Bosma Syndrome (Arhinia with Microphthalmia, SMCHD1)

Congenital craniofacial malformation defined by total or partial absence of the external nose and internal nasal structures, usually associated with developmental ocular anomalies and hypogonadotropic hypogonadism, caused by heterozygous missense variants in the extended ATPase domain of SMCHD1, a gene that is also involved in facioscapulohumeral muscular dystrophy type 2.

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description

Arhinia, the congenital absence of the external nose, nasal cavities and olfactory apparatus, is one of the rarest facial malformations compatible with life. In 1972, the plastic surgeon George Gifford and colleagues published a detailed report of two boys with congenital arhinia, focused on the surgical approach; both had a high-arched palate and one also had maxillary hypoplasia, microphthalmia and iris coloboma [7, 17]. In 1981, James Bosma, a paediatrician at the National Institute of Dental Health of the US National Institutes of Health (NIH), re-evaluated the same patients and described the associated reproductive defects: micropenis, inguinal hernias, cryptorchidism and hypogonadotropic hypogonadism, with low luteinising hormone (LH), follicle-stimulating hormone (FSH) and testosterone, as well as impaired smell and taste and normal intelligence [7, 18]. The eponym designates the triad of arhinia, ocular anomaly and reproductive defect [17]. One of these index patients was re-examined at the age of 69, when he was still on the testosterone replacement started in adolescence and had no signs of muscle disease; a heterozygous pathogenic missense variant in SMCHD1 was then identified [7], later attributed to the substitution p.(Leu141Phe) (patient E1 of the cohort of Shaw and colleagues) [3].

1.2. From familial recurrence to molecular cause

Before the gene was identified, most cases were sporadic, but the recurrence of arhinia, choanal atresia, microphthalmia and cleft palate in two sisters born to healthy parents, described by Ruprecht and Majewski in 1978 with Peters anomaly [8], and the occurrence in an aunt and her niece, with arhinia, choanal atresia, microphthalmia and hypertelorism of variable severity, led Thiele and colleagues to propose autosomal dominant inheritance with reduced penetrance [7, 19]. In Thiele's German family, the 5-year-old proband had complete absence of the nose and nostrils, left microphthalmia, right clinical anophthalmia, hypertelorism, high palate, choanal atresia, preauricular pits and bilateral absence of the 12th ribs, with normal motor and mental development; a maternal aunt with the same picture died 2 hours after birth, and the mother and maternal grandmother had only a broad nasal tip and asymmetric nostrils [8]. In 2001, Olsen and colleagues described a Norwegian infant with a prenatal diagnosis (midface oedema at 17 weeks and absence of the nose confirmed at 25 weeks) and showed on computed tomography the absence of the nasal bones, the cribriform plate and the septal structures (vomer, perpendicular plate of the ethmoid and septal cartilage), and on magnetic resonance imaging the absence of the olfactory bulbs [8]. In 2016, a 19-month-old Mexican boy with arhinia, bilateral clinical anophthalmia, choanal atresia, small penis and cryptorchidism was presented as the 15th published case of BAMS [8]. Graham and Lee reviewed the published cases in 2006 and related the coincidence of nasal and ocular anomalies to the temporal and spatial proximity of the nasal placodes (about 28 days after conception) and the optic vesicle (contact with the ectoderm at 26–27 days; ocular invagination between 34 and 44 days), pointing to genes of the PAX6 network as candidates [18]. In 2007, Sato and colleagues counted 36 published cases and studied five patients, one of whom had a de novo translocation t(3;12)(q13.2;p11.2) and a deletion of about 19 Mb in 3q11.2–q13.31, finding no alterations in the other four [20]. In 2016, Brasseur and colleagues counted fewer than 50 reports and series, tabulated the findings of 14 patients with BAMS and proposed as diagnostic criteria arhinia, maxillary hypoplasia, normal cognition and hypogonadotropic hypogonadism in males [21].

In February 2017, two independent groups simultaneously published the genetic cause. Shaw and colleagues assembled an international consortium of 40 individuals with arhinia (38 families) and identified rare missense variants in SMCHD1 in 84% of probands [5]; Gordon and colleagues found missense variants in the extended ATPase domain of SMCHD1 in all 14 patients studied, all de novo where parental DNA was available [6]. The discovery was unexpected, because SMCHD1 was already known as the main gene of facioscapulohumeral muscular dystrophy type 2 (FSHD2), an adult-onset myopathy without craniofacial or olfactory abnormalities [5, 22].

1.3. Nomenclature and definition of the entities

Orphanet keeps «Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome» (ORPHA:2250) as the preferred name, with the synonyms Bosma arhinia microphthalmia syndrome and Bosma-Henkin-Christiansen syndrome, and ClinVar uses the name «Arrhinia with choanal atresia and microphthalmia syndrome» for OMIM entry 603457 [1, 2]. The Orphanet clinical summary dates from May 2009 and describes only the two original men, so it does not reflect the later genetic series [1]. In the current literature, Bosma syndrome corresponds to the complete triad (arhinia, ocular anomaly and hypogonadism), whereas isolated arhinia and partial phenotypes (hemiarhinia, nasal hypoplasia, isolated anosmia) are regarded as expressions of the same spectrum when associated with SMCHD1 variants [5, 17, 23]. In the cohort of Shaw and colleagues, 84% of individuals with arhinia met the criteria for the triad [5]. A 2025 review by the group that described the North American cohort defined BAMS by complete absence of the external nose, abnormal ocular development (microphthalmia, cataracts, colobomas) and hypogonadism manifested by cryptorchidism, micropenis, absent puberty and infertility [7].

2. Molecular Genetics and Pathophysiology

2.1. The SMCHD1 gene and protein

SMCHD1 is located at 18p11.32 and encodes a protein of 2005 amino acids (NP_056110.2) [3, 24]. It is an atypical member of the structural maintenance of chromosomes (SMC) protein family, with an N-terminal GHKL-type ATPase domain (gyrase, Hsp90, histidine kinase, MutL) and a C-terminal SMC hinge domain [3, 24]. The messenger RNA is expressed in all tissues examined, with highest expression in the testis, ovary and lung [3]. The protein acts as an epigenetic repressor: it establishes and maintains X-chromosome inactivation and silences autosomal gene clusters (protocadherins, Hox genes), imprinted genes and repetitive sequences, including the D4Z4 macrosatellite that contains the DUX4 retrogene at 4q35 [7, 22]. Binding of SMCHD1 to chromatin depends on the LRIF1 protein, which mediates the interaction with H3K9me2/3 nucleosomes, and ATP hydrolysis is required for the selective enrichment of SMCHD1 at specific chromatin regions [25]. SMCHD1 is also required for de novo methylation of D4Z4 in the pluripotent phase, while being dispensable for the maintenance of that methylation [26].

The gene is intolerant of loss of function (pLI = 1.00), with about one heterozygous carrier of a null allele per 10,000 individuals in the Exome Aggregation Consortium (ExAC) [5]. Overall it is not highly intolerant of missense variants (81% of those expected), but exons 1–19, which contain the ATPase domain, show regional constraint (61% of expected missense variants; P = 1.26 × 10⁻⁸), unlike exons 20–48 (95%; P = 0.36) [5].

2.2. Variant spectrum in arhinia and Bosma syndrome

All variants associated with arhinia described to date are heterozygous missense variants located in exons 3–13 of SMCHD1, which encode the extended ATPase domain (residues 111–365, including the downstream domain called the transducer) [5, 11, 22]. In the cohort of Shaw and colleagues, none of the variants was present in ExAC (n = 60,706), and burden analysis of 22,445 genes identified only SMCHD1 with genome-wide significance (P = 2.9 × 10⁻¹⁷; odds ratio 34.4; 95% confidence interval, 95% CI, 18.8–57.9), irrespective of ethnicity [5]. The variants arose de novo in all ten complete simplex trios and segregated with the phenotype in the three multiplex families with parents studied [5]. Gordon and colleagues described de novo mutations in the 11 families with parental DNA available and noted that six of the 14 patients had variants at three adjacent amino acids (Ala134, Ser135 and Glu136), as well as recurrences at His348 (three probands) and Asp420 (two), suggesting mutational hotspots [3]. In 2019, Lemmers and colleagues gathered 41 families with BAMS and found that the variants affected only 20 amino acids, nine of which were recurrent in unrelated families; as 15 of the 25 carriers of identical variants were de novo cases, a founder effect is an unlikely explanation [11].

The genomic positions and the correspondence between protein numbering and the MANE transcript were confirmed in VariantValidator; dashes indicate variants whose genomic position was not normalised [4]. Most ClinVar assertions for these variants were submitted without assertion criteria, so the clinical classification should be redone by the laboratory according to the standards of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [2].

2.3. Mechanism: loss or gain of function

The molecular mechanism is still debated and the sources diverge. Shaw and colleagues showed, in zebrafish larvae, that suppression of smchd1 by morpholinos or by CRISPR/Cas9 editing reproduced three relevant phenotypes (narrowing of the ethmoid plate, microphthalmia and a 45% reduction in the projection length of the terminal nerve, where GnRH3 neurons reside), that normal human messenger RNA corrected these defects and that RNAs carrying the variants p.Ser135Cys, p.Leu141Phe and p.His348Arg, like the FSHD2 variant p.Pro690Ser, did not; overexpression produced no phenotype, so they concluded loss of function [5]. Gordon and colleagues observed increased ATP hydrolysis with three BAMS variants and craniofacial anomalies, including microphthalmia, in Xenopus tadpoles overexpressing the mutant proteins, and proposed gain of function [3, 6]. Gurzau and colleagues confirmed that FSHD2 variants only decrease ATPase activity, whereas many BAMS variants increase it and reduce eye size in Xenopus; a variant described in both diseases increased ATPase activity [28]. In 2026, Constantinescu and colleagues associated BAMS variants with accelerated recruitment of SMCHD1 to the inactive X and faster silencing or increased compaction of that chromosome, which they interpreted as gain of function [25].

On the clinical and epigenetic side, patients with arhinia have the same pattern of D4Z4 hypomethylation in blood as patients with FSHD2: 74% of SMCHD1 variant carriers in the 2017 cohort had hypomethylation, compared with normal methylation in the four patients without a variant and in 16 of the 18 non-carrier relatives [5]. Lemmers and colleagues found that both FSHD2 and BAMS variants produce quantifiable local hypomethylation [11]. This finding, apparently incompatible with a simple gain of function, supports the model of loss of repressor activity in a specific cellular context [22].

2.4. The cranial placode as the cellular target

The olfactory placode gives rise to the nasal skeleton, olfactory neurons and GnRH neurons, and the lens placode gives rise to the anterior structures of the eye; both derive from the most anterior region of the neural plate [22, 29]. Inoue and colleagues knocked out SMCHD1 in H9 human embryonic stem cells and observed that, on differentiation into cranial placode, DUX4 was derepressed and the cells died; induced pluripotent stem cells (iPSCs) from four patients with arhinia and four patients with FSHD2 expressed DUX4 when differentiating into placode cells, with variable degrees of cell death, and herpes simplex virus type 1 (HSV-1) infection amplified DUX4 expression, which led the authors to propose an environmental modifier [22]. In 2026, Rao and colleagues differentiated iPSCs from three patients with BAMS with distinct genotypes and from three controls: the patients' cells produced far fewer pre-placodal cells (about 10% positive for SIX1 and 3% for EYA1, compared with 30–60% in controls), without increased apoptosis, with dysregulation of cell adhesion genes in the transcriptome and methylome and with reduced differentiation into lens and olfactory neurons [29]. The two studies agree on the cranial placode as the vulnerable population but differ on DUX4-mediated cell death, and both are preclinical studies in cellular models [22, 29]. A mouse model carrying the variants p.Leu141Phe and p.Glu136Asp, obtained by CRISPR editing, showed no anomalies at 13.5 days, and heterozygotes with the isolated variant could not be obtained; as DUX4 is not conserved outside Old World primates, mouse and zebrafish models do not reproduce this axis [5].

2.5. Penetrance, expressivity and modifiers

Expressivity is variable within families: in multiplex families, carriers may have complete arhinia, hypoplastic nose, hemiarhinia, isolated anosmia, dental anomalies and asymmetric nostrils, or no signs [3, 5, 22]. In family O (Germany), two sisters with BAMS inherited p.Gln345Arg from their mother, who had anosmia, abnormal dentition and asymmetric nostrils, and the carrier maternal grandmother had only dental and nostril changes [3]. For 19 ExAC missense variants in exons 3–13, the CADD score exceeded the median of the arhinia variants, which reinforces that deleterious SMCHD1 variants are not fully penetrant and may not suffice to cause the malformation [5]. Nor is the phenotype predictable from the variant: the eight patients with p.His348Arg in the cohort of Delaney and colleagues ranged from normal vision and ocular anatomy to bilateral anophthalmia, and there was no correlation with the position of the variant in the three-dimensional structure, with the effect on ATPase activity or with N-terminal dimerisation [27]. In transcriptomic analysis of lymphoblastoid lines, the genes DOK7, TGIF1, KDM6A and ICK, associated with phenotypes with a depressed nasal bridge or tip, emerged as candidate modifiers [5]. The prevailing hypothesis is oligogenic or multifactorial, with a possible contribution from prenatal exposures such as viral infections [7, 22, 30].

2.6. Allelic disorder: facioscapulohumeral muscular dystrophy type 2

In FSHD type 1 (OMIM 158900), the disease results from contraction of the D4Z4 macrosatellite to 1–10 units at 4q35 [31]. FSHD2 (OMIM 158901) is a digenic form of FSHD, in which Lemmers and colleagues identified in 2012 heterozygous loss-of-function variants of SMCHD1 in 15 of 19 families (79%), with D4Z4 methylation below 25% (normal about 50%) [32]. FSHD2 requires a heterozygous pathogenic variant in SMCHD1 (or, more rarely, in DNMT3B, or biallelic variants in LRIF1) and a D4Z4 allele of intermediate size (8–20 units) on a chromosome 4 with the permissive 4qA haplotype; SMCHD1 accounts for about 85% of FSHD2 and less than 5% of all FSHD [9, 11]. In FSHD2 the variants are distributed throughout the gene and include truncating variants, splicing alterations (9.1% at the hotspot of the exon 25 donor site), indels, missense variants and whole-gene deletions, whereas in BAMS they are exclusively missense variants of the extended ATPase domain [11]. In the three-dimensional model of the ATPase domain, FSHD2 variants lie around the ATP-binding site and most BAMS variants in a loop at the dimer interface [11]. The nine recurrent positions in BAMS do not coincide with the FSHD2 variants of the same domain, but p.(Leu107Pro) and p.(Gly137Glu) have been described in both diseases [5, 11]. 18p deletions that include SMCHD1 have been reported as 18p syndrome [9, 33]. The clinical relationship between the two diseases and counselling of carriers are addressed in sections 6 and 8.

2.7. SMCHD1 in other endocrine phenotypes

In a screen of SMCHD1 in 31 patients with idiopathic hypogonadotropic hypogonadism and 43 with combined pituitary hormone deficiency (19 with septo-optic dysplasia), Kinjo and colleagues identified a likely pathogenic variant, p.(Asp398Asn), in a patient with combined pituitary hormone deficiency, optic nerve hypoplasia and relatively low D4Z4 methylation, without variants in other known genes, and proposed SMCHD1 as a rare cause of this spectrum [34]. In a Chinese family with hypogonadotropic hypogonadism, two sisters carried a nonsense variant in CHD7 inherited from their mother, who had a mild phenotype, and NM_015295.3:c.2582T>C in exon 20 of SMCHD1 inherited from their asymptomatic father, which the authors interpreted as digenic inheritance [35]. These findings rest on isolated cases and do not establish SMCHD1 as a gene of isolated hypogonadism.

3. Clinical Spectrum and Manifestations by System

3.1. Reference cohorts

The clinical description rests on three series. The international cohort of Shaw and colleagues included 40 individuals with complete arhinia (23 male and 17 female), collected by questionnaire and medical record review, who represented 24% of the 80 cases published until then and added 21 new cases [5]. Delaney and colleagues studied 51 patients (27 men and 24 women, aged 1 to 75 years) at the NIH and Massachusetts General Hospital between 1996 and 2019, 47 with arhinia and four with subphenotypes (nasal hypoplasia in two, Binder-type absence of the nasal spine in one, hemiarhinia in one), all carriers of rare missense variants in SMCHD1, except one untested member of a family with a known variant; 11 were assessed in person with detailed endocrine studies [27]. In 2025, Patterson, Graham and Shaw compiled 66 cases of BAMS with an SMCHD1 variant (35 female and 31 male), with denominators varying according to the information available in each report [7]. These series partly overlap and are based on referred cases, so the frequencies describe diagnosed patients and not the population of carriers.

3.2. Prenatal and neonatal period

On fetal ultrasound, the findings described are absence of the nose with a flat facial profile, a normal or protruding lip and a normal brain, facial oedema, polyhydramnios and a single umbilical artery [17]. Published cases with a prenatal diagnosis were identified between 18 and 21 weeks [10, 36]. Size at birth is usually normal [17]. Because the newborn is a preferential nasal breather, the absence of a nasal airway causes respiratory distress at birth and difficulty coordinating oral breathing with feeding; many infants require intensive support and tracheostomy, while others are resuscitated with an oral airway and adapt to mouth breathing [7, 12, 17]. Faltering growth in infancy occurs when airway problems compromise feeding [17]. Obstructive sleep apnoea has been documented in patients without a nasal airway [17].

3.3. Face, nose and adjacent structures

In all 40 individuals of the 2017 cohort the arhinia was complete, accompanied in most by a high-arched or cleft palate, absence of the paranasal sinuses, hypoplastic maxilla, nasolacrimal stenosis or atresia and choanal atresia [5]. The nasopharynx ends blindly, the maxilla is poorly pneumatised and there may be skin depressions simulating nostrils without communication with the nasopharynx [12, 17]. Other findings include hypertelorism, telecanthus, a low nasal root, a relatively normal philtrum, bifid uvula, hypodontia of the upper incisors and, occasionally, a smooth philtrum, thin upper lip, single central incisor and minor ear anomalies [17]. Obstruction of the nasolacrimal ducts gives rise to mucoceles and dacryocystoceles [37, 38]. Cone-beam computed tomography in eight patients showed a cribriform plate without perforations [27]. The spectrum includes milder forms, such as hemiarhinia, nasal hypoplasia and isolated anosmia in carriers [5, 23].

3.4. Eyes

Unilateral or bilateral anophthalmia or microphthalmia, iris, uveal or retinal coloboma and cataract are the most frequent ocular anomalies; lens dislocation and glaucoma have also been described, and glaucoma may arise late in structurally abnormal eyes [5, 17]. Six of the 40 individuals in the 2017 cohort had normal ocular anatomy and vision [5], and the ocular phenotype varies even among carriers of the same variant [27].

3.5. Smell, taste and nervous system

Anosmia is universal, owing to the absence of the nose and the olfactory bulbs and tracts; taste is reduced and oral astereognosis has been described [7, 17]. In the Delaney series, scores on the University of Pennsylvania Smell Identification Test (UPSIT) ranged from 6 to 14 out of 40, and the olfactory bulbs or sulci were absent in the 19 patients studied by magnetic resonance imaging [27]. Magnetic resonance imaging shows arhinencephaly, absence of the olfactory sulci and, sometimes, atrophy of the optic chiasm, with normal brain structure in most [17]. Cognition is normal in about three quarters of cases with information; intellectual disability, autism and a thin corpus callosum are occasional [7, 17]. At least 17 adults in the Delaney series attended or completed higher or technical education [27]. Congenital mirror movements, described in X-linked Kallmann syndrome, were present in five of ten patients tested, two of whom had no ANOS1 variant on exome sequencing [27].

3.6. Reproductive axis

The hypogonadism is of hypothalamic origin (congenital GnRH deficiency). In boys it manifests from birth with micropenis and cryptorchidism, and later with small testes and absent puberty; in girls it usually goes unnoticed until adolescence, when puberty fails to progress [7, 39]. In the Delaney series, the five men assessed in person had a history of micropenis or cryptorchidism, testes of 1–3 mL and minimal pubic hair, and the nine adult men studied remotely had no spontaneous puberty and were infertile [27]. LH, FSH, sex steroid and inhibin B concentrations were low in all 27 patients with data, and none of the 11 patients who underwent frequent sampling (every 10 minutes for 8–12 hours) had LH pulses [27]. The remaining anterior pituitary function was normal, including growth hormone (GH) secretion with a physiological nocturnal rise in one patient studied at 16 years, and the hypothalamic-pituitary axis was normal on magnetic resonance imaging, except in one man with pituitary hypoplasia [27].

Females show a broader spectrum. In the Gordon series, the three post-pubertal patients had delayed puberty or menarche abnormalities [8]. The six women assessed in person had primary amenorrhoea, but three reported spontaneous thelarche that stopped at Tanner stage II [27]. Of the 18 women studied remotely, ten were of reproductive age: seven had absent or arrested breast development and primary amenorrhoea, one had arrested thelarche and a single menstruation at 14 years, and two sisters carrying p.(Ser135Asn), those described by Ruprecht and Majewski in 1978, had complete breast development, one with menarche at 16.5 years and the other with menarche at 14 years and regular 25–35-day cycles until menopause at 50 years, despite severe craniofacial dysmorphism [3, 27]. These cases indicate that GnRH neuron migration and function can occur in the complete absence of olfactory structures [27]. In men, stimulation with human chorionic gonadotrophin (hCG) produced small rises in testosterone in several patients, and one patient treated with pulsatile GnRH developed hypergonadotropism with low testosterone and inhibin B, indicating testicular resistance associated with the hypothalamic defect, not explained by cryptorchidism alone [27].

3.7. Growth and other systems

Short stature has been attributed to GH deficiency, described as frequent in a reference work [17] and treated in childhood in one published case [21]; Delaney's endocrine series found, by contrast, normal somatotropic function in the patients studied [27], and a Brazilian patient with hemiarhinia had short stature [23]. Delayed puberty without replacement leads to osteoporosis [17]; the man described by Brasseur sustained osteoporotic fractures after a fall from standing height at 35 years, with low bone mineral density attributed to hypogonadism [8]. Inguinal hernia, scoliosis, flat feet, Achilles tendon shortening and effacement of the aortic sinotubular junction have been described [17, 21]. In the Delaney series, no patient had renal agenesis (ultrasound in 14), severe heart disease (echocardiogram in 12), congenital deafness or hypopigmentation; 31% (4/13) had hypoplastic or absent ribs, in at least two cases due to surgical cartilage harvesting [27]. Patients with BAMS studied with neuromuscular examination and muscle imaging had no signs of muscular dystrophy [40].

3.8. Treated and untreated disease

Without hormone replacement, puberty does not occur in the great majority of patients, and untreated adults remain hypogonadal; with replacement, development of secondary sexual characteristics is achieved, but no cases of biological fertility have been reported [7, 17]. Neonatal survival depends on airway control; beyond that period, most patients have normal intelligence and a long life expectancy, like the index patient, who died at 76 years of unrelated causes [7].

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

Absence of the nose on the fetal profile, with an apparently normal brain and a preserved upper lip, should raise the hypothesis of arhinia and direct the work-up towards distinction from holoprosencephaly [7, 17]. Prenatal identification allows delivery to be planned at a centre able to secure the airway, because the newborn may require intubation or tracheostomy [10, 36]. Ultrasound reliably predicts only very marked nasal hypoplasia [41].

4.2. Newborn and infant

Absence of the nose and nostrils, respiratory distress at birth that improves with an oral airway, and feeding difficulty are the presenting signs [7, 17]. The presence of a normal brain and development, a relatively preserved philtrum and Cupid's bow, and ocular anomalies (microphthalmia, coloboma, cataract) points to Bosma syndrome and not holoprosencephaly [17]. In a boy with arhinia, micropenis and cryptorchidism are early signs of GnRH deficiency and justify hormonal testing during minipuberty [27, 42]. Urgent signs are respiratory obstruction, obstructive apnoea, inability to feed orally and dacryocystocele, which may require surgery [17, 38].

4.3. Childhood and adolescence

In a child with known arhinia or hemiarhinia, short stature should prompt assessment of the somatotropic axis [17, 23]. In adolescence, absent puberty is the main warning sign; in girls, the nasal anomaly may be the only clue to hypogonadotropic hypogonadism, which does not manifest in childhood with micropenis or cryptorchidism [39]. A Brazilian series of nine patients with arhinia, hemiarhinia or BAMS found previously undiagnosed neuroendocrine dysfunction in several patients, including primary hypothyroidism in a case of isolated hemiarhinia, and concluded that endocrine screening is seldom performed [43].

4.4. Relatives

Isolated congenital anosmia, asymmetric nostrils, dental anomalies and a hypoplastic nose in a parent may correspond to carriers of the same SMCHD1 variant [3, 12].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are no consensus-validated diagnostic criteria. Brasseur and colleagues proposed as criteria arhinia, hypoplastic maxilla, normal cognition and, in males, hypogonadotropic hypogonadism [21]; a 2023 Vietnamese report took up the same criteria and added as associated findings microphthalmia with or without coloboma, anosmia, high-arched palate and absence of the paranasal sinuses and olfactory bulbs [44]. The complete triad defines Bosma syndrome; arhinia without ocular anomaly or without hypogonadism, hemiarhinia and nasal hypoplasia fall within the same spectrum when an SMCHD1 variant is identified [5, 23]. Patient C1 of the 2017 cohort, for example, had arhinia and hypogonadism without microphthalmia and had not been regarded by the original authors as Bosma syndrome [3, 8, 45].

5.2. Clinical and imaging assessment

The initial assessment includes a complete dysmorphological examination, a three-generation pedigree with enquiry about anosmia, nasal and dental changes in relatives, and a history of exposures during pregnancy [41]. Computed tomography of the face, with three-dimensional reconstruction, defines the absence of the nasal bones and paranasal sinuses and the maxillary hypoplasia, and is used for surgical planning; brain magnetic resonance imaging assesses the olfactory bulbs and sulci, the midline and the pituitary [12, 27, 45]. A complete ophthalmological assessment documents microphthalmia, coloboma, cataract and intraocular pressure [17].

5.3. Endocrine assessment

Diagnosis of the hypogonadism follows the principles for congenital hypogonadotropic hypogonadism: morning measurement of LH, FSH, testosterone or oestradiol, prolactin, free thyroxine, thyroid-stimulating hormone (TSH), cortisol, insulin-like growth factor 1 (IGF-1) and IGFBP3, to exclude combined pituitary hormone deficiency; inhibin B, anti-Müllerian hormone and GnRH or hCG stimulation tests to assess severity and gonadal function; bone age; bone densitometry; and renal ultrasound [42]. In boys, basal testosterone, LH and FSH concentrations between 14 and 90 days of life (minipuberty) allow early diagnosis; after that period, stimulation testing is used [42]. In published cases, LH and FSH were undetectable or very low (for example, LH <0.1 IU/L and FSH 0.3 IU/L at 13 years, with testosterone 1.1 nmol/L) [43, 45], and frequent sampling showed LH secretion without pulsatility [27]. Olfaction can be documented with the UPSIT [27, 45].

5.4. Genetic testing

The first-line test is sequencing of SMCHD1, by gene panel, exome or sequencing targeted to exons 3–13, where all the arhinia-associated variants described are located [5, 12]. The detection rate was 84% (32/38 probands) in the 2017 cohort and 100% (14/14) in the Gordon series, which included only BAMS [5, 6]; Inoue and colleagues report 86% for the same cohort [22]. These proportions refer to patients referred to research centres and are not equivalent to clinical sensitivity in a healthcare setting. When the exome is used, adequate coverage of exons 3–13 should be confirmed. The case described by Brasseur illustrates the limits of interpretation: exome sequencing of the patient and parents, published in 2016, did not identify a causal variant [8], and the 2017 cohort later found in the same patient the variant p.(Glu136Asp), inherited from the father, who had a diagnosis of limb-girdle muscular dystrophy [3]; an analysis centred on de novo variants does not detect variants inherited from parents with a minimal or different phenotype. In a case without an SMCHD1 variant, chromosomal microarray can detect rearrangements such as the 3q11.2–q13.31 deletion described before the SMCHD1 era [20]. The report should state the gene, the MANE transcript with version (NM_015295.3), the variant in HGVS nomenclature (c. and p.), zygosity, the ACMG/AMP class and, where possible, parental origin [4].

5.5. D4Z4 methylation as a functional test

D4Z4 methylation analysis is a functional test for SMCHD1 variants: in FSHD2, the diagnostic threshold corresponds to methylation at the FseI site below 25% (controls 46.8% ± 14.1%) or a delta1 score below −20% [11]. In arhinia, 74% of variant carriers had hypomethylation similar to that of FSHD2, but some patients with BAMS had normal methylation [3, 5]. Hypomethylation supports the pathogenicity of a variant of uncertain significance, but its absence does not exclude the diagnosis; in FSHD2, 20% (5/19) of the missense variants found in controls were predicted to be pathogenic by two of three algorithms without hypomethylation, which shows the limits of in silico prediction [11]. D4Z4 methylation and characterisation of the 4q35 allele (haplotype and number of units) also identify patients with arhinia who meet the genetic and epigenetic criteria for FSHD2 (section 6.4) [40]; laboratory procedures follow the 2024 best practice guidelines for the genetic diagnosis of FSHD [46]. Long-read sequencing allows the length, haplotype and methylation of D4Z4 alleles to be characterised in a single assay, and was applied in 2026 to two patients with BAMS, in a research setting [47].

5.6. Prenatal and preimplantation diagnosis

The first prenatal diagnosis of total arhinia confirmed after delivery was published in 2000, based on absence of the nose on the fetal profile [48]. Second-trimester ultrasound identifies arhinia from 18 weeks, and fetal magnetic resonance imaging complements the assessment of the brain and face [10, 36, 49]. When the familial variant is known, invasive prenatal diagnosis and preimplantation genetic testing are technically possible, but incomplete penetrance and variable expressivity make it impossible to predict severity from the genotype [5, 27]. In the case of Zemtsov and colleagues, detection at 18 weeks in a fetus without other anomalies, with normal cell-free fetal DNA, karyotype and microarray, led to termination of pregnancy without study of SMCHD1 [10].

5.7. Practical algorithm

Faced with arhinia or hemiarhinia, the first step is to secure the airway and exclude holoprosencephaly by brain magnetic resonance imaging; then sequence SMCHD1 (exons 3–13 at a minimum), with microarray if negative, and study the parents [5, 7]. In parallel, ophthalmological assessment is carried out and, in boys, hormonal testing during minipuberty [27, 42]. A variant of uncertain significance can be re-evaluated with D4Z4 methylation and family segregation [11]. Endocrine assessment is repeated at pubertal age in both sexes, and study of the 4q35 allele can be offered to adult carriers, with prior counselling on the uncertain meaning of the result [40].

6. Differential Diagnosis

6.1. Comparative table

6.2. Holoprosencephaly

Holoprosencephaly is the main diagnosis to exclude in a newborn without a nose. Severe forms may include arhinia or hemiarhinia, midface hypoplasia, clefts and colobomas, as in Bosma syndrome, but development is usually delayed and the reproductive axis is spared [7]. In Bosma syndrome, brain structure is normal in most, and the philtrum and Cupid's bow of the upper lip are relatively preserved, which is a clinical clue [17]. Loss-of-function variants of TGIF1 (holoprosencephaly type 4) may include arhinia, microphthalmia and cleft palate, and TGIF1 emerged as a dysregulated gene in cells from patients with SMCHD1-related arhinia [5].

6.3. CHARGE and congenital hypogonadotropic hypogonadism

CHARGE syndrome shares coloboma, choanal atresia and congenital GnRH deficiency with Bosma syndrome, but the nose is present, with a broad, prominent root, and there is heart disease, ear anomalies and developmental delay [7]. Kallmann syndrome combines anosmia and hypogonadotropic hypogonadism with a normal external nose; mirror movements, considered characteristic of the ANOS1-related form, also occur in SMCHD1-related arhinia [27]. In a boy with arhinia and hypogonadism studied before 2017, no variants were found in KAL1 (now ANOS1), FGFR1, PROK2, PROKR2, FGF8, CHD7 or GNRHR [45]; the patient was later included in the genetic cohort with the variant p.(Leu141Phe) [3].

6.4. Relationship with facioscapulohumeral muscular dystrophy type 2

BAMS and FSHD2 share the gene, some variants and D4Z4 hypomethylation, but the clinical phenotype separates them. In 14 patients with FSHD2 and four relatives carrying N-terminal missense variants, Mul and colleagues found no congenital defects or dysmorphism typical of BAMS; one patient had anosmia after nasal surgery, another hyposmia and one man infertility of unknown cause with normal puberty [30]. In 11 individuals with congenital nasal anomalies and variants in exons 3–11, Mohassel and colleagues identified three (one man and two women, aged 25–51 years) who met the strict genetic and epigenetic criteria for FSHD2 (D4Z4 allele with fewer than 21 units in cis with 4qA and methylation below 30%), without clinical manifestations or muscle imaging changes typical of FSHD2, although their cells expressed DUX4 in vitro [40]. The 2025 review states that there are no reports of BAMS and FSHD2 in the same individual or the same family [7]. There are, however, divergent data: in the 2017 cohort, two probands with arhinia met all four susceptibility criteria (pathogenic variant, hypomethylation below 25%, permissive haplotype and a 4q allele of 11–28 units), and at least one had symptoms suggestive of FSHD2 [5]; and the p.(Glu136Asp) variant of a man with BAMS was inherited from his father, who had a diagnosis of limb-girdle muscular dystrophy without facial dysmorphism [3]. Because a quarter of individuals meeting the genetic criteria for FSHD2 are asymptomatic, and because patients with arhinia who have undergone facial reconstruction may have facial weakness that is difficult to recognise, the risk of FSHD2 in carriers of a BAMS-associated variant has not been quantified [5]. The distinction between the two phenotypes appears to depend on genetic or environmental modifiers that are still unknown [30, 40].

7. Treatments and Risk Management Strategies

7.1. Organisation of care and limits of the evidence

There is no treatment targeting the molecular cause and no specific guideline for Bosma syndrome. Management is symptomatic and multidisciplinary, involving neonatology and intensive care, otorhinolaryngology, plastic and maxillofacial surgery, ophthalmology and oculoplastics, paediatric and adult endocrinology, medical genetics, dentistry, speech and feeding therapy, and psychology [7, 37]. Surgical recommendations rest on case reports and small series, and endocrine recommendations are extrapolated from the guidelines for congenital hypogonadotropic hypogonadism and pubertal induction, an analogous condition in which the same drugs are used [13, 42]. The Endo-ERN guideline recommends that children and adolescents requiring pubertal induction be followed by a multidisciplinary team (recommendation R1.1) [13].

7.2. Airway and feeding in the newborn

Airway control is the first priority [36]. Most newborns were resuscitated with an oral airway and some adapt to oral breathing without further measures, but many require intensive support and tracheostomy because they cannot coordinate oral breathing with feeding [7, 17]. Surgical canalisation of a nasal passage is an alternative, and feeding may require an orogastric tube or gastrostomy [12]. In the case of Tryggestad and colleagues, the tracheostomy was kept until 2 years of age [45]; in the case of Fuller and colleagues, with a prenatal diagnosis at 21 weeks, the newborn was intubated at birth and later had a tracheostomy [36]. Without a functional nasal airway, oral breathing is permanent and is associated with obstructive sleep apnoea [17], and chronic mouth breathing has been associated with gingivitis [12].

7.3. Reconstruction of the nose and midface

Reconstruction is staged and individualised, and most techniques were developed case by case [12]. There are two objectives, which may be pursued separately: creation of a functional nasal airway and construction of an external nose with acceptable facial proportions [12]. Creating an airway depends on the existence of paranasal sinuses and the degree of bone hypoplasia, carries a high operative risk because of the proximity of the palate and maxilla to the skull base, and a risk of total or near-total restenosis; therefore, when breathing is not the main problem, it is reasonable to prioritise the external nose [12].

In constructing the forehead flap, the vascular anatomy may be abnormal: in one patient, computed tomography showed absence of the left supratrochlear foramen, and the flap was based on the right supratrochlear artery, identified by Doppler [12]. Costal cartilage harvesting may explain some of the hypoplastic or absent ribs described in adults [27]. 3D bioprinting of nasal cartilage was used in at least one patient, whose implant had to be removed because of infection [7].

7.4. Lacrimal drainage and eyes

Absence of the nasolacrimal ducts gives rise to mucoceles or dacryocystoceles, which are difficult to drain without a nasal cavity [37]. In partial arhinia, navigation-guided dacryocystorhinostomy into the contralateral nasal cavity, through a septal window, resolved epiphora in a 16-year-old patient, with patency at 6 months [54]. In complete arhinia, dacryocystectomy has been described as an alternative in a patient with BAMS and dacryocystocele [38]. Microphthalmia, coloboma and cataract follow the usual ophthalmological approach, with surveillance for glaucoma [17].

7.5. Hypogonadism: male infant

According to the European consensus on congenital hypogonadotropic hypogonadism, cryptorchidism should be corrected by orchidopexy before 1 year of age, and micropenis may be treated with testosterone, dihydrotestosterone or gonadotrophins between the 1st and 6th month; monitoring includes testicular volume, testosterone, LH, FSH, inhibin B and anti-Müllerian hormone [42]. Published reports of Bosma syndrome do not describe these treatments in infancy, so their application is extrapolated [27, 42].

7.6. Pubertal induction

The Endo-ERN guideline (2022), developed with GRADE methodology, recommends specialist assessment of any girl without signs of puberty at 13 years and of girls with a condition at risk of hypogonadism from 8 years (R2.1), exclusion of spontaneous puberty and treatable causes before induction (R2.3), and initiation of individualised induction at 11 years when hypogonadism is confirmed (R2.4, evidence +OOO), with gradual dose increases over 2–3 years [13]. The 2015 European consensus indicates starting treatment in boys at 14–15 years, earlier when there are specific signs of congenital hypogonadotropic hypogonadism such as anosmia [42]. In Bosma syndrome, anosmia and arhinia are present from birth, which allows diagnosis before pubertal age. For boys with secondary hypogonadism, the guideline suggests discussing two options, testosterone or gonadotrophins (R4.1, +OOO); testosterone does not induce testicular growth or spermatogenesis [13]. Clinical follow-up takes place every 3–6 months, with assessment of pubertal maturation, bone age and growth velocity (R3.6) [13].

Oestrogen doses for pubertal induction are based mainly on experience in Turner syndrome [13]. Bioidentical oestradiol is preferred to ethinylestradiol and conjugated oestrogens, and combined oral contraceptives are not recommended for inducing puberty [13]. Relevant adverse effects of testosterone are rare; priapism has been described with injectable forms, and monitoring includes trough testosterone, haematocrit and, in adults, prostate-specific antigen [13, 42]. The doses in the table come from guidelines for hypogonadotropic hypogonadism and other causes of hypogonadism; their use in Bosma syndrome is an extrapolation to an analogous condition, without a specific trial [13].

7.7. Fertility

No cases of biological fertility have been reported in Bosma syndrome [7]. The two patients treated with pulsatile GnRH in the Delaney series illustrate different responses by sex [27]. One man, induced with testosterone 150 mg intramuscularly per month at 14 years, received at 16 years human menopausal gonadotrophin (hMG) 75 U with hCG 1000 U three times weekly; after 5 months testosterone rose to 447 ng/dL (15.5 nmol/L) and the testes from 2 to 6 mL, the ejaculate obtained by prostatic massage contained no spermatozoa, but testicular biopsy showed Leydig cells, active spermatogenesis up to the spermatid stage and rare spermatozoa [27]. He stopped gonadotrophins because of lack of insurance coverage and, at 42 years, started pulsatile GnRH, increased over 1 year up to 800 ng/kg per bolus (physiological dose 25–50 ng/kg per bolus); testicular volume did not exceed 3–4 mL, peak testosterone was 138 ng/dL (4.8 nmol/L) and FSH rose to 15.6 IU/L with low inhibin B, indicating testicular resistance [27]. A woman who started oestrogens at 16 years received at 23 years pulsatile GnRH 75 ng/kg per intravenous bolus every 90 minutes for 7 days and then every 60 minutes, with a normal pituitary response, a dominant follicle on day 9 and ovulation confirmed on day 21 (with no wish for pregnancy at that time) [7, 27]. In men, the European consensus proposes for fertility hCG alone or with FSH, FSH before hCG, or a GnRH pump; in women, FSH with hCG or pulsatile GnRH [42]. The index patient of the syndrome had three children by in vitro fertilisation with donor sperm [7]. These data come from isolated cases and do not allow the probability of success to be estimated.

7.8. Growth hormone

The sources diverge on the frequency of GH deficiency: a reference work considers it common [17], one published case was treated with GH in childhood [21], and the most detailed endocrine series found normal GH secretion [27]. The indication for treatment therefore follows biochemical demonstration of the deficiency, according to the usual criteria. As there is no published dose for Bosma syndrome, the reference doses are those of the somatropin label for paediatric GH deficiency: 0.16–0.24 mg/kg per week, subcutaneously, divided into 6–7 injections, in the US label of Genotropin® [57], and 0.025–0.035 mg/kg per day or 0.7–1.0 mg/m² per day in the European Summary of Product Characteristics (SmPC) of Omnitrope® [58]. The two dosing regimens are equivalent in order of magnitude (0.16–0.24 mg/kg per week corresponds to about 0.023–0.034 mg/kg per day).

7.9. Regulatory framework

7.10. Trials, research and new developments

There are no registered therapeutic clinical trials for arhinia or Bosma syndrome; a search of ClinicalTrials.gov returned an NIH observational study on the genetics of inherited reproductive disorders (NCT01500447, recruiting since 2012, target of 850 participants, updated in October 2026), which includes patients with congenital hypogonadism, and a completed observational single-patient study with a 3D-printed nasal stent (NCT02559050) [53, 59]. A negative search does not prove that no studies exist in other registries.

The existing studies are descriptive or preclinical, without a comparison group, and do not allow the efficacy of interventions to be estimated. In the last 12 months the following were published: the clinical review of 66 cases (July 2025) [7]; the Brazilian series from the Hospital for Rehabilitation of Craniofacial Anomalies of the University of São Paulo on the neuroendocrine axis in arhinia and hemiarhinia (2026, descriptive study; an erratum was published) [43]; and three preclinical studies from 2026, on cranial placode differentiation in patient iPSCs [29], on the recruitment of SMCHD1 to chromatin [25] and on long-read sequencing of D4Z4 in patients with FSHD and BAMS [47]. Gurzau and colleagues suggested, on the basis of the increased ATPase activity with BAMS variants, that the extended ATPase domain region could be a therapeutic target to increase SMCHD1 activity in FSHD, a preclinical hypothesis [28]; Patterson and colleagues propose patients with BAMS as a model to identify protective factors against FSHD2 [7].

7.11. Anaesthesia, pregnancy and transition

The absence of nasal cavities rules out any nasal access to the airway, and the high-arched or cleft palate and maxillary hypoplasia add difficulty; breathing is oral or through a tracheostomy, which shapes the anaesthetic planning of the multiple reconstructive operations [7, 12, 17]. No reports of pregnancy in women with Bosma syndrome were found in the sources consulted, and no cases of biological fertility have been reported [7]. Transition to adult care should ensure continuity of hormone replacement, monitoring of bone mass and discussion of fertility, as recommended for hypogonadism of paediatric onset [13].

8. Reproductive Options and Family Counselling

8.1. Mode of inheritance and recurrence risk

Bosma syndrome is autosomal dominant. In most cases the variant arises de novo: this was so in all ten complete simplex trios of the 2017 cohort and in the 11 families with parental DNA in the Gordon series [3, 5]. When the tested parents are not carriers, the recurrence risk for siblings is low but not zero, because of the possibility of germline mosaicism, which the sources consulted do not quantify for this gene. When a parent is a carrier, the risk of transmission is 50% in each pregnancy, but the phenotype of the child is not predictable: in multiplex families, carrier parents had isolated anosmia, asymmetric nostrils, dental anomalies, a hypoplastic nose or no signs, and the children complete arhinia [3, 5, 12]. In one example, two half-sisters, one with a hypoplastic nose and the other with complete arhinia, inherited p.(Gln400Leu) from their father with isolated congenital anosmia [3, 7]. Penetrance has not been estimated, and severity does not correlate with the variant [27].

8.2. Testing of relatives

Testing targeted to the familial variant should be offered to the proband's parents, even if they have no signs, and to relatives with anosmia, nasal or dental changes [5, 12]. Bargiela and colleagues suggest that isolated anosmia could come to be used to guide genetic screening before conception, a hypothesis not yet evaluated [12]. In asymptomatic carriers, the result is mainly of reproductive value.

8.3. Carriers and FSHD2

The information given about the risk of FSHD2 should reflect the uncertainty. Reference reviews stress that patients with FSHD2 and their carrier relatives do not develop arhinia and that patients with BAMS do not have muscular dystrophy [7, 30, 40]. However, a minority of patients with arhinia meet the genetic and epigenetic criteria for susceptibility to FSHD2 (3/11 in one series; two probands and five potentially at risk in another), one proband had suggestive symptoms, and one variant was inherited from a father with a diagnosis of muscular dystrophy [3, 5, 40]. As FSHD2 requires a permissive 4qA allele of 8–20 units, present in about 12% of the European population, the risk depends on the D4Z4 genotype of each carrier [11]. Transmission of FSHD2 follows digenic rules.

8.4. Prenatal and preimplantation diagnosis

Arhinia can be identified by ultrasound in the second trimester, between 18 and 21 weeks in published cases, and fetal magnetic resonance imaging complements the assessment [10, 36, 49]. With a known familial variant, prenatal diagnosis by amniocentesis or chorionic villus sampling and preimplantation genetic testing are possible; counselling should explain that the presence of the variant does not predict severity, which ranges from anosmia to complete arhinia [5, 27]. Prenatal diagnosis is also of value for planning delivery with an airway team [10].

8.5. Fertility of the patient

Adult patients with Bosma syndrome require treatment with gonadotrophins or GnRH to attempt fertility, with a limited testicular response in the men studied and a documented ovulatory response in one woman [27]. The risk of transmitting the variant to each child is 50% [5]. Fertilisation with donor gametes is an alternative, used by the index patient [7].

8.6. Counselling of minors

Testing asymptomatic children from affected families is mainly of future reproductive value, since the malformation is evident at birth; in affected children, molecular diagnosis confirms the aetiology and guides endocrine surveillance [5, 39].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

Prevalence is below 1 per million according to Orphanet, an estimate by class and not a population study [1]. The numbers available are counts of published cases: 36 cases of arhinia up to 2007 [20]; fewer than 50 reports of Bosma syndrome up to 2016 [21]; about 80 cases of arhinia without holoprosencephaly in the century before 2017, 17 of them with the complete triad [5]; fewer than 100 cases of arhinia, according to a 2022 reference work [17]; 41 families with BAMS and a characterised variant in 2019 [11]; and 66 cases with an SMCHD1 variant in 2025 [7]. These figures overlap and reflect the collection effort, not incidence.

9.2. Geographical distribution and populations

The cases described come from the USA (NIH and Massachusetts General Hospital cohorts), European countries (Germany, Ireland, Norway, Switzerland, Spain), Mexico, Central America, China, Japan and Vietnam [3, 5, 12, 24, 27, 44, 60]. The patients in the 2017 cohort included different ethnicities, and the association with SMCHD1 remained significant in all of them [5]. The recurrence of the same positions in unrelated families, with many de novo cases, points to mutational hotspots and not to founder variants [11].

9.3. Brazil and Portugal

The Hospital for Rehabilitation of Craniofacial Anomalies of the University of São Paulo, in Bauru, published a patient with hemiarhinia, short stature and hypogonadotropic hypogonadism carrying p.(Glu473Val) [23] and a series of nine patients (three with isolated hemiarhinia, three with hemiarhinia and other malformations and three with BAMS), in which two of the three patients with BAMS had undetectable LH and FSH and one had no abnormalities [43]. A Brazilian case of isolated arhinia diagnosed by fetal magnetic resonance imaging had normal psychological and cognitive development at 8 years [49]. The same p.(Glu473Val) variant was described in a Central American family [12]. The sources consulted do not include Portuguese cases.

9.4. Reference networks and associations

In the European Union, Bosma syndrome falls within ERN CRANIO, for craniofacial and ear, nose and throat anomalies, ERN-EYE, for ocular anomalies, and Endo-ERN, for hypogonadism [14–16]. Orphanet lists expert centres, patient organisations and a French national diagnosis and care protocol on ocular colobomas (Haute Autorité de Santé, 2024) [1]. The Children's Craniofacial Association, based in the USA, supports families with craniofacial malformations [61]. The NIH maintain an observational study open to patients with congenital hypogonadism [59].

10. Illustrative Clinical Case

Bargiela and colleagues described in 2023 two young women from a Central American family, daughters from two different relationships of the same grandfather, both with total arhinia; a third relative with arhinia, from the previous generation, had died, and the mother of one of the young women had congenital anosmia [12]. The first patient had a very short nasal root with two blind-ending skin depressions, zygomas and lateral infraorbital rims with normal projection, an omega-shaped maxilla with reduced vertical, sagittal and transverse dimensions, gingivitis attributed to obligatory mouth breathing and, on imaging, absence of the nasal bones, hypoplasia of the medial maxilla and the nasomaxillary processes and absence of the left supratrochlear foramen [12]. The second patient had marked midface deficiency, absence of the bony and soft-tissue components of the nose, a single blind nasal opening on the left, reduced zygomatic projection, an incomplete cleft of the left upper lip, chin deviation and a canted occlusion [12]. The preoperative photograph of the two patients, in anterior and lateral views, shows the concave facial profile resulting from the maxillary hypoplasia (Figure 2 of the article) [12].

Sanger sequencing of exons 3–13 of SMCHD1 in the two patients and the two mothers identified the heterozygous variant c.1418A>T p.(Glu473Val) in exon 11, in the transducer domain of the ATPase, in both patients and in the mother with anosmia, and not in the mother without signs; the variant was absent from gnomAD and was predicted to be deleterious by SIFT, PolyPhen, MutationTaster and FATHMM, at a position where another variant, p.(Glu473Gln), had already been described in a patient with arhinia [12]. The same variant was later described in a Brazilian patient with hemiarhinia, short stature and hypogonadotropic hypogonadism [23]. As the two patients breathed through the mouth without respiratory failure and had no paranasal sinuses, the team prioritised the external nose: Le Fort II osteotomy with external distraction (1 mm per day for 3 weeks, consolidation of 3 months), forehead expansion up to 120 mL, a paramedian forehead flap over a costal cartilage framework fixed with screws to the root and the anterior nasal spine, pedicle division at 2 weeks and, in one of the patients, reconstruction of the tip and opening of the nostrils with composite grafts from the auricular concha [12]. Both recovered without complications. The report does not describe the endocrine or ophthalmological assessment of the patients, and neither had signs of muscular dystrophy [12]. The approach was defined case by case and does not constitute a validated protocol; creation of a nasal airway, which was not attempted, carries a high risk of restenosis [12].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The period of greatest risk is the neonatal period, because of airway obstruction and feeding difficulty [7, 12]. Beyond that period, most patients have normal intelligence (75%, 37/49 cases with information), and life expectancy does not appear to be reduced: the index patient of the 1972 and 1981 description practised law and was a juvenile court judge, raised a family and died at 76 years of unrelated causes [7]. At least 17 adults in the NIH series attended or completed higher or technical education [27]. Psychosocial adaptation to a visible facial difference and to hypogonadism depends on temperament, resilience and community support, according to reports from adults [7]. Long-term morbidities include permanent anosmia, visual impairment in cases with microphthalmia, the need for lifelong hormone replacement (100% of the 20 cases with information), infertility, the risk of osteoporosis without replacement and the sequelae of reconstructive surgery [7, 17].

11.2. Surveillance

There is no specific surveillance protocol. The table brings together the measures supported by the sources, extrapolated, where indicated, from the guidelines for hypogonadotropic hypogonadism.

12. Summary and Final Considerations

Bosma syndrome combines congenital absence of the nose and olfactory structures with ocular anomalies (microphthalmia, coloboma, cataract) and hypogonadotropic hypogonadism due to congenital GnRH deficiency, usually with normal intelligence. Since 2017 it has been known to be caused, in the great majority of cases, by heterozygous missense variants in exons 3–13 of SMCHD1, which encode the extended ATPase domain of an epigenetic repressor; the variants usually arise de novo, but may be inherited from parents with isolated anosmia or no signs, reflecting incomplete penetrance and variable expressivity. The same gene causes FSHD2, with a different variant spectrum and in combination with a permissive D4Z4 allele; the two diseases share D4Z4 hypomethylation and some variants, but their clinical coexistence has not been established, and the mechanism that separates the two phenotypes remains under study, with data pointing to the cranial placode as the cellular target and to genetic or environmental modifiers. Diagnosis is based on the phenotype, exclusion of holoprosencephaly and sequencing of SMCHD1, with D4Z4 methylation as a complementary functional test. Management is supportive: airway and feeding in the newborn, staged nasal and maxillary reconstruction, lacrimal drainage surgery and ophthalmological care, and sex hormone replacement according to the guidelines for hypogonadotropic hypogonadism, with gonadotrophins or pulsatile GnRH for fertility, so far without reported cases of biological fertility. The evidence consists of case series and preclinical studies, and there is no targeted therapy and there are no ongoing clinical trials.

13. References

1. Orphanet. Hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome (ORPHA:2250). https://www.orpha.net/en/disease/detail/2250
2. National Center for Biotechnology Information. ClinVar: SMCHD1 variants associated with arrhinia with choanal atresia and microphthalmia syndrome [Internet]. https://www.ncbi.nlm.nih.gov/clinvar/?term=SMCHD1%5Bgene%5D
3. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: *614982 – Structural maintenance of chromosomes flexible hinge domain-containing protein 1; SMCHD1. Last edited 30/04/2024. https://omim.org/entry/614982
4. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348. PMID: 28967166.
5. Shaw ND, Brand H, Kupchinsky ZA, Bengani H, Plummer L, Jones TI, et al. SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nat Genet. 2017;49(2):238-248. doi:10.1038/ng.3743. PMID: 28067909. PMC5473428.
6. Gordon CT, Xue S, Yigit G, Filali H, Chen K, Rosin N, et al. De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development. Nat Genet. 2017;49(2):249-255. doi:10.1038/ng.3765. PMID: 28067911.
7. Patterson KJK, Graham JM, Shaw ND. Syndrome of the Month: Bosma Arhinia Microphthalmia Syndrome. Am J Med Genet A. 2025;197(11):e64127. doi:10.1002/ajmg.a.64127. PMID: 40598710.
8. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: #603457 – Arhinia, choanal atresia, microphthalmia, and hypogonadotropic hypogonadism; Bosma arhinia microphthalmia syndrome. Last edited 17/11/2023. https://omim.org/entry/603457
9. Preston MK, Wang LH. Facioscapulohumeral Muscular Dystrophy. 1999 Mar 8 [updated 2025 Jul 10]. In: Adam MP, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–2026. https://www.ncbi.nlm.nih.gov/books/NBK1443/
10. Zemtsov GE, Swartz AE, Kuller JA. Prenatal Diagnosis of Arhinia. AJP Rep. 2022;12(2):e127-e130. doi:10.1055/s-0042-1748521. PMID: 35941965. PMC9356769.
11. Lemmers RJLF, van der Stoep N, Vliet PJV, Moore SA, San Leon Granado D, Johnson K, et al. 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. J Med Genet. 2019;56(10):693-700. doi:10.1136/jmedgenet-2019-106168. PMID: 31243061. PMC6800092.
12. Bargiela M, Kueper J, Serebrakian AT, Browne MR, Brogna S, Peacock ZS, et al. Nasal Construction in Congenital Arhinia Due to Novel SMCHD1 Gene Variant. J Craniofac Surg. 2023;34(3):849-854. doi:10.1097/scs.0000000000009261. PMID: 36944600. PMC10802859.
13. Nordenström A, Ahmed SF, van den Akker E, Blair J, Bonomi M, Brachet C, et al. Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline. Eur J Endocrinol. 2022;186(6):G9-G49. doi:10.1530/eje-22-0073. PMID: 35353710. PMC9066594.
14. ERN CRANIO – European Reference Network for rare and/or complex craniofacial anomalies and ENT disorders. https://www.ern-cranio.eu/
15. ERN-EYE – European Reference Network for rare eye diseases. https://www.ern-eye.eu/
16. Endo-ERN – European Reference Network on rare endocrine conditions. https://endo-ern.eu/
17. Jones KL, Jones MC, del Campo M. Bosma arhinia microphthalmia syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 346–347.
18. Graham JM, Lee J. Bosma arhinia microphthalmia syndrome. Am J Med Genet A. 2006;140(2):189-193. doi:10.1002/ajmg.a.31039. PMID: 16353241.
19. Thiele H, Musil A, Nagel F, Majewski F. Familial arhinia, choanal atresia, and microphthalmia. Am J Med Genet. 1996;63(1):310-313. doi:10.1002/(SICI)1096-8628(19960503)63:1<310::AID-AJMG51>3.0.CO;2-N. PMID: 8723126.
20. Sato D, Shimokawa O, Harada N, Olsen OE, Hou JW, Muhlbauer W, et al. Congenital arhinia: molecular-genetic analysis of five patients. Am J Med Genet A. 2007;143A(6):546-552. doi:10.1002/ajmg.a.31613. PMID: 17304554.
21. Brasseur B, Martin CM, Cayci Z, Burmeister L, Schimmenti LA. Bosma arhinia microphthalmia syndrome: Clinical report and review of the literature. Am J Med Genet A. 2016;170A(5):1302-1307. doi:10.1002/ajmg.a.37572. PMID: 26842768.
22. Inoue K, Bostan H, Browne MR, Bevis OF, Bortner CD, Moore SA, et al. DUX4 double whammy: The transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose. Sci Adv. 2023;9(7):eabq7744. doi:10.1126/sciadv.abq7744. PMID: 36800423. PMC9937577.
23. Kokitsu-Nakata NM, Segarra VCD, Tonello C, Brandão MM, Alonso N, Zechi-Ceide RM. Hemiarhinia caused by a missense variation in SMCHD1: A mild phenotype in the clinical spectrum of Bosma arhinia microphthalmia syndrome. Am J Med Genet A. 2024;194(10):e63640. doi:10.1002/ajmg.a.63640. PMID: 38808953.
24. Yang JL, Gu H, Yuan ZZ, Xie XH, Yang YF, Tan ZP. Identification of a pathogenic SMCHD1 variant in a Chinese patient with bosma arhinia microphthalmia syndrome: a case report. BMC Med Genomics. 2024;17(1):136. doi:10.1186/s12920-024-01907-6. PMID: 38773541. PMC11110391.
25. Constantinescu F, Szczurek AT, Nesterova TB, Wei G, Almeida M, Kelley JR, et al. Selective interaction of SMCHD1 with chromatin is governed by LRIF1 and SMCHD1 ATPase activity. Nat Commun. 2026;17(1):7636. doi:10.1038/s41467-026-74427-9. PMID: 42303997. PMC13434421.
26. Dion C, Roche S, Laberthonnière C, Broucqsault N, Mariot V, Xue S, et al. SMCHD1 is involved in de novo methylation of the DUX4-encoding D4Z4 macrosatellite. Nucleic Acids Res. 2019;47(6):2822-2839. doi:10.1093/nar/gkz005. PMID: 30698748. PMC6451109.
27. Delaney A, Volochayev R, Meader B, Lee J, Almpani K, Noukelak GY, et al. Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose. J Clin Endocrinol Metab. 2020;105(5):dgaa065. doi:10.1210/clinem/dgaa065. PMID: 32034419. PMC7108682.
28. Gurzau AD, Chen K, Xue S, Dai W, Lucet IS, Ly TTN, et al. FSHD2- and BAMS-associated mutations confer opposing effects on SMCHD1 function. J Biol Chem. 2018;293(25):9841-9853. doi:10.1074/jbc.ra118.003104. PMID: 29748383. PMC6016475.
29. Rao VV, Ji X, Heng JYY, Magdinier F, Reversade B, Xue S. Cranial placode differentiation defect in individuals born without a nose. Stem Cell Reports. 2026;21(5):102890. doi:10.1016/j.stemcr.2026.102890. PMID: 41962546. PMC13163215.
30. Mul K, Lemmers RJLF, Kriek M, van der Vliet PJ, van den Boogaard ML, Badrising UA, et al. FSHD type 2 and Bosma arhinia microphthalmia syndrome: Two faces of the same mutation. Neurology. 2018;91(6):e562-e570. doi:10.1212/wnl.0000000000005958. PMID: 29980640. PMC6105048.
31. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: #158900 – Facioscapulohumeral muscular dystrophy 1; FSHD1. Last edited 29/04/2026. https://omim.org/entry/158900
32. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: #158901 – Facioscapulohumeral muscular dystrophy 2, digenic; FSHD2. Last edited 01/05/2023. https://omim.org/entry/158901
33. Gérard L, Delourme M, Tardy C, Ganne B, Perrin P, Chaix C, et al. SMCHD1 genetic variants in type 2 facioscapulohumeral dystrophy and challenges in predicting pathogenicity and disease penetrance. Eur J Hum Genet. 2025;33(6):784-792. doi:10.1038/s41431-024-01781-x. PMID: 39725690. PMC12185756.
34. Kinjo K, Nagasaki K, Muroya K, Suzuki E, Ishiwata K, Nakabayashi K, et al. Rare variant of the epigenetic regulator SMCHD1 in a patient with pituitary hormone deficiency. Sci Rep. 2020;10(1):10985. doi:10.1038/s41598-020-67715-x. PMID: 32620854. PMC7335161.
35. Wang T, Ren W, Fu F, Wang H, Li Y, Duan J. Digenic CHD7 and SMCHD1 inheritance Unveils phenotypic variability in a family mainly presenting with hypogonadotropic hypogonadism. Heliyon. 2024;10(1):e23272. doi:10.1016/j.heliyon.2023.e23272. PMID: 38148819. PMC10750161.
36. Fuller AK, McCrary HC, Graham ME, Skirko JR. The Case of the Missing Nose: Congenital Arhinia Case Presentation and Management Recommendations. Ann Otol Rhinol Laryngol. 2020;129(7):645-648. doi:10.1177/0003489420909415. PMID: 32100546.
37. Varde MA, Ali MJ. Dilemmas in the management of lacrimal drainage anomalies in BOSMA (congenital arhinia-microphthalmia) syndrome. Orbit. 2025;44(1):121-124. doi:10.1080/01676830.2024.2346568. PMID: 38713859.
38. Stenz EC, Nyalakonda RR, McCulley TJ, Chen Y. Dacryocystocele and Subsequent Dacryocystectomy in a Patient With Bosma Arhinia Microphthalmia Syndrome (BAMS): A Case Report and Review of Literature. J Pediatr Ophthalmol Strabismus. 2024;61(2):e16-e18. doi:10.3928/01913913-20240208-01. PMID: 38529747.
39. Hunter JD, Davis MA, Law JR. Hypogonadotropic hypogonadism in a female patient with congenital arhinia. J Pediatr Endocrinol Metab. 2017;30(1):101-104. doi:10.1515/jpem-2016-0082. PMID: 27941181.
40. Mohassel P, Chang N, Inoue K, Delaney A, Hu Y, Donkervoort S, et al. Cross-sectional Neuromuscular Phenotyping Study of Patients With Arhinia With SMCHD1 Variants. Neurology. 2022;98(13):e1384-e1396. doi:10.1212/wnl.0000000000200032. PMID: 35121673. PMC8967428.
41. Firth HV, Hurst JA. Nasal anomalies. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 242–244.
42. Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, et al. Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2015;11(9):547-564. doi:10.1038/nrendo.2015.112. PMID: 26194704.
43. Bustamante LHA, Sanches BCH, Lopes LCP, Segarra VCD, Pittoli SVP, Ceide RMZ, et al. Neuroendocrine Axis Investigation in Patients with Arhinia, Hemiarhinia and Associated Malformations. Cleft Palate Craniofac J. 2026;63(10):3463-3469. doi:10.1177/10556656251406418. PMID: 41451907.
44. Cong NV, Minh LHN, Hoang LH, Do U, Dung NTM. Bosma Arhinia Microphthalmia Syndrome (BAMS): First Report from Vietnam. Cureus. 2023;15(2):e35222. doi:10.7759/cureus.35222. PMID: 36968924. PMC10032420.
45. Tryggestad JB, Li S, Chernausek SD. Hypogonadotropic hypogonadism presenting with arhinia: a case report. J Med Case Rep. 2013;7:52. doi:10.1186/1752-1947-7-52. PMID: 23432817. PMC3599766.
46. Giardina E, Camaño P, Burton-Jones S, Ravenscroft G, Henning F, Magdinier F, et al. Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines. Clin Genet. 2024;106(1):13-26. doi:10.1111/cge.14533. PMID: 38685133. PMC11147721.
47. Xiao LC, Semwal A, St John B, Zeglinski K, Su S, Lancaster J, et al. Complete genetic and epigenetic architecture of D4Z4 macrosatellites in FSHD, BAMS, and reference cohorts with D4Z4End2End. Genome Res. 2026;36(4):827-848. doi:10.1101/gr.280907.125. PMID: 41871882. PMC13138017.
48. Cusick W, Sullivan CA, Rojas B, Poole AE, Poole DA. Prenatal diagnosis of total arhinia. Ultrasound Obstet Gynecol. 2000;15(3):259-261. doi:10.1046/j.1469-0705.2000.00081.x. PMID: 10846785.
49. Castro PT, Matos APP, Ribeiro G, Ribeiro G, Fazecas T, Araujo Júnior E, et al. Isolated congenital arhinia: Fetal magnetic resonance imaging and pediatric computed tomography 3D reconstructions, long-term follow-up and review of the literature. J Clin Ultrasound. 2025;53(1):202-206. doi:10.1002/jcu.23843. PMID: 39295111.
50. Brusati R, Colletti G. The role of maxillary osteotomy in the treatment of arhinia. J Oral Maxillofac Surg. 2012;70(5):e361-8. doi:10.1016/j.joms.2012.01.009. PMID: 22364860.
51. Feledy JA, Goodman CM, Taylor T, Stal S, Smith B, Hollier L. Vertical facial distraction in the treatment of arhinia. Plast Reconstr Surg. 2004;113(7):2061-2066. doi:10.1097/01.prs.0000122218.78595.97. PMID: 15253197.
52. Harrison LM, Anderson SR, Spiller KE, Pak KY, Schmidt SP, Mancho SN. Reconstruction of Congenital Arhinia With Stereolithographic Modeling: Case Correlate and Literature Review. Cleft Palate Craniofac J. 2022;59(4):530-537. doi:10.1177/10556656211012859. PMID: 34291675.
53. Jung JW, Ha DH, Kim BY, Seo BF, Han HH, Kim DH, et al. Nasal Reconstruction Using a Customized Three-Dimensional-Printed Stent for Congenital Arhinia: Three-Year Follow-up. Laryngoscope. 2019;129(3):582-585. doi:10.1002/lary.27335. PMID: 30247752.
54. Ali MJ, Singh S, Naik MN. Image-guided lacrimal drainage surgery in congenital arhinia-microphthalmia syndrome. Orbit. 2017;36(3):137-143. doi:10.1080/01676830.2017.1280059. PMID: 28272904.
55. U.S. Food and Drug Administration. Testosterone enanthate injection (Eugia US LLC; ANDA212659) – prescribing information. DailyMed setid 82a98132-9d5f-40a5-8c4f-f52f2a5de60e; revised 2026-06-12. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=82a98132-9d5f-40a5-8c4f-f52f2a5de60e
56. U.S. Food and Drug Administration. Chorionic gonadotropin for injection (BLA017067) – prescribing information. DailyMed setid 312ee87a-c6c3-6111-e063-6394a90ad8d7; revised 2025-03-25. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=312ee87a-c6c3-6111-e063-6394a90ad8d7
57. U.S. Food and Drug Administration. Genotropin (somatropin) – prescribing information (Pfizer; BLA020280). DailyMed setid ffebf88b-d257-4542-9808-74d9b7167765; revised 2026-08-04. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffebf88b-d257-4542-9808-74d9b7167765
58. European Medicines Agency. Omnitrope (somatropin) – EPAR product information (SmPC). https://www.ema.europa.eu/en/documents/product-information/omnitrope-epar-product-information_en.pdf
59. National Institute of Environmental Health Sciences. The Molecular Basis of Inherited Reproductive Disorders. ClinicalTrials.gov NCT01500447. https://clinicaltrials.gov/study/NCT01500447
60. Atencia Goñi J, Orera Clemente M, Del Valle Diéguez MJ, González Fernández L, González Albarrán O. Clinical report of Bosma arhinia microphthalmia syndrome with a new variant on SMCHD1 gene. A case report. Endocrinol Diabetes Nutr (Engl Ed). 2024;71(3):138-143. doi:10.1016/j.endien.2024.03.011. PMID: 38555111.
61. Children's Craniofacial Association. https://www.ccakids.org/