Overview of adult syndromology

Clinical geneticists and syndromologists have focused predominantly on identifying syndromes in children, driven by the therapeutic imperative of early diagnosis and its implications for the parents’ future family planning. Salomon and Salomon investigated the distribution of children and adult photographs within the renowned textbook “Smith’s Recognizable Patterns of Human Malformation, 8th Edition (2021)” [1]. In the paediatric age group they found 1188 photographs (87 %) compared to 85 photographs in the adult age group (6 %). In October 2023, we analysed the number of publications describing paediatric and adult individuals with genetically confirmed Coffin-Siris syndrome using the following setup (adapted from [2]). The first Coffin-Siris syndrome-related gene was described in 2012 [3]. To include mainly genetically confirmed individuals we searched the scientific database PubMed for “Coffin-Siris syndrome” and limited the results to publications from 2012 onward. This search yielded 221 results. Further narrowing the aforementioned query to publications specifically involving adult patients with Coffin-Siris syndrome (Filter: “Age: Adult: 19+ years”) resulted in 27 matches. A thorough review of these 27 publications revealed that 12 did not include adult patients with Coffin-Siris syndrome. Among the remaining 15 relevant results, seven were publications from predominantly paediatric cohorts with few adult cases, three were publications showing vertical transmission of a pathogenic variant, three were single-case descriptions, and two were predominantly paediatric cohorts with a range extending into adulthood, but with an unknown age structure [2]. In these 15 publications, a total of 25 adult cases were identified some including no or only minimal clinical details. In contrast to this small number of 25 adult individuals, one single cohort with up to 208 mainly paediatric Coffin-Siris syndrome individuals has been published [4].

Using the same analysis in December 2023 the ratios between all publications vs. publications including adult patients (19+ years) was 61 to 7 for Nicolaides-Baraitser syndrome, 427 to 86 for Costello syndrome, 113 to 23 for Cardiofaciocutaneous syndrome and 171 to 20 for Pitt-Hopkins syndrome [5]. Given this rough analysis there are at least 5–9 times more publications including children than adults. However, in most publications including adult individuals, the majority of described individuals are children and paediatric cohorts tend to be larger. Therefore, in clinical practice, the difference in available clinical information appears even more pronounced resulting in difficulties concerning counselling, care, and treatment of adult individuals with rare genetic syndromes.

Taylor and colleagues focused on transition and adult genetics and hereby divided the adult population into two groups [6]: First, the “walking diagnosable”, describing adults that have an undiagnosed, potentially recognizable genetic condition; and second the “walking diagnosed”, describing adults that already received their genetic diagnosis.

To address and improve healthcare for the first group of “walking diagnosable” individuals broader access to and information on genetic testing is needed. To apply a widened testing strategy, primary health care providers would have to be sensitized to the possible occurrence of rare genetic syndromes in their adult patients’ population. In Germany, the government has implemented the Medizinische Zentren für Menschen mit Behinderungen (MZEB) to assure transition and continuity of care of multimorbid children into adulthood and healthcare adapted to their special needs. For more in-depth details on MZEB, please refer to Article “MZEB (Medizinisches Zentrum für Erwachsene mit Behinderungen) Bedburg-Hau – Genetic testing in adults with mental disabilities and developmental and psychiatric disorders” of the present issue. In these centres, many “walking diagnosable” individuals are gathered. Others and we have started to offer genetic testing in and support to these centres. These genetic (re-)evaluations of adults with intellectual disability enable the establishment of genetic diagnosis at a high percentage and often has direct impact on clinical management optimization [7].

The needs of the second group of “walking diagnosed” individuals is broader knowledge of the clinical phenotype and evolving features of the syndrome into adulthood. To investigate the current situation in adult phenotypes in syndromology, we did an extensive but not exhaustive literature search. This search revealed some early publications of larger adult cohorts. In the following we highlight some findings. In 1987, Greenswag published a description on 232 adults with Prader-Willi syndrome [8]. In 1990, Dr. Udwin published a survey based on questionnaires completed by caregivers about 119 adults with Williams syndrome [9]. However, for both syndromes the molecular basis was not completely understood at that time raising the question whether all individuals received the correct diagnosis. Marcelis and colleagues described four adult individuals with Wolf-Hirschhorn syndrome in 2001 [10]. In 2002, Hunter published an update of the clinical history of their previously reported patients with Coffin-Lowry syndrome after 20 years [11]. Both authors highlighted the need for more information about long-term outcomes and follow-ups [10,11]. Binder and colleagues published a survey about 45 adult individuals with Noonan syndrome [12] and Douzgou and colleagues published a families-reported questionnaire-based study on the natural history of 87 adults with Rubinstein-Taybi syndrome [13]. Recently, our group published the first cohort of 35 adult individuals with Coffin-Siris syndrome [14]. We were able to document interesting features in adults with Coffin-Siris syndrome such as obesity and behavioural anomalies.

For other more frequent neurodevelopmental disorders like the 22q11.2 deletion syndrome, an interdisciplinary team of professionals has developed practical management guidelines for affected adult individuals [15]. Likewise, the clinical guideline for the management of Noonan Syndrome developed by the Noonan Syndrome Guideline Development Group (DYSCERNE) and available at the website rasopathiesnet.org includes information about management in adulthood [16], as well as the guidelines on the management of Phelan-McDermid syndrome [17] and Alström syndrome [18].

To enhance genetic counselling for all individuals with rare syndromes and their caregivers, we initiated a study on the evolving phenotypes of rare genetic syndromes. In the following, we will describe four adult individuals with Costello syndrome.

Methods

We performed a data collection using questionnaires through a collaborative effort. Detailed methodology has been described elsewhere [2,14].

Patients were eligible to participate in this study at the age of 18 years or older with a genetically confirmed diagnosis of Costello syndrome. If the individuals had been part of a previous publication, it needed to be cited.

Costello syndrome (CS)

Dr. Costello described this new syndrome with “mental subnormality and nasal papillomata” in 1977 [19]. In 2005, Aoki and colleagues identified heterozygous pathogenic or likely pathogenic variants in HRAS as the genetic basis of the syndrome [20]. Most HRAS variants are highly recurrent and some genotype-phenotype correlations have been reported [21]. In most individuals with CS the causal variant involves the amino acid glycine in position 12, with Gly12Ser being the most prevalent substitution reported in 60–80 % CS-individuals [22,23].

CS presents with characteristic features affecting multiple organ systems. In general, the phenotypic spectrum of CS is broad. Common manifestations include failure to thrive in infancy due to severe postnatal feeding difficulties, short stature, macrocephaly or relative macrocephaly, developmental delay, and intellectual disability. Facial features are distinctive, marked by full lips, a large mouth, full nasal tip, and coarse features. Other notable traits encompass curly and often sparse, fine hair, loose skin with deep palmar and plantar creases, and papillomata in facial and perianal regions. Many CS-affected individuals show hypotonia, orthopaedic issues and cardiac involvement [19–24]. Individuals with CS have an increased cancer risk. In a recent systematic review [23] 9.2 % of the included individuals with CS had cancer and specific standardised incidence ratios for each type of cancer have been calculated.

In the following, we describe phenotypic and genotypic data from four individuals, three females and one male with Costello syndrome. The mean age at data collection was 23.7 years, with a range from 20.2 to 27.1. Individual 4 had been previously reported at the age of 6 years and 8 months (Gripp et al. 2011: Ind CS-PT1[25]).

Individual 1, 2, and 3 had de novo variants in amino acid position 12 of HRAS: Gly12Ala, Gly12Ser, and Gly12Cys, respectively. Individual 4 harboured the well-known HRAS variant Gly13Cys, parental testing had not been performed.

In the following we will describe the clinical findings in the four individuals with genetically confirmed CS. A summary of the clinical results is shown in Table 2.

All individuals present clinical phenotypes related to joint contractures

Individual 3 developed severe contractures during his first years of life leading to hip and knee tenotomies at 13 years of age. He showed motor regression in relation to talipes at the age of 13 years and focal epilepsy at 17 years. Individual 1 also had congenital talipes, which were surgically corrected and developed scoliosis during adolescence. Individuals 2, 3, and 4 had movement restrictions due to congenital and acquired contractures of joints.

Figure 1:

CS-related phenotype. a Individual 1 in childhood (left) and adulthood (27 years of age, right). b. Individual 2 at five (left) and eleven (right) years of age. c. Individual 3 (13 years of age) d. Individual 4 (20 years of age). e. Palmar view of hands with typical loose skin with deep palmar creases (individual 2, 5 years of age).

Conclusions

In the scientific community, there is rising awareness about the lack of phenotypic and genotypic information in adult syndromology and the associated difficulties in counselling and care of these individuals. Others and we have started to fill this knowledge gap (1) by collecting clinical information of homogeneous adult cohorts of individuals with different rare syndromes and (2) by making genetic testing and re-evaluations more accessible to adults with neurocognitive disorders. These studies have yielded important information for healthcare providers and families with young children and adults with these rare syndromes. Further studies with even larger adult cohorts are indispensable in order to provide reliable information for proper counselling and management. These studies need (1) the support of the entire genetic community to collect sufficiently large data sets and (2) improved multidisciplinary management of adult individuals with neurocognitive disorders including the possibility of genetic testing.