International meeting on Wolf-Hirschhorn syndrome: Update on the nosology and new insights on the pathogenic mechanisms for seizures and growth delay.

"An International Meeting on Wolf-Hirschhorn Syndrome (WHS)" was held at The University Hospital La Paz in Madrid, Spain (October 13-14, 2017). One hundred and twenty-five people, including physicians, scientists and affected families, attended the meeting. Parent and patient advocates from the Spanish Association of WHS opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes. These proceedings will review the major points of discussion.

Wolf-Hirschhorn syndrome: A review and update.

Since 4p- was first described in 1961, significant progress has been made in our understanding of this classic deletion disorder. We have been able to establish a more complete picture of the WHS phenotype associated with distal 4p monosomy, and we are working to delineate the phenotypic effects when each gene on distal 4p is hemizygous. Our aim is to provide genotype-specific anticipatory guidance and recommendations to families of individuals with a diagnosis of WHS. In addition, establishing the molecular underpinnings of the disorder will potentially suggest targets for molecular treatments. Thus, the next step is to determine the precise effects of specific gene deletions. As we look forward to deepening our understanding of distal 4p deletion, our focus will continue to be on the establishment of robust genotype-phenotype correlations and the penetrance of these phenotypes. We will continue to follow our WHS cohort closely as they age to determine the presence or absence of some of these comorbidities, including hepatic neoplasms, hematopoietic dysfunction, and recurrence of seizures. We will also continue to refine the critical regions for other phenotypes as we enroll additional (hopefully informative) participants into the research study and as the mechanisms of the genes in these regions are elucidated. New animal models will also be developed to further our understanding of the effects of hemizygosity as well as to serve as models for treatment development.

Affinity for music in Wolf-Hirschhorn syndrome: two case reports.

BACKGROUND: Wolf-Hirschhorn syndrome is a congenital malformation syndrome resulting from deletion of the short arm of chromosome 4. Individuals with Wolf-Hirschhorn syndrome may have a "Greek warrior helmet" appearance, growth retardation, developmental delay, muscular hypotonia, epilepsy, and difficulty with language including verbal communication. An affinity for music has not previously been reported in these patients. PATIENTS: We describe two patients with Wolf-Hirschhorn syndrome who both have a strong affinity for music. One patient is a 20-year-old woman who likes to listen to music all day and can hum many tunes. The other patient is a 9-year-old girl who is calmed by music and received music therapy, with subsequent improvement in her communication skills (eye contact, joint attention, and vocalizations to request music). CONCLUSIONS: Individuals with Wolf-Hirschhorn syndrome may have a strong affinity for music and may benefit from music therapy. Additional studies are needed to investigate the interest in music in individuals with Wolf-Hirschhorn syndrome.

Update on the clinical features and natural history of Wolf-Hirschhorn (4p-) syndrome: experience with 87 patients and recommendations for routine health supervision.

Wolf-Hirschhorn syndrome (WHS) is a well-known multiple congenital anomalies/mental retardation syndrome, firstly described in 1961 by Cooper and Hirschhorn. Its frequency is estimated as 1/50,000-1/20,000 births, with a female predilection of 2:1. The disorder is caused by partial loss of material from the distal portion of the short arm of chromosome 4 (4p16.3), and is considered a contiguous gene syndrome. No single gene deletions or intragenic mutations have been shown to confer the full WHS phenotype. Since the disorder was brought to the attention of geneticists, many additional cases have been published. Only in 1999, however, were the first data on the natural history brought to the attention of the medical community. The purpose of the present study is to help delineate in more detail and over a longer period of time, the natural history of WHS, in order to establish appropriate health supervision and anticipatory guidance for individuals with this disorder. We have collected information on 87 patients diagnosed with WHS (54 females and 33 males) both in USA and Italy. Age at first observation ranged between newborn and 17 years. Twenty patients have been followed from 4 months to 23 years. The deletion proximal breakpoint varied from 4p15.32 to 4p16.3, and, by FISH, was terminal and included both WHSCR. Deletion was detected by standard cytogenetics in 44/87 (50.5%) patients, whereas FISH was necessary in the other 43 (49.5%). Array-CGH analysis at 1 Mb resolution was performed in 34/87 patients, and, in 15/34 (44%), showed an unbalanced translocation leading to both a 4p monosomy and a partial trisomy for another chromosome arm. Six more patients had been previously shown to have an unbalanced translocation by karyotype analysis or FISH with a WHS-specific probe. Sixty-five of 87 patients had an apparent pure, de novo, terminal deletion; and 1/87 a tandem duplication of 4p16.1p16.3 associated with 4p16.3pter deletion. Age at diagnosis varied between 7 months gestation and 16 years. Ninety-three percent had a seizure disorder with a good outcome; 80% had prenatal onset growth deficiency followed by short stature and slow weight gain; 60% had skeletal anomalies; 50% had heart lesions; 50% had abnormal tooth development; and 40% had hearing loss. Distinctive EEG findings were seen in 90%. Structural CNS anomalies were detected in 80%. Global developmental delay of varying degrees was present in all patients. Almost 50% was able to walk either alone or with support. Hypotonia was present in virtually all patients. A global improvement was observed in all individuals, over time. Our survey has also shown how the characteristic facial phenotype tends to be less pronounced in those patients with a smaller deletion, and microcephaly is not observed in the patients with certain cryptic unbalanced translocations.

Síndrome de Wolf-Hirschhorn: reporte de un caso clínico y revisión de la literatura / Wolf-Hirschhorn syndrome: case report and literature review

El síndrome de Wolf-Hirschhorn es un trastorno cromosómico atribuible a una delección parcial del brazo corto del cromosoma 4 (4p-). Está caracterizado por hallazgos craneofaciales típicos en la infancia (“apariencia de guerrero griego” de la nariz, microcefalia, frente alta con glabela prominente, hipertelorismo, cejas muy arqueadas, filtrum corto, boca en carpa, y micrognatia, entre otros), retardo del crecimiento pre y postnatal, hipotonía y retardo del desarrollo. Los pacientes también pueden tener epilepsia y anormalidades que involucran otros órganos. El diagnóstico puede ser realizado por análisis citogenético convencional, el cual detecta la mayoría de los casos. El tratamiento incluye rehabilitación, terapia de lenguaje, drogas antiepilépticas cuando son necesarias, alimentación por gavaje o gastrostomía para las dificultades de la alimentación y terapia de soporte. Femenina de 10 meses de edad, quien presenta anomalías craneofaciales características, pie equinovaro bilateral, hipotonía, reflujo gastroesofágico, epilepsia, retardo del crecimiento y del desarrollo. El diagnóstico fue confirmado por detección de una delección de 4p que involucraba a la región crítica para este síndrome. Esta paciente recibe actualmente rehabilitación, medicación antirreflujo y ácido valproico. Esta condición debe ser reconocida por los pediatras, a fin de poder ofrecer un adecuado manejo a estos pacientes y sus familias.

Wolf-Hirschhorn Syndrome is a cromosomal disorder attributable to partial deletion of the short arm of chromosome 4(4p-). It is characterized by typical craneofacial features in infancy (“Greek warrior appearance” of the nose, microcephaly, high forehead with prominent glabella, hypertelorism, highly arched eyebrows, short philtrum, downturned mouth and micrognathia, among others), pre and postnatal growth retardation, hypotonia and developmental delay. Patients can also have epilepsy and abnormalities that involve other organs. Diagnosis can be made by conventional cytogenetic analysis which detects most of the cases. Treatment includes rehabilitation, speech therapy, antiepileptic drugs when necessary, gavage feeding or gastrostomy for feeding difficulties and standard management of other anomalies. 10 month-old female who presents characteristic craniofacial anomalies, clubfeet, hypotonia, gastroesofageal reflux, epilepsy, growth retardation and developmental delay. Diagnosis was confirmed by detection of a deletion of 4p that involved the critical region of the syndrome. This patient receives rehabilitation, antireflux medication and valproic acid. This condition must be recognized by pediatricians in order to offer adecuated management to these patients and their families.

Influência do tratamento intradisciplinar no desenvolvimento motor na síndrome de wolf-hirschhorn: estudo de caso / Influence of the intradisciplinary team on the motor development in wolf-hirschhorn syndrome: case study

A Síndrome de Wolf-Hirschhorn (SWH) é uma desordem genética incomum, com incidência de 1:50.000 nascidos vivos, descrita pela primeira vez por Hirschhorn, Cooper e Firschein, em 1961. Resulta da microdeleção distal do braço curto do cromossomo 4, mais especificamente em 4p16.3. A condição é normalmente associada com complexa expressão fenotípica que inclui malformações múltiplas com características crânio-facial típicas, e é caracterizada por atraso no desenvolvimento neuropsicomotor (DNPM), retardo mental e de crescimento, microcefalia, hipotonia muscular congênita, crises convulsivas, cardiopatias cong6nitas e anomalias renais, esqueléticas e oftálmicas. Esta pesquisa constitui-se no estudo de um caso relativo a uma criança com a SWH, seis anos e nove meses de idade, sexo masculino, que apresenta, além das características fenotípicas, atraso no DNPM, com a finalidade de verificar a influência da atuação da equipe intra-disciplinar no seu crescimento e desenvolvimento. Para a avaliação do paciente utilizou-se o Teste de Desenvolvimento de Denver, no qual apresentou desenvolvimento m6dio compatível com a idade de seis meses, e o Cartão de Desenvolvimento Neurológico, que também evidenciou atraso no DNPM. A atuação intra-disciplinar - participação conjunta de médicos, fisioterapeuta, terapeuta ocupacional e fonoaudiólogo - trouxe benefícios significativos, visto que a evolução do paciente foi superior a esperada em relação aos relatos da literatura.

The Wolf-Hirschhorn Syndrome (WHS) is an unusual genetic disorder with an incidence of 1 in 50,000 births. It was first described by Hirschhorn, Cooper and Firschein in 1961, and it results from the deletion of the distal short arm of chromosome 4, more specifically 4p 16.3. This condition is normally associated with a complex phenotypic expression that includes multiple malformations with typical cranio¬facial features. It is characterized by delayed neuropsychomotor development (NPMD), severe mental and growth retardation, microcephaly, congenital muscular hypotonia, seizures, congenital heart defect, ophthalmic, skeletal and renal disorders. This paper is a case study involving a male child aged six years and eleven months old, with WHS, presenting all the phenotypic features and NPMD retardation as well. The research intended to verify the influence of the intradisciplinary team on the growth and development of this child. Patient was evaluated with Denver Test of Development, in which presented an average development compatible with a 6-month-old child, and the Neurological Development Card, which resulted in NPMD retardation as well. The actuation of the intradisciplinary team - including physicians. physiotherapists, occupational therapists and speech therapists - has presented very beneficial results, since the patient's evolution was much superior than the expected considering literature reports.