Haddad syndrome

Summary

Haddad syndrome (MONDO:0020493) is a disease caused by PHOX2B (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PHOX2B (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 721
• Phenotypes (HPO): 19

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		60	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0000486	Strabismus	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001518	Small for gestational age	Very frequent (80-99%)
HP:0002251	Aganglionic megacolon	Very frequent (80-99%)
HP:0005957	Breathing dysregulation	Very frequent (80-99%)
HP:0007110	Central hypoventilation	Very frequent (80-99%)
HP:0010536	Central sleep apnea	Very frequent (80-99%)
HP:0012332	Abnormal autonomic nervous system physiology	Very frequent (80-99%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001522	Death in infancy	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0001558	Decreased fetal movement	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)
HP:0001562	Oligohydramnios	Occasional (5-29%)
HP:0003005	Ganglioneuroma	Occasional (5-29%)
HP:0003006	Neuroblastoma	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Haddad syndrome
Mondo ID	MONDO:0020493
Orphanet	99803
ICD-11	1685926536
SNOMED CT	719972004
UMLS	C1859049
MedGen	347052
GARD	0016909
Is cancer (heuristic)	no

Also known as: congenital central alveolar hypoventilation-Hirschsprung disease syndrome · Haddad syndrome · ondine-Hirschsprung disease · ondine-Hirschsprung syndrome

Data availability: 721 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › intestinal disorder › intestinal motility disease › Haddad syndrome

Related subtypes (14): Hirschsprung disease-hearing loss-polydactyly syndrome, Hirschsprung disease-nail hypoplasia-dysmorphism syndrome, oculogastrointestinal muscular dystrophy, Goldberg-Shprintzen syndrome, Hirschsprung disease-ganglioneuroblastoma syndrome, multisystemic smooth muscle dysfunction syndrome, congenital diarrhea 6, intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency, Hirschsprung disease-type D brachydactyly syndrome, familial visceral myopathy, chronic intestinal pseudoobstruction, Hirschsprung disease, Waardenburg-Shah syndrome, megacystis-microcolon-intestinal hypoperistalsis syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

299 uncertain significance, 237 likely benign, 32 conflicting classifications of pathogenicity, 19 benign/likely benign, 8 pathogenic, 3 pathogenic/likely pathogenic, 1 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
6008	NP_003915.2:p.Ala260[(5_9)]	LOC110011216	Pathogenic	no assertion criteria provided
1072410	NM_003924.4(PHOX2B):c.691_698dup (p.Gly234fs)	PHOX2B	Pathogenic	criteria provided, multiple submitters, no conflicts
1457266	NM_003924.4(PHOX2B):c.692del (p.Gly231fs)	PHOX2B	Pathogenic	criteria provided, single submitter
1791033	NM_003924.4(PHOX2B):c.242-1G>A	PHOX2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2095188	NM_003924.4(PHOX2B):c.249C>A (p.Tyr83Ter)	PHOX2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2846183	NM_003924.4(PHOX2B):c.479_480dup (p.Ala161fs)	PHOX2B	Pathogenic	criteria provided, single submitter
2851099	NM_003924.4(PHOX2B):c.195C>A (p.Cys65Ter)	PHOX2B	Pathogenic	criteria provided, single submitter
535775	NM_003924.4(PHOX2B):c.220C>T (p.Gln74Ter)	PHOX2B	Pathogenic	criteria provided, single submitter
658418	NM_003924.4(PHOX2B):c.618del (p.Ser207fs)	PHOX2B	Pathogenic	criteria provided, single submitter
1458842	NM_003924.4(PHOX2B):c.13G>T (p.Glu5Ter)	PHOX2B-AS1	Pathogenic	criteria provided, multiple submitters, no conflicts
2625346	NM_003924.4(PHOX2B):c.42C>A (p.Tyr14Ter)	PHOX2B-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1515387	NM_003924.4(PHOX2B):c.241+1G>A	PHOX2B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
348809	NM_003924.4(PHOX2B):c.773C>A (p.Ala258Glu)	LOC110011216	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
467744	NM_003924.4(PHOX2B):c.771_779del (p.Ala258_Ala260del)	LOC110011216	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
575056	NM_003924.4(PHOX2B):c.749C>G (p.Ala250Gly)	LOC110011216	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1096509	NM_003924.4(PHOX2B):c.654C>T (p.Pro218=)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1319142	NM_003924.4(PHOX2B):c.591C>A (p.Gly197=)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
135034	NM_003924.4(PHOX2B):c.617C>G (p.Pro206Arg)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1365793	NM_003924.4(PHOX2B):c.919G>A (p.Ala307Thr)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1475509	NM_003924.4(PHOX2B):c.544G>A (p.Asp182Asn)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1516514	NM_003924.4(PHOX2B):c.639CGG[3] (p.Gly217del)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1518070	NM_003924.4(PHOX2B):c.662C>T (p.Ala221Val)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1579117	NM_003924.4(PHOX2B):c.42C>T (p.Tyr14=)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1692750	NM_003924.4(PHOX2B):c.933C>T (p.Ser311=)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239594	NM_003924.4(PHOX2B):c.760G>A (p.Ala254Thr)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239596	NM_003924.4(PHOX2B):c.832G>A (p.Gly278Ser)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
348810	NM_003924.4(PHOX2B):c.729A>G (p.Ala243=)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
406404	NM_003924.4(PHOX2B):c.633T>G (p.Asn211Lys)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
406405	NM_003924.4(PHOX2B):c.242-5_242-2dup	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
467725	NM_003924.4(PHOX2B):c.391C>G (p.Leu131Val)	PHOX2B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 28 · Orphanet: 15 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PHOX2B	Definitive	Autosomal dominant	Haddad syndrome	9
ASCL1	Supportive	Autosomal dominant	Haddad syndrome	3
RET	Supportive	Autosomal dominant	Haddad syndrome	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ASCL1	Orphanet:99803	Haddad syndrome
PHOX2B	Orphanet:2151	Hirschsprung disease-ganglioneuroblastoma syndrome
PHOX2B	Orphanet:635	Neuroblastoma
PHOX2B	Orphanet:661	Congenital central hypoventilation syndrome
PHOX2B	Orphanet:99803	Haddad syndrome
RET	Orphanet:146	Differentiated thyroid carcinoma
RET	Orphanet:1848	Renal agenesis, bilateral
RET	Orphanet:247698	Multiple endocrine neoplasia type 2A
RET	Orphanet:247709	Multiple endocrine neoplasia type 2B
RET	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
RET	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
RET	Orphanet:388	Hirschsprung disease
RET	Orphanet:93100	Renal agenesis, unilateral
RET	Orphanet:99361	Isolated familial medullary thyroid carcinoma
RET	Orphanet:99803	Haddad syndrome

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ASCL1	HGNC:738	ENSG00000139352	P50553	Achaete-scute homolog 1	gencc,clinvar
PHOX2B	HGNC:9143	ENSG00000109132	Q99453	Paired mesoderm homeobox protein 2B	gencc,clinvar
RET	HGNC:9967	ENSG00000165731	P07949	Proto-oncogene tyrosine-protein kinase receptor Ret	gencc
PHOX2B-AS1	HGNC:40457	ENSG00000250467		PHOX2B antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ASCL1	Achaete-scute homolog 1	Transcription factor that plays a key role in neuronal differentiation: acts as a pioneer transcription factor, accessing closed chromatin to allow other factors to bind and activate neural pathways.
PHOX2B	Paired mesoderm homeobox protein 2B	Involved in the development of several major noradrenergic neuron populations, including the locus coeruleus.
RET	Proto-oncogene tyrosine-protein kinase receptor Ret	Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN,…

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.25

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	6.9×	0.205
Transcription factor	2	4.1×	0.205
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ASCL1	Transcription factor	no		bHLH_dom, MASH1/Ascl1a-like, HLH_DNA-bd_sf
PHOX2B	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
RET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Cadherin-like_dom
PHOX2B-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
CA1 field of hippocampus	1
ganglionic eminence	1
ventricular zone	1
buccal mucosa cell	1
dorsal motor nucleus of vagus nerve	1
muscle layer of sigmoid colon	1
dorsal root ganglion	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1
adrenal gland	1
left adrenal gland	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ASCL1	143	broad	marker	ganglionic eminence, ventricular zone, CA1 field of hippocampus
PHOX2B	53	tissue_specific	marker	muscle layer of sigmoid colon, buccal mucosa cell, dorsal motor nucleus of vagus nerve
RET	193	broad	marker	substantia nigra pars reticulata, dorsal root ganglion, substantia nigra pars compacta
PHOX2B-AS1	35	tissue_specific	yes	adrenal gland, left adrenal gland, monocyte

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RET	4,203
ASCL1	2,422
PHOX2B	1,215
PHOX2B-AS1	0

Intra-cohort edges

A	B	Sources
ASCL1	PHOX2B	string_interaction
PHOX2B	RET	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RET	P07949	34
PHOX2B	Q99453	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ASCL1	P50553	68.22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 4 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the nephric duct	1	317.2×	0.014	RET
NPAS4 regulates expression of target genes	1	248.3×	0.014	RET
Formation of the ureteric bud	1	248.3×	0.014	RET
Nuclear Events (kinase and transcription factor activation)	1	173.0×	0.014	ASCL1
NGF-stimulated transcription	1	142.8×	0.014	ASCL1
RET signaling	1	129.8×	0.014	RET
Signaling by NTRK1 (TRKA)	1	98.5×	0.015	ASCL1
Signaling by NTRKs	1	90.6×	0.015	ASCL1
RAF/MAP kinase cascade	1	30.5×	0.040	RET
Signaling by Receptor Tyrosine Kinases	1	25.8×	0.042	ASCL1
Signal Transduction	1	5.1×	0.187	ASCL1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
noradrenergic neuron development	2	2246.9×	2e-05	ASCL1, PHOX2B
sympathetic ganglion development	2	1248.3×	4e-05	ASCL1, PHOX2B
motor neuron migration	2	1123.5×	4e-05	ASCL1, PHOX2B
enteric nervous system development	2	660.9×	7e-05	PHOX2B, RET
sympathetic nervous system development	2	624.1×	7e-05	ASCL1, PHOX2B
negative regulation of neuron differentiation	2	181.2×	7e-04	ASCL1, PHOX2B
neuron development	2	170.2×	7e-04	ASCL1, PHOX2B
positive regulation of neuron differentiation	2	132.2×	0.001	ASCL1, PHOX2B
noradrenergic neuron fate commitment	1	5617.3×	0.001	ASCL1
neuroblast fate determination	1	5617.3×	0.001	ASCL1
medullary reticular formation development	1	5617.3×	0.001	PHOX2B
parasympathetic nervous system development	1	5617.3×	0.001	PHOX2B
efferent axon development in a lateral line nerve	1	5617.3×	0.001	PHOX2B
regulation of timing of subpallium neuron differentiation	1	5617.3×	0.001	ASCL1
lung neuroendocrine cell differentiation	1	5617.3×	0.001	ASCL1
carotid body glomus cell differentiation	1	5617.3×	0.001	ASCL1
retrotrapezoid nucleus neuron differentiation	1	5617.3×	0.001	PHOX2B
cellular response to magnetism	1	5617.3×	0.001	ASCL1
embryonic epithelial tube formation	1	2808.7×	0.002	RET
posterior midgut development	1	2808.7×	0.002	RET
vestibular nucleus development	1	2808.7×	0.002	ASCL1
musculoskeletal movement, spinal reflex action	1	2808.7×	0.002	ASCL1
subpallium neuron fate commitment	1	2808.7×	0.002	ASCL1
adrenal chromaffin cell differentiation	1	2808.7×	0.002	ASCL1
cellular response to carbon dioxide	1	2808.7×	0.002	PHOX2B
spinal cord oligodendrocyte cell fate specification	1	1872.4×	0.002	ASCL1
cell differentiation in hindbrain	1	1872.4×	0.002	PHOX2B
cerebral cortex GABAergic interneuron differentiation	1	1872.4×	0.002	ASCL1
hindbrain tangential cell migration	1	1872.4×	0.002	PHOX2B
autonomic nervous system development	1	1872.4×	0.002	PHOX2B

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 3

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RET	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RET	135	4
ASCL1	0	0
PHOX2B	0	0
PHOX2B-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	RET
VANDETANIB	4	RET
NILOTINIB	4	RET
BOSUTINIB	4	RET
GILTERITINIB	4	RET
BRIGATINIB	4	RET
UPADACITINIB	4	RET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RET	1,586	Binding:1573, Functional:10, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RET	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
RET	1,586

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	RET
AFATINIB	4	RET
VEMURAFENIB	4	RET
FEDRATINIB	4	RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	RET
SORAFENIB	4	RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	RET
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET
IBRUTINIB	4	RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	RET
VANDETANIB	4	RET
NILOTINIB	4	RET
BOSUTINIB	4	RET
GILTERITINIB	4	RET
BRIGATINIB	4	RET
UPADACITINIB	4	RET

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RET
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	ASCL1, PHOX2B, PHOX2B-AS1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PHOX2B	0	RET
ASCL1	0	—
PHOX2B-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.