Síndrome de Deleción 22q

Todo lo que necesita saber sobre el Síndrome de Deleción 22q, directamente de los expertos.

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Author and Contributing Experts to this Guide include:

Brenna Bentley Director, Patient Education at YourDNA.com LinkedIn

¿Qué es el síndrome de deleción 22q?

El síndrome de deleción 22q es el síndrome de deleción cromosómica más común, y es casi tan común como el síndrome de Down 1. Se estima que entre 1 en 3,000 a 6,000 niños nacen cada año con 22q, pero ese número probablemente es una subestimación 2.

Las personas con síndrome de deleción 22q tienen una sección del brazo q en el cromosoma 22 que está ausente. La mayoría de las veces, esta eliminación se produjo de forma espontánea, lo que significa que se produjo al azar y no se ve en los padres del paciente.

Las condiciones se denominan síndromes cuando se presentan con una serie de características particulares. El síndrome de deleción 22q, no es diferente.

Hay muchos problemas potenciales, tales como: enfermedades cardíacas congénitas, anomalías del paladar, deficiencia inmunológica, rasgos faciales característicos y problemas de aprendizaje 3. Debido a que hay muchas características de presentación, y cada paciente puede tener solo unos pocos o varios de los síntomas, el diagnóstico puede ser un desafío en algunos casos.

De hecho, los investigadores han identificado más de 180 posibles síntomas del síndrome de deleción 22q. Debido a la amplia gama de síntomas, esta condición ha pasado históricamente por varios nombres diferentes:

  • Síndrome de deleción 22q11
  • 22q11.2DS
  • Síndrome de DiGeorge
  • Síndrome Velocardiofacial (VCFS)
  • Anomalía Conotruncal Síndrome facial
  • Síndrome de Opitz G / BBB
  • Síndrome cardiofacial de Cayler.
  • Síndrome de Sedlackova
  • Síndrome de Shprintzen

Parte de la razón por la que hay tantos nombres diferentes es que los sub-especialistas crearon nombres para varios hallazgos antes de que alguien pudiera vincularlos todos. Por ejemplo, Angelo DiGeorge, MD, un endocrinólogo, se centró en problemas con el calcio 4 mientras que Robert Shprintzen, PhD, un patólogo del habla, se concentró en las diferencias palatales.

Muchos especialistas fueron precisos en sus propias áreas, pero ninguno pudo ver el panorama completo hasta que se desarrolló una prueba de laboratorio para detectar la eliminación cromosómica.

“Es un fenotipo altamente variable. Ningún individuo con 22q será igual a otro”, dijo Emily Palen, una asesora genética licenciada que coordina la clínica especializada en desarrollo 22q, en el Instituto de Medicina del Desarrollo y Autismo de Geisinger en Lewisburg, Pennsylvania.

¿Qué causa el síndrome de deleción 22q?

En términos clínicos, "la eliminación de 22q es causada por una eliminación de aproximadamente tres megabases en el cromosoma 22, en el brazo largo de ese cromosoma", dijo Palen.

La mayoría de los cromosomas tienen dos brazos, un brazo corto llamado "p" y un brazo largo llamado "q". Bajo coloración especial, los cromosomas aparecerán "en bandas".

Para que los investigadores puedan comunicarse claramente sobre los hallazgos, las bandas cromosómicas están numeradas. El nombre, síndrome de deleción 22q11.2, señala la región específica en el cromosoma 22 que está ausente.

"Una eliminación de tres megabase es aproximadamente tres millones de pares basados, o las letras genéticas que forman nuestro código genético. Esos tres millones de pares de bases están ausentes en esa sección del cromosoma. La pérdida de varios genes en esa región causa algunas de las características distintivas de la condición 22q". - Palen

Alrededor del 15% de las personas tienen un tamaño inferior de deleción de genes, lo que a menudo se conoce como eliminaciones "anidadas" o "distales" 5.

La mayoría de los niños con síndrome de deleción 22q carecen de 30 a 40 genes 6. Los investigadores no conocen la función exacta de muchos de estos genes.

Sin embargo, la falta del gen TBX1 en el cromosoma 22 probablemente causa los síntomas físicos más comunes del síndrome, como problemas cardíacos o paladar hendido 7. La pérdida de otro gen (COMT) también puede explicar el mayor riesgo de problemas de conducta y enfermedad mental 8.

Puede ser heredado, pero la mayoría de las veces el 22q surge de novo, lo que significa que es un cambio nuevo que ocurre por primera vez en la familia. Alrededor del 90-95% de las deleciones 22q son nuevas y únicas en el individuo, y no han sido heredadas de ninguno de los padres 9.

En otras palabras, puede ser heredado, pero la mayoría de las veces no lo es.

Signos y síntomas del síndrome de deleción 22q

“Cada persona que tenga esta deleción va a ser diferente a otra. Si nos alejamos y tratamos de encontrar elementos físicos en común, algunas de las características faciales o características físicas que se podrían notar son que las orejas tienden a ser más pequeñas, y quizás un poco cuadradas en la parte superior. Los párpados tienden a estar encapuchados, por lo que la piel entre el hueso orbital y la línea de las pestañas está un poco más caída. El puente de la nariz es más prominente y la barbilla tiende a ser bastante pequeña”, dijo Palen.

“Estos individuos pueden ser un poco más pequeños, más bajos que otros miembros de su familia. Algunas de las otras características de la condición son cosas que no se pueden ver a simple vista”, agregó.

Dependiendo de la edad del paciente, puede haber diferentes señales y síntomas de presentación. Cuando un niño nace por primera vez y a la edad de la infancia, algunos de los signos más comunes son defectos cardíacos congénitos, infecciones frecuentes, habla nasal, bajo nivel de calcio, problemas de alimentación y retrasos en el desarrollo 10.

“Tendemos a ver defectos cardíacos o defectos cardíacos congénitos, anomalías cardíacas que están presentes desde el nacimiento. Puede ser un agujero en el corazón o algo llamado Tetralogía de Fallot, que son algunas anormalidades cardíacas diferentes que ocurren todas al mismo tiempo, o tal vez un arco aórtico interrumpido. Estas son típicamente anormalidades cardíacas que afectan la aorta del corazón", dijo Palen.

Según Palen, “también podemos ver anormalidades palatinas, por lo que las personas con esta condición pueden tener un paladar hendido o una úvula dividida, que es la pequeña campanilla colgante en la parte posterior del paladar. Esa podría estar dividida en dos.

También podemos ver algo llamado insuficiencia velofaríngea. Lo que significa que el paladar suave en la parte posterior no se cierra contra la parte posterior del cuello.

Lo que puede causar el flujo de aire al hablar, que hace que la voz suene un poco diferente.

“Si conversas con un niño pequeño que tiene esta condición, su voz puede sonar un poco diferente a la de otros niños que no tienen esta deleción. Eso generalmente es causado por ese VPI o esa insuficiencia velofaríngea".

A medida que el niño crece y avanza hacia la adolescencia y la edad adulta, pueden surgir nuevas características, como la enfermedad psiquiátrica.

“22q también está asociado con algunas diferencias de salud mental. Esa es generalmente una de las cosas a las que las personas pueden aferrarse.

Si buscas en Google, puedes ver que esta condición está asociada con una condición psiquiátrica llamada esquizofrenia. Eso puede ser muy abrumador para las personas recién diagnosticadas y sus familias.

También podemos ver cosas como mayor ansiedad, diferencias de humor, cosas así”, dijo Palen.

De hecho, hay más de 180 signos y síntomas identificados del síndrome de deleción 22q. Los síntomas más afectados incluyen:

  • Cardiovascular
  • Paladar hendido
  • Dificultades de alimentación
  • Problemas de inmunización
  • Deficiencias de la hormona del crecimiento
  • Desarrollos neurológicos y psicológicos retrasados.
  • Problemas del habla
  • Anomalías renales

Sin embargo, esta no es una lista extensa. El rango de síntomas puede ser bastante amplio, incluyendo defectos congénitos, hallazgos cardíacos, hallazgos craneofaciales / orales, diferencias de aprendizaje, hallazgos del oído / audición, diferencias en el sistema endocrino, deficiencia inmunológica, hallazgos esqueléticos, diferencias en la piel / cabello, y anomalías vasculares. Puede encontrar una lista completa de signos y síntomas en www.22qcentral.com

¿Qué aspecto tiene el síndrome de deleción 22q11.2?

Las personas con síndrome de deleción 22q pueden tener algunas diferencias leves en sus características que podrían ayudar con los diagnósticos. Estas personas pueden tener la boca y la mandíbula pequeña.

Es posible que las esquinas de sus ojos estén ligeramente elevadas y que sus párpados parezcan un poco caídos. También pueden tener la punta de la nariz ancha. Las orejas pueden parecer un poco cuadradas y giradas hacia abajo.

Es importante recordar que estas características a menudo son pequeñas y no todas las personas con síndrome de deleción 22q las tendrán 11

Prevalencia y factores de riesgo para el síndrome de deleción 22q

"Cualquier persona puede tener el síndrome de deleción 22q. No discrimina con respecto al sexo, raza, o algo similar", dijo Palen.

"Sabemos que si alguien es portador de la deleción y tiene esta condición, con cada embarazo hay una probabilidad del 50% de que la deleción pueda transmitirse al niño". Si una persona no lleva la deleción, no podemos decir que hay una probabilidad de cero por ciento, porque es posible que la deleción ocurra independientemente de ser heredada. En cambio, decimos que la persona tiene un bajo riesgo si los padres no son portadores”, agregó.

Al pensar en la prevalencia, puede ser difícil llegar a un número absoluto. Debido a la amplia gama de signos y síntomas, hay un gran rango de estimaciones de prevalencia.

El doctor Scott Hickey es profesor asistente de pediatría clínica a través de la Facultad de Medicina de la Universidad Estatal de Ohio y un genetista clínico certificado y codirector de la Clínica Multidisciplinaria del Centro 22q en el Hospital Nacional de Niños en Columbus, Ohio.

Él estima, "... la prevalencia está en algún lugar entre una de cada 2,000 y una de cada 3,000 personas. Hubo un estudio en 2015 de mujeres embarazadas donde encontraron evidencia de que podría ser tan alto como uno de cada 1,000. Ese fue solo un estudio, y yo diría que es más cercano a uno en 2,000 que a uno en 3,000, lo que lo convierte en el síndrome de microdeleción cromosómica más común".

“En comparación, el síndrome de down probablemente se encuentra en aproximadamente una de cada 1,000 personas. Entonces, el síndrome de Down podría ser aproximadamente el doble de común”, agregó el Dr. Hickey.

No parece haber una mayor prevalencia entre ciertas poblaciones con respecto al síndrome de deleción 22q 12.

“Con respecto a la cuestión sobre ciertas poblaciones, 22q es una condición que parece ocurrir debido a cierta predisposición que todos los humanos tenemos de tener un hijo con esta condición. Esa es una predisposición que creo que atravesaría todas las razas y etnias. Aunque no tengo datos exactos sobre todos los diferentes tipos de pueblos indígenas y todo, esperaríamos que fuera más o menos igual en la mayoría de las poblaciones”, agregó el Dr. Hickey.

Diagnóstico del síndrome de deleción 22q

Si un individuo exhibe algunos de los síntomas mencionados anteriormente, entonces se puede sospechar que es debido al Síndrome de Deleción 22q. Para confirmar el diagnóstico, una muestra de ADN, típicamente de sangre o saliva, deberá enviarse a un laboratorio para su análisis.

Hay varias pruebas diferentes que podrían usarse, pero comúnmente se identifica a través del análisis de microarrays. La hibridación fluorescente in situ (FISH) también es común.

"A veces, si un genetista u otro proveedor ve a un paciente que realmente piensa que tiene 22q, se pueden hacer pruebas muy específicas para buscar solo esa deleción y nada más", dice Palen.

"Otras veces, el proveedor dirá:" Creo que podría ser 22q, pero podría estar equivocado". Tal vez ordenarán una prueba llamada microarrays cromosómicos para buscar cualquier deleción o duplicación en cualquiera de los cromosomas.

"Otros proveedores pueden ofrecer pruebas más amplias, algo llamado secuenciación completa del exoma, que en algunas ocasiones también podemos detectar este tipo de eliminaciones".

La forma en la que hemos diagnosticado el síndrome de deleción 22q ha cambiado con el tiempo.

"A finales de los 90 y principios de los 2000, para hacer el diagnóstico, había que usar fluorescencia en la hibridación SITU o en las pruebas FISH", señaló el Dr. Hickey.

Las instituciones académicas lideraron el camino con las pruebas de microarrays cromosómicos, pero para el 2010, había múltiples sociedades genéticas diferentes que recomendaban las pruebas genéticas como diagnóstico de primera línea para los tipos de presentación de discapacidad intelectual, autismo y anomalías congénitas múltiples.

"Esto requirió que el proveedor dijera:" Creo que esto podría ser el síndrome de deleción 22q. Vamos a comprobarlo. Ahora, como la prueba cromosómica se ha desarrollado con el tiempo, nosotros como genetistas ya no tenemos que ser tan inteligentes. Simplemente podemos emplear una prueba llamada microarrays que analiza los cambios en el número de copias en todos los cromosomas”, dijo el Dr. Hickey.

Ya no hace falta pensar específicamente en el síndrome de deleción 22q. Simplemente podemos decir: "¿Es alguna condición cromosómica?", Y la prueba volverá con los resultados y nos hará saber si se trata del síndrome de deleción 22q", agregó.

Esto puede ser especialmente útil cuando alguien que no sea un proveedor de genética está en primera línea de un diagnóstico. Un médico de atención primaria o un neonatólogo solo necesita tener en cuenta que los síntomas pueden indicar que hay una diferencia cromosómica.

Cuando los genetistas están involucrados, usan dos habilidades diferentes para hacer un diagnóstico. Usan pruebas genéticas e interpretación de las pruebas genéticas, pero también usan dismorfología.

Esto significa buscar físicamente en las patentes patrones específicos como parte del contexto general de lo que está sucediendo.

Según el Dr. Hickey, "si hay un problema médico, observamos las características faciales del bebé. Los niños con síndrome de deleción 22q a menudo tienen una especie de punta nasal bulbosa o redondeada.

Sus orejas a menudo se forman de manera un poco diferente. Tienen un sobre-pliegue más acentuado, y en algunos casos están posicionadas más abajo de lo normal.

Su boca es a menudo más pequeña, con las comisuras apuntando hacia abajo. Su barbilla es más pequeña también. Algunas de estas características reflejan lo que se le llama tono muscular bajo".

"Es importante señalar que los niños con muchas condiciones genéticas diferentes tienen bajo tono muscular. Entonces, solo porque un niño tiene bajo tono muscular, no significa necesariamente que tiene el síndrome de deleción 22q”.

"Si un bebé nace con algún tipo de defecto cardíaco, si tiene un problema de calcio, problemas inmunes, un paladar hendido u otras cosas que podrían hacernos pensar en el síndrome de deleción 22q, entonces esa sería una prueba primaria que quisiéramos hacer."

Un diagnóstico puede tener lugar a casi cualquier edad. Según Palen, algunas personas no son diagnosticadas hasta que tienen entre 30 y 40 años.

Esto podría deberse a que sus síntomas o características son sutiles y leves, o simplemente no fueron diagnosticados como alguien con 22q cuando eran más jóvenes. Otros no se diagnostican porque nunca se reunieron con el proveedor adecuado o nunca se les ordenó una prueba genética.

Opciones de tratamiento y atención para el síndrome de deleción 22q

Cuando a alguien se le diagnostica por primera vez el síndrome de deleción 22q, inevitablemente la primera pregunta que se hace es: "¿Existe una cura?"

Desafortunadamente, en este momento, la respuesta es no.

“No tenemos la capacidad de reemplazar esa sección faltante de 22q. Muchas familias dicen: "Bueno, si falta, ¿no podemos simplemente devolverlo?" No tenemos esa tecnología o esa capacidad en este momento", explicó Palen.

“Su información genética está presente y se encuentra en todos los billones de células de su cuerpo. Por lo tanto, cualquier cosa que se considere "cura" tendría que alcanzar, tener efecto, y cambiar la genética en cada uno de esos billones de componentes básicos de su cuerpo, lo cual es un verdadero desafío", agregó el Dr. Hickey.

Sin embargo, la ventaja es que, en muchos casos, los proveedores son efectivos en el tratamiento y manejo de muchos de los síntomas y características del síndrome de deleción 22q. Gracias a las pautas de manejo, los pacientes con 22q reciben atención coordinada e individualizada de equipos multidisciplinarios de médicos que pueden extraerse de más de 20 especialidades 13.

Después de un diagnóstico inicial, la evaluación estándar y el trabajo para todas las edades generalmente incluyen:

  • Cardiología
  • Endocrinología
  • Inmunología
  • Evaluaciones del habla / lenguaje / desarrollo
  • Una ecografía renal (para revisar los riñones)
  • Radiografías del cuello (en niños con edad suficiente para cooperar y donde los huesos están bien osificados, de 3 a 4 años de edad)
  • Estudios de eliminación en ambos padres cuando estén disponibles

Después de la evaluación inicial, un equipo de atención trabajará con usted para identificar un plan que sea específico para el individuo. Dado que todas las personas con síndrome de deleción 22q son diferentes, la atención y el manejo también serán diferentes.

Algunos ejemplos de atención se pueden encontrar a continuación, con porcentajes extraídos de la investigación del Dr. McDonald-McGinn 14.

Cardiología: Alrededor del 75% de los niños tienen algún tipo de defecto cardíaco, muchos de los cuales requieren cirugía para corregir el problema, a menudo como recién nacidos.

Desarrollo infantil: la mayoría tiene retrasos en las funciones motoras (como caminar) y retrasos en la aparición del habla y diferencias específicas de aprendizaje. Esto requiere ayuda especial en la escuela, incluidos aquellos con características autistas o diferencias de comportamiento como TDAH, TOC, ansiedad, perseveraciones y psicosis.

Sin embargo, todos los niños con 22q se benefician de estrategias de intervención temprana que incluyen cosas como terapia ocupacional, fisioterapia y terapia del habla/lenguaje de señas en la infancia temprana, seguidas de intervenciones específicas de estilo de aprendizaje.

Paladar hendido: el 75% de los niños tienen diferencias en su paladar, lo que permite que los líquidos pasen por la nariz en la infancia (regurgitación nasal) y luego conducen al habla hipernasal. A menudo se realiza una cirugía para aliviar este problema.

Endocrinología: alrededor del 50% de los niños tienen niveles bajos de calcio y algunos niños requieren suplementos de calcio en momentos de enfermedad o estrés, como en la pubertad o después de la operación. Algunos niños tienen problemas de tiroides poco o demasiado activa, y otros tienen deficiencia de la hormona de crecimiento, los cuales son problemas que responden bien al tratamiento.

Otorrino (ENT) y Audiología: las infecciones del oído y la pérdida auditiva son comunes debido a diferencias estructurales, como un anillo vascular o una red laríngea, o están asociadas con el reflujo.

Muchos niños se benefician de la colocación de un tubo auditivo o de audífonos. En algunos casos, se requiere una atención más compleja de un otorrinolaringólogo.

Equipo de gastroenterología / alimentación: el 33% de los niños tienen problemas importantes de alimentación y deglución, como reflujo gastroesofágico (ERGE) y dismotilidad que causa reflujo y estreñimiento. Otros problemas menos comunes incluyen hernia umbilical, mala rotación intestinal, una apertura anal ausente, enfermedad de Hirshsprung o una hernia diafragmática donde las asas intestinales pueden estar en el pecho.

Los problemas de alimentación más comunes se resuelven con asistencia médica por edad escolar.

Inmunología / Reumatología: el 75% de los niños tienen inmunodeficiencia y deben lidiar con infecciones recurrentes, no tienen una respuesta normal a las vacunas y no pueden recibir vacunas virales vivas. La mayoría de los problemas se resuelven en la infancia.

Los pacientes también son más propensos a enfermedades autoinmunes como la artritis reumatoide juvenil, la trombocitopenia idiopática, la neutropenia autoinmune, la enfermedad de Grave y el vitíligo.

Neurología: Raramente, los niños sufren convulsiones que no están relacionadas con sus bajos niveles de calcio y/o diferencias cerebrales estructurales. Ocasionalmente tendrán espina bífida.

Oftalmología: Algunos niños tienen problemas oculares, como párpados caídos, diferencias en el área blanca de los ojos y también en la parte del ojo con color, y diferencias en los músculos oculares. Algunos de estos problemas requieren tratamiento quirúrgico con parches oculares.

Ortopedia: Algunos niños tienen diferencias en la forma en que se forman las vértebras de la columna vertebral en el cuello, lo que provoca una disminución del espacio que rodea la médula espinal en el cuello. Con cirugía a menudo se puede corregir esto.

Otros sufren de diferencias óseas en el pecho, una curvatura de la columna vertebral, costillas adicionales, dedos de manos y pies adicionales, o en algunos casos, fusión prematura de los huesos del cráneo. Todo esto puede ser mejorado a través de la cirugía.

Urología: Un tercio de los niños tienen diferencias en la forma en la que se forman sus riñones o cómo funcionan. Esto incluye riñones malformados, el reflujo renal, problemas con las infecciones, entrenamiento para ir al baño y diferencias en la forma en que se puede formar el sistema genitourinario. Dependiendo del problema, la cirugía correctiva puede ayudar.

Posibles complicaciones del síndrome de deleción 22q

Algunos niños con defectos cardíacos graves y problemas del sistema inmunológico causados por el síndrome de deleción 22q no sobrevivirán el primer año de vida 15. Pero la mayoría de los niños que son tratados a edad temprana sobrevivirán y crecerán hasta la edad adulta.

Debido a que hay tantos síntomas, la posibilidad de complicaciones potenciales es amplia y variará de un paciente a otro.

¿Es posible prevenir el síndrome de deleción 22q?

Alrededor del 90-95% de todos los casos de síndrome de deleción 22q ocurren por casualidad. Por lo tanto, solo el 5-10% de los casos se heredan de uno de los padres 16.

Como tal, no hay realmente ninguna forma de prevenir esta condición.

Si un individuo con síndrome de deleción 22q está considerando comenzar una familia y tiene curiosidad por saber si el niño también tendrá la condición, existen opciones pre conceptivas y prenatales.

Si una pareja con una deleción 22q conocida aún no ha concebido, tienen la opción del diagnóstico genético previo a la implantación. La pareja se sometería primero a la fertilización in vitro, y luego los embriones serían examinados para detectar el síndrome de deleción 22q.

Solo los embriones sin la deleción se implantarían en el útero de la madre.

Después de que una pareja concibe, pueden optar por someterse a pruebas prenatales no invasivas (NIPT). Si los resultados de la prueba vuelven a indicar que 22q podría estar presente, entonces, las personas pueden optar por realizar pruebas de diagnóstico, como una amniocentesis.

Esta prueba analiza las células fetales para ver si hay deleciones o duplicaciones que podrían indicar problemas de desarrollo o problemas médicos, como 22q.

"Es la decisión de cada familia qué información quieren saber sobre su hijo o su embarazo", señaló Palen.

“A veces, si 22q no está en nuestro radar, los padres no son portadores y no hay antecedentes familiares, tal vez vuelvan los hallazgos de la ecografía que son indicativos de esta condición. Podemos ver algunas anomalías cardíacas que sabemos que son más comunes en 22q. Es probable que un proveedor discuta eso con la familia y vea si desea realizar alguna prueba”.

También puede consultar con un asesor genético si tiene preguntas o si desea ayuda para planificar futuros embarazos.

Pronóstico del síndrome de deleción 22q

El pronóstico de alguien con síndrome de deleción 22q ha cambiado en los últimos años. Muchos niños que en el pasado morirían en su infancia, antes de existieran sofisticadas cirugías cardíacas y antibióticos avanzados, ahora están ganando la batalla contra esta condición.

La tasa de mortalidad en los niños es de alrededor del 4% y los que fallecen generalmente lo hacen a una edad muy temprana, en promedio a los 4 meses 17.

“La cuestión de una vida más corta es una pregunta que me hacen muchos padres, y es una pregunta muy cargada de emociones. En respuesta, creo que es importante ser un poco específico al respecto. Por ejemplo, si un niño tiene una diferencia estructural realmente significativa en la anatomía de su corazón, eso siempre afectará la expectativa de vida”, dijo el Dr. Hickey.

“Se sabe que hay otras cosas que afectan la esperanza de vida por sí mismas, incluida la discapacidad intelectual y la esquizofrenia. Existe un riesgo sustancial de afecciones neuropsiquiátricas, como la esquizofrenia, con el síndrome de deleción 22q. Aunque la mayoría no tendrá ese problema. Pero esas cosas también afectan la mortalidad”, agregó el Dr. Hickey.

Esto no quiere decir que quienes sobreviven no experimentan problemas médicos durante toda su vida, porque sí lo hacen.

Y las noticias sobre el pronóstico están mejorando.

“En cada estudio posterior que veo sobre esto, el promedio de edad de supervivencia se alarga. Entonces, creo que eso es alentador”, dijo el Dr. Hickey.

"El último informe que salió de Canadá, de una clínica adulta prominente en Toronto, fue que la edad promedio de muerte era de mediados a finales de los 40 años, lo cual yo se que no es lo que la gente quiere escuchar. Eso también incluye a personas con cardiopatía congénita significativa.

Si un niño no padece una enfermedad cardíaca congénita significativa, creo que esperaríamos más que eso. Creo que con pautas y atención médica moderna, esperamos seguir mejorando con el tiempo".

Qué hacer a continuación: vivir con el síndrome de deleción 22q

Un diagnóstico de síndrome de deleción 22q puede ser impactante y abrumador. Afortunadamente, hay varios recursos que se puede aprovechar para obtener más información y asistencia.

Algunos de estos incluyen:

La Fundación Internacional 22q (International 22q Foundation) proporciona varios recursos para ayudar a las personas afectadas por 22q, buscando mejorar la calidad de vida a través de asociaciones familiares y profesionales.

La fundación 22q Family Foundation tiene varios enlaces en su sitio web para ayudarlo a conectarse con recursos cercanos a usted. Esto incluye varios grupos de apoyo en línea, catalogados por estado.

“22q and You” Center The Children's Hospital of Philadelphia 3401 Civic Center Blvd Philadelphia, PA 19104 USA Phone: (215) 590-2920 Toll-free: (800) 879-2467

Genetic and Rare Diseases (GARD) Information Center PO Box 8126 Gaithersburg, MD 20898-8126 Phone: (301) 251-4925 Toll-free: (888) 205-2311 Website: http://rarediseases.info.nih.gov/GARD/

Chromosome 22 Central – dedicated to support for the disorders of Chromosome 22.

Chromosome Disorder Outreach

National Organization for Rare Disorders/Chromosome 22q11.2 Deletion Syndrome

Referenced Sources

  1. McDonald-McGinn, D. M., Sullivan, K. E., Marino, B., Philip, N., Swillen, A., Vorstman, J. A., . . . Bassett, A. S. (2015). 22q11.2 deletion syndrome. Nat Rev Dis Primers, 1, 15071. doi:10.1038/nrdp.2015.71
  2. Botto, L. D., May, K., Fernhoff, P. M., Correa, A., Coleman, K., Rasmussen, S. A., . . . Campbell, R. M. (2003). A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics, 112(1 Pt 1), 101-107. doi:10.1542/peds.112.1.101
  3. McDonald-McGinn DM, H. H., Emanuel BS, et al. (2020). 22q11.2 Deletion Syndrome.
  4. DiGeorge A. (1965). Discussion on a new concept of the cellular immunology. Journal of Pediatrics, 67, 907-908.
  5. McDonald-McGinn, D. M., & Zackai, E. H. (2008). Genetic counseling for the 22q11.2 deletion. Dev Disabil Res Rev, 14(1), 69-74. doi:10.1002/ddrr.10
  6. McDonald-McGinn, D. M., & Zackai, E. H. (2008). Genetic counseling for the 22q11.2 deletion. Dev Disabil Res Rev, 14(1), 69-74. doi:10.1002/ddrr.10
  7. Jerome, L. A., & Papaioannou, V. E. (2001). DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1. Nat Genet, 27(3), 286-291. doi:10.1038/85845
  8. Vorstman, J. A., Turetsky, B. I., Sijmens-Morcus, M. E., de Sain, M. G., Dorland, B., Sprong, M., . . . Kemner, C. (2009). Proline affects brain function in 22q11DS children with the low activity COMT 158 allele. Neuropsychopharmacology, 34(3), 739-746. doi:10.1038/npp.2008.132
  9. McDonald-McGinn, D. M., Tonnesen, M. K., Laufer-Cahana, A., Finucane, B., Driscoll, D. A., Emanuel, B. S., & Zackai, E. H. (2001). Phenotype of the 22q11.2 deletion in individuals identified through an affected relative: cast a wide FISHing net! Genet Med, 3(1), 23-29. doi:10.1097/00125817-200101000-00006
  10. McDonald-McGinn, D. M., Sullivan, K. E., Marino, B., Philip, N., Swillen, A., Vorstman, J. A., . . . Bassett, A. S. (2015). 22q11.2 deletion syndrome. Nat Rev Dis Primers, 1, 15071. doi:10.1038/nrdp.2015.71
  11. McDonald-McGinn, D. M., Sullivan, K. E., Marino, B., Philip, N., Swillen, A., Vorstman, J. A., . . . Bassett, A. S. (2015). 22q11.2 deletion syndrome. Nat Rev Dis Primers, 1, 15071. doi:10.1038/nrdp.2015.71
  12. McDonald-McGinn, D. M., Kirschner, R., Goldmuntz, E., Sullivan, K., Eicher, P., Gerdes, M., . . . Zackai, E. H. (1999). The Philadelphia story: the 22q11.2 deletion: report on 250 patients. Genet Couns, 10(1), 11-24.
  13. Bassett, A. S., McDonald-McGinn, D. M., Devriendt, K., Digilio, M. C., Goldenberg, P., Habel, A., . . . Vorstman, J. (2011). Practical guidelines for managing patients with 22q11.2 deletion syndrome. J Pediatr, 159(2), 332-339.e331. doi:10.1016/j.jpeds.2011.02.039
  14. McDonald-McGinn, D. M., & Sullivan, K. E. (2011). Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine (Baltimore), 90(1), 1-18. doi:10.1097/MD.0b013e3182060469
  15. Repetto, G. M., Guzmán, M. L., Delgado, I., Loyola, H., Palomares, M., Lay-Son, G., . . . Alvarez, P. (2014). Case fatality rate and associated factors in patients with 22q11 microdeletion syndrome: a retrospective cohort study. BMJ Open, 4(11), e005041. doi:10.1136/bmjopen-2014-005041
  16. McDonald-McGinn, D. M., Tonnesen, M. K., Laufer-Cahana, A., Finucane, B., Driscoll, D. A., Emanuel, B. S., & Zackai, E. H. (2001). Phenotype of the 22q11.2 deletion in individuals identified through an affected relative: cast a wide FISHing net! Genet Med, 3(1), 23-29. doi:10.1097/00125817-200101000-00006
  17. Repetto, G. M., Guzmán, M. L., Delgado, I., Loyola, H., Palomares, M., Lay-Son, G., . . . Alvarez, P. (2014). Case fatality rate and associated factors in patients with 22q11 microdeletion syndrome: a retrospective cohort study. BMJ Open, 4(11), e005041. doi:10.1136/bmjopen-2014-005041

Transcript

Brenna: You are listening to the Rare Disease Connection, a production of Aspect Health and RareDisease.com. Sometimes I find myself thinking about the intricacies of genetics. From just 46 chromosomes comes an entire person. There is so much information packed into each of ourselves, and scientists are just beginning to understand the nuances of us. On this podcast, we've talked about conditions caused by changes in a single gene or conditions involving an entire extra chromosome. Brenna: Today, we're going to talk about what happens when you're missing a region on chromosome 22. Rare Disease Connection and our additional resources on RareDisease.com and YourDNA.com brings together the people whose expertise can explain what you're facing from diagnosis to prognosis to treatment options all the way to questions like, "Who do I talk to? Where are the people who have been through this before?" You'll find those answers here from doctors, geneticists, academics, genetic counselors, patient organizations, other patients and their families, they're all within your reach. We're here to connect you. This is Rare Disease Connection. Brenna: Hey everyone. This is Brenna, Co-Host of Rare Disease Connection and Director of Patient Education at YourDNA.com. Today, I'm going to bring you conversations with three experts on 22q Deletion Syndrome. Before we get started, you should know that this podcast is just the beginning. We have taken the information from this podcast and added additional resources, explanations, links and references for you in a downloadable guide. You can get your free copy by going to RareDisease.com/22q. That's RareDisease.com/22q. So, let's get started. Brenna: Our first guest today is Emily Palen, a licensed genetic counselor currently working at Geisinger's Autism & Developmental Medicine Institute in Lewisburg, Pennsylvania. She has been there since 2016 and coordinates their 22q developmental specialty clinic. Welcome Emily. Brenna: Why don't you start out just telling us a little bit about yourself? Emily Palen: Sure. My name is Emily Palen. I'm a licensed certified genetic counselor and research coordinator at Geisinger's Autism & Developmental Medicine Institute here in Lewisburg, Pennsylvania. I graduated from Boston University's Genetic Counseling Training program in 2016, and I've been here at Geisinger ever since. Part of my work at Geisinger includes coordinating our 22q Specialty Clinic here at the institute. Brenna: That sounds wonderful. Speaking from your experience as a genetic counselor, what immediately comes to mind when you hear 22q deletion? Emily Palen: Yeah. A few different things come to mind. First, is a highly variable phenotype. No individual with 22q is going to be the same as another. I also think about a fierce and loving network of families. They're some of the most incredible families that I've had the privilege of working with. Then something very special to 22q is I feel that the community of researchers and medical providers is highly engaged, supportive and forward thinking. So, those are the main things that come to mind when I think about this particular condition. Brenna: Yeah, all really good things, positive things. Emily Palen: Yeah, definitely. Brenna: Using your experience as a genetic counselor and trying to understand what's actually occurring, what's going on genetically that causes 22q deletion? Emily Palen: Yeah, great question. 22q deletion is caused by about a three megabase deletion on chromosome 22 on the long arm of that chromosome. So, that's about three million based pairs, or the genetic letters that make up our genetic code. So, those three million base pairs are missing from that section of the chromosome. The loss of several genes in that region cause some of the hallmark features of the condition. Brenna: Is this inherited? Is this something that someone has gotten from one of their parents, or were they just born with it? Emily Palen: Yeah, so it can be inherited. As far as we understand it right now, most of the time these deletions, about 90% of the time, arise de novo, meaning that they're new and unique in the individual and weren't inherited from either parent. It's certainly possible that it could have been inherited from a parent in some of the cases. Brenna: Okay, so we know that maybe sometimes it's inherited, but most of the time it's not. Thinking about it as a whole, are there certain people who are more likely to have 22q Deletion Syndrome? What kind of chances to have a child with this condition? Emily Palen: Yeah, great question. Anyone can have 22q Deletion Syndrome. It doesn't discriminate against sex or race or anything like that. Anyone could have this condition. We know that if someone carries the deletion, so if someone has this condition, there's a 50/50 chance with each pregnancy that the deletion could have been passed on to the child. If someone doesn't carry the deletion, we can't say there's a zero percent chance because it's possible the deletion could occur out of the blue. We would say have a low risk if the parent isn't a carrier of that condition. Brenna: Thinking about how we actually make this diagnosis, I guess first time you see a patient, you might walk in. If you were to see pictures of someone with this condition, what would we see? What would someone look like? Emily Palen: Yeah. I'll sound like a broken record throughout this entire recording, but every person will be different from each other that has this deletion. If we pull back and try to find physical commonalities, some of the facial features or physical features that you might notice are ears tend to be smaller and maybe a little bit squared off at the top. Eyelids tend to be hooded, so the skin between the brown bone and the lash line is a little bit droopier. Bridge of the nose is more prominent, and the chin tends to be rather small. Those are some of the facial features that you would see. Individuals might be a little bit smaller, shorter than other members of their family. Some of the other features of the condition are things that you can't see with the naked eye. Brenna: Thinking about those things that we can't see with the naked eye, what are those? What are things that some people should be watching for? Emily Palen: 22q Deletion Syndrome, there are a few things that tend to go along with it. Again, everyone will be different who carries a deletion. We tend to see cardiac defects or congenital heart defects, so cardiac abnormalities that are present from birth. Maybe a hole in the heart or something called Tetralogy of Fallot, which is a few different cardiac abnormalities all occurring at the same time or maybe an interrupted aortic arch. These are typically cardiac abnormalities that affect the aorta of the heart typically. Emily Palen: We may also see palatal abnormalities, so individuals with this condition may have a cleft pallet or a bifid uvula, which is that little dangly bit in the back of your neck at the back of your throat. That might be split in two. We may also see something called velopharyngeal insufficiency . What that means is the soft pallet at the back of your pallet doesn't close against the back of the neck. What that can cause is air flow when speaking that makes the speech sound a little bit different. If you chat with a little kid who has this condition, their speech might sound a little bit different than other kids who don't have this deletion. That's typically caused by that VPI or that velopharyngeal insufficiency. Emily Palen: Individuals with this condition might also have immune deficiencies, so ear infections a lot or getting colds all the time. So, their immune system isn't quite as strong as other people. We usually also see some sort of developmental delay. Maybe that's across the board in all of the developmental domains or maybe in just a couple. We tend to see developmental milestones lagging behind their typical peers. Emily Palen: 22q is also associated with some mental health differences. That's usually one of the things that people can cling onto. If you do any Googling, you may see that this condition is associated with a psychiatric condition called schizophrenia. That can be very overwhelming for newly diagnosed individuals and their families. We can also see things like increased anxiety, mood differences, things like that. Brenna: Thinking about all of those things, and I know how they might not be present in every single person and everyone's going to be different. When does someone receive a diagnosis typically? Is there a typical age? Is there a certain test that they have to undergo? Emily Palen: It totally depends. I know individuals who weren't diagnosed until they were in their 30s or 40s. That might be because maybe their symptoms or their features were more subtle or more mild and they just weren't identified as someone who might have this condition when they were younger. Maybe they just slipped through the cracks in terms of genetic testing. They never met with a provider who had offered that up to them or their families. Emily Palen: In my pediatric practice, our clients with 22q tend to be picked up in the NICU. Usually babies who have 22q may have those cardiac abnormalities that I was talking about or low calcium levels, which can cause seizures and other medical concerns. Maybe a doctor notices that have some other characteristic facial features or physical features consistent with the syndrome. A lot of the little friends that I have who are diagnosed with 22q was because they exhibited those signs or symptoms early on. Emily Palen: The types of tests vary as well. There are many different ways to detect this deletion. Sometimes if a patient is seen by a geneticist or another provider who really thinks that it's 22q, they may do very targeted testing to look for just that deletion and nothing else. Maybe a provider says, "I think it might be 22q, but I might be wrong." They'll maybe order a test called a chromosomal microarray, which will look for any deletion or duplication on any of the chromosomes. 22q would be detected by that technology. Then other providers might offer up broader testing, something called whole exome sequencing, which some of the time we can detect these types of deletions as well. It really all depends. The kind of clinical management or care isn't dictated by which test is ordered. It just kind of clarifies the diagnosis. Brenna: I know you mentioned that you see several individuals who are picked up in the NICU, but I guess going before that, is there any prenatal testing that's available for this condition? Emily Palen: Yes, absolutely. There are many different ways that this might be detected in the prenatal period. Some individuals may choose to pursue non-invasive prenatal screening. Sometimes that screening test might come back indicative of possibilities that this deletion is present. Those individuals may choose to pursue diagnostic testings, such as an amniocentesis, which would be looking at the fetal cells to see if there are any deletions or duplications that might be causative of other developmental concerns or medical concerns such a 22q. Emily Palen: If a parent is a known carrier, so if you have an individual who's known to carry 22q, and their pregnant or family planning, they might choose to pursue that diagnostic testing that I mentioned and amniocentesis or not. It's every family's choice what information they want to know about their child or their pregnancy. Sometimes if 22q isn't on our radar, the parent isn't a carrier, there's no family history, nothing like that, maybe ultrasound findings come back that are indicative of this condition. Maybe they notice some cardiac abnormalities that we know are more common in 22q. So, the provider would likely discuss that with the family and see if they'd like to pursue any testing. Brenna: Is there a cure? Emily Palen: Yeah. That's a question I get from a lot of our families who are newly diagnosed. At this time, we don't have the ability to replace that missing section of 22q. A lot of families say, "Well, if it's missing, can't we just put it back?" We don't have that technology or that ability right now. The bright side of 22q is we're really good at treating and managing all of the symptoms and features. If someone has immune deficiency, we'll get them set up with immunology. If they have cardiac defects, we'll get them set up with cardiology. Emily Palen: So, there's very clear protocols and guidelines that we can follow to take the best care of these individuals that we can. But, no, at this time we don't have a cure or a way to correct that genetic deletion. Brenna: In closing, you've seen a lot of individuals and families who have this condition. What's your best advice for someone who's just been diagnosed or who has a loved one who was just diagnosed? Emily Palen: I think the first thing that comes to mind is to tell that individual or their family that they're not alone. 22q is one of the most common microdeletion syndromes. There are many medical providers and researchers who are dedicated to taking the best possible care of these individuals. So, if and when you or your loved one or family members are ready, the 22q community is going to be here with open arms. They're some of the most engaged and supportive individuals I've ever met. So, the community is really strong. I think that can be very, very helpful for some individuals facing a new diagnosis for themselves or their family member. Brenna: Thank you, Emily, for joining us today. Brenna: Whether you've interacted with a genetic counselor yet or not, they play an invaluable role in the journey of anyone diagnoses with a rare genetic disease. If you have questions about 22q Deletion Syndrome, I would recommend looking at NSGC.com to find a genetic counselor near you. Brenna: Our next guest is Doctor Scott Hickey. He's a clinical geneticist at Nationwide Children's Hospital in Columbus, Ohio. Doctor Hickey works on a number of different specialty clinics, one of which being the 22q Center Multidisciplinary Clinic. Brenna: Thank you for taking the time to speak with us today. Why don't you start out by just telling us a little bit about yourself? Doctor Hickey: Yeah, my name is Scott Hickey. I'm an assistant professor of clinical pediatrics through the Ohio State University College of Medicine in affiliation with Nationwide Children's Hospital in Columbus, Ohio. I'm a board certified general pediatrician and board certified clinical geneticist. I'm the staff geneticist and one of the co-directors of our 22q Center through our hospital, which is a multidisciplinary clinic for patients with 22q11 Deletion Syndrome. Brenna: Thinking about your experience as a pediatrician and as a clinical geneticist, what immediately comes to mind when you hear 22q Deletion Syndrome? Doctor Hickey: Well, it's one of those conditions that's quite variable in terms of the extent to which it effects the quality of patients. So, everybody can be quite different, and everybody has their own unique set of challenges. I think that's one of the reasons that it's important for a medical system and hospital to have resources across a wide range of disciplines to help provide for these patients. Brenna: Thinking about 22q Deletion Syndrome as a whole, how common is this condition? Is it more prevalent in certain populations or areas of the world? Doctor Hickey: Well, I think the vast estimates are that the prevalence is somewhere between one in 2,000 and one in 3,000 people. There was a study in 2015 of pregnant women where they suggested that ... they found evidence that it could be as high as one in 1,000. That was just one study, and I would tend toward it being closer to one in 2,000 to one in 3,000, which does make it the most common chromosomal microdeletion syndrome. By comparison, down syndrome is probably found in about one in 1,000 people. So, down syndrome might be about twice as common. Doctor Hickey: It is interesting because most people in the general public when you talk to them, I often use down syndrome as a point of reference, because most people are familiar with that. Whereas for whatever reason with 22q Deletion Syndrome, most people have not. In terms of the question of certain populations, I doubt it. It's a condition that really it's a recurrent condition due to some specific predisposition that all humans have to possibly have a child with this condition. That's really a predisposition that I think we would expect would cut across all races and ethnicities. Although I don't have exact data across all different types of indigenous people and everything, we would expect it would be about the same in most populations. Brenna: Sure. Absolutely. Throughout your career in working with this condition, what has surprised you the most? Doctor Hickey: Well, I think it's the variability of the condition, because a lot of things have changed in terms of genetic testing technology. In the late 90s and the early 2000s, in order to make the diagnosis, you had to use fluorescence in situ hybridization or FISH testing, which was, without getting into the technical parts of it, required the provider to say, "I think this might be 22q Deletion Syndrome. Let's check." Now the way that chromosomal testing has developed over time, we as geneticists don't have to be quite as smart anymore. We can just employ a test called a microarray that looks at copy number changes across all the chromosomes. Doctor Hickey: So, we don't really have to ask questions. We don't have to think of 22q Deletion Syndrome. We can just say, "Is it any chromosome condition?", and it will come back and let us know if it's 22q Deletion Syndrome. What we learned from that is that in many cases, even though we weren't thinking of that condition specifically, that's what turned out to be the cause. So, it always looked like what we thought it would look like because that's what we were looking for. Now we've seen all the many other different ways that this condition can present to doctors. Brenna: Right. As you casted a larger net, you were able to identify patients who might have had symptoms or signs that might not have been the traditional symptoms or signs initially looked for. Doctor Hickey: Right. That's correct. That's also helpful, because it's not always a genetics provider. In fact, it's often not a genetics provider who's evaluating these patients on the frontline. It might be a primary care physician. It might be a neonatologist. It might be in another specialty because of some other health condition that is kind of the first thing that gets pediatrician's concerned. So, it's helpful to have a test now that allows them to just sort of ask a general question, "Could it be any chromosome difference?" Then it comes back that it's a 22q deletion without requiring the expertise of a geneticist looking at the patient with a little more detail or eye toward that question. Brenna: Sure. That's the first line test for intellectual disability, development delays. It's typically a go-to for that microarray, right? Doctor Hickey: Right. Chromosomal microarray really became quite popular clinically in around 2006 to 2008 range, depending what institution you're at. The academic institutions, I think, tended to be a little bit more on the cutting edge, so to speak, side of that. Then by 2010, there were multiple different genetic societies recommending that as the frontline test for intellectual disability, autism, multiple congenital anomalies type of presentation. Brenna: Keeping in this [inaudible 00:21:11] with diagnosis, if you were able to see these patients, I know often you're stating geneticists aren't always the frontline, but when you are completing a physical exam, are there certain features that might make you suspicious of this condition? Doctor Hickey: As geneticists, I guess we have two different skillsets that are sort of our area of expertise. One of them is genetic testing and the interpretation of genetic testing. The other one is what's called dysmorphology, which refers to looking at babies, children, patients and looking for specific patterns in the way that they look in the context of whatever's going on. So, I think it's important to sort of preface it by we look for these things in babies who are having some sort of problem. It's a different situation if you see features in a baby who's otherwise healthy and growing and developing normal. Doctor Hickey: So, in the context of some sort of medical concern, a lot of it is looking at the baby's facial features. So, children with 22q Deletion Syndrome are often described as having a sort of bulbous or rounded nasal tip. Their ears are often formed a little bit differently. They're a little overfolded and in low set in some cases. Then their mouth is often small with the corners of their mouth are downturned. Then their chin is often small. Some of these features are reflective of what's called low muscle tone. Doctor Hickey: Children with 22q Deletion Syndrome often have low muscle tone. It's important to point out that children with lots and lots of different genetic conditions have low muscle tone. So, just because a child has low muscle tone, I wouldn't necessarily say that they have 22q Deletion Syndrome. If a baby is born with a certain type of heart defect, if they have a calcium problem, immune problems, a cleft pallet or other things that might make us think of 22q Deletion Syndrome, then that would be a first line test that we'd want to do. Brenna: It sounds like you really have to take the whole picture into account. Doctor Hickey: Yes, that definitely correct. That's a really important point, because my experience in dealing with patient families is that there's always this question of sort of what does that little particular point mean like, "You see this on a baby. What does that mean?" It's a really important overarching point that we're not looking at one thing. We're looking at the whole picture and the context. Doctor Hickey: Anything individually doesn't necessarily mean anything. This is sort of the process of being a doctor. You take this concern that the parent or another doctor has. You take the way that the baby looks. You take the lab test results. Everything gets put together. Then you sort of take all of that data to try to figure out what you think about the situation. So, there's not sort of, "Well, what's the one thing that's important?" If you're thinking that way, that's not the way doctors think. Brenna: That's probably important when we think about care and management, because this condition can be so variable from person to person. Just knowing that you have 22q Deletion Syndrome probably doesn't say, "This is the exact treatment and management." You're probably having to look at what that specific patient needs. Doctor Hickey: Right. Yeah. That's a really good point too. Even other doctors who aren't involved in genetics, they have this idea that I can look at a report and a piece of paper and then tell them what the patient looks like. It grants me a lot of power that I don't really have. So, yes, everyone is an individual and has their own individual set of challenges. I think really always care is going to be tailored to the individual patient. Doctor Hickey: What we use, the diagnosis of 22q Deletion Syndrome, we take that at the start of a road map or these are the risks that we're aware of based on that information. These are the things that we think we need to look out for. There are certain guidelines that have been out there since 2011. Then there's whatever's going on with the patient or their family. Then we kind of either add some things or we take some things out depending on their specific situation or preferences or concerns or whatever. So, you get the diagnosis, and those guidelines are a start for what you need to do, but then you take the individual situation for sure. Brenna: With all that in mind, my next question is probably not exactly fair without speaking about an actual patient in front of you. Doctor Hickey: It's okay. Brenna: Just sort of thinking generally, if you did have that textbook fit all of the check marks 22q Deletion Syndrome patient, what would care and management look like generally? Doctor Hickey: Well, we use the guidelines from Journal of Pediatrics in 2011. So, they're always going to ... When we make the diagnosis, there is just a checklist of things that should be looked for. Really, there's no recommendation to change that based on the age of the patient. So, it's really interesting because this is the condition that may be diagnosed prenatally based on a concern on, for example, before the baby's born. It might be diagnosed right after the baby's born. Might be diagnosed in early childhood. I've seen a handful of young adults with some psychiatric challenges who are diagnosed around college age or even a little bit after that. Doctor Hickey: There's really no recommendation to sort of do the whole kit and kaboodle no matter what age somebody is. So, we're always going to recommend an echocardiogram or an ultrasound of the heart, recommend calcium testing due to concerns for difference in parathyroid activity. Always going to recommend immune system testing, renal ultrasound to look for the structure of the kidneys. Doctor Hickey: Speech and language therapy is often a very integral part of this condition, because they may have a cleft pallet, but if they don't, they still might have what's called velopharyngeal insufficiency, which is weakness of the muscles and the structures that are separating the mouth cavity from the nasal cavity. So, their voice may have this hyper nasal intonation to it that makes it difficult for others to understand them. Increasingly, that is recognized to be an issue that is, in some cases, amendable to surgical therapy. So, that might be apart of the care, having a scope that goes and looks at the function of the structures that they close off, the connection between the two cavities. So, that is usually a standard part of care as well. Doctor Hickey: We'll always tell families about the genetic inheritance of the condition. We offer testing to parents if they would like it. It's a new genetic change about 93% of the time, so it's only inherited five to seven percent of the time. So, it's usually not inherited. It's important in genetics, as you know one of our really central tenets is non-directiveness, so we offer genetic testing. We don't tell people that they have to get it or not to get it. We just explain the facts, and families can decide on their own. Brenna: It sounds like you have great guidelines and management options and even some surgical and treatment options. At this point, is there a cure for this condition? Doctor Hickey: No. Generally, put it in the groping of a chromosome condition. Another aspect of genetics is that your genetic information is present and found in all of the trillions of cells of your body. So, anything that would be considered "cure" would have to reach and have its effect and change the genetics in every one of those trillions of building blocks of your body, which is just a real challenge. Doctor Hickey: The typical deletion or missing information in 22q Deletion Syndrome includes around, depending on your definition of what a gene is, includes about 70 genes. So, you have, at least at the outset in theory, 70 genes that aren't working correctly. There may be effects on other genes that are outside the deletion. Where we are in medical science, as least as far as I understand it is, we're making some in-roads in therapies, at least targeted therapies, for the genetic difference in single gene disorders. So, where you have one gene that's not functioning properly, usually a gene that has lost a function and is not doing at all what it's supposed to do. Doctor Hickey: That's what I would consider the low hanging fruit of cures and therapies and genetics. Something like this that's a chromosomal condition is going to be many years down the line after we get the hang of single gene disorders, which we still really haven't done. Those therapies are really only available for a handful of conditions. Brenna: That's a lot of information and a lot of cells to work on. Just the last couple of questions, I know you've seen patients at a variety of ages, but in general, is there shortened life expectancy for individuals with 22q Deletion Syndrome? Doctor Hickey: Well, obviously I get asked that a lot by parents, and it's a very emotionally charged question. So, I think it's important to be kind of specific about it. If a child has a really significant structural difference in the anatomy of their heart, that is always going to effect life expectancy. So, that's true in 22q Deletion Syndrome and not in other children who don't have 22q Deletion Syndrome. Doctor Hickey: In terms of how this has been looked at, I think those are really ... I would piece people into separate buckets there the way that I thought about them. There are other things that are known to effect life expectancy just in and of themselves and by themselves, including intellectual disability and then schizophrenia. There is a substantial risk for neuropsychiatric conditions such as schizophrenia and 22q Deletion Syndrome. Although, the majority won't have that issue. So, those things effect mortality too. Doctor Hickey: Each subsequent study that I see on this, the median age of survival gets longer. So, I think that's encouraging. The last report that came out of Canada of an adult clinic, a prominent adult clinic in Toronto was that the median age of death was in the mid to late 40s, which I know is not what people want to hear. You have to understand that also includes people with significant congenital heart disease. If a child doesn't have significant congenital heart disease, I think we would expect more than that. I think with guidelines and modern medical care, I think we expect to continue to improve over time. Brenna: My final question of today is, what's one thing you would like people to leave this podcast knowing about 22q Deletion Syndrome? Doctor Hickey: Well, it's a little bit of a restatement of what we mentioned before. In genetics, I always like to bring up to other providers and families sometimes that a diagnosis isn't necessarily a prognosis. Again, I can't look at that sheet of paper and have it serve as a crystal ball for a person's future. It does, as we mentioned, offer a road map for care. I think that's why it's important to make the diagnosis so we understand what's going and we know what to look out for in the future. Hopefully if further issues are going to develop, we will catch them early and be able to make interventions and prove things by catching them early. Doctor Hickey: Again, that everyone is different. We had to learn this over many years as our technology changes that we thought we had an idea of how this condition looked and that people were all going to all develop all these problems. Then later, we developed a new test and started testing more people and then found that lots of people had it that didn't have any of those problems that we thought they should have. I think it's just important to understand that the diagnosis is not the prognosis. Brenna: Thank you, Doctor Hickey, for spending time with us today. Brenna: If you have a loved one who was recently diagnosed with 22q Deletion Syndrome, it is important that you identify physicians familiar with this condition. You can go to 22qFamilyFoundation.org to see a list of specialty clinics and find one near you. Brenna: Our final guest today is Keisha Fonnell. Keisha's son, Rowen, was diagnosed with 22q Deletion Syndrome when he was two years old after numerous visits with specialists. Thank you for joining us today, Keisha, and for sharing your story. Brenna: Why don't you start off just by telling us a little bit about yourself? Keisha Fonnell: Well, I am 36 years old. I am a mother to two beautiful children, one of which is a little extra special because he has 22q Deletion Syndrome. I think that's probably our biggest thing in our life and our family. Brenna: When you first hear 22q Deletion Syndrome, what initially comes to mind? Keisha Fonnell: A little bit of everything, fear of the unknown. Mostly we don't always know what's next with him. Then hope obviously because there's a lot of research going on right now. There's a lot of education going on right now. I didn't even know what it was before my son was diagnosed. I've been an OPN since 2004, and I had never heard of that syndrome before. I worked both in the elderly setting, and then also with children, I work with [inaudible 00:36:34]. I have seen a good many syndromes but not that one. Brenna: So, it was new information for you when you got that diagnosis? Keisha Fonnell: Very. Brenna: Let's back up a little bit. Why don't you introduce us to your son? Tell us a little bit about him. Keisha Fonnell: Okay. Well, Rowen is seven. He'll be eight real soon. He's awesome. He has got a great sense of humor. He's very loving to his family. He is mild in the respect that his cognitive abilities are much higher than I think we previously expected. He's in first grade, and he's in mainstream school. He does still have some therapies and things like that, but he's doing really well right now. Brenna: Yeah, that's great to hear. Thinking about how you got this diagnosis, when did you first become aware that your son might be different from other children? Keisha Fonnell: Well, day one of life, they told us that he had multiple heart defects. But 22q wasn't one of the screening blood tests. It should be. I would like it to be, but it wasn't. So, that was the first time we realized something was wrong. Then he wasn't able to latch. He had a lot of nasal regurgitation, a lot of reflux. I found myself taking him to a lot of specialty appointments. I would say around six months, he stopped meeting milestones. He would sit but not unless you propped him. After that, he stopped meeting his milestones and therapy started shortly thereafter. Keisha Fonnell: It was not until he was a little over two years old that we met Doctor Chalman at the AZMI Clinic. That appointment was for something else and turned into a diagnosis, which was both bittersweet because I could finally put a name to what was going on, but then at the same time you were putting a name to what was going on. That appointment was meant for, to my understanding, it was supposed to get more language therapy. The more we talked, the more he started asking me questions, the more I realized it was going in a different direction. We got the diagnosis about two weeks later. He called me on the phone. Brenna: What was that process like for you, you know, waiting to get that diagnosis? Keisha Fonnell: I believe I was in denial. That's 100%. Doctor Chalman is wonderful. He's changed our life. He was positive that the test would come back positive, and he told me that afterwards. For those two weeks or so, I was certain there was just no way. It had to be something else. It was sort of denial really. When he called me, he was wonderful. You know when you're going to get bad news and when you're going to get good news it sounds different on the phone? If it's good news, someone's just going to be like, "Hey, guess what?" That's not ... I knew. He was just like, "Are you alone? Is there someone with you? Can you sit down?" That's when I knew he was going to tell me. Keisha Fonnell: He said, "Yeah, your son has 22q Deletion Syndrome." He said, "The first thing I need you to do is go see a genetic counselor immediately." He said, "We have those resources, and we need you to talk to them right away so that you can be properly educated and we can get started." Brenna: That must have been quite some news to hear. Keisha Fonnell: Yes. It stopped us in our tracks. It was good to give a reason for all the things that was happening. Everyone kept ... Certain people were throwing around autism and things like that, and I just really didn't think that was quite what was wrong. There were other bits to it, and there were other things that were going undiagnosed that he diagnosed when we were there. That's when we realized that he had velopharyngeal insufficiency and he had a submucosal cleft pallet that no one had noticed yet. Even though we knew he had a bifid uvula, no one had realized even with the speech and everything else that was going on. Keisha Fonnell: He gave us so many diagnoses and so many things that we could go ahead and start checking off the list. That makes you feel good when you check something off the list. It's like, "Okay, moving to the next thing," and just making sure that we're doing our best for Rowen at all times. Brenna: It sounds like maybe after meeting with Doctor Chalman as well as a genetic counselor and hearing about different signs and symptoms, things started to line up with what you were seeing in your son. Keisha Fonnell: Yeah, but it was really scary. You don't know what's next. You don't know if he's going to be okay. You know there's surgeries coming up. None of these appointments are great. Everybody there is wonderful, but you don't want to have to be doing that with your kiddo. Brenna: Going through that process with it being scary, is there something you wish you would have known or heard that maybe would have made the process a little bit better for you? Keisha Fonnell: If someone could have told me that it was going to be okay when it the big part of it was over and the surgeries were over, maybe I could've been a little stronger. I think I was a good, strong mom for him, but I was scared. I would tell anybody that if you're going through something like this with your kiddo, seek out your own therapy. Be sure to validate yourself, your own feelings, your own journey, because it's important to keep yourself going so that you can be there for your child. Rowen went through a lot of things that he didn't fully understand, and I had to be the one there. So, it helps to talk to other people about that. Brenna: I think that's great advice. I think that's something more families should hear as a whole. So, once you've received your diagnosis, you started marking off those check boxes, as you were saying. What has therapy and management looked like for you and for Rowen? Keisha Fonnell: Management has looked like a lot of appointments, regular blood work. Then we sought out CHOP in Philadelphia. They have a 22q NU Department, an entire clinic that actually fully understand my child and what's been going on. The doctor there has been studying the syndrome since 1983. Her and several other doctors wrote a book that she gave me. They're full of knowledge. They're constantly researching, which they have us do like spit in a vial, things like that just so they can keep learning. Keisha Fonnell: He's had multiple surgeries. He had his cleft repaired at CHOP. That was two different surgeries a year apart. That surgeon's fabulous. There's been a lot of therapy, everything, occupational therapy, physical therapy, vision therapy, speech therapy and we do therapeutic writing. Brenna: It seems like that's a lot of appointments for you to keep up with and to make sure everyone's getting to you at a right time. Keisha Fonnell: Mm-hmm (affirmative). You have to advocate. You have to stand your ground as a mom. A lot of times, you meet a doctor who doesn't know what your child has. You actually have to start from the beginning and be like, "This is what 22q is." I've met a lot of doctors who still try to call it the DiGeorge. They'll be like, "Well, he has this, this and this." I'm like, "Well, no, actually he doesn't. It's more on the velocardial facial side. So, it was more this, this and this versus what you're talking about." It makes a big difference. They need to know that he has this before we get started with anything else. You have to understand our history. Brenna: That seems like then probably going to a place like CHOP where people already understand what's going on and have that baseline extremely beneficial. Keisha Fonnell: It was crazy to meet her for the first time, because it was almost like she knew us, and Doctor Chalman the same way. When he would start to talk to me and describe my child, even though this was literally our first appointment, it's crazy to meet someone who already knows and it's very comforting. You realize that someone else is fully aware of what's going on, and they have ideas like, "When your child's like nine, you need to have this x-ray," or, "We need to do this yearly," or, "Have you seen this doctor yet?" It's nice to have somebody who is already on the same page. Brenna: Outside of having obviously these fabulous support resources and these physicians, has there been anything else that's been super helpful for you support-wise throughout your journey? Keisha Fonnell: We use the CSIU. So, we had home therapy and we use a private therapy, KidWorks. They have been wonderful along the way. I would say that my biggest support has been my family, 100% my family. Everybody understands we're going through a journey. Everyone has helped. There's no judgment. I think my family's been the main reason we've gotten through everything really and truly. Brenna: Is there any particular organizations or support groups that you would recommend to other families who have 22q Deletion Syndrome? Keisha Fonnell: I don't even have a Facebook. So, I am not apart of any groups. I can tell you that I do 22q at the Zoo every year. I love meeting new families, whether they have a new diagnoses or they're new to the area or they traveled from somewhere. Talking with other families that are going through something similar is very therapeutic. All our stories are different, because all our kids are a little different. I would say, I mean organizations-wise, it's mostly the hospitals and therapies that we've had. Brenna: Thanks so much for spending time with us today. Just in closing, what's your best advice either to another mom or other family members who might have just found out that their child or another loved one has 22q Deletion Syndrome? Keisha Fonnell: I would tell you to take a big deep breath and strap in, because it's going to be a journey. It's going to be an adventure. As long as you have the support around you, you'll get through it. It's a journey, and you have to validate yourself and you have to advocate for your child. That's the most important. Brenna: Thank you, Keisha, for introducing us today to Rowen and sharing your story. Brenna: For many families, the diagnostic journey can be long, but don't give up. You are not alone. For additional resources and connection to other families, you can go to the International 22q Foundation website at 22q.org. Brenna: In closing, we have had the chance to talk to three experts today in 22q Deletion Syndrome, but this is just the beginning. We have taken all of today's information and included it in a free downloadable guide. You can get your free guide by going to RareDisease.com/22q. We would love to connect with you. If you need to talk to someone, we're standing by. Go to RareDisease.com/help. We are waiting for you. Rare Disease Connection is a production of Aspect Health and RareDisease.com. Thanks for joining us.

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