Agatino Battaglia

Neurodevelopmental disorders (NDDs) are a class of childhood-onset conditions that affect brain development and function. NDDs have a heterogeneous etiology, a wide genetic and clinical variability and generally lead to impaired cognition, communication, psychomotor skills, and adaptive behavior. These disorders include intellectual disability (ID), autism spectrum disorder (ASD), and developmental and epileptic encephalopathies that manifest during childhood. Over the past 2 decades, genetic research has discovered more than 1,500 genes in different signaling pathways that are involved in NDDs, including many transcriptional regulators such as DNA/histone modifiers and chromatin-regulatory protein complexes. These same investigations have led to the accessibility and availability of next-generation sequencing in the assessment of children with NDDs in the clinical setting. The advances have dramatically altered the approach to the genetic diagnostic assessment of the child with NDDs and have increased the diagnostic yield of genetic testing in the pediatric setting. The purpose of this review is to provide the historical background to the rational assessment of child with an NDD and present a perspective on the current evaluation given the modern repertoire available to the pediatric practitioner facing this challenge in the clinical setting.

Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies.

Changes in medical intervention over the last decade have improved outcomes for individuals with trisomy 18, the second most common human aneuploidy syndrome at birth. As children with trisomy 18 live longer, a shared concern of medical experts and parents is the occurrence and treatment of seizures. Previously published surveillance guidelines for this condition have not addressed seizure management. Using parent-reported data collected as part of the Tracking Rare Incidence Syndromes project, we report on the prevalence, course, and management of seizures in individuals with trisomy 18. Twenty-eight percent (52/186) of individuals diagnosed with trisomy 18 in our retrospective cohort experienced generalized, focal, or mixed seizures at some point in their lifetime. For many individuals, seizures were effectively managed by broad-spectrum anti-seizure medications. Correlation analysis showed that focal and generalized seizures were more likely to occur in individuals who had previously experienced infantile spasms or central apnea. Electroencephalogram testing should be considered as part of a standard screening approach in individuals with trisomy 18 to enable early diagnosis and treatment of seizures. An international registry that incorporates parent-reported and clinical data for patients with trisomy 18 may facilitate ongoing research and recruitment into clinical trials for seizure management.

Nuclear Factor I B (NFIB) haploinsufficiency has recently been identified as a cause of intellectual disability (ID) and macrocephaly. Here we report on two new individuals carrying a microdeletion in the chromosomal region 9p23‐p22.3 containing NFIB. The first is a 7‐year 9‐month old boy with developmental delays, ID, definite facial anomalies, and brain and spinal cord magnetic resonance imaging findings including periventricular nodular heterotopia, hypoplasia of the corpus callosum, arachnoid cyst in the left middle cranial fossa, syringomyelia in the thoracic spinal cord and distal tract of the conus medullaris, and a stretched appearance of the filum terminale. The second is a 32‐year‐old lady (the proband' mother) with dysmorphic features, and a history of learning disability, hypothyroidism, poor growth, left inguinal hernia, and panic attacks. Her brain magnetic resonance imaging findings include a dysmorphic corpus callosum, and a small cyst in the left choroidal fissure that marks the hippocampal head. Array‐based comparative genomic hybridization identified, in both, a 232 Kb interstitial deletion at 9p23p22.3 including several exons of NFIB and no other known genes. Our two individuals add to the knowledge of this rare disorder through the addition of new brain and spinal cord MRI findings and dysmorphic features. We propose that NFIB haploinsufficiency causes a clinically recognizable malformation‐ID syndrome.

Since Hirschhorn's description in 1961, the history and chronology of the clinical, cytogenetic, and molecular characterization of Wolf‐Hirschhorn syndrome (WHS) elegantly demonstrates the remarkable advances in genetic technology over the last six decades that have paralleled the delineation of the phenotype. After mention in the Human Chromosome Newsletter of a child with a visible deletion of the top of a B chromosome group, 4–5, Hirschhorn and colleagues companioned their report with that of Wolf et al. in Humangenetik in 1965, and the condition was recognized and named. The 1960–1970s witnessed the description of many of the now classic chromosome disorders, including WHS, while HRB allowed for the recognition of chromosome syndromes with smaller deletions/duplications. FISH probes, developed in the next two decades, enabled the characterization of the critical region of WHS and improved clinical diagnosis with subtelomeric probes. Cytogenomic microarray in the early‐mid 2000s led to both improved diagnosis of WHS patients and documentation of microdeletions of WHSC1 loss of function variants, displaying some cardinal features of the phenotype (face, growth, and developmental delay).

The experience of art provides the visitor of a museum or gallery with the opportunity to contemplate and share the human condition both from the physical and psychological point of view. Because of the accessibility and the number of museums throughout Europe, classical European art as both sculpture and painting, affords the viewer the opportunity to experience life from one part of the world over centuries of history. These museums occasionally exhibit pieces showing a person with a human disorder and physical differences. On viewing such artwork, practitioners of health care, especially dysmorphologists, usually find themselves observing such pieces within the context of their practice. In this essay, the coauthors reflect on paintings and sculptures which remind us of our patients with similar physical and medical conditions. Various works of art also provide the opportunity to observe and view the human face from many vantage points and times in history. Several paintings are cited to illustrate the central themes of the Commentary: the human circumstance of disease and differences and the skill of observing and describing the human face.

Wolf–Hirschhorn syndrome (WHS) is a contiguous gene disorder consisting of prenatal and postnatal growth deficiency, distinctive craniofacial features, intellectual disability, and seizures. The condition is caused by a partial loss of material from the distal portion of the short arm of chromosome 4 (4p16.3). While there are many reports of individuals with WHS, useful data on long‐term survival and life status of adults with the syndrome are very limited. There are only 11 reports of individuals over the age of 18 years in the literature. Establishing the medical manifestations of adults with WHS would be helpful in establishing appropriate health supervision guidelines. This study was one component of a two‐part investigation on adults with WHS. This patient‐reported outcomes study (PROS) was accomplished by using the registry of rare diseases at Sanford Research, Coordination of Rare Diseases (CoRDS)at Sanford. Thirty family members or caretakers of 30 adults with WHS/4p‐ entered into the CoRDS registry and completed some or all of the survey data. Twelve caretakers completed the recently‐added survey on activities of daily living. Two of the individuals with WHS were partly independent while 10 required total care. The results provide novel information on daily life and independence in adults with WHS. Importantly, the majority of caretakers reported that the adults were in good health. The data from both parts of the study will contribute to our knowledge of the natural history of the syndrome and guide in establishing appropriate health supervision guidelines for adults with WHS.

Wolf–Hirschhorn syndrome (WHS) is a contiguous gene disorder, clinically delineated by prenatal and postnatal growth deficiency, distinctive craniofacial features, intellectual disability, and seizures. The disorder is caused by partial loss of material from the distal portion of the short arm of chromosome 4 (4p16.3). Although more than 300 persons with WHS have been reported in the literature, there is sparse, if any, long‐term follow‐up of these individuals and thus little knowledge about course and potential further complications and health risks during adulthood and advanced age. This study attempted to assess medical conditions and function of adult individuals with WHS. It was one component of a two‐part investigation on adults with WHS. The other part of the study is the patient‐reported outcomes study reported elsewhere. About 35 individuals with WHS (26 females; nine males), aged between 19 and 55 years were recruited. About 25 individuals were personally observed at the IRCCS Stella Maris Foundation by A.B. and followed up between 5 and 20 years; and 10 were recruited from the 4p‐Support Group, The United States. Of note, 23/35 (66%) are close to total care. About 11 out of 35 (31%) were partly self‐independent, requiring supervision on certain daily routines, and 1 out of 35 (3%) was fully independent. However, a positive perspective is given by the overall good health enjoyed by the 66% of our cohort of individuals. Overall, quality of life and level of function into adulthood appear to be less critical than anticipated from previous studies.

“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.

1p36 deletion syndrome is a well‐described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., “birth history was notable in 50% of the cases for varying degrees of perinatal distress.” Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of “hypoxic insult” was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder.