I'll load the search tools and check the literature before writing the report.

Obesity, Hyperphagia, and Developmental Delay (OBHD; MONDO:0013483)

How reliable this is. I ran two web searches. Most PubMed, PMC and OMIM pages were not reachable, and one fetch of the POU3F2 paper failed. Items marked [verified] come from those search results. Items marked [recalled] come from my background knowledge and have not been checked. Items marked [not found] are things I could not locate. Check every PMID with just fetch-reference before use. I give no verbatim abstract quotes, because I could not read any abstract in full. The one quoted phrase in section 3 is search-snippet text, not a confirmed abstract quote, so re-copy it from the abstract before using it as a snippet. Where I could not confirm a CURIE, I say so.

1. Disease information

• Overview. OBHD is an autosomal dominant neurodevelopmental disorder. It presents as global developmental delay and hyperphagia that leads to obesity. Some patients have seizures. Reported minor features are hypotonia, autistic-like behavior, and, in a few cases, streak ovaries. [verified] (MalaCards, MedGen, PhenoDis aggregates).
• Identifiers [verified]:
• OMIM 613886
• MONDO:0013483
• MedGen C3151303
• MeSH supplementary record C563938
• Synonym: OBHD
• Orphanet and ICD codes: not checked.
• Data origin. The OMIM entry is built from a handful of case-level reports, not from large cohorts.

Sources: MedGen C3151303, MalaCards OBHD, PhenoDis, LOVD disease 03483.

2. Etiology

• Causal gene. NTRK2 (TrkB, 9q21.33). It is the only gene linked to the OMIM entry [verified].
• Index case. Yeo et al. (Nat Neurosci 2004, PMID:15494731 per search; I recalled 15494728, so confirm which is right) described an 8-year-old boy. He had a de novo heterozygous missense variant, p.Tyr722Cys (Y722C), severe obesity and a complex developmental syndrome. The variant impaired receptor autophosphorylation and MAPK signaling [verified].
• Cohort data. Gray et al. (Int J Obes 2007) tested four rare NTRK2 variants found among 198 obese children. Only Y722C impaired signaling, and it also reduced BDNF-induced neurite outgrowth [verified]. A Manchester-affiliated paper, "Functional characterization of human NTRK2 mutations identified in patients with severe early-onset obesity", appeared in the search results. I did not get its PMID, so I do not know if it is the same study.
• Pathway parallel. Gray et al. (Diabetes 2006, PMID:17130481) described a girl with a de novo inversion disrupting BDNF. She had hyperphagia, severe early-onset obesity, hyperactivity and cognitive impairment [verified]. This implicates the ligand as well as the receptor.
• Risk factors. No environmental or gene-environment data were found. No protective factors are known.
• Related genes (not NTRK2). These are separate entities. Check whether they should be handled as their own entries before attaching them here:
• POU3F2: a 2023 AJHG report of a monoallelic truncating variant in a family with syndromic obesity, plus ten more individuals with autism spectrum disorder (ASD), neurodevelopmental disorder (NDD) and adolescent-onset obesity [verified, via search summary].
• GNB1 and GNAS: conference abstracts only. Treat them as weak and uncurated [verified as abstracts].

3. Phenotypes (suggested HPO terms)

HPO IDs below are from memory. Look each one up before binding it. Frequencies are unknown, because the evidence is a few cases.

• Onset: childhood.
• Quality-of-life data: none found.

The search summary phrase usable as a lead is "global developmental delay and hyperphagia resulting in obesity". It came from an aggregator, so re-copy it from the abstract of a cached source.

4. Genetic and molecular information

• Gene: NTRK2, HGNC lowercase form hgnc:<id>. I did not confirm the ID, so look it up with runoak.
• Variant: p.Tyr722Cys (Y722C). It is missense, de novo, heterozygous and germline. It causes partial loss of function: impaired autophosphorylation and MAPK signaling [verified].
• Allele frequency, ClinVar classification, ClinGen validity: not checked. Run just check-gene-validity and just list-gene-validity for ClinGen status.
• Modifier genes: none known.
• Epigenetic and chromosomal data: none found.

5. Environmental information

No environmental, lifestyle or infectious contributors were found. Leave environmental: empty. If you want a waiver, use the review_notes "Left deliberately uncited." convention, with a recorded search.

6. Mechanism and pathophysiology

Causal chain: 1. A de novo heterozygous NTRK2 missense variant (Y722C) is the initiating lesion. This is demonstrated [verified]. 2. The variant impairs TrkB kinase autophosphorylation and downstream MAPK signaling. This is demonstrated in vitro [verified]. 3. Weaker BDNF-TrkB signaling reduces neurite outgrowth and neuronal function. Neurite outgrowth reduction was shown in vitro [verified]. The broader neuronal-function claim is inferred. 4. The reduced signaling plausibly affects hypothalamic feeding circuits. This is inferred here. The BDNF-haploinsufficiency case and mouse literature [recalled, not checked] support the idea. Leaving it as "inferred" avoids overclaiming. 5. Disrupted feeding control leads to hyperphagia, then obesity. 6. In parallel, impaired TrkB-dependent neurodevelopment contributes to developmental delay, autism-like behavior, hypotonia and seizures. This is inferred.

• Suggested GO terms (unchecked): neurotrophin TRK receptor signaling pathway, MAPK cascade, positive regulation of neuron projection development, regulation of feeding behavior.
• Cell types (unchecked): hypothalamic neurons; neuron (CL:0000540, recalled).
• Immune, metabolomic and single-cell data: none found.

7. Anatomical structures

Central nervous system, especially the hypothalamus, plus cerebral cortex and hippocampus (BDNF-TrkB targets, recalled). Obesity is the downstream peripheral consequence. UBERON IDs need to be looked up.

8. Temporal development

Childhood onset. Course and critical periods are not characterized in the sources I found.

9. Inheritance and population

• Inheritance: autosomal dominant, with the index variant de novo [verified].
• Prevalence: not found. This is extremely rare, with a handful of reported cases.
• Penetrance, expressivity and founder effects: not found.

10. Diagnostics

Genetic testing is the diagnostic route. Sequencing NTRK2 in a child with early-onset obesity, hyperphagia and developmental delay is reasonable. In practice this means a severe early-onset obesity gene panel or exome. No dedicated criteria or biomarkers were found. Recommended differentials, from my background knowledge: - MC4R and other leptin-melanocortin pathway defects - Prader-Willi syndrome - SIM1 variants - 16p11.2 deletions - Chung-Jansen syndrome (PHIP)

I have not verified any of these.

11. Prognosis

Not found.

12. Treatment

No NTRK2-specific therapy was found. Supportive care is the usual approach: dietary and behavioral management, environmental food restriction, developmental therapies and seizure management. Setmelanotide has been approved for some monogenic obesities, but I did not find it linked to NTRK2. Do not curate it for this disease. Suggested NCIT terms, from the CLAUDE.md common list: Supportive Care (NCIT:C15747), Dietary Intervention (NCIT:C15447), Rehabilitation (NCIT:C15315). I did not search ClinicalTrials.gov.

13. Prevention

Genetic counseling (NCIT:C15240) applies. Because the index variant was de novo, recurrence risk is low unless there is germline mosaicism.

14. Other species

Not researched. Mouse is the relevant species. NCBITaxon:10090 and NCBI Gene IDs were not looked up.

15. Model organisms

I could not find the citation for the TrkB hypomorph mouse studies (the Xu/Xie 2008 reference). [not found]. From memory, TrkB hypomorphic mice and BDNF-deficient mice develop hyperphagic obesity. Treat that as a lead, not a citation, until a PMID is found and the abstract checked. Run just fetch-reference on any candidate PMID before it goes in the entry.

Suggested next steps

1. Fetch and cache PMID 15494731 (confirm the correct Yeo number), 17130481, and the Gray 2007 and Manchester NTRK2 papers.
2. Look up every CURIE, including the HGNC ID for NTRK2.
3. Search for a recent NTRK2 review and any newer NTRK2 cases. I did not find any.
4. Decide how to handle POU3F2, GNB1 and GNAS: separate entries or OUT_OF_SCOPE. Do not fold them into this entry.

Sources

• MedGen C3151303
• MalaCards: OBHD
• PhenoDis: OBHD
• LOVD disease 03483
• MeSH C563938
• Functional characterization of human NTRK2 mutations (Manchester)
• Gray et al., Int J Obes (Nature)
• PMC2413291, appeared in results, not read
• POU3F2 paper, PMC10257002, appeared in results but fetch failed
• ESPE 2023 abstract on GNB1

Reference Validation

Checked with linkml-reference-validator 0.3.0.

2 of 4 references resolved; the rest could not be looked up either way.

Term Validation

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

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:0002591 (1 mention) - the report calls it "Hyperphagia"; HP calls it Polyphagia, and lists "Hyperphagia" among its other names
• HP:0000752 (1 mention) - the report calls it "Hyperactivity (BDNF-pathway cases)"; HP calls it Hyperactivity

Every term resolved, and every label the report gave matched.