ARTICLE
Auteur(s) : Leslie G. Biesecker
National Institute of Health, National Human Genome Research
Institute, Bethesda, MD, USA
Presented at the International Symposium on Hypothalamic
Hamartoma and Epilepsy, Montreal Neurological Institute, Montreal,
Canada, November 29th 2001.
(*) The opinions expressed here are those the author and do not
necessarily represent the official opinions of the NIH or any other
institution to which he is affiliated.
There is a group of heritable syndromes that includes
hypothalamic hamartoma (HH) as a manifestation. It is important for
neurologists who care for patients with HH to be sufficiently
familiar with these syndromes to allow proper evaluation and
treatment of these patients, because in general, syndromic
hypothalamic hamartomas have different manifestations compared to
non-syndromic ones. The second part of this paper summarizes recent
data on the molecular etiology of syndromic HH to highlight
opportunities to advance our understanding of the molecular
pathology of HH in general.
Heritable syndromes that include hypothalamic hamartoma
Pallister-Hall syndrome
Nearly all patients with Pallister-Hall syndrome (PHS) have a HH
[1]. The disorder is well characterized and includes HH,
polydactyly, laryngeal malformations including bifid epiglottis or
laryngeal cleft, imperforate anus, pulmonary segmentation
anomalies, and other less common manifestations. There is a
striking range of severity of PHS, with some patients presenting
with severe, life-threatening manifestations in the nursery [2] and
others presenting with excellent health, normal intellect and
malformations that are sufficiently subtle that many
non-geneticists would miss the fact that the patient has a syndrome
of any kind. Pallister-Hall syndrome is inherited in an autosomal
dominant pattern [3]. Some patients (generally mildly affected),
are members of families with many affected members, whereas others
may be the first affected in their family, and are more likely to
be severe.
The most surprising finding in PHS is that many of the patients
have no symptoms arising from the HH. Although biased ascertainment
precludes accurate estimates, probably fewer than half of the
patients have symptoms that are definitely or possibly caused by
the hamartoma. In many cases, it is difficult to know if a
particular symptom in a particular patient is or is not directly
attributable to the hamartoma. In any pleiotropic malformation
syndrome that involves the central nervous system, there may be a
combination of obvious and subtle or cryptic anatomic or functional
abnormalities. Current imaging and diagnostic technology cannot
detect a number of important CNS abnormalities, so although it may
be tempting to attribute all symptoms to the identifiable
abnormality, this may not be true.
A major distinction of PHS-associated CNS manifestations is that
when they are present, they are generally mild and treatable. We
estimate that 20-25% of patients with PHS have gelastic or other
forms of epilepsy. Again, these are generally mild with most
patients having infrequent seizures that are responsive to
carbamazepine, lamotrigine, or gabapentin. Some patients have other
types of seizures, and although they are also generally treatable,
they are more difficult to control than the simple gelastic
seizures. Another 15-20% of patients have learning disabilities,
developmental delay, or mental retardation. Again, at the mild end
of this spectrum it is very difficult to know if the dysfunction is
attributable to the HH, because the symptomatology is so common in
the general population.
Behavioral disorders may be present in about 5% of patients and
therefore do not appear to be elevated compared to background
rates. An additional medical complication of HH in patients with
PHS is disruption of the neuroendocrine axis. Some newborns with
PHS present with panhypopituitarism in the nursery, which is a
medical emergency. More commonly, they may present in childhood
with short stature, as the result of growth hormone deficiency, or
precocious puberty. The former is readily treated with exogenous
growth hormone and the latter is treated with GnRH antagonists.
The medical diagnostic evaluation of the HH should be limited to
magnetic resonance imaging. There are a variety of MRI modalities
that can be used to distinguish the HH from other lesions in this
region of the brain. The claim has been made that the HH is
isointense to gray matter on all pulse sequences, but that is now
out of date. The HH of PHS can have a distinct or non-homogenous
signal on T2 or FLAIR sequences. The size and position of the HH
can vary. Most are within the hypothalamic floor and expand
supero-laterally into the hypothalamus. Some displace the optic
chiasm anteriorly and/or the midbrain or midbrain and pons
posteriorly. In the context of other typical PHS malformations and
typical MRI imaging characteristics, the HH should not be biopsied
or removed. There have been no patients in the NIH series where
biopsy or removal has altered management or improved symptoms.
Removal of an HH can cause endocrine deficiency.
As can be seen from this description, the typical PHS patient
has no symptoms attributable to the hamartoma, or mild to moderate
symptoms that are generally responsive to treatment. This
description encompasses most, but not all patients with PHS, as we
have recently identified one family with two siblings affected by
PHS who have intractable seizures, severe mental retardation, and
behavioral difficulties. So the typical (but not every) PHS
patients is very different from the typical non-syndromic HH
patient who may manifest high frequency, complex seizures that are
refractory to treatment, severe and progressive mental deficiency,
and moderate to severe behavioral disturbances.
Oral-facial-digital syndromes
The oral-facial-digital syndromes (OFD) are themselves a group
of disorders with overlapping manifestations [4]. There are
presently 12 subtypes of this group and the boundaries that
separate these subtypes are not well-defined. Furthermore, there
are patients described in the literature who do not fit any defined
subtype or who have features of more than one subtype. The main
features of the OFD include oral manifestations (cleft palate,
tongue hamartomas, buccal frenulae), facial dysmorphic features,
and limb anomalies (polydactyly and limb reduction defects).
Central nervous system malformations including hypothalamic
hamartomas are uncommon, but have been recognized in a number of
published and unpublished cases [5, 6]. There are very little data
on the neurological or endocrine manifestations of these
hamartomas, so generalizations cannot be made.
Bardet-Biedl syndrome
The Bardet-Biedl syndrome (BBS) comprises polydactyly, obesity,
diabetes, pigmentary retinopathy, cystic renal dysplasia, and
learning disability or mental retardation [7]. It is inherited in
an autosomal recessive pattern and can be caused by mutations in at
least seven different genes, four of which have been identified
[8]. There is one published and one unpublished case of BBS with
hypothalamic hamartoma [9]. Neither of these patients had symptoms
directly referable to the hamartoma, which was detected when an MRI
scan was performed for other reasons.
Unclassifiable syndromes
There are a number of patients with HH and other malformations
where the malformations do not match a recognizable pattern. These
include patients who have features that partially overlap with the
above noted syndromes and patients whose features appear unique.
These are individually, extremely rare occurrences.
Pathophysiology of syndromic hypothalamic hamartomas
Although the syndromes that include an HH are phenotypically
distinct from isolated or non-syndromic HH, they can be exploited
to understand the developmental biology of the normal and abnormal
hypothalamus, and ultimately the hamartoma. The heritable nature of
these disorders means that the genes that are mutated in affected
patients can be determined. The identification of genes that, in
the mutant state, cause hypothalamic hamartomas, suggests that the
normal function of these genes are important for the normal
development and function of the hypothalamus. In addition to the
individual genes that are identified as mutated in patients with
HH, the genes function in genetic pathways or genetic networks that
jointly determine the molecular homeostasis of the cell.
Furthermore, since these syndromes can each manifest HH and have
substantial overlap in addition to HH, the hypothesis can be made
that the genes that are mutated in these disorders interact with
each other during development. The understanding of a perturbation
of a genetic, developmental or homeostatic pathway provides
opportunities for therapy, as all of the gene products of that
pathway are potential therapeutic targets. It is reasonable to
hypothesize that perturbation in the same genetic pathway that can
cause a syndromic HH can also cause a non-syndromic HH. For these
reasons, the molecular genetic analysis of syndromic HH may be a
very fruitful pathway for understanding the etiology and treatment
of sporadic, non-syndromic HH.
Molecular pathology of syndromic hypothalamic hamartomas
The disorder for which the most is known in this regard is the
Pallister-Hall syndrome. This syndrome is caused by mutations in
the GLI3 zinc finger transcription factor gene [10].
GLI3 is a transcription factor that regulates the expression
of a number of other genes, which are considered to be downstream
of GLI3 (that is, they are regulated by GLI3).
GLI3 is known to be a part of the sonic hedgehog (SHH)
pathway, which is an extracellular signaling ligand important in
central nervous system morphogenesis [11]. The presence or absence
of the SHH ligand is the primary trigger of this pathway, and binds
to the patched receptor, which in turn signals to the smoothened
cell membrane protein. The patched protein triggers a cytoplasmic
protein complex that includes GLI3. In the presence of SHH,
the GLI3 transcription factor is released intact and
migrates to the nucleus to activate downstream genes. In the
absence of SHH, GLI3 appears to be processed by a protease
into a shorter form that represses downstream genes. In patients
with PHS, all mutations in the gene cause the production of a
truncated version of the protein, which is functionally identical
to the processed, repressor form of the protein [12]. Thus, the
mutations in patients with PHS remove the ability of SHH to switch
GLI3 between the repressor and activator state. The
SHH/GLI3 pathway is composed of more than 13 gene
products or proteins. This suggests that these 13 gene
products all have a role in hypothalamic development or function.
Indeed, although mutations in SHH do not cause HH, SHH has been
shown to be necessary for the regulation of proliferation of some
types of neural cells [13].
As noted above, patients with the Bardet-Biedl syndrome can
occasionally have an HH and in addition, the obesity phenotype of
BBS may be attributable to hypothalamic dysfunction. There are four
genes that have been found to be mutated in patients with BBS.
These include BBS1, BBS2, BBS4, and
BBS6/MKKS. Current understanding of these genes is limited,
being much less specific than that of GLI3. However,
BBS6 appears to be a chaperonin on the basis of sequence
comparisons [14]. Chaperonins are proteins that function to fold
polypeptide strands as they emerge from the synthesizing ribosome
and can refold proteins that have become denatured or unfolded from
chemical or physical effects. This suggests that there are proteins
involved in the formation of an HH that are susceptible to these
environmental stressors and that interventions to reduce these
stressors or increase the ability of the cells to tolerate such
stressors may effect the pathogenesis of the HH.
The only genes that are known to cause the oral-facial-digital
syndromes are CXORF5 (which causes OFD type I [15]) and
GLI3, which can cause atypical forms of OFD
(L. Biesecker, unpublished results). OFD type 1 patients
are not known to have HH, so that gene may not be part of the
pathogenesis of HH. Again, since GLI3 mutations can cause
OFD with HH, this supports the importance of the SHH/GLI3
pathway in this process.
Conclusion
Hypothalamic hamartomas can be isolated, or part of a multiple
malformation syndrome. Syndromic HH generally have milder symptoms
than do non-syndromic (isolated) HH, but likely arise from similar
pathogenetic mechanisms. Because the molecular pathogenesis of
syndromic HH is a tractable scientific problem, the study of these
lesions may lead to insights into all forms of HH. Neurologists and
geneticists should be aware of the similarities and differences
among these types of HH for research and clinical purposes. Modern
molecular genetics allows for rapid and detailed molecular study of
syndromic HH as they are often heritable. In the clinic, the
differences between syndromic and isolated HH are important for
accurate diagnosis, optimal management, and proper assessment of
recurrence risks. Ultimately, the goal is to understand the
pathophysiology of all HH, but the path to that understanding may
lie with the rarer, syndromic lesions. n
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