμε για να πάρουν τροφή, και παρουσιάζουν μια γενικευμένη ληθαργική κατάσταση.

Η συμπεριφορά των ατόμων με σύνδρομο Σμιθ-Μαγκίνις περιλαμβάνει διαταραχές ύπνου, στερεοτυπική συμπεριφορά και δυσπροσαρμοστική και αυτο-βλαπτική συμπεριφορά, δεν γίνεται αντιληπτή πριν τους 18 μήνες, και συνεχίζει να αλλάζει σε όλη τη διάρκεια της παιδικής ηλικίας και ενήλικης ζωής τους. Οι διαταραχές ύπνου χαρακτηρίζονται από διακεκομμένους και μικρούς κύκλους ύπνου με συχνές αφυπνίσεις κατά την διάρκεια της νύχτας και νωρίς το πρωί και υπερβολικό νυσταγμό κατά τη διάρκεια της μέρας. Οι διαταραχές αυτές σχετίζονται με ανεστραμμένο 24ωρο ρυθμό έκκρισης μελατονίνης και αποτελεί χρόνιο πρόβλημα.

Η παιδική ηλικία και η ενήλικη ζωή χαρακτηρίζονται από έλλεψη προσοχής, υπερκινητικότητα, δυσπροσαρμοστικές συμπεριφορές όπως συχνές εκρήξεις, απαίτηση προσοχής του περιβάλλοντος, παρορμητικότητα, διάσπαση προσοχής, ανυπακοή, επιθετικότητα, δυσκολίες στις αφοδευτικές λειτουργίες, αυτοτραυματιστικές συμπεριφορές (ξύλο, δάγκωμα, τσίμπημα, εισαγωγή αντικειμένων στις σωματικές κοιλότητες και τράβηγμα νυχιών στα χέρια και τα πόδια). Δύο στερεοτυπικές συμπεριφορές, σπασμωδική πίεση του άνω κορμού ή αυτο-εναγκαλισμός και γλείψιμο των χεριών και γύρισμα σελίδων φαίνεται να είναι χαρακτηριστική στο σύνδρομο Σμίθ-Μαγγίνις. Επιπλέον στερεοτυπικές συμπεριφορές περιλαμβάνουν το να βάζουν αντικείμενα ή το χέρι τους στο στόμα, να τρίζουν τα δόντια τους, να ταλαντεύονται μπρος-πίσω και να στριφογυρνούν αντικείμενα.

Δεν υπάρχουν αρκετά ερευνητικά δεδομένα για το προσδόκιμο της ζωής, παρόλα αυτά το γηραιότερο άτομο με σύνδρομο Σμιθ-Μαγκίνις είναι σήμερα περίπου 85 ετών. Θα έλεγε κανείς πως, καθώς το σύνδρομο δεν επηρεάζει κάποιο ζωτικό όργανο, ισχύει γενικά ό,τι ισχύει και για γενικό πληθυσμό των ατόμων με αναπηρίες.

Διάγνωση

Η διάγνωση του συνδρόμου Σμιθ-Μαγκίνις επιβεβαιώνεται είτε με τον εντοπισμό της απώλειας του μικρού βραχίονα του χρωμοσώματος 17. Συχνά αυτή η απώλεια παραβλέπεται ιδιαίτερα όταν υπάρχουν ενδείξεις για άλλο γενετικό πρόβλημα.

Κλινική διάγνωση

Η κλινική διάγνωση συνιστάται σε άτομα που παρουσιάζουν ένα περίπλοκο συνδυασμό συμπτωμάτων, όπως: διακριτή εμφάνιση προσώπου που γίνεται πιο εμφανής με την πάροδο του χρόνου, ελλαττωμένος μυϊκός τόνος με δυσκολίες στη λήψη τροφής, υστέρηση ανάπτυξης, μικρές σκελετικές ανωμαλίες, μικρός κορμός, βραχυδακτυλία, οφθαλμολογικές και ωτορινολαρυγγικές ανωμαλίες, καθυστέρηση της έναρξης της ομιλίας με ή χωρίς απώλεια ακοής και συμπτώματα περιφερειακής νευροπάθειας. Καρδιακές και νεφρικές ανωμαλίες και χειλιοσχιστία παρουσιάζονται λιγότερο συχνά. Όλα τα άτομα με σύνδρομο Σμιθ-Μαγκίνις έχουν ένα βαθμό γνωστικών βλαβών και νοητικής υστέρησης. Στη χαρακτηριστική συμπεριφορά του συνδρόμου περιλαμβάνεται διαταραχή ύπνου και στερεοτυπικές και δυσπροσαρμοστικές συμπεριφορές.

Η διαταραχή του ύπνου είναι χρόνια και σχετίζεται με ανωμαλίες στον 24ωρο ρυθμό της έκκρισης μελατονίνης. Τα εμφανή χαρακτηριστικά ενδέχεται να είναι ήπια κατά τη βρεφική και πρώτη παιδική ηλικία, γεγονός που καθυστερεί την τελική διάγνωση ως τη σχολική ηλικία όπου η χαρακτηριστική όψη του προσώπου και οι συμπεριφορές είναι ευκολότερα αναγνωρίσιμες.

Η συχνότητα εμφάνισης του συνδρόμου σύνδρομο Σμίθ-Μαγγίνις είναι ίδια για αγόρια και κορίτσια.

Διαφορική διάγνωση

Το διακρίνεται από άλλα σύνδρομα που προκαλούν αναπτυξιακή υστέρηση, βρεφική υποτονικότητα, μικρό κορμό, χαρακτηριστική όψη προσώπου και συμπεριφορές, όπως τα σύνδρομα VCF, ΝτιΤζόρτζ, Πρέιντερ-Γουίλι, Γουίλιαμς, Ντάουν, και εύθραυστου χρωμοσώματος Χ. Η διάκριση επιβεβαιώνεται με γενετική ή μοριακή ανάλυση.

Κλινικά, σε πολλά παιδιά με σύνδρομο Σμίθ-Μαγγίνις γίνονται ψυχιατρικές διαγνώσεις, συμπεριλαμβανομένου του αυτισμού και ή/και σύνδρομο ελλειμματικής προσοχής ή/και διαταραχές διάθεσης λόγω καθυστέρησης της ανάπτυξης της ομιλίας και δυσπροσαρμοστικών και στερεοτυπικών συμπεριφορών.

Είναι σύνηθες να καθυστερείται η διάγνωση. Βρέφη με σύνδρομο Σμίθ-Μαγγίνις λαμβάνουν λανθασμένα διάγνωση για σύνδρομο Down εξαιτίας της υποτονικότητας, και τα ιδιαίτερα χαρακτηριστικά του προσώπου και/ή την συγγενή καρδιοπάθεια.

Συχνότητα εμφάνισης

Το σύνδρομο Σμίθ-Μαγγίνις υπολογίζεται 1 άτομο ανά 25.000 γεννήσεις, αλλά πρόκειται μάλλον για υποεκτίμηση. Υπολογίζεται πως η πραγματική εμφάνιση του συνδρόμου είναι 1 ανά 15.000 γεννήσεις. Η πλειονότητα των περιπτώσεων έχουν διαγνωστεί τα τελευταία 5-10 χρόνια ως αποτέλεσμα καλύτερων γενετικών διαγνωστικών μεθόδων. Το σύνδρομο εμφανίζεται διεθνώς και σε όλες τις φυλετικές ομάδες.

Γενετική συμβουλευτική

Όλες σχεδόν οι περιπτώσεις με σύνδρομο Σμίθ-Μαγγίνις συμβαίνουν de novo. Υπάρχουν μεμονωμένες αναφορές για περίπλοκες κληρονομικές χρωμοσωματικές ανακατατάξεις που έχουν ως αποτέλεσμα την απώλεια του χρωματοσώματος 17 και συνεπώς σύνδρομο Σμίθ-Μαγγίνις.

Εάν τα αποτελέσματα της γενετικής ανάλυσης των γονέων είναι φυσιολογικά, η πιθανότητα εμφάνισης σύνδρομο Σμίθ-Μαγγίνις σε επόμενη εγκυμοσύνη είναι μικρότερος του 1%. Στη σπάνια περίπτωση περίπλοκων κληρονομικών ανακατατάξεων, είναι δυνατός ο προγεννητικός έλεγχος.

Αντιμετώπιση

Μετά τη διάγνωση του σύνδρομο Σμίθ-Μαγγίνις χρειάζεται να γίνουν μια σειρά από εξετάσεις και αξιολογήσεις ώστε να καθοριστεί η ιατρική αγωγή. Ιδανικά η αξιολόγηση και οι συνακόλουθες παρεμβάσεις πρέπει να είναι διεπιστημονικές και να περιλαμβάνουν αξιολογήση από εργοθεραπευτή και λογοπεδικό και παιδιατρική εξέταση ως βάση για το εξατομικευμένο εκπαιδευτικό πρόγραμμα.

Η αντιμετώπιση / αγωγή περιλαμβάνει:

* διαρκή παρακολούθηση από παιδίατρο και εμβολιασμό
* πρόγραμμα πρώιμης παρέμβασης ήδη από τη βρεφική ηλικία και ακολούθως προγράμματα ειδικής αγωγής και ειδικής επαγγελματικής κατάρτισης
* λογοθεραπεία, εργοθεραπεία, φυσιοθεραπεία και ειδική αισθητηριακή …

Κατά την πρώτη παιδική ηλικία, η λογοθεραπεία πρέπει να εστιάζεται στην εκτίμηση και την αντιμετώπιση προβλημάτων κατάποσης και στην βέλτιστη ανάπτυξη των …

Η ανάπτυξη των δεξιοτήτων των σχετικών με την κατάποση και την ομιλία απαιτεί την αύξηση των αισθητηριακών ερεθισμάτων, εξάσκηση των …., αύξηση της μυϊκής δύναμης και μείωση της υπερευαισθησίας.

Η χρήση νοηματικής γλώσσας και προγραμμάτων συνολικής επικοινωνίας ως συμπληρωματκών της λογοθεραπείας φαίνεται να βελτιώνει τις επικοινωνιακές δεξιότητες και επιδρά θετικά στην συμπεριφορά. Η ικανότητα ανάπτυξης γλώσσας φαίνεται ότι εξαρτάται από την πρώιμη χρήση της νοηματικής γλώσσας και την παρέμβαση λογοπεδικών.

Δεν υπάρχουν επιστημονικά δεδομένα για το ποιο είναι το ιδανικό θεραπευτικό σχήμα.

Υπάρχουν ενδείξεις πως τα ψυχοτρόπα φάρμακα μπορεί να βελτιώσουν την προσοχή και /ή να μειώσουν την υπερκινητικότητα. Κανένα σχήμα δεν φαίνεται να έχει σταθερά αποτελέσματα.

Οι θεραπείες συμπεριφοράς είναι κεντρικές στην διαχείριση της συμπεριφοράς. Τεχνικές ειδικής παιδαγωγικής με εξατομικευμένη καθοδήγηση και καλά δομημένο σταθερό πρόγραμμα βοηθούν στον έλεγχο των εκρήξεων στο σχολικό περιβάλλον.

Η αντιμετώπιση της διαταραχής του ύπνου παραμένει πρόκληση για τους ειδικούς και γονείς.

Μετάφραση:
Μαρία Θεοδωρακοπούλου [[mlk1710]], μεταφράστρια και φοιτήτρια στο Παιδαγωγικό Τμήμα Ειδικής Αγωγής στο Πανεπιστήμιο Θεσσαλίας.

Πηγή:
"Parents and Researchers Interested in Smith-Magenis Syndrome (PRISMS)", Αμερικανικός φορέας για οικογένειες ανθρώπων με σύνδρομο Σμίθ-Μαγγίνις.

Σημείωση:
Η μετάφραση έγινε εθελοντικά για λογαριασμό του NOESI.gr.

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Disease characteristics

Smith-Magenis syndrome (SMS) is characterized by distinctive facial features, developmental delay, cognitive impairment, and behavioral abnormalities. The facial appearance is characterized by a broad square-shaped face, brachycephaly, prominent forehead, synophrys, upslanting palpebral fissures, deep-set eyes, broad nasal bridge, marked mid-facial hypoplasia, short, full-tipped nose with reduced nasal height, micrognathia in infancy changing to relative prognathia with age, and a distinct appearance of the mouth, with fleshy everted upper lip with a "tented" appearance. Cognitive and adaptive functioning vary; the majority of individuals with SMS function in the mild to moderate range of mental retardation. The behavioral phenotype, which includes significant sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors, is generally not recognized until 18 months or older, and continues to change throughout early childhood to adulthood. Infancy is characterized by feeding difficulties, failure to thrive, hypotonia, prolonged napping or need to awaken for feeds, and generalized lethargy. The sleep disturbances are associated with an inverted melatonin circadian rhythm and remain a chronic, lifelong problem. Childhood and adulthood are characterized by inattention, hyperactivity, maladaptive behaviors including frequent outbursts/temper tantrums, attention seeking, impulsivity, distractibility, disobedience, aggression, toileting difficulties, and self-injurious behaviors (SIB) including self-hitting, self-biting, and/or skin picking, inserting foreign objects into body orifices (polyemoilokomania), and yanking finger nails and/or toenails (onchyotillomania). Two stereotypic behaviors, spasmodic upper-body squeeze or "self hug" and hand licking and page flipping ("lick and flip"), seem to be specific to SMS. Additional stereotypies include: mouthing objects or insertion of hand in mouth, teeth grinding, body rocking, and spinning or twirling objects.

Diagnosis/testing. The diagnosis of SMS is confirmed either by detection of an interstitial deletion of the short arm of chromosome 17 band p11.2 (del17p11.2) by G-banded cytogenetic analysis and/or by fluorescence in situ hydridization (FISH). A visible interstitial deletion of chromosome 17p11.2 can be detected in all individuals with the common deletion by a routine G-banded analysis provided the resolution is adequate (550 band or higher). It is not uncommon for the deletion to be overlooked particularly when the indication for the cytogenetic study is other than SMS. Molecular cytogenetic analysis by FISH using a DNA probe specific for the SMS critical region is required in cases of sub-microscopic deletions and/or to resolve equivocal cases. Molecular genetic testing of RAI1, the only gene known to account for a majority of features in SMS, is clinically available for individuals in whom a FISH-detectable deletion has been excluded.

Genetic counseling. Smith-Magenis syndrome is caused by deletion or mutation of the RAI1 gene. Virtually all cases of SMS occur de novo. Familial chromosome complex rearrangements leading to del(17)(p11.2) and SMS are rare but have been reported. If parental chromosome analysis is normal, the risk to subsequent pregnancies is likely to be less than 1%. The small recurrence risk takes into account potential germline mosaicism. In the rare instance of a complex familial chromosomal rearrangement, prenatal testing is available for pregnancies at risk using a combination of routine cytogenetic studies and FISH.
Diagnosis

Clinical Diagnosis

The clinical diagnosis of SMS is suspected in individuals who present with a complex pattern of findings, including a subtly distinctive facial appearance (see Clinical Description) that becomes more evident with age; mild to moderate infantile hypotonia with feeding difficulties and failure to thrive; minor skeletal anomalies; short stature; brachydactyly; ophthalmologic and otolaryngologic abnormalities; early speech delays with and without associated hearing loss; and signs of peripheral neuropathy. Cardiac and renal anomalies and cleft palate occur less frequently. All individuals with SMS have some level of cognitive impairment and developmental delay. A distinct neurobehavioral phenotype exists that includes sleep disturbance and stereotypic and maladaptive behaviors [Finucane et al 1994 , Dykens & Smith 1998 , Smith et al 1998a , Finucane et al 2001]. Sleep disturbance is chronic and is associated with an abnormal circadian rhythm of melatonin [Potocki, Glaze et al 2000 ; De Leersnyder et al 2001]. The phenotypic features can be subtle in infancy and early childhood, frequently delaying diagnosis to school age when the characteristic facial appearance and behavioral phenotype may be more readily apparent.
Testing

Cytogenetic testing. Clinical diagnosis of SMS requires detection of an interstitial deletion of 17p11.2 by G-banded cytogenetic analysis and/or by FISH analysis. The 17p11.2 deletion must include the RAI1 gene. A visible interstitial deletion of chromosome 17p11.2 can be detected in all individuals with the common deletion by a routine G-banded analysis provided the resolution is adequate ( >=550 band). Studies indicate that approximately 90% have a FISH-detectable deletion, with about 70% having the common approximately 3.5-Mb deletion [Vlangos et al 2003 , Potocki et al 2003]. It is not uncommon for the deletion to be overlooked particularly when the indication for the cytogenetic study is other than SMS. Thus, repeat cytogenetic study including FISH is indicated for individuals with prior "normal" routine cytogenetic analysis in whom a diagnosis of SMS is strongly suspected.
Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by at least one US CLIA-certified laboratory or a clinical laboratory outside the US. GeneTests does not independently verify information provided by laboratories and does not warrant any aspect of a laboratory's work; listing in GeneTests does not imply that laboratories are in compliance with accreditation, licensure, or patent laws. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene. RAI1 is the only gene known to account for the majority of features in Smith-Magenis syndrome [Slager et al 2003].

Molecular genetic testing: Clinical uses

* Diagnostic testing
* Confirmatory diagnostic testing
* Prenatal diagnosis

Molecular genetic testing: Clinical methods

*

FISH. Approximately 70% of individuals with SMS who have a 17p11.2 deletion have a common 3.5-Mb deletion. Other affected individuals have atypical deletions (smaller or larger) involving 17p11.2 [Potocki et al 2003 , Vlangos et al 2003]. All 17p11.2 deletions associated with SMS include a deletion of RAI1 [Vlangos et al 2005]. Molecular cytogenetic analysis by FISH using a DNA probe specific for the SMS critical region (D17S258 or other probe containing RAI1) is clinically available and detects approximately 95-100% of 17p11.2 deletions. Not all commercially available FISH probes contain RAI1 [Vlangos et al 2005]. Such testing is required in cases of sub-microscopic deletions and/or to resolve equivocal cases.
*

Sequence analysis. Sequence analysis (particularly of exon 3, in which all mutations have been found to date) detects RAI1 mutations when cytogenetic and FISH studies do not detect the 17p11.2 deletion [Slager et al 2003].

Table 1 summarizes molecular genetic testing for this disorder.
Table 1. Molecular Genetic Testing Used in Smith-Magenis Syndrome
Test Methods

Mutations Detected

Mutation Detection Rate

Test Availability
FISH 1

Deletion 17p11.2

~90%

Clinical
Testing
Sequence analysis

Sequence alterations in RAI1

Unknown
1. FISH probe that contains RAI1 or D17S258
Testing Strategy for a Proband

* First, cytogenetic analysis at greater than 550-band resolution should be performed.
* If cytogenetic testing is normal, FISH testing should be performed. The probe used must contain RAI1 or D17S258 [Vlangos et al 2005]; some commercial probes used in past that did not contain RAI1 or D17S258 may have given a false negative result.
* If FISH testing (RAI1 or D17S258 probe) does not reveal a deletion, sequencing of RAI1 should be considered.

Genetically Related Disorders

Persons with larger deletions extending distally to include PMP22 are also at risk for hereditary neuropathy with liability to pressure palsies (HNPP).

Persons with duplication 17p11.2 harbor the recombination reciprocal of the SMS deletion and differ phenotypically and behaviorally from those with SMS [Potocki, Chen et al 2000].
Clinical Description
Natural History

Smith-Magenis syndrome is a microdeletion syndrome associated with a clinically recognizable phenotype that includes physical, developmental, and behavioral features (Table2). Males and females are affected equally. The facial appearance is characterized by a broad square-shaped face, brachycephaly, prominent forehead, synophrys, mildly upslanting palpebral fissures, deep-set eyes, broad nasal bridge, mid-facial hypoplasia, short, full-tipped nose with reduced nasal height, micrognathia in infancy changing to relative prognathia with age, and a distinct appearance of the mouth, with fleshy everted upper lip with a "tented" appearance. With progressing age, the facial appearance becomes more distinctive and coarse, with persisting mid-facial hypoplasia, relative prognathism, and heavy brows with a "pugilistic" appearance. Evidence of an increased frequency of dental anomalies, specifically tooth agenesis (especially premolars) and taurodontism in SMS was recently reported [Tomona et al 2005, submitted for publication].

As with many genetic mental retardation syndromes, SMS has a wide degree of variability in cognitive and adaptive functioning, with the majority of individuals with SMS functioning in the mild to moderate range of mental retardation [Greenberg et al 1996]. The behavioral phenotype, which includes sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors, is generally not recognized until 18 months or older, and continues to change throughout early childhood to adulthood [Dykens & Smith 1998 , Smith et al 1998a]. The sleep disturbance is characterized by fragmented and shortened sleep cycles with frequent nocturnal and early morning awakenings and excessive daytime sleepiness [Greenberg et al 1996 ; Smith et al 1998b ; Potocki, Glaze et al 2000 ; De Leersnyder et al 2001 ; Smith & Duncan 2005]. An abnormal (inverted) circadian rhythm of melatonin has been identified in SMS [Potocki, Glaze et al 2000 ; De Leersynder et al 2001].
Table 2. Clinical Features of Smith-Magenis Syndrome
Frequency

System

Finding
>75% of individuals

Craniofacial/
skeletal

* Brachycephaly
* Midface hypoplasia
* Relative prognathism with age
* Broad, square-shaped face
* Everted, "tented" upper lip
* Deep-set, close-spaced eyes
* Short broad hands
* Dental anomalies (missing premolars; taurodauntism)

Otolaryngologic abnormalities

* Middle ear and laryngeal anomalies
* Hoarse, deep voice

Neuro/
behavioral

* Cognitive impairment/developmental delay
* Generalized complacency/lethargy (infancy)
* Infantile hypotonia
* Sleep disturbance
* Inverted circadian rhythm of melatonin
* Stereotypic behaviors
* Self-injurious behaviors
* Speech delay
* Hyporeflexia
* Signs of peripheral neuropathy
* Oral-sensory-motor dysfunction (early childhood)

Common features (50-75% of individuals)

* Hearing loss
* Short stature
* Scoliosis
* Mild vetriculomegaly of brain
* Tracheobronchial problems
* Velopharyngeal insufficiency (VPI)
* Ocular abnormalities (iris anomalies; microcornea)
* REM sleep abnormalities
* Hypercholesterolemia/hypertriglyceridemia
* History of constipation
* Abnormal EEG without overt seizures

Less common (25-50% of individuals)

* Cardiac defects
* Thyroid function abnormalities
* Seizures
* Immune function abnormalities (esp. low IgA)

Occasional (<25% of individuals)

* Renal/urinary tract abnormalities
* Seizures
* Forearm abnormalities
* Cleft lip/palate
* Retinal detachment

Smith et al 1986 , Stratton et al 1986 , de Rijk-van Andel et al 1991 , Finucane et al 1994 , Greenberg et al 1996 , Chen et al 1997 , Allanson et al 1999 , Smith & Gropman 2001 , Smith et al 2002 , Potocki et al 2003
Infant

Physical features. Prenatal histories are notable for decreased fetal movement in 50% of individuals with SMS. The infant with SMS is generally born at term, with normal birth weight, height, and head circumference. Height and weight gradually decelerate in early infancy. While the head circumference remains generally within the normal range, in about 20% of children with SMS the head circumference is less than the third percentile for age [Smith & Gropman 2001].

The subtle facial dysmorphology in infancy, often characterized by midface hypoplasia, short upturned nose, fleshy everted upper lip with a "tented" appearance, and micrognathia are recognizable in early infancy. Feeding difficulties leading to failure to thrive are common, including marked oral motor dysfunction with poor suck and swallow, textural aversion, and gastroesophogeal reflux. Infantile hypotonia is reported in virtually all cases, accompanied by hyporeflexia (84%) and generalized lethargy and complacency, similar to that found in Down syndrome.

Neurobehavioral features. Delayed gross and fine motor skills and expressive language skills occur in the first year of life in individuals with SMS. Issues related to sensory integration are frequently noted.

The typical SMS sleep pattern is characterized by fragmented and shortened sleep cycles for age with frequent nocturnal arousals/awakenings and excessive daytime sleepiness [Greenberg et al 1996 , Smith et al 1998b , Smith & Duncan 2005]. Parents usually do not recognize significant sleep problems before 12-18 months of age; they often describe their infants as "perfect" babies with "smiling" dispositions, who cry infrequently and are "good sleepers." However, recent actigraphy-estimated sleep suggests that the disrupted sleep pattern begins as early as nine months of age and shows a progressive decline from infancy through childhood [Duncan et al 2003]. Crying is infrequent and often hoarse, and the vast majority of infants show markedly decreased babbling and vocalizations for age.
Childhood/School Age

Physical features. The facial appearance of SMS becomes more recognizable in early childhood and is accompanied by the emergence of the SMS behavioral phenotype. Ocular abnormalities, including strabismus, progressive myopia, iris anomalies, and/or microcornea, are usually recognized and may progress with age. Mild to moderate scoliosis, most commonly of the mid-thoracic region, is seen in approximately 60% of affected individuals age four years and older. Underlying vertebral anomalies are seen in only a few individuals with SMS. Hands and feet remain small and short stature (height <5th percentile) is frequently observed (67%). Markedly flat or highly arched feet and unusual gait are generally observed. Constipation problems are frequently reported.

Otolaryngologic problems are common throughout childhood. Otitis media is frequent (three or more episodes/year), often leading to tympanostomy tube placement (85%), and risk for conductive hearing loss (65%). Laryngeal anomalies are common, including polyps, nodules, edema, or partial vocal cord paralysis. Velopharyngeal insufficiency and/or structural vocal fold abnormalities without reported vocal hyperfunction are seen in the vast majority of individuals with SMS. Oral sensory motor dysfunction is a major issue, including lingual weakness, asymmetry and/or limited mobility, weak bilabial seal (64%), palatal abnormalities (64%), and open-mouth posture with tongue protrusion and frequent drooling. Sinusitis requiring antibiotics is frequently reported.

The high incidence of otolaryngologic findings provides a physiologic explanation for the functional impairments in voice (hoarseness) and may contribute to the marked expressive speech delays. With appropriate intervention and a total communication program that includes sign/gesture language, verbal speech generally develops by school age; however, articulation problems generally persist. Speech intensity may be mildly elevated with a rapid rate and moderate explosiveness, accompanied by hypernasality and harsh, hoarse vocal quality. Hearing loss impairment is found in over two-thirds of individuals. Hypercholesterolemia is recognized in over 50% of persons with SMS and should be monitored and treated with diet or medication if necessary.

Neurobehavioral features. Developmental delays are evident in early childhood, and the majority of older children and adults function within the mild to moderate range of retardation. A cognitive profile has been described with relative weaknesses observed in sequential processing and short-term memory; relative strengths were found in long-term memory and perceptual closure (i.e., a process whereby an incomplete visual stimulus is perceived to be complete; "parts of a whole").

The behavioral phenotype of SMS is evident by early childhood/school age and escalates with age, often coinciding with expected life-cycle stages: 18-24 months; school age; and onset of puberty. Head banging may begin as early as 18 months. Sensory integration issues are present and persist throughout childhood. Most individuals with SMS exhibit inattention with/without hyperactivity. Maladaptive behaviors are prevalent and represent the major management problem for families and caretakers. These include frequent outbursts/temper tantrums, attention-seeking (especially from adults), impulsivity, distractibility, disobedience, aggression, self injury, and toileting difficulties. While age and degree of developmental delay correlate with maladaptive behaviors, the degree of sleep disturbance emerges as the strongest predictor of maladaptive behavior [Dykens & Smith 1998]. Self-injurious behaviors (SIB) occur in the vast majority of individuals with SMS after age two years. The most common include self-hitting (71%), self-biting (77%), and/or skin picking (65%) [Dykens & Smith 1998]. The overall prevalence of SIB increases with age, as does the number of different types of SIB exhibited [Finucane et al 2001]. A direct correlation exists between the number of different types and extent of SIB exhibited and the level of intellectual functioning. Two behaviors distinctive to SMS, nail yanking (onychotillomania) [Greenberg et al 1991] and insertion of foreign objects into body orifices (polyemboilokomania), are seen in 25-30% of affected individuals. Nail yanking generally does not become a major problem until later childhood. Mouthing of hands or objects appears to persist from early childhood.

Two stereotypic behaviors, the spasmodic upper-body squeeze or "self-hug" and a hand licking and page flipping ("lick and flip") behavior provide an effective clinical diagnostic marker for the syndrome [Finucane et al 1994 , Dykens et al 1997 , Dykens & Smith 1998]. Additional stereotypies include mouthing objects or insertion of hand in mouth(54-69%), teeth grinding (54%), body rocking (43%), and spinning or twirling objects (40%).

Significant sleep disturbance is reported in the vast majority of children and adults with SMS and represents a major issue for caretakers, who themselves may become sleep deprived. Disrupted sleep becomes a major problem in early childhood. Studies of individuals with SMS confirm difficulties falling asleep, frequent and prolonged night-time awakenings, and excessive daytime sleepiness. With increasing age, the number and frequency of naps increases and total sleep time at night decreases. Diminished REM sleep was documented in over half of those undergoing polysomnography [Greenberg et al 1996 , Potocki et al 2000]. Recent research findings confirm an inversion of normal circadian rhythm of melatonin, suggesting that aberrant melatonin synthesis and/or degradation may be the underlying cause of the sleep disturbance common in individuals with SMS [Potocki et al 2000 , De Leersnyder et al 2001]. Another consideration is that melatonin secretion may not suppress to light in individuals with SMS, a theory that is currently being investigated. Management strategies that improve night-time sleep may decrease the level of maladaptive daytime behaviors.

It should be noted that sexual and/or child abuse may be wrongly suspected secondary to self-inflicted injuries and/or insertion of objects in body orifices (e.g., vaginal insertion).
Adolescent

Physical features. The facial appearance becomes more angulated, with persisting midface hypoplasia and relative prognathism, frontal bossing with synophrys, heavy brows (often pugilistic) and a general coarsening. Puberty generally occurs within the normal time frame; however, precocious puberty and delayed sexual maturation have been seen.

Neurobehavioral features. Behaviors generally escalate with pubertal onset, and sleep disturbance remains a concern. Polyemboilokomania and onchyotillomania may become more prevalent.
Adult

Not enough longitudinal data are available to accurately determine life expectancy; however, the oldest known living individual with SMS is currently in her mid 80's. One would expect that in the absence of major organ involvement, the life expectancy would not differ from that of the cognitively impaired population at large.

Physical features. The facial appearance is coarser with persisting midface hypoplasia and relative prognathism as a result of pointed chin. As in adolescence, scoliosis becomes more severe with age and short stature may or may not persist [Smith et al 2004]. Behavioral outbursts, aggression and SIB may continue, but many have noted a relative "calming" of behavior in adulthood.
Genotype-Phenotype Correlations

Parental origin of the 17p deletion has not been documented to affect the phenotype, suggesting that imprinting does not play a role in the expression of the typical Smith-Magenis syndrome phenotype.

Individuals so far reported with RAI1 mutations are obese, do not exhibit short stature, and do not have organ system involvement [Slager et al 2003 , Bi et al 2004 , Girirajan et al 2005]. All other features typically associated with SMS are seen in individuals with mutations in RAI1. The effects of possible modifier genes within 17p11.2 are not known.
Prevalence

The birth incidence is estimated at 1/25,000 births [Greenberg et al 1991], but this probably represents an underestimate. The actual prevalence may be closer to 1/15,000. The vast majority of cases have been identified in the last five to ten years as a result of improved cytogenetic techniques. The syndrome has been identified worldwide, in all ethnic groups.
Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

SMS should be distinguished from other syndromes that include developmental delay, infantile hypotonia, short stature, distinctive facies, and a behavioral phenotype. These include 22q11.2 deletion syndrome [including velocardiofacial (VCF) syndrome, DiGeorge syndrome], Prader-Willi syndrome (PWS), Williams syndrome , Down syndrome (trisomy 21; in the newborn period), and fragile X syndrome . These can be distinguished using cytogenetic and/or molecular analysis. Clinically, many children with SMS are given psychiatric diagnoses � including autism and/or attention deficit/hyperactivity disorder (ADHD),obsessive-compulsive disorder (OCD), attention deficit disorder (ADD) and/or mood disorders � because of speech delays and maladaptive and stereotypic behaviors.

Delayed diagnosis of SMS is quite common. A prior "normal" chromosome analysis in individuals with SMS where there is clinical suspicion of SMS warrants repeat cytogenetic analysis using FISH specific probes for SMS. Infants with SMS are often thought to have Down syndrome based on the findings of infantile hypotonia, facial stigmata suggestive of this diagnosis (brachycephaly, flat mid face, upslanting palpebral fissures), and/or congenital heart disease. The authors suggest that failure to confirm trisomy 21 in a child with suggestive findings warrants further analysis by FISH using a SMS-specific probe.
Management

Management involves evaluation for manifestations of SMS and treatment to mitigate symptoms.

Evaluations. At the time of diagnosis of SMS, a series of baseline evaluations are recommended to guide medical management, including the following:

* Complete review of systems at the time of diagnosis
* Physical and neurological examination
* Renal ultrasound examination to evaluate for possible renal/urologic anomalies (~20% of individuals with SMS)
* Echocardiogram to evaluate for possible cardiac anomalies (<45% of individuals with SMS); follow-up depending upon the severity of any cardiac anomaly identified
* Spine radiographs to evaluate for possible vertebral anomalies and scoliosis (~60%)
* Routine blood chemistries, qualitative immunoglobulins, fasting lipid profile, and thyroid function studies
* Ophthalmologic evaluation with careful attention to evidence of strabismus, microcornea, iris anomalies and refractive error. Treatment with corrective lenses as indicated.
* Comprehensive speech/language pathology evaluation, with special emphasis during early childhood
* Assessment of caloric intake, signs and symptoms of gastroesophageal reflux (GER), swallowing abilities and oral motor skills with referral as warranted for full diagnostic evaluation
* Otolaryngologic evaluation to assess ear, nose, and throat problems, with specific attention to ear physiology and palatal abnormalities (clefting; velopharyngeal insufficiency). Recurrent otitis media may require treatment with tympanostomy tubes.
* Audiologic evaluation at regular intervals to monitor for conductive and/or sensorineural hearing loss. Amplification may be required.
* Multidisciplinary developmental evaluation, including assessment of motor, speech, language, personal-social, general cognitive, and vocational skills
* Early evaluation by physical and/or occupational therapists and implementation of services as needed
* Sleep history with particular attention to sleep/wake schedules and respiratory function. Sleep diaries may prove helpful in documenting sleep/wake schedules. Evidence of sleep-disordered breathing warrants polysomnogram and overnight sleep study to evaluate for obstructive sleep apnea.
* Assessment of family support and psychosocial and emotional needs to assist in designing family interventions
* Parental chromosome analysis to permit accurate recurrence risks and provision of genetic counseling

Recommended annually:

* Multidisciplinary team evaluation is optimal, including physical, occupational and speech therapy evaluations, and pediatric assessment to assist in development of Individualized Educational Program (IEP). Periodic neurodevelopmental assessments and/or developmental/behavioral pediatric consultation can be an important adjunct to the team evaluation.
* Thyroid function
* Fasting lipid profile
* Routine urinalysis
* Monitoring for scoliosis
* Ophthalmologic evaluation
* Otolaryngologic follow-up for assessment and management of otitis media and other sinus abnormalities
* Audiologic evaluation at regular internals to monitor for conductive or sensorineural hearing loss

Recommended as clinically indicated:

* EEG in individuals who have clinical seizures to guide the choice for antiepileptic agent. For those without overt seizures, EEG may be helpful to evaluate for possible sub-clinical events in which treatment may improve attention and/or behavior. A change in behavior or attention warrants re-evaluation.
* Urologic workup if history of frequent urinary tract infections
* Neuroimaging (MRI or CT scan) in accordance with findings, such as seizures, and/or motor asymmetry
* Individuals with SMS documented to have larger deletions extending into 17p12:
o Specific screening for adrenal function; and
o Detailed assessment and attention to peripheral neurologic function in individuals with SMS with large deletions involving the PMP22 gene, which is associated with hereditary neuropathy with liability to pressure palsy (HNPP)
* Monitoring for hypercholesterolemia and medical treatment if indicated

Treatment recommendations include the following:

* Ongoing pediatric care with regular immunizations
* From early infancy, referrals for early childhood intervention programs, followed by ongoing special education programs and vocational training in later years
* Therapies including speech/language, physical and occupational, and especially sensory intregration
o During early childhood, speech/language pathology services should initially focus on identifying and treating swallowing and feeding problems as well as optimizing oral sensory motor development.
o Therapeutic goals of increasing sensory input, fostering movement of the articulators, increasing oral motor endurance and decreasing hypersensitivity are needed to develop skills related to swallowing and speech production.
o The use of sign language and total communication programs as adjuncts to traditional speech/language therapy is felt to improve communication skills and also have a positive impact on behavior. The ability to develop expressive language appears dependent upon the early use of sign language and intervention by speech/language pathologists.
* Published data about the optimal intervention and behavioral strategies in SMS are limited to anecdotal and experiential findings.
o Use of psychotropic medication may increase attention and/or decrease hyperactivity. No single regimen shows consistent efficacy.
o Behavioral therapies are integral in behavioral management. Special education techniques that emphasize individualized instruction, structure, and routine can help minimize behavioral outbursts in the school setting.
o Therapeutic management of the sleep disorder in SMS remains a challenge for physicians and parents. There are no published well-controlled treatment trials. Early anecdotal reports of therapeutic benefit from melatonin remain encouraging. Dosages of 2.5 mg to 5.0 mg (6 mg maximum) taken at bedtime have been tried, providing general improvement of sleep without reports of major adverse reactions. However, melatonin dispensed over-the-counter is not regulated by the FDA; thus, dosages may not be exact. No formal melatonin treatment trials have been conducted. A monitored trial of four to six weeks on low-dose (1-3 mg) melatonin may be worth considering in affected individuals with major sleep disturbance. A single uncontrolled study of nine individuals with SMS treated with oral ί-1-adrenergic antagonists (acebutolol 10 mg/kg) reported suppression of daytime melatonin peaks and subjectively improved behavior [De Leersnyder et al 2001]. This treatment, however, did not restore nocturnal plasma concentration of melatonin. A second uncontrolled trial by the same group [De Leersynder et al 2003] combined the daytime dose of acebutolol with an evening oral dose of melatonin (6 mg at 8PM) and found that nocturnal plasma concentration of melatonin was restored and nighttime sleep improved with disappearance of nocturnal awakenings. Parents also reported subjective improvements in daytime behaviors with increased concentration. The contraindications to using ί-1-adrenergic antagonists must also be considered, including asthma, pulmonary problems, cardiovascular disease, and diabetes mellitus. Prior to beginning any trial, the child's medical status must be considered. It is also beneficial to have an understanding of the child's baseline sleep pattern.
o Enclosed bed system
* Respite care and family psychosocial support help assure the optimal environment for the affected individual.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.
Mode of Inheritance

Smith-Magenis syndrome is caused by deletion or mutation of the RAI1 gene on chromosome 17p11.2.
Risk to Family Members

Parents of a proband

* Virtually all cases of SMS occur de novo. There is no evidence to suggest an obvious parental age contribution for the deletion.
* One case reported by Zori et al (1993) identified maternal mosaicism for del(17)(p11.2). Other cases of parental mosaicism are known but not reported [S Elsea, personal communication].
* Familial chromosomal complex rearrangements leading to del(17)(p11.2) and SMS are rare, but have been reported [Zori et al 1993 , Yang et al 1997 , Park et al 1998]. Consequently, chromosome analysis of the parents should be performed for all newly diagnosed cases.

Sibs of a proband

* The risk to sibs depends on the results of parental chromosome analysis.
* If parental chromosome analysis is normal, the risk to sibs of the proband is likely less than 1% (because germline mosaicism in a parent is a possibility).
* If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and is dependent upon the specific chromosome rearrangement and the possibility of other variables.

Offspring of a proband

* No instances of individuals with SMS having an affected child have been reported.
* Theoretically, the offspring of an individual with SMS have a 50% risk of having SMS.
* Fertility issues in SMS remain unstudied.

Other family members of a proband. The risk to other family members depends upon the genetic status of the proband's parents. If a parent is found to have a chromosome abnormality, his or her family members are at risk and can be offered chromosome analysis and FISH.

Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
Carrier Detection

If a parent of the proband is found to have a balanced chromosome rearrangement, at-risk family members can be tested by chromosome analysis and FISH.
Prenatal Testing

High-risk pregnancies. Because SMS usually occurs as the result of a de novo deletion of 17p11.2, virtually all individuals with SMS represent a single occurrence in a family. In the rare instance of a complex familial chromosomal rearrangement, prenatal testing is available for pregnancies at risk using a combination of routine cytogenetic studies and FISH on fetal cells obtained by chorionic villus sampling (CVS) at 10-12 weeks' gestation or amniocentesis usually performed at about 15-18 weeks' gestation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Low-risk pregnancies. Unsuspected prenatal detection of del(17)(p11.2) has been reported among women undergoing amniocentesis for other reasons. At least two cases have been detected prenatally following amniocentesis performed because of low maternal serum AFP (MSAFP) on routine screening [Fan & Farrell 1994 ; Thomas et al 2000 ; personal observation].
Molecular Genetics

Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED.

Molecular Genetics of Smith-Magenis Syndrome
Gene Symbol

Chromosomal Locus

Protein Name
RAI1

17p11.2

Retinoic acid-induced protein 1
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.

OMIM Entries for Smith-Magenis Syndrome
182290

SMITH-MAGENIS SYNDROME; SMS
607642

RETINOIC ACID-INDUCED GENE 1; RAI1

Genomic Databases for Smith-Magenis Syndrome
Gene Symbol

Entrez Gene

GeneCards

GDB

GenAtlas
RAI1

607642

RAI1

9958236

RAI1
For a description of the genomic databases listed, click here.

Chromosomal locus: Smith-Magenis syndrome is a contiguous gene deletion syndrome. A common deletion interval spanning approximately 3.5 Mb is identified in about 70% of cases [Potocki et al 2003 , Vlangos et al 2003]. The SMS critical region maps to 17p11.2 and spans less than 1.0 Mb. Dominant mutations in the RAI1 gene have been identified in individuals with the SMS phenotype who do not have a detectable 17p11.2 deletion [Slager et al 2003].
Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

* Association of Smith-Magenis France (ASM France)
http://membres.lycos.fr/asm17france/

* National Library of Medicine Genetics Home Reference
Smith-Magenis syndrome

* Parents and Researchers Interested in Smith-Magenis Syndrome (PRISMS)
PO Box 741914
Dallas, TX 75374-1914
Phone: 972-231-0035
Fax: 413-826-6539
Email: info@prisms.org
www.prisms.org

* Smith-Magenis Syndrome Foundation in United Kingdom
PO Box 3352 Ascot
Berkshire SL5 8WS
United Kingdom
Phone: (+44) 0288 7750050
Email: info@smith-magenis.co.uk
www.smith-magenis.co.uk

Resources Printable Copy

References
Topic Search
Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Authors:

Ann CM Smith, MA, DSc (hon), CGC
Judith E Allanson, MD
Sarah H Elsea, PhD, FACMG
Brenda M Finucane, MS, CGC
Barbara Haas-Givler, MEd
Andrea Gropman, MD, FAAP, FACMG
Kyle P Johnson, MD
James R Lupski, MD, PhD, FAAP, FACMG, FAAAS
Ellen Magenis, MD, FAAP, FACMG
Lorraine Potocki, MD, FACMG
Beth Solomon, MS
About the Authors / Author History

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