Bosma Arhinia Microphthalmia Syndrome

Mendelian MONDO:0011323 Pathograph 8 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, typically de novo, with evidence for altered chromatin regulation, neural crest migration defects, and disrupted nasal and craniofacial development.

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1
Definitions
1
Inheritance
4
Pathophys.
32
Phenotypes
8
Pathograph
1
Genes
2
Treatments
10
References
1
Deep Research
📘

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
Autosomal dominant inheritance
Show evidence (2 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.
⚙

Pathophysiology

4
SMCHD1 ATPase-domain epigenetic dysregulation
Heterozygous SMCHD1 missense variants in the extended ATPase domain alter the epigenetic regulator's activity, producing disease-specific chromatin and methylation effects distinct from the broader SMCHD1 variant spectrum seen in FSHD2.
SMCHD1 link
chromatin organization link ⚠ ABNORMAL
Downstream
Neural crest migration and AKT signaling imbalance SMCHD1 variant effects alter neural crest transcriptional and signaling programs relevant to craniofacial morphogenesis.
Show evidence (2 references)
PMID:28067911 SUPPORT Model Organism
"in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles."
Xenopus functional assays support gain-of-function behavior for BAMS-associated SMCHD1 variants.
PMID:31243061 SUPPORT Human Clinical
"BAMS-associated SMCHD1 variants result in quantifiable local DNA hypomethylation."
Patient methylation analyses support altered local epigenetic regulation.
Neural crest migration and AKT signaling imbalance
Patient-derived neural crest cells show altered PI3K/AKT-related signaling, extracellular matrix and cell-adhesion programs, and reduced migration, providing a cellular mechanism for craniofacial malformations.
neural crest cell link
neural crest cell migration link ↓ DECREASED
Downstream
Abrogated nasal and olfactory development Neural crest migration and signaling imbalance disrupts nasal and olfactory structural development.
Show evidence (3 references)
PMID:34209568 SUPPORT In Vitro
"identify pathways associated with the BAMS phenotype and related neural crest defects"
Patient-derived neural crest cell analyses were designed to identify BAMS-relevant neural crest pathways.
PMID:34209568 SUPPORT In Vitro
"defects in neural crest migration might contribute to the craniofacial anomalies in BAMS."
The study directly links impaired neural crest migration to BAMS craniofacial anomalies.
PMID:34209568 SUPPORT In Vitro
"BAMS NCSCs are characterized by an overall decrease in the expression of a number genes required for NCSC migration"
Patient-derived neural crest stem cells show reduced expression of migration genes.
Abrogated nasal and olfactory development
SMCHD1-linked developmental disruption impairs formation of the external nose, nares, paranasal sinuses, and olfactory bulbs or placode-related structures.
nose development link ↓ DECREASED
Downstream
Craniofacial, ocular, and reproductive malformation syndrome Nasal and olfactory developmental disruption is accompanied by ocular, midface, dental, and reproductive anomalies.
Show evidence (3 references)
PMID:28067911 SUPPORT Human Clinical
"SMCHD1 as a key player in nasal development"
The discovery paper explicitly identifies SMCHD1 as important for nasal development.
PMID:28067909 SUPPORT Model Organism
"CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes."
Zebrafish modeling supports a causal link between altered smchd1 and arhinia-relevant development.
PMID:36968924 SUPPORT Human Clinical
"absence of paranasal sinuses and olfactory bulbs."
A clinical report supports absent paranasal sinus and olfactory bulb anatomy as part of BAMS.
Craniofacial, ocular, and reproductive malformation syndrome
The downstream clinical syndrome combines arhinia or severe nasal hypoplasia, ocular hypoplasia or microphthalmia, hyposmia or anosmia, dental and palatal anomalies, inguinal hernia, and hypogonadotropic hypogonadism with generally normal intelligence.
Show evidence (2 references)
PMID:6802865 SUPPORT Human Clinical
"Two males, 9-11 and 29-31 years of age, with severe hypoplasia of the nose, hypoplasia of the eyes, sensory abnormalities of taste and smell, and hypogonadism were studied."
The original syndrome report supports the combined nasal, ocular, sensory, and hypogonadal phenotype.
PMID:16353241 SUPPORT Human Clinical
"severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence."
This clinical review/case report summarizes the characteristic multisystem phenotype.
⬡

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.
●

Phenotypes

32
Breast 1
Gynecomastia FREQUENT Gynecomastia (HP:0000771)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000771 | Gynecomastia | Frequent (79-30%)"
Orphanet lists gynecomastia as frequent.
Digestive 1
Inguinal hernia VERY_FREQUENT Inguinal hernia (HP:0000023)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000023 | Inguinal hernia | Very frequent (99-80%)"
Orphanet lists inguinal hernia as very frequent.
Endocrine 2
Hypogonadotropic hypogonadism FREQUENT Hypogonadotropic hypogonadism (HP:0000044)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000044 | Hypogonadotropic hypogonadism | Frequent (79-30%)"
Orphanet lists hypogonadotropic hypogonadism as frequent.
Hypogonadism VERY_FREQUENT Hypogonadism (HP:0000135)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000135 | Hypogonadism | Very frequent (99-80%)"
Orphanet lists hypogonadism as very frequent.
Eye 5
Cataract VERY_FREQUENT Cataract (HP:0000518)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000518 | Cataract | Very frequent (99-80%)"
Orphanet lists cataract as very frequent.
Microphthalmia FREQUENT Microphthalmia (HP:0000568)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000568 | Microphthalmia | Frequent (79-30%)"
Orphanet lists microphthalmia as frequent.
Visual loss FREQUENT Visual loss (HP:0000572)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000572 | Visual loss | Frequent (79-30%)"
Orphanet lists visual loss as frequent.
Blindness FREQUENT Blindness (HP:0000618)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000618 | Blindness | Frequent (79-30%)"
Orphanet lists blindness as frequent.
Optic atrophy OCCASIONAL Optic atrophy (HP:0000648)
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 Cryptorchidism (HP:0000028)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000028 | Cryptorchidism | Frequent (79-30%)"
Orphanet lists cryptorchidism as frequent.
Head and Neck 5
Cleft palate OCCASIONAL Cleft palate (HP:0000175)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000175 | Cleft palate | Occasional (29-5%)"
Orphanet lists cleft palate as occasional.
Bifid uvula OCCASIONAL Bifid uvula (HP:0000193)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000193 | Bifid uvula | Occasional (29-5%)"
Orphanet lists bifid uvula as occasional.
Choanal atresia FREQUENT Choanal atresia (HP:0000453)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000453 | Choanal atresia | Frequent (79-30%)"
Orphanet lists choanal atresia as frequent.
Anosmia VERY_FREQUENT Anosmia (HP:0000458)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000458 | Anosmia | Very frequent (99-80%)"
Orphanet lists anosmia as very frequent.
Hyposmia VERY_FREQUENT Hyposmia (HP:0004409)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0004409 | Hyposmia | Very frequent (99-80%)"
Orphanet lists hyposmia as very frequent.
Other 17
Submucous cleft hard palate OCCASIONAL Submucous cleft hard palate (HP:0000176)
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 Abnormal midface morphology (HP:0000309)
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 Hypoplasia of the maxilla (HP:0000327)
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 Anophthalmia (HP:0000528)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000528 | Anophthalmia | Frequent (79-30%)"
Orphanet lists anophthalmia as frequent.
Iris coloboma FREQUENT Iris coloboma (HP:0000612)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000612 | Iris coloboma | Frequent (79-30%)"
Orphanet lists iris coloboma as frequent.
Amblyopia FREQUENT Amblyopia (HP:0000646)
Show evidence (1 reference)
ORPHA:2250 SUPPORT Other
"HP:0000646 | Amblyopia | Frequent (79-30%)"
Orphanet lists amblyopia as frequent.
Tooth malposition VERY_FREQUENT Tooth malposition (HP:0000692)
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 External genital hypoplasia (HP:0003241)
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 Failure of eruption of permanent teeth (HP:0006352)
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.
Hypoplasia of penis VERY_FREQUENT Hypoplasia of penis (HP:0008736)
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 Abdominal wall muscle weakness (HP:0009023)
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 Aplasia/Hypoplasia involving the nose (HP:0009924)
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 Aplasia of the nose (HP:0009927)
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 Single naris (HP:0009932)
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 Dacryocystocele (HP:0030752)
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 Hypoplasia of the olfactory bulb (HP:0040326)
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 Absent nares (HP:0100596)
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 missense variants, usually de novo)
Show evidence (5 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.
+ 2 more references
💊

Treatments

2
Staged nasal and midface reconstruction
Action: surgical repair MAXO:0009072
Selected patients may undergo staged midface advancement, tissue expansion, and nasal construction to address absent nasal and midface structures.
Target Phenotypes: Aplasia of the nose ↗ Abnormal midface morphology ↗
Show evidence (2 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.
Genetic counseling
Action: genetic counseling MAXO:0000079
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.
{ }

Source YAML

click to show 
name: Bosma Arhinia Microphthalmia Syndrome
creation_date: "2026-05-07T07:20:00Z"
updated_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, typically de novo, with evidence for altered
  chromatin regulation, neural crest migration defects, and 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 aggregates legacy names and xrefs for BAMS. 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.
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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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
  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 (Orphanet structured-database record)"
    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.
prevalence:
- population: Worldwide
  percentage: <1 per 1,000,000
  notes: Orphanet classifies BAMS as ultra-rare worldwide.
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome (Orphanet structured-database record)"
    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.
progression:
- phase: Onset
  age_range: Antenatal to neonatal
  notes: >-
    Core nasal and ocular malformations are congenital and may be detected
    antenatally or at birth, while pubertal and reproductive manifestations are
    recognized later.
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Neonatal"
    explanation: Orphanet records neonatal onset.
genetic:
- name: SMCHD1 ATPase-domain missense variants
  gene_term:
    preferred_term: SMCHD1
    term:
      id: hgnc:29090
      label: SMCHD1
  association: Heterozygous missense variants, usually de novo
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    BAMS-associated variants cluster in the SMCHD1 extended ATPase domain and
    appear phenotypically distinct from FSHD2-associated SMCHD1 loss-of-function
    or hypomorphic mechanisms.
  evidence:
  - reference: ORPHA:2250
    reference_title: "Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome (Orphanet structured-database record)"
    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: 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 epigenetic dysregulation
  description: >-
    Heterozygous SMCHD1 missense variants in the extended ATPase domain alter
    the epigenetic regulator's activity, producing disease-specific chromatin
    and methylation effects distinct from the broader SMCHD1 variant spectrum
    seen in FSHD2.
  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:28067911
    reference_title: De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles."
    explanation: Xenopus functional assays support gain-of-function behavior for BAMS-associated SMCHD1 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: "BAMS-associated SMCHD1 variants result in quantifiable local DNA hypomethylation."
    explanation: Patient methylation analyses support altered local epigenetic regulation.
  downstream:
  - target: Neural crest migration and AKT signaling imbalance
    description: SMCHD1 variant effects alter neural crest transcriptional and signaling programs relevant to craniofacial morphogenesis.
- name: Neural crest migration and AKT signaling imbalance
  description: >-
    Patient-derived neural crest cells show altered PI3K/AKT-related signaling,
    extracellular matrix and cell-adhesion programs, and reduced migration,
    providing a cellular mechanism for craniofacial malformations.
  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
  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: "identify pathways associated with the BAMS phenotype and related neural crest defects"
    explanation: Patient-derived neural crest cell analyses were designed to identify BAMS-relevant neural crest pathways.
  - 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 study directly links impaired neural crest migration to BAMS craniofacial anomalies.
  - 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 stem cells show reduced expression of migration genes.
  downstream:
  - target: Abrogated nasal and olfactory development
    description: Neural crest migration and signaling imbalance disrupts nasal and olfactory structural development.
- name: Abrogated nasal and olfactory development
  description: >-
    SMCHD1-linked developmental disruption impairs formation of the external
    nose, nares, paranasal sinuses, and olfactory bulbs or placode-related
    structures.
  biological_processes:
  - preferred_term: nose development
    modifier: DECREASED
    term:
      id: GO:0043584
      label: nose development
  evidence:
  - 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: "SMCHD1 as a key player in nasal development"
    explanation: The discovery paper explicitly identifies SMCHD1 as important for nasal development.
  - 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: Zebrafish modeling supports a causal link between altered smchd1 and arhinia-relevant development.
  - 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: A clinical report supports absent paranasal sinus and olfactory bulb anatomy as part of BAMS.
  downstream:
  - target: Craniofacial, ocular, and reproductive malformation syndrome
    description: Nasal and olfactory developmental disruption is accompanied by ocular, midface, dental, and reproductive anomalies.
- name: Craniofacial, ocular, and reproductive malformation syndrome
  description: >-
    The downstream clinical syndrome combines arhinia or severe nasal
    hypoplasia, ocular hypoplasia or microphthalmia, hyposmia or anosmia,
    dental and palatal anomalies, inguinal hernia, and hypogonadotropic
    hypogonadism with generally normal intelligence.
  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: "Two males, 9-11 and 29-31 years of age, with severe hypoplasia of the nose, hypoplasia of the eyes, sensory abnormalities of taste and smell, and hypogonadism were studied."
    explanation: The original syndrome report supports the combined nasal, ocular, sensory, and hypogonadal phenotype.
  - 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: This clinical review/case report summarizes the characteristic multisystem phenotype.
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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000193 | Bifid uvula | Occasional (29-5%)"
    explanation: Orphanet lists bifid uvula as occasional.
- 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 (Orphanet structured-database record)"
    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: 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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000528 | Anophthalmia | Frequent (79-30%)"
    explanation: Orphanet lists anophthalmia as frequent.
- 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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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: 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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009932 | Single naris | Very frequent (99-80%)"
    explanation: Orphanet lists single naris as very frequent.
- 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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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 (Orphanet structured-database record)"
    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: MAXO:0000487
      label: clinical assessment
  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: MAXO:0000127
      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: MAXO:0000487
      label: clinical assessment
  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.
treatments:
- name: Staged nasal and midface reconstruction
  description: >-
    Selected patients may undergo staged midface advancement, tissue expansion,
    and nasal construction to address absent nasal and midface structures.
  treatment_term:
    preferred_term: surgical repair
    term:
      id: MAXO:0009072
      label: surgical repair
  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.
- name: Genetic counseling
  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: MAXO:0000079
      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.
references:
- reference: ORPHA:2250
  title: Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome
  found_in:
  - Bosma_Arhinia_Microphthalmia_Syndrome-deep-research-fallback.md
  findings:
  - statement: >-
      Orphanet provides the BAMS definition, inheritance, onset, prevalence,
      SMCHD1 gene association, and 32 HPO phenotype-frequency rows.
    supporting_text: "SMCHD1 | structural maintenance of chromosomes flexible hinge domain containing 1 | hgnc:29090 | Disease-causing germline mutation(s) in"
- reference: ORPHA:1135
  title: Arrhinia-choanal atresia-microphthalmia syndrome
  found_in:
  - Bosma_Arhinia_Microphthalmia_Syndrome-deep-research-fallback.md
  findings:
  - statement: ORPHA:1135 is a sparse legacy cross-reference record for the arrhinia-choanal atresia-microphthalmia syndrome name.
    supporting_text: "Arrhinia-choanal atresia-microphthalmia syndrome"
- reference: PMID:6802865
  title: "Hypoplasia of the nose and eyes, hyposmia, hypogeusia, and hypogonadotrophic hypogonadism in two males."
  found_in:
  - Bosma_Arhinia_Microphthalmia_Syndrome-deep-research-fallback.md
  findings:
  - statement: The original Bosma report described severe nasal and ocular hypoplasia, taste/smell impairment, hypogonadism, hernias, cryptorchidism, and normal intelligence.
    supporting_text: "Two males, 9-11 and 29-31 years of age, with severe hypoplasia of the nose"
- reference: PMID:16353241
  title: Bosma arhinia microphthalmia syndrome.
  found_in:
  - Bosma_Arhinia_Microphthalmia_Syndrome-deep-research-fallback.md
  findings:
  - statement: A clinical review/case report summarized the characteristic Bosma syndrome phenotype and candidate developmental pathways.
    supporting_text: "severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell"
- reference: PMID:28067911
  title: De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.
  found_in:
  - Bosma_Arhinia_Microphthalmia_Syndrome-deep-research-fallback.md
  findings:
  - statement: A discovery series identified de novo SMCHD1 ATPase-domain missense variants in BAMS and provided model-organism functional support.
    supporting_text: "missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain"
- reference: PMID:28067909
  title: SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.
  found_in:
  - Bosma_Arhinia_Microphthalmia_Syndrome-deep-research-fallback.md
  findings:
  - statement: An independent sequencing cohort found SMCHD1 ATPase-domain missense variants in 84% of arhinia probands and model-supported arhinia-relevant phenotypes.
    supporting_text: "Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation"
- 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.
  found_in:
  - Bosma_Arhinia_Microphthalmia_Syndrome-deep-research-fallback.md
  findings:
  - statement: SMCHD1 mutation-spectrum analysis supports BAMS-specific ATPase-domain localization and local DNA hypomethylation.
    supporting_text: "in BAMS, pathogenic variants are restricted to the extended 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.
  found_in:
  - Bosma_Arhinia_Microphthalmia_Syndrome-deep-research-fallback.md
  findings:
  - statement: Patient-derived neural crest cells show AKT-signaling and migration defects relevant to BAMS craniofacial anomalies.
    supporting_text: "defects in neural crest migration might contribute to the craniofacial anomalies in BAMS."
- reference: PMID:36968924
  title: "Bosma Arhinia Microphthalmia Syndrome (BAMS): First Report from Vietnam."
  found_in:
  - Bosma_Arhinia_Microphthalmia_Syndrome-deep-research-fallback.md
  findings:
  - statement: A recent case report summarizes clinical diagnostic criteria and additional anatomic findings.
    supporting_text: "Criteria for diagnosis consist of arhinia, midface hypoplasia"
- reference: PMID:36944600
  title: Nasal Construction in Congenital Arhinia Due to Novel SMCHD1 Gene Variant.
  found_in:
  - Bosma_Arhinia_Microphthalmia_Syndrome-deep-research-fallback.md
  findings:
  - statement: A congenital arhinia pedigree supports targeted SMCHD1 sequencing and staged nasal/midface reconstruction.
    supporting_text: "A staged surgical approach was applied."
📚

References & Deep Research

References

10
ORPHA:2250
Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome
1 finding
Orphanet provides the BAMS definition, inheritance, onset, prevalence, SMCHD1 gene association, and 32 HPO phenotype-frequency rows.
"SMCHD1 | structural maintenance of chromosomes flexible hinge domain containing 1 | hgnc:29090 | Disease-causing germline mutation(s) in"
ORPHA:1135
Arrhinia-choanal atresia-microphthalmia syndrome
1 finding
ORPHA:1135 is a sparse legacy cross-reference record for the arrhinia-choanal atresia-microphthalmia syndrome name.
"Arrhinia-choanal atresia-microphthalmia syndrome"
PMID:6802865
Hypoplasia of the nose and eyes, hyposmia, hypogeusia, and hypogonadotrophic hypogonadism in two males.
1 finding
The original Bosma report described severe nasal and ocular hypoplasia, taste/smell impairment, hypogonadism, hernias, cryptorchidism, and normal intelligence.
"Two males, 9-11 and 29-31 years of age, with severe hypoplasia of the nose"
PMID:16353241
Bosma arhinia microphthalmia syndrome.
1 finding
A clinical review/case report summarized the characteristic Bosma syndrome phenotype and candidate developmental pathways.
"severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell"
PMID:28067911
De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.
1 finding
A discovery series identified de novo SMCHD1 ATPase-domain missense variants in BAMS and provided model-organism functional support.
"missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain"
PMID:28067909
SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.
1 finding
An independent sequencing cohort found SMCHD1 ATPase-domain missense variants in 84% of arhinia probands and model-supported arhinia-relevant phenotypes.
"Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation"
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.
1 finding
SMCHD1 mutation-spectrum analysis supports BAMS-specific ATPase-domain localization and local DNA hypomethylation.
"in BAMS, pathogenic variants are restricted to the extended ATPase domain."
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.
1 finding
Patient-derived neural crest cells show AKT-signaling and migration defects relevant to BAMS craniofacial anomalies.
"defects in neural crest migration might contribute to the craniofacial anomalies in BAMS."
PMID:36968924
Bosma Arhinia Microphthalmia Syndrome (BAMS): First Report from Vietnam.
1 finding
A recent case report summarizes clinical diagnostic criteria and additional anatomic findings.
"Criteria for diagnosis consist of arhinia, midface hypoplasia"
PMID:36944600
Nasal Construction in Congenital Arhinia Due to Novel SMCHD1 Gene Variant.
1 finding
A congenital arhinia pedigree supports targeted SMCHD1 sequencing and staged nasal/midface reconstruction.
"A staged surgical approach was applied."

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.