"RARE" disorders in child and adult psychiatry

[Posted on 1st November 2022 by Christopher Gillberg]

There are so many acronyms these days: ADHD, ASD, DCD, ID, LD, RAD, PANS/PANDAS, CP, EP, PDA/EDA, ESSENCE, and the list goes on. – Did you ever hear about or see the acronym BPS? No? Well, it is one that has not had sufficient impact “on the scene” - but should have been imprinted in the minds of all psychiatrists and pediatricians long ago.

BPS stands for “Behavioural Phenotype Syndromes” and is a catch-all concept for behavioural, cognitive, and emotional disorders that have a known cause/associated biological background factor (also referred to as “etiology”). Most of the syndromes included under the BPS acronym have some “typical” “physical/somatic” signs or symptoms associated with them.

BPS, in common-day parlance is now often referred to - and described in public websites – as “rare disorders”, even though there is no longer any clear definition of what might be considered “rare”. Many of the rare disorders/BPS have a prevalence of more than 1 in 1000 individuals in the general population (e.g., Down syndrome), and, in that sense, is definitely not so rare. In fact, at least one of the syndromes included under the BPS umbrella is very common in most countries (and I am talking about Fetal Alcohol Spectrum Disorder (FSAD) in this instance).

I would like to include a table here in which I list some of the most important “rare disorders”/BPS, syndromes that everybody involved in the field of ESSENCE should have at the very least heard or read about so that they can become properly evaluated and intervened for in clinical practice, schools, and within families.

Some of the most important BPS in psychiatry

• Fetal alcohol spectrum disorder
• Fetal valproate spectrum disorder
• Neurofibromatosis
• Down
• 22q11 deletion
• Klinefelter (XXY)
• XYY (“Supermale” in the old literature)
• Turner (XO)
• XXX (“Superfemale” in the old literature)
• Rett
• Noonan
• Fragile X
• Williams
• Sturge-Weber
• Prader-Willi and Angelman
• Tuberous sclerosis
• Moebius
• Marfan
• Ehlers Danlos

Most of the BPS have a known or partially established genetic cause with specific chromosomal or gene abnormalities linked to them – albeit many of them appear “out of the blue” without there being a family history. However, some are caused by toxic/teratogenic factors operating during pregnancy and affecting the neural and otherwise physical development of the growing fetus (exemplified by FASD, and the thalidomide, valproic acid, and misoprostol embryopathy syndromes).

I wrote a textbook on Clinical Child Neuropsychiatry back in the early 2000s (Gillberg 2003). It includes a large chapter specifically on BPS. Interestingly, in spite of the enormous growth in terms of genetic research and understanding of how our chromosomes and genes influence development, for many of the BPS, knowledge development has been slow, and what was true 20 years ago is still the common truth about the individual syndrome. For people interested and wanting to learn more about BPS (and about ESSENCE more generally), that old book is still worth browsing through.

I will go on here to say a little bit more about some of the syndromes listed in the table, but do not consider this text as the final word, just a little about some things relating to BPS that most people either seem to have forgotten about, or actually got it wrong. – I will include a number of sub-headings so as not to have you read a whole mass of text without any kind of guideline as to what the next section will be all about. Please excuse the abundant use of quote-unquote in the text; reason being that I want to be able to use language that can be understood outside of the medical community, and many of the terms used are “translations” into everyday common parlance words or concepts.

BPS/rare disorders and ESSENCE

All the disorders/syndromes listed in the table either first present as “ESSENCE” or have ESSENCE associated with them (with or without clinicians actually recognizing or willing to “diagnose” the ESSENCE problems). For instance, most cases of FASD first present to clinicians as “ADHD-suspected” or come to attention because nurses or parents worry about the child´s overall (including intellectual) development. Only a minority of cases with FASD are first suspected of having a “maternal alcohol-in-pregnancy” background. Conversely, children with Down syndrome are often believed to be the most “non-autism-possible” cases in spite of the “barn-door” autism staring both the clinician and the parents in the eye.

Severe ESSENCE affects at least one in ten children. Taken together, all the BPS or so-called rare disorders affect at least one in forty children. Given that virtually all children with BPS also have ESSENCE, BPS (including FASD) is present in one in four of all children diagnosed with ESSENCE (e.g., ADHD, autism, DCD, Tourette, intellectual disability etc.). Unfortunately, only a fraction of this large subgroup in ESSENCE now gets a proper diagnosis of the underlying BPS.

FASD

Mothers who meet criteria for alcoholism and drink throughout the first trimesters of pregnancy are at extreme risk of having a baby who later will meet all the criteria for FASD. This has been known for decades. There is still no evidence that mothers who drink “a little” in pregnancy (even though “a little” is as difficult to define as “rare” is in “rare disorders) will go on to have a child who meets criteria for FASD.

FASD usually presents with ESSENCE, cardiac problems, a characteristic facial appearance, abnormal growth patterns, and eye abnormalities that are in themselves a very good marker for a correct diagnosis. Children, as they grow up very often come across as “happy in spite of ADHD and other cognitive problems”.

FASD occurs in at least 1 in 100 children, probably more. Given that virtually all with FASD have some kind of ESSENCE, this means that one in ten or more of children with ESSENCE has an “FASD-background”. The rate of FASD has not gone down in recent years in spite of the costly propaganda that pregnant women generally should never even have one drop of alcohol.

What is needed in the field of FASD is a total change of approach: preventative measures in childhood and adolescence (preschool and school info), directed help and information to families with known alcoholism, and particularly intensive measures to help women with alcoholism both before they get pregnant and in pregnancies.

Alcoholism is strongly influenced by genetic factors. Individuals with ESSENCE have a much-increased risk of various kinds of alcohol and substance abuse problems (including risk for tobacco smoking and having great difficulty stopping smoking). Individuals with ESSENCE (mothers to be, fathers to be) have a very high genetic risk of having children with ESSENCE. Disentangling the effect on the growing fetus of alcohol and of genes in such families is an important remit for clinicians (and affected families), pediatricians, GPs, child, and adult psychiatrists alike, so that reasonable conclusions regarding the “cause” of the child´s ESSENCE may be drawn. Attributing “blame” (e.g., “you caused your child´s disability by drinking in pregnancy”) should be avoided, if at all possible.

Neurofibromatosis/NF, tuberous sclerosis/TS and Ito´s hypomelanosis/IH

NF, TS and IH all belong to the group of phakomatoses or neurocutaneous disorders, i.e., conditions that have combined problems affecting the nervous system and the skin. All three have a very variable clinical severity, ranging from very severe (such as in TS with the combination of typical skin problems, intellectual disability, autism, hyperactivity and epilepsy plus hypopigmented skin areas and benign skin tumors), through moderate (such as in NF with ADHD, borderline intellectual functioning, hypopigmented skin areas and so called café-au-lait skin spots and small benign tumors here and there in the skin) to mild (such as in IH with hypopigmentation and DCD) and “subclinical” (such as in TS with a white hair lock, NF with café-au-lait spots and IH with hypopigmentation areas only).

The point to be made here is to always consider the possibility of an underlying neurocutaneous disorder in cases presenting as “ESSENCE”!

Fragile X and the premutation syndrome

Individuals – particularly boys - with the full Fragile X syndrome (FRAX) (who have a mutated FMR1 gene) often present with autism in the first few years of life. This may be combined with hyperactivity and concern about overall intellectual development. Boys with FRAX usually have a gaze avoidance pattern from early in life (unlike most other children with autism who do not actively avoid gaze contact in early life), and, as they grow older, develop a “turning-away-on-greeting-pattern” when meeting new people. Girls with FRAX may have the same type of problems as boys, but in the majority of female cases the problems are much less obvious, and there are even those who do not have any obvious ESSENCE type problems at all.

FRAX is a so-called “trinucleotide repeat expansion syndrome”. In non-FRAX cases the trinucleotide cytosine-guanine-guanine (building blocks of the DNA-molecule) in the FMR1 gene (on the X chromosome) is repeated 5-44 times (with a few even up to 54), and in FRAX more than 200 times. Those individuals (males and females) with 55-200 CGG repeats in the FMR1 gene have so called premutations that can turn into full mutations when transmitted to the next generation.

Children with the full FRAX have almost always inherited their genetic disorder from their mother (who, in turn, will have inherited the premutation from either her father or her mother).

Premutation FRAX often leads to mild/moderate ESSENCE problems. The most typical of these are in the domain of executive functioning and problems with attention, planning and organising oneself are very common. Some women with the premutation may have early menopause and ovarian insufficiency. In some cases of premutation (both women and – perhaps particularly – men) after age 50 years a combination of tremors and balance problems occur and may lead to assessment for suspected Parkinson´s disorder or other severe neurological disorders.

There is currently no specific treatment for FRAX, but many individuals (children and adults) with the disorder (and those with premutation) are helped by interventions including medications that are helpful in “non-FRAX” cases. Also, new medications affecting the GABA-glutamate balance in the nervous systems are currently under investigation and may become specific treatment options in the near future.

Down syndrome

There is much to be said about Down syndrome but there is good information available on many other websites and I shall not go into detail about the background or clinical presentation here. Instead, I will say a few words about the misunderstanding that Down syndrome is “the opposite of autism”.

Children with Down syndrome have long been described as extremely sociable, happy, smiling, people-friendly etc, and in many older studies of individuals with autism, individuals with Down syndrome have been included as “controls” because they were believed to have the same level of cognitive function as those with autism, but to not have any IQ-related social/communication impairments.

Studies by our group have shown – decades ago - that it is indeed possible for people with Down syndrome to have all the symptoms of autism (and that “the autism” has been one of their major reasons for overall social functioning impairments). – New studies by Elisabeth Fernell and Ulrika Wester Oxelgren have shown that autism is extremely common in Down syndrome, and, also that many have overlapping problems in the field of ADHD. One should expect that more than 40% of individuals with Down syndrome have autism or ADHD (or very often both).

Conclusion? Well, screen for autism in pre-school and autism and ADHD in all school-age children with Down syndrome – and consider new avenues to proper assessment, and “intervention” and “treatment” in cases that are “screen-positive”.

Ehlers Danlos syndrome

Recently, there has been an enormous surge regarding interest in the “connective tissue disorder” Ehlers-Danlos syndrome/EDS, in parallel with the discovery that ESSENCE is very common in individuals with hypermobile joints in fingers, arms, feet and legs.

There are at least 13 different variants of hypermobility syndromes (possibly all linked to specific gene mutations/alterations in the so-called COL-genes that lead to collagen/connective tissue abnormalities), often collectively referred to as EDS or EDS-like disorder. The syndromes are clinically recognisable through a symptom presentation of (all or almost all of) combined ligamental laxity, joint pain, (sub)cutaneous bleedings, hypermobile joints, hypotonia, fatigue, ADHD full disorder or many symptoms (at least one in four, in typical EDS cases much more common), other ESSENCE including ASD, pain syndromes, sleep problems, gastrointestinal disorders (heartburn), low vitamin D, bone density reduced, rectal and mitral valve prolapse, and herniations (umbilicus, elsewhere).

In all individuals presenting with EDS-symptoms, ESSENCE should be assessed for, and conversely, in all individuals with ESSENCE, one should “look out for” the possibility of there being and underlying EDS or EDS-like disorder.

Rajna Knez in our group is an expert in the field.

Marfan syndrome, Sotos syndrome, and sex chromosome anomalies

Marfan and Sotos syndromes show characteristic growth abnormalities, as do some of the sex chromosome “aneuploidies” (too many or too few sex chromosomes).

Individuals with Marfan syndrome (which is usually inherited in “dominant fashion”) are usually of average or above intellectual ability, tall and thin with long hands and feet, thin fingers arms and legs, cardiac abnormalities and mild/moderate ESSENCE problems often associated with depression, fatigue and anxiety.

People with Sotos syndrome (which is genetic but usually appears without a family history) are born “big” with a big head and very large distance between the eyes and show a variety of ESSENCE including DCD, borderline intellectual functioning or intellectual disability, low muscle tone, and ADHD with ODD/aggressive behaviours.

Boys with an extra Y or extra X chromosome (Klinefelter syndrome) and girls with an extra X chromosome all have very high rates of ESSENCE (including high rates of borderline intelligence/intellectual disability) and are usually quite or indeed very tall. Girls lacking an X chromosome (Turner syndrome), on the other hand, are usually quite short and often have dyslexia and non-verbal learning problems.

In summary, individuals with growth abnormalities or unusual growth patterns (body or head or both) should always be considered from the point of view of the syndromes mentioned and be assessed for “comorbid” ESSENCE.

Williams syndrome

This genetic syndrome, characterized by a typical facial appearance, cardiac abnormalities, some degree of intellectual disability and usually a complex presentation of ESSENCE (often autistic-like), is mentioned here because of the almost “diagnostic” interest in other people. Many individuals with Williams syndrome, in spite of meeting full criteria for autism, may have a special interest in “humans”/”other people” and although superficially “shy and avoidant”, come across as “socially extremely interested”.

Moebius syndrome, thalidomide embryopathy and valproate syndrome

The three “syndromes” listed have little in common other than being strongly associated with autism. All three have been proven to often be associated with a specific teratogenic agent (i.e., a drug or other substance that has harmed the fetus during intrauterine development and led to a birth defect).

Moebius syndrome (paralysis of the facial nerve and of the nerve that innervates outward eye movement – on one or both sides of the face) is perhaps of particular interest here given that it is rare in most parts of the world but common in Brazil, where it has been linked to maternal ingestion of misoprostol (Cytotec) during pregnancy. It is associated with a very high rate of “classic autism”, pointing to the possibility that brainstem damage – which usually underlies Moebius syndrome – can lead to classic autism.

Similar pathogenetic mechanisms have been proposed to underlie thalidomide (Neurosedyn) embryopathy (thalidomide now only used for treatment of some skin and cancer disorder) and fetal valproate syndrome (valproate is very often used in the treatment of epilepsy and bipolar disorder).

Conclusions to be drawn in this context: be aware that certain drugs used in (particularly the first trimester of) pregnancy can affect the fetus negatively and lead to ESSENCE and a variety of physical problems in the developmental period of the child – and throughout life.

22q11del syndrome

This syndrome will be the subject of an upcoming blog by our new expert in the field, Lena Wallin.

Concluding remarks

Well, if you have managed to trawl through this wordy text, you will not need to be told what the conclusions are. Nevertheless, here are some of the most important ones:

• Rare disorders (or BPS) are quite common if you lump them all together.
• Such disorders often underlie ESSENCE.
• Most of the rare disorders have a very large subgroup (often the majority of the whole group) with ESSENCE with or without overall cognitive abilities being severely affected.
• In any case being assessed for ESSENCE, think about the possibility that a so-called BPS (including FASD) might be the most important underlying factor/cause.

Thanks for putting up with me, and hope that you found the blog to be of interest or at least of some use to you!

Christopher Gillberg

Reference

Gillberg, C (2003). Clinical Child Neuropsychiatry. Cambridge University Press