Gaze Palsy, Familial Horizontal, With Progressive Scoliosis 2 (HGPPS2 / Developmental Split-Brain Syndrome): Research Report

Scope and sourcing. This report is built mainly from six references already cached in this repository: PMID:28250456, 38585553, 33141514, 29068161, 38516134 and 15105459. Quotes from them were read from the cached abstract or full text. Two web searches were also run: one for newer case reports and one for the mouse knockout paper. Anything not checked against a source is marked [unverified] and should be treated as a lead.

Several resources could not be used because they need authorization: the claude.ai PubMed, OLS, bgpt and Noctua connectors. As a result, no ontology CURIE below was looked up in this session. Every term ID is a suggested lead and must be checked with runoak, the term caches or just validate-terms before it goes into an entry.

1. Disease Information

Overview. HGPPS2 is an ultra-rare autosomal recessive disorder of axon guidance caused by biallelic loss-of-function variants in DCC, the gene for the netrin-1 receptor "deleted in colorectal carcinoma". In ROBO3-related HGPPS1, the midline-crossing failure is limited to the hindbrain and spinal cord. In HGPPS2 it affects commissures along the whole neuraxis.

• Rahikkala et al. 2024 (PMID:38585553, Mol Syndromol; abstract): "Horizontal gaze palsy with progressive scoliosis-2 (HGPPS2, MIM 617542) with impaired intellectual development aka developmental split-brain syndrome is an ultra-rare congenital disorder caused by pathogenic biallelic variants in the deleted in colorectal cancer (DCC) gene."
• Jamuar et al. 2017 (PMID:28250456, Nat Genet), the defining paper: "Here we report a new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability."

Identifiers

Synonyms: HGPPS2; Horizontal gaze palsy with progressive scoliosis 2 with impaired intellectual development; Developmental split-brain syndrome (DSBS). PMID:29068161 uses "developmental split brain syndrome (DSBS, MIM# 617542)".

Data basis: aggregated case reports, about 8 published patients from 5 families. There are no registry or EHR data.

2. Etiology

• Cause: biallelic germline loss-of-function variants in DCC on 18q21.2. Marsh et al. 2018 (PMID:29068161): "Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS)."
• Consanguinity is a recurrent risk context: a Saudi family with first-cousin parents (PMID:28250456) and a consanguineous Pakistani family (PMID:33141514).
• Environmental, protective and gene–environment factors: none reported. This is a monogenic developmental disorder.
• Possible modifiers: Jamuar et al. attribute the variable mirror movements to "additional, as yet uncharacterized, background genetic modifier effects". This is speculation and is not established.

3. Phenotypes

The phenotypes below come from about 8 patients, so frequencies are qualitative. Rahikkala 2024 (PMID:38585553) summarizes them: "HGPPS2 phenotype caused by biallelic DCC variants appears to be fully penetrant and shows a similar clinical presentation including developmental delay, intellectual disability, neuromuscular scoliosis, horizontal gaze palsy, agenesis of corpus callosum, and the absence of cerebral commissures."

Supporting quotes:

• Imaging, Family 1 (PMID:28250456): "Pons and midbrain structures were hypoplastic, and there was a large midline cleft throughout the extent of the brainstem contributing to a butterfly shaped medulla."
• Tractography (PMID:28250456): "In place of the normal pattern of interdigitating callosal fibers, no commissural tracts were evident, either on tractography or FA maps." The same paper adds that the disorganization "was not limited to commissural fibers, but was strongly evident in associational and subcortical fibers as well."
• Mirror movements (PMID:28250456): "while the proband in Family 1 exhibited mirror movements, the affected individuals in Family 2 and 3 did not."

Quality of life: no formal QoL instruments (EQ-5D, SF-36) have been reported. The functional burden comes from intellectual disability, the need for scoliosis care, and compensatory head movements for horizontal gaze. That last point is extrapolated from HGPPS1 [unverified for HGPPS2].

4. Genetic / Molecular Information

Causal gene: DCC (hgnc:2701; OMIM 120470; 18q21.2). The gene has 29 exons and encodes a 1447-amino-acid, 159 kDa single-pass transmembrane protein of the immunoglobulin superfamily, with 4 Ig and 6 fibronectin type III repeats (PMID:29068161, PMID:28250456).

Reported HGPPS2 alleles (all homozygous):

• Count: "three different homozygous pathogenic frameshift variants, one homozygous missense variant, and an intragenic duplication in the DCC gene have been reported in 8 patients" (PMID:38585553).
• Family 1 deletion: "Disruption of these features strongly predicts that this mutation represents a functional null." (PMID:28250456)
• Possible genotype–phenotype gradient for Family 3: "This finding suggests that weaker biallelic mutations in DCC may cause milder phenotypes, although additional cases will be required to confirm this." (PMID:28250456)
• Functional consequence: loss of function. All variants are germline. ClinVar classifications and gnomAD frequencies were not checked in this session. The papers state the variants are absent from ExAC, EVS, dbSNP and 1000 Genomes.
• Allelic disorders of the same gene (relevant to counselling and differential diagnosis): monoallelic DCC variants cause congenital mirror movements (MRMV1, MIM 157600) and/or isolated ACC (MIM 217990), with incomplete penetrance (PMID:29068161). The LOVD locus database is https://databases.lovd.nl/shared/genes/DCC.
• Copy-number testing: two of the five alleles are CNVs. Rahikkala concludes: "The analysis of duplications and deletions in the DCC should be included in the routine genetic diagnostic evaluation of patients with suspected HGPPS2."
• Epigenetic or chromosomal abnormalities: none reported beyond the intragenic CNVs.

5. Environmental Information

None. There are no known environmental, lifestyle or infectious contributors. This section is not applicable.

6. Mechanism / Pathophysiology

Causal chain

1. Biallelic DCC loss-of-function variants (deletion, frameshift, duplication, or possibly hypomorphic missense) lead to absent or nonfunctional DCC receptor on growth cones of developing commissural axons. This is demonstrated at the RNA level for the exon-1 deletion and inferred for the other variants.
2. Loss of DCC results in failure to transduce netrin-1 midline attraction and long-range signalling (PMID:29068161). In the hindbrain and spinal cord, the DCC–ROBO3 complex that silences Slit repulsion is also lost (PMID:28250456: "Robo3 forms a direct molecular complex with DCC that silences repulsion from Slits … and enhances attraction to Netrins"). The human DCC–ROBO3 link is inferred from the overlap with HGPPS1 and from mouse work.
3. Commissural axons fail to cross the midline at every level of the neuraxis. This leads to branching consequences:
4. 3a. Forebrain: agenesis of the corpus callosum and the anterior and hippocampal commissures. Probst bundles form instead.
5. 3b. Brainstem: absent pontine crossing fibers and failed decussation of the superior cerebellar peduncles, producing the midline cleft or split pons and the butterfly medulla. The failure of crossing gaze pathways results in horizontal gaze palsy. The exact crossing tract has not been shown in humans; the authors write of "shared brainstem crossing defects disrupting pathways controlling conjugate gaze".
6. 3c. Spinal cord: defective left–right interneuron circuits are thought to lead to unbalanced paraspinal muscle activity and progressive scoliosis. The authors call this speculative: "We speculate that scoliosis may pertain to unbalanced paraspinal muscle activity due to defective spinal interneuron circuits." It is supported only by Netrin-1/Dcc-deficient mice.
7. 3d. Non-commissural white matter: broad disorganization of associational and subcortical tracts with reduced FA. A possible additional role of DCC/netrin in oligodendrocyte myelin regulation is a hypothesis only. Together these probably contribute to intellectual disability and developmental delay (inferred: "cognitive deficits may at least partially be attributable to non-commissural forebrain white matter abnormalities").
8. Corticospinal-tract laterality is variable. This may result in mirror movements in some patients. The mechanism is unclear; partial and complete loss of DCC may differ.

Checklist detail (term IDs to verify)

7. Anatomical Structures Affected

• Primary: CNS commissures, namely the corpus callosum, anterior commissure, hippocampal commissure, superior cerebellar peduncle decussation and transverse pontine fibers. Also the pons, midbrain and medulla oblongata.
• Secondary: the vertebral column (scoliosis) and extraocular motor control.
• UBERON leads [verify]: corpus callosum, anterior commissure, hippocampal commissure, pons, medulla oblongata, midbrain, superior cerebellar peduncle, cerebral white matter, vertebral column.
• Laterality: midline and bilateral by nature. Scoliosis direction is not described.

8. Temporal Development

• Onset: congenital. The malformation forms prenatally, and the gaze palsy is present from birth.
• Progression: scoliosis appears and worsens through childhood and adolescence (PMID:33141514). Cognitive and brain-structure features are static.
• Duration: lifelong. Remission is not applicable.
• Critical periods: scoliosis surveillance during the growth years. The window for commissure formation is embryonic, which is the axon-guidance window, inferred from mouse data.

9. Inheritance and Population

• Inheritance: autosomal recessive (HP:0000007). The Pakistani family shows co-segregation: "the parents were heterozygous carriers of the mutation, in accordance with an autosomal recessive inheritance pattern" (PMID:33141514).
• Penetrance: described as full penetrance for biallelic loss of function (PMID:38585553). Heterozygous carriers are usually unaffected but are at risk of the allelic dominant conditions (mirror movements or isolated ACC) with incomplete penetrance.
• Expressivity: variable for mirror movements, and possibly milder with missense alleles.
• Anticipation and germline mosaicism: none reported.
• Epidemiology: about 8 patients and 5 families worldwide (Mexico, Saudi Arabia, Pakistan, Syria, and Family 3 of unstated origin). There is no prevalence or incidence figure. Use CASES_IN_LITERATURE with ULTRA_RARE.
• Founder effects and carrier frequency: unknown.
• Sex ratio: too few cases to estimate.

10. Diagnostics

Brain MRI and DTI. Look for the combination of agenesis of the corpus callosum, absent anterior and hippocampal commissures, a split pons, a butterfly medulla, and an absent midbrain "red dot". That combination with horizontal gaze palsy and intellectual disability points to DCC rather than ROBO3.

Genetic testing. - Exome or genome sequencing plus CNV analysis of DCC, which is mandatory because 2 of 5 alleles are CNVs. - Targeted DCC sequencing with ddPCR/qPCR for deletions or duplications. - Homozygosity mapping helps in consanguineous families. For example, the Pakistani family had loss of heterozygosity at 18q21.1–21.3 (PMID:33141514).

Other tests. Orthoptic and ocular-motility examination; spine radiographs; developmental assessment.

Differential diagnosis

Screening: no newborn or population screening. Cascade carrier testing and prenatal or preimplantation testing are possible once the familial variants are known.

11. Outcome / Prognosis

• No survival or mortality data. The affected patients reported were alive in childhood to young adulthood; the Pakistani family included adolescents and adults, per MeSH age tags.
• Morbidity comes from intellectual disability, progressive scoliosis (which may need surgery), and the gaze limitation.
• No prognostic biomarkers. The only proposed modifier of severity is allele type (null versus missense), and that is unproven.

12. Treatment

There is no disease-modifying therapy, no trial, and no pharmacogenomics. Management is supportive and draws on HGPPS1 and scoliosis practice [no HGPPS2-specific outcome data].

No gene therapy, ASO or cell therapy has been developed.

13. Prevention

• Primary: none.
• Secondary and tertiary: spine surveillance through growth to allow early scoliosis intervention; developmental surveillance.
• Counselling: 25% recurrence risk for carrier couples. Discuss carrier testing in consanguineous families and prenatal or preimplantation testing. Note the separate dominant risk to heterozygous relatives (mirror movements or isolated ACC).

14. Other Species / Natural Disease

• No naturally occurring animal disease is known. OMIA was not searched [unverified].
• DCC and netrin signalling is conserved from C. elegans (unc-40) and Drosophila (frazzled) to vertebrates. PMID:28250456 calls the pathway "evolutionarily conserved from C. elegans through vertebrates".

15. Model Organisms

Dcc knockout mouse. Fazeli et al. 1997, Nature 386:796–804, PMID:9126737. The PMID comes from a web search and is not cached; run just fetch-reference PMID:9126737 before citing. - Inactivating Dcc caused axonal-projection defects resembling those in netrin-1-deficient mice and had no intestinal tumour phenotype. - Jamuar notes that Netrin-1 and DCC knockout mice "are also acallosal". - Recapitulates: forebrain commissure agenesis. - Limitations: perinatal lethality is commonly reported [unverified], which limits study of scoliosis and cognition. Brainstem crossing defects are "less consistently predicted from animal studies" (PMID:28250456). - Fidelity: high for ACC, low or unknown for gaze palsy and scoliosis.

Netrin-1–deficient mice. These show disrupted spinal left–right interneuron circuits and are the basis of the scoliosis hypothesis (PMID:28250456, refs 29–30; primary PMIDs [not retrieved]).

Zebrafish dcc mutants. These show hindbrain startle-circuit abnormalities (PMID:28250456; primary PMID [not retrieved]).

Kanga (Dcc^kanga) mouse. A spontaneous allele that removes the P3 intracellular domain and causes corticospinal and spinal midline defects with a hopping gait. This is a [lead, unverified].

Other systems: no iPSC or organoid model of HGPPS2 has been reported.

Gaps and recommendations for curation

1. Fetch and cite PMID:9126737 for the mouse model. Search for primary PMIDs for the Netrin-1 interneuron, zebrafish and kanga papers.
2. Look up every HPO, GO, CL, UBERON and NCIT term listed above. None were checked in this session because the OLS connector needs authorization.
3. No case reports after 2024 were found in a standard web search. The count of about 8 patients is current as of PMID:38585553.
4. The mechanism behind scoliosis and the specific gaze-pathway tract are hypotheses. Model them with directness: INDIRECT or as an EMERGING mechanistic hypothesis rather than as established edges.
5. The existing KB entry, kb/disorders/Gaze_Palsy_Familial_Horizontal_With_Progressive_Scoliosis_2.yaml, already cites five of the six references above.

Sources - Jamuar et al. 2017, PMID:28250456 — https://www.nature.com/articles/ng.3804.pdf - Rahikkala et al. 2024, PMID:38585553 — https://www.utupub.fi/items/21c918e6-1e57-4076-bbcd-562f429bd836/full ; https://oulurepo.oulu.fi/handle/10024/48657 ; https://research.utu.fi/converis/portal/detail/Publication/380543436 - Zaka et al. 2021, PMID:33141514 (cached abstract) - Marsh et al. 2018, PMID:29068161 (cached) - Xie et al. 2024, PMID:38516134 (cached) - Jen et al. 2004, PMID:15105459 (cached) - Fazeli et al. 1997, PMID:9126737 — https://www.nature.com/articles/386796a0 ; https://pesquisa.bvsalud.org/ses/resource/es/mdl-9126737 ; https://wi.mit.edu/news/deleted-colorectal-cancer-dcc-gene-plays-role-wiring-mouse-brain-and-spinal-cord

Reference Validation

Checked with linkml-reference-validator 0.3.0.

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• MONDO:0054602 (1 mention) - the report calls it "MONDO"; MONDO calls it gaze palsy, familial horizontal, with progressive scoliosis, 2
• HP:0001263 (1 mention) - the report calls it "most"; HP calls it Global developmental delay
• HP:0001249 (1 mention) - the report calls it "most (one patient described as "modest")"; HP calls it Intellectual disability
• GO:0005042 (1 mention) - the report calls it "already in the entry"; GO calls it netrin receptor activity

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• HP:0001274 (1 mention) - the report calls it "all imaged"; HP calls it Agenesis of corpus callosum, and lists "Callosal agenesis" among its other names
• NCIT:C15240 (1 mention) - the report calls it "Genetic counselling"; NCIT calls it Genetic Counseling