Bosma Arhinia Microphthalmia Syndrome

Mendelian MONDO:0011323 Pathograph 50 Show in embeddings browser Multiple congenital anomalies/dysmorphic syndrome without intellectual disability Congenital hypogonadotropic hypogonadism

Bosma arhinia microphthalmia syndrome is an ultra-rare congenital malformation syndrome characterized by arhinia or severe nasal hypoplasia, choanal or nasopharyngeal obstruction, ocular hypoplasia or microphthalmia, olfactory and taste impairment, dental and midface anomalies, and hypogonadotropic hypogonadism with otherwise usually preserved intelligence. Most molecularly explained cases involve heterozygous missense variants in the ATPase domain of SMCHD1. Variants are commonly de novo, although inherited disease with markedly variable expressivity is documented. Patient-derived cell studies implicate both impaired neural-crest migration and defective cranial-placode differentiation and adhesion in disrupted nasal and craniofacial development.

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1
Mappings
1
Definitions
1
Inheritance
7
Pathophys.
38
Phenotypes
4
Gaps
50
Pathograph
1
Genes
6
Medical Actions
1
Differentials
1
Datasets
1
Trials
2
Models
21
References
1
Deep Research
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
🔗

Mappings

MONDO
MONDO:0011323 arhinia, choanal atresia, and microphthalmia
skos:exactMatch MONDO
MONDO:0011323 is the current disease identifier used by this entry and by the definitive ClinGen SMCHD1 assertion; it consolidates the legacy Orphanet names represented by ORPHA:2250 and ORPHA:1135.
📘

Definitions

1
Orphanet BAMS definition
The Orphanet record defines BAMS by severe nasal hypoplasia, ocular hypoplasia, hyposmia, hypogeusia, and hypogonadotropic hypogonadism.
OTHER
Show evidence (2 references)
ORPHA:2250 SUPPORT Other
"This syndrome is characterized by the association of severe nasal hypoplasia, hypoplasia of the eyes, hyposmia, hypogeusia and hypogonadotropic hypogonadism."
Orphanet provides the structured clinical definition.
PMID:28067911 SUPPORT Human Clinical
"Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects."
The SMCHD1 discovery series supports the core arhinia and ocular defect definition.
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Expression ranges from anosmia-only carriers to complete arhinia with ocular, craniofacial, and reproductive manifestations.
Autosomal dominant inheritance Expressivity: VARIABLE
Show evidence (3 references)
ORPHA:2250 SUPPORT Other
"Autosomal dominant"
Orphanet records autosomal dominant inheritance.
PMID:28067911 SUPPORT Human Clinical
"All mutations were de novo where parental DNA was available."
The discovery series supports predominantly de novo heterozygous SMCHD1 variants.
PMID:36944600 SUPPORT Human Clinical
"The affected patients and anosmic parent were found to have a novel SMCHD1 gene variant p.E473V."
The affected pedigree documents inherited SMCHD1-associated disease and variable expression from anosmia in a parent to arhinia in offspring.
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Discussions and Knowledge Gaps

4
Do all BAMS-associated SMCHD1 ATPase-domain variants act through increased ATPase activity or another coherent gain-of-function mechanism?
INTERPRETATION OPEN bams_allelic_function
Attached to
genetic#SMCHD1 ATPase-domain missense variants pathophysiology#SMCHD1 ATPase-domain chromatin regulatory alteration
Many tested BAMS variants increase ATPase activity, whereas patient methylation changes overlap FSHD2 and at least one recurrent variant has been observed across phenotypes. A single gain-of-function label would therefore overstate the available allele-by-allele evidence.
Show evidence (2 references)
PMID:29748383 SUPPORT In Vitro
"whether BAMS is associated with loss- or gain-of-function mutations in SMCHD1 is unclear."
The functional study states the unresolved allelic-mechanism question directly.
PMID:28067909 SUPPORT Human Clinical
"We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders."
Shared variants and methylation effects complicate a simple disease-specific binary mechanism.
What are the relative and interacting contributions of neural-crest and cranial-placode defects to human BAMS anatomy?
EMERGING HYPOTHESIS OPEN bams_developmental_cell_lineages
Attached to
pathophysiology#Neural crest transcriptional, adhesion, and migration dysregulation pathophysiology#Cranial placode differentiation and adhesion defect pathophysiology#Disrupted nasal, olfactory, and midfacial development
Independent patient-derived-cell studies support both lineages. Neither model yet establishes their temporal interaction, contribution to ocular and reproductive findings, or quantitative importance across variants.
Show evidence (2 references)
PMID:34209568 SUPPORT In Vitro
"defects in neural crest migration might contribute to the craniofacial anomalies in BAMS."
The earlier model supports a contributory neural-crest mechanism.
PMID:41962546 SUPPORT In Vitro
"Together our research suggests that BAMS is caused by impaired differentiation to cranial placode cells and changes in cell adhesion"
The 2026 study adds a placodal mechanism that must be integrated with neural-crest evidence.
Which genetic, epigenetic, or developmental modifiers determine expression from isolated anosmia to complete arhinia and multisystem BAMS?
KNOWLEDGE GAP OPEN bams_inherited_expressivity
Attached to
inheritance#Autosomal dominant inheritance genetic#SMCHD1 ATPase-domain missense variants
Predominantly de novo discovery cohorts coexist with an inherited pedigree in which an anosmic parent transmitted the same variant to offspring with arhinia. Recurrence counseling and prediction therefore require more than a de-novo-versus-inherited distinction.
Show evidence (1 reference)
PMID:36944600 SUPPORT Human Clinical
"The affected patients and anosmic parent were found to have a novel SMCHD1 gene variant p.E473V."
The pedigree directly demonstrates inherited variable expressivity.
What are the typical longitudinal airway, visual, endocrine, reproductive, reconstructive, and psychosocial outcomes across the BAMS lifespan?
KNOWLEDGE GAP OPEN bams_lifespan_natural_history
Attached to
progression#Childhood, puberty, and adult course clinical_burden#
Available evidence is dominated by neonatal reports, cross-sectional case descriptions, and single-person adult narratives. It supports possible favorable adaptation but cannot define complication rates, treatment timing, or a typical longitudinal trajectory.
Show evidence (1 reference)
PMID:34194860 SUPPORT Human Clinical
"His story and experiences with the health-care system offer insight into some factors that may be pertinent to resilience and lifelong adjustment for patients with similar conditions"
A single lifespan case is informative but cannot establish population natural history.
⚙

Pathophysiology

7
SMCHD1 ATPase-domain chromatin regulatory alteration
BAMS-associated heterozygous missense variants cluster in the extended SMCHD1 ATPase domain and alter ATP hydrolysis, protein conformation, and local methylation. Many tested BAMS alleles increase ATPase activity, but shared alleles and incomplete functional testing make a universal gain-of-function label premature.
SMCHD1 hgnc:29090 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SMCHD1 (hgnc:29090). hgnc:29090 is a gene from the HUGO Gene Nomenclature Committee.
chromatin organization GO:0006325 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromatin organization (GO:0006325). GO:0006325 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Neural crest transcriptional, adhesion, and migration dysregulation Altered SMCHD1 regulation changes neural-crest extracellular-matrix, receptor-signaling, and migration programs.
Cranial placode differentiation and adhesion defect Patient SMCHD1 variants are associated with impaired differentiation toward cranial-placode cells and altered adhesion programs.
Ocular developmental disruption SMCHD1 ATPase-domain variants are linked to ocular malformation through incompletely defined developmental intermediates.
GnRH deficiency and variable reproductive-axis development The route from SMCHD1 dysregulation to GnRH deficiency is unresolved and does not uniformly require absent olfactory structures.
Unresolved body-wall developmental consequences Inguinal hernia and abdominal-wall weakness are recurrent clinical associations, but their route from SMCHD1 is unknown.
Show evidence (2 references)
PMID:29748383 SUPPORT In Vitro
"many BAMS mutations can result in elevated ATPase activity and decreased eye size in Xenopus"
Functional testing supports increased ATPase activity for many, but not necessarily all, BAMS alleles.
PMID:31243061 SUPPORT Human Clinical
"BAMS-associated SMCHD1 variants result in quantifiable local DNA hypomethylation."
Patient methylation analyses establish an epigenetic consequence without resolving a single allelic mechanism.
Neural crest transcriptional, adhesion, and migration dysregulation
Patient-derived neural crest stem cells show altered extracellular-matrix, cell-adhesion, PDGFR, ERBB3, integrin, and PI3K/AKT programs together with reduced migration. This is a plausible contributor to craniofacial malformation rather than a fully demonstrated in-vivo sequence.
neural crest cell CL:0011012 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural crest cell (CL:0011012). CL:0011012 is a cell type from the Cell Ontology.
neural crest cell migration GO:0001755 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neural crest cell migration (GO:0001755). GO:0001755 is a biological process from the Gene Ontology. ↓ DECREASED cell adhesion GO:0007155 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cell adhesion (GO:0007155). GO:0007155 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Disrupted nasal, olfactory, and midfacial development Reduced neural-crest migration is proposed to impair craniofacial morphogenesis.
Show evidence (1 reference)
PMID:34209568 SUPPORT In Vitro
"downregulation of PDGFRα or β and ERBB3, cMET and integrins or changes in ECM composition converged toward a defect in cell–cell contacts, cell-substratum adhesion, and cell migration in BAMS NCSCs."
The patient-derived model identifies convergent adhesion and migration defects.
Cranial placode differentiation and adhesion defect
BAMS patient-derived induced pluripotent stem cells differentiate poorly toward the cranial-placode lineage and show transcriptomic and methylomic dysregulation of cell adhesion without overt apoptosis.
ectodermal placode development GO:0071696 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ectodermal placode development (GO:0071696). GO:0071696 is a biological process from the Gene Ontology. ↓ DECREASED cell adhesion GO:0007155 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cell adhesion (GO:0007155). GO:0007155 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Disrupted nasal, olfactory, and midfacial development Impaired cranial-placode differentiation and adhesion provide a second human-cell route to failed nasal development.
Show evidence (1 reference)
PMID:41962546 SUPPORT In Vitro
"Combined transcriptome and DNA methylome analyses further revealed dysregulation in cell adhesion but without overt apoptosis."
The 2026 study defines the placodal adhesion phenotype in patient-derived cells.
Disrupted nasal, olfactory, and midfacial development
Neural-crest and cranial-placode abnormalities converge on deficient development of the external nose, nares, nasal airway, paranasal sinuses, olfactory structures, palate, maxilla, teeth, and adjacent lacrimal anatomy.
nose development GO:0043584 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased nose development (GO:0043584). GO:0043584 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Absent nares
Aplasia of the nose
Aplasia/Hypoplasia involving the nose
Single naris
Choanal atresia
Anosmia
Hyposmia
Hypoplasia of the olfactory bulb
Abnormal midface morphology
Hypertelorism
Hypoplasia of the maxilla
Cleft palate
Submucous cleft hard palate
Bifid uvula
High palate
Abnormality of taste sensation
Paranasal sinus hypoplasia
Failure of eruption of permanent teeth
Tooth malposition
Dacryocystocele
Lacrimal duct atresia
Feeding difficulties
Show evidence (2 references)
PMID:41962546 SUPPORT Human Clinical
"The embryonic development of the nose involves direct contributions from both the neural crest and cranial placodes."
The current cellular study supports convergence of both developmental lineages.
PMID:36968924 SUPPORT Human Clinical
"absence of paranasal sinuses and olfactory bulbs."
Human anatomy confirms downstream nasal, sinus, and olfactory structural disruption.
Ocular developmental disruption
BAMS includes a variable ocular-developmental spectrum from microphthalmia or anophthalmia to coloboma, cataract, optic atrophy, amblyopia, and visual loss. Xenopus data support altered eye development, but the precise human cellular route from SMCHD1 remains unresolved.
eye morphogenesis GO:0048592 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal eye morphogenesis (GO:0048592). GO:0048592 is a biological process from the Gene Ontology. ⚠ ABNORMAL camera-type eye morphogenesis GO:0048593 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal camera-type eye morphogenesis (GO:0048593). GO:0048593 is a biological process from the Gene Ontology. ⚠ ABNORMAL
eye UBERON:0000970 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in eye (UBERON:0000970). UBERON:0000970 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Microphthalmia
Anophthalmia
Amblyopia
Blindness
Visual loss
Optic atrophy
Iris coloboma
Cataract
Show evidence (1 reference)
PMID:29748383 SUPPORT Model Organism
"many BAMS mutations can result in elevated ATPase activity and decreased eye size in Xenopus"
The model supports altered eye development but does not reproduce the full human ocular spectrum.
GnRH deficiency and variable reproductive-axis development
Congenital arhinia is strongly associated with absent or reduced pulsatile GnRH activity, especially in males, but some females retain spontaneous pubertal development or a normal reproductive axis. Human data therefore support association rather than a uniform olfactory-dependent migration failure.
gonadotropin secretion GO:0032274 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased gonadotropin secretion (GO:0032274). GO:0032274 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Hypogonadotropic hypogonadism
Hypogonadism
External genital hypoplasia
Hypoplasia of penis
Cryptorchidism
Gynecomastia
Show evidence (2 references)
PMID:32034419 SUPPORT Human Clinical
"All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity."
Detailed phenotyping directly establishes GnRH deficiency in affected males.
PMID:32034419 SUPPORT Human Clinical
"The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis."
Female findings establish clinically important reproductive-axis variability.
Unresolved body-wall developmental consequences
Inguinal hernia and abdominal-wall weakness recur in structured and historical BAMS descriptions, but no disease-specific molecular or cellular route currently explains them.
Downstream
Inguinal hernia
Abdominal wall muscle weakness
Show evidence (1 reference)
PMID:6802865 SUPPORT Human Clinical
"Each patient had bilateral inguinal hernias, one or two undescended testes, and hypogonadotrophic hypogonadism."
The original report establishes the body-wall association.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Bosma Arhinia Microphthalmia Syndrome 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

38
Breast 1
Gynecomastia FREQUENT HP:0000771 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gynecomastia (HP:0000771). HP:0000771 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000771 | Gynecomastia | Frequent (79-30%)"
Orphanet lists gynecomastia as frequent.
Digestive 2
Inguinal hernia VERY_FREQUENT HP:0000023 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inguinal hernia (HP:0000023). HP:0000023 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000023 | Inguinal hernia | Very frequent (99-80%)"
Orphanet lists inguinal hernia as very frequent.
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33784779 SUPPORT Human Clinical
"An orogastric tube was placed, and drinking training and a special pacifier improved coordination and drinking performance."
A molecularly confirmed neonatal case documents early feeding difficulty and response to feeding adaptation.
Endocrine 2
Hypogonadotropic hypogonadism FREQUENT HP:0000044 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogonadotropic hypogonadism (HP:0000044). HP:0000044 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000044 | Hypogonadotropic hypogonadism | Frequent (79-30%)"
Orphanet lists hypogonadotropic hypogonadism as frequent.
Hypogonadism VERY_FREQUENT HP:0000135 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogonadism (HP:0000135). HP:0000135 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000135 | Hypogonadism | Very frequent (99-80%)"
Orphanet lists hypogonadism as very frequent.
Eye 6
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33784779 SUPPORT Human Clinical
"In addition to a complete nasal agenesis, hypertelorism, a Gothic palate, bilateral microphthalmus, and iris coloboma were found."
The neonatal case directly documents hypertelorism.
Cataract VERY_FREQUENT HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000518 | Cataract | Very frequent (99-80%)"
Orphanet lists cataract as very frequent.
Microphthalmia FREQUENT 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)
ORPHA:2250 SUPPORT Other
"HP:0000568 | Microphthalmia | Frequent (79-30%)"
Orphanet lists microphthalmia as frequent.
Visual loss FREQUENT HP:0000572 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visual loss (HP:0000572). HP:0000572 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000572 | Visual loss | Frequent (79-30%)"
Orphanet lists visual loss as frequent.
Blindness FREQUENT HP:0000618 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Blindness (HP:0000618). HP:0000618 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000618 | Blindness | Frequent (79-30%)"
Orphanet lists blindness as frequent.
Optic atrophy OCCASIONAL HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000648 | Optic atrophy | Occasional (29-5%)"
Orphanet lists optic atrophy as occasional.
Genitourinary 1
Cryptorchidism FREQUENT HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000028 | Cryptorchidism | Frequent (79-30%)"
Orphanet lists cryptorchidism as frequent.
Head and Neck 8
Cleft palate OCCASIONAL HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000175 | Cleft palate | Occasional (29-5%)"
Orphanet lists cleft palate as occasional.
Bifid uvula OCCASIONAL HP:0000193 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bifid uvula (HP:0000193). HP:0000193 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000193 | Bifid uvula | Occasional (29-5%)"
Orphanet lists bifid uvula as occasional.
High palate HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36968924 SUPPORT Human Clinical
"On presentation, she was noted to have congenital arhinia, bilateral microphthalmia, vision loss, mouth-breathing, an unclear speaking voice, a high arched or cleft palate, and a hypoplastic maxilla."
The adult case directly documents a high-arched palate.
Abnormality of taste sensation HP:0000223 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of taste sensation (HP:0000223). HP:0000223 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:6802865 SUPPORT Human Clinical
"Each was unable to recognize the smell of any vapor (Type I hyposmia), and had severe impairment of recognition of any tastant (recognition hypogeusia)"
The original two-patient report directly documents recognition hypogeusia.
Choanal atresia FREQUENT HP:0000453 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Choanal atresia (HP:0000453). HP:0000453 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000453 | Choanal atresia | Frequent (79-30%)"
Orphanet lists choanal atresia as frequent.
Anosmia VERY_FREQUENT HP:0000458 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anosmia (HP:0000458). HP:0000458 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000458 | Anosmia | Very frequent (99-80%)"
Orphanet lists anosmia as very frequent.
Lacrimal duct atresia HP:0000564 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lacrimal duct atresia (HP:0000564). HP:0000564 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38713859 SUPPORT Human Clinical
"Lacrimal drainage anomalies are secondary to absent nasolacrimal duct and usually present as dilated lacrimal sac or mucoceles."
The lacrimal-management review directly documents absent nasolacrimal ducts in BOSMA.
Hyposmia VERY_FREQUENT HP:0004409 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyposmia (HP:0004409). HP:0004409 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0004409 | Hyposmia | Very frequent (99-80%)"
Orphanet lists hyposmia as very frequent.
Other 18
Submucous cleft hard palate OCCASIONAL HP:0000176 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Submucous cleft hard palate (HP:0000176). HP:0000176 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000176 | Submucous cleft hard palate | Occasional (29-5%)"
Orphanet lists submucous cleft hard palate as occasional.
Abnormal midface morphology VERY_FREQUENT HP:0000309 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal midface morphology (HP:0000309). HP:0000309 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000309 | Abnormal midface morphology | Very frequent (99-80%)"
Orphanet lists abnormal midface morphology as very frequent.
Hypoplasia of the maxilla FREQUENT HP:0000327 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the maxilla (HP:0000327). HP:0000327 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000327 | Hypoplasia of the maxilla | Frequent (79-30%)"
Orphanet lists maxillary hypoplasia as frequent.
Anophthalmia FREQUENT HP:0000528 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anophthalmia (HP:0000528). HP:0000528 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000528 | Anophthalmia | Frequent (79-30%)"
Orphanet lists anophthalmia as frequent.
Iris coloboma FREQUENT HP:0000612 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Iris coloboma (HP:0000612). HP:0000612 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000612 | Iris coloboma | Frequent (79-30%)"
Orphanet lists iris coloboma as frequent.
Amblyopia FREQUENT HP:0000646 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Amblyopia (HP:0000646). HP:0000646 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000646 | Amblyopia | Frequent (79-30%)"
Orphanet lists amblyopia as frequent.
Tooth malposition VERY_FREQUENT HP:0000692 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tooth malposition (HP:0000692). HP:0000692 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000692 | Tooth malposition | Very frequent (99-80%)"
Orphanet lists tooth malposition as very frequent.
External genital hypoplasia VERY_FREQUENT HP:0003241 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is External genital hypoplasia (HP:0003241). HP:0003241 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0003241 | External genital hypoplasia | Very frequent (99-80%)"
Orphanet lists external genital hypoplasia as very frequent.
Failure of eruption of permanent teeth VERY_FREQUENT HP:0006352 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure of eruption of permanent teeth (HP:0006352). HP:0006352 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0006352 | Failure of eruption of permanent teeth | Very frequent (99-80%)"
Orphanet lists failure of eruption of permanent teeth as very frequent.
Paranasal sinus hypoplasia HP:0006784 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Paranasal sinus hypoplasia (HP:0006784). HP:0006784 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36968924 SUPPORT Human Clinical
"Her paranasal sinuses were ossified and underdeveloped."
Cross-sectional imaging directly documents underdeveloped paranasal sinuses.
Hypoplasia of penis VERY_FREQUENT HP:0008736 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of penis (HP:0008736). HP:0008736 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0008736 | Hypoplasia of penis | Very frequent (99-80%)"
Orphanet lists hypoplasia of penis as very frequent.
Abdominal wall muscle weakness FREQUENT HP:0009023 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal wall muscle weakness (HP:0009023). HP:0009023 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0009023 | Abdominal wall muscle weakness | Frequent (79-30%)"
Orphanet lists abdominal wall muscle weakness as frequent.
Aplasia/Hypoplasia involving the nose FREQUENT HP:0009924 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia/Hypoplasia involving the nose (HP:0009924). HP:0009924 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0009924 | Aplasia/Hypoplasia involving the nose | Frequent (79-30%)"
Orphanet lists nose aplasia/hypoplasia as frequent.
Aplasia of the nose VERY_FREQUENT HP:0009927 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia of the nose (HP:0009927). HP:0009927 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0009927 | Aplasia of the nose | Very frequent (99-80%)"
Orphanet lists aplasia of the nose as very frequent.
Single naris VERY_FREQUENT HP:0009932 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Single naris (HP:0009932). HP:0009932 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0009932 | Single naris | Very frequent (99-80%)"
Orphanet lists single naris as very frequent.
Dacryocystocele OCCASIONAL HP:0030752 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dacryocystocele (HP:0030752). HP:0030752 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0030752 | Dacryocystocele | Occasional (29-5%)"
Orphanet lists dacryocystocele as occasional.
Hypoplasia of the olfactory bulb VERY_FREQUENT HP:0040326 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the olfactory bulb (HP:0040326). HP:0040326 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0040326 | Hypoplasia of the olfactory bulb | Very frequent (99-80%)"
Orphanet lists olfactory bulb hypoplasia as very frequent.
Absent nares VERY_FREQUENT HP:0100596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent nares (HP:0100596). HP:0100596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0100596 | Absent nares | Very frequent (99-80%)"
Orphanet lists absent nares as very frequent.
🧬

Genetic Associations

1
SMCHD1 ATPase-domain missense variants (Heterozygous ATPase-domain missense variants, commonly de novo but sometimes inherited with variable expressivity)
Gene: SMCHD1 hgnc:29090 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SMCHD1 (hgnc:29090). hgnc:29090 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (6 references)
ORPHA:2250 SUPPORT Other
"SMCHD1 | structural maintenance of chromosomes flexible hinge domain containing 1 | hgnc:29090 | Disease-causing germline mutation(s) in"
Orphanet records SMCHD1 as a disease-causing germline gene.
PMID:28067911 SUPPORT Human Clinical
"missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied."
The discovery series directly identifies disease-causing SMCHD1 ATPase-domain missense variants.
PMID:28067909 SUPPORT Human Clinical
"Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain."
An independent sequencing study supports the high fraction of arhinia/BAMS probands with constrained SMCHD1 ATPase-domain missense variants.
+ 3 more references
🗃️

External Assertions

2
Orphanet BAMS structured disease record
Orphanet structured disease record ORPHA:2250
ORPHA:2250 supplies the disease definition, synonyms, inheritance, onset, prevalence, SMCHD1 gene association, and HPO phenotype-frequency rows used in this entry.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"SMCHD1 | structural maintenance of chromosomes flexible hinge domain containing 1 | hgnc:29090 | Disease-causing germline mutation(s) in"
Orphanet identifies SMCHD1 as the disease-causing germline gene for this BAMS record.
Orphanet legacy arrhinia-choanal atresia-microphthalmia record
Orphanet structured disease record ORPHA:1135
ORPHA:1135 is retained as a sparse legacy cross-reference-only record for arrhinia-choanal atresia-microphthalmia syndrome.
Show evidence (1 reference)
ORPHA:1135 SUPPORT Other
"Arrhinia-choanal atresia-microphthalmia syndrome"
Orphanet records the legacy syndrome name that MONDO includes among BAMS synonyms/xrefs.
💊

Medical Actions

6
Neonatal airway stabilization
Category: Therapeutic
Complete nasal obstruction requires immediate individualized airway planning. Oral or pharyngeal airway splinting may suffice in a stable newborn, whereas intubation followed by tracheostomy may be required for respiratory distress; the evidence is limited to case-based management.
Target Phenotypes: Aplasia of the nose HP:0009927 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Aplasia of the nose (HP:0009927). HP:0009927 is a phenotype from the Human Phenotype Ontology. Choanal atresia HP:0000453 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Choanal atresia (HP:0000453). HP:0000453 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33784779 SUPPORT Human Clinical
"Airway management was achieved by splinting through a Mayo tube which was subsequently replaced by a pharyngeal endotracheal tube without signs of respiratory failure."
A molecularly confirmed newborn was stabilized without immediate tracheostomy.
PMID:32100546 SUPPORT Human Clinical
"Upon birth, the patient was subsequently intubated, followed by tracheostomy due to complete nasal obstruction."
A second SMCHD1-positive infant required invasive airway stabilization.
Neonatal feeding adaptation
Category: Therapeutic Action: feeding therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is feeding therapy, annotated with Swallowing Therapy (NCIT:C156237). NCIT:C156237 is a clinical intervention from the NCI Thesaurus. Ontology label: Swallowing Therapy NCIT:C156237
Early feeding difficulty can be managed with enteral access when needed, drinking training, and adapted feeding equipment while coordination and growth are assessed.
Target Phenotypes: Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33784779 SUPPORT Human Clinical
"An orogastric tube was placed, and drinking training and a special pacifier improved coordination and drinking performance."
The neonatal case directly supports the described feeding measures.
Staged nasal and midface reconstruction
Category: Therapeutic Action: surgical repairNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical repair, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Selected patients may undergo staged midface advancement, tissue expansion, and nasal construction to address absent nasal and midface structures. Timing and technique are individualized because evidence comes from very small case series and early surgery can affect midfacial growth.
Target Phenotypes: Aplasia of the nose HP:0009927 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Aplasia of the nose (HP:0009927). HP:0009927 is a phenotype from the Human Phenotype Ontology. Abnormal midface morphology HP:0000309 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Abnormal midface morphology (HP:0000309). HP:0000309 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:36944600 SUPPORT Human Clinical
"A staged surgical approach was applied."
This case series directly supports staged surgical reconstruction.
PMID:36944600 SUPPORT Human Clinical
"nasal construction with a forehead flap that was placed over a costochondral framework derived from rib cartilage."
The case series describes nasal construction technique for congenital arhinia.
PMID:33784779 SUPPORT Human Clinical
"In the absence of respiratory problems and appropriate growth, however, there is no urgent indication for early plastic surgical treatment, given the inherent risks of sepsis and growth disorders in the midface."
The neonatal report supports individualized timing and cautions against automatic early reconstruction.
Customized postoperative nasal stenting
Category: Therapeutic Action: surgical repairNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical repair, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
A customized three-dimensional-printed silicone stent has been used after nasal-passage reconstruction to reduce restenosis while mucoepithelium regenerates. Evidence is a single congenital-arhinia case and does not establish comparative efficacy or BAMS-specific generalizability.
Target Phenotypes: Aplasia of the nose HP:0009927 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Aplasia of the nose (HP:0009927). HP:0009927 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30247752 SUPPORT Human Clinical
"Three years after stent removal, respiratory function, nasal passage structure, and external nose shape were maintained without additional medical care."
The three-year case follow-up documents durable anatomy and respiratory function after customized stenting.
clinicaltrials:NCT02559050 SUPPORT Human Clinical
"A 7-year-old arhinia patient receives nasal reconstruction with nasal cavity reconstruction and is aided with the application of a 3D-printed nasal stent to prevent nasal cavity constriction."
The registry summary documents the single-participant device intervention but not a BAMS genotype or comparative outcome.
Early multidisciplinary craniofacial, lacrimal, and endocrine follow-up
Category: Monitoring Action: clinical assessmentNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is clinical assessment, annotated with Clinical Evaluation (NCIT:C124351). NCIT:C124351 is a clinical intervention from the NCI Thesaurus. Ontology label: Clinical Evaluation NCIT:C124351
Coordinated follow-up should include genetics, plastic and craniofacial surgery, ophthalmic plastics, otorhinolaryngology, and endocrinology, with particular attention to lacrimal drainage anatomy and pubertal development. The best operation for complete bilateral absence of the nasal cavity remains uncertain.
Show evidence (1 reference)
PMID:38713859 SUPPORT Human Clinical
"A multidisciplinary team from the specialties of genetics, plastic surgery, ophthalmic plastics and reconstructive surgery, otorhinolaryngology, and endocrinology should get involved very early on for better continuity of care."
The lacrimal-management review explicitly recommends early multidisciplinary continuity.
Genetic counseling
Category: Counseling / Informational 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
Counseling addresses de novo and inherited SMCHD1 variants, autosomal dominant transmission, variable expressivity from anosmia to arhinia, and recurrence risk.
Show evidence (1 reference)
PMID:36944600 SUPPORT Human Clinical
"the variable expressivity ranging from anosmia to arhinia could improve clinical genetic screens for risk stratification of individuals with anosmia on passing on arhinia to their children."
This supports genetic counseling around SMCHD1 variable expressivity and reproductive risk.
🔬

Diagnosis

3
Clinical diagnostic criteria
Clinical diagnosis integrates arhinia or severe nasal hypoplasia, midface hypoplasia, ocular anomalies, anosmia or hyposmia, hypogonadotropic hypogonadism, and normal intellectual development.
clinical assessment NCIT:C124351 NCI Thesaurus (NCIT)
Results: A compatible congenital craniofacial, ocular, olfactory, and endocrine pattern supports BAMS.
Show evidence (1 reference)
PMID:36968924 SUPPORT Human Clinical
"Criteria for diagnosis consist of arhinia, midface hypoplasia (with a hypoplastic maxilla), hypogonadotropic hypogonadism, and normal intellectual abilities."
This case report states core clinical diagnostic criteria.
SMCHD1 molecular testing
Sequencing or targeted analysis of SMCHD1, especially exons encoding the extended ATPase domain, can support a molecular diagnosis and clarify familial recurrence risk.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: A heterozygous pathogenic SMCHD1 ATPase-domain missense variant supports molecular diagnosis.
Show evidence (2 references)
PMID:28067909 SUPPORT Human Clinical
"Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation"
Sequencing evidence supports SMCHD1 testing in arhinia/BAMS.
PMID:36944600 SUPPORT Human Clinical
"Targeted sequencing was carried out on DNA samples from the 2 affected patients, 1 anosmic and 1 healthy parent, to identify variants in exons 3 to 13 of SMCHD1"
Targeted SMCHD1 sequencing is directly used in a congenital arhinia pedigree.
Craniofacial and olfactory anatomy imaging
Cross-sectional craniofacial imaging assesses the absent or hypoplastic nose, paranasal sinuses, nasopharynx, olfactory bulbs, orbits, and surgical planning anatomy.
clinical assessment NCIT:C124351 NCI Thesaurus (NCIT)
Results: Absent or hypoplastic nasal, sinus, or olfactory-bulb structures support BAMS anatomy.
Show evidence (2 references)
PMID:6802865 SUPPORT Human Clinical
"Their nasal skeleton, demonstrated by tomoradiography, had grown in early embryological form."
The original clinical description used imaging to characterize the nasal skeleton.
PMID:36968924 SUPPORT Human Clinical
"Her paranasal sinuses were ossified and underdeveloped."
Imaging/anatomic assessment supports paranasal sinus involvement.
📈

Progression

3
Congenital onset
Age: Antenatal to neonatal
Nasal, ocular, olfactory, and midfacial malformations arise prenatally and may be detected by fetal imaging or recognized immediately after birth.
Show evidence (2 references)
ORPHA:2250 SUPPORT Other
"Age of onset: Antenatal"
Orphanet records antenatal onset.
ORPHA:2250 SUPPORT Other
"Age of onset: Neonatal"
Orphanet records neonatal onset.
Neonatal stabilization and feeding adaptation
Age: Birth and early infancy
Complete nasal obstruction can make airway stabilization the immediate priority. Feeding coordination may initially require enteral access, training, and adapted equipment. Need for intubation or tracheostomy varies, and early reconstructive surgery is not automatically indicated when breathing and growth are adequate.
Show evidence (2 references)
PMID:33784779 SUPPORT Human Clinical
"Airway management was achieved by splinting through a Mayo tube which was subsequently replaced by a pharyngeal endotracheal tube without signs of respiratory failure."
The molecularly confirmed neonatal case documents non-tracheostomy airway stabilization.
PMID:33784779 SUPPORT Human Clinical
"An orogastric tube was placed, and drinking training and a special pacifier improved coordination and drinking performance."
The same case documents early feeding adaptation.
Childhood, puberty, and adult course
Age: Childhood through adulthood
Congenital structural and sensory manifestations persist. Reconstructive choices are individualized as the face grows; absent or delayed sexual maturation may become evident around puberty. Adult outcome can be favorable with intact cognition and individualized medical and psychosocial support, but systematic longitudinal cohorts are unavailable.
Show evidence (2 references)
PMID:34194860 SUPPORT Human Clinical
"His successful adjustment even in the face of significant early life challenges demonstrates that positive outcomes are attainable for individuals with significant developmental errors."
A lifespan case documents favorable adult adaptation despite major congenital and endocrine manifestations.
PMID:36968924 SUPPORT Human Clinical
"It is characterized by nasal and ophthalmic abnormalities, as well as disturbances in puberty and sexual development."
The adult report supports later recognition of reproductive-axis manifestations.
📊

Prevalence

2
Worldwide
Point Prevalence ≤0.1 per 100,000 <1 in 1,000,000
Orphanet classifies BAMS as ultra-rare worldwide.
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:6802865"
Orphanet reports worldwide point prevalence below one per million.
Published worldwide literature through 2023
Cases In Literature Ultra Rare
A 2023 case report estimated that approximately 100 cases had been identified worldwide. This is a literature-case count rather than a denominator-based prevalence estimate and should not be combined numerically with the Orphanet point-prevalence class.
Show evidence (1 reference)
PMID:36968924 SUPPORT Human Clinical
"Bosma arhinia microphthalmia syndrome (BAMS) is a rare condition, with about 100 cases identified worldwide."
The report provides a literature-level approximate case count.
⚖️

Clinical Burden

High
Complete or severe nasal agenesis can create neonatal airway and feeding risk, while visual impairment, altered speech and breathing, endocrine and reproductive consequences, and staged craniofacial care impose substantial lifelong functional and multidisciplinary burden. Expression is variable: some carriers have anosmia alone and adults with severe anatomy can achieve good adaptation, so a disease-level HIGH rating does not imply uniformly poor outcome.
Show evidence (2 references)
PMID:33784779 SUPPORT Human Clinical
"Initial stabilization after birth is often a challenge in patients with nasal agenesis. They are often intubated immediately postpartum and electively tracheotomized."
The neonatal report documents potentially intensive initial airway care.
PMID:36968924 SUPPORT Human Clinical
"On presentation, she was noted to have congenital arhinia, bilateral microphthalmia, vision loss, mouth-breathing, an unclear speaking voice, a high arched or cleft palate, and a hypoplastic maxilla."
The adult case illustrates persistent multisystem functional consequences.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Bosma Arhinia Microphthalmia Syndrome:

Arrhinencephaly and holoprosencephaly spectrum
Overlapping Features Severe midline facial malformations can suggest arrhinencephaly or a holoprosencephaly-spectrum disorder. The original BAMS patients instead retained the medial falx attachment and had normal intelligence, supporting a distinct developmental pattern with potential for normal cognition.
Distinguishing Features
  • Preserved medial structure of attachment of the falx cerebri argues against arrhinencephaly in the original syndrome.
  • Normal forebrain anatomy and preserved intellectual development favor BAMS over severe holoprosencephaly-spectrum disease.
  • Heterozygous SMCHD1 ATPase-domain variation supports BAMS when the phenotype is compatible.
Show evidence (1 reference)
PMID:6802865 SUPPORT Human Clinical
"These patients do not fall within the spectrum of arrhinencephaly because of the presence of medial structure of attachment of the falx cerebri and because of their normal intelligence."
The original report explicitly states and anatomically explains this differential.
📊

Related Datasets

1
Neural crest stem-cell transcriptomes from BAMS, FSHD, and control iPSC lines geo:GSE173251
Bulk RNA-seq of human induced-pluripotent-stem-cell-derived neural crest stem cells from BAMS, FSHD1, FSHD2, and control samples. The dataset underlies the extracellular-matrix, receptor-signaling, adhesion, and migration analysis used in the BAMS cellular mechanism.
human BULK RNA SEQ n=12 Illumina HiSeq 4000
iPSC-derived neural crest stem cell CL:0011012 Cell Ontology (CL) Relation: this dataset samples this sample type This dataset samples iPSC-derived neural crest stem cell, annotated with neural crest cell (CL:0011012). CL:0011012 is a sample type from the Cell Ontology.
Conditions: BAMS patient-derived neural crest stem cells FSHD1 patient-derived neural crest stem cells FSHD2 patient-derived neural crest stem cells Control neural crest stem cells
PMID:34209568
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE173251 SUPPORT In Vitro
"To gain further insights into the specificity of SMCHD1 mutations and identify pathways associated with the disease phenotypes, we have derived induced pluripotent stem cells from patients affected with BAMS or FSHD. We then differentiated these cells into neural crest stem cells, corresponding..."
The GEO record supplies the accession, organism, cell model, disease comparisons, and assay.
🔬

Clinical Trials

1
NCT02559050 NOT_APPLICABLE COMPLETED
Completed single-participant observational/device study of nasal-cavity reconstruction supported by a customized three-dimensional-printed stent in congenital arhinia. The registry does not establish a BAMS or SMCHD1 diagnosis and does not provide comparative efficacy evidence.
Target Phenotypes: Aplasia of the nose HP:0009927 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Aplasia of the nose (HP:0009927). HP:0009927 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT02559050 SUPPORT Human Clinical
"A 7-year-old arhinia patient receives nasal reconstruction with nasal cavity reconstruction and is aided with the application of a 3D-printed nasal stent to prevent nasal cavity constriction."
The registry supports phenotype-targeted relevance but not disease-specific assignment or efficacy.
🐁

Animal Models

2
Embryos assayed with BAMS-associated SMCHD1 ATPase-domain missense variants Xenopus laevis
Biochemical and Xenopus assays show that many BAMS variants increase SMCHD1 ATPase activity and reduce eye size. This supports altered-protein function and an ocular-developmental effect, but it does not establish a universal mechanism for every allele or reproduce the full human syndrome.
Decreased eye size
Species
Xenopus laevis
Genotype
Embryos assayed with BAMS-associated SMCHD1 ATPase-domain missense variants
Genes
SMCHD1 hgnc:29090 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns SMCHD1 (hgnc:29090). hgnc:29090 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:29748383 SUPPORT Model Organism
"many BAMS mutations can result in elevated ATPase activity and decreased eye size in Xenopus"
The study directly couples variant biochemistry to an ocular phenotype in Xenopus.
CRISPR/Cas9-mediated alteration of smchd1 Danio rerio
CRISPR alteration of zebrafish smchd1 produced arhinia-relevant phenotypes, providing developmental support for SMCHD1 involvement without fully recapitulating human BAMS.
Arhinia-relevant craniofacial phenotypes
Species
Danio rerio
Genotype
CRISPR/Cas9-mediated alteration of smchd1
Genes
smchd1 hgnc:29090 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns smchd1 (hgnc:29090). hgnc:29090 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:28067909 SUPPORT Model Organism
"CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes."
The discovery cohort provides the direct zebrafish result.
{ }

Source YAML

click to show 
name: Bosma Arhinia Microphthalmia Syndrome
creation_date: "2026-05-07T07:20:00Z"
description: >-
  Bosma arhinia microphthalmia syndrome is an ultra-rare congenital
  malformation syndrome characterized by arhinia or severe nasal hypoplasia,
  choanal or nasopharyngeal obstruction, ocular hypoplasia or microphthalmia,
  olfactory and taste impairment, dental and midface anomalies, and
  hypogonadotropic hypogonadism with otherwise usually preserved intelligence.
  Most molecularly explained cases involve heterozygous missense variants in
  the ATPase domain of SMCHD1. Variants are commonly de novo, although inherited
  disease with markedly variable expressivity is documented. Patient-derived
  cell studies implicate both impaired neural-crest migration and defective
  cranial-placode differentiation and adhesion in disrupted nasal and
  craniofacial development.
category: Mendelian
disease_term:
  preferred_term: arhinia, choanal atresia, and microphthalmia
  term:
    id: MONDO:0011323
    label: arhinia, choanal atresia, and microphthalmia
parents:
- Multiple congenital anomalies/dysmorphic syndrome without intellectual disability
- Congenital hypogonadotropic hypogonadism
synonyms:
- BAMS
- Bosma arhinia-microphthalmia syndrome
- Bosma-Henkin-Christiansen syndrome
- Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome
- Arrhinia-choanal atresia-microphthalmia syndrome
notes: >-
  MONDO:0011323 is the current aggregate disease concept and is the identifier
  used by the definitive ClinGen SMCHD1 assertion. In the local Orphadata
  snapshot, ORPHA:2250 contains the usable structured disease record with
  definition, inheritance, SMCHD1, onset, epidemiology, and HPO phenotype rows;
  ORPHA:1135 is a sparse legacy cross-reference record only. Those cached
  Orphanet records retain obsolete exact cross-references to MONDO:0016393 and
  MONDO:0015238, respectively, so they are not used as the current MONDO mapping.
external_assertions:
- name: Orphanet BAMS structured disease record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:2250
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=2250
  description: >-
    ORPHA:2250 supplies the disease definition, synonyms, inheritance, onset,
    prevalence, SMCHD1 gene association, and HPO phenotype-frequency rows used
    in this entry.
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SMCHD1 | structural maintenance of chromosomes flexible hinge domain containing 1 | hgnc:29090 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies SMCHD1 as the disease-causing germline gene for this BAMS record.
- name: Orphanet legacy arrhinia-choanal atresia-microphthalmia record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:1135
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=1135
  description: >-
    ORPHA:1135 is retained as a sparse legacy cross-reference-only record for
    arrhinia-choanal atresia-microphthalmia syndrome.
  evidence:
  - reference: ORPHA:1135
    reference_title: "Arrhinia-choanal atresia-microphthalmia syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Arrhinia-choanal atresia-microphthalmia syndrome"
    explanation: Orphanet records the legacy syndrome name that MONDO includes among BAMS synonyms/xrefs.
definitions:
- name: Orphanet BAMS definition
  definition_type: OTHER
  description: >-
    The Orphanet record defines BAMS by severe nasal hypoplasia, ocular
    hypoplasia, hyposmia, hypogeusia, and hypogonadotropic hypogonadism.
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This syndrome is characterized by the association of severe nasal hypoplasia, hypoplasia of the eyes, hyposmia, hypogeusia and hypogonadotropic hypogonadism."
    explanation: Orphanet provides the structured clinical definition.
  - reference: PMID:28067911
    reference_title: De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects."
    explanation: The SMCHD1 discovery series supports the core arhinia and ocular defect definition.
inheritance:
- name: Autosomal dominant inheritance
  expressivity: VARIABLE
  description: >-
    Expression ranges from anosmia-only carriers to complete arhinia with
    ocular, craniofacial, and reproductive manifestations.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance.
  - reference: PMID:28067911
    reference_title: De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All mutations were de novo where parental DNA was available."
    explanation: The discovery series supports predominantly de novo heterozygous SMCHD1 variants.
  - reference: PMID:36944600
    reference_title: Nasal Construction in Congenital Arhinia Due to Novel SMCHD1 Gene Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected patients and anosmic parent were found to have a novel SMCHD1 gene variant p.E473V."
    explanation: >-
      The affected pedigree documents inherited SMCHD1-associated disease and
      variable expression from anosmia in a parent to arhinia in offspring.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_high: 0.1
  notes: Orphanet classifies BAMS as ultra-rare worldwide.
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:6802865"
    explanation: Orphanet reports worldwide point prevalence below one per million.
- population: Published worldwide literature through 2023
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A 2023 case report estimated that approximately 100 cases had been
    identified worldwide. This is a literature-case count rather than a
    denominator-based prevalence estimate and should not be combined
    numerically with the Orphanet point-prevalence class.
  evidence:
  - reference: PMID:36968924
    reference_title: "Bosma Arhinia Microphthalmia Syndrome (BAMS): First Report from Vietnam."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bosma arhinia microphthalmia syndrome (BAMS) is a rare condition, with about 100 cases identified worldwide."
    explanation: The report provides a literature-level approximate case count.
progression:
- phase: Congenital onset
  age_range: Antenatal to neonatal
  notes: >-
    Nasal, ocular, olfactory, and midfacial malformations arise prenatally and
    may be detected by fetal imaging or recognized immediately after birth.
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Antenatal"
    explanation: Orphanet records antenatal onset.
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Neonatal"
    explanation: Orphanet records neonatal onset.
- phase: Neonatal stabilization and feeding adaptation
  age_range: Birth and early infancy
  notes: >-
    Complete nasal obstruction can make airway stabilization the immediate
    priority. Feeding coordination may initially require enteral access,
    training, and adapted equipment. Need for intubation or tracheostomy varies,
    and early reconstructive surgery is not automatically indicated when
    breathing and growth are adequate.
  evidence:
  - reference: PMID:33784779
    reference_title: "[A Newborn Suffering from Arhinia: Neonatologic Challenges During Primary Care of the Newborn With Bosma Arhinia Microphthalmia Syndrome (BAMS)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Airway management was achieved by splinting through a Mayo tube which was subsequently replaced by a pharyngeal endotracheal tube without signs of respiratory failure.
    explanation: The molecularly confirmed neonatal case documents non-tracheostomy airway stabilization.
  - reference: PMID:33784779
    reference_title: "[A Newborn Suffering from Arhinia: Neonatologic Challenges During Primary Care of the Newborn With Bosma Arhinia Microphthalmia Syndrome (BAMS)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An orogastric tube was placed, and drinking training and a special pacifier improved coordination and drinking performance.
    explanation: The same case documents early feeding adaptation.
- phase: Childhood, puberty, and adult course
  age_range: Childhood through adulthood
  notes: >-
    Congenital structural and sensory manifestations persist. Reconstructive
    choices are individualized as the face grows; absent or delayed sexual
    maturation may become evident around puberty. Adult outcome can be favorable
    with intact cognition and individualized medical and psychosocial support,
    but systematic longitudinal cohorts are unavailable.
  evidence:
  - reference: PMID:34194860
    reference_title: "Good Outcome for an Individual with Severe Facial Anomalies and Hypogonadotropic Hypogonadism: A Consequence of His Cognitive Function, Pragmatic Approach, and Temperament."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His successful adjustment even in the face of significant early life challenges demonstrates that positive outcomes are attainable for individuals with significant developmental errors.
    explanation: A lifespan case documents favorable adult adaptation despite major congenital and endocrine manifestations.
  - reference: PMID:36968924
    reference_title: "Bosma Arhinia Microphthalmia Syndrome (BAMS): First Report from Vietnam."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is characterized by nasal and ophthalmic abnormalities, as well as disturbances in puberty and sexual development.
    explanation: The adult report supports later recognition of reproductive-axis manifestations.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Complete or severe nasal agenesis can create neonatal airway and feeding
    risk, while visual impairment, altered speech and breathing, endocrine and
    reproductive consequences, and staged craniofacial care impose substantial
    lifelong functional and multidisciplinary burden. Expression is variable:
    some carriers have anosmia alone and adults with severe anatomy can achieve
    good adaptation, so a disease-level HIGH rating does not imply uniformly
    poor outcome.
  evidence:
  - reference: PMID:33784779
    reference_title: "[A Newborn Suffering from Arhinia: Neonatologic Challenges During Primary Care of the Newborn With Bosma Arhinia Microphthalmia Syndrome (BAMS)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Initial stabilization after birth is often a challenge in patients with nasal agenesis. They are often intubated immediately postpartum and electively tracheotomized.
    explanation: The neonatal report documents potentially intensive initial airway care.
  - reference: PMID:36968924
    reference_title: "Bosma Arhinia Microphthalmia Syndrome (BAMS): First Report from Vietnam."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On presentation, she was noted to have congenital arhinia, bilateral microphthalmia, vision loss, mouth-breathing, an unclear speaking voice, a high arched or cleft palate, and a hypoplastic maxilla.
    explanation: The adult case illustrates persistent multisystem functional consequences.
genetic:
- name: SMCHD1 ATPase-domain missense variants
  gene_term:
    preferred_term: SMCHD1
    term:
      id: hgnc:29090
      label: SMCHD1
  association: Heterozygous ATPase-domain missense variants, commonly de novo but sometimes inherited with variable expressivity
  relationship_type: CAUSATIVE
  notes: >-
    BAMS-associated variants cluster in the SMCHD1 extended ATPase domain and
    are phenotypically distinct from the broader FSHD2-associated SMCHD1
    spectrum. Many tested BAMS variants increase ATPase activity, but this is
    not established for every allele and shared variants or methylation effects
    complicate a universal gain-of-function model.
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SMCHD1 | structural maintenance of chromosomes flexible hinge domain containing 1 | hgnc:29090 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records SMCHD1 as a disease-causing germline gene.
  - reference: PMID:28067911
    reference_title: De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied."
    explanation: The discovery series directly identifies disease-causing SMCHD1 ATPase-domain missense variants.
  - reference: PMID:28067909
    reference_title: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain."
    explanation: An independent sequencing study supports the high fraction of arhinia/BAMS probands with constrained SMCHD1 ATPase-domain missense variants.
  - reference: PMID:31243061
    reference_title: SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localisation of variants in the ATPase domain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in BAMS, pathogenic variants are restricted to the extended ATPase domain."
    explanation: A mutation-spectrum study supports BAMS-specific ATPase-domain localization.
  - reference: PMID:36944600
    reference_title: Nasal Construction in Congenital Arhinia Due to Novel SMCHD1 Gene Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected patients and anosmic parent were found to have a novel SMCHD1 gene variant p.E473V."
    explanation: The inherited pedigree prevents modeling every BAMS-associated variant as de novo.
  - reference: CGGV:assertion_b2f2b442-3afa-4427-8e9b-3dc2485790aa-2022-05-20T042139.263Z
    reference_title: "SMCHD1 / arhinia, choanal atresia, and microphthalmia (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SMCHD1 | HGNC:29090 | arhinia, choanal atresia, and microphthalmia | MONDO:0011323 | AD | Definitive"
    explanation: ClinGen classifies the SMCHD1-arhinia, choanal atresia, and microphthalmia gene-disease relationship as definitive with autosomal dominant inheritance.
pathophysiology:
- name: SMCHD1 ATPase-domain chromatin regulatory alteration
  description: >-
    BAMS-associated heterozygous missense variants cluster in the extended
    SMCHD1 ATPase domain and alter ATP hydrolysis, protein conformation, and
    local methylation. Many tested BAMS alleles increase ATPase activity, but
    shared alleles and incomplete functional testing make a universal
    gain-of-function label premature.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  genes:
  - preferred_term: SMCHD1
    term:
      id: hgnc:29090
      label: SMCHD1
  biological_processes:
  - preferred_term: chromatin organization
    modifier: ABNORMAL
    term:
      id: GO:0006325
      label: chromatin organization
  evidence:
  - reference: PMID:29748383
    reference_title: FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      many BAMS mutations can result in elevated ATPase activity and decreased eye size in Xenopus
    explanation: Functional testing supports increased ATPase activity for many, but not necessarily all, BAMS alleles.
  - reference: PMID:31243061
    reference_title: SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localisation of variants in the ATPase domain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BAMS-associated SMCHD1 variants result in quantifiable local DNA hypomethylation."
    explanation: Patient methylation analyses establish an epigenetic consequence without resolving a single allelic mechanism.
  downstream:
  - target: Neural crest transcriptional, adhesion, and migration dysregulation
    description: Altered SMCHD1 regulation changes neural-crest extracellular-matrix, receptor-signaling, and migration programs.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered transcription of extracellular-matrix, PDGFR, ERBB3, integrin, and AKT-pathway genes
    evidence:
    - reference: PMID:34209568
      reference_title: AKT Signaling Modifies the Balance between Cell Proliferation and Migration in Neural Crest Cells from Patients Affected with Bosma Arhinia and Microphthalmia Syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        BAMS NCSCs are characterized by an overall decrease in the expression of a number genes required for NCSC migration
      explanation: Patient-derived neural-crest cells connect BAMS-associated SMCHD1 variation to a migration-gene program.
  - target: Cranial placode differentiation and adhesion defect
    description: Patient SMCHD1 variants are associated with impaired differentiation toward cranial-placode cells and altered adhesion programs.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered placodal transcriptome and DNA methylome
    - dysregulated cell-adhesion programs
    evidence:
    - reference: PMID:41962546
      reference_title: Cranial placode differentiation defect in individuals born without a nose.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, we differentiated patient-derived induced pluripotent stem cells toward the cranial placode lineage and found that they exhibited significant differentiation defects.
      explanation: The 2026 patient-derived-cell study directly supports the placodal differentiation branch.
  - target: Ocular developmental disruption
    description: SMCHD1 ATPase-domain variants are linked to ocular malformation through incompletely defined developmental intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29748383
      reference_title: FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        many BAMS mutations can result in elevated ATPase activity and decreased eye size in Xenopus
      explanation: Xenopus eye-size effects support an ocular branch, but the human developmental intermediates remain unresolved.
  - target: GnRH deficiency and variable reproductive-axis development
    description: The route from SMCHD1 dysregulation to GnRH deficiency is unresolved and does not uniformly require absent olfactory structures.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32034419
      reference_title: Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function
      explanation: The human cohort supports a reproductive-axis branch while cautioning against a simple olfactory-dependence model.
  - target: Unresolved body-wall developmental consequences
    description: Inguinal hernia and abdominal-wall weakness are recurrent clinical associations, but their route from SMCHD1 is unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16353241
      reference_title: Bosma arhinia microphthalmia syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence.
      explanation: The clinical association is established, but no intervening body-wall mechanism is defined.
- name: Neural crest transcriptional, adhesion, and migration dysregulation
  description: >-
    Patient-derived neural crest stem cells show altered extracellular-matrix,
    cell-adhesion, PDGFR, ERBB3, integrin, and PI3K/AKT programs together with
    reduced migration. This is a plausible contributor to craniofacial
    malformation rather than a fully demonstrated in-vivo sequence.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: neural crest cell
    term:
      id: CL:0011012
      label: neural crest cell
  biological_processes:
  - preferred_term: neural crest cell migration
    modifier: DECREASED
    term:
      id: GO:0001755
      label: neural crest cell migration
  - preferred_term: cell adhesion
    modifier: ABNORMAL
    term:
      id: GO:0007155
      label: cell adhesion
  evidence:
  - reference: PMID:34209568
    reference_title: AKT Signaling Modifies the Balance between Cell Proliferation and Migration in Neural Crest Cells from Patients Affected with Bosma Arhinia and Microphthalmia Syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      downregulation of PDGFRα or β and ERBB3, cMET and integrins or changes in ECM composition converged toward a defect in cell–cell contacts, cell-substratum adhesion, and cell migration in BAMS NCSCs.
    explanation: The patient-derived model identifies convergent adhesion and migration defects.
  downstream:
  - target: Disrupted nasal, olfactory, and midfacial development
    description: Reduced neural-crest migration is proposed to impair craniofacial morphogenesis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced cranial neural-crest migration and altered extracellular-matrix interactions
    evidence:
    - reference: PMID:34209568
      reference_title: AKT Signaling Modifies the Balance between Cell Proliferation and Migration in Neural Crest Cells from Patients Affected with Bosma Arhinia and Microphthalmia Syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "defects in neural crest migration might contribute to the craniofacial anomalies in BAMS."
      explanation: The authors explicitly frame neural-crest migration as a contributing, not exclusive, mechanism.
- name: Cranial placode differentiation and adhesion defect
  description: >-
    BAMS patient-derived induced pluripotent stem cells differentiate poorly
    toward the cranial-placode lineage and show transcriptomic and methylomic
    dysregulation of cell adhesion without overt apoptosis.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: ectodermal placode development
    modifier: DECREASED
    term:
      id: GO:0071696
      label: ectodermal placode development
  - preferred_term: cell adhesion
    modifier: ABNORMAL
    term:
      id: GO:0007155
      label: cell adhesion
  evidence:
  - reference: PMID:41962546
    reference_title: Cranial placode differentiation defect in individuals born without a nose.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Combined transcriptome and DNA methylome analyses further revealed dysregulation in cell adhesion but without overt apoptosis.
    explanation: The 2026 study defines the placodal adhesion phenotype in patient-derived cells.
  downstream:
  - target: Disrupted nasal, olfactory, and midfacial development
    description: Impaired cranial-placode differentiation and adhesion provide a second human-cell route to failed nasal development.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired placodal differentiation
    - dysregulated placodal cell adhesion
    evidence:
    - reference: PMID:41962546
      reference_title: Cranial placode differentiation defect in individuals born without a nose.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Together our research suggests that BAMS is caused by impaired differentiation to cranial placode cells and changes in cell adhesion
      explanation: The study directly proposes placodal differentiation and adhesion as a cellular basis of BAMS.
- name: Disrupted nasal, olfactory, and midfacial development
  description: >-
    Neural-crest and cranial-placode abnormalities converge on deficient
    development of the external nose, nares, nasal airway, paranasal sinuses,
    olfactory structures, palate, maxilla, teeth, and adjacent lacrimal anatomy.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: nose development
    modifier: DECREASED
    term:
      id: GO:0043584
      label: nose development
  evidence:
  - reference: PMID:41962546
    reference_title: Cranial placode differentiation defect in individuals born without a nose.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The embryonic development of the nose involves direct contributions from both the neural crest and cranial placodes.
    explanation: The current cellular study supports convergence of both developmental lineages.
  - reference: PMID:36968924
    reference_title: "Bosma Arhinia Microphthalmia Syndrome (BAMS): First Report from Vietnam."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "absence of paranasal sinuses and olfactory bulbs."
    explanation: Human anatomy confirms downstream nasal, sinus, and olfactory structural disruption.
  downstream:
  - target: Absent nares
    causal_link_type: DIRECT
    evidence: &nasal_midface_manifestation_evidence
    - reference: ORPHA:2250
      reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This syndrome is characterized by the association of severe nasal hypoplasia, hypoplasia of the eyes, hyposmia, hypogeusia and hypogonadotropic hypogonadism.
      explanation: Orphanet establishes the core nasal, ocular, olfactory, taste, and endocrine manifestation set.
    - reference: PMID:36968924
      reference_title: "Bosma Arhinia Microphthalmia Syndrome (BAMS): First Report from Vietnam."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Additional important findings are microphthalmia with or without coloboma, anosmia, maxillary hypoplasia, a high-arched palate, and absence of paranasal sinuses and olfactory bulbs.
      explanation: The clinical report supports the connected nasal, olfactory, midfacial, palatal, and ocular manifestations.
    - reference: PMID:16353241
      reference_title: Bosma arhinia microphthalmia syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence.
      explanation: The syndrome review supports the broader clinical connections.
  - target: Aplasia of the nose
    causal_link_type: DIRECT
    evidence: *nasal_midface_manifestation_evidence
  - target: Aplasia/Hypoplasia involving the nose
    causal_link_type: DIRECT
    evidence: *nasal_midface_manifestation_evidence
  - target: Single naris
    causal_link_type: DIRECT
    evidence: *nasal_midface_manifestation_evidence
  - target: Choanal atresia
    causal_link_type: DIRECT
    evidence: *nasal_midface_manifestation_evidence
  - target: Anosmia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - absent or hypoplastic olfactory bulbs and nasal olfactory structures
    evidence: *nasal_midface_manifestation_evidence
  - target: Hyposmia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - hypoplastic olfactory structures
    evidence: *nasal_midface_manifestation_evidence
  - target: Hypoplasia of the olfactory bulb
    causal_link_type: DIRECT
    evidence: *nasal_midface_manifestation_evidence
  - target: Abnormal midface morphology
    causal_link_type: DIRECT
    evidence: *nasal_midface_manifestation_evidence
  - target: Hypertelorism
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered midfacial morphogenesis
    evidence:
    - reference: PMID:33784779
      reference_title: "[A Newborn Suffering from Arhinia: Neonatologic Challenges During Primary Care of the Newborn With Bosma Arhinia Microphthalmia Syndrome (BAMS)]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In addition to a complete nasal agenesis, hypertelorism, a Gothic palate, bilateral microphthalmus, and iris coloboma were found.
      explanation: A molecularly confirmed neonatal BAMS case directly documents hypertelorism.
  - target: Hypoplasia of the maxilla
    causal_link_type: DIRECT
    evidence: *nasal_midface_manifestation_evidence
  - target: Cleft palate
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered midfacial and palatal morphogenesis
    evidence: *nasal_midface_manifestation_evidence
  - target: Submucous cleft hard palate
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered palatal morphogenesis
    evidence: *nasal_midface_manifestation_evidence
  - target: Bifid uvula
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered palatal morphogenesis
    evidence: *nasal_midface_manifestation_evidence
  - target: High palate
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered midfacial and palatal morphogenesis
    evidence: *nasal_midface_manifestation_evidence
  - target: Abnormality of taste sensation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *nasal_midface_manifestation_evidence
  - target: Paranasal sinus hypoplasia
    causal_link_type: DIRECT
    evidence: *nasal_midface_manifestation_evidence
  - target: Failure of eruption of permanent teeth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: &dental_manifestation_evidence
    - reference: ORPHA:2250
      reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0006352 | Failure of eruption of permanent teeth | Very frequent (99-80%)"
      explanation: Orphanet directly records failure of permanent-tooth eruption.
    - reference: ORPHA:2250
      reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000692 | Tooth malposition | Very frequent (99-80%)"
      explanation: Orphanet directly records tooth malposition.
  - target: Tooth malposition
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *dental_manifestation_evidence
  - target: Dacryocystocele
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - absent nasolacrimal duct
    evidence:
    - reference: PMID:38713859
      reference_title: Dilemmas in the management of lacrimal drainage anomalies in BOSMA (congenital arhinia-microphthalmia) syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Lacrimal drainage anomalies are secondary to absent nasolacrimal duct and usually present as dilated lacrimal sac or mucoceles.
      explanation: The review supplies the anatomical intermediate connecting arhinia to lacrimal-sac dilation.
  - target: Lacrimal duct atresia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38713859
      reference_title: Dilemmas in the management of lacrimal drainage anomalies in BOSMA (congenital arhinia-microphthalmia) syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Lacrimal drainage anomalies are secondary to absent nasolacrimal duct and usually present as dilated lacrimal sac or mucoceles.
      explanation: The review directly identifies absent nasolacrimal duct as the anatomical lesion.
  - target: Feeding difficulties
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - neonatal oral-airway coordination difficulty
    evidence:
    - reference: PMID:33784779
      reference_title: "[A Newborn Suffering from Arhinia: Neonatologic Challenges During Primary Care of the Newborn With Bosma Arhinia Microphthalmia Syndrome (BAMS)]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        An orogastric tube was placed, and drinking training and a special pacifier improved coordination and drinking performance.
      explanation: The molecularly confirmed neonatal case connects altered craniofacial anatomy with early feeding support needs.
- name: Ocular developmental disruption
  conforms_to: "ocular_morphogenesis_failure#Disrupted Optic Cup and Globe Morphogenesis"
  description: >-
    BAMS includes a variable ocular-developmental spectrum from microphthalmia
    or anophthalmia to coloboma, cataract, optic atrophy, amblyopia, and visual
    loss. Xenopus data support altered eye development, but the precise human
    cellular route from SMCHD1 remains unresolved.
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: eye morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0048592
      label: eye morphogenesis
  - preferred_term: camera-type eye morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0048593
      label: camera-type eye morphogenesis
  locations:
  - preferred_term: eye
    term:
      id: UBERON:0000970
      label: eye
  evidence:
  - reference: PMID:29748383
    reference_title: FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      many BAMS mutations can result in elevated ATPase activity and decreased eye size in Xenopus
    explanation: The model supports altered eye development but does not reproduce the full human ocular spectrum.
  downstream:
  - target: Microphthalmia
    causal_link_type: DIRECT
    evidence: &ocular_manifestation_evidence
    - reference: PMID:6802865
      reference_title: "Hypoplasia of the nose and eyes, hyposmia, hypogeusia, and hypogonadotrophic hypogonadism in two males."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Each patient had impaired visual function with cataracts and colobomata.
      explanation: The original report directly documents structural eye disease and impaired visual function.
    - reference: ORPHA:2250
      reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This syndrome is characterized by the association of severe nasal hypoplasia, hypoplasia of the eyes, hyposmia, hypogeusia and hypogonadotropic hypogonadism.
      explanation: Orphanet establishes ocular hypoplasia as a defining manifestation.
  - target: Anophthalmia
    causal_link_type: DIRECT
    evidence: *ocular_manifestation_evidence
  - target: Amblyopia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - congenital structural eye abnormality
    evidence: *ocular_manifestation_evidence
  - target: Blindness
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - severe congenital ocular malformation
    evidence: *ocular_manifestation_evidence
  - target: Visual loss
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - microphthalmia, coloboma, cataract, or optic-nerve involvement
    evidence: *ocular_manifestation_evidence
  - target: Optic atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *ocular_manifestation_evidence
  - target: Iris coloboma
    causal_link_type: DIRECT
    evidence: *ocular_manifestation_evidence
  - target: Cataract
    causal_link_type: DIRECT
    evidence: *ocular_manifestation_evidence
- name: GnRH deficiency and variable reproductive-axis development
  description: >-
    Congenital arhinia is strongly associated with absent or reduced pulsatile
    GnRH activity, especially in males, but some females retain spontaneous
    pubertal development or a normal reproductive axis. Human data therefore
    support association rather than a uniform olfactory-dependent migration
    failure.
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: gonadotropin secretion
    modifier: DECREASED
    term:
      id: GO:0032274
      label: gonadotropin secretion
  evidence:
  - reference: PMID:32034419
    reference_title: Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity.
    explanation: Detailed phenotyping directly establishes GnRH deficiency in affected males.
  - reference: PMID:32034419
    reference_title: Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis.
    explanation: Female findings establish clinically important reproductive-axis variability.
  downstream:
  - target: Hypogonadotropic hypogonadism
    causal_link_type: DIRECT
    evidence: &reproductive_manifestation_evidence
    - reference: PMID:32034419
      reference_title: Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency
      explanation: Human endocrine phenotyping directly supports hypogonadotropic hypogonadism.
    - reference: ORPHA:2250
      reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This syndrome is characterized by the association of severe nasal hypoplasia, hypoplasia of the eyes, hyposmia, hypogeusia and hypogonadotropic hypogonadism.
      explanation: Orphanet defines hypogonadotropic hypogonadism as a core manifestation.
  - target: Hypogonadism
    causal_link_type: DIRECT
    evidence: *reproductive_manifestation_evidence
  - target: External genital hypoplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - deficient gonadotropin and gonadal steroid signaling
    evidence: *reproductive_manifestation_evidence
  - target: Hypoplasia of penis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - deficient gonadotropin and androgen signaling
    evidence: *reproductive_manifestation_evidence
  - target: Cryptorchidism
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - deficient fetal gonadotropin and androgen signaling
    evidence: *reproductive_manifestation_evidence
  - target: Gynecomastia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *reproductive_manifestation_evidence
- name: Unresolved body-wall developmental consequences
  description: >-
    Inguinal hernia and abdominal-wall weakness recur in structured and
    historical BAMS descriptions, but no disease-specific molecular or cellular
    route currently explains them.
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:6802865
    reference_title: "Hypoplasia of the nose and eyes, hyposmia, hypogeusia, and hypogonadotrophic hypogonadism in two males."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each patient had bilateral inguinal hernias, one or two undescended testes, and hypogonadotrophic hypogonadism.
    explanation: The original report establishes the body-wall association.
  downstream:
  - target: Inguinal hernia
    causal_link_type: DIRECT
    evidence: &body_wall_manifestation_evidence
    - reference: PMID:6802865
      reference_title: "Hypoplasia of the nose and eyes, hyposmia, hypogeusia, and hypogonadotrophic hypogonadism in two males."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Each patient had bilateral inguinal hernias"
      explanation: The original two-patient report directly documents bilateral inguinal hernias.
    - reference: ORPHA:2250
      reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0009023 | Abdominal wall muscle weakness | Frequent (79-30%)"
      explanation: Orphanet directly records abdominal-wall weakness.
  - target: Abdominal wall muscle weakness
    causal_link_type: DIRECT
    evidence: *body_wall_manifestation_evidence
phenotypes:
- category: Gastrointestinal
  name: Inguinal hernia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000023 | Inguinal hernia | Very frequent (99-80%)"
    explanation: Orphanet lists inguinal hernia as very frequent.
- category: Genitourinary
  name: Cryptorchidism
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000028 | Cryptorchidism | Frequent (79-30%)"
    explanation: Orphanet lists cryptorchidism as frequent.
- category: Endocrine
  name: Hypogonadotropic hypogonadism
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypogonadotropic hypogonadism
    term:
      id: HP:0000044
      label: Hypogonadotropic hypogonadism
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000044 | Hypogonadotropic hypogonadism | Frequent (79-30%)"
    explanation: Orphanet lists hypogonadotropic hypogonadism as frequent.
- category: Endocrine
  name: Hypogonadism
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypogonadism
    term:
      id: HP:0000135
      label: Hypogonadism
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000135 | Hypogonadism | Very frequent (99-80%)"
    explanation: Orphanet lists hypogonadism as very frequent.
- category: Craniofacial
  name: Cleft palate
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000175 | Cleft palate | Occasional (29-5%)"
    explanation: Orphanet lists cleft palate as occasional.
- category: Craniofacial
  name: Submucous cleft hard palate
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Submucous cleft hard palate
    term:
      id: HP:0000176
      label: Submucous cleft hard palate
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000176 | Submucous cleft hard palate | Occasional (29-5%)"
    explanation: Orphanet lists submucous cleft hard palate as occasional.
- category: Craniofacial
  name: Bifid uvula
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Bifid uvula
    term:
      id: HP:0000193
      label: Bifid uvula
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000193 | Bifid uvula | Occasional (29-5%)"
    explanation: Orphanet lists bifid uvula as occasional.
- category: Craniofacial
  name: High palate
  description: A high-arched palate may accompany the severe midfacial malformation.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:36968924
    reference_title: "Bosma Arhinia Microphthalmia Syndrome (BAMS): First Report from Vietnam."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On presentation, she was noted to have congenital arhinia, bilateral microphthalmia, vision loss, mouth-breathing, an unclear speaking voice, a high arched or cleft palate, and a hypoplastic maxilla.
    explanation: The adult case directly documents a high-arched palate.
- category: Sensory
  name: Abnormality of taste sensation
  description: Hypogeusia or severe impairment of tastant recognition accompanies olfactory dysfunction.
  phenotype_term:
    preferred_term: Abnormality of taste sensation
    term:
      id: HP:0000223
      label: Abnormality of taste sensation
  evidence:
  - reference: PMID:6802865
    reference_title: "Hypoplasia of the nose and eyes, hyposmia, hypogeusia, and hypogonadotrophic hypogonadism in two males."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each was unable to recognize the smell of any vapor (Type I hyposmia), and had severe impairment of recognition of any tastant (recognition hypogeusia)
    explanation: The original two-patient report directly documents recognition hypogeusia.
- category: Craniofacial
  name: Abnormal midface morphology
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal midface morphology
    term:
      id: HP:0000309
      label: Abnormal midface morphology
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000309 | Abnormal midface morphology | Very frequent (99-80%)"
    explanation: Orphanet lists abnormal midface morphology as very frequent.
- category: Craniofacial
  name: Hypertelorism
  description: Increased distance between the orbits has been documented in molecularly confirmed neonatal BAMS.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:33784779
    reference_title: "[A Newborn Suffering from Arhinia: Neonatologic Challenges During Primary Care of the Newborn With Bosma Arhinia Microphthalmia Syndrome (BAMS)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to a complete nasal agenesis, hypertelorism, a Gothic palate, bilateral microphthalmus, and iris coloboma were found.
    explanation: The neonatal case directly documents hypertelorism.
- category: Craniofacial
  name: Hypoplasia of the maxilla
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypoplasia of the maxilla
    term:
      id: HP:0000327
      label: Hypoplasia of the maxilla
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000327 | Hypoplasia of the maxilla | Frequent (79-30%)"
    explanation: Orphanet lists maxillary hypoplasia as frequent.
- category: Craniofacial
  name: Choanal atresia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Choanal atresia
    term:
      id: HP:0000453
      label: Choanal atresia
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000453 | Choanal atresia | Frequent (79-30%)"
    explanation: Orphanet lists choanal atresia as frequent.
- category: Olfactory
  name: Anosmia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Anosmia
    term:
      id: HP:0000458
      label: Anosmia
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000458 | Anosmia | Very frequent (99-80%)"
    explanation: Orphanet lists anosmia as very frequent.
- category: Ophthalmologic
  name: Cataract
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000518 | Cataract | Very frequent (99-80%)"
    explanation: Orphanet lists cataract as very frequent.
- category: Ophthalmologic
  name: Anophthalmia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Anophthalmia
    term:
      id: HP:0000528
      label: Anophthalmia
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000528 | Anophthalmia | Frequent (79-30%)"
    explanation: Orphanet lists anophthalmia as frequent.
- category: Ophthalmologic
  name: Lacrimal duct atresia
  description: The nasolacrimal duct may be absent, producing lacrimal-sac dilation or mucoceles.
  phenotype_term:
    preferred_term: Lacrimal duct atresia
    term:
      id: HP:0000564
      label: Lacrimal duct atresia
  evidence:
  - reference: PMID:38713859
    reference_title: Dilemmas in the management of lacrimal drainage anomalies in BOSMA (congenital arhinia-microphthalmia) syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lacrimal drainage anomalies are secondary to absent nasolacrimal duct and usually present as dilated lacrimal sac or mucoceles.
    explanation: The lacrimal-management review directly documents absent nasolacrimal ducts in BOSMA.
- category: Ophthalmologic
  name: Microphthalmia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000568 | Microphthalmia | Frequent (79-30%)"
    explanation: Orphanet lists microphthalmia as frequent.
- category: Ophthalmologic
  name: Visual loss
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Visual loss
    term:
      id: HP:0000572
      label: Visual loss
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000572 | Visual loss | Frequent (79-30%)"
    explanation: Orphanet lists visual loss as frequent.
- category: Ophthalmologic
  name: Iris coloboma
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Iris coloboma
    term:
      id: HP:0000612
      label: Iris coloboma
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000612 | Iris coloboma | Frequent (79-30%)"
    explanation: Orphanet lists iris coloboma as frequent.
- category: Ophthalmologic
  name: Blindness
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Blindness
    term:
      id: HP:0000618
      label: Blindness
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000618 | Blindness | Frequent (79-30%)"
    explanation: Orphanet lists blindness as frequent.
- category: Ophthalmologic
  name: Amblyopia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Amblyopia
    term:
      id: HP:0000646
      label: Amblyopia
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000646 | Amblyopia | Frequent (79-30%)"
    explanation: Orphanet lists amblyopia as frequent.
- category: Ophthalmologic
  name: Optic atrophy
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000648 | Optic atrophy | Occasional (29-5%)"
    explanation: Orphanet lists optic atrophy as occasional.
- category: Dental
  name: Tooth malposition
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Tooth malposition
    term:
      id: HP:0000692
      label: Tooth malposition
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000692 | Tooth malposition | Very frequent (99-80%)"
    explanation: Orphanet lists tooth malposition as very frequent.
- category: Endocrine
  name: Gynecomastia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Gynecomastia
    term:
      id: HP:0000771
      label: Gynecomastia
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000771 | Gynecomastia | Frequent (79-30%)"
    explanation: Orphanet lists gynecomastia as frequent.
- category: Genitourinary
  name: External genital hypoplasia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: External genital hypoplasia
    term:
      id: HP:0003241
      label: External genital hypoplasia
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003241 | External genital hypoplasia | Very frequent (99-80%)"
    explanation: Orphanet lists external genital hypoplasia as very frequent.
- category: Olfactory
  name: Hyposmia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hyposmia
    term:
      id: HP:0004409
      label: Hyposmia
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004409 | Hyposmia | Very frequent (99-80%)"
    explanation: Orphanet lists hyposmia as very frequent.
- category: Dental
  name: Failure of eruption of permanent teeth
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Failure of eruption of permanent teeth
    term:
      id: HP:0006352
      label: Failure of eruption of permanent teeth
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006352 | Failure of eruption of permanent teeth | Very frequent (99-80%)"
    explanation: Orphanet lists failure of eruption of permanent teeth as very frequent.
- category: Craniofacial
  name: Paranasal sinus hypoplasia
  description: Paranasal sinuses may be absent or markedly underdeveloped.
  phenotype_term:
    preferred_term: Paranasal sinus hypoplasia
    term:
      id: HP:0006784
      label: Paranasal sinus hypoplasia
  evidence:
  - reference: PMID:36968924
    reference_title: "Bosma Arhinia Microphthalmia Syndrome (BAMS): First Report from Vietnam."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her paranasal sinuses were ossified and underdeveloped."
    explanation: Cross-sectional imaging directly documents underdeveloped paranasal sinuses.
- category: Genitourinary
  name: Hypoplasia of penis
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypoplasia of penis
    term:
      id: HP:0008736
      label: Hypoplasia of penis
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008736 | Hypoplasia of penis | Very frequent (99-80%)"
    explanation: Orphanet lists hypoplasia of penis as very frequent.
- category: Musculoskeletal
  name: Abdominal wall muscle weakness
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abdominal wall muscle weakness
    term:
      id: HP:0009023
      label: Abdominal wall muscle weakness
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009023 | Abdominal wall muscle weakness | Frequent (79-30%)"
    explanation: Orphanet lists abdominal wall muscle weakness as frequent.
- category: Craniofacial
  name: Aplasia/Hypoplasia involving the nose
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia involving the nose
    term:
      id: HP:0009924
      label: Aplasia/Hypoplasia involving the nose
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009924 | Aplasia/Hypoplasia involving the nose | Frequent (79-30%)"
    explanation: Orphanet lists nose aplasia/hypoplasia as frequent.
- category: Craniofacial
  name: Aplasia of the nose
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Aplasia of the nose
    term:
      id: HP:0009927
      label: Aplasia of the nose
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009927 | Aplasia of the nose | Very frequent (99-80%)"
    explanation: Orphanet lists aplasia of the nose as very frequent.
- category: Craniofacial
  name: Single naris
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Single naris
    term:
      id: HP:0009932
      label: Single naris
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009932 | Single naris | Very frequent (99-80%)"
    explanation: Orphanet lists single naris as very frequent.
- category: Gastrointestinal
  name: Feeding difficulties
  description: Neonatal oral feeding may require enteral support, training, and adapted equipment.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:33784779
    reference_title: "[A Newborn Suffering from Arhinia: Neonatologic Challenges During Primary Care of the Newborn With Bosma Arhinia Microphthalmia Syndrome (BAMS)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An orogastric tube was placed, and drinking training and a special pacifier improved coordination and drinking performance.
    explanation: A molecularly confirmed neonatal case documents early feeding difficulty and response to feeding adaptation.
- category: Ophthalmologic
  name: Dacryocystocele
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Dacryocystocele
    term:
      id: HP:0030752
      label: Dacryocystocele
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030752 | Dacryocystocele | Occasional (29-5%)"
    explanation: Orphanet lists dacryocystocele as occasional.
- category: Neurological
  name: Hypoplasia of the olfactory bulb
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypoplasia of the olfactory bulb
    term:
      id: HP:0040326
      label: Hypoplasia of the olfactory bulb
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0040326 | Hypoplasia of the olfactory bulb | Very frequent (99-80%)"
    explanation: Orphanet lists olfactory bulb hypoplasia as very frequent.
- category: Craniofacial
  name: Absent nares
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Absent nares
    term:
      id: HP:0100596
      label: Absent nares
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100596 | Absent nares | Very frequent (99-80%)"
    explanation: Orphanet lists absent nares as very frequent.
diagnosis:
- name: Clinical diagnostic criteria
  description: >-
    Clinical diagnosis integrates arhinia or severe nasal hypoplasia, midface
    hypoplasia, ocular anomalies, anosmia or hyposmia, hypogonadotropic
    hypogonadism, and normal intellectual development.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: A compatible congenital craniofacial, ocular, olfactory, and endocrine pattern supports BAMS.
  evidence:
  - reference: PMID:36968924
    reference_title: "Bosma Arhinia Microphthalmia Syndrome (BAMS): First Report from Vietnam."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Criteria for diagnosis consist of arhinia, midface hypoplasia (with a hypoplastic maxilla), hypogonadotropic hypogonadism, and normal intellectual abilities."
    explanation: This case report states core clinical diagnostic criteria.
- name: SMCHD1 molecular testing
  description: >-
    Sequencing or targeted analysis of SMCHD1, especially exons encoding the
    extended ATPase domain, can support a molecular diagnosis and clarify
    familial recurrence risk.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: A heterozygous pathogenic SMCHD1 ATPase-domain missense variant supports molecular diagnosis.
  evidence:
  - reference: PMID:28067909
    reference_title: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation"
    explanation: Sequencing evidence supports SMCHD1 testing in arhinia/BAMS.
  - reference: PMID:36944600
    reference_title: Nasal Construction in Congenital Arhinia Due to Novel SMCHD1 Gene Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted sequencing was carried out on DNA samples from the 2 affected patients, 1 anosmic and 1 healthy parent, to identify variants in exons 3 to 13 of SMCHD1"
    explanation: Targeted SMCHD1 sequencing is directly used in a congenital arhinia pedigree.
- name: Craniofacial and olfactory anatomy imaging
  description: >-
    Cross-sectional craniofacial imaging assesses the absent or hypoplastic
    nose, paranasal sinuses, nasopharynx, olfactory bulbs, orbits, and surgical
    planning anatomy.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: Absent or hypoplastic nasal, sinus, or olfactory-bulb structures support BAMS anatomy.
  evidence:
  - reference: PMID:6802865
    reference_title: "Hypoplasia of the nose and eyes, hyposmia, hypogeusia, and hypogonadotrophic hypogonadism in two males."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their nasal skeleton, demonstrated by tomoradiography, had grown in early embryological form."
    explanation: The original clinical description used imaging to characterize the nasal skeleton.
  - reference: PMID:36968924
    reference_title: "Bosma Arhinia Microphthalmia Syndrome (BAMS): First Report from Vietnam."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her paranasal sinuses were ossified and underdeveloped."
    explanation: Imaging/anatomic assessment supports paranasal sinus involvement.
differential_diagnoses:
- name: Arrhinencephaly and holoprosencephaly spectrum
  description: >-
    Severe midline facial malformations can suggest arrhinencephaly or a
    holoprosencephaly-spectrum disorder. The original BAMS patients instead
    retained the medial falx attachment and had normal intelligence, supporting
    a distinct developmental pattern with potential for normal cognition.
  distinguishing_features:
  - Preserved medial structure of attachment of the falx cerebri argues against arrhinencephaly in the original syndrome.
  - Normal forebrain anatomy and preserved intellectual development favor BAMS over severe holoprosencephaly-spectrum disease.
  - Heterozygous SMCHD1 ATPase-domain variation supports BAMS when the phenotype is compatible.
  evidence:
  - reference: PMID:6802865
    reference_title: "Hypoplasia of the nose and eyes, hyposmia, hypogeusia, and hypogonadotrophic hypogonadism in two males."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients do not fall within the spectrum of arrhinencephaly because of the presence of medial structure of attachment of the falx cerebri and because of their normal intelligence.
    explanation: The original report explicitly states and anatomically explains this differential.
treatments:
- name: Neonatal airway stabilization
  action_category: THERAPEUTIC
  description: >-
    Complete nasal obstruction requires immediate individualized airway
    planning. Oral or pharyngeal airway splinting may suffice in a stable
    newborn, whereas intubation followed by tracheostomy may be required for
    respiratory distress; the evidence is limited to case-based management.
  treatment_term:
    preferred_term: airway management
  target_phenotypes:
  - preferred_term: Aplasia of the nose
    term:
      id: HP:0009927
      label: Aplasia of the nose
  - preferred_term: Choanal atresia
    term:
      id: HP:0000453
      label: Choanal atresia
  evidence:
  - reference: PMID:33784779
    reference_title: "[A Newborn Suffering from Arhinia: Neonatologic Challenges During Primary Care of the Newborn With Bosma Arhinia Microphthalmia Syndrome (BAMS)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Airway management was achieved by splinting through a Mayo tube which was subsequently replaced by a pharyngeal endotracheal tube without signs of respiratory failure.
    explanation: A molecularly confirmed newborn was stabilized without immediate tracheostomy.
  - reference: PMID:32100546
    reference_title: "The Case of the Missing Nose: Congenital Arhinia Case Presentation and Management Recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Upon birth, the patient was subsequently intubated, followed by tracheostomy due to complete nasal obstruction.
    explanation: A second SMCHD1-positive infant required invasive airway stabilization.
- name: Neonatal feeding adaptation
  action_category: THERAPEUTIC
  description: >-
    Early feeding difficulty can be managed with enteral access when needed,
    drinking training, and adapted feeding equipment while coordination and
    growth are assessed.
  treatment_term:
    preferred_term: feeding therapy
    term:
      id: NCIT:C156237
      label: Swallowing Therapy
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:33784779
    reference_title: "[A Newborn Suffering from Arhinia: Neonatologic Challenges During Primary Care of the Newborn With Bosma Arhinia Microphthalmia Syndrome (BAMS)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An orogastric tube was placed, and drinking training and a special pacifier improved coordination and drinking performance.
    explanation: The neonatal case directly supports the described feeding measures.
- name: Staged nasal and midface reconstruction
  action_category: THERAPEUTIC
  description: >-
    Selected patients may undergo staged midface advancement, tissue expansion,
    and nasal construction to address absent nasal and midface structures.
    Timing and technique are individualized because evidence comes from very
    small case series and early surgery can affect midfacial growth.
  treatment_term:
    preferred_term: surgical repair
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Aplasia of the nose
    term:
      id: HP:0009927
      label: Aplasia of the nose
  - preferred_term: Abnormal midface morphology
    term:
      id: HP:0000309
      label: Abnormal midface morphology
  evidence:
  - reference: PMID:36944600
    reference_title: Nasal Construction in Congenital Arhinia Due to Novel SMCHD1 Gene Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A staged surgical approach was applied."
    explanation: This case series directly supports staged surgical reconstruction.
  - reference: PMID:36944600
    reference_title: Nasal Construction in Congenital Arhinia Due to Novel SMCHD1 Gene Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nasal construction with a forehead flap that was placed over a costochondral framework derived from rib cartilage."
    explanation: The case series describes nasal construction technique for congenital arhinia.
  - reference: PMID:33784779
    reference_title: "[A Newborn Suffering from Arhinia: Neonatologic Challenges During Primary Care of the Newborn With Bosma Arhinia Microphthalmia Syndrome (BAMS)]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the absence of respiratory problems and appropriate growth, however, there is no urgent indication for early plastic surgical treatment, given the inherent risks of sepsis and growth disorders in the midface.
    explanation: The neonatal report supports individualized timing and cautions against automatic early reconstruction.
- name: Customized postoperative nasal stenting
  action_category: THERAPEUTIC
  description: >-
    A customized three-dimensional-printed silicone stent has been used after
    nasal-passage reconstruction to reduce restenosis while mucoepithelium
    regenerates. Evidence is a single congenital-arhinia case and does not
    establish comparative efficacy or BAMS-specific generalizability.
  treatment_term:
    preferred_term: surgical repair
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Aplasia of the nose
    term:
      id: HP:0009927
      label: Aplasia of the nose
  evidence:
  - reference: PMID:30247752
    reference_title: "Nasal Reconstruction Using a Customized Three-Dimensional-Printed Stent for Congenital Arhinia: Three-Year Follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three years after stent removal, respiratory function, nasal passage structure, and external nose shape were maintained without additional medical care.
    explanation: The three-year case follow-up documents durable anatomy and respiratory function after customized stenting.
  - reference: clinicaltrials:NCT02559050
    reference_title: Nasal Reconstruction Using a Customized 3D-printed Nasal Stent for Congenital Arhinia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 7-year-old arhinia patient receives nasal reconstruction with nasal cavity reconstruction and is aided with the application of a 3D-printed nasal stent to prevent nasal cavity constriction.
    explanation: The registry summary documents the single-participant device intervention but not a BAMS genotype or comparative outcome.
- name: Early multidisciplinary craniofacial, lacrimal, and endocrine follow-up
  action_category: MONITORING
  description: >-
    Coordinated follow-up should include genetics, plastic and craniofacial
    surgery, ophthalmic plastics, otorhinolaryngology, and endocrinology, with
    particular attention to lacrimal drainage anatomy and pubertal development.
    The best operation for complete bilateral absence of the nasal cavity
    remains uncertain.
  treatment_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:38713859
    reference_title: Dilemmas in the management of lacrimal drainage anomalies in BOSMA (congenital arhinia-microphthalmia) syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A multidisciplinary team from the specialties of genetics, plastic surgery, ophthalmic plastics and reconstructive surgery, otorhinolaryngology, and endocrinology should get involved very early on for better continuity of care.
    explanation: The lacrimal-management review explicitly recommends early multidisciplinary continuity.
- name: Genetic counseling
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Counseling addresses de novo and inherited SMCHD1 variants, autosomal
    dominant transmission, variable expressivity from anosmia to arhinia, and
    recurrence risk.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:36944600
    reference_title: Nasal Construction in Congenital Arhinia Due to Novel SMCHD1 Gene Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the variable expressivity ranging from anosmia to arhinia could improve clinical genetic screens for risk stratification of individuals with anosmia on passing on arhinia to their children."
    explanation: This supports genetic counseling around SMCHD1 variable expressivity and reproductive risk.
animal_models:
- species: Xenopus laevis
  genotype: Embryos assayed with BAMS-associated SMCHD1 ATPase-domain missense variants
  description: >-
    Biochemical and Xenopus assays show that many BAMS variants increase
    SMCHD1 ATPase activity and reduce eye size. This supports altered-protein
    function and an ocular-developmental effect, but it does not establish a
    universal mechanism for every allele or reproduce the full human syndrome.
  genes:
  - preferred_term: SMCHD1
    term:
      id: hgnc:29090
      label: SMCHD1
  associated_phenotypes:
  - Decreased eye size
  evidence:
  - reference: PMID:29748383
    reference_title: FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      many BAMS mutations can result in elevated ATPase activity and decreased eye size in Xenopus
    explanation: The study directly couples variant biochemistry to an ocular phenotype in Xenopus.
- species: Danio rerio
  genotype: CRISPR/Cas9-mediated alteration of smchd1
  description: >-
    CRISPR alteration of zebrafish smchd1 produced arhinia-relevant phenotypes,
    providing developmental support for SMCHD1 involvement without fully
    recapitulating human BAMS.
  genes:
  - preferred_term: smchd1
    term:
      id: hgnc:29090
      label: SMCHD1
  associated_phenotypes:
  - Arhinia-relevant craniofacial phenotypes
  evidence:
  - reference: PMID:28067909
    reference_title: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes."
    explanation: The discovery cohort provides the direct zebrafish result.
datasets:
- accession: geo:GSE173251
  title: Neural crest stem-cell transcriptomes from BAMS, FSHD, and control iPSC lines
  description: >-
    Bulk RNA-seq of human induced-pluripotent-stem-cell-derived neural crest
    stem cells from BAMS, FSHD1, FSHD2, and control samples. The dataset
    underlies the extracellular-matrix, receptor-signaling, adhesion, and
    migration analysis used in the BAMS cellular mechanism.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_types:
  - preferred_term: iPSC-derived neural crest stem cell
    term:
      id: CL:0011012
      label: neural crest cell
    cell_type_term:
      preferred_term: neural crest cell
      term:
        id: CL:0011012
        label: neural crest cell
  sample_count: 12
  conditions:
  - BAMS patient-derived neural crest stem cells
  - FSHD1 patient-derived neural crest stem cells
  - FSHD2 patient-derived neural crest stem cells
  - Control neural crest stem cells
  platform: Illumina HiSeq 4000
  publication: PMID:34209568
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE173251
    reference_title: GEO Accession viewer
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      To gain further insights into the specificity of SMCHD1 mutations and identify pathways associated with the disease phenotypes, we have derived induced pluripotent stem cells from patients affected with BAMS or FSHD. We then differentiated these cells into neural crest stem cells, corresponding to the cell type that is mainly affected in BAMS and analyzed their transcriptome by RNA Seq.
    explanation: The GEO record supplies the accession, organism, cell model, disease comparisons, and assay.
clinical_trials:
- name: NCT02559050
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Completed single-participant observational/device study of nasal-cavity
    reconstruction supported by a customized three-dimensional-printed stent in
    congenital arhinia. The registry does not establish a BAMS or SMCHD1
    diagnosis and does not provide comparative efficacy evidence.
  target_phenotypes:
  - preferred_term: Aplasia of the nose
    term:
      id: HP:0009927
      label: Aplasia of the nose
  evidence:
  - reference: clinicaltrials:NCT02559050
    reference_title: Nasal Reconstruction Using a Customized 3D-printed Nasal Stent for Congenital Arhinia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 7-year-old arhinia patient receives nasal reconstruction with nasal cavity reconstruction and is aided with the application of a 3D-printed nasal stent to prevent nasal cavity constriction.
    explanation: The registry supports phenotype-targeted relevance but not disease-specific assignment or efficacy.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: CGGV:assertion_b2f2b442-3afa-4427-8e9b-3dc2485790aa-2022-05-20T042139.263Z
      reference_title: "SMCHD1 / arhinia, choanal atresia, and microphthalmia (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "SMCHD1 | HGNC:29090 | arhinia, choanal atresia, and microphthalmia | MONDO:0011323 | AD | Definitive"
      explanation: ClinGen establishes a definitive autosomal-dominant gene-disease relationship.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011323
      label: arhinia, choanal atresia, and microphthalmia
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0011323 is the current disease identifier used by this entry and by
      the definitive ClinGen SMCHD1 assertion; it consolidates the legacy
      Orphanet names represented by ORPHA:2250 and ORPHA:1135.
discussions:
- discussion_id: bams_allelic_function
  prompt: >-
    Do all BAMS-associated SMCHD1 ATPase-domain variants act through increased
    ATPase activity or another coherent gain-of-function mechanism?
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - genetic#SMCHD1 ATPase-domain missense variants
  - pathophysiology#SMCHD1 ATPase-domain chromatin regulatory alteration
  rationale: >-
    Many tested BAMS variants increase ATPase activity, whereas patient
    methylation changes overlap FSHD2 and at least one recurrent variant has
    been observed across phenotypes. A single gain-of-function label would
    therefore overstate the available allele-by-allele evidence.
  evidence:
  - reference: PMID:29748383
    reference_title: FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      whether BAMS is associated with loss- or gain-of-function mutations in SMCHD1 is unclear.
    explanation: The functional study states the unresolved allelic-mechanism question directly.
  - reference: PMID:28067909
    reference_title: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders.
    explanation: Shared variants and methylation effects complicate a simple disease-specific binary mechanism.
- discussion_id: bams_developmental_cell_lineages
  prompt: >-
    What are the relative and interacting contributions of neural-crest and
    cranial-placode defects to human BAMS anatomy?
  kind: EMERGING_HYPOTHESIS
  status: OPEN
  attaches_to:
  - pathophysiology#Neural crest transcriptional, adhesion, and migration dysregulation
  - pathophysiology#Cranial placode differentiation and adhesion defect
  - pathophysiology#Disrupted nasal, olfactory, and midfacial development
  rationale: >-
    Independent patient-derived-cell studies support both lineages. Neither
    model yet establishes their temporal interaction, contribution to ocular
    and reproductive findings, or quantitative importance across variants.
  evidence:
  - reference: PMID:34209568
    reference_title: AKT Signaling Modifies the Balance between Cell Proliferation and Migration in Neural Crest Cells from Patients Affected with Bosma Arhinia and Microphthalmia Syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "defects in neural crest migration might contribute to the craniofacial anomalies in BAMS."
    explanation: The earlier model supports a contributory neural-crest mechanism.
  - reference: PMID:41962546
    reference_title: Cranial placode differentiation defect in individuals born without a nose.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Together our research suggests that BAMS is caused by impaired differentiation to cranial placode cells and changes in cell adhesion
    explanation: The 2026 study adds a placodal mechanism that must be integrated with neural-crest evidence.
- discussion_id: bams_inherited_expressivity
  prompt: >-
    Which genetic, epigenetic, or developmental modifiers determine expression
    from isolated anosmia to complete arhinia and multisystem BAMS?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - inheritance#Autosomal dominant inheritance
  - genetic#SMCHD1 ATPase-domain missense variants
  rationale: >-
    Predominantly de novo discovery cohorts coexist with an inherited pedigree
    in which an anosmic parent transmitted the same variant to offspring with
    arhinia. Recurrence counseling and prediction therefore require more than a
    de-novo-versus-inherited distinction.
  evidence:
  - reference: PMID:36944600
    reference_title: Nasal Construction in Congenital Arhinia Due to Novel SMCHD1 Gene Variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected patients and anosmic parent were found to have a novel SMCHD1 gene variant p.E473V."
    explanation: The pedigree directly demonstrates inherited variable expressivity.
- discussion_id: bams_lifespan_natural_history
  prompt: >-
    What are the typical longitudinal airway, visual, endocrine, reproductive,
    reconstructive, and psychosocial outcomes across the BAMS lifespan?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - progression#Childhood, puberty, and adult course
  - clinical_burden#
  rationale: >-
    Available evidence is dominated by neonatal reports, cross-sectional case
    descriptions, and single-person adult narratives. It supports possible
    favorable adaptation but cannot define complication rates, treatment
    timing, or a typical longitudinal trajectory.
  evidence:
  - reference: PMID:34194860
    reference_title: "Good Outcome for an Individual with Severe Facial Anomalies and Hypogonadotropic Hypogonadism: A Consequence of His Cognitive Function, Pragmatic Approach, and Temperament."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His story and experiences with the health-care system offer insight into some factors that may be pertinent to resilience and lifelong adjustment for patients with similar conditions
    explanation: A single lifespan case is informative but cannot establish population natural history.
biochemical: []
environmental: []
references:
- reference: ORPHA:2250
  title: Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome
- reference: ORPHA:1135
  title: Arrhinia-choanal atresia-microphthalmia syndrome
- reference: PMID:6802865
  title: "Hypoplasia of the nose and eyes, hyposmia, hypogeusia, and hypogonadotrophic hypogonadism in two males."
- reference: PMID:16353241
  title: Bosma arhinia microphthalmia syndrome.
- reference: PMID:28067911
  title: De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.
- reference: PMID:28067909
  title: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.
- reference: PMID:31243061
  title: SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localisation of variants in the ATPase domain.
- reference: PMID:34209568
  title: AKT Signaling Modifies the Balance between Cell Proliferation and Migration in Neural Crest Cells from Patients Affected with Bosma Arhinia and Microphthalmia Syndrome.
- reference: PMID:36968924
  title: "Bosma Arhinia Microphthalmia Syndrome (BAMS): First Report from Vietnam."
- reference: PMID:36944600
  title: Nasal Construction in Congenital Arhinia Due to Novel SMCHD1 Gene Variant.
- reference: CGGV:assertion_b2f2b442-3afa-4427-8e9b-3dc2485790aa-2022-05-20T042139.263Z
  title: "SMCHD1 / arhinia, choanal atresia, and microphthalmia (Definitive)"
- reference: PMID:29748383
  title: FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function.
- reference: PMID:30247752
  title: "Nasal Reconstruction Using a Customized Three-Dimensional-Printed Stent for Congenital Arhinia: Three-Year Follow-up."
- reference: PMID:32034419
  title: Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.
- reference: PMID:32100546
  title: "The Case of the Missing Nose: Congenital Arhinia Case Presentation and Management Recommendations."
- reference: PMID:33784779
  title: "[A Newborn Suffering from Arhinia: Neonatologic Challenges During Primary Care of the Newborn With Bosma Arhinia Microphthalmia Syndrome (BAMS)]."
- reference: PMID:34194860
  title: "Good Outcome for an Individual with Severe Facial Anomalies and Hypogonadotropic Hypogonadism: A Consequence of His Cognitive Function, Pragmatic Approach, and Temperament."
- reference: PMID:38713859
  title: Dilemmas in the management of lacrimal drainage anomalies in BOSMA (congenital arhinia-microphthalmia) syndrome.
- reference: PMID:41962546
  title: Cranial placode differentiation defect in individuals born without a nose.
- reference: url:https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE173251
  title: GEO Accession viewer
- reference: clinicaltrials:NCT02559050
  title: Nasal Reconstruction Using a Customized 3D-printed Nasal Stent for Congenital Arhinia
review_notes: >-
  The 2026 re-review incorporates the newly reported patient-derived
  cranial-placode differentiation defect and separates it from the earlier
  neural-crest migration model. The pathograph now contains seven evidence-graded
  nodes and 45 evidence-backed causal edges, with explicit directness and
  known-versus-unknown intermediates. All 38 represented phenotypes are
  connected, including newly added taste, high-palate, hypertelorism,
  lacrimal-duct, paranasal-sinus, and neonatal-feeding findings, and the
  previously orphaned dacryocystocele. The review distinguishes the definitive
  SMCHD1 gene-disease relationship from the still-provisional claim that every
  BAMS allele is gain of function, documents inherited variable expressivity,
  retains separate point-prevalence and literature-case estimates, and adds
  neonatal-to-adult progression, high but variable burden, a stated
  arrhinencephaly differential, six source-backed management actions, two animal
  models, GSE173251, and four open discussions. NCT02559050 is retained only as a
  one-participant congenital-arhinia device study; its registry text does not
  establish BAMS or SMCHD1, and an official ClinicalTrials.gov API query for the
  exact disease name on 2026-07-24 returned no studies. The current MONDO mapping
  follows the definitive ClinGen assertion rather than obsolete MONDO
  identifiers preserved in the two cached Orphanet records. New caches were
  generated only with just fetch-reference. No disease-modifying treatment is
  established.
📚

References & Deep Research

References

21
ORPHA:2250
Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome
No top-level findings curated for this source.
ORPHA:1135
Arrhinia-choanal atresia-microphthalmia syndrome
No top-level findings curated for this source.
PMID:6802865
Hypoplasia of the nose and eyes, hyposmia, hypogeusia, and hypogonadotrophic hypogonadism in two males.
No top-level findings curated for this source.
PMID:16353241
Bosma arhinia microphthalmia syndrome.
No top-level findings curated for this source.
PMID:28067911
De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.
No top-level findings curated for this source.
PMID:28067909
SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.
No top-level findings curated for this source.
PMID:31243061
SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localisation of variants in the ATPase domain.
No top-level findings curated for this source.
PMID:34209568
AKT Signaling Modifies the Balance between Cell Proliferation and Migration in Neural Crest Cells from Patients Affected with Bosma Arhinia and Microphthalmia Syndrome.
No top-level findings curated for this source.
PMID:36968924
Bosma Arhinia Microphthalmia Syndrome (BAMS): First Report from Vietnam.
No top-level findings curated for this source.
PMID:36944600
Nasal Construction in Congenital Arhinia Due to Novel SMCHD1 Gene Variant.
No top-level findings curated for this source.
CGGV:assertion_b2f2b442-3afa-4427-8e9b-3dc2485790aa-2022-05-20T042139.263Z
SMCHD1 / arhinia, choanal atresia, and microphthalmia (Definitive)
No top-level findings curated for this source.
PMID:29748383
FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function.
No top-level findings curated for this source.
PMID:30247752
Nasal Reconstruction Using a Customized Three-Dimensional-Printed Stent for Congenital Arhinia: Three-Year Follow-up.
No top-level findings curated for this source.
PMID:32034419
Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.
No top-level findings curated for this source.
PMID:32100546
The Case of the Missing Nose: Congenital Arhinia Case Presentation and Management Recommendations.
No top-level findings curated for this source.
PMID:33784779
[A Newborn Suffering from Arhinia: Neonatologic Challenges During Primary Care of the Newborn With Bosma Arhinia Microphthalmia Syndrome (BAMS)].
No top-level findings curated for this source.
PMID:34194860
Good Outcome for an Individual with Severe Facial Anomalies and Hypogonadotropic Hypogonadism: A Consequence of His Cognitive Function, Pragmatic Approach, and Temperament.
No top-level findings curated for this source.
PMID:38713859
Dilemmas in the management of lacrimal drainage anomalies in BOSMA (congenital arhinia-microphthalmia) syndrome.
No top-level findings curated for this source.
PMID:41962546
Cranial placode differentiation defect in individuals born without a nose.
No top-level findings curated for this source.
No top-level findings curated for this source.
clinicaltrials:NCT02559050
Nasal Reconstruction Using a Customized 3D-printed Nasal Stent for Congenital Arhinia
No top-level findings curated for this source.

Deep Research

1
Bosma Arhinia Microphthalmia Syndrome Deep Research Fallback ▸

Bosma Arhinia Microphthalmia Syndrome Deep Research Fallback

Scope

This fallback artifact supports curation of Bosma arhinia microphthalmia syndrome (BAMS), represented by MONDO:0011323 and the structured Orphanet record ORPHA:2250.

Structured Sources

  • ORPHA:2250 provides the usable disease definition, synonyms, autosomal dominant/unknown inheritance rows, antenatal/neonatal onset, ultra-rare worldwide prevalence, SMCHD1 gene association, OMIM xref, and 32 HPO phenotype-frequency rows.
  • ORPHA:1135 is a sparse legacy cross-reference record for arrhinia-choanal atresia-microphthalmia syndrome. It does not include definition, phenotype, gene, inheritance, or epidemiology rows.

PubMed Sources Used

  • PMID:6802865: original Bosma report describing severe nasal/ocular hypoplasia, smell/taste impairment, hypogonadism, hernias, cryptorchidism, and normal intelligence.
  • PMID:16353241: clinical review/case report summarizing the syndrome and developmental candidate pathways.
  • PMID:28067911: SMCHD1 discovery series with de novo ATPase-domain missense variants and Xenopus functional evidence.
  • PMID:28067909: independent arhinia/BAMS sequencing cohort and zebrafish model evidence.
  • PMID:31243061: SMCHD1 mutation-spectrum study distinguishing BAMS-associated ATPase-domain variants from FSHD2.
  • PMID:34209568: patient-derived neural crest cell study supporting AKT, extracellular-matrix, adhesion, and migration defects.
  • PMID:36968924: recent case report with diagnostic criteria and anatomic findings.
  • PMID:36944600: congenital arhinia pedigree with targeted SMCHD1 sequencing and staged nasal construction.

Curation Boundaries

  • All ORPHA:2250 HPO phenotype rows are represented with Orphanet frequency evidence.
  • Treatment curation is limited to staged nasal/midface reconstruction and genetic counseling because these have direct cached evidence. Endocrine treatment was not added because the cached abstracts used here do not provide a quotable treatment-support snippet.
  • The entry treats ORPHA:1135 as a legacy alias/cross-reference record rather than as a separate subtype because the local record is sparse and lacks subtype-defining clinical content.

Provider Attempts

  • timeout 75s just research-disorder falcon Bosma_Arhinia_Microphthalmia_Syndrome was terminated by the timeout (signal 15 / exit 124) before producing a provider artifact.
  • timeout 75s just research-disorder openai Bosma_Arhinia_Microphthalmia_Syndrome was terminated by the timeout (signal 15 / exit 124) before producing a provider artifact.

The curation was completed from structured Orphanet rows and cached PubMed evidence to avoid blocking on provider availability.