HHAT-related chondrodysplasia with 46,XY disorder of sex development

Mendelian MONDO:0010814 Pathograph 30 Show in embeddings browser hereditary disease

An autosomal recessive multiple congenital anomaly syndrome caused by biallelic HHAT variants, listed historically as chondrodysplasia-pseudohermaphroditism syndrome and now more often as Nivelon-Nivelon-Mabille syndrome or HHAT-related multiple congenital anomaly syndrome. The phenotype spans microcephaly, cerebellar vermis hypoplasia, holoprosencephaly, agenesis of the corpus callosum, intellectual disability, short stature and skeletal dysplasia, microphthalmia or anophthalmia, and 46,XY gonadal dysgenesis presenting as female external genitalia. HHAT is the acyltransferase that attaches palmitate to Hedgehog ligands, a modification required for their multimerisation and long-range signalling potency, so the syndrome is what happens when every Hedgehog ligand - Sonic, Indian and Desert - is under-modified at once. That explains its otherwise puzzling combination: SHH governs midline forebrain and craniofacial patterning, IHH the growth plate, DHH testicular cord formation and fetal Leydig cell differentiation. It remains the only reported human disease of Hedgehog ligand lipidation.

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1
Inheritance
8
Pathophys.
19
Phenotypes
2
Gaps
30
Pathograph
1
Genes
4
Medical Actions
3
Differentials
1
Models
1
References
🏷

Classifications

ISDS Skeletal Nosology
spondylometaphyseal dysplasias
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic HHAT variants, reported as homozygous missense changes and one homozygous in-frame deletion in consanguineous or related families, with healthy heterozygous parents.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:24784881 SUPPORT Human Clinical
"homozygous in the patient and heterozygous in the parents"
Segregation consistent with autosomal recessive inheritance.
PMID:24784881 SUPPORT Human Clinical
"In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (HHAT) gene."
Establishes recessive inheritance and the homozygous causal variant.
PMID:33749989 SUPPORT Human Clinical
"The parents were healthy and found to be carriers of this sequence variant while it was absent in the unaffected elder female sibling."
Segregation evidence consistent with recessive inheritance in an independent family.
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Discussions and Knowledge Gaps

2
What are the radiographic features of the chondrodysplasia in HHAT-related disease, and do they justify its placement among the spondylometaphyseal dysplasias?
KNOWLEDGE GAP OPEN gap_hhat_skeletal_phenotype_uncharacterised
Attached to
pathophysiology#Skeletal Dysplasia with Short Stature phenotypes#Short stature phenotypes#Skeletal dysplasia
The nosology places this syndrome in the spondylometaphyseal group, but the published reports describe the skeletal component only as "skeletal dysplasia" or as a generalised chondrodysplasia with micromelia, brachydactyly and a bell-shaped thorax, without the vertebral and metaphyseal radiographic detail that the group name asserts. Every other row in the group is defined radiographically. Two further things point the same way. MONDO gives MONDO:0010814 no skeletal dysplasia parent at all, placing it under syndromic disease, hereditary disease and 46,XY disorder of sex development. And mechanistically the disorder sits apart: the other five group-12 members act through matrix, secretion or growth-plate metabolism, while this one is a morphogen-range defect that happens to include cartilage among its targets. The phenotype has been delineated carefully for its neurological, ocular and gonadal features, and a comparable radiographic series has not been published - unsurprising given that most reported conceptuses did not survive, but it leaves the classification resting on less evidence than the rest of the group. Recording the mismatch matters because a curator using group 12 as a proxy for a radiographic phenotype will be misled by this member. The classification itself follows the nosology as a transcription, per the schema's guidance that this axis transcribes an expert committee's placements rather than inferring them.
Proposed experiments
Radiographic reappraisal of the reported HHAT skeletal phenotype
exp_hhat_radiographic_reappraisal
Obtain and re-read the original skeletal surveys of the reported patients, scoring specifically for vertebral and metaphyseal involvement against the criteria used for the other group-12 disorders, and refer the finding to the ISDS Nosology Committee.
Would support
pathophysiology#Skeletal Dysplasia with Short Stature
Would refute
pathophysiology#Skeletal Dysplasia with Short Stature
Supporting outcome
  • Documented platyspondyly with metaphyseal irregularity would confirm the committee's placement on radiographic grounds and close the question.
Refuting outcome
  • Absence of a vertebral-plus-metaphyseal pattern would make this a placement of convenience for a syndromic chondrodysplasia and a candidate for regrouping in a future revision.
Show evidence (2 references)
PMID:33749989 SUPPORT Human Clinical
"Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression."
The most detailed published delineation, which still describes the skeletal component only as "skeletal dysplasia".
PMID:24784881 SUPPORT Human Clinical
"The first sibling displayed severe dwarfism with generalized chondrodysplasia, a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and coloboma of both optic discs."
The founding skeletal description is generalised rather than specifically spondylometaphyseal, which is the basis of the question.
How wide is the HHAT phenotype, and is a complete null ever compatible with live birth?
KNOWLEDGE GAP OPEN hhat_phenotype_breadth_and_null_lethality
Attached to
disease#HHAT-related chondrodysplasia with 46,XY disorder of sex development
The replication question this gap originally recorded has been answered. The 2014 authors searched large skeletal-disorder and DSD cohorts without finding a second family; eight patients were on record by 2025 and a further four were then reported from two unrelated families, so the gene-disease relationship is replicated and the single-family framing no longer holds. What the newer series changes is the phenotype rather than the genotype - ptosis and marked visual impairment appeared for the first time, and microphthalmia joined coloboma in the ocular spectrum, which is the signature of a boundary still being set by who happens to be looked at. Two things stay open. The original search was framed by chondrodysplasia-plus-DSD and would have missed a milder or differently weighted presentation. And because Hedgehog signalling is required across so many systems, a complete null may be embryonic-lethal and so never ascertained as a syndrome at all - every reported allele is missense or an in-frame deletion.
Proposed experiments
Phenotype-agnostic search for biallelic HHAT variants
exp_hhat_phenotype_agnostic_variant_search
Query large aggregated sequencing datasets and matchmaking services for biallelic HHAT variants without conditioning on chondrodysplasia or DSD, and separately assess whether HHAT is depleted of biallelic loss-of-function in population reference data to the degree expected of an embryonic-lethal gene.
Would support
pathophysiology#Biallelic HHAT Variants in the MBOAT Domain
Would refute
disease#HHAT-related chondrodysplasia with 46,XY disorder of sex development
Supporting outcome
  • Further unrelated families with biallelic HHAT variants and an overlapping phenotype would extend the allelic and phenotypic series.
Refuting outcome
  • Biallelic HHAT carriers with no chondrodysplasia and no DSD would argue that the reported syndrome requires something beyond the HHAT genotype alone.
Show evidence (3 references)
PMID:24784881 SUPPORT Human Clinical
"This suggests that the frequency of pathogenic variants of HHAT is extremely low within the general population, which would explain the absence of other listed cases of Nivelon-Nivelon-Mabille syndrome."
The founding authors' reading of their failed search. Later reports found the additional families this inference argued against, so it is retained as the 2014 position rather than the current one.
PMID:40326711 SUPPORT Human Clinical
"Ptosis and marked visual impairment were present only in the current study."
Features appearing for the first time in the ninth-to-twelfth patients is the signature of a phenotype whose boundary is still being drawn by ascertainment.
PMID:24784881 SUPPORT INDIRECT Human Clinical
"It is possible that other mutations in the HHAT locus may lead to severe defects in HHAT"
The authors raise the possibility of a broader allelic spectrum, which is the alternative to simple rarity recorded in this gap.
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Pathophysiology

8
Biallelic HHAT Variants in the MBOAT Domain
The reported disease alleles - G287V, L257P and the in-frame T122del - fall in or near the conserved membrane-bound O-acyltransferase (MBOAT) domain that carries the enzyme's catalytic activity. That clustering is the structural counterpart of the functional result: the mutant enzyme cannot palmitoylate its substrates.
HHAT hgnc:18270 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HHAT (hgnc:18270). hgnc:18270 is a gene from the HUGO Gene Nomenclature Committee.
palmitoyltransferase activity GO:0016409 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves palmitoyltransferase activity (GO:0016409), qualified as loss of function. GO:0016409 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Failure of Hedgehog Ligand Palmitoylation Loss of HHAT acyltransferase activity leaves SHH, IHH and DHH without their N-terminal palmitate.
Show evidence (2 references)
PMID:24784881 SUPPORT In Vitro
"This mutation occurred in the conserved membrane bound O-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH."
Locates the variant in the catalytic domain and demonstrates the functional consequence experimentally.
PMID:33749989 SUPPORT Human Clinical
"The Leu257 residue also lies in the MBOAT domain."
Confirms that a second independent family's variant falls in the same catalytic domain.
Failure of Hedgehog Ligand Palmitoylation
Hedgehog proteins are covalently modified with both cholesterol and palmitate, and those lipids are what allow the ligand to multimerise and to signal at a distance rather than only to its immediate neighbours. Without palmitoylation the ligand is made and secreted but is a weak, short-range morphogen. Because HHAT acts on all three mammalian Hedgehog ligands, one enzyme defect attenuates three developmental programmes at once.
protein palmitoylation GO:0018345 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein palmitoylation (GO:0018345). GO:0018345 is a biological process from the Gene Ontology. ↓ DECREASED
endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Downstream
Attenuated Hedgehog Signalling Across Multiple Developmental Fields Under-modified ligand means weakened Hedgehog pathway output in every tissue that depends on it.
Show evidence (3 references)
PMID:24784881 SUPPORT In Vitro
"This gene encodes an endoplasmic reticulum protein, HHAT, which catalyzes the transfer of palmitate onto hedgehog ligands."
Establishes the enzyme's compartment and reaction.
PMID:24784881 SUPPORT Other
"Post-translational covalent attachment of cholesterol and palmitate to Hh proteins are critical for multimerization and long range signaling potency."
Establishes why loss of the palmitate specifically degrades long-range signalling.
PMID:30912300 SUPPORT Human Clinical
"encoding an enzyme required for the attachment of palmitoyl residues that are critical for multimerization and long and short range hedgehog signaling"
Independent statement of the enzyme's role in Hedgehog signalling range.
Attenuated Hedgehog Signalling Across Multiple Developmental Fields
The common node from which the syndrome's separate features descend. Mouse Hhat loss of function recapitulates most of the human testicular, skeletal, neuronal and growth phenotypes, which is the strongest evidence that the diverse human features share this single upstream cause rather than reflecting a contiguous-gene effect or coincidence.
smoothened signaling pathway GO:0007224 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased smoothened signaling pathway (GO:0007224). GO:0007224 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Testicular Dysgenesis with 46,XY Disorder of Sex Development Desert Hedgehog signalling from Sertoli cells is the arm that fails in the gonad.
Midline Forebrain and Craniofacial Maldevelopment Sonic Hedgehog patterns the ventral midline of the forebrain and the face; attenuating it produces the holoprosencephaly end of the spectrum.
Cerebellar Hypoplasia A distinct Hedgehog-dependent developmental programme from the ventral midline one, and the arm for which the independent human evidence is strongest.
Microcephaly with Neurodevelopmental Impairment Reduced brain growth with intellectual disability, present across the reported families.
Skeletal Dysplasia with Short Stature Indian Hedgehog is the growth-plate Hedgehog ligand, and its attenuation is the presumed route to the chondrodysplasia.
Show evidence (2 references)
PMID:24784881 SUPPORT Human Clinical
"Overall, these data emphasize the essential role played by post-translational lipid modification of Hh ligands in mediating patterning of many aspects of the body, including the testis, limbs, axial skeleton and the central nervous system."
Names lipid modification of hedgehog ligands as mediating patterning of the testis, limbs, axial skeleton, and central nervous system — the four affected systems of this syndrome.
PMID:24784881 SUPPORT Model Organism
"Consistent with the patient phenotype, HHAT was found to be expressed in the somatic cells of both XX and XY gonads at the time of sex determination, and Hhat loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans."
Mouse genetics establishing that one enzyme's loss reproduces the multi-system human phenotype.
Testicular Dysgenesis with 46,XY Disorder of Sex Development
Gonadal dysgenesis in a 46,XY individual, presenting as female external genitalia. HHAT is expressed in the somatic cells of both XX and XY gonads at the time of sex determination, and the defect is downstream of Sertoli cell commitment - the cells are specified, but testis cord formation and fetal Leydig differentiation fail.
Sertoli cell CL:0000216 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sertoli cell (CL:0000216). CL:0000216 is a cell type from the Cell Ontology. Leydig cell CL:0000178 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Leydig cell (CL:0000178). CL:0000178 is a cell type from the Cell Ontology.
Animal models
Hhat loss-of-function mouse Mouse recapitulates Hhat loss of function in mice reproduces the gonadal arm of the syndrome, and localises the requirement for palmitoylated Desert Hedgehog to a specific step of testis morphogenesis.
Downstream
Gonadal dysgenesis Failure of testis cord formation and fetal Leydig differentiation is the gonadal dysgenesis itself, read at the level of the organ.
Primary amenorrhea A dysgenetic testis cannot support puberty, so menarche never occurs despite normal external female genitalia.
Show evidence (3 references)
PMID:24784881 SUPPORT Human Clinical
"The left gonad contained large inclusions of immature testicular tissue mainly composed of dysplastic immature seminiferous tubules"
The histological description of the dysgenetic gonad.
PMID:24784881 SUPPORT Human Clinical
"The right gonad was hypoplastic and largely composed of fibroblastic and endothelial tissues."
Documents the contralateral gonadal histology.
PMID:24784881 SUPPORT Human Clinical
"Furthermore, they provide the first clinical evidence of the essential role played by lipid modification of Hh proteins in human testicular organogenesis and embryonic development."
States the human significance of the gonadal phenotype.
Midline Forebrain and Craniofacial Maldevelopment
Holoprosencephaly, agenesis of the corpus callosum, microphthalmia or anophthalmia, and a characteristic face with deep-set eyes, small irides and an everted upper lip - the ventral midline programme that Sonic Hedgehog patterns.
Downstream
Holoprosencephaly Incomplete cleavage of the ventral forebrain, the canonical readout of attenuated Sonic Hedgehog signalling at the midline.
Agenesis of corpus callosum Callosal agenesis, the commissural consequence of the same midline patterning failure.
Microphthalmia Small globes; Hedgehog signalling sets eye-field size as well as optic fissure closure.
Optic disc coloboma Failure of optic fissure closure, a recognised consequence of deficient Sonic Hedgehog signalling in the developing eye.
Iris hypoplasia The anterior-segment component of the same ocular Hedgehog signature.
Deeply set eye Part of the recognisable craniofacial appearance produced by the midline patterning defect.
Ptosis Reported for the first time in the 2025 series. No mechanism has been proposed and it may reflect ascertainment rather than a distinct developmental route.
Myopia Refractive error identified at adolescent follow-up, plausibly secondary to the globe and anterior-segment maldevelopment rather than an independent feature.
Show evidence (1 reference)
PMID:33749989 SUPPORT Human Clinical
"Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression."
Names the midline forebrain and craniofacial features of this node within the delineated spectrum.
Cerebellar Hypoplasia
A small cerebellar vermis. This is a separate Hedgehog-dependent programme from the ventral midline one, and the feature that a molecularly confirmed sibship established as implicating HHAT in cerebellar development specifically.
Downstream
Cerebellar vermis hypoplasia Hypoplasia of the vermis, whose granule precursors proliferate under Sonic Hedgehog control.
Show evidence (1 reference)
PMID:33749989 SUPPORT Human Clinical
"Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression."
Names the cerebellar feature within the delineated spectrum.
Microcephaly with Neurodevelopmental Impairment
Microcephaly with intellectual disability, and early infantile seizures in some patients.
Downstream
Microcephaly Reduced brain growth, present across the reported families.
Intellectual disability Whether it follows from the reduced brain growth, the cerebellar hypoplasia, or the seizures is not established.
Seizure Early infantile onset seizures in a molecularly confirmed sibship; the route from attenuated Hedgehog signalling to cortical hyperexcitability has not been worked out.
Show evidence (1 reference)
PMID:33749989 SUPPORT Human Clinical
"Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression."
Names microcephaly and intellectual disability within the delineated spectrum.
Skeletal Dysplasia with Short Stature
Chondrodysplasia with short stature, the feature that places the syndrome in the skeletal nosology at all. It is the least well characterised arm of the phenotype: the reports describe it as skeletal dysplasia without the radiographic detail that would let it be typed within the spondylometaphyseal group.
chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
Animal models
Hhat loss-of-function mouse Mouse recapitulates Hhat loss of function in mice reproduces the testicular, skeletal, neuronal and growth defects seen in patients, which is what allows the human phenotype to be attributed to the enzymatic lesion rather than to a coincidental second variant.
Downstream
Short stature Indian Hedgehog drives the growth-plate proliferative programme, so attenuating it shortens the long bones.
Skeletal dysplasia The generalised chondrodysplasia, which is the feature the ISDS group-12 assignment rests on.
Micromelia Limb shortening, the appendicular expression of the patterning defect.
Brachydactyly Short digits - the distal limb field is among the most Hedgehog-dependent structures in the body.
Bell-shaped thorax A narrow, bell-shaped chest from the axial skeletal involvement.
Show evidence (1 reference)
PMID:33749989 SUPPORT Human Clinical
"Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression."
Records short stature and skeletal dysplasia in the delineated spectrum, at the level of detail the literature provides.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for HHAT-related chondrodysplasia with 46,XY disorder of sex development Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

19
Eye 4
Microphthalmia HP:0000568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microphthalmia (HP:0000568). HP:0000568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33749989 SUPPORT Human Clinical
"Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression."
Records microphthalmia-anophthalmia in the delineated spectrum.
Deeply set eye HP:0000490 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Deeply set eye (HP:0000490). HP:0000490 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33749989 SUPPORT Human Clinical
""Chondrodysplasia-pseudo-hermaphroditism syndrome" (MIM# 600092) described by Nivelon et al. is the first clinical report of a family with an affected female with short stature, skeletal dysplasia, microcephaly, deep-set eyes, small iris, everted upper lip and sex reversal with a karyotype of 46, XY."
Records the facial features in the founding description.
Ptosis OCCASIONAL HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40326711 SUPPORT Human Clinical
"Ptosis and marked visual impairment were present only in the current study."
The authors flag both features as new to their series, which is why the record is OCCASIONAL and explicitly provisional.
Myopia FREQUENT HP:0000545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopia (HP:0000545). HP:0000545 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24784881 SUPPORT Human Clinical
"identified mild mental retardation, muscular hypertrophy, myopia and other facial anomalies such as upslanting palpebral fissures, puffy eyelids, large mouth"
Names the myopia among the adolescent follow-up findings.
Genitourinary 2
Gonadal dysgenesis HP:0000133 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gonadal dysgenesis (HP:0000133). HP:0000133 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24784881 SUPPORT Human Clinical
"In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (HHAT) gene."
Records testicular dysgenesis with 46,XY DSD as a defining feature.
Primary amenorrhea OBLIGATE HP:0000786 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Primary amenorrhea (HP:0000786). HP:0000786 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24784881 SUPPORT Human Clinical
"The karyotype was 46,XY but the patient exhibited clinical features of a 46,XY DSD with complete gonadal dysgenesis (CGD), including normal external female genitalia, lack of pubertal development, primary amenorrhea"
The clinical definition of the disorder of sex development, naming the amenorrhoea and the absent puberty.
Head and Neck 1
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33749989 SUPPORT Human Clinical
"Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression."
Records microcephaly in the delineated spectrum.
Limbs 2
Micromelia OBLIGATE HP:0002983 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micromelia (HP:0002983). HP:0002983 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24784881 SUPPORT Human Clinical
"The first sibling displayed severe dwarfism with generalized chondrodysplasia, a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and coloboma of both optic discs."
Names micromelia alongside the thoracic and digital features.
Brachydactyly OBLIGATE HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24784881 SUPPORT Human Clinical
"The first sibling displayed severe dwarfism with generalized chondrodysplasia, a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and coloboma of both optic discs."
Names brachydactyly among the limb features.
Musculoskeletal 1
Skeletal dysplasia OBLIGATE HP:0002652 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skeletal dysplasia (HP:0002652). HP:0002652 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40326711 SUPPORT Human Clinical
"exhibiting distinct phenotypic features including 46,XY gonadal dysgenesis, microcephaly, microphthalmia, ocular coloboma, skeletal dysplasia, and cerebellar vermis hypoplasia"
Names skeletal dysplasia among the core features in the four most recently reported patients, independently of the founding sibship.
Nervous System 5
Cerebellar vermis hypoplasia HP:0001320 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar vermis hypoplasia (HP:0001320). HP:0001320 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30912300 SUPPORT Human Clinical
"We report two siblings with microcephaly, early infantile onset seizures, and cerebellar vermis hypoplasia, in whom whole exome sequencing revealed a novel homozygous missense"
Direct report of cerebellar vermis hypoplasia in a molecularly confirmed sibship.
Holoprosencephaly OCCASIONAL HP:0001360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Holoprosencephaly (HP:0001360). HP:0001360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33749989 SUPPORT Human Clinical
"Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression."
Records holoprosencephaly in the delineated spectrum.
Agenesis of corpus callosum HP:0001274 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agenesis of corpus callosum (HP:0001274). HP:0001274 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33749989 SUPPORT Human Clinical
"Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression."
Records callosal agenesis in the delineated spectrum.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33749989 SUPPORT Human Clinical
"Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression."
Records intellectual disability in the delineated spectrum.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30912300 SUPPORT Human Clinical
"We report two siblings with microcephaly, early infantile onset seizures, and cerebellar vermis hypoplasia, in whom whole exome sequencing revealed a novel homozygous missense"
Records early infantile seizures in a molecularly confirmed sibship.
Growth 1
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33749989 SUPPORT Human Clinical
""Chondrodysplasia-pseudo-hermaphroditism syndrome" (MIM# 600092) described by Nivelon et al. is the first clinical report of a family with an affected female with short stature, skeletal dysplasia, microcephaly, deep-set eyes, small iris, everted upper lip and sex reversal with a karyotype of 46, XY."
The founding clinical description, recording short stature with skeletal dysplasia.
Other 3
Bell-shaped thorax OBLIGATE HP:0001591 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bell-shaped thorax (HP:0001591). HP:0001591 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24784881 SUPPORT Human Clinical
"The first sibling displayed severe dwarfism with generalized chondrodysplasia, a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and coloboma of both optic discs."
Names the thoracic morphology.
Optic disc coloboma OBLIGATE HP:0000588 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic disc coloboma (HP:0000588). HP:0000588 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24784881 SUPPORT Human Clinical
"The first sibling displayed severe dwarfism with generalized chondrodysplasia, a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and coloboma of both optic discs."
Names the bilateral optic disc coloboma and the iris hypoplasia.
Iris hypoplasia OBLIGATE Hypoplasia of the iris HP:0007676 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the iris (HP:0007676). HP:0007676 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24784881 SUPPORT Human Clinical
"The first sibling displayed severe dwarfism with generalized chondrodysplasia, a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and coloboma of both optic discs."
Names the iris hypoplasia.
🧬

Genetic Associations

1
HHAT (Causal biallelic variant)
Gene: HHAT hgnc:18270 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HHAT (hgnc:18270). hgnc:18270 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 references)
PMID:24784881 SUPPORT Human Clinical
"Analysis of WES results using an autosomal recessive model revealed a homozygous G287V missense mutation in the hedgehog acyl-transferase ( HHAT) gene."
The gene-discovery result and the founding causal allele.
PMID:33749989 SUPPORT Human Clinical
"The Gly287 residue lies in the highly conserved MBOAT (Membrane bound acyl transferase) domain"
Places the founding family's allele in the catalytic MBOAT domain. The same change is designated p.Gly150Val on the short isoform in that report, which is the source of the numbering caution recorded here.
PMID:33749989 SUPPORT Human Clinical
"In this family, they identified a biallelic missense variant, c.770C > T, p.(Leu257Pro) in exon 7 of HHAT (NM_001122834.3) as the likely cause of the multiple malformation syndrome (Abdel-Salam et al., 2019)."
Records the second family's allele.
+ 2 more references
💊

Medical Actions

4
Hormone Replacement Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Complete gonadal dysgenesis with hypergonadotrophic hypogonadism requires sex hormone replacement to induce and maintain secondary sexual characteristics and to protect bone, in line with standard management of 46,XY complete gonadal dysgenesis. The reported patient's course — absent pubertal development and primary amenorrhoea — establishes the need.
Show evidence (1 reference)
PMID:24784881 SUPPORT INDIRECT Human Clinical
"including normal external female genitalia, lack of pubertal development, primary amenorrhea"
Establishes the hypogonadism that makes hormone replacement the standard indication; it evidences the need rather than a trialled protocol in this disorder, hence INDIRECT.
Gonadectomy and Gonadal Surveillance
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Dysgenetic gonadal tissue in a 46,XY individual carries a recognised risk of germ cell tumour, and the reported patient's gonads were removed and examined histologically. Surveillance or gonadectomy is a standing consideration in 46,XY complete gonadal dysgenesis, decided with the individual concerned.
Show evidence (1 reference)
PMID:24784881 SUPPORT INDIRECT Human Clinical
"Histology confirmed the testicular dysgenesis and identified persistent"
Gonadal tissue was available for histology, which documents that gonadectomy was performed; the report does not evaluate the intervention, hence INDIRECT.
Multidisciplinary supportive care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No disease-modifying therapy exists and there is no prospect of one directed at the enzyme. Care is supportive across neurology, endocrinology, ophthalmology and orthopaedics, and the disorder carries a substantial perinatal mortality - one reported family lost two of three affected pregnancies.
Target Phenotypes: Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33749989 SUPPORT Human Clinical
"In this report, we describe the third family with multiple malformations in three pregnancies with a novel biallelic in-frame deletion, c.365_367del; (p.Thr122del) in exon 5 of HHAT in the living proband."
Three affected pregnancies with one living proband, which is the basis for the perinatal mortality noted here; no treatment is described in this literature.
Genetic counselling with prenatal testing
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Recessive recurrence risk of 25%. Counselling matters more than usual here because affected pregnancies have repeatedly been identified prenatally on microcephaly, growth restriction and skeletal dysplasia, and because a 46,XY fetus may present with female external genitalia.
Show evidence (2 references)
PMID:24784881 SUPPORT Human Clinical
"The patient familial history indicates that the patient and sibling were conceived by a healthy, non-consanguineous caucasian couple"
Two affected children of unaffected non-consanguineous parents is the pedigree that recurrence-risk counselling has to address.
PMID:33749989 SUPPORT Human Clinical
"The couple terminated their second pregnancy at 21 weeks of gestation in view of intra uterine growth retardation, microcephaly and skeletal dysplasia."
A documented prenatal identification on exactly the findings this entry names.
🔬

Diagnosis

3
Clinical recognition of the multisystem pattern (Microcephaly with cerebellar vermis hypoplasia, skeletal dysplasia and 46,XY gonadal dysgenesis.)
The combination that identifies the disorder is microcephaly with cerebellar vermis hypoplasia, skeletal dysplasia and short stature, and 46,XY gonadal dysgenesis. Any one of the three in isolation has many causes; together they are close to specific.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33749989 SUPPORT Human Clinical
"Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression."
The delineated spectrum from which the recognisable combination is drawn.
Karyotype in a phenotypically female infant
A 46,XY karyotype in a phenotypic female with microcephaly and skeletal dysplasia is what converts a nonspecific malformation syndrome into this specific diagnosis.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: 46,XY karyotype with female external genitalia.
Show evidence (1 reference)
PMID:33749989 SUPPORT Human Clinical
""Chondrodysplasia-pseudo-hermaphroditism syndrome" (MIM# 600092) described by Nivelon et al. is the first clinical report of a family with an affected female with short stature, skeletal dysplasia, microcephaly, deep-set eyes, small iris, everted upper lip and sex reversal with a karyotype of 46, XY."
The founding case, in which the karyotype is what defined the syndrome.
HHAT sequencing
Molecular confirmation, by exome sequencing in every reported family. Variants should be reported against a stated RefSeq isoform, since the two HHAT isoforms give different protein designations for the same change.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Biallelic HHAT variants in or near the MBOAT domain.
Show evidence (2 references)
PMID:24784881 SUPPORT Human Clinical
"A 244K aCGH analysis performed on genomic DNA extracted from blood cells of the patient did not reveal any chromosomal rearrangements that could account for the pathology."
Documents exclusion of a structural cause before the exome analysis.
PMID:33749989 SUPPORT Human Clinical
"We did proband-parents trio exome sequencing and identified a biallelic in-frame deletion c.365_367del; (p.Thr122del) in exon 5 of HHAT."
Documents trio exome sequencing as the diagnostic route.
📊

Prevalence

1
Worldwide
Cases In Literature <1 in 1,000,000
Ultra-rare. Twelve patients are on record: eight reported up to 2025, plus four new patients from two unrelated families in a 2025 series. Three families had been reported at the time of the 2021 delineation, the third contributing three affected conceptuses. The founding 2014 report noted that an explicit search through large skeletal-disorder and DSD cohorts had found no second family - a statement about ascertainment in 2014, since superseded.
Show evidence (3 references)
PMID:33749989 SUPPORT Human Clinical
"In this report, we describe the third family with multiple malformations in three pregnancies with a novel biallelic in-frame deletion, c.365_367del; (p.Thr122del) in exon 5 of HHAT in the living proband."
Establishes the number of reported families at the 2021 delineation.
PMID:40326711 SUPPORT Human Clinical
"To date, only eight patients with NNMS have been reported in the literature. In this study, four new patients from two unrelated families were presented"
Gives the current caseload - twelve patients across multiple families - which supersedes the founding report's single-family framing.
PMID:24784881 SUPPORT Human Clinical
"Despite an extensive search through large cohorts of patients suffering from skeletal disorders and/or DSD, we have not been able to identify a second familial case with a pathogenic mutation in the HHAT locus."
Documents the deliberate, unsuccessful 2014 search for further cases. Recorded as the ascertainment state at gene discovery, not as the current caseload - further families were reported subsequently.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from HHAT-related chondrodysplasia with 46,XY disorder of sex development:

Holoprosencephaly spectrum from SHH pathway variants
Overlapping Features Variants in SHH itself and in its pathway cause holoprosencephaly with midline craniofacial anomalies. The gonadal and skeletal features are what point past those genes to HHAT, since only HHAT acts on all three Hedgehog ligands at once.
Distinguishing Features
  • 46,XY gonadal dysgenesis, which SHH-pathway holoprosencephaly does not cause
  • Chondrodysplasia with short stature from attenuated Indian Hedgehog signalling
Show evidence (1 reference)
PMID:24784881 SUPPORT In Vitro
"This mutation occurred in the conserved membrane bound O-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH."
Establishes that HHAT acts on more than one Hedgehog ligand, which is why its phenotype exceeds that of any single-ligand defect.
Other Causes of 46,XY Gonadal Dysgenesis
Overlapping Features SRY, NR5A1, MAP3K1, DHH and WT1 variants all cause 46,XY gonadal dysgenesis. What distinguishes HHAT is that the gonadal defect never comes alone: the same enzyme lesion attenuates Indian and Sonic Hedgehog signalling as well, so a chondrodysplasia and a midline brain malformation accompany it.
Distinguishing Features
  • Generalised chondrodysplasia with severe short stature
  • Severe microcephaly with cerebellar vermis hypoplasia
  • Ocular coloboma and iris hypoplasia
Show evidence (2 references)
PMID:24784881 SUPPORT Other
"Unfortunately, in many cases the genetic aetiology of DSD is unknown, indicating that our knowledge of the factors mediating sex determination is limited."
Establishes the heterogeneous and often unsolved background against which this syndromic form has to be distinguished.
PMID:24784881 SUPPORT Human Clinical
"In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (HHAT) gene."
The DSD is explicitly syndromic and accompanied by chondrodysplasia, which is what separates it from isolated 46,XY gonadal dysgenesis.
Other Spondylometaphyseal Dysplasias
Overlapping Features The other five members of ISDS group 12 are defined by a vertebral and metaphyseal radiographic pattern and act through matrix, secretion or growth-plate metabolism. This disorder is a morphogen-range defect whose skeletal component is generalised, and it is the only member with a disorder of sex development.
Distinguishing Features
  • 46,XY gonadal dysgenesis, absent from every other group-12 disorder
  • Severe microcephaly with cerebellar vermis hypoplasia
  • Generalised rather than specifically spondylometaphyseal skeletal involvement
Show evidence (1 reference)
PMID:24784881 SUPPORT Human Clinical
"The first sibling displayed severe dwarfism with generalized chondrodysplasia, a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and coloboma of both optic discs."
The published skeletal description is generalised rather than specifically spondylometaphyseal, which is the basis of the distinction.
🐁

Animal Models

1
Hhat loss-of-function mouse
Mice lacking functional Hhat, used to test whether the human syndrome follows from loss of Hedgehog palmitoylation. The model reproduces most of the human phenotype across all four affected systems, which is what allows the diverse human features to be attributed to a single enzymatic lesion.
Species
Mouse
Genotype
Hhat loss of function
Publication
PMID:24784881
Pathograph links
Skeletal Dysplasia with Short Stature recapitulates fidelity: high Hhat loss of function in mice reproduces the testicular, skeletal, neuronal and growth defects seen in patients, which is what allows the human phenotype to be attributed to the enzymatic lesion rather than to a coincidental second variant.
Limitations: The recapitulation is stated as covering most, not all, of the human defects, and the mouse model is a loss of function rather than a knock-in of a human allele, so it does not test any specific variant. The mouse gonadal phenotype also cannot model the 46,XY sex-reversal presentation directly.
Show evidence (1 reference)
PMID:24784881 SUPPORT Model Organism
"Hhat loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans"
States the scope of the recapitulation across all four affected organ systems.
Testicular Dysgenesis with 46,XY Disorder of Sex Development recapitulates fidelity: moderate Hhat loss of function in mice reproduces the gonadal arm of the syndrome, and localises the requirement for palmitoylated Desert Hedgehog to a specific step of testis morphogenesis.
Limitations: The mouse gonadal phenotype cannot model the 46,XY sex-reversal presentation directly, and the model is a loss of function rather than a knock-in of a human allele, so it does not test any specific variant.
Readouts
Testis cord formation and fetal Leydig cell differentiation
Direction: DECREASED
Interpretation: Sertoli cell commitment is preserved while cord formation and fetal Leydig differentiation fail, localising the requirement for palmitoylated Desert Hedgehog to a specific step of testis morphogenesis.
Show evidence (1 reference)
PMID:24784881 SUPPORT Model Organism
"In the developing testis, HHAT is not required for Sertoli cell commitment but plays a role in proper testis cord formation and the differentiation of fetal Leydig cells."
Reports the developmental readout behind this measurement.
Show evidence (1 reference)
PMID:24784881 SUPPORT Model Organism
"Hhat loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans"
States the scope of the recapitulation across all four affected organ systems.
{ }

Source YAML

click to show 
name: HHAT-related chondrodysplasia with 46,XY disorder of sex development
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  An autosomal recessive multiple congenital anomaly syndrome caused by biallelic
  HHAT variants, listed historically as chondrodysplasia-pseudohermaphroditism
  syndrome and now more often as Nivelon-Nivelon-Mabille syndrome or
  HHAT-related multiple congenital anomaly syndrome. The phenotype spans
  microcephaly, cerebellar vermis hypoplasia, holoprosencephaly, agenesis of the
  corpus callosum, intellectual disability, short stature and skeletal dysplasia,
  microphthalmia or anophthalmia, and 46,XY gonadal dysgenesis presenting as
  female external genitalia. HHAT is the acyltransferase that attaches palmitate
  to Hedgehog ligands, a modification required for their multimerisation and
  long-range signalling potency, so the syndrome is what happens when every
  Hedgehog ligand - Sonic, Indian and Desert - is under-modified at once. That
  explains its otherwise puzzling combination: SHH governs midline forebrain and
  craniofacial patterning, IHH the growth plate, DHH testicular cord formation
  and fetal Leydig cell differentiation. It remains the only reported human
  disease of Hedgehog ligand lipidation.
disease_term:
  preferred_term: chondrodysplasia with 46,XY disorder of sex development
  term:
    id: MONDO:0010814
    label: chondrodysplasia-pseudohermaphroditism syndrome
parents:
- hereditary disease
synonyms:
- Nivelon-Nivelon-Mabille syndrome
- HHAT-related multiple congenital anomaly syndrome
- chondrodysplasia-pseudohermaphroditism syndrome
classifications:
  isds_skeletal_category:
  - classification_value: spondylometaphyseal_dysplasias
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger,
      Ferreira, Mortier et al., PMID:36779427), Table 1 group 12
      "Spondylometaphyseal dysplasias (SMD)", row NOS 12-0060
      "Chondrodysplasia-pseudohermaphroditism syndrome, HHAT-related"
      (MIM 600092, autosomal recessive). The nosology retains the 1992 name of
      the condition; this entry uses a current one and keeps the historical
      form as a synonym so the nosology row and the MONDO class both remain
      findable.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic HHAT variants, reported as homozygous missense changes and one
    homozygous in-frame deletion in consanguineous or related families, with
    healthy heterozygous parents.
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY
      disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      homozygous in the patient and heterozygous in the parents
    explanation: >-
      Segregation consistent with autosomal recessive inheritance.
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (HHAT) gene.
    explanation: >-
      Establishes recessive inheritance and the homozygous causal variant.
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The parents were healthy and found to be carriers of this sequence variant while it was absent in the unaffected elder female sibling.
    explanation: >-
      Segregation evidence consistent with recessive inheritance in an
      independent family.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Ultra-rare. Twelve patients are on record: eight reported up to 2025, plus
    four new patients from two unrelated families in a 2025 series. Three
    families had been reported at the time of the 2021 delineation, the third
    contributing three affected conceptuses. The founding 2014 report noted that
    an explicit search through large skeletal-disorder and DSD cohorts had found
    no second family - a statement about ascertainment in 2014, since superseded.
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this report, we describe the third family with multiple malformations in three pregnancies with a novel biallelic in-frame deletion, c.365_367del; (p.Thr122del) in exon 5 of HHAT in the living proband.
    explanation: >-
      Establishes the number of reported families at the 2021 delineation.
  - reference: PMID:40326711
    reference_title: >-
      Four New Patients of HHAT-Related Multiple Congenital Anomalies Syndrome (Nivelon-Nivelon-Mabille Syndrome) and a Comprehensive Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only eight patients with NNMS have been reported in the literature. In
      this study, four new patients from two unrelated families were presented
    explanation: >-
      Gives the current caseload - twelve patients across multiple families -
      which supersedes the founding report's single-family framing.
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite an extensive search through large cohorts of patients suffering from
      skeletal disorders and/or DSD, we have not been able to identify a second
      familial case with a pathogenic mutation in the HHAT locus.
    explanation: >-
      Documents the deliberate, unsuccessful 2014 search for further cases.
      Recorded as the ascertainment state at gene discovery, not as the current
      caseload - further families were reported subsequently.
pathophysiology:
- name: Biallelic HHAT Variants in the MBOAT Domain
  biological_scale: MOLECULAR
  description: >-
    The reported disease alleles - G287V, L257P and the in-frame T122del -
    fall in or near the conserved membrane-bound O-acyltransferase (MBOAT)
    domain that carries the enzyme's catalytic activity. That clustering is the
    structural counterpart of the functional result: the mutant enzyme cannot
    palmitoylate its substrates.
  genes:
  - preferred_term: HHAT
    term:
      id: hgnc:18270
      label: HHAT
  molecular_functions:
  - preferred_term: palmitoyltransferase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0016409
      label: palmitoyltransferase activity
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This mutation occurred in the conserved membrane bound O-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH.
    explanation: >-
      Locates the variant in the catalytic domain and demonstrates the
      functional consequence experimentally.
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Leu257 residue also lies in the MBOAT domain.
    explanation: >-
      Confirms that a second independent family's variant falls in the same
      catalytic domain.
  downstream:
  - target: Failure of Hedgehog Ligand Palmitoylation
    description: >-
      Loss of HHAT acyltransferase activity leaves SHH, IHH and DHH without
      their N-terminal palmitate.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24784881
      reference_title: >-
        Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This mutation occurred in the conserved membrane bound O-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH.
      explanation: >-
        Direct demonstration that the mutant enzyme fails to palmitoylate
        Hedgehog ligands.
- name: Failure of Hedgehog Ligand Palmitoylation
  biological_scale: MOLECULAR
  description: >-
    Hedgehog proteins are covalently modified with both cholesterol and
    palmitate, and those lipids are what allow the ligand to multimerise and to
    signal at a distance rather than only to its immediate neighbours. Without
    palmitoylation the ligand is made and secreted but is a weak,
    short-range morphogen. Because HHAT acts on all three mammalian Hedgehog
    ligands, one enzyme defect attenuates three developmental programmes at
    once.
  biological_processes:
  - preferred_term: protein palmitoylation
    modifier: DECREASED
    term:
      id: GO:0018345
      label: protein palmitoylation
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY
      disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This gene encodes an endoplasmic reticulum protein, HHAT, which catalyzes the transfer of palmitate onto hedgehog ligands.
    explanation: >-
      Establishes the enzyme's compartment and reaction.
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Post-translational covalent attachment of cholesterol and palmitate to Hh proteins are critical for multimerization and long range signaling potency.
    explanation: >-
      Establishes why loss of the palmitate specifically degrades long-range
      signalling.
  - reference: PMID:30912300
    reference_title: >-
      Biallelic novel missense HHAT variant causes syndromic microcephaly and cerebellar-vermis hypoplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      encoding an enzyme required for the attachment of palmitoyl residues that are critical for multimerization and long and short range hedgehog signaling
    explanation: >-
      Independent statement of the enzyme's role in Hedgehog signalling range.
  downstream:
  - target: Attenuated Hedgehog Signalling Across Multiple Developmental Fields
    description: >-
      Under-modified ligand means weakened Hedgehog pathway output in every
      tissue that depends on it.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24784881
      reference_title: >-
        Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The Hedgehog (Hh) family of secreted proteins act as morphogens to control embryonic patterning and development in a variety of organ systems.
      explanation: >-
        Establishes the breadth of developmental programmes the pathway
        controls, and so the breadth of the consequence.
- name: Attenuated Hedgehog Signalling Across Multiple Developmental Fields
  biological_scale: TISSUE
  description: >-
    The common node from which the syndrome's separate features descend. Mouse
    Hhat loss of function recapitulates most of the human testicular, skeletal,
    neuronal and growth phenotypes, which is the strongest evidence that the
    diverse human features share this single upstream cause rather than
    reflecting a contiguous-gene effect or coincidence.
  biological_processes:
  - preferred_term: smoothened signaling pathway
    modifier: DECREASED
    term:
      id: GO:0007224
      label: smoothened signaling pathway
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY
      disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, these data emphasize the essential role played by post-translational lipid modification of Hh ligands in mediating patterning of many aspects of the body, including the testis, limbs, axial skeleton and the central nervous system.
    explanation: >-
      Names lipid modification of hedgehog ligands as mediating patterning of the testis, limbs,
      axial skeleton, and central nervous system — the four affected systems of this syndrome.
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistent with the patient phenotype, HHAT was found to be expressed in the somatic cells of both XX and XY gonads at the time of sex determination, and Hhat loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans.
    explanation: >-
      Mouse genetics establishing that one enzyme's loss reproduces the
      multi-system human phenotype.
  downstream:
  - target: Testicular Dysgenesis with 46,XY Disorder of Sex Development
    description: >-
      Desert Hedgehog signalling from Sertoli cells is the arm that fails in the
      gonad.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Loss of DHH signalling to the fetal Leydig and peritubular myoid lineages.
    evidence:
    - reference: PMID:24784881
      reference_title: >-
        Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In the developing testis, HHAT is not required for Sertoli cell commitment but plays a role in proper testis cord formation and the differentiation of fetal Leydig cells.
      explanation: >-
        Localises the gonadal defect downstream of Sertoli cell commitment, at
        cord formation and fetal Leydig differentiation.
  - target: Midline Forebrain and Craniofacial Maldevelopment
    description: >-
      Sonic Hedgehog patterns the ventral midline of the forebrain and the face;
      attenuating it produces the holoprosencephaly end of the spectrum.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33749989
      reference_title: >-
        Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression.
      explanation: >-
        Records holoprosencephaly and the associated midline features among the
        consequences of HHAT loss.
  - target: Cerebellar Hypoplasia
    description: >-
      A distinct Hedgehog-dependent developmental programme from the ventral
      midline one, and the arm for which the independent human evidence is
      strongest.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30912300
      reference_title: >-
        Biallelic novel missense HHAT variant causes syndromic microcephaly and cerebellar-vermis hypoplasia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The phenotypic overlap with the family we report herein provides further evidence implicating HHAT in cerebellar development and the pathogenesis of this rare spectrum.
      explanation: >-
        Independent human evidence implicating HHAT specifically in cerebellar
        development.
  - target: Microcephaly with Neurodevelopmental Impairment
    description: >-
      Reduced brain growth with intellectual disability, present across the
      reported families.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30912300
      reference_title: >-
        Biallelic novel missense HHAT variant causes syndromic microcephaly and cerebellar-vermis hypoplasia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report two siblings with microcephaly, early infantile onset seizures, and cerebellar vermis hypoplasia, in whom whole exome sequencing revealed a novel homozygous missense
      explanation: >-
        Documents microcephaly and seizures in a molecularly confirmed sibship.
  - target: Skeletal Dysplasia with Short Stature
    description: >-
      Indian Hedgehog is the growth-plate Hedgehog ligand, and its attenuation
      is the presumed route to the chondrodysplasia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33749989
      reference_title: >-
        Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        HHAT knockout mice showed that the loss of function of HHAT can cause severe malformations that include holoprosencephaly, acrania, agnathia, dwarfism, skeletal defects, osteochondrogenic defects, and variation of sexual characteristics
      explanation: >-
        Mouse knockout evidence including the skeletal and osteochondrogenic
        defects this node describes.
- name: Testicular Dysgenesis with 46,XY Disorder of Sex Development
  biological_scale: ORGANISM
  cell_types:
  - preferred_term: Sertoli cell
    term:
      id: CL:0000216
      label: Sertoli cell
  - preferred_term: Leydig cell
    term:
      id: CL:0000178
      label: Leydig cell
  description: >-
    Gonadal dysgenesis in a 46,XY individual, presenting as female external
    genitalia. HHAT is expressed in the somatic cells of both XX and XY gonads
    at the time of sex determination, and the defect is downstream of Sertoli
    cell commitment - the cells are specified, but testis cord formation and
    fetal Leydig differentiation fail.
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY
      disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The left gonad contained large inclusions of immature testicular tissue mainly composed of dysplastic immature seminiferous tubules
    explanation: >-
      The histological description of the dysgenetic gonad.
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY
      disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The right gonad was hypoplastic and largely composed of fibroblastic and endothelial tissues.
    explanation: >-
      Documents the contralateral gonadal histology.
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, they provide the first clinical evidence of the essential role played by lipid modification of Hh proteins in human testicular organogenesis and embryonic development.
    explanation: >-
      States the human significance of the gonadal phenotype.
  downstream:
  - target: Gonadal dysgenesis
    causal_link_type: DIRECT
    description: >-
      Failure of testis cord formation and fetal Leydig differentiation is the
      gonadal dysgenesis itself, read at the level of the organ.
  - target: Primary amenorrhea
    causal_link_type: DIRECT
    description: >-
      A dysgenetic testis cannot support puberty, so menarche never occurs
      despite normal external female genitalia.
- name: Midline Forebrain and Craniofacial Maldevelopment
  biological_scale: ORGANISM
  description: >-
    Holoprosencephaly, agenesis of the corpus callosum, microphthalmia or
    anophthalmia, and a characteristic face with deep-set eyes, small irides and
    an everted upper lip - the ventral midline programme that Sonic Hedgehog
    patterns.
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression.
    explanation: >-
      Names the midline forebrain and craniofacial features of this node within
      the delineated spectrum.
  downstream:
  - target: Holoprosencephaly
    causal_link_type: DIRECT
    description: >-
      Incomplete cleavage of the ventral forebrain, the canonical readout of
      attenuated Sonic Hedgehog signalling at the midline.
  - target: Agenesis of corpus callosum
    causal_link_type: DIRECT
    description: >-
      Callosal agenesis, the commissural consequence of the same midline
      patterning failure.
  - target: Microphthalmia
    causal_link_type: DIRECT
    description: >-
      Small globes; Hedgehog signalling sets eye-field size as well as optic
      fissure closure.
  - target: Optic disc coloboma
    causal_link_type: DIRECT
    description: >-
      Failure of optic fissure closure, a recognised consequence of deficient
      Sonic Hedgehog signalling in the developing eye.
  - target: Iris hypoplasia
    causal_link_type: DIRECT
    description: The anterior-segment component of the same ocular Hedgehog signature.
  - target: Deeply set eye
    causal_link_type: DIRECT
    description: >-
      Part of the recognisable craniofacial appearance produced by the midline
      patterning defect.
  - target: Ptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reported for the first time in the 2025 series. No mechanism has been
      proposed and it may reflect ascertainment rather than a distinct
      developmental route.
  - target: Myopia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Refractive error identified at adolescent follow-up, plausibly secondary to
      the globe and anterior-segment maldevelopment rather than an independent
      feature.
- name: Cerebellar Hypoplasia
  biological_scale: ORGANISM
  description: >-
    A small cerebellar vermis. This is a separate Hedgehog-dependent programme
    from the ventral midline one, and the feature that a molecularly confirmed
    sibship established as implicating HHAT in cerebellar development
    specifically.
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression.
    explanation: >-
      Names the cerebellar feature within the delineated spectrum.
  downstream:
  - target: Cerebellar vermis hypoplasia
    causal_link_type: DIRECT
    description: >-
      Hypoplasia of the vermis, whose granule precursors proliferate under Sonic
      Hedgehog control.
- name: Microcephaly with Neurodevelopmental Impairment
  biological_scale: ORGANISM
  description: >-
    Microcephaly with intellectual disability, and early infantile seizures in
    some patients.
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression.
    explanation: >-
      Names microcephaly and intellectual disability within the delineated
      spectrum.
  downstream:
  - target: Microcephaly
    causal_link_type: DIRECT
    description: >-
      Reduced brain growth, present across the reported families.
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Whether it follows from the reduced brain growth, the cerebellar
      hypoplasia, or the seizures is not established.
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Early infantile onset seizures in a molecularly confirmed sibship; the
      route from attenuated Hedgehog signalling to cortical hyperexcitability
      has not been worked out.
- name: Skeletal Dysplasia with Short Stature
  biological_scale: ORGANISM
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  description: >-
    Chondrodysplasia with short stature, the feature that places the syndrome in
    the skeletal nosology at all. It is the least well characterised arm of the
    phenotype: the reports describe it as skeletal dysplasia without the
    radiographic detail that would let it be typed within the
    spondylometaphyseal group.
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression.
    explanation: >-
      Records short stature and skeletal dysplasia in the delineated spectrum,
      at the level of detail the literature provides.
  downstream:
  - target: Short stature
    causal_link_type: DIRECT
    description: >-
      Indian Hedgehog drives the growth-plate proliferative programme, so
      attenuating it shortens the long bones.
  - target: Skeletal dysplasia
    causal_link_type: DIRECT
    description: >-
      The generalised chondrodysplasia, which is the feature the ISDS group-12
      assignment rests on.
  - target: Micromelia
    causal_link_type: DIRECT
    description: Limb shortening, the appendicular expression of the patterning defect.
  - target: Brachydactyly
    causal_link_type: DIRECT
    description: >-
      Short digits - the distal limb field is among the most
      Hedgehog-dependent structures in the body.
  - target: Bell-shaped thorax
    causal_link_type: DIRECT
    description: A narrow, bell-shaped chest from the axial skeletal involvement.
phenotypes:
- name: Gonadal dysgenesis
  category: Genitourinary
  diagnostic: true
  description: >-
    Testicular dysgenesis in a 46,XY individual, presenting as female external
    genitalia. The original 1992 family's proband was a phenotypic female with a
    46,XY karyotype.
  phenotype_term:
    preferred_term: Gonadal dysgenesis
    term:
      id: HP:0000133
      label: Gonadal dysgenesis
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (HHAT) gene.
    explanation: >-
      Records testicular dysgenesis with 46,XY DSD as a defining feature.
- name: Microcephaly
  category: Neurologic
  diagnostic: true
  description: >-
    Microcephaly is present across the reported families and is often the
    presenting finding, prenatally or in infancy.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression.
    explanation: >-
      Records microcephaly in the delineated spectrum.
- name: Cerebellar vermis hypoplasia
  category: Neurologic
  diagnostic: true
  description: >-
    A small cerebellar vermis, present in both siblings of the second reported
    family and the finding that most directly implicates HHAT in cerebellar
    development.
  phenotype_term:
    preferred_term: Cerebellar vermis hypoplasia
    term:
      id: HP:0001320
      label: Cerebellar vermis hypoplasia
  evidence:
  - reference: PMID:30912300
    reference_title: >-
      Biallelic novel missense HHAT variant causes syndromic microcephaly and cerebellar-vermis hypoplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report two siblings with microcephaly, early infantile onset seizures, and cerebellar vermis hypoplasia, in whom whole exome sequencing revealed a novel homozygous missense
    explanation: >-
      Direct report of cerebellar vermis hypoplasia in a molecularly confirmed
      sibship.
- name: Holoprosencephaly
  category: Neurologic
  frequency: OCCASIONAL
  description: >-
    Holoprosencephaly is part of the spectrum, and is the expected consequence of
    attenuated Sonic Hedgehog signalling at the ventral forebrain midline. It is
    also seen in Hhat knockout mice.
  phenotype_term:
    preferred_term: Holoprosencephaly
    term:
      id: HP:0001360
      label: Holoprosencephaly
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression.
    explanation: >-
      Records holoprosencephaly in the delineated spectrum.
- name: Agenesis of corpus callosum
  category: Neurologic
  description: >-
    Callosal agenesis, another midline forebrain consequence.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression.
    explanation: >-
      Records callosal agenesis in the delineated spectrum.
- name: Microphthalmia
  category: Ophthalmologic
  description: >-
    Microphthalmia or anophthalmia; the original family's proband had small
    irides and deep-set eyes.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression.
    explanation: >-
      Records microphthalmia-anophthalmia in the delineated spectrum.
- name: Intellectual disability
  category: Neurologic
  description: >-
    Intellectual disability in surviving individuals, alongside the structural
    brain anomalies.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression.
    explanation: >-
      Records intellectual disability in the delineated spectrum.
- name: Seizure
  category: Neurologic
  description: >-
    Early infantile onset seizures were present in both siblings of the second
    reported family.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:30912300
    reference_title: >-
      Biallelic novel missense HHAT variant causes syndromic microcephaly and cerebellar-vermis hypoplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report two siblings with microcephaly, early infantile onset seizures, and cerebellar vermis hypoplasia, in whom whole exome sequencing revealed a novel homozygous missense
    explanation: >-
      Records early infantile seizures in a molecularly confirmed sibship.
- name: Short stature
  category: Growth
  diagnostic: true
  description: >-
    Short stature with skeletal dysplasia; the original 1992 proband had short
    stature and skeletal dysplasia alongside the sex reversal, and intrauterine
    growth restriction was noted in an affected fetus.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      "Chondrodysplasia-pseudo-hermaphroditism syndrome" (MIM# 600092) described by Nivelon et al. is the first clinical report of a family with an affected female with short stature, skeletal dysplasia, microcephaly, deep-set eyes, small iris, everted upper lip and sex reversal with a karyotype of 46, XY.
    explanation: >-
      The founding clinical description, recording short stature with skeletal
      dysplasia.
- name: Deeply set eye
  category: Craniofacial
  description: >-
    Deep-set eyes with small irides and an everted upper lip make up the
    recognisable facial appearance.
  phenotype_term:
    preferred_term: Deeply set eye
    term:
      id: HP:0000490
      label: Deeply set eye
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      "Chondrodysplasia-pseudo-hermaphroditism syndrome" (MIM# 600092) described by Nivelon et al. is the first clinical report of a family with an affected female with short stature, skeletal dysplasia, microcephaly, deep-set eyes, small iris, everted upper lip and sex reversal with a karyotype of 46, XY.
    explanation: >-
      Records the facial features in the founding description.
- name: Skeletal dysplasia
  category: Skeletal
  frequency: OBLIGATE
  description: >-
    A generalised chondrodysplasia. This is the phenotype the whole ISDS group-12
    assignment rests on, so it is stated explicitly rather than left implicit in
    the short-stature record: the published description is of generalised
    skeletal dysplasia, not of the vertebral-plus-metaphyseal pattern that
    defines the other five members of the group.
  phenotype_term:
    preferred_term: Skeletal dysplasia
    term:
      id: HP:0002652
      label: Skeletal dysplasia
  evidence:
  - reference: PMID:40326711
    reference_title: >-
      Four New Patients of HHAT-Related Multiple Congenital Anomalies Syndrome (Nivelon-Nivelon-Mabille Syndrome) and a Comprehensive Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      exhibiting distinct phenotypic features including 46,XY gonadal dysgenesis,
      microcephaly, microphthalmia, ocular coloboma, skeletal dysplasia, and
      cerebellar vermis hypoplasia
    explanation: >-
      Names skeletal dysplasia among the core features in the four most recently
      reported patients, independently of the founding sibship.
- name: Micromelia
  category: Skeletal
  frequency: OBLIGATE
  description: Marked shortening of the limbs.
  phenotype_term:
    preferred_term: Micromelia
    term:
      id: HP:0002983
      label: Micromelia
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first sibling displayed severe dwarfism with generalized chondrodysplasia,
      a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly
      with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and
      coloboma of both optic discs.
    explanation: Names micromelia alongside the thoracic and digital features.
- name: Brachydactyly
  category: Skeletal
  frequency: OBLIGATE
  description: Short digits.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first sibling displayed severe dwarfism with generalized chondrodysplasia,
      a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly
      with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and
      coloboma of both optic discs.
    explanation: Names brachydactyly among the limb features.
- name: Bell-shaped thorax
  category: Skeletal
  frequency: OBLIGATE
  description: A narrow, bell-shaped chest.
  phenotype_term:
    preferred_term: Bell-shaped thorax
    term:
      id: HP:0001591
      label: Bell-shaped thorax
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first sibling displayed severe dwarfism with generalized chondrodysplasia,
      a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly
      with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and
      coloboma of both optic discs.
    explanation: Names the thoracic morphology.
- name: Primary amenorrhea
  category: Genitourinary
  frequency: OBLIGATE
  description: >-
    Primary amenorrhoea with absent pubertal development, in a 46,XY individual
    with normal external female genitalia and hypergonadotrophic hypogonadism.
  phenotype_term:
    preferred_term: Primary amenorrhea
    term:
      id: HP:0000786
      label: Primary amenorrhea
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The karyotype was 46,XY but the patient exhibited clinical features of a 46,XY
      DSD with complete gonadal dysgenesis (CGD), including normal external female
      genitalia, lack of pubertal development, primary amenorrhea
    explanation: >-
      The clinical definition of the disorder of sex development, naming the
      amenorrhoea and the absent puberty.
- name: Optic disc coloboma
  category: Ophthalmologic
  frequency: OBLIGATE
  description: >-
    Coloboma of both optic discs - a failure of optic fissure closure, and one of
    the recognised consequences of deficient Sonic Hedgehog signalling in the
    developing eye.
  phenotype_term:
    preferred_term: Optic disc coloboma
    term:
      id: HP:0000588
      label: Optic disc coloboma
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first sibling displayed severe dwarfism with generalized chondrodysplasia,
      a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly
      with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and
      coloboma of both optic discs.
    explanation: Names the bilateral optic disc coloboma and the iris hypoplasia.
- name: Iris hypoplasia
  category: Ophthalmologic
  frequency: OBLIGATE
  description: Hypoplastic irides, part of the anterior-segment Hedgehog signature.
  phenotype_term:
    preferred_term: Hypoplasia of the iris
    term:
      id: HP:0007676
      label: Hypoplasia of the iris
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first sibling displayed severe dwarfism with generalized chondrodysplasia,
      a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly
      with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and
      coloboma of both optic discs.
    explanation: Names the iris hypoplasia.
- name: Ptosis
  category: Ophthalmologic
  frequency: OCCASIONAL
  description: >-
    Drooping of the upper eyelid, reported for the first time in the 2025 series
    and not present in the earlier patients. Whether it is a genuine part of the
    phenotype or an ascertainment artefact of a small series is not yet clear.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:40326711
    reference_title: >-
      Four New Patients of HHAT-Related Multiple Congenital Anomalies Syndrome (Nivelon-Nivelon-Mabille Syndrome) and a Comprehensive Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ptosis and marked visual impairment were present only in the current study.
    explanation: >-
      The authors flag both features as new to their series, which is why the
      record is OCCASIONAL and explicitly provisional.
- name: Myopia
  category: Ophthalmologic
  frequency: FREQUENT
  description: Myopia, identified at follow-up in adolescence.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified mild mental retardation, muscular hypertrophy, myopia and other
      facial anomalies such as upslanting palpebral fissures, puffy eyelids, large
      mouth
    explanation: Names the myopia among the adolescent follow-up findings.
biochemical: []
genetic:
- name: HHAT
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: HHAT
    term:
      id: hgnc:18270
      label: HHAT
  notes: >-
    Biallelic variants clustering in or near the MBOAT catalytic domain.
    Reported alleles are p.Gly287Val (long isoform numbering; p.Gly150Val on the
    short isoform), p.Leu257Pro and the in-frame p.Thr122del, with three further
    novel variants in the 2025 series. Note that the same substitution carries
    two different protein designations depending on which RefSeq isoform is used,
    which is a practical trap when comparing reports. The founding family's
    variant was the only one surviving an autosomal recessive filtering model in
    the exome, and is absent from dbSNP.
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of WES results using an autosomal recessive model revealed a
      homozygous G287V missense mutation in the hedgehog acyl-transferase ( HHAT)
      gene.
    explanation: The gene-discovery result and the founding causal allele.
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Gly287 residue lies in the highly conserved MBOAT (Membrane bound acyl transferase) domain
    explanation: >-
      Places the founding family's allele in the catalytic MBOAT domain. The
      same change is designated p.Gly150Val on the short isoform in that report,
      which is the source of the numbering caution recorded here.
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this family, they identified a biallelic missense variant, c.770C > T, p.(Leu257Pro) in exon 7 of HHAT (NM_001122834.3) as the likely cause of the multiple malformation syndrome (Abdel-Salam et al., 2019).
    explanation: >-
      Records the second family's allele.
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The Gly287 residue is a highly conserved amino acid which, when mutated, leads
      to a non-functional HHAT protein that lacks the ability to palmitoylate
      hedgehog proteins.
    explanation: >-
      Establishes both the conservation of the residue and the functional
      consequence of substituting it.
  - reference: PMID:40326711
    reference_title: >-
      Four New Patients of HHAT-Related Multiple Congenital Anomalies Syndrome (Nivelon-Nivelon-Mabille Syndrome) and a Comprehensive Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whole exome analysis revealed three novel variants of the HHAT gene
    explanation: >-
      Three further pathogenic HHAT variants beyond the previously reported
      alleles, establishing an allelic series rather than a single recurrent
      allele.
environmental: []
treatments:
- name: Hormone Replacement Therapy
  description: >-
    Complete gonadal dysgenesis with hypergonadotrophic hypogonadism requires sex
    hormone replacement to induce and maintain secondary sexual characteristics and to
    protect bone, in line with standard management of 46,XY complete gonadal
    dysgenesis. The reported patient's course — absent pubertal development and
    primary amenorrhoea — establishes the need.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:24784881
    reference_title: "Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including normal external female genitalia, lack of pubertal development,
      primary amenorrhea
    explanation: >-
      Establishes the hypogonadism that makes hormone replacement the standard
      indication; it evidences the need rather than a trialled protocol in this
      disorder, hence INDIRECT.
- name: Gonadectomy and Gonadal Surveillance
  description: >-
    Dysgenetic gonadal tissue in a 46,XY individual carries a recognised risk of germ
    cell tumour, and the reported patient's gonads were removed and examined
    histologically. Surveillance or gonadectomy is a standing consideration in 46,XY
    complete gonadal dysgenesis, decided with the individual concerned.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:24784881
    reference_title: "Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histology confirmed the testicular dysgenesis and identified persistent
    explanation: >-
      Gonadal tissue was available for histology, which documents that gonadectomy
      was performed; the report does not evaluate the intervention, hence INDIRECT.
- name: Multidisciplinary supportive care
  description: >-
    No disease-modifying therapy exists and there is no prospect of one directed
    at the enzyme. Care is supportive across neurology, endocrinology,
    ophthalmology and orthopaedics, and the disorder carries a substantial
    perinatal mortality - one reported family lost two of three affected
    pregnancies.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this report, we describe the third family with multiple malformations in three pregnancies with a novel biallelic in-frame deletion, c.365_367del; (p.Thr122del) in exon 5 of HHAT in the living proband.
    explanation: >-
      Three affected pregnancies with one living proband, which is the basis for
      the perinatal mortality noted here; no treatment is described in this
      literature.
- name: Genetic counselling with prenatal testing
  description: >-
    Recessive recurrence risk of 25%. Counselling matters more than usual here
    because affected pregnancies have repeatedly been identified prenatally on
    microcephaly, growth restriction and skeletal dysplasia, and because a
    46,XY fetus may present with female external genitalia.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY
      disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient familial history indicates that the patient and sibling were conceived by a healthy, non-consanguineous caucasian couple
    explanation: >-
      Two affected children of unaffected non-consanguineous parents is the pedigree that
      recurrence-risk counselling has to address.
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The couple terminated their second pregnancy at 21 weeks of gestation in view of intra uterine growth retardation, microcephaly and skeletal dysplasia.
    explanation: >-
      A documented prenatal identification on exactly the findings this entry
      names.
diagnosis:
- name: Clinical recognition of the multisystem pattern
  description: >-
    The combination that identifies the disorder is microcephaly with cerebellar
    vermis hypoplasia, skeletal dysplasia and short stature, and 46,XY gonadal
    dysgenesis. Any one of the three in isolation has many causes; together they
    are close to specific.
  presence: >-
    Microcephaly with cerebellar vermis hypoplasia, skeletal dysplasia and
    46,XY gonadal dysgenesis.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression.
    explanation: >-
      The delineated spectrum from which the recognisable combination is drawn.
- name: Karyotype in a phenotypically female infant
  description: >-
    A 46,XY karyotype in a phenotypic female with microcephaly and skeletal
    dysplasia is what converts a nonspecific malformation syndrome into this
    specific diagnosis.
  results: 46,XY karyotype with female external genitalia.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      "Chondrodysplasia-pseudo-hermaphroditism syndrome" (MIM# 600092) described by Nivelon et al. is the first clinical report of a family with an affected female with short stature, skeletal dysplasia, microcephaly, deep-set eyes, small iris, everted upper lip and sex reversal with a karyotype of 46, XY.
    explanation: >-
      The founding case, in which the karyotype is what defined the syndrome.
- name: HHAT sequencing
  description: >-
    Molecular confirmation, by exome sequencing in every reported family.
    Variants should be reported against a stated RefSeq isoform, since the two
    HHAT isoforms give different protein designations for the same change.
  results: Biallelic HHAT variants in or near the MBOAT domain.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY
      disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 244K aCGH analysis performed on genomic DNA extracted from blood cells of the patient did not reveal any chromosomal rearrangements that could account for the pathology.
    explanation: >-
      Documents exclusion of a structural cause before the exome analysis.
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We did proband-parents trio exome sequencing and identified a biallelic in-frame deletion c.365_367del; (p.Thr122del) in exon 5 of HHAT.
    explanation: >-
      Documents trio exome sequencing as the diagnostic route.
differential_diagnoses:
- name: Holoprosencephaly spectrum from SHH pathway variants
  description: >-
    Variants in SHH itself and in its pathway cause holoprosencephaly with
    midline craniofacial anomalies. The gonadal and skeletal features are what
    point past those genes to HHAT, since only HHAT acts on all three Hedgehog
    ligands at once.
  distinguishing_features:
  - 46,XY gonadal dysgenesis, which SHH-pathway holoprosencephaly does not cause
  - Chondrodysplasia with short stature from attenuated Indian Hedgehog signalling
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This mutation occurred in the conserved membrane bound O-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH.
    explanation: >-
      Establishes that HHAT acts on more than one Hedgehog ligand, which is why
      its phenotype exceeds that of any single-ligand defect.
- name: Other Causes of 46,XY Gonadal Dysgenesis
  description: >-
    SRY, NR5A1, MAP3K1, DHH and WT1 variants all cause 46,XY gonadal dysgenesis.
    What distinguishes HHAT is that the gonadal defect never comes alone: the
    same enzyme lesion attenuates Indian and Sonic Hedgehog signalling as well,
    so a chondrodysplasia and a midline brain malformation accompany it.
  distinguishing_features:
  - Generalised chondrodysplasia with severe short stature
  - Severe microcephaly with cerebellar vermis hypoplasia
  - Ocular coloboma and iris hypoplasia
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY
      disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Unfortunately, in many cases the genetic aetiology of DSD is unknown, indicating that our knowledge of the factors mediating sex determination is limited.
    explanation: >-
      Establishes the heterogeneous and often unsolved background against which this syndromic
      form has to be distinguished.
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (HHAT) gene.
    explanation: >-
      The DSD is explicitly syndromic and accompanied by chondrodysplasia, which
      is what separates it from isolated 46,XY gonadal dysgenesis.
- name: Other Spondylometaphyseal Dysplasias
  description: >-
    The other five members of ISDS group 12 are defined by a vertebral and
    metaphyseal radiographic pattern and act through matrix, secretion or
    growth-plate metabolism. This disorder is a morphogen-range defect whose
    skeletal component is generalised, and it is the only member with a disorder
    of sex development.
  distinguishing_features:
  - 46,XY gonadal dysgenesis, absent from every other group-12 disorder
  - Severe microcephaly with cerebellar vermis hypoplasia
  - Generalised rather than specifically spondylometaphyseal skeletal involvement
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first sibling displayed severe dwarfism with generalized chondrodysplasia,
      a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly
      with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and
      coloboma of both optic discs.
    explanation: >-
      The published skeletal description is generalised rather than specifically
      spondylometaphyseal, which is the basis of the distinction.
animal_models:
- name: Hhat loss-of-function mouse
  species: Mouse
  genotype: Hhat loss of function
  publication: PMID:24784881
  description: >-
    Mice lacking functional Hhat, used to test whether the human syndrome follows
    from loss of Hedgehog palmitoylation. The model reproduces most of the human
    phenotype across all four affected systems, which is what allows the diverse
    human features to be attributed to a single enzymatic lesion.
  modeled_mechanisms:
  - target: Skeletal Dysplasia with Short Stature
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Hhat loss of function in mice reproduces the testicular, skeletal, neuronal
      and growth defects seen in patients, which is what allows the human
      phenotype to be attributed to the enzymatic lesion rather than to a
      coincidental second variant.
    limitations: >-
      The recapitulation is stated as covering most, not all, of the human
      defects, and the mouse model is a loss of function rather than a knock-in
      of a human allele, so it does not test any specific variant. The mouse
      gonadal phenotype also cannot model the 46,XY sex-reversal presentation
      directly.
    evidence:
    - reference: PMID:24784881
      reference_title: >-
        Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Hhat loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans
      explanation: >-
        States the scope of the recapitulation across all four affected organ
        systems.
  - target: Testicular Dysgenesis with 46,XY Disorder of Sex Development
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Hhat loss of function in mice reproduces the gonadal arm of the syndrome,
      and localises the requirement for palmitoylated Desert Hedgehog to a
      specific step of testis morphogenesis.
    limitations: >-
      The mouse gonadal phenotype cannot model the 46,XY sex-reversal
      presentation directly, and the model is a loss of function rather than a
      knock-in of a human allele, so it does not test any specific variant.
    readouts:
    - name: Testis cord formation and fetal Leydig cell differentiation
      target: Testicular Dysgenesis with 46,XY Disorder of Sex Development
      direction: DECREASED
      interpretation: >-
        Sertoli cell commitment is preserved while cord formation and fetal
        Leydig differentiation fail, localising the requirement for
        palmitoylated Desert Hedgehog to a specific step of testis
        morphogenesis.
      evidence:
      - reference: PMID:24784881
        reference_title: >-
          Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In the developing testis, HHAT is not required for Sertoli cell commitment but plays a role in proper testis cord formation and the differentiation of fetal Leydig cells.
        explanation: Reports the developmental readout behind this measurement.
    evidence:
    - reference: PMID:24784881
      reference_title: >-
        Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Hhat loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans
      explanation: >-
        States the scope of the recapitulation across all four affected organ
        systems.
discussions:
- discussion_id: gap_hhat_skeletal_phenotype_uncharacterised
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What are the radiographic features of the chondrodysplasia in HHAT-related
    disease, and do they justify its placement among the spondylometaphyseal
    dysplasias?
  attaches_to:
  - pathophysiology#Skeletal Dysplasia with Short Stature
  - phenotypes#Short stature
  - phenotypes#Skeletal dysplasia
  rationale: >-
    The nosology places this syndrome in the spondylometaphyseal group, but the
    published reports describe the skeletal component only as "skeletal
    dysplasia" or as a generalised chondrodysplasia with micromelia,
    brachydactyly and a bell-shaped thorax, without the vertebral and
    metaphyseal radiographic detail that the group name asserts. Every other row
    in the group is defined radiographically. Two further things point the same
    way. MONDO gives MONDO:0010814 no skeletal dysplasia parent at all, placing
    it under syndromic disease, hereditary disease and 46,XY disorder of sex
    development. And mechanistically the disorder sits apart: the other five
    group-12 members act through matrix, secretion or growth-plate metabolism,
    while this one is a morphogen-range defect that happens to include cartilage
    among its targets. The phenotype has been delineated carefully for its
    neurological, ocular and gonadal features, and a comparable radiographic
    series has not been published - unsurprising given that most reported
    conceptuses did not survive, but it leaves the classification resting on less
    evidence than the rest of the group. Recording the mismatch matters because a
    curator using group 12 as a proxy for a radiographic phenotype will be misled
    by this member. The classification itself follows the nosology as a
    transcription, per the schema's guidance that this axis transcribes an expert
    committee's placements rather than inferring them.
  evidence:
  - reference: PMID:33749989
    reference_title: >-
      Hedgehog acyl-transferase-related multiple congenital anomalies: Report of an additional family and delineation of the syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly, small cerebellar vermis, holoprosencephaly, agenesis of corpus callosum, intellectual disability, short stature, skeletal dysplasia, microphthalmia-anophthalmia, and sex reversal constitute the phenotypic spectrum of this condition with variable expression.
    explanation: >-
      The most detailed published delineation, which still describes the
      skeletal component only as "skeletal dysplasia".
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first sibling displayed severe dwarfism with generalized chondrodysplasia,
      a narrow, bell-shaped thorax, micromelia, brachydactyly, severe microcephaly
      with cerebellar vermis hypoplasia, facial anomalies, hypoplastic irides, and
      coloboma of both optic discs.
    explanation: >-
      The founding skeletal description is generalised rather than specifically
      spondylometaphyseal, which is the basis of the question.
  proposed_experiments:
  - experiment_id: exp_hhat_radiographic_reappraisal
    name: Radiographic reappraisal of the reported HHAT skeletal phenotype
    description: >-
      Obtain and re-read the original skeletal surveys of the reported patients,
      scoring specifically for vertebral and metaphyseal involvement against the
      criteria used for the other group-12 disorders, and refer the finding to
      the ISDS Nosology Committee.
    would_support:
    - pathophysiology#Skeletal Dysplasia with Short Stature
    supporting_outcome:
    - >-
      Documented platyspondyly with metaphyseal irregularity would confirm the
      committee's placement on radiographic grounds and close the question.
    would_refute:
    - pathophysiology#Skeletal Dysplasia with Short Stature
    refuting_outcome:
    - >-
      Absence of a vertebral-plus-metaphyseal pattern would make this a placement
      of convenience for a syndromic chondrodysplasia and a candidate for
      regrouping in a future revision.
- discussion_id: hhat_phenotype_breadth_and_null_lethality
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - disease#HHAT-related chondrodysplasia with 46,XY disorder of sex development
  prompt: >-
    How wide is the HHAT phenotype, and is a complete null ever compatible with
    live birth?
  rationale: >-
    The replication question this gap originally recorded has been answered. The
    2014 authors searched large skeletal-disorder and DSD cohorts without finding
    a second family; eight patients were on record by 2025 and a further four
    were then reported from two unrelated families, so the gene-disease
    relationship is replicated and the single-family framing no longer holds.
    What the newer series changes is the phenotype rather than the genotype -
    ptosis and marked visual impairment appeared for the first time, and
    microphthalmia joined coloboma in the ocular spectrum, which is the signature
    of a boundary still being set by who happens to be looked at. Two things stay
    open. The original search was framed by chondrodysplasia-plus-DSD and would
    have missed a milder or differently weighted presentation. And because
    Hedgehog signalling is required across so many systems, a complete null may
    be embryonic-lethal and so never ascertained as a syndrome at all - every
    reported allele is missense or an in-frame deletion.
  evidence:
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This suggests that the frequency of pathogenic variants of HHAT is extremely low
      within the general population, which would explain the absence of other listed
      cases of Nivelon-Nivelon-Mabille syndrome.
    explanation: >-
      The founding authors' reading of their failed search. Later reports found
      the additional families this inference argued against, so it is retained as
      the 2014 position rather than the current one.
  - reference: PMID:40326711
    reference_title: >-
      Four New Patients of HHAT-Related Multiple Congenital Anomalies Syndrome (Nivelon-Nivelon-Mabille Syndrome) and a Comprehensive Literature Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ptosis and marked visual impairment were present only in the current study.
    explanation: >-
      Features appearing for the first time in the ninth-to-twelfth patients is
      the signature of a phenotype whose boundary is still being drawn by
      ascertainment.
  - reference: PMID:24784881
    reference_title: >-
      Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is possible that other mutations in the HHAT locus may lead to severe defects
      in HHAT
    explanation: >-
      The authors raise the possibility of a broader allelic spectrum, which is
      the alternative to simple rarity recorded in this gap.
  proposed_experiments:
  - experiment_id: exp_hhat_phenotype_agnostic_variant_search
    name: Phenotype-agnostic search for biallelic HHAT variants
    description: >-
      Query large aggregated sequencing datasets and matchmaking services for
      biallelic HHAT variants without conditioning on chondrodysplasia or DSD,
      and separately assess whether HHAT is depleted of biallelic
      loss-of-function in population reference data to the degree expected of an
      embryonic-lethal gene.
    would_support:
    - pathophysiology#Biallelic HHAT Variants in the MBOAT Domain
    supporting_outcome:
    - >-
      Further unrelated families with biallelic HHAT variants and an overlapping
      phenotype would extend the allelic and phenotypic series.
    would_refute:
    - disease#HHAT-related chondrodysplasia with 46,XY disorder of sex development
    refuting_outcome:
    - >-
      Biallelic HHAT carriers with no chondrodysplasia and no DSD would argue
      that the reported syndrome requires something beyond the HHAT genotype
      alone.
progression: []
clinical_trials: []
datasets: []
notes: >-
  Curated to complete ISDS Nosology group 12 (Spondylometaphyseal dysplasias),
  row NOS 12-0060. The entry name uses current terminology for the sex
  development phenotype; MONDO:0010814's canonical label retains the historical
  "pseudohermaphroditism" wording and is reproduced exactly on disease_term as
  term validation requires, with the historical name kept as a synonym so the
  nosology row stays findable. An open knowledge gap records that the skeletal
  phenotype has never been characterised radiographically at the level the
  group placement implies.

  This entry is the merge of two independently curated entries for
  MONDO:0010814 that reached the repository at the same time - one on main under
  this filename, and one on the ISDS group-12 branch as
  Chondrodysplasia-Pseudohermaphroditism_Syndrome.yaml. The surviving file keeps
  main's name and its per-organ decomposition of the Hedgehog phenotype, and
  takes from the branch entry its Hhat-null mouse model, the 2025 four-patient
  series (PMID:40326711), the skeletal, ocular and gonadal phenotype records,
  the differential diagnoses, and the pathophysiology-to-phenotype wiring. The
  superseded history records were moved into this slug directory with
  target.superseded_by blocks.
references:
- reference: PMID:36779427
  title: "Nosology of genetic skeletal disorders: 2023 revision."
  findings: []
📚

References & Deep Research

References

1
PMID:36779427
Nosology of genetic skeletal disorders: 2023 revision.
No top-level findings curated for this source.